Boger Course

I. II. III.
Conformational Analysis Kinetics and Thermodynamics of Organic Reactions Reaction Mechanisms and Conformational Effects on Reactivity
IV V. VI. VII.
Oxidation Reactions Oxidation of Alcohols Reduction Reactions Hydroboration - Oxidation (Reduction - Oxidation)
VIII. Enolate Chemistry IX. X. XI. XII. Metalation Reactions Key Ring Forming Reactions Olefin Synthesis Conjugate Additions: Organocuprate 1,4-Additions
XIII. Synthetic Analysis and Design XIV. Combinatorial Chemistry
Conformational Analysis Dale L. Boger
I. Conformational Analysis
A. Acyclic sp3-sp3 Systems: Ethane, Propane, Butane
eclipsed H 1. Ethane H H H H HH H H H 1.0 kcal 60 rotation HH staggered H H H H H H H H H 3 rel. E 2 (kcal) 1 E E E
3.0 kcal
S 0 60 120
S 180 240
S 300 360
60 rotation
dihedral angle
H H - Two extreme conformations, barrier to rotation is 3.0 kcal/mol. eclipsed H CH3 H H 1.3 kcal staggered H H CH3 H H H H 60 rotation H H H 1.0 kcal each 4 rel. E 3 (kcal) 2 1 E E E
2. Propane
3.3 kcal
S 0 60 120
S 180 240
S 300 360
H CH3 HH HH
CH3 60 rotation
dihedral angle
H - Barrier to rotation is 3.3 kcal/mol. - Note: H/H (1.0 kcal) and Me/H (1.3 kcal) eclipsing interactions are comparable and this is important in our discussions of torsional strain.
fully eclipsed (synperiplanar) 3. Butane H3C H H CH3 H H
gauche (synclinal) H3C H H H CH3
eclipsed (anticlinal) H3C H H
staggered (antiperiplanar) H3C H H
H H CH3 H H CH3 gauche interaction 4.0 kcal 1.3 kcal each 0.9 kcal H3C H3C CH3 CH3 H CH3 60 rotation H 60 rotation H CH3 60 rotation H H HH HH HH H H CH3 H H H CH3 H 1.0 kcal each 6 5 4 rel. E (kcal) 3 2 1 FE E
6.0 kcal
1.0 kcal FE E - Note: the gauche butane interaction and its magnitude (0.9 kcal) are very important and we will discuss it frequently.
G
0.9 kcal
3.6 kcal
G S 180 240 300 360
60
120
dihedral angle
Modern Organic Chemistry The Scripps Research Institute 4. Substituted Ethanes - There are some exceptions to the lowest energy conformation. Sometimes, a gauche conformation is preferred over staggered if X,Y are electronegative substituents. cf: Kingsbury J. Chem. Ed. 1979, 56, 431.
X H H H gauche Y H
X H H
X H H H Y staggered H H
X H H
Egauche < Estaggered if X = OH, OAc and Y = Cl, F
5. Rotational Barriers H
H H H
H
CH3 H
H
CH3 H3C
H
CH3
H
H
H
H
H
CH3
H
CH3
2.88 kcal/mol (3.0 kcal/mol
3.40 kcal/mol 3.3 kcal/mol
4.70 kcal/mol 3.9 kcal/mol)
- Experimental - Simple prediction
- The rotational barrier increases with the number of CH3/H eclipsing interactions. H
H H H H H
H H
H
H
H
H
2.88 kcal/mol (3.0 kcal/mol
1.07 kcal/mol 1.0 kcal/mol)
- Experimental - Simple prediction
- The rotational barrier increases with the number of H/H eclipsing interactions.
B. Cyclohexane and Substituted Cyclohexanes, A Values (G)

1. Cyclohexane 5 6 4 Hax 1 Heq 3 2 chair 4 3 5 2 6 Heq 1 Hax chair
Ea = 10 kcal
4 atoms in plane H HH H H HH H H H H H H HH H HH H
H half chair (rel E = 10 kcal)
H H H twist boat (rel E = 5.3 kcal)
H half chair (rel E = 10 kcal)
Conformational Analysis Dale L. Boger - Chair conformation (all bonds staggered) Hax Hax Hax Heq Heq Hax Hax Hax - Rapid interconversion at 25 C (Ea = 10 kcal/mol, 20 kcal/mol available at 25 C). - Hax and Heq are indistinguishable by 1H NMR at 25 C. - At temperatures < 70 C, Heq and Hax become distinct in 1H NMR. Heq Heq
- Boat conformation
2.9 kcal flagpole interaction H Hax H Heq H H Hax H Hax H Heq 1.0 kcal each (4x)
H H
- Rel E = 6.9 kcal, not local minimum on energy surface. - More stable boat can be obtained by twisting (relieves flagpole interaction somewhat). - Twist boat conformation (rel E = 5.3 kcal) does represent an energy minimum. - The boat conformation becomes realistic if flagpole interactions are removed, i.e. O X
- Half chair conformation H HH H H - Energy maximum (rel E = 10.0 kcal) half chair half chair H HH D.H.R. Barton received the 1969 Nobel Prize in Chemistry for his contributions to conformational analysis, especially as it relates to steroids and six-membered rings. Barton Experientia 1950, 6, 316.
10 rel E (kcal) 5
10 kcal
twist boat
5.3 kcal
0 chair
chair
Modern Organic Chemistry The Scripps Research Institute 2. Substituted Cyclohexanes - Methylcyclohexane H H CH3 H CH3 H 1.8 kcal more stable G = RT(ln K) 1.8 x 1000 1.99 x 298 = ln K
- The gauche butane interaction is most often identifiable as 1,3-diaxial interactions.
H H H H
CH3 H H H H
H CH3 H
2 gauche butane interactions 2 x 0.9 kcal = 1.8 kcal (experimental 1.8 kcal)
0 gauche butane interactions
- A Value (G) = Free energy difference between equatorial and axial substituent on a cyclohexane ring. Typical A Values R F Cl Br I OH OCH3 OCOCH3 NH2 NR2 CO2H CO2Na CO2Et SO2Ph A Value (kcal/mol) 0.25 0.52 0.5-0.6 0.46 0.7 (0.9) 0.75 0.71 1.8 (1.4) 2.1 1.2 (1.4) 2.3 1.1 2.5 R CN C CH ca. 0.5 kcal ca. 0.7 kcal (2nd atom effect very small) NO2 CH=CH2 CH3 CH2CH3 nC H 3 7 nC H 4 9 CH(CH3)2 C(CH3)3 C6H5 A Value (kcal/mol) Small, linear 0.2 groups 0.41 1.1 1.7 1.8 2nd atom 1.9 (1.8) effect very 2.1 small 2.1 2.1 >4.5 (ca. 5.4) 3.1 (2.9)
- Note on difference between iPr and tBu A values. H H H CH3 CH3

iPr
group can position H toward "inside,"
H3C H H
CH3 CH3
but tBu group cannot. Very serious interaction, 7.2 kcal.

- Determination of A value for tBu group. 0.9 kcal CH3 7.2 kcal H3C H H CH3 H H 0.9 kcal
G = (9.0 kcal 3.6 kcal) = 5.4 kcal
H H
CH3 H CH3 H CH3
0.9 kcal each
7.2 kcal + (2 x 0.9 kcal) = 9.0 kcal 4 x 0.9 kcal = 3.6 kcal
- Note on interconversion between axial and equatorial positions. H Cl H Cl
t1/2 = 22 years at 160 C
Even though Cl has a small A value (i.e., small G between rings with equatorial and axial Cl group), the Ea (energy of activation) is high (it must go through half chair conformation).
trans-1,2-dimethylcyclohexane
H H H CH3 H CH3 CH3 H 2.7 kcal/mol more stable CH3 H H H H CH3 H H H H H H H H CH3 CH3 H H H H H H
cis-1,2-dimethylcyclohexane
CH3 H CH2 H E = 0 kcal/mol H CH3 H CH2 H H H H H H H H H H H CH2 CH3 H H H H CH2 H CH3
H CH3
H H H
4 x (gauche interaction) 4 x (0.9 kcal) = 3.6 kcal
CH3 CH3
H2/Pt
CH3 CH3
G = 1.87 kcal/mol (exp) G = 1.80 kcal/mol (calcd)
Modern Organic Chemistry The Scripps Research Institute
trans-1,3-dimethylcyclohexane
H H CH3 H H H CH3 H H H H CH3 H H H H CH3 H H H CH3 H H H CH3 H H H CH3 H H H H H CH3 H CH3
cis-1,3-dimethylcyclohexane
H CH3 CH3 CH3 CH3
CH3 H H H CH3 H
H CH3 H
2 x (gauche interaction) + 1 x (Me-Me 1,3 diaxial int) 2 x (0.9 kcal) + 3.7 kcal = 5.5 kcal
0 x (gauche interaction) 0 x (0.9 kcal) = 0 kcal
CH3
H2/Pt
CH3
CH3
CH3
G = 1.80 kcal/mol (exp and calcd)
- Determination of energy value of Me-Me 1,3-diaxial interaction. CH3 CH3 CH3 H CH3 3 x Me-Me 1,3-diaxial interaction CH3 CH3 H CH3 CH3 H H2/Pt 500 C H CH3 CH3 H CH3 H CH3 CH3 CH3 H CH3
CH3
2 x (gauche interaction) + 2 x (gauche interaction) + 1 x (Me-Me 1,3 diaxial int) = 1 x (Me-Me 1,3 diaxial int) = 2 x (0.9 kcal) + ? 2 x (0.9 kcal) + ?
G = 3.7 kcal/mol (exp) So, Me-Me 1,3-diaxial interaction = 3.7 kcal/mol.
1,3-diaxial interactions R/R OH/OH OAc/OAc OH/CH3 CH3/CH3 G 1.9 kcal 2.0 kcal 2.4 (1.6) kcal 3.7 kcal
G of common interactions ax OH ax H ax OH eq OH eq CH3 0.45* 1.9 0.35 0.35 ax CH3 0.9 1.6 0.35 0.9 eq OH 0.0 0.35 0.35 0.35
*1/2 of A value
C. Cyclohexene
One 1,3-diaxial interaction removed One 1,3-diaxial interaction reduced pseudoequatorial pseudoaxial - half-chair - Ea for ring interconversion = 5.3 kcal/mol - the preference for equatorial orientation of a methyl group in cyclohexene is less than in cyclohexane because of the ring distortion and the removal of one 1,3-diaxial interaction (1 kcal/mol)
D. Decalins
trans-decalin
H HH H H H H H two conformations equivalent H H H H H H H H H H 0.0 kcal H H H H H H H H H H H H 3 gauche interactions 3 x 0.9 kcal = 2.7 kcal H H H H H H
cis-decalin
E between cis- and trans-decalin = 2.7 kcal/mol
trans-9-methyldecalin
H H CH3 H H H H H H
cis-9-methyldecalin
H CH3 H H CH3 H H H H
two conformations equivalent H H H H H H H H H H H CH3 H H H H H H H H H H H H H CH3 H H
4 gauche interactions 4 x 0.9 = 3.6 kcal
5 gauche interactions 5 x 0.9 = 4.5 kcal
E between cis- and trans-9-methyldecalin = 0.9 kcal/mol
E. 1,3-Dioxanes
O O R O O R - Less preference for R group to be equatorial because the lone pair has a smaller steric requirement than a C-H bond (G lower). - In fact, some polar substituents (i.e. F, NO2, SOCH3, +NMe , etc) prefer axial position. 3 O O R
F. Acyclic sp3-sp2 Systems

- Key references - Origin of destabilization for eclipsed conformations: Lowe Prg. Phys. Org. Chem. 1968, 6, 1. Oosterhoff Pure Appl. Chem. 1971, 25, 563. Wyn-Jones, Pethrick Top. Stereochem. 1970, 5, 205. Quat. Rev. Chem. 1969, 23, 301. Brier J. Mol. Struct. 1970, 6, 23. Lowe Science 1973, 179, 527.
- Molecular orbital calculations: Repulsion of overlapping filled orbitals: Pitzer
Acc. Chem. Res. 1983, 16, 207.
- Propionaldehyde:
Butcher, Wilson Allinger, Hickey Allinger Allinger Herschbach Geise
J. Chem. Phys. 1964, 40, 1671. J. Mol. Struct. 1973, 17, 233. J. Am. Chem. Soc. 1969, 91, 337. J. Am. Chem. Soc. 1968, 90, 5773. J. Chem. Phys. 1958, 28, 728. J. Am. Chem. Soc. 1980, 102, 2189.
- Propene:
- 1-Butene:
- Allylic 1,3-strain:
Houk, Hoffmann Hoffmann
J. Am. Chem. Soc. 1991, 113, 5006. Chem. Rev. 1989, 89, 1841.
Conformational Analysis Dale L. Boger 1. Acetaldehyde O H HH eclipsed H HO H H relative energies (kcal) Exp MM2 0.0 0.0 1.0 1.11.2 H O H
60 rotation
H H H
60 rotation
bisected H O H HH
2 rel E (kcal) 1 E 0 60 B E 120 180 B E 240 300 360 B
dihedral angle - Two extreme conformations. - Barrier to rotation is 1.0 kcal/mol. - H-eclipsed conformation more stable.
2. Propionaldehyde O Me HH eclipsed H Me O H H relative energies (kcal) Exp MM2 Ab initio 0.0 0.0 0.0 1.25, 2.28 2.1 1.7 0.8, 0.9, 1.0 0.8, 0.9 0.4 unknown 1.0, 2.31.7, 1.5 0.7 H O H O H H Me eclipsed Me HH HO H H H O H
60 rotation
H Me H
60 rotation
60 rotation
H H
Me bisected H O H H Me
bisected Me O H
2 rel E (kcal) 1 B1 E2 E1 0 60 120 180 240 300 B2 B1 E2 E1 360 - J. Chem. Phys. 1964, 40, 1671. - J. Mol. Struct. 1973, 17, 233. - J. Am. Chem. Soc. 1969, 91, 337.
dihedral angle O
tBu
120 rotation H
O H H H tBu H-eclipsed - Alkyl eclipsed conformation more stable than H-eclipsed and exceptions occur only if alkyl group is very bulky (i.e., tBu). - Because E differences are quite low, it is difficult to relate ground state conformation to experimental results. All will be populated at room temperature.
HH alkyl eclipsed relative energies (kcal) Exp 2.5
0.0
Modern Organic Chemistry The Scripps Research Institute 3. Propene H H HH eclipsed H HH C 2 H H relative energies (kcal) Exp MM2 0.0 0.0 2.0 2.12.2 C H 60 rotation H H H H H bisected H H2C H HH 2 rel E (kcal) 1 E 0 60 E 120 180 E 240 300 360 B B B C H 60 rotation H
dihedral angle - Two extreme conformations - Barrier to rotation is 2.0 kcal/mol Note: H H O vs. H H C H H H 60 rotation H H H H H
4. 1-Butene H Me HH eclipsed H MeH C 2 H H relative energies (kcal) Exp MM2 Ab initio 0.0, 0.2, 0.4, 0.5 0.5, 0.7 0.6 3 2 rel E (kcal) 1 E1 0 H
tBu
H 60 rotation H
H H Me H
H 60 rotation H H
H Me eclipsed Me HH HH C 2 H H
Me bisected H H2C H H Me
bisected Me H2C H
1.41.7 (2.6) -
0.0 0.0 0.0
1.41.8 (2.6) 2.0
B2 B1 E2 60 H C H H 120 180 E2 240 300 B1 E1 360
H 120 rotation H H
dihedral angle - There is an additional destabilization of placing the alkyl group eclipsed with C=C. This is due to the larger steric size of olefinic CH compared to carbonyl C=O. - The eclipsed conformations (even with an -tBu) are both more stable than the bisected conformations.
HH eclipsed (E1) relative energies (kcal) Exp B1, B2 > E1 >> E2
H tBu eclipsed (E2)
10
Conformational Analysis Dale L. Boger 5. E-2-Pentene H Me HH eclipsed H H Me C Me H H C Me 60 rotation H H H Me H bisected Me H C Me H C Me 60 rotation H H H Me eclipsed Me HH H H C Me H H H C Me 60 rotation H H H H C Me H
Me bisected H H C Me H
H Me
relative energies (kcal) Exp MM2 0.0 (0.00.4) 0.6 3 2 rel E (kcal) 1 E1 0 6. Z-2-Pentene Me Me HH eclipsed H Me Me C H H H C H 60 rotation H Me H Me H bisected Me Me C H H C H 30 rotation H 60 B2 B1 E2 120 180 E2 240 300 B1 E1 360 - Analogous to 1-butene. 1.41.7 (2.6) 0.0 0.0 1.51.8 (2.6)
dihedral angle Me H Me H perpendicular Me HH Me C H H H H Me H C H H 30 rotation H Me H H Me eclipsed Me H H H Me C H H H 60 rotation H Me H H H H
Me bisected
H Me
relative energies (kcal) MM2 3.9 4.9

5 E1 B1
0.0
B1 E1
0.6
0.5
H H H
H CH3 CH3
rel E (kcal)
4 3 2 1 P1 0 60 120 180 240 E2 B2 E2 P1 300 360 dihedral angle
H H3C H
- Serious destabilizing interaction, often referred to as allylic 1,3-strain (A 1,3-strain).
CH3 H - The analogous H/CH3 eclipsing interaction in the bisected conformation is often referred to as allylic 1,2-strain (A 1,2-strain).
11
Modern Organic Chemistry The Scripps Research Institute 7. 3-Methyl-1-butene H H C Me Me H H bisected Me H2C Me relative energies (kcal) Ab initio 2.43.0 3 2 rel E (kcal) 1 E1 E2 0 60 120 180 240 300 360 E1 - J. Am. Chem. Soc. 1991, 113, 5006. - Chem. Rev. 1989, 89, 1841. 0.731.19 B2 2.602.94 B2 0.0 HH MeH C 2 H 60 rotation Me H Me eclipsed Me H H C H H H H 60 rotation Me C H 60 rotation H H Me Me eclipsed Me H Me HH C 2 H Me H C H H
Me bisected Me H2C H
B1
B1
dihedral angle
8. 4-Methyl-2-pentene Me H C Me Me H H bisected Me 60 rotation Me H Me eclipsed C H H Me H 60 rotation Me C H 60 rotation H Me H Me Me eclipsed C H H
Me bisected
Me Me C H Me
HH
Me Me C H
Me H H
Me Me C H H
H Me
Me H C H
Me H Me
relative energies (kcal) Ab initio 3.44.3 6 4 rel E (kcal) 2 E2 0 60 120 180 240 300 360 B1 E1? E1? B2 B2 B1 - Only H-eclipsed conformation is reasonable. 4.95.9 0.0
dihedral angle
12
G. Anomeric Effect
1. Tetrahydropyrans (e.g., Carbohydrates) R H
C C X
O OR'
R R'O
H O
C C H
X X = OR'
Dipoles opposed preferred
R = H, preferred conformation. G = 0.85 kcal/mol
Dipoles aligned destabilizing
- generally 02 kcal/mol, depends on C2/C3 substituents - effect greater in non-polar solvent
Comprehensive Org. Chem. Vol. 5, 695. Comprehensive Het. Chem. Vol. 3, 629. Review: Tetrahedron 1992, 48, 5019.
1. A value for R group will be smaller, less preference for equatorial vs axial C3 or C5 substituent since one 1,3-diaxial interaction is with a lone pair versus CH bond. 2. Polar, electronegative group (e.g., OR and Cl) adjacent to oxygen prefers axial position. 3. Alkyl group adjacent to oxygen prefers equatorial position. 4. Electropositive group (such as +NR3, NO2, SOCH3) adjacent to oxygen strongly prefers equatorial position. Reverse Anomeric Effect - Explanations Advanced: 1. Dipole stabilization opposing dipoles, stabilizing 2. Electrostatic repulsion minimizes electrostatic repulsion between lone pairs and the electronegative substituent C C OR H C C H OR maximizes destabilizing electrostatic interaction between electronegative centers (charge repulsion) C C OR H C C H OR dipoles aligned, destabilizing
3. Electronic stabilization * n orbital stabilizing interaction n electron delocalization into * orbital C C H C C H OR no stabilization possible
4. Gauche interaction involving lone pairs is large (i.e. steric) 1 lone pair / OR gauche interaction + 1 C/OR gauche interaction (0.35 kcal/mol) C C OR H C C H OR 2 lone pair / OR gauche interactions, but would require that they be ~1.2 kcal/mol
13
Modern Organic Chemistry The Scripps Research Institute 2. Anomeric Effect and 1,3-Dioxanes H
O
O R
lone pair / R interaction 1. Polar, electronegative C2/C4 substituents prefer axial orientation. 2. The lone pair on oxygen has a smaller steric requirement than a CH bond. G is much lower, lower preference between axial and equatorial C5 substituent 3. Polar electropositive groups C2 equatorial position preferred: C5 axial position may be preferred for F, NO2, SOCH3, +NMe3.
tBu
CH3
CH3 H H
O
tBu
preferred conformation Eliel J. Am. Chem. Soc. 1968, 90, 3444.
A Value (kcal/mol) for Substituents on Tetrahydropyran and 1,3-Dioxane versus Cyclohexane Group CH3 Et iPr tBu Cyclohexane 1.8 1.8 2.1 >4.5 Tetrahydropyran C2 2.9 1,3-Dioxane C2 4.0 4.0 4.2 1,3-Dioxane C5 0.8 0.7 1.0 1.4
3. Exo Anomeric Effect preferred orientation 55 O O R 1 R/OR gauche Rel. E = 0.35 kcal/mol 55 O H2C R Kishi J. Org. Chem. 1991, 56, 6412.
R R
H O
H O
R
O -axial-glycosides
1 R/R gauche 0.9 kcal/mol H

H
2 gauche 1.25 kcal/mol H

R
H
H
14
H. Strain
Cyclic Hydrocarbon, Heats of Combustion/Methylene Group (gas phase) Ring Size 3 4 5 6 7 8 9 Hc (kcal/mol) 166.3 163.9 158.7 157.4 158.3 158.6 158.8 Ring Size 10 11 12 13 14 15 16 Hc (kcal/mol) 158.6 158.4 157.8 157.7 157.4 157.5 157.5
strain free
largely strain free
1. Small rings (3- and 4-membered rings): small angle strain For cyclopropane, reduction of bond angle from ideal 109.5 to 60 27.5 kcal/mol of strain energy. For cyclopropene, reduction of bond angle from ideal 120 to 60 52.6 kcal/mol of strain energy. To form a small ring in synthetic sequences, must overcome the energy barrier implicated in forming a strained high energy product. 2. Common rings (5-, 6-, and 7-membered rings): - largely unstrained and the strain that is present is largely torsional strain (Pitzer strain). 3. Medium rings (8- to 11-membered rings): a. large angle strain - bond angles enlarged from ideal 109.5 to 115120. - bond angles enlarged to reduce transannular interactions. b. steric (transannular) interactions - analogous to 1,3-diaxial interactions in cyclohexanes, but can be 1,3-, 1,4-, or 1,5- ...
c. torsional strain (Pitzer strain) in cyclohexanes 60 H

H H H
in medium rings - deviation from ideal of 60 and approach an eclipsing interaction. C C 40 (CH2)n
H
H
just like gauche butane.
4. Large rings (12-membered and up): - little or no strain.
15
I. pKa of Common Organic Acids

Acid cyclohexane ethane benzene ethylene Et2NH NH3 (ammonia) toluene, propene (C6H5)3CH DMSO (CH3S(O)CH3) C6H5NH2 HC CH CH3CN CH3CO2Et CH3SO2CH3 CH3CONMe2 aliphatic ketones (CH3)3CCOCH(CH3)2 (CH3)3CCOCH3 CH3COCH3 CH3COC6H5 (CH3)3COH C6H5C CH pKa 45 42 37 36 36 35 35 2833 31 27 25 25 25 2327 25 2023 23 21 20 19 19 19 Acid (CH3)2CHOH CH3CH2OH cyclic ketones e.g. cyclohexanone CH3OH CH3CONHCH3 PhCH2COPh H2O cyclopentadiene CH2(CO2Et)2 CH2(CN)2 CH3COCH2CO2Et CH3NO2 phenol R3NH+Cl HCN CH3CH2NO2 CH3COCH2COCH3 CH2(CN)CO2Et CH3CO2H pyHCl C6H5NH3+Cl pKa 18 17 17 17 16 (1618) 1617 16 16 15 13 11 11 10 10 10 9 9 9 9 5 5 5
XH
H+ + X
Ka = [H+][X] [HX]
pKa = logKa = log[H+] Increase in pKa means decrease in [H+] and acidity Decrease in pKa means increase in [H+] and acidity
For more extensive lists, see: The Chemist's Companion, p 584. House, p 494.
Familiarity with these pKa's will allow prediction/estimation of acidities of other compounds. This is important, since many organic reactions have a pKa basis (i.e., enolate alkylations).
16
Kinetics and Thermodynamics of Organic Reactions Dale L. Boger
II. Kinetics and Thermodynamics of Organic Reactions

A. Free Energy Relationships
G = H TS The equilibrium for the reaction can be described by ln Keq = G RT To achieve a high ratio of two products (desired product and undesired product) in a thermodynamically controlled reaction (i.e. under reversible conditions) you need the following G's:
K (25 C)
2 (67:33) 5 (83:17) 9 (90:10) 20 (95:5) 99 (99:1) 999 (99.9:0.1)
G (kcal/mol) 0.41 0.95 1.30 1.74 2.73 4.09
K (0 C)
2.1 5.7 10.9 27.5 (68:32) (85:15) (92:18) (96:4)
G (kcal/mol) 0.41 0.95 1.30 1.80
K (78 C)
2.9 11.6 28.5 103.3 (75:25) (92:8) (97:3) (99:1)
G (kcal/mol) 0.41 0.95 1.30 1.80
Hydrogenation reaction: H2C CH2 + H2
H H H2C CH2
bonds broken 1 1 C C H H 163 kcal/mol 104 kcal/mol 267 kcal/mol
bonds formed 1 2 C C C H 88 kcal/mol 2 x 98 kcal/mol 284 kcal/mol
-Overall reaction is exothermic -> G = 17 kcal/mol, so reaction is favorable, spontaneous. -To calculate equilibrium constant: ln Keq = 2.303 log Keq log Keq Keq G RT = 17 kcal x 1000 cal/mol / (298 K) x 1.99 = 12.45 = 2.8 x 1012
- But experimentally this reaction is very slow. - Molecule rate (experimentally) = 1012 molecules/sec 6.023 x 1023 molecules/mol mole rate = = 2 x 104 years 12 molecules/sec) x (60 sec/min) x (60 min/hour) (10 x (24 hour/day) x (365 day/year) i.e., 2 x 104 years to hydrogenate one mole of ethylene (without catalyst).
17
Modern Organic Chemistry The Scripps Research Institute E Guncat. = 33.87 kcal
Gcat. = 20 kcal
Transition State: A transition state (TS) possesses a defined geometry and charge delocalization but has no finite existence. At TS, energy usually higher and although many reactant bonds are broken or partially broken, the product bonds are not yet completely formed.
G = 17 kcal
H2C=CH2
H3CCH3
reaction coordinate
uncatalyzed reaction catalyzed reaction
B. Transition State Theory

G = H TS - Free Energy of Activation (G) - Enthalpy of Activation (H): Difference in bond energy between reactants and the transition state. - Entropy of Activation (TS): S usually negative, making the change more endothermic. From G = H TS , G = RT ln K G = 33.9 kcal/mol G = 20 kcal/mol
for uncatalyzed H2 reaction catalyzed H2 reaction and for the rate for uncatalyzed H2 reaction catalyzed H2 reaction
k = 1.0 1012 mol/sec k = 1.0 1022 mol/sec
C. Intramolecular Versus Intermolecular Reactions

CH3OH + CH3 O C OH O OH OH O O OH OH H+ k3 O S3 H+ k1 H+ k2 CH3 O C OCH3 O O S2 S1
k3 > k2 > k1
TS1 > TS2 > TS3 > 0 S1 < S2 < S3 < 0 G3 < G2 < G1
18

- Intramolecular versus intermolecular reactions benefit from a far more favorable entropy of activation (S). - In forming small rings, ring strain developing in the product decelerates the rate of reaction (large H) and that can offset the favorable S rate acceleration. O OH OH Examples: H2O 25 C Rel. Rate 70 1.0 10000 1000 2 (CH2)n NH n H+ very slow O (CH2)n NH2 Ring size 3 4 5 6 7 O Br aq DMSO 50 C n O O O O
Br
Ring size Rel. Rate 3 4 5 6 7 8 9 10 21.7 5.4 103 1.5 106 1.7 104 97.3 1.00 1.12 3.35
Ring size Rel. Rate 11 12 13 14 15 16 17 18 8.51 10.6 32.2 41.9 45.1 52.0 51.2 60.4
- gem dimethyl effect Rel. Rate HO HO HO aq. NaOH Cl Cl O Cl 39000 18 C O 325 O 1.0
Compare to relative rates of intermolecular SN2 displacement where the more substituted alkoxide reacts slowest: CH3OH OH OH + CH3Cl + CH3Cl + CH3Cl k1 k2 k3 O O O k1 > k2 > k3 > k4
OH
+ CH3Cl
k4
De Tar J. Am. Chem. Soc. 1980, 102, 4505. Winnik Chem. Rev. 1981, 81, 491. Mandolini J. Am. Chem. Soc. 1978, 100, 550. Illuminati J. Am. Chem. Soc. 1977, 99, 2591. Mandolini, Illuminati Acc. Chem. Res. 1981, 14, 95. For the intramolecular case: The reactive conformation is more favorable and populated to a greater extent in the more substituted case One must consider both length of chain (i.e., ring size being formed) and nature of atoms in the chain (i.e., conformation, hybridization).
19
D. Kinetic and Thermodynamic Control

For competitive reactions: transition state: possesses a defined geometry, charge delocalization, but has no finite existence G Gc GB Free E of Activation GB G thermodynamic product C A B reaction coordinate kinetic product
Gc
If this is an irreversible reaction, most of the reaction product will be B (kinetic product). If this is a reversible reaction, most will be C (more stable, thermodynamic product). OLi Me LDA O Me LDA OLi Me
thermodynamic product more favorable G
kinetic product more favorable G
A beautiful example of this was observed in the kinetic versus thermodynamic asymmetric Dieckmann-like condensation illustrated below. The most stable product (lower G) was observed upon conducting the reaction under equilibrating conditions for the reversible reaction while the alternative kinetic product (lower G) was observed when the reaction was conducted under lower temperature and nonequilibrating conditions (kinetic conditions).
TBDMSO HN Me XcOC N BOC OBn
Kinetic control: 5 - 7:1 diastereomers NBOC
TBDMSO
Thermodynamic control: single diastereomer HN NBOC XcOC
TBDMSO
LDA N THF O 58% 78 C O O 30 min
NC Me N BOC OBn
LDA
NBOC
THF Me N 81% BOC OBn 78 to 40 C
epi-(+)-Duocarmycin A
(+)-Duocarmycin A
20
Thermodynamic control: single TBDMSO diastereomer HN Me XcOC N BOC OBn NBOC
(+)-Duocarmycin A Kinetic control: 5 - 7:1 diastereomers NBOC Xc HN OC
TBDMSO
TBDMSO
LDA
NC Me N BOC OBn
LDA
NBOC
N THF O 81% O 78 to 40 C O
THF Me N 58% BOC OBn 78 C, 30 min
Divergent Control of C6-Stereochemistry Kinetic control: 5 - 7:1 diastereomers NBOC Thermodynamic control: single diastereomer NBOC HN XcOC
TBDMSO
TBDMSO
LDA
NC Me N BOC OBn
LDA
NBOC
N THF O 58% O 78 C O 30 min
THF Me N 81% BOC OBn 78 to 40 C
Chelated Z-enolate
R = CO2tBu > CHO
(+)-Duocarmycin A
anti-carbonyls
iPr Me O O N N N Li O R
O N iPr N Me
Li O N R iPr
Me NH O N N R O
E = 0.76 kcal/mol
iPr O
O N O NH N R
Me
Boger J. Am. Chem. Soc. 1997, 119, 311.
E. Hammond Postulate
The geometry of the transition state for a step most closely resembles the side (i.e., reactant or product) to which it is closer in energy. Transition state can not be studied experimentally has zero lifetime (transient species) information obtained indirectly Hammond postulate Examples: 1) Thermoneutral reactions: CH31I +
2I
CH32I
1I
21

2I
H
1I 1I
H H
2I
H T.S. E
symmetrical
Thermoneutral reaction transition state resembles both starting material and product equally s p
2) For reactions which proceed through an intermediate: solvolysis of tertiary alcohol A [X] X: discrete intermediate R R C OH R R C R R B
HCl
Cl
R R C R Cl
T.S. T.S. I s p
G. A. Olah received the 1994 Nobel Prize in Chemistry for his contributions to carbocation chemistry. Resemble the geometry of the carbocation intermediate and not that of the reactant (alcohol) or product (alkyl chloride).
Intermediate (for this reaction it will be C+ so T.S. I ) Notes a. 20 kcal/mol energy available at 25 C for free energy of activation. b. Increase reaction temperature, increase the rate of reaction. c. Decrease reaction temperature, decrease the rate of reaction, but increase the selectivity of the reaction. Hammond J. Am. Chem. Soc. 1955, 77, 334. Casin J. Chem. Ed. 1975, 52, 76.
F. Principle of Microscopic Reversibility

The forward or reverse reactions, run under identical conditions, must proceed by the same mechanism i.e., if forward reaction proceeds via intermediate X A then reverse reaction also goes through X. B [X] A [X] B
22
Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger
III. Reaction Mechanisms and Conformational Effects on Reactivity

A. Ester Hydrolysis
pKa = 15 CH3 O C OEt OH CH3 O C OEt OH pKa = 5 CH3 O C OH CH3 O C O
sp2
sp3
+ OEt pKa = 17
+ EtOH
Reaction driven to completion by final, irreversible step (compare pKa = 17 to pKa = 5). a O CH3 C OEt c OH a CH3 O C OH OEt b b HO O + H2C OEt H2O O + O CH3 EtOH O + CH3 OEt CH3 + HO OEt
- So, possible competing reaction is -H removal, but pKa difference means equilibrium strongly favors ester and OH, i.e.; O HO + CH3 C OCH2CH3 O H2O + H2C C OCH2CH3
- To deprotonate an ester, must use a strong base which is non-nucleophilic, such as tBuOK or LDA. O H2C C OCH2CH3
CH3COOCH2CH3 pKa = 25
1. tBuOK (pKa of tBuOH = 19) generates low concentration of anion, and a significant amount of ester always present self (Claisen) condensation 2. LDA (pKa of iPr2NH = 36) generates a high concentration of enolate and thus is a good base to carry out stoichiometric alkylation of ester
23
Modern Organic Chemistry The Scripps Research Institute 1. Kinetics of Ester Hydrolysis (Stereochemistry and Rates of Reactions)
NaOH
tBu
COOEt
tBu
OEt O OH
tBu
COOH
Steric Effect COOEt

tBu
no way to avoid a severe tBu-like 1,3-diaxial interaction

H
tBu
NaOH
OH OEt
COOH
tBu
A value = 1.2 kcal
A value = 2.3 kcal
ktrans = 19.8 kcis
95 : 5
The rate determining step for ester hydrolysis is the formation of tetrahedral intermediate and the ratio of ktrans/kcis >> 1.
Eliel J. Am. Chem. Soc. 1961, 83, 2351. - Difference in rates much greater than expected if simply considering the difference in either the product or reactant A values. - Reaction of axial ester decelerated due to more severe developing 1,3-diaxial interactions in transition state (i.e., an axial tBu-like group).
2. Same effect is observed, but to a lesser extent with acetate hydrolysis O

tBu
O CH3 OH ktrans
tBu
OH CH3
OH
tBu
O O
tBu
O CH3 OH kcis A value = 0.7 kcal/mol OH

tBu tBu
OH CH3
ktrans = 6.65 kcis effect is smaller because of the more remote distance of the steric interactions
Similarly, the rates of acetylation are ktrans / kcis = 3.7 Eliel J. Am. Chem. Soc. 1966, 88, 3334.
24
B. Alcohol Oxidations
O + HO Cr OH O ( CrO3 + H2O ) fast OH Cr O OH
R R'
H OH
R R'
H O
O Cr O OH
slow
R O R' +
O
tBu
OH
fast
tBu
Cr O O
slow OH ktrans
O
tBu
OH
tBu
O
H
Cr O
H
OH slow kcis O
tBu
fast
tBu
kcis = 4 ktrans
The rate determining step for the alcohol oxidation is break down of the chromate ester with cleavage of CH bond and OCr bond. Destabilizing 1,3-diaxial interactions in cis chromate ester accelerate its breakdown to the ketone (would be slower if the slow step for the reaction were formation of chromate ester). Eliel J. Am. Chem. Soc. 1966, 88, 3327.
C. SN2 Reactions
PhS
H H
tBu
SPh
X
PhS Na inversion ktrans
tBu
less stable product formed and proceeds through a less stable T.S.
trans
H H
tBu
cis'
X PhS Na inversion kcis

tBu
SPh
cis
PhS
trans'
25

The free energy of activation (Ea, or G) for reaction of the trans isomer is higher due to steric interactions felt in the transition state (interactions of incoming nucleophile with axial H's).
G E
cis
kcis > ktrans G greater than G of products.
cis' trans
G
- The reaction of the trans isomer is kinetically slower and thermodynamically less favorable.
trans'
reaction coordinate
D. Elimination Reactions
B H X E2 elimination H must have a good orbital overlap (i.e., via trans antiperiplanar orientation of CH bond and CX bond). Stereoelectronic Effect trans antiperiplanar H
- Alternatively, if dihedral angle = 0 (i.e., eclipsed X and H), elimination can take place (orbital overlap good). 1.0 ~ 1.3 kcal B H
H
H Cl
Cl H
H
HH 1.0 kcal
1.0 kcal
eclipsed conformation is 3.03.3 kcal/mol higher in E, so elimination takes place mainly through trans periplanar arrangement.
- Alternate mechanisms also possible: E1 mechanism E1cB mechanism
D A B H
A B
D E
H X
H H
via free carbocation
large groups (A,E) trans
26
Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger Acyclic Substrate Examples: EtONa CH3 CH3CH CH C2H5 69% CH3 C2H5 51% CH3CH CH2 C2H5 Br Anti elimination 0.5 kcal Br
H Et H
trans
C2H5
18%
cis
Br
H
Et
EtONa H 18%
H Et Me
H
H
Me E = 0.9 kcal
Me H 0.9 kcal
cis
trans is more stable than cis (1.0 kcal/mol)

0.5 kcal H Et EtONa 51% H Me H
Br
Et H
Br Et
H
H
H
Me
Me H
trans
For other possible mechanisms: Syn elimination 1.0 ~ 1.3 kcal

H Br Et
1.0 Br Me
H
H
H Et H
H Et Me 4.0 kcal
HH
Me
cis
1.0 ~ 1.3 kcal

H Br H
syn elimination also strongly favors formation of trans product

Et
1.3 Br Et Me
H
H H H
H Me
Et
Me 1.3 kcal
trans
Both are very much destablized relative to anti-elimination T.S. / conformations. Neither contribute to ground state conformation of bromide at room temperature. And, there is another product formed: H Et H
H
Br
H H
Br H H CH3Et
H H H
Br
H H
Br
H
H
Et
CH3
H
Et
H H H
or
H H
Et
HH
27
Modern Organic Chemistry The Scripps Research Institute Cyclic Substrate Consider E2 elimination of
Cl
Cl
neomenthyl chloride
menthyl chloride
Look at all conformations of each:
0.45 kcal 0.25 kcal

H
0.25 kcal
2.1 kcal
H
2.1 kcal
H
Cl
H CH3 Cl
H
H CH3 Cl CH3 0.25 kcal C 4.55 kcal/mol more stable k2 reactive conformer because it is the only one that can achieve a trans antiperiplanar relationship between the H atom and the Cl > 4 kcal/mol energy difference between ground state conformation and the reactive conformation 0.25 kcal Cl
H
0.9 kcal CH3
H E= ~3.4 kcal/mol >99 :1 ratio for A : B
1.8 kcal A B
~1.52.0 kcal D
k1
CH3 +
CH3
CH3
78 : 22
only product !
The reaction of the neomenthyl chloride is much faster (k1/k2 = 193:1) From D (menthyl chloride) only one product is possible CurtinHammett principle : Ground state conformation need not be decisive in determining product of a reaction.
28
E. Epoxidation by Intramolecular Closure of Halohydrins

Must involve backside displacement geomerical constraints ! CH3 HO
Br
CH3 K2CO3 O 72 h, 25 C
H backside attack not geometrically feasible

Br
OH CH3 CH3 O
Br
5 ~ 10 kcal
CH3
H available at room temperature
reaction proceeds through very minor conformation
Again, ground state conformation of reactant is not a determinant in reaction product (CurtinHammett principle). Another example: Br CH3 Br K2CO3 O H CH3 CH3
OH
1 min, 25 C
reaction much faster and proceeds from a ground state conformation
F. Epoxide Openings (SN2)

(a) CH3 CH3 (b) O Nu O nucleophile can attack at either carbon atom (b) twist boat conformation CH3 SPh
O atom under attack in epoxide moves towards Nu:
sp2.27
(a)
O H3C SPh 1,3-diaxial CH3 SPh OH O chair conformation HO more stable product
H3C SPh
less stable product This is the only product formed!
Product ratio dependent on Ea (i.e., relative energy of two T.S.), route (a) proceeding through chair conformation and destabilizing 1,3-diaxial interaction is of lower energy than route (b) proceeding through twist boat T.S. - Conformational effects determine regioselectivity
29
G. Electrophilic Additions to Olefins
Follows same principles
CH3
Br2 Br attacks from the less hindered face
Br
CH3
Br Br HH Br
CH3
transdiaxial opening
PhSX, PhSeX, or HgX2
PhS
CH3 reversible HH X
SPh CH3 kinetic product H

a b b
H
CH3
CH3 X
X
a
X twist boat episulfonium ion
H3C
X X
CH3
X
H HX
kinetic
thermodynamic
CH3 PhS X H PhS

X
CH3 thermodynamic product H
- Conformational effects control regioselectivity and stereochemistry But, it is not always possible to obtain the thermodynamic product must have the 2030 kcal/mol of energy required and a mechanism to reverse the reaction.
30
H. Rearrangement Reactions
pinacol pinacolone rearrangement O
HO CH3 CH3
OH
CH3
HO + H+
OH2
CH3 pinacolone
Prototype of rearrangement: heteroatom: O M.G. migrating group L.G. leaving group OH2+ OSO2R N2+ diazonium ion This process is conformationally dependent!
NH2
H O N OH (HONO, H2ONO - protonated)
H2 OH N N OH
OH2 NH N OH
NH N OH HCl + NaNO2
+ N2
N N
NH N OH2
The course of rearrangement is conformationally dependent: A value of NH2/NH3+ (1.81.4 kcal) H H

H NH2 H
H E = 1.6 ~ 2.2 kcal
OH
NH2
gauche (0.350.9 kcal)
OH
A value of OH (0.7 kcal) backside attack N OH
HONO
Stereoelectronic Effect
N2 OH H trans periplanar arrangement O only product observed
31
Modern Organic Chemistry The Scripps Research Institute Compare to: NH2
H
N2+ HONO H
H
H H H O
OH H Stereoelectronic effects dominate the control of regioselectivity H

NH2
~ 50:50 mixture
both good: "trans"-diaxial relationships H
both products observed
H OH O
N2+
Explain the following results:
H3C
HO
NH2 H HONO H3C

H
CH3
O CH3
CH3
N O 2
H CH3 H3C NH2 H OH H3C N H3C 2 O H H3C H NH2 CH3 H3C HONO
H
+
H3C
HONO
H3C
H3C H
HO
CH3 H
CH3 O
OH
N2+ CH3 H3C H NH2 OH HONO H3C H3CH N2+ OH CH3 H
H3C
CH3 O
32
Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger - Additional examples HO OSO2Ar KOtBu 89% Me O H H H Me Me O H OSO2Ar migrating bond
Bchi J. Am. Chem. Soc. 1966, 88, 4113. O O O O AcO AcO AcO Heathcock J. Am. Chem. Soc. 1982, 104, 1907. O CH3 O
O ArO2SO
I. Pericyclic Reactions
1. Conservation of Orbital Symmetry, FMO Analysis - Concerted reactions where there is a single transition state and no intermediates proceed through cyclic transition states. - Cyclic transition state corresponds to an allowed arrangement of participating orbitals that can maintain a bonding interaction between the reaction components throughout the course of the reaction. This dictates features of relative reactivity, regioselectivity, and diastereoselectivity. - This also established and formalized the viability of utilizing Frontier Molecular Orbitals (FMO) composed of the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) to analyze pericyclic reactions. Woodward, Hoffmann The Conservation of Orbital Symmetry, Academic: New York, 1970. J. Am. Chem. Soc. 1965, 87, 395. Fukui Acc. Chem. Res. 1971, 4, 57; Angew. Chem., Int. Ed. Eng. 1982, 21, 801. Encouraged by E. J. Corey, Hoffmann began examining mechanistic problems in organic chemistry and, as a junior fellow at Harvard, entered into a collaboration with R. B. Woodward that combined his insights in MO theory with Woodward's knowledge of experimental pericyclic reactions. This led to five papers in 1965 before he was 30 years old, that were the foundation of what we now refer to as the Woodward-Hoffmann rules.
R. Hoffmann received the 1981 Nobel Prize in Chemistry for the launch and development of the concept of orbital symmetry conservation.
K. Fukui received the 1981 Nobel Prize in Chemistry for his Frontier Orbital theory of chemical reactivity.
This followed and was not included in the 1965 Nobel Prize in Chemistry awarded to R. B. Woodward for his contributions to the "art of organic synthesis".
33
Modern Organic Chemistry The Scripps Research Institute 2. Electrocyclic Reactions - This is composed of a series of reactions in which a ring closure occurs with formation of a single bond at the ends of a linear, conjugated system of electrons and the corresponding reverse reaction with ring opening. System electrons Thermal Reaction Ground State (HOMO) conrotatory h Reaction Excited State (LUMO)
4 e
disrotatory
6 e
disrotatory
conrotatory
8 e
conrotatory
disrotatory
2 e
disrotatory
conrotatory
4 e
conrotatory
disrotatory
4 e
conrotatory
disrotatory
6 e
disrotatory
conrotatory
4 e thermal reaction (ground state, HOMO)

R
R - Stereochemistry dictated by orbital symmetry allowed reaction course
R conrotatory movement
R bonding interaction
6 e thermal reaction (ground state, HOMO)

R R
R disroratory movement
bonding interaction
- Generalization: No. of electrons 4n electrons (n = 0,1,...) 4n + 2 electrons (n = 0,1,...) Thermal conrotatory disrotatory h disrotatory conrotatory
34
Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger 3. Cycloadditions and Cycloreversions - These are discussed in terms of suprafacial or antarafacial addition to the ends of a system. Suprafacial Antarafacial
- Generalization: Total electrons 4n Allowed in Ground State ms + na ma + ns 4n + 2 ms + ns ma + na - Notations orbital type

, ,
Allowed in Excited State ms + ns ma + na ms + na ma + ns
2s
number of e
suprafacial (s) or antarafacial (a)
- Diels-Alder Reaction (6 e), Ground State Thermal Reaction Normal Diels-Alder Reaction HOMO diene bonding interaction LUMO dienophile [4s + 2s] cycloaddition - Suprafacial with respect to both reacting components and this defines the orientation with which the two reactants approach, boat transition state. - The FMO analysis may also be used to predict relative rates, regioselectivity, and diastereoselectivity (endo effect) and we will discuss this in detail along with the Diels-Alder reaction. - [2 + 2] Cycloaddition (4 e) Ground State (thermal) bonding interactions LUMO (antarafacial) HOMO (suprafacial) Excited State (h) LUMO (suprafacial) bonding interactions Excited state HOMO (SOMO) (suprafacial) [2a + 2s] cycloaddition - Antarafacial with respect to one olefin and suprafacial with respect to the second, dicates perpendicular approach to permit bonding. [2s + 2s] cycloaddition - Suprafacial with respect to both olefins. Inverse Electron Demand Diels-Alder Reaction LUMO diene bonding interaction HOMO dienophile
35
Modern Organic Chemistry The Scripps Research Institute 4. Sigmatropic Rearrangements - Class of reactions characterized by migration of an allylic group from one end of a system to the other. - Generalization: Total electrons 4n Ground State antara - supra supra - antara supra - supra antara - antara Excited State antara - supra supra - antara antara - supra supra - antara
4n + 2
- These include a wide range of rearrangements including [1,3]-, [1,5]-, [1,7]-, [3,3]-, and [2,3]sigmatropic reactions which we will discuss in detail.
J. Subtle Conformational and Stereoelectronic Effects on Reactivity and Reaction Regioselectivity

1. Kinetics, Stereochemistry, and Reaction Mechanisms - Two of the cornerstones of defining a mechanism rest with the establishment of the stereochemistry of the reaction in conjunction with kinetic studies of the reaction. - For example, for a reaction that might entail acid or base catalysis, it is common to examine the pH rate profile. OH OH
+ H2O O optically active 1 OH : OH 15 single enantiomer with clean inversion of absolute stereochemistry therefore SN2, not SN1, ring opening.
acid-catalyzed reaction (k = 0.093 M1s1)
- Below pH 4, H+ catalyzed reaction dominates. - Above pH 4 (pH 412), the uncatalyzed direct SN2 addition reaction dominates.
kobs
uncatalyzed reaction (k = 4.2 x 105 s1)
0 2 4 6 pH Boger J. Org. Chem. 1998, 63, 8004. 8 10 12
36
Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger 2. Substituent Effects - These can be quantitated using a Hammett treatment and can provide insights into reaction mechanisms. = 0.3 : small, almost negligible effect = 3.0 : huge effect R
C7
- C7 substituents (R) have little effect on reactivity - N substituent (R') has a pronounced effect on reactivity and even subtle perturbations will change reactivity greatly (-SO2R -CO2R, 10 x)
N R'
values are characterized in a log scale - The negative value indicates + charge buildup in the rate-determining step of the reaction.
- 5.2 - 5.4 - 5.6 - 5.2
r = 1.0 = 0.30
-OMe -H -CN
-CONCH3
- 5.4
R'
-CO2CH3
- 5.6
log k
- 5.8 - 6.0 - 6.2 - 6.4 - 0.4
log k
-COEt
- 5.8 - 6.0
= slope
- 0.2 0.0 0.2 0.4 0.6 0.8
- 6.2 - 6.4 - 0.2
r = 0.983 = 3.0
0.0 0.2
-SO2Et
0.4 0.6 0.8
p Boger J. Am. Chem. Soc. 1994, 116, 5523. J. Org. Chem. 1996, 61, 1710 and 4894. 3. Structure versus Reactivity and Reaction Regioselectivity
- Structure can have a pronounced effect on reactivity and reaction regioselectivity. One nice example of this can be illustrated with a series of analogues related to CC-1065 and the duocarmycins which are potent antitumor antibiotics that derive their biological properties from a sequence-selective DNA alkylation reaction. The reactivity changes that one sees as a consequence of the loss of the vinylogous amide stabilization are related to the source of DNA alkylation catalysis.
Binding-induced conformational change: shape-selective catalysis MeO2C HN O N O N H OMe OMe OMe MeO2C HN 1 O N 2 O N H OMe OMe OMe 1 = 2540 2 = 0
- DNA bound agent adopts helical conformation, twist adjusted at linking amide. - DNA bound agent maintains full amide. (2 = 0) - Vinylogous amide stabilization diminished. (1 = 2540) - Cyclohexadienone structure destabilized. - Shape-dependent catalysis: Preferential activation in AT-rich minor groove. Binding induced twist greatest in the narrower, deeper AT-rich minor groove. - Shape-selective recognition: Preferential binding in AT-rich minor groove. Boger J. Am. Chem. Soc. 1997, 119, 4977 and 4987. Boger, Garbaccio Bioorg. Med. Chem. 1997, 5, 233.
37
- N-Acylation and its effect on vinylogous amide and cyclopropane conjugation.

(+)-CBI (+)-N-BOC-CBI ()-CBQ ()-N-BOC-CBQ ca. 1050 x increase in reactivity
vs
vs
and
O 1.337 A
N H
O 1.390 A
N OtBu
t1/2 = 920 h (pH 3)

X-ray
1.508
9a
O t1/2 = 133 h (pH 3)
O 1.336 A
N H
O 1.415 A
t1/2 = 91 h (pH 3) t1/2 = stable (pH 7)

X-ray
O OtBu t1/2 = 2.1 h (pH 3) t1/2 = 544 h (pH 7)
1.521 12.7 1.468

9 8b 9 9a
1.525 16.5 1.468 40.9 1.539

9b 10 10a
1.528 19.8 1.445 36.4 1.543

9b 10 10a
28.7 1.476 28.7
8b
45.0 1.544
1.532
- N-acylation decreases the cross-conjugated vinylogous amide conjugation, increases the cyclopropane conjugation and bond lengths, and increases cyclopropane reactiviity. This can be observed in the corresponding X-ray crystal structures. - Amide twist effect on the vinylogous amide and cyclopropane conjugation.
1 = 6.9 O 1.390 A H catalyzed reaction Uncatalyzed reaction and rates X-ray

1.521
9a
1 = 34.2 O 1.415 A O N OtBu O O N
1 = 86.4
N OtBu O
OtBu
1.428 A 104 x increase in reactivity
t1/2 = 133 h (pH 3) t1/2 = stable (pH 7)

- Decreases vinylogous amide cross-conjugation
t1/2 = 2.1 h (pH 3) t1/2 = 544 h (pH 7)

- Increases cyclopropane conjugation (bond lengths)
t1/2 = 0.03 h (pH 3) t1/2 = 2.1 h (pH 7)

- Increases cyclopropane reactivity
1.528 16.5
9b 9 10a
1.565
11a
28.7
38.5
8b
10b 10
40.9 1.543
28.7 1.525
11
18.5
1.544
regioselectivity:
> 20 : 1
3:2
< 1 : 20 complete reversal of reaction regioselectivity
- Note the change in solvolysis regioselectivity where the stereoelectronically aligned cyclopropane bond is the bond which is cleaved. The stereoelectronically aligned bond is that which is positioned to best overlap with the developing -system of the product phenol. - In each case, the ring expansion occurred with generation of a single enantiomer by a SN2 mechanism. Boger J. Org. Chem. 1997, 62, 5849; J. Am. Chem. Soc. 1997, 119, 4977.
38
K. Methods for the Synthesis of Optically Active Materials

Morrison Asymmetric Syntheses, Academic: New York, 1983; Vol. 15. Note: A summary of approaches which will be highlighted throughout the following material. 1. Partial Synthesis - From readily available, naturally-derived optically active materials, examples include a. Progesterone from sapogenin diosgenin. b. Synthetic penicillins from the fermentation product 6-aminopenicillanic acid (6-APA). c. Vitamin D3 (1-hydroxycholecalciferol) from cholesterol. 2. Resolution a. Diastereomeric salts and selective crystallization. b. Diastereomeric derivatization and chromatography or selective crystallization. c. Direct chromatographic resolution of enantiomers on an optically active stationary support. d. Enzymatic resolution. e. Kinetic resolution with selective production of desired enantiomer or selective consumption of undesired enantiomer. Advantage: Both enantiomers are made available.
Disadvantage: 1/2 of the material is wasted if only one enantiomer is desired. Ambiguous assignment of absolute configuration. See: Jacques, Collet, Wilen Enantiomers, Racemates, and Resolutions, Wiley: New York, 1981. 3. Synthesis from Chiral Pool - Readily available, abundant or naturally occurring starting materials. a. Carbohydrates b. Amino acids c. -Hydroxy carboxylic acids d. Terpenes e. Readily available, abundant natural products 4. Asymmetric Synthesis a. Optically active reagent (Stoichiometric) b. Optically active chiral auxiliary incorporated into substrate (Stoichiometric) c. Optically active catalyst (Catalytic) See: Koskinen Asymmetric Synthesis of Natural Products; Wiley: New York, 1993. Gawley, Aube Principles of Asymmetric Synthesis; Elsevier: Amsterdam, 1996. 5. Microbial, Enzymatic, or Catalytic Antibody Transformation See: Wong, Whitesides Enzymes in Synthetic Organic Chemistry; Pergamon: Oxford, 1994.
O. Wallach, a colleague and collaborator of A. Kekule, received the 1910 Nobel Prize in Chemistry for his work on essential oils that converted the field of natural products from a disorganized collection of confusing observations into a complete, organized and integrated field. He established the isoprene rule.
39
40
Oxidation Reactions Dale L. Boger
IV. Oxidation Reactions

A. Epoxidation Reactions: Oxidation of Carbon-Carbon Double Bonds
Comprehensive Org. Syn.; Vol. 1, 819; Vol. 7, pp. 357 and 390 (asymmetric).
O R O
H O
O + C C R OH +
1. Peracid Reactivity Rate increases: R = CH3 < C6H5 < m-ClC6H4 < H < p-NO2C6H4 < pKa of acid (RCO2H): 4.8 4.2 3.9 3.8 3.4 2.9 CO2H < CF3 0
The lower the pKa, the greater the reactivity (i.e., the better the leaving group).
2. Mechanism R R O O O H R + O O O H O O O H
Butterfly mechanism (usual representation) Bartlett Rec. Chem. Prog. 1950, 11, 47.
Refined representation: trans antiperiplanar arrangement of O-O bond and reacting alkene, n-* stabilization by reacting lone pair in plane.
The synchronicity of epoxide C-O bond formation and an overall transition state structure postulated using ab initio calculations and experimental kinetic isotope effects. Singleton, Houk J. Am. Chem. Soc. 1997, 119, 3385. 3. Stereochemistry a. Stereochemistry of olefin is maintained: diastereospecific. b. Reaction rate is insensitive to solvent polarity implying concerted mechanism without intermediacy of ionic intermediates. c. Less hindered face of olefin is epoxidized. R R R R O CH2Cl2 O R=H R = CH3 20 min, 25 C 24 h, 25 C 99% < 10% 1% 90% Brown J. Am. Chem. Soc. 1970, 92, 6914. + R R
m-CPBA
41

4. Chemoselectivity
_
Electrophilic reagent: most nucleophilic C=C reacts fastest. > RO > > R > > EWG >
- Examples O
m-CPBA cis : trans 1 : 1

10 C, 1 h
C6H5CO3H CHCl3, 10 min 0 C
O Concave face hindered toward peracid attack HO2C O H H 80% OH H Convex face open to peracid attack H CO2H OH O
HO2C
O C6H5CO3H
OH
C6H6 - dioxane 25 C, 24 h
Hckel Chem. Ber. 1955, 88, 346. Woodward Tetrahedron 1958, 2, 1. Tamm, C. Helv. Chim. Acta 1975, 58, 1162.
5. Diastereoselectivity a. Endocyclic Olefins Rickborn J. Org. Chem. 1965, 30, 2212. Destabilizing steric interaction between reagent and axial Me H Me H Me + H Me 87 : 13 O H Me H Attack principally from this face H Me Me H Me
m-CPBA
Me 25 C, Et2O
42
Oxidation Reactions Dale L. Boger R Me G H O R Me G O vs. Me H O H Me Me O O O H Me O H O
Small difference for products: but larger difference for reagent approach in transition state.
b. Exocyclic Olefins more hindered face Me Me Me less hindered face

_
RCO3H
Me Me Me
O +
Me Me Me
less stable product 75% 80% 83% 25% 20% 17%
Solvent dependent
CCl4 C6H6 CH2Cl2 or CHCl3
Henbest J. Chem. Soc., Chem. Commun. 1967, 1085.

_
The effective size of the reagent increases with increasing solvent polarity, i.e. the solvation shell of the reagent increases in size. Small reagent preference: axial attack and 1,3-diaxial interactions vary with size of the reagent H H H H H H H H 41 H H : H H + H 59 H H O
RCO3H
Large reagent preference: equatorial attack and 1,2-interactions (torsional strain) are relatively invariant with the size of the reagent
Carlson J. Org. Chem. 1967, 32, 1363.
43
Modern Organic Chemistry The Scripps Research Institute c. Allylic Alcohols (endocyclic)
Henbest J. Chem. Soc. 1957, 1958; Proc. Chem. Soc. 1963, 159. OR O
m-CPBA
OR + 43% 9%
OR
R = COCH3 R=H
20 C C6H6 5 C C6H6
57% 91%
38% yield 86% yield
_ Diastereoselectivity
OH
and rate (ca. 10x) of reaction accelerated by unprotected allylic alcohol. O O OH OH m-CPBA +
tBu tBu
tBu
Prefers equatorial position, locking conformation of substrate
4%
96%
Original proposal for the origin of selectivity: R H O 120 R O O O H R = H, tBu HO H H R 120 H-bonding to proximal peroxide oxygen directs epoxidation to the same face as OH group and accelerates/facilitates the reaction.
Equivalent to the ground state eclipsed conformation of acyclic allylic alcohols:
_ Metal-catalyzed epoxidations of allylic alcohols exhibit a more powerful directing effect and rate acceleration (ca. 1000x). Metal bound substrate (as an alkoxide) delivers olefin to metal bound peroxide (tighter association than H-bonding). OH O
tBuOOH
OH +
tBu
OH
VO(acac)2
tBu
tBu
83%
0%
100%
Sharpless Aldrichimica Acta 1979, 12, 63.

_
This may also be utilized to chemoselectively epoxidize an allylic alcohol vs. unactivated olefin.
44
Oxidation Reactions Dale L. Boger d. Allylic Alcohols (exocyclic) small reagent Early transition state and the asynchronous bond formation places the reagent further from 1,3-interactions. H H
tBu
m-CPBA
large reagent
O +
tBu
R2 R1
tBu
R2 R1 axial
R2 R1 equatorial H(R2)
R1 H H H CH3 H OH OH OCH3 OCH3
R2 H OH OCH3 OCH3 OAc H CH3 H CH3 Equatorial substitution Axial substitution blocks equatorial reagent delivery 69 60 60 88 75 11 13 83 83 : : : : : : : : : 31 40 40 12 25 89 87 17 17 HO
axial OH directs epoxidation to the syn-face of the exocyclic double bond
Vedejs and Dent J. Am. Chem. Soc. 1989, 111, 6861.
e. Acyclic Allylic Alcohols Generalizations: HO R

2
Eclipsed Conformations in m-CPBA Epoxidation H H R1 R4 R3 R

2
R1
R4 R3
HO
OH R2 R1
O R R3 H
4
OH R2 R1 HO
R4 R3
Threo Product
Erythro Product
OMet R2 R1 H R4 R3 R2 H
R1 R4 R3 OMet
Bisected Conformations in Metal-Catalyzed Epoxidation
45

_Examples
R1
threo
OH R1 = Me
erythro
40 80 39 80 42 85
m-CPBA VO(acac)2, tBuOOH m-CPBA VO(acac)2, tBuOOH m-CPBA VO(acac)2, tBuOOH
60 20 61 20 58 15
= Et
H vs. alkyl eclipsing HO interaction with H H double bond has little H H to no effect on R1 selectivity. H eclipsing interaction slightly threo more stable. R1
= iPr
H,H eclipsing in erythro T.S. favored over H,alkyl eclipsing in threo T.S.
H H
H H OMet erythro
R2
R1 OH
threo
erythro
Me
Me H H
R1,R2 = Me
m-CPBA VO(acac)2, tBuOOH m-CPBA VO(acac)2, tBuOOH
45 5 41 2
55 95 59 98
Erythro slightly favored due to Me,Me gauche interaction in threo T.S.
HO
erythro
Me
R1 = Me R2 = nBu
H,Bu eclipsing in erythro T.S. favored over Me,Bu eclipsing in threo T.S.
Bu H
H H OMet erythro
R1
threo
R4 OH R1,R4 = Me
erythro
36 71 Similar to R4 = H. R4 does not sterically influence either T.S. The R1 steric effect predominates.
m-CPBA VO(acac)2, tBuOOH
64 29
R1
threo
OH R3 R1,R3 = Me
erythro
5 29 Large 1,3-allylic strain avoided. HO H Me H H Me
m-CPBA VO(acac)2, tBuOOH
95 71
threo
Me Me Me OH
threo m-CPBA VO(acac)2, tBuOOH

95 86
erythro
5 14 Large 1,3-allylic strain avoided. H Me
OMet Me Me
threo
46
Oxidation Reactions Dale L. Boger f. Refined Models for Directed Epoxidation of Acyclic Allylic Alcohols R
_
Peracid Mediated Epoxidation
Sharpless Tetrahedron Lett. 1979, 4733.
1. Trans antiperiplanar arrangement of O-O bond with alkene C=C. O H H H H 2. H-bonding to distal oxygen of peroxide through the lone pair out of O the plane of reaction. Top View 3. Lone pair in plane of reaction provides lone pair (n-) stabilization. 120o 4. Secondary isotope effect suggests that the formation of the C-O bonds is asynchronous.
O O
Eclipsed Conformations in m-CPBA Epoxidation HO R2 R1 H R4 R3
Sharpless Aldrichimica Acta 1979, 12, 63. H R2 HO R1 R4 R3
OH O R2 R1 H
O R4 R3 R4 R3 R1
OH R2 H
threo product
_
erythro product
Transition-metal Catalyzed Epoxidation 1. Trans antiperiplanar arrangement 2. 50o dihedral angle R O O O R Met O
O Met
Top View
3. In-plane lone pair 4. Lone pair bisects C=C bond
Curtin-Hammett Principle: - The reactive conformation is not necessarily related to the ground state conformation. - The substrate is forced into a non-ground state conformation due to the geometrical constraints of the reaction. Bisected Conformations in Metal-Catalyzed Epoxidation OMet R2 R4 R1 H R3 R2 H R1 R4 R3 OMet
OH O R2
O R4 R3 R4 R3 R1
OH R2 H
R1 H Threo Product
Erythro Product
47
Modern Organic Chemistry The Scripps Research Institute Take Home Problem Epoxidation of 3 of the 4 olefins below is diastereoselective; the fourth is not. Why? BnO Me Me OH H BnO Me OH Me O BnO Me BnO Me H Me OH OH BnO Me Me O BnO Me + O references: Kishi Tetrahedron Lett. 1980, 21, 4229. Tetrahedron Lett. 1979, 20, 4343 and 4347. g. Homoallylic Alcohols OH Ph Me Me VO(OnPr)3 tBuOOH CH2Cl2, 95% H L Ph Me H OTBDPS
_ _
O BnO Me O
Me OH H OH
BnO
OH
OH H
60%
BnO Me H
OH
40%
OH L Ot O Me Bu Ph Me
Me OTBDPS
OTBDPS
Alternative chair has two axial substituents. Intramolecular oxygen delivery occurs through most stable chair-like transition state. VS.
OAc Ph Me Me
m-CPBA CH2Cl2, 25 C 94%

Ph
major Me H OAc OTBDPS Ph
OAc
Me OTBDPS
Me 5:1
OTBDPS
minor
H-Eclipsed conformation from least hindered face _ Not a directed epoxidation! _ Diastereoselectivity still good and through H-eclipsed conformation.
_ Epoxidation
Schreiber Tetrahedron Lett. 1990, 31, 31. Hanessian J. Am. Chem. Soc. 1990, 112, 5276.
48
Oxidation Reactions Dale L. Boger h. Other Directed Epoxidations

_
Studies suggest axial -NHCBZ delivers syn epoxide while equatorial does not. R NHCBZ R = NHCBZ = CH2OH = CH2OAc = CO2Me = CH2OTBDMS R O NHCBZ 100 100 100 100 0 0 0 0 0 100 + O NHCBZ R
m-CPBA
CH2Cl2, 25 C
86% 83% 72% 59% 54%
Presence of H-bonding, directing substituent enhances rate and yield of reaction.
Witiak J. Med. Chem. 1989, 32, 214. Rotella Tetrahedron Lett. 1984, 30, 1913.
O X
iPr
O X
iPr
m-CPBA
CH2Cl2, 25 C O
X + O
iPr
n n = 1, X = NH X=O n = 2, X = NH X=O 80%
n 20 3 20 3
n 1 1 1 1
Mohamadi Tetrahedron Lett. 1989, 30, 1309.
OH
OH O O +
OH O O
H2O2 / NaOH / MeOH / 0 C Ti(iPrO)4 / tBuOOH / CH2Cl2 / 15 C
40 >99
: :
60 1
Ollis Tetrahedron Lett. 1991, 32, 2687.
49
Modern Organic Chemistry The Scripps Research Institute 6. Scope and Limitations Peracid + O
a. Olefin geometry is maintained. b. Reaction is diastereospecific: the stereochemistry of the reactant and product bear a definite relationship to one another. c. Reaction can be buffered to prevent epoxide opening. The pKa of parent acid is much lower than that of the peracid, and the peracid is not nearly as acidic. Reaction requires the protonated peracid so the buffer must not deprotonate the peracid but should deprotonate the product carboxylic acid. H2O2 HCOOH H Na2CO3 / NaHCO3 CH3COOH / NaOAc CF3CO3H / Na2HPO4 - NaH2PO4 e.g. HCOOH HCO3H H O OH O O H OH OH
NaOH
These reagents can be used as a buffer when the peracids are used as epoxidation reagents.
pKa 3.6 pKa 7.1
CH3COOH pKa 4.8 CH3CO3H pKa 5.2
So, choose bases (Na2CO3, NaHCO3, Na2HPO4) to deprotonate only the RCOOH formed.
d. Also, at higher temperatures, a free radical scavenger may be used to avoid peracid decomposition. e. Common Side Reactions 1. Baeyer-Villiger reactions of ketones (and aldehydes) O e.g.
m-CPBA
O not O
When peracids are used to oxidize olefins to epoxides in the presence of carbonyl functionality (ketones or aldehydes), protection of the carbonyl group may be necessary. may choose to select a reagent which attacks olefins preferentially. N
_ One
2. Oxidation of amines
_
m-CPBA
+N
Nitrogen must be protected (e.g., as amide) or another reagent selected. N R
3. Imine oxidation
m-CPBA
O N R R R + R R S O O
4. Sulfur oxidation
m-CPBA
S O
m-CPBA
CO3H CO2H CO3H
Typical Peracids CO3H CF3CO3H O2N O2N CO3H
Cl
50
Oxidation Reactions Dale L. Boger 7. Epoxidation of Electron-Deficient Olefins a. ,-unsaturated esters: can choose a strong peracid or vigorous reaction conditions CF3CO3H Me Me Emmons J. Am. Na2HPO4 Chem. Soc. 1955, 77, 84% 89. CH2Cl2, reflux CO2CH3 O CO2CH3 Ph CO2CH3
m-CPBA CH2Cl2, reflux
Ph O CO2CH3 47% MacPeek J. Am. Chem. Soc. 1959, 81, 680.
b. ,-unsaturated ketones: Baeyer-Villiger competes with epoxidation O R R1
Epoxidation Baeyer-Villiger Reaction Solution: different conditions (reagents) are needed
B. Additional Methods for Epoxidation of Olefins

1. H2O2, NaOH O H2O2, NaOH OH O O O O 70%
The following reaction is diastereoselective (but not diastereospecific): a single stereoisomer of the product is formed which bears no relationship to the reactant. Me CO2CH3 H2O2, NaOH Me H O Me CO2CH3 Me OCH3 OH2O2, NaOH Me CO2CH3 Me
Me
The reaction occurs via a reversible process: Me Me CO2CH3 Similarly,

tBuOOH/Triton
Me HO H O
Me
CO2CH3 Me
B Ph3COOH/R4NOH tBuOOH/nBuLi 2. Peroxyimidate RCN

_
Payne J. Org. Chem. 1961, 26, 651. Corey J. Am. Chem. Soc. 1988, 110, 649. Clegg Tetrahedron 1988, 29, 4889.
H2O2 R
NH O O O H + R
O NH2
This reagent permits the use of neutral reaction conditions. Unlike m-CPBA, the reagent behaves as a large reagent and thus approaches from the equatorial face of an exocyclic double bond. O + small reagent large reagent O
m-CPBA PhCN / H2O2
59 14
41 86
51
Modern Organic Chemistry The Scripps Research Institute 1,3 H Carlson J. Org. Chem. 1967, 32, 1363. (m-CPBA & PhCN/H2O2) Vedejs J. Am. Chem. Soc. 1989, 111, 6861. (m-CPBA) H
m-CPBA
small reagent, but the interaction will increase with the size of the reagent
H H 1,2
PhCN/H2O2 larger reagent, but the interaction will not vary with size, predominately equatorial attack
_Analogous
reagent:
Ph N C O + H2O2
Ph
H N O
O H
Christl Angew. Chem., Int. Ed. Eng. 1980, 19, 458.
Mechanism Problem Provide mechanism for: AcO H O AcO
m-CPBA, CHCl3
AcO 5 C then , 160 C H
m-CPBA, CHCl3
AcO H 5 C then , 160 C O H Johnson J. Org. Chem. 1961, 26, 4563. H OO O H + O O OH
Why does this reaction need to be heated to 160 C? Me AcO H H reagent attack from this face Me half-chair conformation OAc
OAc Me H O H
Me + O O H O
Me O O
H H+
52
Oxidation Reactions Dale L. Boger 3. Sulfur Ylides Me

tBu
O Me Me
_
Me
S CH2 77%
O 87
tBu
+ O : 13
tBu
S+ Me I
nBuLi,
<0 C
Me Me S CH2
dimethylsulfonium methylide small reagent that prefers axial delivery
This is kinetic control: reaction gives the thermodynamically less stable epoxide product. S+ H H
tBu tBu
O
tBu
Equatorial Delivery 1,2-interaction disfavored
O 13%
O S+ H H
tBu
tBu
Axial Delivery 1,3-interaction favored over 1,2
87%
tBu
Me O S+ CH2 Me 89%
O 0
tBu
+ O : 100
tBu
thermodynamic product
Me O S+ CH3 Me I
Me O S+ CH2 Me Corey, Chaykovsky J. Am. Chem. Soc. 1965, 87, 1353. OH S+ H

tBu
NaH, THF reflux
dimethyloxo sulfonium methylide small reagent that prefers axial attack
tBu
equatorial attack
tBu
rapidly goes on to product
O 100%
O
O
tBu
axial attack predominant
S+
H H
tBu
fails to go on to product
OH H S+
backside attack not possible due to destabilizing 1,3-interactions For this reaction: Initial reaction is reversible and is not capable of generating the axial delivery product because of the destabilizing 1,3-interactions in the transition state required for epoxide closure.
53
Modern Organic Chemistry The Scripps Research Institute Summary of Exocyclic Epoxide Formation Note: defined conformation of 6-membered ring required for comparisons or X X=O X = CH2 X=O S axial attack O X X X equatorial attack X O
m-CPBA
O S+ CH2NH H O
X = CH2
R O R = large group Sulfur ylides deliver "CH2" Peroxides deliver "O" Learn reagents by: 1) Conditions required 2) Advantages and disadvantages 3) Competitive reactions 4) Stereochemistry limitations / highlights
4. Dimethyl Dioxirane (DMDO) O O A mild neutral reagent Murray J. Am. Chem. Soc. 1986, 108, 2470. Acc. Chem. Res. 1989, 22, 205. Peracid reaction suffers from H+ catalyzed epoxide opening Adam Tetrahedron Lett. 1989, 30, 4223. Curci Tetrahedron Lett. 1989, 30, 257. CF3 Excellent for oxidation of O highly substituted enol ethers O CH3 O Boyd Tetrahedron Lett. 1989, 30, 123.
DMDO O O acetone, 96% O O O O O O
O O BnO BnO OBn R3SiO O BnO BnO OBn R3SiO O O O
Crandall J. Org. Chem. 1988, 53, 1338. Tetrahedron Lett. 1988, 29, 4791.
Danishefsky J. Am. Chem. Soc. 1989, 111, 6661. Useful for glycosidation reactions.
O OSiR3
stable and characterizable Danishefsky J. Org. Chem. 1989, 54, 4249.
54
Oxidation Reactions Dale L. Boger 5. Summary of Other Methods of Epoxide Formation a. Cyclization of Halohydrins + X2 + H2O HO X X
tBu tBu
OH-
X equatorial H2O OH CH2X 10 18 45 30 10

tBu
axial H2O NXSH2O CH2X

tBu t OH + Bu
O + major 90 31 : vs
tBu
tBu
: Increased NCS-H2O 90 : reagent size NBS-H2O 82 yields increased : NIS-H2O 55 equatorial Analogous results observed with: approach Br , ClCH CH Cl 70 : 2 2 2 : Br2, MeOH 90
minor 10
69 : For m-CPBA, complementary stereochemistries
-The electrophilic reagents behave as small reagents and approach from the axial direction Chiappe J. Org. Chem. 1995, 60, 6214. -For acyclic systems: E+ LUMO electrophile HOMO alkene Houk Acc. Chem. Res. 1990, 23, 107. b. Cyclization of 1,2-diols R OH OH L TsCl -Large or electropositive group R R O
OTs
OH _ primary alcohol > secondary alcohol for tosylation reaction c. Epoxides from carbonyl compounds d. O + O + O + R H X = OR, R, Li Cl R R1 S CH2 O S CH2O O + Cl X N R O O R O O R R1 O e.
Kobrich Angew. Chem., Int. Ed. Eng. 1972, 11, 473.
f.
Darzen's Condensation: First Example: Erlenmeyer Ann. 1892, 271, 161. Generalized by Darzen through years 19041937 O Compt. rend. 1904, 139, 1214. Comprehensive Org. Syn., Vol. 2, pp. 409. Newman, Magerlein Org. React. 1968, 5, 413. Asymmetric variants Evans Chiral Oxazolidinone Lantos J. Am. Chem. Soc. 1986, 108, 4595.
55
C. Catalytic Asymmetric Epoxidation

1. Sharpless Catalytic Asymmetric Epoxidation (AE Reaction) Key references: Asymmetric Synthesis: Vol. 5, Morrison, J.D. Ed., Acad. Press, Chapters 7 and 8. Reviews: Katsuki, Martin Org. React. 1996, 48, 1. Comprehensive Org. Syn.; Vol. 7, pp. 389-436. Sharpless J. Am. Chem. Soc. 1980, 102, 5974; 1987, 109, 5765; 1981, 103, 6237; 1984, 106, 6430; 1991, 113, 106, 113; 1987, 109, 1279. 1. The enantiofacial selectivity of the reaction is general and dependable for assignments. D-(-)-DIPT R2 R
3
R1 OH
tBuOOH,
Ti(OiPr)
R2 O R
3
R1
CH2Cl2, -20 C, DET or DIPT 4 A molecular sieves
OH anhydrous
L-(+)-DIPT
2. Selectivity is catalyst dependent Ti(OiPr)4 Al(OtBu)3 MoO2(acac)2 VO(OiPr)3 Sn(OiPr)4 95% ee 5% ee 15% ee 17% ee NR Zr(OiPr)4 Hf(OiPr)4 Nb(OEt)3 Ta(OiPr)5 10% ee 3% ee 5% ee 39% ee
3. Chemical Conversion unsubstituted trans-disubstituted cis-disubstituted 1,1-disubstituted trans-1,1,2-trisub. cis-1,1,2-trisub. 1,2,2-trisubstituted R 1 = R2 = R3 = H R1, R3 = H R2, R3 = H R1 = R2 = H R1 = H R2 = H R3 = H 95% ee >95% ee 85-95% ee 85-95% ee >95% ee >90% ee >95% ee
yield 15% (isolation problematic) 70-90% 70-90% 70-90% 70-90% 70-90% 70-80%
56
Oxidation Reactions Dale L. Boger 4. Sharpless asymmetric epoxidation is one of the best known and practical asymmetric reactions utilized in organic synthesis. Discovered in 1980, this catalytic process utilizes an optically active ligand to direct a transition metal catalyzed reaction. Epoxidation from a single face of a prostereogenic allylic alcohol: H H E O RO HO OH E O Ti O RO R' O O Ti O RO2C CO2R OE O tBu C2 symmetry RO E = CO2R (Useful in ligand design- predictable and repetitive structural units which reduce number of diastereomeric transition states)
a. Match of Ti / Tartrate such that a single complex dominates the chemistry. The concentration of each complex in the mixture of complexes is dictated by thermodynamic considerations. However, it could not be predicted that a single species would dominate the Ti-tartrate equilibrium mixture and that this species would be so kinetically active. The tartrate-Ti complex is perfectly matched and slight deviations in the ligand structure or change in the metal alkoxide reduces the effectiveness of the reaction.
b. Ligand acceleration of reaction. This is not essential but extremely beneficial. It ensures that the enantioselective version of the reaction (the one in which the auxiliary ligand is present) will be the most viable kinetic pathway.
c. Steric and stereoelectronic features of reaction control enantioselectivity.
Stereoelectronic: 1. Alkyl peroxide is activated by bidentate coordination to the Ti(IV) center. 2. The olefin is constrained to attack the coordinated peroxide along the O-O bond axis. (stereoelectronic effect) 3. The epoxide C-O bonds are formed simultaneously. Steric factors: 1. Bulky hydroperoxide is forced to adopt a single orientation when bound in a bidentate fashion. 2. The allylic alkoxide is thereby restricted to reaction at a single coordination site on the metal center. Steric interactions of the bound substrate with the catalyst framework provide for the kinetic resolution patterns. 3. Efficient catalytic turnover provided by the labile coordinated ester, permitting rapid alkoxide-alcohol exchange.
57
Modern Organic Chemistry The Scripps Research Institute Scope Epoxidation with Titanium-Tartrate Catalysts unsubstituted (R1 = R2 = R3 = H) R3 R2 = CH3 R2 = n-C10H21 R2 = (CH2)3CH=CH2 R2 = Me3Si R2 = tBu R2 = Ar R2 = CH2OBn R2 = O O R2 = BnO O R2 = BnO R2 = BnO R2 = Ph O O BnO >93% ee OSiEt3 R R = OBn, OH 90% ee 91% ee 92% ee 96% ee O 1,1-disubstituted (R1 = R2 = H) R3 = -cyclohexyl R3 = n-C14H29 R3 = tBu R3 = R2 = Ph R3 = Me, R2 = Et R3 = Me, R2 = AcO R3 = Me, R2 = O >95% ee 92% >95% ee >95% ee 85% ee >95% ee >95% ee >95% ee 81% 51% 82% 83% 84% 55% 70-88% O >99% ee 70% O >99% ee 76% O R2 R1 OH 95% ee >95% ee >95% ee >95% ee >95% ee >95% ee 95% ee 98% ee >95% ee yield 15% 45% 79% 80% 60% 0-90% 85% 78-85%
trans-disubstituted (R1 = R3 = H)
>95% ee
70%
cis-disubstituted
(R2
R3
= H)
R1
= n-C10H21 R1 = CH2Ph R1 = CH2OBn O R1 =
trans-1,1,2-trisubstitued (R1 = H)
87% 79% 70%
cis-1,1,2-trisubstituted (R2 = H)
1,2,2-trisubstituted (R3 = H) tetrasubstituted
O R3 = CH3, R1= Bn R2 = (CH2)2CH=C(CH3)2, R1 = CH3 R2 = CH3, R1 = (CH2)2CH=C(CH3)2 R3 = CH3, R2 = Ph, R1 = Bn OH
91% ee >95% ee 94% ee 94% ee 94% ee
90% 77% 79% 90% 90%
58
Oxidation Reactions Dale L. Boger Allylic Alcohols Undergoing Kinetic Resolution with Relative Rates >15 at -20 oC R4 R3 R2 R5 OH R1
R1 = n-C6H13 R1 = (CH2)2Ph R1 = R1 = cyclohexyl R1 =
O O
R1 = n-C4H9, R3 = CH3 R1 = cyclohexyl, R3 = CH3 R1 = n-C4H9, R4 = Et or CH3 R1 = cyclohexyl, R4 = CH3 R1 = Et, R4 = Ph R1 = CH2CH(CH3)2, R4 = CH3 R1 = R5 = CH3 R1 = Et, R4 = n-C6H13
OH HO
OH
Poor Substrates for Asymmetric Epoxidation or Kinetic Resolution Catalyzed by Titanium-Tartrates
Ph OH
tBu
O O
tBu
BnO
O O OH
OH
OH
OH
OH
OBn O OH OH O O O H3CO2C
CH3O OH OH OH
OH OH
OH Ph OH
OH
tBu
OH
tBu
OH
59
Modern Organic Chemistry The Scripps Research Institute 5. Kinetic Resolution Sharpless J. Am. Chem. Soc. 1981, 103, 6237. Pure Appl. Chem. 1983, 55, 589.
_
Sharpless epoxidation product is different from the directed oxidation of allylic alcohols by peracids (m-CPBA). Sharpless Epoxidation
HO R
O H
HO R H
m-CPBA
HO R
O H
OH
(1.2 equiv.) 1.0 equiv. Ti(OiPr)4, 0.6 equiv. tBuOOH, CH2Cl2, 20 C, 15 h
L-(+)-DIPT
O OH H +
O OH H H
OH
racemic
98
(R)-enantiomer recovered
relative rates = kS / kR = 104 (S)-enantiomer reacts
1.0 equiv. Ti(OiPr)4 1.5 equiv. D-(-)-DIPT 0.4 equiv. tBuOOH CH2Cl2, 20 C OH
O + OH 27% yield >95% ee OH 33% yield 72% ee
0.8 equiv. Ti(OiPr)4 0.8 equiv. L-(+)-DET 0.8 equiv. tBuOOH CH2Cl2, 20 C
O OH 75% yield 95% ee
Roush J. Org. Chem. 1982, 47, 1371.
HO
Me OH
HO
Me OH
OH Sato Tetrahedron Lett. 1987, 28, 6351. I OH Sharpless epoxidation Kinetic resolution
OH
60
Oxidation Reactions Dale L. Boger 6. Total Synthesis of the L-Hexoses Sharpless, Masamune Science 1983, 220, 949. Tetrahedron 1990, 46, 245. "Reagent-Control" Strategy: selection of reagent dictates ultimate absolute stereochemistry of reaction products irrespective of stereofacial bias of substrate. "Substrate-Control" Strategy: stereochemistry of reaction products dictated by the inherent stereofacial bias of the substrate. Masamune Angew. Chem., Int. Ed. Eng. 1985, 97, 1. Sharpless Chemica Scripta 1985, 25, 71. O O OH O O OH O O OH
O O erythro threo Reagent Product Ratio (threo:erythro) 1 : 1.4 achiral reagents m-CPBA 1 : 1.8 "substrate control" VO(acac)2-TBHP iPr) -TBHP 1 : 2.3 Ti(O 4 iPr) -(-)-tartrate_TBHP "matched pair" 1 : 90 Ti(O 4 iPr) -(+)-tartrate_TBHP "mismatched pair" 22 : 1 Ti(O 4 "reagent control" -Reiterative two-carbon extension cycle employed for the synthesis of all L-hexoses: OR'OR' Homologation R-CH-CH-CH=CH-CH2-OH R-CH=CH-CH2-OH OR'OR' Homologation R-CHO OR'OR' Pummerer Reaction Ti(OiPr)4, (+)-DIPT, tBuOOH, CH Cl 2 2 4A mol. sieves 20 C, 92% (>20:1) O OR >95% ee CHO AcO SPh O O OR K2CO3, MeOH, 93% (>20:1) O OR DIBAL-H 84% (>20:1) O O OR CHO O R-CH-CH-CH2-SPh AE AE
R-CH-CH-CHO
And so on... O R-CH-CH-CH2-OH * * Payne Rearrangement AcO O O SPh m-CPBA; Ac2O, NaOAc 93% OR SPh O O OR Diverging Intermediate
OH RO R = CHPh2
OH PhSH, 0.5 N NaOH, tBuOH, reflux (4:1); (MeO)2CMe2, cat. POCl3, 71%
erythro corresponds to C4 and C5 of allose, altrose, mannose, and glucose
threo corresponds to C4 and C5 of gulose, idose, talose, and galactose
61
Modern Organic Chemistry The Scripps Research Institute CHO O O OR O OR CHO O
erythro
Ph3P=CHCHO benzene; NaBH4 MeOH OH
threo
Ph3P=CHCHO benzene; NaBH4 MeOH OH
O O OR (+)-AE 76% (>20:1) OH O O O

tBuOH,
O O OR ()-AE 84% (>20:1) OH O O O O O O OR

tBuOH,
(+)-AE 71% (>20:1) OH
()-AE 73% (>20:1) OH O O O OR

tBuOH,
PhSH NaOH reflux (16:1) 77% O O O O
OR
tBuOH,
SPh
PhSH NaOH reflux (7:3) 63%
SPh O O
PhSH NaOH reflux (7:1) 79% O O
SPh
PhSH NaOH reflux (15:1) 86%
OR
O O OR OR b CHO OH HO HO HO HO HO OH
L-Mannose
O O OR d CHO HO OH HO HO OH
L-Glucose
SPh O O O O OR f g CHO OH OH OH HO OH OH
L-Talose
a CHO HO HO HO HO OH
L-Allose
c CHO OH OH
e CHO HO HO OH HO OH
L-Gulose
h CHO HO OH OH HO OH
L-Galactose
CHO OH HO OH HO
L-Idose
OH L-Altrose
For a, c, e, and g: 1. Pummerer reaction, 2. DIBAL-H, 3. Deprotection. For b, d, f, and h: 1. Pummerer reaction, 2. K2CO3/MeOH, 3. Deprotection.
62
Oxidation Reactions Dale L. Boger -Payne Rearrangement Payne J. Org. Chem. 1962, 27, 3819. Base-catalyzed (aq. NaOH) migration of ,-epoxy alcohols: O CH3 CH3 OH 8% O 0.5 N NaOH 1h HO CH3 O 92% OH CH3 O 7%, erythro H CH3 CH3 H CH3 O H CH2OH OH CH3 O
58% O H 44% OH CH3 CH3 CH3 O OH
42%, threo OH CH3 CH3 CH3
CH3 H
H CH2OH
93%
O 56%, erythro
H CH3
CH3 CH3 OH 5%
95%, threo
1. In general, the more substituted epoxide is favored as the reaction product. 2. However, steric factors and relative alcohol acidities (1 > 2 > 3) are additional factors which determine the ultimate composition of the equilibrium mixture. 3. The more reactive epoxide can be trapped by strong nucleophiles (e.g., PhSH). ROCH2 H O H CH2OH OH PhSH ROCH2 O ROCH2 OH SPh OH
Emil Fischer attended the lectures of A. Kekule, worked with A. Baeyer as a student and received the 1902 Nobel Prize in Chemistry for his work on carbohydrate and purine syntheses. Discoverer of the Fischer indole synthesis using arylhydrazones, he utilized phenylhydrazine to derivatize carbohydrates as crystalline solids for characterization that enabled him to elucidate their chemistry and structure. From the work of Le Bel and van't Hoff he knew glucose must have 16 stereoisomers and in the now classic studies synthesized most of them and established the correct configuration of glucose. He proposed structures for uric acid, caffeine, theobromide, xanthine, and guanine and later synthesized theophylline and caffeine (1895), uric acid (1897), and coined the term purine. By 1900 he prepared more than 130 derivatives including hypoxanthine, xanthine, theobromide, adenine, and guanine. In 1914, he made glucose derivatives and from them the nucleosides. He is responsible for the "lock and key" analogy for describing enzyme-substrate interactions, prepared the D- and L-amino acids with fractional crystallization resolution and made a peptide of 18 amino acids. He is also among the first to implement safety precautions (ventilation) and designed the first exhaust system put into general use.
W. Haworth received the 1937 Nobel Prize in Chemistry for his investigations on the structure determination of carbohydrates (cyclic-monosaccharides, disaccharides, and polysaccharides) including their derivitization as methyl ethers and vitamin C. The latter was accepted with wide acclaim and Haworth was also one of the first to prepare vitamin C, the first vitamin to be prepared by synthesis. This made it available to the world population for the treatment of scurvy, eliminating the need for treatment with fresh limes or lemons.
63
Modern Organic Chemistry The Scripps Research Institute 2. Jacobsen Epoxidation -Unactivated alkenes Jacobsen J. Am. Chem. Soc. 1991, 113, 7063. d disfavored by bulky phenyl groups Ph Ph H H a Me N Mn O
tBu
Me H H
Ph
Ph N Cl O
tBu
R1 b Me disfavored by phenyl group N Mn R2 O

tBu
R1 N Cl O
tBu
Me
R2
side-on perpendicular approach to metal oxo species
1 c disfavored by tBu groups 2 3 4 5
R1 Me H Me H
R2 Me Me tBu tBu
Styrene still low 70% ee Ph Me 5 mol% cat. + NaOCl 88% 54% 87% 56% 81% CH2Cl2 84% ee 49% ee 80% ee 55% ee 92% ee Ph H O 1R,2S 1S,2R 1S,2R 1S,2R 1S,2R Me H
R,R-1 S,S-2 S,S-3 S,S-4 S,S-5

catalyst 5 Ph
Me Me O
84% 67% 72%
92% ee 92% ee 98% ee
cat. 0.04 equiv 0.04 equiv 0.02 equiv
p-ClC6H4
O 96% NC O O Ph CO2Me 65% 89% ee 0.10 equiv 63% 94% ee 0.15 equiv 97% ee 0.03 equiv
The above studies focused on steric effects of the catalyst.
64

_
Electronic effects of the catalyst Jacobsen J. Am. Chem. Soc. 1991, 113, 6703. R N Mn R N Cl O
tBu
Hammett Plot 2 X log enant. ratio 1 O
O
tBu
1 2
R = Ph = (CH2)4 0.8
1a X = OMe 96% ee = Me 1b =H 1c = Cl 1d = NO2 22% ee 1e
-0.4
-0.2
0.2
0.4
0.6
1. G 2.0 kcal/mol 2. 1e / 1a krel = 4
-Example 0.05 equiv cat. 5 equiv NMO 2 equiv m-CPBA NBOC 78 C, 30 min 70%, 92% ee OBn H N
tBu
(para substituent) - conformational effects on catalyst? - provoke changes in Mn-oxo bond length? - reactivity vs transition state structure: the less reactive catalyst providing a tighter, more product-like T.S. OH Bu3P ADDP 72% OR H2, Pd-C 97% O R = Bn R=H NBOC
O NBOC Dibal-H 86% OBn
NBOC
H N Mn Cl O
tBu tBu
O
tBu
Boger, Boyce Synlett 1997, 515.
3. Chiral Dioxiranes
Examples of trans and trisubstituted olefins Ph 1 Ph H
O H O O O
O oxone, CH3CN O
O H O O
Ph O
O O O 1
C3H 7 Ph
catalytic amounts
(pH 10, K2CO3) H O Ph 73% yield >95% ee C3H7 H OTBS 80% yield H O OTBS 93% ee Ph O 69% yield 91% ee
Shi J. Am. Chem. Soc. 1996, 118, 9806. J. Am. Chem. Soc. 1997, 119, 11224. J. Org. Chem. 1997, 62, 2328.
- pH 10 (K2CO3) supresses Baeyer-Villiger reaction of ketone precursor.
65
Modern Organic Chemistry The Scripps Research Institute O Note the stereoelectronic O alignment of lone pair with spiro T.S. Spiro R R O O R R
consistent with
vs
Planar
Transition State
Yang J. Am. Chem. Soc. 1996, 118, 11311; 1998, 120, 5943. O O O 10 mol% 1, 5 equiv oxone, NaHCO3 CH3CN-H2O, 25 C 9095% yield 3276% ee 56% ee Ph O
X Ph Ph
Ph
1 X=H 2 X = Cl 3 X = Br 4 X=I
47% ee 76% ee 75% ee 32% ee
5 6 7 8
X = Me
OXONE = 2KHSO5KHSO4K2SO4
X = CH2OCH3 66% ee O X= O X = SiMe3 44% ee 71% ee
4. Polymer Supported Poly Amino Acids (CHCH2)n polyleucine: 92% yield, 99% ee O N H H N n Ph O General for Ph H2O2, NaOH toluene, catalyst Ar O Ph H H O O Ph
Ar : 8398%; 8799% ee
Itsuno J. Org. Chem. 1990, 55, 6047. Vega Angew. Chem., Int. Ed. Eng. 1980, 19, 929.
D. Stoichiometric Asymmetric Epoxidation

1. Chiral Peracids
_ To date, ee's are modest (<10%) CO2H _ Not catalytic, but rather stoichiometric reagent CO3H Ewins J. Chem. Soc., Chem. Commun. 1967, 1085. Montanari J. Chem. Soc., Chem. Commun. 1969, 135. Rebek J. Am. Chem. Soc. 1980, 102, 5602. Curci J. Chem. Soc., Chem. Commun. 1984, 155.
2. Chiral N-sulfamyloxaziridines Bn N N S Ph O O
2
C6F5 H
O 65% ee
_ _
Good ee's Stoichiometric reagent
Davis J. Am. Chem. Soc. 1983, 105, 3123. Tetrahedron Lett. 1986, 27, 5079. Tetrahedron 1989, 45, 5703.
66
E. Baeyer-Villiger and Related Reactions

Comprehensive Org. Syn. Vol. 7, pp 671-688. Org. React. 1957, 9, 73; 1993, 43, 251.
A. Baeyer received the 1905 Nobel Prize in Chemistry for his work on dyes (indigo). He also discovered barbituric acid and named it after his girlfriend Barbara. Baeyer, Villiger Ber. 1899, 32, 3625. Ber. 1900, 33, 858.
1. Baeyer-Villiger Reaction O O R R2 O H O R1
O R O R1
NaOH R
O O H
R1OH
Note: Sometimes the Baeyer-Villiger reaction is used not only for preparing carboxylic acids or esters, but also for ROH.
_
Mechanism:
(Peracid nucleophilic addition reaction) R OO O O R2 R O O R1 + R2 O O-
R R1
_
Peracids
R1
Notes:
1. Alkyl group that migrates does so with retention of configuration. 2. The more electron-rich (most-substituted) alkyl group migrates in preference (in general). talkyl > salkyl > benzyl > phenyl > nalkyl > methyl Thus, methyl ketones invariably provide acetates.
_
Examples: Friess J. Am. Chem. Soc. 1949, 71, 2571.
C6H5CO3H, CHCl3, 25 C
O O 71%
CHO Ogala J. Org. Chem. 1969, 34, 3985. X X=H X = OCH3
O C6H5CO3H MeOH-H2O, 5 C X 90% 19% CH3CO3H O OH + X 0% 73%
O O
Meinwald J. Am. Chem. Soc. 1960, 82, 5235. O
2 h, 25 C, 88%
O
_
Nucleophilic attack from least hindered exo face. Most substituted (electron-rich) carbon migrates. O
Migrating C-C bond and O-O bond must be trans-antiperiplanar
O O OO R
trans-periplanar
_
Antiperiplanar arrangement of C-Rm bond and the breaking O-O bond (stereoelectronic requirement). Hydroxyl lone pair or O-H bond antiperiplanar to the migrating C-Rm bond.
O H O Rm R O
67
Modern Organic Chemistry The Scripps Research Institute Me Sauers J. Am. Chem. Soc. 1961, 83, 2759. Me Me CH3CO3H NaOAc, HOAc 5 d, 25 C, 94% O Me Me Me O O O R H
_
_ In contrast to simple expectations, the less electron-rich bond migrates due to stereoelectronic considerations.
_
Nucleophilic attack from endo face, exo face blocked by Me's. Reaction much slower than norbornone.
O trans-periplanar bonds 2. Benzylic Hydroperoxide Rearrangement

_
Alternative to Baeyer-Villiger Reaction Would be oxidized by peracid BF3OEt2, H2O2 R O O + RLi or NaBH4
N H R OH
N+ BF 3 H O+ BF3 H
OH
N H
R = H, CH3
Boger, Coleman J. Org. Chem. 1986, 51, 5436. J. Am. Chem. Soc. 1987, 109, 2717. Tetrahedron Lett. 1987, 28, 1027.
CH3O2C HN CH3O HO NH CH3 CH3 BF3OEt2, H2O2 81%
CH3O2C HN CH3O N R OH
R=H R = CONH2 (PDE-I) R = COCH3 (PDE-II) OBn OH TsOH, H2O2 CO2CH3 NHCBZ 3. Carboxy Inversion Reaction Me H O Me H Ph O Cl Me H Ph O O O O Ar + Ar O H O O O O Ar 60% CO2CH3 NHCBZ OBn OH Boger, Yohannes J. Org. Chem. 1987, 52, 5283.
m-CPBA
With Retention
Ph
O
Me Ph
68
Oxidation Reactions Dale L. Boger 4. Urea-H2O2: a safe alternative to H2O2 Heaney Synlett 1990, 533.
ON+ N+ OS N N S
O O O O Ph O Ph
OH
OH H2N
O NH2 HO-OH
6 6
OH O O
O O O OMe OMe O O O
69
F. Beckmann Rearrangement and Related Reactions

_ An analogous rearrangement reaction can be utilized to prepare lactams and amides. 1. Beckmann Rearrangement Heldt Org. React. 1960, 11, 1 Gawley Org. React. 1988, 35, 1. Comprehensive Org. Syn., Vol. 7, pp 689-702. H N O H H N 95% O
O Ph S 12 h, 0 C O H2O
_ Prepared from the oxime. Beckmann Ber. 1886, 89, 988. _ A wide range of leaving groups and catalysts have been utilized. 1. Group anti to oxime leaving group migrates. 2. The alkyl group migrates with retention of configuration. H2NOSO3H HCO2H 97%
N H 95%
+ O 5%
NH
Note: Isomerization of oxime or its activated derivative may occur under the reaction conditions and fragmentation to a nitrile may compete when the migrating center is 3.
OH
NH
+ retention
NH O 2% 10% 57% 95% Smith Org. React. 1946, 3, 337. Comprehensive Org. Syn., Vol. 6, pp 806-816.
POCl3, pyridine SOCl2, pyridine 20% aq. H2SO4 HCl / Et2O 2. Curtius Rearrangement
98% 90% 43% 5%
Curtius Ber. 1890, 23, 3023. (initially not recognized) O RCO2H R N3 R N C O H2O or ROH H RNH2 or R N O O R
_ (PhO) P(O)N (DPPA) is a useful reagent for the direct conversion of carboxylic acids to acyl azides 2 3 under in situ conditions for the rearrangement. Shiori, Yamada Tetrahedron 1974, 30, 2151. _ R group migrates with retention of configuration.
70
Oxidation Reactions Dale L. Boger -Examples NO2 MeO N HO2C BnO MeO OMe N CO2Me DPPA, Et3N Me H2N BnO MeO OMe Me MeO N N CO2Me Boger, Panek (streptonigrin) J. Am. Chem. Soc. 1985, 107, 5745. NO2
MeO2C HO2C Br
CO2Me DPPA, Et3N Me C6H6, reflux 72%
MeO2C H2N Br
CO2Me Me Boger (lavendamycin) J. Org. Chem. 1985, 50, 5782.
Br BnO
N HO2C MOMO MeO
OMe DPPA, Et3N Me C6H6, reflux 86%
Br BnO
N H2N MOMO MeO
OMe Me Boger (streptonigrone) J. Am. Chem. Soc. 1993, 115, 10733.
OMe
OMe
R O
CO2H
DPPA, Et3N
tBuOH
NHBOC
OBn X = H, Br, CN, OMe Boger
OBn
O n = 1-3
J. Org. Chem. 1995, 60, 1271; 1996, 61, 1710 and 4894; 1997, 62, 5849. J. Am. Chem. Soc. 1994, 116, 11335. Synlett 1997, 515.
71
Modern Organic Chemistry The Scripps Research Institute 3. Hofmann Rearrangement Lane Org. React. 1946, 3, 267. Comprehensive Org. Syn., Vol. 6, pp 806-816. O NH2 R N H Br R O N Br O C N R
O R
Hofmann Ber. 1881, 14, 2725. N N CONH2 OTBS >80% MeO MeO NaOBr, CH3OH 40 C; then 60 C N NHCO2Me OTBS Boger, Coleman (PDE-I, PDE-II, CC-1065) J. Org. Chem. 1986, 51, 3250. J. Am. Chem. Soc. 1987, 109, 2717.
_ Reagents employed include basic hypohalides, Pb(OAc) , PhI(OCOCF ) , PhIO. 4 3 2 _ R group migrates with retention of configuration.
4. Schmidt Reaction
Schmidt Angew. Chem. 1928, 36, 511. Wolff Org. React. 1946, 3, 307. Comprehensive Org. Syn., Vol. 6, pp 817-821.
The Schmidt Reaction is a general name for what are three individual reactions: A. Conversion of Ketones to Amides H2O O R R HN3 and OH R R N H N N -H2O R N N N R -H+ tautomerization R O N H R Protic or Lewis Acid R = alkyl, aryl catalyst
- Most studied of Schmidt variants, similar to Beckmann Rearrangement. - Asymmetric variant (Aube) utilizes chiral alkyl azide donors which provide products in high diastereoselectivity. - Bicyclic ketones slightly favor migration of less substituted group, opposite of Beckmann. - Reactivity: dialkyl ketone > alkyl,aryl ketone > diaryl ketone > carboxylic acid or alcohol. O Bn CO2Et NaN3, 2.5 equiv MeSO3H, 9 equiv CHCl3, reflux, 83% >95% ee O NH Bn Georg Bioorg. Med. Chem. Lett. 1991, 1, 125.
CO2Et retention of configuration
O OH +
tBu
N3
1) BF3OEt2; 2) NaHCO3, 90%; 3) PCC 4) NaH, THF, 57%
O NH
N N O N
tBu
tBu
Aube J. Am. Chem. Soc. 1995, 117, 8047. one diastereomer
72
Oxidation Reactions Dale L. Boger B. Conversion of Carboxylic Acids to Amines O R OH + HN3 H+ cat. H2O
R N C O
R-NH2
- Acid catalyst usually H2SO4, PPA, TFA-TFAA, or sometimes Lewis acid. - Good results when R = alkyl, hindered alkyl or aryl. - Advantage in process length over Hofmann and Curtius Rearrangements, but more drastic conditions. - Mechanism controversy. Hayes J. Org. Chem. 1979, 44, 3682. O R Koldobskii Russ. Chem. Rev. 1978, 47, 1084. H O O + HN3 R N N N R N N N
H+ OH -H2O R
R-NH2 H CO2H CO2H NaN3, H2SO4 CHCl3, 76% Me H NH2 NH2
R N C O
Sato Tetrahedron: Asymmetry 1992, 3, 5.
Me
C. Conversion of Aldehydes to Nitriles O R H + HN3 H+ cat.
- Acid catalyst usually H2SO4, can be Lewis acid. - Schmidt reaction is the usual byproduct under these conditions to provide formamide. - More common method is to convert aldehyde to oxime with hydroxylamine, followed by dehydration. - Aromatic aldehydes are good substrates. O NaN3, SiCl4 MeCN, 50% Br Br N H CHO NaN3, H2SO4 70% MeO HO NC Elmorsy Tetrahedron Lett. 1995, 36, 2639. N H CN Houff J. Org. Chem. 1957, 22, 344.
MeO HO
73
Modern Organic Chemistry The Scripps Research Institute 5. Lossen Rearrangement Lane Org. React. 1946, 3, 269 and 366. Comprehensive Org. Syn., Vol. 6, pp 821-823 (basic conditions) pp 824-825 (neutral/acidic) Lossen Liebigs Ann. Chem. 1872, 161, 347. O R1 OH O R1 N H OR2 O R1 N OR2
R2X
base
-OR2 R1 N C O
N H Hydroxamic acid -prepared readily from carboxylic acids, esters or acyl halides
- R2X usually AcCl, ArSO2Cl, RPO2Cl - rate of reaction proportional to the acidity of leaving group conjugate acid - R1 migrates with retention of configuration
O F F O H O H O O N O S O O H3NOH NH OH
TsCl; NaOH, H2O 80%
O F F OH NH2 H Braish Syn. Commun. 1992, 22, 3067.
NaOH, H2O 80% H O
NH2 OH Bauer J. Org. Chem. 1959, 24, 1293.
74
G. Olefin Osmylation (Dihydroxylation)

RCO3H O O versus H O O Os O O Os(VIII) electrophilic, large reagent + O O Os O O H Diastereospecific H2O H O R H OH + OH OH epoxide opening OH NaOH OH
trans-1,2-diol
HO O Os O HO Os(VI)
cis-1,2-diol
First use: Criegee Justus Liebigs Ann. Chem. 1936, 522, 75. Milas J. Am. Chem. Soc. 1936, 58, 1302. 1. Mechanism + O O Os O O [2+2] OO Os O O or :L O [3+2] O O Os O L [3 + 2] Mechanism: Bseken Recl. Trav. Chim. 1922, 41, 199. Criegee Angew. Chem. 1938, 51, 519. Criegee Justus Liebigs Ann. Chem. 1942, 550, 99. product
[2 + 2] Mechanism: Sharpless J. Am. Chem. Soc. 1977, 99, 3120. Jorgensen Chem. Rev. 1990, 90, 1483. Sharpless Angew. Chem. Int. Ed. Eng. 1993, 32, 1329. 2. Scope
Comprehensive Org. Syn., Vol. 7, pp 437-448.
Chem. Rev. 1980, 80, 187.
1. OsO4 is an electrophilic reagent, and it behaves as a large reagent. 2. Strained, unhindered olefins react faster than unstrained, sterically hindered olefins. 3. Electron-rich olefins react faster than electron-deficient olefins. 4. Diastereospecific, with attack on the C=C from the least hindered face. - but OsO4 is expensive, volatile, and toxic - various improvements: 1) only catalytic amount of OsO4 used 2) use of an equivalent osmium salt (K2OsO2(OH)4) Examples: H2O2, cat. OsO4 tBuOOH, cat. OsO 4 O or N O (NMO) N O
J. Am. Chem. Soc. 1936, 58, 1302; 1937, 59, 2345; Synthesis 1989, 295. Sharpless J. Org. Chem. 1978, 43, 2063. Tetrahedron Lett. 1976, 1973; Tetrahedron Lett. 1980, 21, 449.
Note: Johnson-Lemieux Oxidation (NaIO4 and catalytic OsO4 cleaves C=C bonds, forms diol and then aldehyde: J. Org. Chem. 1956, 21, 478). R R cat. OsO4 NaIO4 HO H R OH H R O 2 R H
-Alternative reagents to OsO4: KMnO4: Synthesis 1987, 85. Yields rarely as high as OsO4 but less hazardous and less expensive especially for large scale RuO4 or RuO2-2H2O/RuCl3-H2O + cooxidant More vigorous than OsO4 and olefin cleavage is observed
75
Modern Organic Chemistry The Scripps Research Institute 3. Diastereoselectivity a. Endocyclic Olefins OsO4 OH OH from least hindered side OsO4 -endocyclic allylic alcohols OH OsO4 100%
120o OH
OsO4 from least hindered side
OH OH OH
Note: m-CPBA comes in cis to the allylic -OH, but OsO4 comes in trans to the allylic -OH. So, we obtain: OsO4 HO OH
m-CPBA
m-CPBA
OsO4
OH HO OsO4 100% HO
OH OH OH HO
HO
OH HO
OsO4 OH HO OsO4 HO OH OH OH > 50:1 OsO4 trans to allylic alcohol Predominant conformation at 25 C HOHO OH
OsO4
OH
OH OsO4
OH OH OH 4:1
76
Oxidation Reactions Dale L. Boger b. Acyclic Systems - OsO4 is delivered from face opposite the allylic hydroxyl group in the preferred (H-eclipsed) ground state conformation.
m-CPBA (cis to allylic alcohol 120)

R4 R3 HO R2 R1 OsO4 (trans to allylic alcohol 120)
120o
R2 HO R1 H
R4 R3
- Kishi model (empirical model). So, for the OsO4 oxidation: HO R2 R1 R4 R3 OsO4 HO R2 R1OH H R4
Tetrahedron Lett. 1983, 24, 3943, 3947. Tetrahedron 1984, 40, 2247.
R2 R4 R3 OH OH OH OH 4 R or R1 2 R3 R OH
HO R1 H
R3 OH
- Preferred ground state conformation (higher diastereoselection when R3 is not H). - Also observed with allylic ethers OR RO OsO4 RO OR OH OR OH RO
1) electronic effects:
OH OH erythro threo : R = Bn 8.9 1 : R = CO2CH3 2 1 : R = COC6H4-NO2 1 1 electronic effect of alkoxy substituent directs osmylation to reverse face OBn OH BnO OH 7:1, modest selectivity
2) steric effects: BnO
OBn
OsO4
- Higher diastereoselectivity of Z vs. E isomer implies eclipsed conformation important. OX R2 R2 OX R1 OX R1 OsO4 R1 OsO4 R2 OH R2 OH OX R1 OH OH OX R1 HO Me moderate to high selectivity high selectivity OH OX R1 < 8:1, modest selectivity (anti 1,2-diol relationship)
OsO4
- As R1 increases in size relative to OX, the selectivity increases. - X-effect (steric effect): smaller X provides better selectivity.
77
Modern Organic Chemistry The Scripps Research Institute - There are two additional empirical models used to explain the acyclic allylic alcohol induced diastereoselectivity: 1. Houk Model (inside alkoxy model): Science 1981, 231, 1108. H R2 R1 2. Vedejs Model: J. Am. Chem. Soc. 1989, 111, 6861. H R2 R1 R3 4 OX R H2 R SiR3 c. Exocyclic Olefins: Vedejs J. Am. Chem. Soc. 1989, 111, 6861. ax. OsO4 R2 R1 eq. H2O-acetone O NO (NMO) R2 H OH OCH3 OCH3 OAc SCH3 H CH3 H CH3 CH3 H ax. 14 <5 <5 20 8 <5 33 14 88 90 67 92
tBu
OX R3 R4
non ground state conformation
OsO4 is large reagent; steric effects between reagent & allylic substituent are important factors selectivity increases: a) OH > OR b) now E > Z c) with very large R1: inside alkoxy or anti Si
3. Panek: J. Am. Chem. Soc. 1990, 112, 4873.
R2 XO R4
tBu
H H
axial attack
OH R2
equatorial attack OH +
tBu
OH OH R2
R1
R1
R1 OsO4 is a large reagent, prefers equatorial attack H H H CH3 H H OH OH OCH3 OCH3 OAc SCH3
eq. 86 95 95 80 92 95 67 86 12 10 33 8
Consistent with Kishi empirical model Inconsistent with Houk model
Exception:
OsO4 axial R2
RO d. H-Bonding and Directed Dihydroxylation OH OH
H-bonding? Equatorial attack predominates, except with axial OCH3, OAc, SMe: In these cases, equatorial attack further retarded and proceeds at even slower rate (kinetic studies)
OH OH + OH
tBu tBu
OsO4
axial OH
tBu
tBu
OH
OH
OH
cat. OsO4, NMO, acetone-H2O 1 equiv OsO4, CH2Cl2 (anhydrous)
94:6 (90%) 75:25 (97%)
competing H-bonding delivery reduces diastereoselectivity
78
Oxidation Reactions Dale L. Boger TMEDA OR OR OH +

tBu tBu
OR OH
tBu
OH 85:15 63:37 45:55 4:96 95:5 OH
OH
N N O Os O O O
tBu
H O
cat. OsO4, NMO, acetone-H2O 1 equiv OsO4, CH2Cl2 cat. OsO4, Me3NO, CH2Cl2 1 equiv OsO4, TMEDA, CH2Cl2, 78 oC R = CH3: 1 equiv OsO4, CH2Cl2 OH
R = H:
(91%) OsO4 (45%) competing H-bond delivery equatorial OH (55%) H-bond delivery (91%) no H-bonding OH OH + OH OH H-bond delivery OH OH OH HO + OH H-bond delivery OH OH HO + HO OH O H-bond delivery OH
cat. OsO4, NMO, acetone-H2O 1 equiv OsO4, TMEDA, CH2Cl2, 78 oC OH HO HO
OH 80:20 12:88 (76%) OH
cat. OsO4, NMO, acetone-H2O 1 equiv OsO4, TMEDA, CH2Cl2, 78 oC
75:25 5:95 (54%) OH
HO HO O
HO HO O 94:6 14:86
cat. OsO4, NMO, acetone-H2O 1 equiv OsO4, TMEDA, CH2Cl2, 78 oC
(63%)
- OsO4-TMEDA can also be utilized to effect chemoselectivity by preferentially oxidizing allylic alcohols over unactivated (non allylic -OH) double bonds. Donohue Tetrahedron Lett. 1996, 37, 3407; Tetrahedron Lett. 1997, 38, 5027.
4. Comparison of Diol Stereochemistry Generated by Different Methods a. m-CPBA H
m-CPBA
H+, H2O
OH OH
trans-diol
H -Epoxidation from least CH3 H hindered face CH3
CH3 H O H
H2O CH3
trans diaxial opening of epoxide
m-CPBA H
79
b. OsO4
H OsO4 H
CH3 OH CH3 OH
cis-diol
H OsO4 H - cis dihydroxylation from least hindered face (OsO4 is a large reagent) c. Via Bromohydrin H Br2 or NBS H H2O; NaOH
H+, H2O
OH OH
trans-diol
- Epoxidation on most hindered face of olefin (to give different epoxide from m-CPBA oxidation),
trans diaxial ring opening (to give same hydrolysis product as from m-CPBA oxidation) CH3 OH trans diaxial trans diaxial H CH3 CH3 OH opening of epoxide attack O H H Br CH3 CH3 H CH3 CH3 Br H2O OH H bromonium ion H H formation on least CH3 Br hindered face H
-Corey Tetrahedron Lett. 1982, 23, 4217: cis dihydroxylation from most hindered olefin face. Br OH d. Prevost Compt. rend. 1933, 196, 1128. Br O H I2 PhCO2Ag Me H I H H Ph Me Me O O I Ph Me O O Me Me NaOH O H2O OCOPh trans-dibenzoate OH OH Ph Me C O O OH Me Me O O CN NaH O O CN 1) H O+ 3 2) NaOH OH OH
OH OH
- Neighboring Group Participation
O2CPh trans Me anti opening
trans-diol
PhCO2 H 1) I2 PhCO2Ag 2) H2O, H
e. Woodward J. Am. Chem. Soc. 1958, 80, 209.
- Complements OsO4 reaction (i.e. cis dihydroxylation from most hindered face)
Ph Me O O
OH2 H2O Me trap
NaOH H2O
cis-diol
-Same intermediate as Prevost, but different conditions (+ H2O)
80
H. Asymmetric Dihydroxylation Reaction Catalyzed by OsO4 and Related Reagents

1. Catalytic Methods Sharpless Catalytic Asymmetric Dihydroxylation (AD) Reaction, Review: Chem. Rev. 1994, 94, 2483.
J. Am. Chem. Soc. 1980, 102, 4263. J. Am. Chem. Soc. 1988, 110, 1968. J. Am. Chem. Soc. 1989, 111, 1123. Tetrahedron Lett. 1989, 30, 2041. Tetrahedron Lett. 1990, 31, 2833, 2999, 3817. J. Org. Chem. 1991, 56, 4585.
R1 R2 H R3 H R3 R1 R2
J. Org. Chem. 1992, 57, 2768. J. Am. Chem. Soc. 1992, 114, 7568, 7570. Tetrahedron Lett. 1993, 34, 7375. J. Org. Chem. 1993, 58, 3785 J. Am. Chem. Soc. 1994, 116, 1278. Angew. Chem., Int. Ed. Eng. 1996, 35, 448.
DHQD: dihydroquinidine (R = H) Et N DHQ: dihydroquinine (R = H) Et N O R H
DHQD R
1
R2
K2OsO2(OH)4 or OsO4 K3Fe(CN)6, K2CO3 tBuOH-H O 2 H 3 H R R3 OH HO
DHQ MeO R1 R2
R O H
OMe
HO
OH First Generation Ligands (Alk = DHQ or DHQD) PHN MEQ Me N O O-Alk O-Alk O-Alk O O-Alk CLB Cl
Second Generation Ligands (Alk = DHQ or DHQD) PHAL Alk-O Alk-O N N Ph O-Alk N N PYR Ph O-Alk AQN O O-Alk
Catalyst: OsO4 (1.25 mol%) or K2OsO2(OH)4 (0.05 mol%, nonvolatile) Solvent: tBuOH or cyclohexane, H2O, K2CO3 Ligands: DHQD or DHQ (0.2 to 0.004 mol%) Oxidant to recycle OsO4: K3Fe(CN)6 Note: Ligand accelerated catalysis, Sharpless Angew. Chem., Int. Ed. Eng. 1995, 34, 1059. -Addition of pyr led to marked increase in rate of formation of cyclic osmate ester from alkene and OsO4. First noted by Criegee Justus Liebigs Ann. Chem. 1936, 522, 75; 1940, 550, 99. -The "Criegee effect" (or the facilitation of osmylation step by nitrogen donor) has been examined with quinuclidine and cinchona alkaloid ligands: Sharpless J. Am. Chem. Soc. 1994, 116, 1278, 8470. -Results: Good to excellent selectivity (ee%) for: R1 R R2 R2 R1 R3 R1 R2 84-93% ee
74-93% ee 82-88% ee Poor selectivity for: R1 R2
94-99% ee R3 R1 R2 R4
81

2. Stoichiometric methods -Tomioka J. Am. Chem. Soc. 1987, 109, 6213. Ph N Ph Using 1 as a chiral ligand, good selectivity for: R R2 R1 R3 R2 R1 R1 1 N Ph O Ph
Poor selectivity for: R2
- Product does not seem to reflect most favorable steric approach for [3 + 2] cycloaddition but is more easily rationalized by [2 + 2]. H H OsO4 (+)-1 Ph H O O O R2 H Ph Os Ph R1 R3 N O N Ph Ph X-ray structure OsO4 ()-1 stoichiometric reagent (LiAlH4 to reduce off osmate ester) O Ph CO2Me Ph Et Ph ee: 90% Ph 95% Ph 97% Et 90% MeO2C 93% 83% 26% 41%
-Corey J. Am. Chem. Soc. 1989, 111, 9243.

Ph Ph R2 H NH HN H C2-symmetry in ligand Os (6 coordinate) nucleophilic equatorial oxygen electrophilic axial oxygen N O N Os R1 O O O Ligand accelerated reaction OsO4, 90 C, 2 h R2 Ph 92% ee R1 82-98% ee 60% ee
Ph
-Other stoichiometric reagents: Chem. Lett. 1986, 131. Chem. Commun. 1989, 665. Tetrahedron Lett. 1986, 27, 3951. J. Org. Chem. 1989, 54, 5834. Tetrahedron Lett. 1990, 31, 1741. Tetrahedron 1993, 49, 10793. 3. Examples -Total synthesis of Bouvardin and RA-VII: Boger J. Am. Chem. Soc. 1994, 116, 8544. O OH I Ti(OiPr)4 (+)-DIPT, tBuOOH I 90%, >98% ee PDC (AE) OH R I R = CH2OH R = CO2H OH CO2CH3 I AD mix- I CO2CH3 OR R=H R = SO2Ar NaN3 I N3 OH CO2CH3 CO2H NHMe
90%, >95% ee (AD)
82
Oxidation Reactions Dale L. Boger -Vancomycin central amino acid: Boger J. Org. Chem. 1996, 61, 3561; J. Org. Chem. 1997, 62, 4721. OCH3 OBn BnO AD-mix- 97%, 87% ee (AD) HO TBDMSCl 85% BnO OCH3 OBn OCH3 OBn 1) DPPA BnO Ph3P-DEAD 2) Ph3P, 65% OR R=H R = TBDMS BnO OCH3 OBn + NHCBZ 1 recrystallization 1x : OH BnO OCH3 OBn H2N OTBDMS
tBuO C 2
BnO
OCH3 OBn
BnO
OCH3 OBn
NHCBZ
CBZN(Cl)Na 4 mol% K2OsO2(OH)4 5 mol% (DHQD)2-PHAL 50% nPrOH/H2O (AA)
HO
CBZNH
7 69%, 96% ee 64%, >99% ee
O O
-Luzopeptin Htp amino acid: Boger J. Org. Chem. 1998, 63, 6421; J. Am. Chem. Soc. 1999, 121, 1198. OH AD-mix- 1) NaN3 CO2Bn 80%, >99% ee 2) Ph3P O OH O OH CO2Bn 87 x 93% CO2Bn CO2Bn (AD) N R O O N OR NH2 O R=H NosCl R = Nos 68% -Prediction of absolute stereochemistry is so firmly documented that it may be used to assign absolute stereochemistry. However, there are a few rare exceptions to be aware of, for example: Boger J. Am. Chem. Soc. 1997, 119, 311. Boger J. Am. Chem. Soc. 1996, 118, 2301. NCOPh SnBu3 NC OBn NCOPh BF3 Et2O 89% NC OBn NHCOPh NHCOPh reversed enantioselectivity OR cat OsO4 NMO, 95% or HO NHCOPh TBDMSOTf 75%
(DHQD)2-PHAL NC OBn 70%, 78% ee NHCOPh (AD) R=H TsCl, Bu2SnO R = Ts 94% TBDMSO
OTs TBDMSO NHCOPh NaH 97% NC OBn NHCOPh
TBDMSO
NC PhCON H
NCOPh NH2NH2 EtOH 65% OBn
NC RN H
NR
(+) and ent-(-)duocarmycin A
OBn R=H R = BOC
Chiralcel OD resolution, = 2.30 -Appears to be general for the class of olefins ArCH2CH=CH2
BOC2O; TFA, 88%
83
I. Sharpless Catalytic Asymmetric Aminohydroxylation (AA)

- Reviews: Transition Metals for Fine Chemicals and Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998.
Angew. Chem. Int. Ed. Eng. 1996, 35, 451, 2810 and 2813. Angew. Chem. Int. Ed. Eng. 1997, 36, 1483 and 2637.
J. Am. Chem. Soc. 1998, 120, 1207. Tetrahedron Lett. 1998, 39, 2507 and 3667.
- Development of AA reaction (reactions generally run with 4 mol% catalyst (K2OsO2(OH)4) and 5 mol% ligand ((DHQ)2-PHAL or (DHQD)2-PHAL): in situ generation and reactions of RN=OsO3.
a. Sulfonamide variant -,-unsaturated esters: Ph CO2CH3
O Cl R S N O Na cat. K2OsO2(OH)4 (DHQ)2-PHAL 81% ee (64%)
O O S HN R CO2CH3 Ph OH
R= Me3Si
p-Tol
Me
1:1 CH3CN-H2O 1:1 nPrOH-H2O 1:1 nPrOH-H2O
Reductive cleavage of sulfonamides requires harsh conditions (Birch 95% ee (65%) reduction, Red-Al, or 33% HBr/AcOH). 70% ee (48%) Sulfonamide cleaved with Bu4NF in CH3CN 83:17 regioselectivity
-,-unsaturated amides: no enantioselection, AA gives racemic products. -reaction works well without a ligand. O Ph TsN(Cl)Na cat. K2OsO2(OH)4 TsHN NMe2
tBuOH-H
2O
1) MsCl, Et3N NMe2 2) Et N or DBU 3 Ph
Ts N NMe2 O
Ph
OH 5:1 regioselectivity, racemic (94%)
b. Carbamate variant -,-unsaturated esters: Ph CO2CH3 RO O
Cl N
O Na HN Ph OR CO2CH3 OH Amine can be deprotected by hydrogenolysis. Amine can be deprotected by acid. O Na HN Ph O CO2iPr OH SiMe3
cat. K2OsO2(OH)4 (DHQ)2-PHAL 1:1 nPrOH-H2O 1:1 nPrOH-H2O 2:1 nPrOH-H2O 94% ee (65%) 99% ee (78%) 78% ee (71%) Cl N O cat. K2OsO2(OH)4 (DHQ)2-PHAL
R=
Bn Et tBu
Me3Si Ph CO2iPr
99% ee (70%) Carbamate cleaved with Bu4NF in CH3CN.
84
Oxidation Reactions Dale L. Boger -Reversal of regioselectivity using (DHQ)2-AQN ligand CO2CH3 CBZN(Cl)Na cat. K2OsO2(OH)4 (DHQ)2-AQN NHCBZ OH A Ph OH CO2CH3 NHCBZ 95% ee (58%) 79:21 regioselectivity
Ph
-Styrenes: 3 equiv BnOC(O)N(Cl)Na BnO cat. K2OsO2(OH)4 BnO 1:5 nPrOH-H2O
OH + BnO B NHCBZ 97% ee (76%) 88:12 A:B
-Influence of ligand and solvent on regioselectivity: solvent ligand nPrOH-H O (DHQ)2-PHAL 2 (DHQ)2-AQN CH3CN-H2O
A:B 88:12 25:75
- However, enantioselectivities for B regioisomers are poor (0-80% ee).
- tBu carbamate based AA affords slightly poorer regioselectivities and yields compared to benzyl carbamate series, but enantioselectivities approach 100% in both cases: NHBOC OH BnO C OH + BnO O HN RO2CN(Cl)Na cat. K2OsO2(OH)4 (DHQ)2-PHAL 99% ee (70%) >10:1 regioselectivity 98% ee (70%) 88:12 regioselectivity 97% ee (48%) 86:14 regioselectivity OR OH D NHBOC 99% ee (68%) 83:17 C:D
tBuO CN(Cl)Na 2
BnO
cat. K2OsO2(OH)4 2:1 nPrOH-H2O (DHQ)2-PHAL
R= Me3Si
Bn
tBu
-Oxidation of -arylglycinols to corresponding -arylglycines, see: Boger J. Org. Chem. 1996, 61, 3561. NHCBZ OH BnO 80:20 mixture of regioisomers c. Amide variant NHAc CO2iPr NH3Cl CO2H NHCBZ TEMPO, NaOCl 80% BnO COOH
Ph
CO2
iPr
AcNHBr/LiOH
Ph
10% HCl
Ph
cat. K2OsO2(OH)4 OH 1:1 tBuOH-H2O 99% ee, 81% (DHQ)2-PHAL (>10:1 regioselectivity)
OH 77% overall
85
86
Oxidations of Alcohols Dale L. Boger
J. Ozonolysis

P. Crutzen, M. Molina, and F. S. Rowland shared the 1995 Nobel Prize in Chemistry for their work in atmospheric chemistry, particularly concerning the formation and decomposition of the protective ozone layer.
-Electrophilic reagent, rate: electron-rich > neutral > electron-deficient olefin -Chemoselectivity: OMe O O3, MeOH; Me2S CO2Me CO2Me H 85-90%
CO2Me CHO
-O3 exhibits very light blue color, ozonolysis complete when color persists -Controlled ozonolysis (very reactive agent): KI-starch: characteristic blue color O3 sensitive dyes with varying reactivities and detect color disappearance: Mitscher Synthesis 1980, 807. -Oxidative workup: H2O2, KMnO4, Cr(VI), RuO4 -> ketones, carboxylic acids -Reductive workup: NaBH4, LiBH4 -> alcohols Me2S, Ph3P, Zn/HOAc, H2N , H2, Pd/CaCO3 -> aldehydes, ketones S H2N
-Mechanism, Review: Criegee Angew. Chem., Int. Ed. Eng. 1975, 14, 745. O R R O O 1,3-dipolar carbonyl oxide O O O O O + (Criegee zwitterion) R cycloreversion 1,3-dipolar R O R R R cycloaddition R RR in situ R R 1,3-dipolar reduction O O cycloaddition O O -Zn/HOAc Note: Alternative recombination -Me2S RR Note: Ozonide explosive mechanisms observed with -Ph3P when isolated or concentrated. ozonide ketone vs. aldehyde ozonides. R R R R
V. Oxidation of Alcohols
Stoichiometries: 3 R2CHOH + 2 CrO3 + 6 H+ 5 R2CHOH + 2 MnO4 + 6 H+ 3 R2CHOH + 2 MnO4 3 R2C=O + 2 Cr3+ + 6 H2O 5 R2C=O + 2 Mn2+ + 8 H2O 3 R2C=O + 2 Mn2+ + 2 H2O
A. Chromium-based Oxidation Reagents

1. Collins Reagent: Collins Tetrahedron Lett. 1968, 3363; Org. Syn. 1972, 52, 5. -CrO3-pyr2, alkaline oxidant -Hygroscopic, red crystalline complex -Can also be isolated and stored, but usually generated in situ by CrO3 + pyr (Sarett Reagent) J. Am. Chem. Soc. 1953, 75, 422. Note: Add CrO3 to pyr, not pyr to CrO3 (inflames) -Good for acid sensitive substrates -Radcliffe modification: in situ preparation and use in CH2Cl2, J. Org. Chem. 1970, 35, 4000. H OH O RCH2OH RCOOH RCHO no over oxidation
87
Modern Organic Chemistry The Scripps Research Institute 2. Jones Reagent: Jones J. Chem. Soc. 1953, 2548; J. Chem. Soc. 1946, 39. CrO3 in aq. H2SO4/acetone H2Cr2O7 H 2O 2 H2CrO4
-Acetone solvent serves to protect substrate from over oxidation -Not good for oxidations of acid sensitive substrates H OH H2O R O OH H OH
RCH2OH
RCHO
RCOOH
-Acidic oxidation conditions, H+ catalyzed reactions possible -Another common side reaction for primary alcohol oxidation: RCH2OH RCHO RCH2OH R OCH2R H OH hemiacetal RCOOCH2R ester
Solution: run under dilute reaction conditions to circumvent esterification
-Brown oxidation: run under two phase reaction conditions, Et2O-H2O, J. Org. Chem. 1971, 36, 387. -[R4N]2Cr2O7 Synth. Commun. 1980, 75. Oxidation of allylic/benzylic alcohols under neutral conditions. 3. Pyridinium Chlorochromate (PCC): Corey and Suggs Tetrahedron Lett. 1975, 2647. O Cr Cl O O H N HCl + CrO3 + pyr - Chloride facilitates formation of chromate ester (slow step in oxidation reaction) - Stable, commercially available reagent
-Reaction usually carried out in CH2Cl2 -Rates: RCH2OH and R2CHOH R OH > O R H RCHO R2C=O
no over oxidation
-Usually only need 1-2 equiv of Cr(VI) reagent (Jones & Collins usually require 6 equiv) -PCC slightly acidic which can cause side reactions, for example:
PCC OH O
H+ OH
-H+ OH O
-To avoid H+ catalyzed side reaction, use sodium acetate buffer:
PCC OH NaOAc CHO
-Can take advantage of acidity in PCC reaction (Boger and Corey Tetrahedron Lett. 1978, 2461): O CHO 78% CHO 41% O
88
Oxidations of Alcohols Dale L. Boger OH 55% O OH 62% O
OH R = CH3, 68% R = Ph, 69% R -Oxidation of 3, allylic alcohols MeLi O OH Me PCC O O Cr O
O H O Cr O O
O Me Me Me [3,3]-sigmatropic rearrangement, Dauben J. Org. Chem. 1977, 42, 682.
-Aromatic amine effect: dampens reactivity so only selective oxidation of allylic alcohols may be observed PCC, pyr (2%) in CH2Cl2 Chem. Phys. Lipids 1980, 27, 281. PCC, 3,5-dimethylpyrazole (2%) in CH2Cl2 J. Org. Chem. 1983, 48, 4766. PCC, benzotriazole (2%) in CH2Cl2 Synth. Commun. 1985, 15, 393. MS accelerate rate of oxidation (PCC and PDC) -3 A J. Chem. Soc., Perkin Trans. 1 1982, 1967. -Pyridinium fluorochromate, related stable reagent that is slightly less acidic (Corey and Suggs) - Other related reagents include bipyridinium chlorochromate (BPCC), DMAP chlorochromate, quinolinium chlorochromate, and pyrazinium chlorochromate. 4. Pyridinium Dichromate (PDC): Corey Tetrahedron Lett. 1979, 399. PDC CH2Cl2 RCH2OH DMF MeOH
RCHO RCO2H RCO2Me
N H
Cr2O7-2
2
CrO3 + pyr + H2O
-Stable, commercially available reagent -Not as acidic as PCC -Oxidations slower than PCC or other oxidation reagents -Can selectively oxidize 1 alcohols to aldehyde or carboxylic acid depending on solvent -2 alcohols oxidize only slowly- sometimes require an acid catalyst (pyridinium trifluoroacetate or 3 A MS) - Note: Original reagent made in search of more acidic reagent, attempted preparation of pyridinium trifluoroacetyl chromate (Boger, Ph.D. dissertation, Harvard Univ., 1980). -Other related reagents include nicotinium dichromate, quinolinium dichromate, and imidazolium dichromate - Note: Cr based reagents will oxidize amines and sulfides. Substrates with these functional groups must be oxidized with other reagents (PDC will sometimes leave sulfides unaffected). 5. CrO3-H5IO6: Zhao and Reider Tetrahedron Lett. 1998, 39, 5323. -Catalytic in CrO3 (1-2%, Industrial scale chromium-based oxidations) -1 alcohols -2 alcohols carboxylic acids with no racemization ketones CO2H Ph NHCBZ OH 98%
Ph
2.5 equiv H5IO6 OH 1.1 mol% CrO3 Ph wet CH3CN NHCBZ 0 oC, 83%
Ph O
89
B. Manganese-based Oxidation Reagents

1. Manganese Dioxide (MnO2) -Very mild oxidizing reagent, special "activated" MnO2 preparation required -Selectively oxidizes allylic and benzylic alcohols to aldehyde or ketone -Requires nonpolar solvent (CH2Cl2, CHCl3, pentane, benzene, etc.) -Oxidizing reagent : substrate = 10:1 (10 wt. equiv) OH OH MnO2 CHO HO MnO2 O OH
-No isomerization of conjugated double bond. Cr-based reagent will cause problem due to H+ catalysis -NiO2: alternative reagent that behaves similar to MnO2 -Oxidize alcohol to ester, no isomerism of C=C bond (Corey and Ganem J. Am. Chem. Soc. 1968, 90, 5616) MnO2 R CH2OH cat HOAc R NaCN, MeOH OH CHO R CN H R O CN MeOH R CO2Me
2. KMnO4 a. KMnO4/H2SO4 RCOOH -Good for RCH2OH -Reaction runs in aqueous solution because of the insolubility of KMnO4 in organic solvents b. KMnO4 in tBuOH-5% NaH2PO4 aqueous buffer (Masamune Tetrahedron Lett. 1986, 27, 4537). -For highly oxygenated systems where multiple side reaction pathways are present with other oxidants 5 min, 25 C 98% TBDMSO
TBDMSO
CHO OMOM
CO2H OMOM
3. R4NMnO4 -Same capabilities as KMnO4 but soluble in organic solvents 4. Cu(MnO4)-6H2O and BaMnO4 OH CO2H OH OH BaMnO4 C6H6 O OH
Lee J. Am. Chem. Soc. 1983, 105, 3188; J. Org. Chem. 1982, 47, 2790. Hauser J. Am. Chem. Soc. 1984, 106, 1862. Jefford J. Chem. Soc., Chem. Commun. 1988, 634. Hahn Tetrahedron Lett. 1989, 30, 2559.
90
Oxidations of Alcohols Dale L. Boger
C. Other Oxidation Reagents

1. RCH2OH or R2CHOH oxidation a. Sodium Hypochlorite (NaOCl): Used primarily to oxidize alcohols or aldehydes to carboxylic acids. RCH2OH RCHO RCOOH
b. Sodium Chlorite (NaOCl2) Pinnick Tetrahedron 1981, 37, 2091. Also Calcium Hypochlorite (Ca(OCl)2): McDonald Tetrahedron Lett. 1993, 34, 2741. H2O RCO2H NaOCl2 RCH2OH MeOH RCO2Me -Good for oxidation of sensitive aldehydes to carboxylic acids c. Ag2O and Ag2CO3 RCH2OH Ag2O RCHO Ag2CO3 Celite or AgO
RCOOH
2. m-CPBA and NaIO4 (Amine and sulfide oxidation) NaIO4 R S R R O S
m-CPBA
R
O O S R R
3. TPAP, [Pr4NRuO4] 5% TPAP NMO CH2Cl2, 4 MS R
HO
CO2Et TPAP 93%
CO2Et
HO
OHC
4. Dess-Martin Oxidation: Dess and Martin J. Am. Chem. Soc. 1978, 100, 300; J. Am. Chem. Soc. 1979, 101, 5294; J. Org. Chem. 1983, 48, 4155; J. Am. Chem. Soc. 1991, 113, 7277. AcO OAc I OAc O O MeO OH HO I O IBX O OH R OH R R OH R O R R O R Ph O R R OH Ph OH Ph OH H R O Ph OH O H O -periodinane -CH2Cl2, 25 oC O O MeO RCH2OH R2CHOH RCHO R2C=O O O CHO
Danishefsky, Coleman J. Am. Chem. Soc. 1991, 113, 3850.
- Precursor to Dess-Martin reagent - Insoluble in almost all organic solvents but is soluble in DMSO and oxidations in this solvent work effectively (25 C): Frigerio Tetrahedron Lett. 1994, 35, 8019.
91
Modern Organic Chemistry The Scripps Research Institute 5. Nitroxide: Torii J. Org. Chem. 1990, 55, 462; Skarzewski Tetrahedron Lett. 1990, 31, 2177. OCOR OH 1 N O OH 1 Ph OH CHO Ph 1 OH CH Cl 2 2 OH 25 C 72 h, 95% O O
6. Trityl Cation: Jung J. Am. Chem. Soc. 1976, 98, 7882. TMSO H OTMS Ph3C+BF4 CH2Cl2 25 C 3 carbon H abstracted faster 7. Pt-O2: Fuchs and Hutchinson J. Am. Chem. Soc. 1987, 109, 4755. -Good for oxidation of 1 alcohols directly to carboxylic acids HO HO2C Pt-O2 acetone-H2O C5H11 HO 8. Via Hypohalite Just Tetrahedron Lett. 1980, 21, 3219. Doyle Tetrahedron Lett. 1980, 21, 2795. Nozaki Tetrahedron Lett. 1982, 23, 539. -For example: (Bu3Sn)2O, Br2 OH HO HO O OH OMe Br2 (Bu3Sn)2O CHCl3, reflux Hannessian Synthesis 1981, 394. Kanemitsu Chem. Pharm. Bull. 1989, 37, 2394. Stevens Tetrahedron Lett. 1982, 23, 4647. NIS, Bu4NI NaBrO3, CAN NaOCl, HOAc OH 57% HO C5H11 OH O OTMS + Ph3CH
NiBr2, (PhCO2)2 OH HO O O OH
OMe
Mechanism: O X H B: OH (Bu3Sn)2O Br2 CH2Cl2
(Bu3Sn)2O OH OH Br2 CH2Cl2 O OH
OH
OH
Tetrahedron Lett. 1976, 4597.
2 alcohol > 1 alcohol
9. Oppenauer Oxidation: see Meerwein-Pondorff-Verley reduction, Review: Org. React. 1951, 6, 207. SePh OH Cl3CCHO Al2O3 55 C, 24 h SePh O - Suitable for oxidation of 2 alcohol in the presence of 1 alcohol which do not react - Good for oxidation of substrates containing easily oxidized functional groups
Posner Angew. Chem., Int. Ed. Eng. 1978, 17, 487; Tetrahedron Lett. 1977, 3227; 1976, 3499. OH CH3O CH3 Boger J. Org. Chem. 1984, 49, 4045. Al(OiPr)3 toluene 110 C, 1.5 h 72% CH3O CH3 O
92
Oxidations of Alcohols Dale L. Boger 10. Ruthenium Tetroxide (RuO4) RCH2OH RCO2H R2CHOH R2C=O -in situ generation from RuO2-NaIO4 or RuO2-NaOCl: from RuCl3-H5IO6:
Tetrahedron Lett. 1970, 4003. J. Org. Chem. 1987, 52, 1149.
Sharpless J. Org. Chem. 1988, 53, 5187. J. Org. Chem. 1981, 46, 3936. -Note: RuO4 attacks C=C bonds and will cleave 1,2-diols. 11. TEMPO -with cat. NaOCl or NaBrO2: RCO2H RCH2OH J. Org. Chem. 1985, 50, 1332. TEMPO CH2Cl2 J. Org. Chem. 1987, 52, 2559. RCHO J. Org. Chem. 1990, 55, 462. Dess and Martin J. Org. Chem. 1983, 48, 4155. Corey J. Am. Chem. Soc. 1996, 118, 1229. Smith J. Am. Chem. Soc. 1989, 111, 5761. Tetrahedron Lett. 1982, 2335. NaBrO2 MeCN
-with cat. Ca(OCl)2:
D. Swern Oxidation and Related Oxidation Procedures

1. Swern Oxidation: J. Org. Chem. 1976, 41, 957 and 3329. O DMSO + Cl O DMSO + TFAA Cl CH3 S Cl CH3 CH3 S O CH3 CF3 O Reviews: Chem. Rev. 1967, 67, 247. Tetrahedron 1978, 34, 1651. Synthesis 1981, 165. [DMSO-(COCl)2] Org. React. 1990, 34, 297.
[DMSO-TFAA]
-Also DMSO-Ac2O, DMSO-SO3/pyr, DMSO-SOCl2, DMSO-Cl2 2. Corey-Kim Oxidation: Tetrahedron Lett. 1974, 287; J. Am. Chem. Soc. 1972, 94, 7586. O CH3 CH3 S + N Cl [DMS-NCS] S Cl CH3 CH3 O 3. Moffatt-Pfitzner Oxidation (DCC-DMSO): J. Am. Chem. Soc. 1963, 85, 3027; J. Am. Chem. Soc. 1965, 87, 5670. O N C N S
DMSO + -Mechanism: 1. RCH2OH +
N C N
[DMSO-DCC]
O N C N H + B: R C O S B: CH3 H CH3
CH3 RCH2O S CH3 RCHO + Me2S CH3 RCH2O S B: CH2 H CH3 H R C O S CH2 H +
O H H N C N
2. RCH2OH +
CH3 S X CH3
RCHO + Me2S
N X = Cl or O C HN
93
Modern Organic Chemistry The Scripps Research Institute -All Swern type complexes react with alcohols, in presence of base, to give "activated alcohol complexes". -Examples: OH OH O OH OH MnO2 or PCC H OH CHO CHO OH O -Other oxidants cleave diol C-C bond -Swern oxidation run under very mild conditions (usually 78 C to 50 C) HO H O O O
OH OH
Swern
Boger J. Org. Chem. 1990, 55, 1519. Boger J. Org. Chem. 1991, 56, 2115. Boger Tetrahedron Lett. 1989, 30, 2037.
-Fredericamycin A: Boger J. Am. Chem. Soc. 1995, 117, 11839. MOMO MeO OMe OH TFAA-DMSO DBU OBn OH BnO EtO MOMO MeO MeO O BBr3; air TsOH-NaBr MOMO BnO O BnO EtO N O OH O HO O N H MeO N O OH 78 C, 1 h 78 C to 25 C, 20 h MOMO MeO MeO OH TFAA-DMSO Et3N O BnO EtO O N
MOMO
MOMO BnO
Fredericamycin A
Note: Kornblum oxidation, J. Am. Chem. Soc. 1957, 79, 6562 via DMSO oxygen based displacement of halide (usually activated: benzylic or -keto halide) to provide aldehyde or ketone. - Common byproducts of Swern oxidations are (methylthio)methyl ethers and the amount varies with DMSO coactivator and reaction temperature. It is derived from alcohol trap of a Pummerer rearrangement intermediate: CH2=+SCH3. Note: Pummerer rearrangement is also a formal oxidation reaction Pummerer Chem Ber. 1909, 42, 2282; Chem Ber. 1910, 43, 1401. O S Ac2O Ph AcO OAc S CO2Et H H AcO
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et OAc
Reviews: Org. React. 1991, 40, 157. Comprehensive Org. Syn., Vol. 7, pp 194-206.
94
Reduction Reactions Dale L. Boger
VI. Reduction Reactions

A. Conformational Effects of Carbonyl Groups on Reactivity
O H H sp2 sp3 120 109.5 introduces torsional strain Dihedral angle 4 O Eclipsed conformation of carbonyl
H Hax
This torsional strain accounts for the increased reactivity of six-membered ring cyclic ketones over acyclic ketones. H O H NuH OH H Nu
Overall, the addition to cyclohexanones is favorable: 1. gain 1,3-diaxial interactions (A value = 0.7 kcal/mol for OH) 2. lose the torsional strain (~3-5 kcal/mol) - So, additions to cyclic ketones are thermodynamically and kinetically favorable. 1. Reversible Reactions O HCN reversible reaction HO CN
Keq for
cyclohexanone acyclic ketone
~ ~
70
- Thermodynamically more favorable for cyclohexanone due to the loss of torsional strain. - Thermodynamic effect of sp2 hybridization: the strain free acyclic system does not suffer the strain destabilization of the ground state, so little gain going from sp2-> sp3. 2. Irreversible Reactions (kinetic effect is pertinent) O LiAlH4
HO
Rate (k) for
cyclohexanone acyclic ketone
~ ~
335
*Implication: One can selectively reduce a cyclic carbonyl in the presence of an acyclic carbonyl: under kinetic or thermodynamic conditions. - Synthetic consideration: may not have to protect acyclic ketone.
95
Modern Organic Chemistry The Scripps Research Institute 3. Additional Conformational Effects O H H H Boat destabilization reduced Only ~2.7 kcal/mol higher in energy H O
-Cyclohexanones potentially have more accessible conformations available. 0.6 kcal/mol Me H O Theoretical prediction (0.9 kcal/mol), actually this 1,3-diaxial Me - H interaction is only about 0.6 kcal/mol. This difference (0.3 kcal/mol) in energies observed between theoretical and experimental results is due to the fact that the sp2 carbonyl carbon moves these groups (Me and H) further away from each other: bond angle of 120 vs. 109.5.
A = 1.8 kcal/mol 1/2 = 0.9 kcal/mol Predicted!
- Substituents on the ring benefit from a reduced A value since one axial substituent is removed and the opened bond angle of the carbonyl further reduces the remaining 1,3-diaxial interaction (greater distance).
B. Reactions of Carbonyl Groups

- Three primary reactions which we will discuss relative to nucleophilic addition: O Nucleophilic addition: X H Me (or R) -Deprotonation: (enolate formation) O X H Me (or R) Addition of e-, formation of radical anion: O X H Me (or R) e X O H Me (or R) O Base X Me (or R) Nu HO Nu X H Me (or R)
- Each reagent will display competitive reactions among the three primary pathways. Nature of each reagent and the nature of X will determine the course.
C. Reversible Reduction Reactions: Stereochemistry

- Meerwein-Pondorff-Verley Reduction (the reverse reaction is the Oppenauer Oxidation). O + Al O
tBu iPrOH
Reversible Reduction Review: Djerassi Org. React. 1951, 6, 207. OH OH +

tBu
95
t : Bu
96
- Mechanism: Reversible Intramolecular Hydride Transfer. O Al H

tBu
O O axial H delivery H H
tBu
H H
Al
O Al H O
tBu
O equatorial H delivery
tBu
Al O H
H H Steric interaction
H H
- Since it is freely reversible, one obtains the most stable alcohol from the reduction. The reaction is driven to completion by use of excess reagent and by distilling off the acetone formed in the reaction. - But, the A value of OH = 0.7 kcal/mol and K = e-G/RT would predict a 72:28 ratio. Why does the experimental result give better selectivity than the prediction (95:5 > 72:28)? - We must not only consider the A value, but the larger 1,2-destabilizing steric interactions of the isopropoxy group in the transition state for the equatorial delivery of the hydride: that is, the larger E in the transition state.
D. Irreversible Reduction Reactions: Stereochemistry of Hydride Reduction Reactions and Other Nucleophilic Additions to Carbonyl Compounds
1. Cyclic Ketones a. Examples H H
tBu
O LiAlH4 H H
tBu
H H H H H OH +
tBu
OH H H H H H
: 10 90 Nearly the same ratio obtained under these kinetic and the above thermodynamic conditions.
Why?
H H Al Li H 1,3-interactions H O H H Li
H H Al H H H H
- Difference in the relative rates: 1,2-interactions slow the equatorial addition by a factor of ~ 10 favor axial hydride delivery - LiAlH4 = small reagent
1,2-interactions - 1,3-interactions are more remote (i.e., smaller), when compared to the 1,2-interactions (larger). - The destabilizing 1,3-interactions increase as the size of the reagent increases or with the size of the 1,3-diaxial substituents while the 1,2-interactions are not nearly so sensitive to the size of reagents or the size of the substituents.
97
Modern Organic Chemistry The Scripps Research Institute - For the reduction of cyclohexanone and derivatives, we see the following generalizations: Small H Reagent H O H Large H Reagent R Examples: Me Me H Me H O Me LiAlH4 Me H Me H 45 : OH H Me + Me H Me H 55 H OH H H
Increased steric hinderance of the 1,3-diaxial interactions (Me/reagent) make axial hydride delivery more difficult. O LiAlH4 OH H + H : 0 H OH
Me Me H H H
Me Me
Me Me
H H H 100
H H
Serious 1,3-interactions preclude axial delivery of the hydride, but the axial Me's have no effect on the 1,2-interactions. O Me Reagent Me Me H H LiAlH4 NaBH4 LiAl(OMe)3H H Me H 52 - 63 55 - 64 92 - 98 : : : OH H Me + Me H Me H 37 - 48 36 - 45 2 - 8 H OH
Me Me
Larger reagent: greater selectivity for equatorial H delivery. Effect of the size of the reagent H
tBu
O H H H
B H-K+
H H
tBu
OH OH + H
tBu
H H 3.5 H
H H H
96.5
Much larger reagent! Now, even the 1,3-H/reagent interactions are large while the 1,2-torsional interactions are not affected. Brown J. Am. Chem Soc. 1972, 94, 7154.
98
Reduction Reactions Dale L. Boger - Comparison of Diastereoselectivity of Hydride Reducing Reagents. O

tBu
O Me % axial OH 25 24 69 36 98 >99 13 Me
Me Me
Me O O % endo OH 86 89 98 94 99.6 >99 Me
Me
Reagent % axial OH NaBH4 20 LiAlH4 8 LiAl(OMe)3H 9 LiAl(OtBu)3H 9 (sBu)3BHLi 93 (Me2CHCHMe)3BHLi >99 LiMeBH3 2
% axial OH 58 63 92-98 95 99.8 66
O % endo OH 14 8 1 6 0.4 no reaction -
Brown J. Am. Chem. Soc. 1970, 92, 709; 1972, 94, 7159; 1976, 98, 3383. - Stereochemistry of Other Representative Nucleophilic Additions to Cyclohexanones. Me O O O tBu Me Me Me Reagent MeLi/Et2O MeMgI/Et2O EtMgBr/Et2O PhMgBr/Et2O PhLi % axial OH 65 53 71 49 58 % axial OH 85 84 95 91 88 % axial OH 100 100 100 100 Note: Typically alkyllithium reagents behave as large nucleophiles and approach from the equatorial direction
Ashby Chem. Rev. 1975, 75, 521.
V. Grignard received the 1912 Nobel prize in Chemistry for his discovery of the role of organomagnesium halides in organic synthesis which he made as a graduate student working with P. A. Barbier. b. Origin of Diastereoselectivity
Axial attack RH R
Note: The direction of attack is not from the axial or equatorial vector, but with a 109.5 approach of the nucleophile. no O yes Steric Interactions H O H H H yes no Eclipsed Conformation Torsional Strain
versus
Hax H
Felkin - equatorial attack (largely torsional strain - when R = H, worse than axial attack mode)
- Stereoelectronic effects 90 R O R
(105 5) 109.5 R versus O R
Dunitz angle: Tetrahedron 1974, 30, 1563. Good overlap and ~ approaches bond angle required of sp3 hybridization. Better - overlap (FMO) for nucleophilic addition.
99
Modern Organic Chemistry The Scripps Research Institute - Cyclic Ketones: Steric vs. Torsional Interactions. Nu Ha Ha Ha OH Ha - As the nucleophile gets larger, this steric interaction with the C3 - axial H gets worse - equatorial approach becomes the preferred line of attack. - For C3 and C5-H substituents, this torsional interaction is worse than the steric interaction of Nu- / C3 and C5-H's (for small, unhindered Nu-).
He He
Ha
Nu
- All H reductions have transition states that resemble reactant geometry. - Diastereoselectivity is influenced by: 1) Steric interactions (1,3-diaxial interactions) 2) Torsional strain (1,2-interactions) 3) Remote electronic effects (electrostatic interactions) - In contrast to early theories of "product development control" / late transition state vs "steric approach control" / early transition state. c. Baldwin's Rules and Dunitz Angle of Attack Recent review: Acc. Chem. Res. 1993, 26, 476. Dunitz angle of attack: Tetrahedron 1974, 30, 1563. - Nucleophile addition to carbonyl compound takes place not at 90 (perpendicular) to the C=O, but at an angle of ~105 5 sp2 = 105 5 Nu R O R R R O Nu X Nu SN2 sp3 = 180 sp = 120 Nu 120 120
- First detailed by Eschenmoser Helv. Chem. Acta 1970, 53, 2059. - Expanded and elaborated to: Baldwin's Rules for Ring Closure J. Chem. Soc., Chem. Commun. 1974, 734, 736. - Vector analysis and approach trajectory on sp2, sp, and sp3 systems. - For intramolecular reactions the favored pathways are those where the length and nature of the linking chain enables the terminal atoms to achieve proper geometry for reaction. sp3 = tet sp2 = trig sp = dig
Exo XY XX Y Baldwin's Rules Rule 1: tetrahedral (sp3) systems (a) 3 to 7-exo-tet are favored (b) 5 to 6-endo-tet are disfavored Y
Endo X Y
Rule 2: trigonal (sp2) systems (a) 3 to 7-exo-trig are favored (b) 3 to 5-endo-trig are disfavored (c) 6 to 7-endo-trig are favored
Rule 3: digonal (sp) systems (a) 3 to 4-exo-dig are disfavored (b) 5 to 7-exo-dig are favored (c) 3 to 7-endo-dig are favored
100
Reduction Reactions Dale L. Boger -Baldwin: Approach Vector Analysis (Vector Sum establishes the approach of reagent). O 1. Amides R N R 1 Nu R
1
Nu R
O N R R1
1
nonequivalent contributions of each resonance form
O R Nu 2. Carboxylate Nu R N R R1
1
O not R N R Nu R1
1
line of attack is weighted average of the two contributing resonance forms
O O R
O O Nu equivalent and Nu- approaches over (eclipsing) the R group
O R Nu3. Cyclohexenones O O
Nu
Nu
substituents in the C5 and C6 position will have a more significant effect on the rate and the stereochemical outcome O
Nu Examples: Nu CH3 -face O -face H H major
locked trans diaxial ring fusion preferential axial delivery of reagent equatorial OH is major product addition of Nu- from -face (equatorial delivery) suffers from repulsive interaction with axial Me
LiAlH4 CH3 HO H H
Houk and Trost J. Org. Chem. 1991, 56, 3656.
70~90%
101
Modern Organic Chemistry The Scripps Research Institute - vs. H O H
HCH3 HO single 1,3-diaxial interaction major H
CH3
major product
- but H O
H CH3 Large H/CH3 interaction H H major H O CH3 Smaller H/CH3 interaction H HO CH3 OH CH3 H
- With enones, the substituents in the 5,6-positions play a more dominant role in determining stereochemical outcome of nucleophilic addition to the carbonyl. 2. Acyclic Carbonyl Groups Review: Comprehensive Org. Syn., Vol. 1, pp 49-75. - Cram's Rule D. J. Cram was awarded the 1987 Nobel prize in Chemistry for his "host - guest" complex studies.
J. Am. Chem Soc. 1952, 74, 5828. Empirical and no mechanistic interpretation is imposed on model J. Am. Chem Soc. 1959, 81, 2748. (chelation-controlled addition) Helv. Chim. Acta 1953, 36, 308. (1,3-induction) Tetrahedron Lett. 1968, 2199, 2205. Tetrahedron Lett. 1976, 155, 159. Nouv. J. Chim. 1977, 1, 61.
V. Prelog received the 1975 Nobel prize in Chemistry for his research into stereochemistry of organic molecules and reactions.
- Prelog - Felkin model: (or Felkin-Ahn)
a. Cram's Rule O - Empirical Model Nu S RL M S NuL O M R
- Large group L eclipsed with R and not the carbonyl, Nu approach from side of small (S) group. - Stereoselectivity observed usually modest. - But, most populated (most stable) conformation of acyclic ketone would be the eclipsed carbonyl conformation.
102
Reduction Reactions Dale L. Boger Nu R' R RL RM O R R' RL O R Nu O RL R Nu RL
O R' RMR' RM This is not the observed stereochemistry! Note: Reaction is not from the ground state carbonyl eclipsed RL conformation, i.e., the ground state conformation is not the reactive conformation (Curtin-Hammett Principle). RM b. Felkin (-Ahn) Model - Large group (L) trans antiperiplanar to forming bond versus O L R M S Nu O M L S R Nu S R the sterically next most demanding substituent is gauche to carbonyl M O L M Nu OL R S minimizes torsional strain (Pitzer strain) in transition state (Felkin Model)
Same as Cram Product: sterically most demanding group is perpendicular to the plane of the carbonyl, anti to incoming nucleophile - Here, L is either the largest group (sterically) or the group whose bond to the -carbon provides the greatest -* overlap (e.g. halide, alkoxy groups). - Computational studies of Ahn confirmed this is the most stable transition state and extended it to -chloroketones. In the latter case, this minimizes destabilizing electrostatic interactions between the halogen (electronegative group) and the incoming nucleophile. Ahn further refined the Felkin Model, i.e., Felkin-Ahn Model, as shown below O L Nu
O S versus L R M Nu
S R
Nucleophile prefers approach that minimizes torsional strain and incorporates Burgi-Dunitz trajectory. Primary interaction is now between the Nu and the small or medium substituent.
Nu R O R
Preferred Note: Karabatose proposed a similar model as an alternative to the original Cram empirical rationalization based on computational studies that suggested the most favored conformation would have the medium-sized group eclipsing the carbonyl and addition of H occurs from the side of the small substituent. M O Nu Nu S R L S
OH L
Karabatose J. Am. Chem. Soc. 1967, 89, 1367.
The model incorporating the Burgi-Dunitz angle has been even further refined to reflect the impact of substantially different sized R groups on the carbonyl. As the size difference between the two substituents increases, the incoming nucleophile would try to avoid the larger one and the approach vector would be tilted away from the normal plane by an angle referred to as the Flippin-Lodge angle (FL). Nu RS FL Heathcock Aldrichchim. Acta 1990, 23, 99.
RL
Nu-
103
Modern Organic Chemistry The Scripps Research Institute Examples: O O Cl Johnson J. Am. Chem. Soc. 1968, 90, 6225. Cl O R Et H Me HO R Me Cl Et H HO H Me R Et Cl O MeMgCl 75 C, THF O HO Me Me H Cl 92% H HO Me Cl Et R H Me O R Et Nu O H
-First observed in cyclic systems: Cornforth
J. Chem. Soc. 1959, 112 and 2539. J. Chem. Soc. 1957, 158.
J. W. Cornforth received the 1975 Nobel prize in Chemistry jointly with V. Prelog for outstanding intellectual achievement on the stereochemistry of reactions catalyzed by enzymes.
Cl axial
-For cyclic ketones Axial
-For acyclic ketones R' H O S M L A O H D R' O
H Equatorial
Allylic bonds prefer to be staggered (axial attack) with respect to the incoming nucleophile rather than eclipsing (equatorial attack). c. Cieplak Model Nu-
J. Am. Chem. Soc. 1981, 103, 4540.

vacant * O * O
H
* O O
adjacent bonds considered
axial attack stabilization
equatorial attack stabilization
1. C-H bond is more electron-rich, better e-donation in stabilization of the developing * of bond formation than C-C bond, therefore axial approach preferred. 2. C-O > C-H > C-C > C-S. 3. Nucleophile can affect intensity of effect, * (LUMO of developing bond). LUMO, effect, overlap/stabilization (a) Electron donation of solvent (polarity) will increase *, LUMO, overlap, axial attack. equatorial attack.
equatorial attack, i.e. preferentially axial attack (b) Counterion effect: its ability to complex/stabilize *, lower * (c) Electron-rich Nu: * nucleophile, overlap/effect,
effect,
axial attack
4. Heteroatom at 4-position exhibits preference for axial attack: n - * stabilization.
104
Reduction Reactions Dale L. Boger d. Additional Models - Product development/steric approach control Dauben: J. Am. Chem. Soc. 1956, 78, 2579. - Torsional strain (preference for staggered conformation in the transition state) Felkin: Houk:
Houk-Trost: - Principles of least motion Yates:
Tetrahedron Lett. 1968, 2199, 2205. J. Am. Chem. Soc. 1987, 109, 908. J. Am. Chem. Soc. 1988, 110, 3228. Science 1986, 231, 1108. J. Am. Chem. Soc. 1991, 113, 5018. J. Am. Chem. Soc. 1993, 115, 10992. Angew. Chem., Int. Ed. Eng. 1992, 31, 1019. cf. Chemtracts: Org. Chem. 1988, 1, 65. J. Am. Chem. Soc. 1987, 109, 5560.
higher level calculations than Ahn or Cieplak: C-C > C-H electron donation. remote-through space electrostatics and torsional effects account for Cieplak observations.
J. Am. Chem. Soc. 1974, 96, 3141.
- Stereoelectronic control and smallest change in conformation Toromanoff: Tetrahedron 1980, 36, 2809. - Electrostatic model Kahn, Hehre, Chamberlin:
J. Am. Chem. Soc. 1987, 109, 650, 663, 666. J. Am. Chem. Soc. 1986, 108, 7396, 7399. Tetrahedron Lett. 1973, 23, 4307. Tetrahedron 1974, 30, 3349. J. Am. Chem. Soc. 1976, 98, 4054. J. Am. Chem. Soc. 1984, 106, 4849.
- Electronic nonequivalence of carbonyl faces Klein: - Dissymmetric -electron clouds Fukui: Burgess, Liotta:
- Antiperiplanar approach of Nu to other bonds - Preferential attack antiperiplanar to the best electronic acceptor Ahn: Tetrahedron Lett. 1976, 155, 159. Nouv. J. Chem. 1977, 1, 61. Top. Curr. Chem. 1980, 88, 145. Dunitz, Eschenmoser: Helv. Chim. Acta 1980, 63, 1158. - Preferential attack antiperiplanar to the best electronic donor Cieplak Model: J. Am. Chem. Soc. 1981, 103, 4540. J. Chem. Soc., Perkin Trans. 1 1997, 530. - Others Ashby: Wigfield: - Bent bond or Tau-bond model Vogel, Eschenmoser: Winter: - Hyperconjugation Coxon, Luibrand:
J. Org. Chem. 1976, 41, 2890. J. Org. Chem. 1976, 41, 2396; 1977, 42, 1108. Chem. Lett. 1987, 215. J. Chem. Educ. 1987, 64, 587. Tetrahedron Lett. 1993, 34, 7097.
105
Modern Organic Chemistry The Scripps Research Institute e. Comparative Examples of Diastereoselection - Diastereoselection depends on the size of the ketone substituent. Kobayashi, Ohno J. Am. Chem. Soc. 1988, 110, 4826. Me R O 1 Me R O 2 From 1 R = Ph R = Ph R = Ph R = Ph R=
nBuLi
SiMe3
Nu
Me Nu R Me3Si OH Felkin Product Me + R
Me Nu HO SiMe3 Bu4NF Me Nu + R Nu OH From 2 5:1 4:1 2:1 1.7:1 1.6:1 1.9:1 1:1 2.5:1 3.5:1 2:1 1.5:1 2:1 R Me Et iPr tBu ratio 74 : 26 76 : 24 83 : 17 98 : 2 L O M L Nu R S O M
S Nu SiMe3
Nu
Note: Desilylation proceeds with complete retention (>99:1): Hudrlik J. Am. Chem. Soc. 1982, 104, 6809.
OH
> 100:1 > 40:1 > 100:1 11:1 > 30:1 > 100:1 > 30:1 11:1 15:1 21:1 > 100:1 3.5:1 Me
MeLi SiMe3 MgBr

nBuLi
Note: Typical Felkin diastereoselection is modest. Note: Diastereoselection is increased dramatically with very large ketone substituent.
MeLi SiMe3 MgBr R=

nBuLi
MeLi SiMe3 MgBr Me Ph O R Ph
Increase size, increase diastereoselectivity
R OH
Felkin Tetrahedron Lett. 1968, 2199 and 2205. Diastereoselectivity for reduction with LiAlH4 R = tBu > iPr > Et > Me
- Diastereoselectivity depends on size of nucleophile. Me Ph O Bu 1) TMSLi 2) Bu4NF > 50:1 Ph Me Bu OH Felkin Product Me Ph Me OH LiAlH4 (sBu)3BHLi 74 >99 26 <1 + Ph Complementary stereochemistry to that illustrated with acylsilanes.
Me Ph O Me
Nu
Me Me OH Yamamoto J. Am. Chem. Soc. 1988, 110, 4475.
106
Reduction Reactions Dale L. Boger f. Chelation-controlled Addition - Review: Acc. Chem. Res. 1993, 26, 462. - 1,2-chelation-controlled additions (-chelation-controlled additions) also formulated by Cram: J. Am. Chem. Soc. 1959, 81, 2748.
So please do not refer to as anti-Cram addition as many have!

Met XO Nu S L S Nu OMet X R L Can usually provide excellent diastereoselectivity
1,2-chelation X = OH, OR Nu S R L Nu H RL R R O O Met R Nu RS RL R OH OH Axial delivery on most stable chair-like transition state R O O Nu S Met R L OR OH
RS 1,3-chelation
syn-1,3-diol
Asymm. Syn. Vol. 2, 125.
- Examples of 1,2-chelation-control - Nicolaou J. Am. Chem. Soc. 1980, 102, 6611. O O O O O H R MeMgBr >95:5
Zoapatanol synthesis O O HO H R
Me
-But to invert the stereochemistry O O O H R O Me BrMg O O Zoapatanol - Still J. Am. Chem. Soc. 1980, 102, 2117, 2118 and 2120. CH3 O O H O OTBS Ph MgBr O H O Monensin synthesis Me OH OTBS Ph O HO H R
Me
TBS =
Si
50:1 Stereoselectivity
- Note that non chelation-controlled additions exhibit relatively modest stereoselectivities, but chelation-controlled additions can exhibit very good stereocontrol.
107
Modern Organic Chemistry The Scripps Research Institute H BnO O O Met H R O O Met Nu- = PhMgI MeMgBr or MeLi LiAlH4 (sBu)3BHLi (sBu)3BHLi 100:0 100:0 84:16 100:0 78:22 Nu O HO R OAc H MeMgBr BnO Me OH H Nuc H O OAc H
R = CH3 Ph Ph Ph CH3 - Chelation Model Nu Met OO H R - Felkin Model R H Note: here Felkin model will predict wrong product Nu
O Nu H OH
R chelation-controlled product O R O H Nu Felkin model predicted product chelation product Felkin product H C7H15 + HO Bu I MEMO Bu OH II I II OH
H C7H15 O O O O MEM protecting group

nBuM
H C7H15 MEMO
78 C
solvent M = MgBr " " " pentane CH2Cl2 Et2O THF
I 90 93.5 90 100
II 10 6.5 10 0
solvent
Still Tetrahedron Lett. 1980, 21, 1031. Me C7H15 O O R
M = Li pentane 67 33 " CH2Cl2 75 25 " Et2O 50 50 " THF 41 59 Note: Li is less able to coordinate to two O atoms and THF has good solvation capabilities (ie., removes Li+; no -chelation control) Me
Nu
H Nu
C7H15 OH
OR
M chelation model
chelation-controlled product
108
Two models provide different products

Me H RO Nu OC7H15 Felkin model H C7H15 RO O R = MEM = MOM = MTM = CH2Ph = CH2OCH2Ph = THP Still Tetrahedron Lett. 1980, 21, 1031. H C7H15 RO O R = CH2Ph R = TBS MeMgCl MeLi MeMgCl MgCl Et2O THF Et2O THF Nu 78 C H C7H15 RO HO Bu > 99:1 60:40 60:40 10:90 chelation-controlled Note: Silyl ether poor for chelation-control. Felkin addition
nBuMgBr
Me H Nu RO HO C7H15
_ _ _
H Me
Nu
C7H15 OH
OR
Felkin model predicted product H C7H15 RO HO Bu > 99:1 > 99:1 > 99:1 99.5:0.5 99:1 75:25
THF, 78 C
Note: THP poor for chelation-control.
Reetz J. Chem. Soc., Chem. Commun. 1986, 1600.
OH R1 O versus OTBS Note: TBS very good at suppressing chelation. R1 O R2 1) Red-Al toluene, 78 C R1 2) Bu4NF R2 Zn(BH4)2 Et2O, 0 C R1
OH R2 OH
anti-1,2-diol chelation-controlled addition

77-99 : 23-1
OH R2 OH
syn-1,2-diol Felkin addition

76-98 : 24-2
Nakata Tetrahedron Lett. 1983, 24, 2653 and 2661. OH K-selectride R OBn 90:10 Felkin addition THF, 95 C R OBn O Zn(BH4)2 Et2O, 30 C R OBn 95:5 chelation-controlled OH
Note: Red-Al was anti selective due to coordination of OBn Tsuji Tetrahedron Lett. 1985, 26, 5139.
109
Modern Organic Chemistry The Scripps Research Institute RO LiAlH4 O OH R = Bn R = TBS Et2O, 10 C THF, 20 C 98 5 RO + RO OH 2 95 chelation-controlled Felkin addition
Note: OTBS does not chelate
; :
Overman Tetrahedron Lett. 1982, 23, 2355.
-1,3-Chelation-Controlled Additions (-chelation-controlled additions): - First highly selective method was developed with R3B/NaBH4 and later with Et2BOCH3-NaBH4 in THF-MeOH: Pai Tetrahedron 1984, 40, 2233. Shapiro Tetrahedron Lett. 1987, 28, 155. (syn:anti 98:2) - Dibal-H (> 92:8 syn:anti) Kiyooka Tetrahedron Lett. 1986, 27, 3009.
L Chelation control with external H delivery H R' O M
L O H R'' _ _ _
Note: Typically easy to achieve chelationcontrolled syn-1,3-diol. OH R' OH
H H OH O R' R'' Axial H or Nu delivery

R' R'' H
L O M L O
R'' syn-1,3-diol
OH O L B L O R'' H R'
OH R''
Controlled with internal Hdelivery R'
anti-1,3-diol
- Examples of anti-1,3-diol preparation: Evans, Carreira, Chapman J. Am. Chem. Soc. 1988, 110, 3560. O
tBu tBu
H OH + 90 : no reaction
tBu
OH H 10
NaBH4 Me4NBH(OAc)3
110

OH
tBu
O
tBu
H OH OH
tBu
OH
OH H
NaBH4 Me4NBH(OAc)3
1 300
: :
1 1
HOAc, low temperature protonates carbonyl, activation for reduction, no reduction without HOAc - Note that Me4NBH(OAc)3 is unreactive toward carbonyl unless carbonyl oxygen is protonated. - The key to success is the lack of reactivity of the reagent in the intermolecular reaction, which permits formation of complex: AcO O OAc HO internal axial hydride delivery H
OH O Me4NBH(OAc)3 Me HOAc 92% H O O Me H OH O Me4NBH(OAc)3 Me HOAc 84% H H O O axial alkyl group, but no destabilizing 1,3-diaxial interactions OAc B R H Me OAc H OAc B R H OAc
OH
OH
Me 98:2 has two equatorial substituents, on the chair-like transition state excellent diastereoselectivity
OH OH
Me 98:2
still observe excellent diastereoselectivity
-Also, works with
O H R
Si H O R2
iPr SiHO 2
+ Lewis acid (to activate carbonyl) Lewis acid activation O R2 1) SnCl4, 80 C OH OH
OH O R1 R2
iPr SiHCl 2
Et3N, DMAP
R1
R1 R2 2) HF internal H delivery anti-1,3-diol
Davis Tetrahedron 1988, 44, 3761.
111
Modern Organic Chemistry The Scripps Research Institute g. Felkin Addition to Other -Systems - Reetz Angew. Chem., Int. Ed. Eng. 1989, 28, 1706. R H NBn2 CO2Et Bu2CuLi R H H Bu CO2Et
NBn2 >95:5 (R = CH2Ph) H CO2Et R Bu _ _ _ H R Bu CO2Et NBn2
NBn2 - Felkin Model H H Nu But, R H NBn2 H R CO2Et (Bu ) H H H
CO2Et CO2Et Bu2CuLi R H
_ _ _
NBn2 Bu
CO2Et
NBn2 CO2Et
>95:5 (R = CH2Ph)
Bu R H NBn2 H
smaller interaction CO2Et CO2Et R H
_ _ _
Bu H compared with NBn2 H H CO2Et R CO2Et Nu (Bu ) H R H Bu serious destabilizing interaction - Rationalize the following results: R H CO2Et NBn2 R = CH3 R = PhCH2 R= R = TBDMSOCH2
tBuOOH
CH(CO2Et)2 NBn2
CO2Et NBn2 CO2Et
KOtBu THF/NH3 46% 60% 68% 80%
R H
O NBn2 > 96
CO2Et
+ :
R H
O NBn2 4
CO2Et
112
E. Aluminum Hydride Reducing Agents

- LiAlH4 coordinates with carbonyl oxygen and activates it towards reduction. O H Li H Al H H H O H Al H H O H Al O H H O O
k1 FAST
k2
k3
k4
- Rate of addition decreases as additional alkoxy groups are placed on Al: k1 > k2 > k3 > k4, especially for hindered ketones. - The aluminum alkoxide hydrides are stable in that they do not disproportionate. - Reagents have been designed which are less reactive, thus more selective: - Reactivity: LiAlH4 > LiAl(OR)H3 > LiAl(OR)2H2 > LiAl(OR)3H 3 ROH
LiAlH4 - Most common are LiAlH(OCH3)3 and - Examples:
LiAlH(OR)3
LiAlH(OtBu)3
more reactive towards nucleophiles H LiAlH4 H O H O O H H H LiAlH(OR)3 0 C, Et2O H O O H H H HO H H
OH
OH
Chemoselectivity: differentiation between competitive functional groups vs. Regioselectivity: differentiate between orientations.
- Lithium trialkoxyaluminumhydrides can be chemoselective.
113
O OH +
OH
NaBH4 H LiAlH4 LiAlH(OCH3)3 LiAlH(OtBu)3
36 - 45 37 - 48 2-8 4 - 12
: : : :
55 - 64 52 - 63 92 - 98 88 - 96
- this is actually dimeric in solution, so effective bulk greater than LiAlH(OtBu)3
- degree of stereocontrol is concentration dependent with LiAlH(OCH3)3 (dimer and higher aggregates) but not LiAlH(OtBu)3 (monomeric)
F. Borohydride Reducing Agents
- Borohydrides (Na+, Li+, K+, Zn2+) are nucleophilic H sources. - Alkoxyborohydrides (RO)3BH tend to disproportionate.
Na (RO)3BH
NaBH4
- Therefore, k1 ~ k2 ~ k3 ~ k4 for the stepwise reactions and you can't typically moderate the reactivity (electronically) by introducing alkoxy substituents. - However, substitution with bulky alkyl groups on boron will moderate reactivity and diastereoselectivity.
114
Reduction Reactions Dale L. Boger O CH3 LiAlH4 75 OH CH3 + : 25 OH CH3
BH3THF
74
26
21 2 Li-Selectride 3 K-Selectride 3 - NOTE: on diborane B2H6 = H H H B B H H H 2 BH3 BHK BHLi BH
79
<1
>99
<1
>99
2 H3B
- THF optimally provides uncomplexed, monomeric BH3 available for reduction (or other reactions). - In ether (B2H6), or in the presence of amines (BH3NR3), less reactive borane-complexes are formed. B2H6 BH3THF BH3OEt2 BH3SMe2 BH3NR3 H3B stable B2H6 2 BH3 O H3B not stable NR3
reactions of B2H6 in Et2O or in the presence of 3 amines will be slower than reactions run in THF
- NaBH4 requires activation of the carbonyl by hydrogen-bonding with alcoholic solvent for reductions. Therefore the reactions are run in alcoholic solvents. The reagent slowly reacts with solvent: MeOH (30 min) > EtOH (slow) > iPrOH (stable) > tBuOH (stable). H O R R O R'
H B H H H - But trialkylborohydrides (R3BHM+) are reactive enough to use in ethereal solvents (e.g., THF) and don't require this activation of C=O by solvent.
115
Modern Organic Chemistry The Scripps Research Institute - LiBH4 is also more reactive than NaBH4 (Li+ coordinates better to carbonyl oxygen, activating the carbonyl toward attack by H ). - Differences in reactivity can give rise to Chemoselectivity: OH
O O
NaBH4
O O
LiBH4
House, pp 71-105 (discussion of reducing agent choice) pp 1-44 (catalytic hydrogenation) pp 107-144 (BH3) pp 145-227 (Li/NH3) pp 228-256 (NH2NH2) OH Carbonyl Reduction Reagents: Larock pp. 528-552. Chem. Soc. Rev. 1976, 5, 23. Tetrahedron 1979, 25, 449. J. Am. Chem. Soc. 1981, 103, 4540. J. Org. Chem. 1991, 56, 4718. Top. Stereochem. 1979, 11, 53.
HO
G. Hydride Reductions of Functional Groups

Substrate RCOCl
decreasing reactivity
LiAlH4
Product RCH2OH RCH2OH RCH(OH)R' OH RCH2OH + R'-OH
RCHO RCOR'
RCH2NR'2
H R
H NR'2
O RCOOR' RCOO (slow)
RCHO
H 2O
OAlR2 R H NR'2 LiAlH4 RCONR'2
RCH2OH RCH2NH2 or RCHO
requires vigorous H reductant to further reduce this R N Al
RC N
RCH2NH2 or RCHO
- DIBAL-H + RC N (at 0 C) gives good yields of RCHO
116
Reduction Reactions Dale L. Boger Substrate continued decreasing reactivity OH R' R LiAlH4 Product
N R
NH2 or R' R
NHOH R'
RNO2 RCH2X X = Br, Cl, I, OSO2R RCHX R' O NR'2 R H
RNH2 RCH3 RCH2R'
O - Reductions of R
O R H R
O NR'2 R
OAl NR'2 R N R'
R'
LiAlH4 R NR'2
OH R NR'2 H
H+ R
OH NR'2 quench
best procedure is use of DIBAL as reducing agent at 78 C - quench with MeOH at 78 C to avoid over reduction.
- or other specially selected amides will cleanly give aldehyde: enlisting these electrons disrupt the aromaticity of pyrazole O R N N Al O LiAlH4 Et2O, 0 C (-20 C) R N N R very slow N N H
1.
breakdown to iminium ion intermediate very slow Ried Angew. Chem. 1958, 70, 165. O 2. R N O Al R N very slow
no longer aromatic
LiAlH4
H R N
too strained Brown J. Am. Chem. Soc. 1961, 83, 2016 and 4549.
117
Modern Organic Chemistry The Scripps Research Institute 3. Weinreb amide - A more recent and now widely employed method for controlled reduction and nucleophilic addition (i.e. RLi) to carboxamides was introduced by Weinreb (Tetrahedron Lett. 1981, 22, 3815). Al N Me OMe H3O Ph
O Ph N Me OMe LiAlH4
H Ph
O H
Chelation stabilizes intermediate which does not breakdown during the reaction, but only upon workup. O N Me OMe DIBAL-H 0 C 74% O OMe DIBAL-H N 0 C Me 76% O N Me OMe LiAlH4 BOCHN 88% O H O H + 3% OH O H
BOCHN
Castro Synthesis 1983, 676. 4. The Rosenmund reduction is a much older method that may be utilized to convert carboxylic acids to aldehydes via the acid chloride. RCO2H RCOCl H2 Pd/BaSO4 RCHO
Rosenmund Chem. Ber. 1921, 54, 425. Review: Org. React. 1948, 4, 362. Burgstahler Synthesis 1976, 767. 5. Bu3SnH will selectively reduce selenoesters to aldehydes without further reduction by a free radical mechanism. O R Bu3SnH SePh 80 C Bu3Sn O R acyl radical Bu3SnSePh O Bu3SnSePh R - Also possible to promote decarbonylation prior to H reduction to achieve conversion to the Bu3SnH corresponding hydrocarbon.
Pfenninger Helv. Chim. Acta 1980, 63, 2328.
118
Reduction Reactions Dale L. Boger - Review of RCOX RCHO: Comprehensive Org. Syn., Vol. 8, pp. 259 and 283.
6. McFadyen-Stevens reduction: J. Chem. Soc. 1936, 584. O R N H NHTs B: R CO2Me NH NH X = OCH3 X=H N O N R CHO NH NH 34% 39% O H
Boger J. Org. Chem. 1988, 53, 1405. (Prodigiosin) - Reactions of Borane (BH3) an electrophilic reagent
Substrate O Carboxylic acids may be selectively reduced in the presence of a wide range of functional groups. RCOOH RHC CHR' RCONR'2 RCHO, RCOR' decreasing reactivity RC N (slow) (very slow, Lewis acid activation required) R B O 3 X
Product RCH2OH RCH2CH(B)R' RCH2NR'2 RCH2OH, RCH(OH)R' RCH2NH2 OH RCH2OH NH2 RCH2OH no reaction or NHOH
Amides may be reduced selectively in the presence of esters.
O RCOOR' NOR RCOCl
RCOO , RNO2 But: see Tetrahedron Lett. 1982, 23, 2475.
119
H. Characteristics of Hydride Reducing Agents

Borohydrides 1. NaBH4 - Review: Aldrichim. Acta 1979, 12, 3. - Mild reducing agent used primarily for the reduction of aldehydes and ketones. - Also available as NaBD4, NaBT4 (although somewhat less reactive) for labelling. - H+ workup of NaBH4 reductions may form BH3 (if excess NaBH4 used) might react with other functional groups (this is the origin of the discovery of BH3 and its hydroboration of alkenes). - NaBH4 reacts with H2O, CH3OH at 25 C ca. 30 min reacts only slowly with EtOH (good solvent), is stable in iPrOH or tBuOH and can also be used in diglyme but the reduction is very slow.
2. NaCNBH3 - Less reactive than NaBH4. - Stable in aqueous solutions - at pH > 3 (permits activation of C=O by protonation). - Can be used in CH3OH. - Can be used in THF but reduction very slow. - Reductive amination: O N R
H2NR
NaCNBH3 pH 3-6
relatively unreactive toward NaCNBH4 R
H+ Under acidic conditions the protonated imine is more reactive than starting ketone or aldehyde.
HN
very good way to make 2 amines
- Review: Comprehensive Org. Syn., Vol. 8, pp 25-78. This review also discusses the diastereoselectivity of cyclic/acyclic imine/iminium reductions with comparisons to the corresponding ketone. Many similarities but also many important distinctions.
120
Reduction Reactions Dale L. Boger 3. LiBH4 - More reactive than NaBH4 (Li activates C=O by coordination). - Can be used in THF, diglyme and non protic solvents. - Excellent reagent for mild reductions. O OEt OH 98%
- clean 1,2-reduction! - NaBH4 does not typically reduce esters 4. Me4NBH4, Et4NBH4 - Soluble in nonpolar aprotic solvents (e.g., THF, benzene). 5. Zn(BH4)2 - Good in instances of potential competing 1,4-reduction. - Zn+2 coordinates to and activates carbonyl. - Good for chelation-controlled reductions. O OH + OH
Zn(BH4)2 NaBH4 - Review: Narasimhan Aldrichim. Acta 1998, 31, 19. 6. NaBH4/CeCl3 (catalytic amount (0.1 equiv))
96% 59%
4% 41%
- Luche J. Am. Chem. Soc. 1981, 103, 5454; 1978, 100, 2226. - Readily enolizable carbonyl can be reduced. - also true of other nucleophiles O RMgBr RLi - clean addition, no enolization O RMgX O R RMgX CeCl3 OH CeCl3 R OH
Imamoto J. Am. Chem. Soc. 1989, 111, 4392.
121
Modern Organic Chemistry The Scripps Research Institute - No conjugate reduction: clean 1,2-reduction. -Reagent comparisions for 1,2- vs. 1,4-reduction O O
Reagent LiAlH4 NaBH4 NaBH4/CeCl3 LiAlH4/CeCl3 DIBAL-H DIBAL-H/nBuLi 9-BBN LiAlH(OMe)3 LiAlH(OtBu)3 7. NaBH4-CoCl2 - Selective reduction of nitriles.
1,2 : 85 : 0 : 97 : 64 : 98 : 99 : >99 : 90 : 0 :
1,4 15 100 3 36 2 1 1 10 100
(100%) (100%) (100%) (99%) (81%) (83%) (85%)
1,2 : 94 : 59 : >99 : 98 : 98 : 94 : >99 : 95 : 22 :
1,4 6 41 1 2 2 6 1 5 78
(97%) (90%) (100%) (100%) (100%) (96%) (85%)
!!! Masamune J. Chem. Soc., Chem Commun. 1970, 213. Brown J. Org Chem. 1977, 42, 1197.
H2N NC CO2Et Ganem J. Am. Chem. Soc. 1982, 104, 6801 - But will also reduce olefins, allylic alcohols, and ketones. OMOM MOMO MOMO OMOM CO2Et
OH Swato Chem. Pharm. Bull. 1990, 33, 361. 8. Me4NBH(OAc)3 and NaBH(OAc)3 - Unreactive, no intermolecular ketone reductions.
OH
- OAc can exchange with substrate alcohol and provides opportunity for intramolecular reductions (CH3CN-HOAc). Used to form anti-1,3-diols from acyclic -hydroxyketones. 9. KBH(OiPr)3 - Stable (does not undergo disproportionation reaction as with other alkoxy BH), mild reagent. - Used in THF and only reduces aldehydes and ketones; bulky reagent so it gives equatorial attack on cyclohexanones.
122
Reduction Reactions Dale L. Boger H B 10. 9-BBN - Stable solid; more stable and less reactive/more selective. - Gives good 1,2- vs. 1,4-reduction selectivity. - Very selective reagent.
11. Li-Selectride 3 BHLi
K-Selectride 3 BHK
- Large reagents, near exclusive cyclohexanone equatorial Hdelivery. - Very bulky. - Very reactive and give preferential 1,4-reduction. O OBR3 can alkylate these enolates
Ganem J. Org. Chem. 1976, 41, 2194. 12. LiBHEt3 (Super Hydride) - Very powerful (stronger than LiAlH4), so good for reductions which are otherwise slow. O H R X R OH H
13. NaBH4-HSCH2CH2SH - Used in THF.
H S B H S
- Guida J. Org. Chem. 1984, 49, 3024. RCO2Et PhCO2iPr PhCO2tBu PhCN PhCONH2 PhCH2NH2 Yet powerful enough to reduce amides RCH2OH PhCH2OH
THF 83%
Note the selectivity available
123
Modern Organic Chemistry The Scripps Research Institute Aluminum Hydrides 14. LiAlH4 - LiAlD4 and LiAlT4 are also available for labelling. - Reductions can be conducted in ether, THF, DME, diglyme. - Workup best conducted by 1,2,3 method: for 1.0 g LiAlH4 used, add 1 mL H2O (slowly) then 2 mL of 10% aqeous NaOH, then 3 mL H2O Al salts are now easily filtered 15. NaAlH4 - Not quite as reactive as LiAlH4, but still quite strong reducing agent. - THF, DME, diglyme solvents. 16. LiAlH(OtBu)3 LiAlH(OEt)3 LiAlH(OMe)3
this is the largest reagent (due to aggregation) of the three
- Use in THF, diglyme. - Review on alkoxyaluminum hydrides: Org. React. 1985, 34, 1; 1988, 36, 249. 17. NaAlH2(OCH2CH2OMe)2 = REDAL-H OH benzene 80 C COOCH3 OH powerful reducing agent
OH xylene 140 C
CH3
OH - Xylene, benzene, toluene good solvents. - Good for epoxide openings (especially if able to be directed by proximal OH), halide and sulfonate reduction.
124
Reduction Reactions Dale L. Boger 18. 2 AlH R - Good for RC N RCHO via H - Because there is no metal cation (Li+, K+, etc.) in the reagent, very good for directed reductions (i.e., chelation-controlled reductions). - Good for 1,2- vs. 1,4-reduction. H CO2Et NBOC 80% H OH NBOC NAl = DIBAL-H
- Also good for RCOOR'
RCHO O Al R OR' H to get RCHO, quench must be conducted at 78 C (use MeOH or HOAc as proton source, H2O freezes into a solid) then warm to 25 C
via
stable at 78 C but breaks down at higher temperatures to give alcohol (upon further reduction)
- Also, use of noncoordinating hydrocarbon solvent (toluene) provides better control than THF for reductions to RCHO. 19. AlH3 AlH3-NR3 - Park J. Org. Chem. 1990, 55, 2968. RCO2H RCH2OH
Cl
CO2Et
Cl
OH OH
O2N O
COCl
O 2N
NMe2
NMe2
CN
NH2
125
Modern Organic Chemistry The Scripps Research Institute 20. Bu3SnH-Bu4NX, X = Cl, F R F R Sn R H
- Shibata Chem. Lett. 1991, 307. Br Br
O O
OH OH
- Can alkylate intermediate directly: O Bu3SnH Bu4NCl OSnR3 OR'
R'X
OCH3 Ph O 21. PhMe2SiH OH Ph OBn Felkin addition 96 : 4 1) PhMe2SiH Ph Bu4NF, HMPA, 0 C 2) KOH 82% O Bu3SnH Bu4NF 81% Ph
OCH3 100% Felkin addition OH
OH 1) PhMe2SiH TFA, 0 C 2) KOH 72% Ph OBn chelation-type control 93 : 7
OBn
Fujita J. Org. Chem. 1988, 53, 5405 and 5415.
22. (EtO)3SiH/catalytic Ti(OiPr)4 - No solvent, stable to air. - Reduces esters to alcohols in the presence of a wide variety of functional groups.
RCO2Et
RCH2OH
- Buchwald J. Org. Chem. 1992, 57, 3751.
126
I. Asymmetric Carbonyl Reductions

- Review: Comprehensive Org. Syn., Vol. 3, pp 159.
- Itsuno Org. React. 1998, 52, 395. 1. Catalytic Asymmetric Reduction - Corey J. Am. Chem. Soc. 1987, 109, 5551. Ph H HN Ph B H O BH3 Ph H Ph H N O H 3B B H H N H3B Ph Ph B H O H 3B N B H Ph Ph O H O RL - Corey J. Am. Chem. Soc. 1987, 109, 7925. (catalytic) - Corey Tetrahedron Lett. 1989, 30, 6275. H N -naph O -naph R >90% ee R R O B N O H 2B H RS vs. RL in plane carbonyl lone pair complexes boron coordinates anti to large substituent (in plane)
H N
Ph Ph O
B H Better catalyst 80-97% ee
RS
RS RL
B R
R = H, Bn, CH3, Bu - Corey J. Am. Chem. Soc. 1994, 116, 8516. H N O R CCl3 Ph Ph B Bu O H OH O BH O N3 H R COCl 80-98% R CCl3
intramolecular H delivery through boat-like T. S.
OH N3
H R
Cl Cl
92-98% ee
N3 H R
H2 Pd-C CO2H 88-98%
H2N H R CO2H
- General, catalytic, enantioselective synthesis of -amino acids. - Corey J. Am. Chem. Soc. 1992, 114, 1906; Tetrahedron Lett. 1992, 33, 3431, 3435. - Review: Corey Angew. Chem., Int. Ed. Eng. 1998, 37, 1985.
127

2. Stoichiometric Reagents for Asymmetric Carbonyl Reductions - Bothner-By J. Am. Chem. Soc. 1951, 73, 846 (camphor ligand and first report of an asymmetric reduction with optically active reagent). Most subsequent efforts have used chirally modified LiAlH4. OH - LiAlH4/N-methylephedrine Ph NMe2 O R HO H R
R = Me 75 % ee R = Et 62 % ee R = iPr 30 % ee R = tBu 36 % ee Mosher J. Am. Chem. Soc. 1972, 94, 9254; J. Org. Chem. 1973, 38, 1870. Me Ph N Li R Al OH R
R= O O > 90% 89% ee
HO H
R-alcohol
- Vigneron Tetrahedron Lett. 1974, 2065; 1979, 2683; Tetrahedron 1976, 32, 939; used in cationic cyclization approach to steroids. - Early work with acetylenic ketones, W. S. Johnson HO O O asymmetric total synthesis of steroids via cation-olefin cyclizations 84% ee O O
Johnson J. Am. Chem. Soc. 1977, 99, 8339. Me2N Me2N N Li AlH2 O O 92% 47% ee Seebach Chem. Ber. 1974, 107, 1748. - LiAlH4/N-methylephedrine/N-ethylaniline or N-ethyl 2-pyridylamine (high ee's for enones: >90% ee) - Koga Tetrahedron Lett. 1980, 21, 2753. HO H
128
Reduction Reactions Dale L. Boger O - BINAL-H Li H O Al O OEt R = Me R = Et R = nPr R OH R
(R) - BINAL-H
95% ee 98% ee 100% ee
R = nBu 100% ee R = iPr 71% ee R = tBu 44% ee
Noyori J. Am. Chem. Soc. 1984, 106, 6709.
O N N O
(S)-BINAL-H 73% 99.9% ee
O N N ()-mappicine OH
Boger J. Am. Chem. Soc. 1998, 120, 1218. Cl B Ipc2BCl O Cl Ipc B H O Ph CH3 Me OH H 72% 98% ee
Midland J. Org. Chem. 1989, 54, 159. Brown J. Org. Chem. 1989, 54, 4504. 3. Enzyme-catalyzed Ketone Reductions have been extensively used in organic synthesis - Review: Comprehensive Org. Syn., Vol. 3, pp 183.
129
J. Catalytic Hydrogenation
- Amine and sulfur-containing groups will tend to poison catalysts (especially Pd/C). H Li/NH3 H O H H H2 - Pd/C P. Sabatier received the 1912 Nobel Prize in Chemistry for his contributions to catalysis, especially the hydrogenations of unsaturated organic compounds. O H 93% : 7% - Comprehensive Org. Syn., Vol. 8, pp. 417 and 533. - Comprehensive Org. Syn., Vol. 8, pp. 471. - Comprehensive Org. Syn. Vol. 8, 479. - Comprehensive Org. Syn. Vol. 8, 524. Solvent EtOH-HCl EtOH DMF EtOAc Et2O hexane MeOH nPrOH tBuOH
cis : trans
93 : 7 53 : 47 79 : 21 57 : 43 58 : 42 48 : 52 41 : 59 68 : 32 91 : 9
1. H2 delivery from least hindered face of double bond. 2. Cis - H2 delivery - activity of catalysts toward C=C: Pd > Rh > Pt > Ni > Ru 3. Increasing substitution on olefin decreases reactivity. - note potential isomerization of olefin and H-migration/allylic exchange in D2/T2 hydrogenations 4. Alkynes are more reactive than alkenes. Reagents have been developed to selectively prepare olefins from alkynes without over reduction: - Lindlar catalyst: Pd(BaSO4) - only reduce alkyne to alkene (cis)
R R R' H
R' H slow
R'
5. Many kinds of catalyst, but most common are 5% ~ 10% Pd/C or PtO2 H2
PtO2
Pto
130
Reduction Reactions Dale L. Boger - PtO2 is particularly good for imine reduction to amines. NR' R R" HNR' R H R"
- Amines will poison Pd/C catalyst, but not Pt(0). - Raney-Ni (Ra-Ni) also useful (especially for removing sulfide groups). - (Ph3P)3RhCl Wilkinson's catalyst (homogeneous). - a homogeneous catalyst (e.g., dissolve in organic solvent for reaction). - Review: Org. React. 1976, 24, 1. - One of the earliest, successful examples of catalytic asymmetric synthesis entailed the homogeneous hydrogenation of enamides to provide amino acid derivatives G. Wilkinson received the Nobel Prize in Chemistry in 1973 for deducing the structure of metallocenes.
CO2H NHAc DIOP 73% ee DIPAMP 34% ee
H2, 1 atm Rh-diphosphine* NORPHOS BPPM 90% ee 99% ee
CO2H NHAc
BINAP 98% ee
BPPFA 93% ee
Kagan J. Chem. Soc., Chem. Commun. 1971, 481. Knowles (Monsato) J. Chem. Soc., Chem. Commun. 1972, 10; J. Am. Chem. Soc. 1977, 99, 5946.
K. Dissolving Metal Reductions

1. Birch Reduction - Reviews: Comprehensive Org. Syn., Vol. 8, 489. Org. React. 1992, 42, 1 (aromatic ring reduction). Org. React. 1984, 23, 1 (carbonyl and enone reductions). H R R' R H R'
trans alkene - most stable product

- First reported by Wooster J. Am. Chem. Soc. 1937, 59, 596. - Extensively developed by Birch Quart. Rev., Chem. Soc. 1950, 4, 69.
131
Modern Organic Chemistry The Scripps Research Institute b. Solvent system - Typical solvent system NH3 : : 2 THF 1 : :
tBuOH
- Liquid NH3 (bp 33 oC) is used to dissolve metal, ether cosolvent (Et2O or THF) is used to dissolve substrate, and a proton source tBuOH; EtOH; MeOH; - If proton source is absent: NH3 NH2 isomerization of diene and overreduction NH2 is used to quench the reaction.
NH2
NH3
further reduction
- Be sure to use an argon atmosphere, not N2 which forms lithium nitrides.
c. Mechanism - Molecular Orbital Calculations: Radom J. Am. Chem. Soc. 1980, 102, 6430. e ROH Lio H H site of greatest e density ROH H H Li H H NH2 H H NH3 Lio Li e
further reduction
132
Reduction Reactions Dale L. Boger d. Regioselectivity - Site of protonation of the radical anion is determined by site of maximum edensity. - Radom J. Am. Chem. Soc. 1980, 102, 4074. OCH3 Li(0) e OCH3 OCH3 ROH
H H OCH3 Li(0) e H H H H OCH3 ROH H H OCH3
anion stabilized by EWGs COOH Li(0) e COOLi Li(0) e H H H H COOLi ROH H H H COOLi COOLi COOLi ROH
D = OH, OR, NR2, SR, PR2 (electron-donating groups) W W
W = COOH
COO
CONR2, SiMe3, Ar (electron-withdrawing groups) - but CO2R, COR, CHO Li/NH3 CH2O , so they are part of donor (D) grouping.
133
Modern Organic Chemistry The Scripps Research Institute e. Common application: hydrogenolysis R Li/NH3 or H2, Pd/C PhCH3 + RO
Ph
5 - 10% Pd on C as catalyst H2 can be replaced by HCOONH4 or as the source of H2 and is a
transfer hydrogenation: Comprehensive Org. Syn., Vol. 8, 955. f. Examples Me Me - Krapcho J. Am. Chem. Soc. 1959, 81, 3658.
CONMe2
CONMe2 - Schultz J. Org. Chem. 1986, 51, 4983.
OMe
OMe
- Dryden J. Org. Chem. 1961, 26, 3237.
O N
OMe N
OMe - Magnus Tetrahedron Lett. 1997, 38, 1341.
OMe
OMe
- can also be used for enone reduction and/or reductive alkylation with alkylative trap of the final enolate
H /H2O MeO H O O MeO Robinson annulation type product used extensively in steroid synthesis.
134
Reduction Reactions Dale L. Boger H O H H CH3O H Li/NH3 dioxane ether NH4Cl CH3O 78% Johnson J. Org. Chem. 1963, 28, 1856. Dryden J. Org. Chem. 1961, 26, 3237. - As opposed to H O H H CH3O H H2 (1 atm) 5% Pd/C EtOH H CH3O H H more stable product trans ring fusion H H H O
cis stereochemistry
O
- or more vigorous Birch conditions: H O H H CH3O H H H O 2. Dissolving Metal Carbonyl Reduction a. Ketone Reduction - Review: Comprehensive Org. Syn., Vol. 8, 107. - Rule: O
tBu
OH H+
Li/NH3 H
tBuOH
H H CH3O H
THF OH
via enone reduction with protonation (ROH present), carbonyl reduction (to give most stable equatorial alcohol) and aromatic ring reduction.
H Li/NH3 Et2O, tBuOH

tBu
OH 98:2
Birch reduction forms the most stable product.
- Exception: Li/NH3 EtOH O sterically hindered or strained ketones 87 endo H OH : : H 13 exo
+ OH
135
Modern Organic Chemistry The Scripps Research Institute - Mechanism: O

tBu
e
tBu
O Li ROH
tBu
OH
Li(0) e
OH
tBu
H ROH
tBu
OH
Li(0)
Li
Special variants of this reaction include the: b. Acyloin Condensation CO2Me (H2C)4 CO2Me Na toluene TMSCl OSiMe3 OSiMe3
Comprehensive Org. Syn., Vol. 3, 613. Org. React. 1976, 23, 259.
- Mechanism: diketyl generation and diradical coupling or: O OMe (H2C)4 OMe O OMe O O O O - Sheehan J. Am. Chem. Chem. 1950, 72, 3376. - Bloomfield J. Org. Chem. 1975, 40, 393. - Bloomfield Tetrahedron Lett. 1968, 591. c. Pinacol Coupling - Review: Comprehensive Org. Syn., Vol. 3, 563. O 2 d. McMurry Coupling Zn-Cu/TiCl3 LiAlH4/TiCl3 Mg-Hg/TiCl4 - diol product McMurry J. Org. Chem. 1977, 42, 2655. olefin product McMurry J. Am. Chem. Soc. 1983, 105, 1660. Corey J. Org. Chem. 1976, 41, 260. O O e O O e O O O e O OMe (H2C)4 OMe O O O OMe e OMe O
136
Reduction Reactions Dale L. Boger e. Radical-Alkyne/Alkene Addition - The ketyl (radical anion) can be trapped in intramolecular reactions: - Stork J. Am. Chem. Soc. 1979, 101, 7107. O O O H Li/NH3 or Na/NH3 O O OH
O O O H f. Reductive Alkylation O CH3 H Li(0) e Li O Li CH3 H O O
O O
OH ROH CH3 H enol radical Li(0) e
Et2O NH3 pKa 35~36 tBuOH pK 16~18 a
ROH second equivalent O CH3 CH3 H H O MeI (E ) CH3 H H regiospecific enolate generation H transfer OH
Li
CH3 H
L. Other Reduction Methods

1. Diimide Reduction - Review: Org. React. 1991, 40, 91. N N H + H CO2H CO2H CO2H H CO2H Me H H CO2H CO2H CO2H H Me CO2H
137
Modern Organic Chemistry The Scripps Research Institute - Mechanism: N N H H H + H N N
(N2)
- Cis delivery of H2 - From least hindered face of olefin - trans > cis olefin (rate) - Rate decreases with substitution of olefin - C=O, NO2, CN, S O , S S
complements H2/cat. same results but: many functional groups are stable to conditions/reagent
stable
O O
KO2CN=NCO2K 78 C
O O
no reduction of endoperoxide
Adam J. Org. Chem. 1977, 42, 3987. - Formation (generation) of reagents (diimide) i. H2O2 /H2NNH2 ii. recent method O H H S N NH O H N N H old method
Me
Base
N N H H
- related to McFadyen-Stevens Reduction. iii. KO2C N N CO2K CO2K cat H 25 C, CO2 (anhydrous) H N N H
N N KO2C
iv. retro Diels Alder reaction
NH NH - Example of use: H H N N
NH NH
Ph
Br
Ph
Br
- Other reduction methods would give substantial debromination.
138
Hydroboration-Oxidation Dale L. Boger
VII. Hydroboration - Oxidation (Reduction - Oxidation)

- Review: Comprehensive Org. Syn., Vol. 8, pp. 703-732.
A. Mechanism
H R + R'2BH R BR2' H2O2 NaOH R H OH + B(OH)3
OH R' B R' O OR' B OR' O
H R
R' B R' O O H
H R
H R
- anti-Markovnikov addition of H2O to C=C
H H H B B H H H
BH3 BH3
H B
H B
- rate - Increased by electron-donating substituents on olefins. - Increased by strain of olefins. - Increased by decreased steric hinderance of olefins. The reaction is characterized by a slight tendency for H (H) to add to carbon most capable of stabilizing a charge or, in other words, for the nucleophilic carbon to attack the electrophilic B. However, it is also characterized by a nonpolar transition state where the rate of reaction and regioselectivity are determined principally by steric factors with unsymmetrical olefins.
BH3 BH )2
B2H6 diisoamylborane (Sia2BH) H. C. Brown (Purdue University) received the Nobel Prize in Chemistry (1979) for the discovery and development of the hydroboration reaction.
BH2 H B
thexylborane (ThxBH2)
9-BBN
139
B. Regioselectivity
1. Steric Effects C4H9CH CH2 BH3THF Sia2BH 9-BBN 6 : 94 1 : 99 0.1 : 99.9 C6H5CH CH2 19 : 81 2 : 98 H H C C CH3 43 : 57 5 : 95 0.2 : 99.8 CH2 <1 >99 2 98
- diisoamylborane
larger than BH3THF and more selective.
2. Electronic Effects X BH3THF X + BR2' H X=H OCH3 Cl CF3 81 93 73 66 : : : : R CH3 19 7 27 34 BR2' H X
R1 R2 100 : 0
OEt Me3Si 95 : 5 R2
CH3 CH3 R = iPr R = SiMe3
= = Me R1 = R2 = Et
R1
43 : 57 5 : 95 95 : 5
BH3 Sia2BH BH3
Me3Si 50 : 50 5 : 95 0 : 100
vs (BH3) (Sia2BH) (9-BBN)
Bu 6 : 94 1 : 99 0.1 : 99.9
C. Diastereoselectivity
1. Endocyclic Olefins CH3 Me
tBu
2% 13% H CH3 - predominant attack from least hindered face.
Me
tBu
H 36% 48%
140
Hydroboration-Oxidation Dale L. Boger - cis addition H B - from least hindered side - least substituted position H3C
tBu
H CH3 H B H 38% 43% H H

tBu
H
tBu
with BH3THF
tBu
tBu
H Me H 57% Better with bulkier boranes Me
with BH3THF
Me Me
H 62% with BH3THF 2. Exocyclic Olefins 33% R 67% 3. Acyclic Olefins OR R1 Me Me BH3THF R1 larger than CH3 R1
OH
OR
Me
Me
OH O Me H CH2OBn Me 1) BH3THF 2) H2O2, NaOH O Me 89% de Kishi J. Am. Chem. Soc. 1979, 101, 259. (Monensin) CH2OBn Me
B H Me H H Me OR
Considering the top case: attack on least hindered face of H-eclipsed conformation R1/BH2 interactions are worse than Me/BH2 interactions
R1
Kishi Aldrichim. Acta 1980, 13, 23. Burgess Tetrahedron Lett. 1989, 30, 395.
141
Modern Organic Chemistry The Scripps Research Institute 4. Allylic Alcohols and Ethers - Cyclic allylic alcohols and ethers.
OR
OR OH +
OR + OH
OR OH +
OR
OH 2 0 0 1 8 1 10 19 13 9 13 11
R=H R = Bn R = SiMe2tBu
83 68 74
18 7 2
5 72 13 72 13 86
9-BBN
catechol borane/Rh(I) Evans J. Am. Chem. Soc. 1988, 110, 6917.
H OR H H H B
Minor 9-BBN reaction: OR H H Major - Least hindered face opposite alkoxy group. - Regioselectivity avoids a R2B/H 1,3-diaxial interaction.
- Acyclic allylic alcohols and ethers OR

nBu
OR 1) 9-BBN 2) H2O2, HO +
nBu
OR OH
nBu
OH Me
Me
syn
R=H R = TBDMS 8 11
anti
92 89
- Reaction takes place from H-eclipsed conformation and cis to the smaller OR group.
minor H3C
nBu nBu
H H H
B attack on face syn to smaller alkoxy substituent in the H-eclipsed conformation. B
RO
H H B major
H3C RO
major
142
Hydroboration-Oxidation Dale L. Boger
D. Metal-Catalyzed Hydroboration
- Diastereoselectivity can be reversed with catecholborane and Rh(I) catalyst (i.e., Wilkinson's catalyst). O OR
nBu
BH O Rh(I)
nBu
OR + OH Me syn 75 96
nBu
OR OH Me anti 25 4
R=H R = TBDMS - Exocyclic allylic alcohols and ethers OR 1) 9-BBN 2) H2O2, HO
OR OH +
OR OH
R=H R = TBDMS
50 39 9-BBN
90 96
50 61
10 4
catecholborane/catalytic Rh(I)
Evans J. Am. Chem. Soc. 1988, 110, 6917. B H 9-BBN No distinguishing steric interactions B H -Review of transition metal-catalyzed hydroboration: Beletskaya and Pelter Tetrahedron 1997, 53, 4957. B H H L B Rh L O Cl O reductive elimination H B Rh L O Cl O
RO
RhClL3
RhClL2
+L
L B Rh L Cl
RhClL3
- This was utilized in the synthesis of the unusual L-gulose sugar found in the disaccharide of bleomycin A2 key step: inversion of stereochemistry to convert readily available D-mannose to L-gulose derivative BH O (Ph3P)3RhCl 82% 50:1 HO HO OBn O OBn bleomycin A2 OAc
O HO HO OH
D-Mannose
OBn OH HO
OBn OAc
OBn
143
E. Directed Hydroboration
Ph2PO O 1. O 2. H2O2, NaOH 3. Ac2O > 10:1, 55% Ph P Ph O B H OAc > 50:1, 82% B H OAc OAc Ph Ph P B O
Ph2PO
O 1. O 2. H2O2, NaOH 3. Ac2O B H
OAc
Evans J. Am. Chem. Soc. 1988, 110, 6917. versus OH catechol borane major OH catechol borane OH OH OH
F. Asymmetric Hydroboration
major
OH
BH HB (
BH2
BH
)2
Masamune J. Am. Chem. Soc. 1985, 107, 4549.
Dilongifolyborane (Lgf2BH)
trans-2,5-dimethylborolane
IpcBH2
Ipc2BH
monoisopinocamphenylborane
- Brown Tetrahedron 1981, 37, 3547; J. Org. Chem. 1981, 46, 2988; 1982, 47, 5065. OH CO2Me Ipc BH 2 45% 95% ee CO2Me
O O 1. MsCl 2. NaOH
prostaglandins
Partridge J. Am. Chem. Soc. 1973, 95, 7171.
144
Hydroboration-Oxidation Dale L. Boger OH NBOC
NBOC
OBn
1. Ipc2BH 2. NaBO3 73% 83% ee
NBOC
OBn Boger Synlett 1997, 515.
Type I
Type II
Type III
Type IV
% ee for Asymmetric Hydroboration Type I Ipc2BH 30 IpcBH2 1.5 Lgf2BH borolane 1.4
II
98
24
78
95
III
13
73
97
IV
14
53
70
94
IV
22
66
62
97
- Models H M M H Me H
IpcBH2
H L M Me H H H H Me
Ipc2BH
L L H H Me
145
146
Enolate Chemistry Dale L. Boger
VIII. Enolate Chemistry

Enolate Alkylations:
Comprehensive Org. Syn., Vol. 3, 1.
Formation of Enolates: Comprehensive Org. Syn., Vol. 2, 99. Aldol Condensation:
Comprehensive Org. Syn., Vol. 2, 133, 181 and 239.
Reformatsky Reaction: Comprehensive Org. Syn., Vol. 2, 277. Acylation of Enolates: Enol Ethers: Metalloenamines: Hydrazones:
Comprehensive Org. Syn., Vol. 2, 796. Comprehensive Org. Syn., Vol. 2, 595 and 629. Comprehensive Org. Syn., Vol. 2, 475. Comprehensive Org. Syn., Vol. 2, 503.
A. Acidic Methylene Compounds (i.e., Malonates)

- -Deprotonation pKa ~20 O H base O O RX alkylation formation of C-C bond
Keq
- Use of a base which stoichiometrically deprotonates the ketone completely: (i.e. Keq > 100) O ONa + pKa = 17 O NaNH2 is Keq > 100? O+ H+ + NH3 pKa = 35
Ka = 10-17
NH2O
H+
NH3 O-
Ka = 1035
NH2-
NH3
1018
Therefore, a good deprotonation (essentially all ketone deprotonated) Note: need to have pKa difference of 2 pKa units to get Keq = 100.
147
Modern Organic Chemistry The Scripps Research Institute 1. Estimation of pKa H C
W = Cl W= O
inductive stabilization , NO2, etc. resonance stabilization H
O CH3 pKa = 20; CH3 pKa = 45;
pKa = 35-37
- an increase in acidity of H results in a faster deprotonation (kinetic effect) as well as a stabilization of anion formed (thermodynamic effect).
H R R W
Group (-W) alkyl halogen
pKa effect (units) ~1-2 ~1-2 ~5-7 (decrease in acidity)
Note both due to inductive effects
~5-7 RS ~3-5
both depend on favorable orbital overlap to allow resonance stabilization
Others: NO2 > COR >SO2R > CO2R, CN > SOR, Ph
Compound O CH3 O O OCH3 O O O O H O H H 2O O H 2C H O CH3 NR H NR2 O H
p Ka 20 13 11 9 5 14 25
Note
ketone better enolate stabilizer than ester
~same as acetic acid
15
148
Enolate Chemistry Dale L. Boger 2. Ketone-Enol Tautomerism
O R CH3 R
OH CH2 - generally << 1% enol
OH R
E+ R
O E CH2
CH2 << 1%
- Usually not likely to form a bond with an electrophile since not present in high concentration - However, some ketones do exist in high enol concentration and react via enol
Compound O
Enol content
0.0004% O
< 0.002% OH CO2Et CO2Et 40% (neat) 60% (EtOH)
O 100%(neat) 95% (H2O) 2-14% (cyclohexane)
OH OH
O CO2Et
CO2Et
10-13% (EtOH) 50% (cyclohexane)
intramolecular H-bond
OH O
16% (H2O) 63% (EtOH) 92% (cyclohexane) 3% (H2O) 31% (EtOH) 55% (cyclohexane)
OH O
149
Modern Organic Chemistry The Scripps Research Institute - If a compound has a vinyl spacer, the reactivity parallels that of the parent compound.
1,3-Cyclohexadione in its enol form is a vinylogous carboxylic acid and it exhibits many properties of a RCOOH, including low pKa, O-alkylation. O O ~ = OH OH
OH
O base O O
nBuBr
O
nBu
O + OH OnBu 37% VINYLOGY RULE analogous to RCOOH -> RCOOnBu
15%
O Nuc
O analogous to RCOCl -> RCONuc Cl Nuc
vinylogous acid chloride
3. Acetoacetic Ester Synthesis
O OCH3
NaOCH3 CH3OH
ONa O OCH3
nBuBr,
O OCH3
nBu
pKa = 13 NaH THF O
nBuBr
pKa =16 stable, can be isolated (deprotonation equilibrium
74%
K = 99.9 -> 99% deprotonated)

O OCH3
nBu
~70%
NaH: strong base, operates in range up to pKa = 35. Sometimes kinetically slow, sometimes difficult to reproduce. It is insoluble and the reaction is heterogeneous. Thought that trace OH might be active base. Therefore, deliberately add 0.05-0.1 equiv. CH3OH to obtain reproducible reaction.
150
Enolate Chemistry Dale L. Boger - The product can be further alkylated:
O H pKa now 1-2 units higher than parent
O
nBu
i) NaH OCH3 ii) nC5H11Br
O
nBu
O
nC H 5 11
OCH3
80% concentration of parent enolate vs. concentration of product enolate in monoalkylation reaction is very high (> 90:10) -> monoalkylation fairly clean.
- Hydrolysis and decarboxylation gives -substituted ketones: H
O CH3 R
O NaOH R' OCH3 then H3O+ workup CH3
O R
O O R'
180-220 C CH3
O R' R
4. Malonic Ester Alkylation
i) NaOMe, MeOH CH3O2C CO2CH3 ii) RX CH3O2C
R CO2CH3
NaOH CH3O2C
R CO2CH3
75-90% NaOH R HO O H O (CO2) RCH2COOH requires higher temperature than acetoacetate decarboxylation O R NaO2C CO2Na R NaOH CH3O2C CO2Na CH3O2C COONa R
H3O+
NC O CH3OOC
NC
CN related stabilized enolates
SO2Ph
CH3OOC
CN
can be removed reductively
151
Modern Organic Chemistry The Scripps Research Institute 250 C no reaction HO2C O O O H O OH violates Bredts Rule, bridgehead olefin
5. Enolates: C- vs. O-Alkylation
- Ketones which are more acidic tend to give more O-alkylation. e.g. O 37% O-alkylation 15% C-alkylation OH CH3 OH + 66 100 : : 33 0
OH
NaOH CH3X
OCH3
X=I - The more reactive the alkylating agent, the more O-alkylation observed X = OTs
O - Rarely see O-alkylation of ketone enolates often see O-alkylation of stabilized enolates e.g., -diketones and -keto esters
localized, harder anion
softer, more diffuse anion reacts with softer alkylating agents (RI, RBr)
- tends to react with harder electrophiles (CH3OTs, Me3OBF4 ) Meerwein's salt more reactive or more ionized = harder
- Intramolecular constraints can affect course of C- vs. O-alkylation
HO NaOH
O H
OTs
OTs
100%
152
Enolate Chemistry Dale L. Boger Cl N N H Cl N MeO2C N H OH O R NaH MeO2C O duocarmycin SA N H O OH R N N H O R
NaH
O (+)-CC-1065
OH
N O
R DEAD-Ph3P Mitsunobu alkylation MeO2C N H OH
N O
Boger Chem. Rev. 1997, 97, 787.
- Mitsunobu alkylation Mitsunobu, Yamada, Mukaiyama Bull. Chem. Soc., Jpn. 1967, 40, 935. Review: Mitsunobu Synthesis 1981, 1. Hughes Org. React. 1992, 42, 335; Castro Org. React. 1983, 29, 1. - Mechanism: Ph3P OPPh3 R1 R2 + + EtO2CN NCO2Et EtO2CNH NHCO2Et HX X SN2 displacement R1 EtO2CN NHCO2Et PPh3 X X R2 R1
OH R2
HX: pKa typically <15 (RCO2H, phenols, imides, malonates, -keto esters) Related reagents including Ph3P/CCl4, Ph3P/NXS are used to convert an alcohol to the corresponding halide. - Factors which favor O-alkylation 1. Polar solvent: HMPA O Me2N P NMe2 NMe2 CH3 O S CH 3 polar, aprotic solvents: a. separate metal cation from enolate oxygen, making oxygen more free to react b. coordinate electrophile, activate and increase their reactivity c. increase rate of reaction
DMSO
DMF
Me2NCHO
2. Large, noncoordinating metal cation: - again, frees up oxygen to react M+ O R' R M = R4N >K > Na > Li
O-alkylation
C-alkylation
rate of reaction
ion pair separation of charge, harder more reactive anion
lithium essentially covalently coordinated to O
153
Modern Organic Chemistry The Scripps Research Institute 3. Aggregation/Solubility: Homogeneous, monomeric enolates Heterogeneous, aggregate enolates Li enolates tend to be more aggregated O H R 4. Structure of alkylating agent a. Leaving group: (hard alkylating agents) for R-X: (soft alkylating agents) R'
O-alkylation C-alkylation
hard for RX to get to O atom, so reacts at C
X = Me3O > OTs > Cl > Br > I
O-alkylation
O COOCH3
nBuX
C-alkylation
O COOCH3
nBu
K2CO3 100 C
OnBu COOCH3
Solvent
X Cl Cl Cl Cl Br I
C- : O-alkylation rel % products

90 : 10 81 : 19 53 : 47 54 : 46 67 : 33 >99 : 1
O-alkylation
Polarity of solvent
acetone CH3CN DMSO DMF
For C-alkylation: I > Br > Cl
DMF DMF
b. Degree of substitution of alkylating agent: O COOEt RBr no solvent O COOEt R

nC
3H7Br
OR + COOEt
97 73
: :
3 27
more sterically hindered, so "harder"
Br
Br ,
Ph
Br
mainly C-alkylation
154
Enolate Chemistry Dale L. Boger O + OH X O O
works well in polar, aprotic solvents (ie., HMPA, DMSO), or even K2CO3, acetone will work
B. Enolate Structure
- Actually exist as higher aggregates in solution: dimer-tetramer. - Originally suggested by House J. Org. Chem. 1971, 36, 2361. - Supported by NMR studies: Jackman Tetrahedron 1977, 33, 2737. - Confirmed by X-ray: Dunitz Helv. Chim. Acta 1981, 64, 2617.
see also: Seebach J. Am. Chem. Soc. 1985, 107, 5403. Lynch Tetrahadron Lett. 1989, 30, 447. 1.99 A 1.94 A Li Li CH3 CH3 CH3 1.45 A
tBu
Li O
1.35 A CH2 1.34 A
tetramer aggregates bond lengths, angles much like those of enol ether.
1.477 A O 1.495 A O 1.356 A 1.378 A 1.659 A
tBu
O vs 1.35 A O Li
1.407 A 1.304 A
t Si BuPh2 1.37 A
Ketone Enolates: O Ph OM Ph M negative charge, M+ on oxygen. Note: not really an equilibrium; these are resonance structures.
Keq < 1 for most metals (Li, Na, K, MgX, ZnX)

> 1 for M = HgI
155
Modern Organic Chemistry The Scripps Research Institute Ester Enolates: OR M OM O OR
Keq < 1 for Li
Keq > 1 for ZnBr (Reformatsky reagents)
C. Enolate Alkylations: -Facial Stereoselectivity

1. Stereoelectronic Effects - The attacking electrophile must obey the principle of maximum overlap of the participating orbitals by perpendicular approach to the plane of atoms which constitute the enolate (enol) function.
E+ R1 M O H R2 E
E+ R1 O H R2 R2 OLi
R1 H
- Also applies to protonation in reprotonation reaction:
R1 M O
H R2
H+ -H+
H H R2 O R2 R1 H
- Nucleophilic addition to carbonyl compound takes place not at 90 (perpendicular) but at an angle of 105 5 Dunitz Tetrahedron 1974, 30, 1563. - Same applies to enolate alkylations LUMO of E+ electrophile angle not 90 R2 H O R'
enolate HOMO
156
Enolate Chemistry Dale L. Boger - Ramifications:

tBu
trans
O or H
O
tBu
LDA
tBu
OM
E+
tBu
cis
E O
O H H base removal of axial proton

tBu
E+ predominant trans product observed OM axial attack proceeds through a chair-like T.S.
- In order to get cis, must proceed through a boat-like T.S.!
tBu
H
tBu
cis
OM E E+
- Therefore
E
OM
O E O E
Energy of activation for formation of the more stable cis product is higher because it involves a boat-like T.S.
reaction coordinate Corey, Sneen J. Am. Chem. Soc. 1956, 78, 6269 (origin of axial alkylation). They also introduced the term stereoelectronic effect to describe this behavior. This was the pioneering work that led to the now widespread predictions about reactions and reaction products based on orbital alignment or overlap and provided the term "stereoelectronic" effect.
157
Modern Organic Chemistry The Scripps Research Institute - Examples of stereoelectronic control axial alkylation chair-like transition state O
tBu tBu
equatorial alkylation via twist boat T.S. H H O

tBu
E+ A
R E+ E+ A O
tBu
E E+ E
OM
OM
tBu
O
tBu
O +
tBu
R E
E R
House J. Org. Chem. 1968, 33, 935. Caine J. Org. Chem. 1969, 34, 3070.
M Li Li Li Li Li Li
R H H H H Et Me CN COOCH3
E Et3O+BF4 EtI MeI DOAc HOAc CD3I CH3I CH3I
axial 51 54 55 70 80 70 77 83 : : : : : : : :
equatorial 49 46 45 30 20 30 23 17
less reactive enolates (so more selective)
Li Li
Kuehne J. Org. Chem. 1970, 35, 161, 171.
2. Steric Effects H - Stereoelectronic effects equivalent for exocyclic enolates. - Relatively insensitive to alkylating agent and conditions. Behavior as a large reagent preferring equatorial delivery. - Transition states for enolate alkylations are thought to be REACTANT-LIKE. House J. Org. Chem. 1968, 33, 943. Krapcho J. Org. Chem. 1980, 45, 3236. H
tBu
E+ ax
COX X OM eq eq
tBu
E major product E
H H
E+
ax
tBu
COX minor product
X CH3 OCH3 OCH3
E MeI MeI
nBuBr
eq : ax 25 C 78 C 78 C 85 : 15 84 : 16 87 : 13
158
Enolate Chemistry Dale L. Boger OLi E+ R O E via R R E+ OLi H major E+
D. Enolate Generation
1. Soluble Bases - NaNH2, LiNH2, KNH2 strong bases, but insoluble in conventional organic solvents
- Soluble secondary amine derived bases

nBuLi
N H pKa = 35
pKa 45
N Li
= LDA
readily available, soluble; amine byproduct is low MWt, volatile, and easily removed. The anion is also nonnucleophilic (relatively hindered)
- Aggregates: Williard J. Org. Chem. 1993, 58, 1. - Other widely used bases:
= N Li
Lithium isopropylcyclohexylamide (LICA) very hindered base
N Li
Lithium 2,2,6,6-tetramethylpiperidide ("FAT ALBERT", LTMP) very hindered
Me3Si
N M
SiMe3
M = Li
Lithium hexamethyldisilazide (LHMDS or LHDS)
= Na Sodium hexamethyldisilazide (NaHMDS) =K Potassium hexamethyldisilazide (KHMDS)
N Li adamantyl adamantyl
now available Corey Org. Syn. 1987, 65, 166.
N Li
Collum Tetrahedron Lett. 1993, 34, 5213.
159
Modern Organic Chemistry The Scripps Research Institute Reviews: Conia House Fleming Fleming Fleming d'Angelo Evans
Rec. Chem. Prog. 1963, 24, 43. Rec. Chem. Prog. 1967, 28, 99. Chimica 1980, 34, 265. Synthesis 1982, 521. Synthesis 1977, 509. Tetrahedron 1976, 32, 2979 (Methods for regiospecific enolate generation). Asymm. Synthesis, Morrison, Ed., Vol. 3, 1.
2. Kinetic and Thermodynamic Enolates LDA O (TMSCl quench) OTMS + 84% kinetic enolate 7% OTMS + 9% OTMS
Et3N TMSCl DMF, 60 h
13%
58%
29%
thermodynamic enolate H Ph3CLi (1.05 equiv) (TMSCl trap) H conditions for kinetic enolate formation 13 O H Ph3CLi (0.95 equiv) HMPA some ketone always present, so deprotonation-reprotonation equilibrium 3. Regiospecific Enolate Generation - In the above case, the 2,3 enolate cannot be cleanly obtained directly, but other approaches to this have been developed. H Li, NH3 O TMSCl TMSO H isolated MeLi LiO Me4Si H H conditions for thermodynamic enolate formation 53 : 47 : 87 TMSO H + TMSO H H
See: Stork
J. Am. Chem. Soc. 1961, 83, 2965; 1965, 87, 275.
160
Enolate Chemistry Dale L. Boger - Representive enolate selectivities: O CH3CCH2Bu 100 0 (LDA, 78 C) O CH3CCH2Me 71 O CH3CCH2N 29 (LDA, 0 C) O Me CH3CCH Me 99 1 (KHMDS, 78 C) O CH3 18 O Me Ph CH3 N C CO2CH3 H2 82 (LDA, 78 C)
O Me MeCH2CCH Me
Me Ph
95 O
5 (LDA, 0 C) Ph N
75
25 (LDA, 78 C) O
CO2Me
LDA: 33 : 67 (kinetic) LHMDS: 2 : 98 (thermodynamic)
99 : 1 (LDA, 0 C)
>99 : 1 (LDA, 78 C)
Albizati J. Am. Chem. Soc. 1990, 112, 6965. O OCH3 O NMe2 Me Bu 85 : 15 (LDA, 78 C) 98 : 2 (LDA, 78 C) 91 : 9 (LDA, 25 C) 98 : 2 (LHMDS, thermodynamic) Albizati J. Am. Chem. Soc. 1990, 112, 6965. O C OMe CH3 O
CH3
O C
CH3
CH3
100 : 0 (LDA, 78 C) O CH3
100 : 0 (LDA, 78 C) O O
CH3 100 : 0 (LDA, 78 C) Me 20 : 80 (LDA, 78 C) Me
OnBu 100 : 0 (LHMDS, 78 C)
O Me 100 : 0 (LDA, 78 C)
O CH3 0 : 100 (NaH, 100 C) thermodynamic enolate formation
Taken from: Evans Asymm. Synthesis, Morrison, Ed., Vol. 3, 1.
161
Modern Organic Chemistry The Scripps Research Institute - Enantio- or diastereoselective protonation of ketone enolates deprotonation: Majewski Can. J. Chem. 1994, 72, 1699. Simpkins Tetrahedron Lett. 1992, 33, 8141. 1989, 30, 7241. protonation: Fehr Angew. Chem., Int. Ed. Eng. 1994, 33, 1764. 4. Cyclic Carbonyl Compounds - site of deprotonation - enolate geometry fixed O CH3 OM CH3 + OM CH3
Base LDA (0 C, THF) KHMDS (78 C) Ph3CLi (78 C) potassium bases not as effective for kinetic enolate generation. Ph3CK (78 C) Ph3CLi NaH Ph3CK 5. Acyclic Carbonyl Compounds - Two issues: i. site of deprotonation ii. geometry of enolate formed
Control kinetic " " " thermodynamic " "
Selectivity 99 95 90 67 10 26 38 : : : : : : : 1 5 10 33 90 74 62
cis
OM CH3 OM
Z-enolate (Zusammen)
O R CH3
trans
R CH3 - Also: the enolate has two diastereotopic faces: For E-enolate looking from this face R Me M O R Me
E-enolate (Entgegen)
OM counterclockwise = si
si face
re face
looking from this face
MO
R Me clockwise = re
162
Enolate Chemistry Dale L. Boger - ASIDE: Geometry of enolate can be determined by Claisen rearrangement:
Z-enolate
O R O
OTMS R O
OTMS
E-enolate
- Claisen rearrangement known to proceed through chair-like T.S.: OTMS R Me relative amounts easily determined by 1H NMR OTMS H R O R Me OTMS O O
Me H
OTMS
Z-enolate
Me
E-enolate
A. Acyclic Ketones Me Me O Me Me OLi Me + Me OLi
Base very hindered amide base LTMP (78 C) LTMP/HMPA LDA LICA LHMDS (PhMe2Si)2NLi
Z
14 92 23 35 66 100 : : : : : :
E
86 8 77 65 34 0 kinetic enolate thermodynamic enolate
163
Modern Organic Chemistry The Scripps Research Institute - Thermodynamic enolate formation Me Me OLi HMPA Me + Me O Me Me O Me + Me OLi
or may take place by reversible aldol addition
OLi
Rathke J. Am. Chem. Soc. 1980, 102, 3959.
O R1 R2 R1
OLi R2 +
LiO R1 R2
Z-enolate
E-enolate
R1 Et Note: As R1 becomes sterically more demanding, Z-enolate increases or predominates even under kinetic conditions. Et Et
iPr iPr iPr tBu tBu
R2 Me Me Me Me Me Me Me Me Me Ph Ph Ph LDA LTMP LTMP-LiBr LDA LTMP LTMP-LiBr LDA LTMP LTMP-LiBr LDA LTMP LTMP
Z
23 14 2 37 33 5 98 95 95 7 8 3
E
77 86 98 63 67 95 2 5 5 93 92 97 best conditions for E-enolate (kinetic)
Note: As R2 becomes sterically more demanding, E-enolate selectivity increases under kinetic conditions: Ph > Me.
tBu
Z-enolate only very large R1
Me Me Me
Collum J. Am. Chem. Soc. 1991, 113, 9571.
164
Enolate Chemistry Dale L. Boger B. Acyclic Esters - Similar to ketones: O R1O R2 R1O OLi R2 OLi + R1O R2
Z
thermodynamic enolate (more stable)
E
kinetic enolate
R1 Me
tBu
R2 Me Me Et Et Et Et
base LDA LDA LDA LDA/HMPA LDA LDA/HMPA
Z
5 5 9 84 5 77
: : : : : : :
E
95 95 91 16 95 23 kinetic thermodynamic
Me Me
tBu tBu
Role of HMPA: increase rate of equilibration, break up enolate aggregation
Ireland J. Org. Chem. 1991, 56, 650 and 3572. kinetic E-enolate OLi CO2Et OEt 94 7 15 + OEt : : : 6 93 85 thermodynamic Z-enolate OLi
LDA LDA LDA
THF THF-45% DMPU THF-23% HMPA
165
Modern Organic Chemistry The Scripps Research Institute - Silyl Ketene Acetals Otera Synlett 1994, 213. O OR R = tBu EtMe2C Ph3C LDA LDA LDA R3SiCl OSiR3 + OR >99 97 >99 : : : 1 3 1 OSiR3 OR
LDA
99
iPr
LDA LDA LDA LDA LDA-HMPA or DMPU " " " " "
83 83 84 87 4 3 13 13 26 28
: : : : : : : : : :
17 17 16 13 96 97 87 87 74 72
bornyl Et Me Me Et bornyl
iPr
EtMe2C
tBu
C. Acyclic Amides give only Z-enolate O R2N R1 R2N OLi R1 + R2N LiO R1
Z-enolate
R Et R1 CH3 base LDA LDA
E-enolate E
: : 3 3
Z
>97 >97
(CH2)4 CH3
166
Enolate Chemistry Dale L. Boger 6. Ireland Transition State Model for Deprotonation - For Cyclic Ketones: a
J. Am. Chem. Soc. 1976, 98, 2868.

O b R
a H O R1 N R1 Li H A LiNR21
b R O R1 N R1 Li H B 1,3-diaxial R, R1
OLi R R1-H interaction < R1-R interaction ketone R = CH3 Ph OCH3 NMe2 base LDA LDA LDA LDA A vs. 99 : 1 >99 : 1 85 : 15 98 : 2 B
OLi R
1,3-diaxial interaction
iPr, iPr, iPr, iPr,
CH3 Ph OCH3 NMe2
- More hindered bases (tBu2NLi, LiHMDS, LTMP) would increase selectivity for kinetic enolate formation (1,3-diaxial interactions even larger in T.S. for thermodynamic enolate formation) - For Acyclic Ketones, Esters, and Amides: O X H O R1 N R'1 Li H O H Me H X a Me LiNR12 b R1 N Me X A (1,2) strain (torsional strain) OLi Me in most instances, kinetically favored X Me 1,3-diaxial interaction R1 Me O Li H H very little A (1,2) strain X
LiO X
E-enolate
Z-enolate thermodynamically more stable enolate
167
Modern Organic Chemistry The Scripps Research Institute - Example: O X Me X Me LDA LiO + X OLi Me
E-enolate
Z-enolate
X OCH3 OtBu Et
iPr tBu
LDA
E:Z
95 : 5 95 : 5 77 : 23 40 : 60 0 : 100 0 : 100 0 : 100 X getting larger, so A (1,2) steric interaction outweighs the Me/R1 1,3-diaxial interaction Me/R1 1,3-diaxial interaction worse than Me/X A (1,2) interaction
Ph NEt2
- NOTE: model only applicable for conditions which would promote coordination of base (Li cation) with carbonyl. It breaks down with polar solvents, crown ether, HMPA conditions for deprotonation.
E. Alkylation Reactions: Stereochemistry

1. Exocyclic Enolates i. 1,2-Stereocontrol in Exocyclic Enolates OM X R H E+ R H major OM X R allylic (1,3) strain E+ X R E O X + H R E O X
E+ OM
R COX E
for R = CH3, X = OMe G > 3.7 kcal/mol R OM H R X H OM X R COX E
H-eclipsed conformation
168
Enolate Chemistry Dale L. Boger COOCH3 Me LDA MeI Me COOCH3 Me + Me COOCH3 Me
Krapcho J. Org. Chem. 1980, 45, 3236. COOCH3 Me
80 Me COOCH3 Me
20 Me COOCH3 Me
LDA MeI
95
: Me COOEt Me +
5 COOEt Me Me MeO
COOEt Me MeO Ph3CNa MeI 82% MeO 98
Hogg J. Am. Chem. Soc. 1948, 70, 161.
- Also true for other common ring sizes:
CO2Me OMe OMe LDA Br 72%
CO2Me OMe OMe >95 : 5
Heathcock Tetrahedron Lett. 1979, 2115. CO2Me LDA MeI 92% 85 Clark Syn. Commun. 1979, 325. O H O O H H ii) RX reductive alkylation R = CH3 R = Et Weiss, Coscia Tetrahedron 1964, 20, 357. i) Li, NH3 tBuOH (0.95 equiv) O O 65% 43% only product H H H O R Me CO2Me + Me CO2Me
15
169
Modern Organic Chemistry The Scripps Research Institute ii. 1,3-Stereocontrol CO2Me LDA H R MeI R major R = CH3 R = OCH3 Krapcho J. Org. Chem. 1980, 45, 3236. E+ H H R reactive conformation E+ 90 78 : : + H R minor 10 22 H MeO2C Me Me CO2Me
OM OMe R
OM OMe
E+ equatorial delivery of electrophile
but axial R group
iii. 1,4-Stereocontrol Me COOCH3 LDA MeI H R R = tBu OCH3 Krapcho J. Org. Chem. 1980, 45, 3236. E+ H H R eq E+ reactive conformation Again, equatorial attack predominates due to destabilizing steric interactions for axial approach of electrophile. OM OR1 ax OM OR1 R H R 84 84 : : + H R 16 16 Me
COOCH3
CH3OOC
170
Enolate Chemistry Dale L. Boger House J. Org. Chem. 1968, 33, 943. Ziegler, Wender J. Am. Chem. Soc. 1971, 93, 4318. CN LDA MeI
tBu tBu tBu
Me CN +
Me CN
7176% COOH Li, NH3 0.95 equiv

tBu tBuOH tBu
2429% R COOH R COOH +

tBu tBu
LiO
OLi RX then H3O+
Van Bekkum Recl. Trav. Chim. Pays-Bas 1971, 90, 137. E+ Me Me Me OM H E+ Surprising given the distance, but Schllkopf subsequently put such observations to effective use. OM
RX MeI EtBr
iPrBr
45 88 93
: : :
55 12 7
Steric Effects?
pronounced effect of size of alkylating agent on stereoselectivity.
2. Endocyclic Enolates a. 1,2-Stereocontrol OM R2X R1 H R1 major R2X MeI MeI Br 88 75 89 : : : 12 25 11 O R2 + H R1 H O R2
R1 vinyl group sterically smaller, so stereoselectivity lower

nBu
CH=CH2 Me
Posner J. Am. Chem. Soc. 1975, 97, 107. Coates J. Org. Chem. 1974, 39, 275.
E+ R1 H axial attack preferred on stereoelectronic and steric grounds
LiO
ax H E+
171
Modern Organic Chemistry The Scripps Research Institute b. 1,3-Stereocontrol O NaOtAm CH3I 70% O CH3
trans delivery
tBu
tBu
Conia Bull. Soc. Chim., Fr. 1966, 3881 and 3886.
73 : 27 - tBu group in preferred equatorial position
NaO E+ c. 1,4-Stereocontrol OLi CH3

tBu
Rt
Bu
- axial attack favored on stereoelectronic basis no steric bias for either face
O CD3I
tBu
CH3 CD3
O +
tBu
CD3 CH3
83 House J. Org. Chem. 1973, 38, 1000. E+ axial

tBu
17
preferred stereoelectronic approach from most stable conformation with tBu equatorial
Me H d. 1,5-Stereocontrol O Ph Me
OLi
tBuOK
PhO Me one isomer
MeI >95%
Ireland J. Org. Chem. 1970, 35, 570.
Ph MO Me E+ reaction from preferred conformation where Me group vs Ph adopts pseudo axial position
preferred stereoelectronic approach
172
Enolate Chemistry Dale L. Boger 3. Other Conformationally Inflexible Systems - Exocyclic Enolates of a Fixed Conformation
MeI 74% H LiO OMe H CO2Me more severe 1,3-diaxial interaction E+ Welsch J. Org. Chem. 1977, 42, 2879; J. Am. Chem. Soc. 1977, 99, 549. CH3 OMe OLi E+ E+ exo endo LiO E+ E+ OLi H E+ Equilibration: - Confined Endocyclic Enolates R CD3I LiO H via E+ H H But LiO H stereoelectronic preference for axial alkylation LiO H E+ preference for equatorial alkylation through twist boat H O CD3 H 83 5 : : E+ CH3 R + R Ph3CNa MeI H 97 47 : : 3 53 Corey J. Am. Chem. Soc. 1962, 84, 2611. OMe LDA MeI Me COOMe + H Me This leads to a further enhancement of the preferred equatorial delivery of electrophile. >100 : 1
- Exocyclic Norbornanes
COOMe
97 : 3 strong exo preference Krapcho J. Org. Chem. 1980, 45, 3236. O Me O H Me
H CD3 17 (R = H) 95 (R = CH3) severe 1,3-diaxial steric interaction
Matthews J. Chem. Soc., Chem. Commun. 1970, 38 and 708.
173
Modern Organic Chemistry The Scripps Research Institute E+ Me

-
Me vs. O H E+
O H
- Similarly R MeI LiO H Me NC O - Predict the major product for Me base RX R O H O
Me
R + H R = H 79 : 21 R = Me 6 : 94 + 9:1 NC O Me O Me
H R Me
CN
Kuehne J. Org. Chem. 1970, 35, 161.
base O R1X R H R = CN, CO2Me
? Kuehne J. Org. Chem. 1970, 35, 171. Morris J. Org. Chem. 1972, 37, 789.
Stork J. Am. Chem. Soc. 1961, 83, 2965; 1965, 87, 275. OLi MeI H H 20 : O Me + H 80 axial attack H H H OLi O Me
House, Trost J. Org. Chem. 1965, 30, 2502. H O Ar H MeI

tBuOK
O Me Ar H 32 : +
O Me Ar H 68 O Me Ar + H
H equatorial attack (preferred)
O Ar MeI
tBuOK
O Me
Ar
H removes one 1,3-diaxial interaction for axial alkylation through chair-like T.S.
H 90 :
10
174

4. Conjugate Addition/Alkylation: Stereochemistry - There are also many examples of tandem conjugate addition/alkylation reactions and conjugate reduction/alkylation reactions that combine elements of both the conjugate addition or reduction with the subsequent alkylation.
Li N S
tBu tBu
1Li
N S R1
R2X
R2 N S
tBu
R1
R2X
tBu
BT H R1Li axial attack

tBu
H H R1
S N Li
R2
tBu
N R1 S
Corey and Boger Tetrahedron Lett. 1978, 5, 9, and 13.
F. Asymmetric Alkylations
Conformational or Intraannular Chirality Transfer 1. Schllkopf asymmetric amino acid synthesis: O HO NH2 N (S)-valine CH3O N Li OCH3 alkylation on face opposite iPr group (1,4-stereocontrol) E+ then H3O+ > 90% de H2N O E OH
Angew. Chem., Int. Ed. Eng. 1979, 18, 863; 1981, 20, 798 and 977. Liebigs Ann. Chem. 1981, 696 and 2407. Synthesis 1981, 966 and 969.
2. Seebach: HO
O R OH
tBuCHO
O HO R E OH
H3O+ O
O E O
tBu
R but restored by virtue of alkylation diastereoselectively
O R O
tBu
OLi H LDA E+
tBu
O O
R chirality destroyed
Seebach J. Am. Chem. Soc. 1983, 105, 5390. Frter Tetrahedron Lett. 1981, 22, 4221.
175
Modern Organic Chemistry The Scripps Research Institute Chelation Enforced Chirality Transfer 3. H OH R COOR' LDA (1st equiv) H OLi R COOR' LDA (2nd equiv) O R H OH O R E E+ = =
nBuBr
H Li O H
OR'
E+ OR' H R
Li
Li OR'
Br
96 : 4 97 : 3
Z-enolate (note that normally get E-enolate from esters)
removal of axial proton (much more sterically accessible)
Seebach Angew. Chem., Int. Ed. Eng. 1981, 20, 971. Helv. Chim. Acta 1980, 63, 197, 2005. Frter Tetrahedron Lett. 1981, 22, 425. Helv. Chim. Acta 1979, 62, 2825; 1980, 63, 1383. Kraus Tetrahedron Lett. 1977, 18, 4575. 4. Evans' chiral imide auxiliaries: J. Am. Chem. Soc. 1982, 104, 1737.
N-acyl oxazolidinones
O N O LDA E+ from face opposite iPr group Li O O alkylation R N O O R H N E O O
O R
Z-enolate
E+ = BnBr, 120 : 1
- and O R N Me O O Ph LDA R O
Li O N E+ Me O Ph alkylation opposite Me and Ph group R H O N E Me Ph O O
Z-enolate
Access to either enantiomer new chiral centers created which have opposite absolute configuration.
- Factors responsible for high diastereoselectivity: a. formation of Z-enolate (exclusively). b. chelation results in formation of rigid template, single conformation. c. -facial selectivity results from sterics of alkylation.
176
Enolate Chemistry Dale L. Boger Extraannular Chirality Transfer 5. Schllkopf Liebigs Ann. Chem. 1981, 439. H-eclipsed H Me Ph N N O R LDA H Me N Ph OLi R N Ph Br -60 C H Me N Ph O R N Ph
>95 : 5 R = CH3, BnBr, 94%, >97 : 3 R = Et, BnBr, 85%, 97.5 : 2.5 RS Stereoelectronic Steric Me Me Me Me Me Me Me Me Me Me RL OEt OPh
tBu
(E+ = D2O) 10 : 1 10 : 1 9:1 8:1 7.5 : 1 7:1 5:1 3:1 2.3 : 1 1.4 : 1 See: Mohrig J. Am. Chem. Soc. 1997, 119, 479. RS E with control of enolate geometry available, reaction via H-eclipsed conformation might be facially selective. To date, this has not been extensively examined with acyclic systems. H RL R O R
OtBu StBu OMe CF3 Ph

iPr
Et
6. Schllkopf Tetrahedron Lett. 1979, 20, 3929. Me N Ph H LDA E+ Me LiN Ph H E+ Me N Ph H E E+ = MeI, 3.2 : 1
Through Space Interactions/Blocking Groups 7. H O R O H O O R
with certain esters of chiral alcohols, could see enantioselectivity via conformational control
H and carbonyl are eclipsed in much preferred conformation
177
Modern Organic Chemistry The Scripps Research Institute Me N Ph R' Me R' N O Ph O H H O H OLi E+ E-enolate
re face is blocked
O O H O H O
LICA THF kinetic enolate generation
H's eclipsed with carbonyls in ground state conformation
si face alkylation
LICA THF-HMPA thermodynamic enolate generation (via equilibration) Xc O
R' H E 1
Me HN O Ph O R' H O H OLi E+
H E+ (si face attack) Xc O 2 R' E
Z-enolate
R' CH2Ph Me Me solvent THF THF THF-HMPA E+ MeI BnBr BnBr 1:2 95 : 5 94 : 6 30 : 70 yield 95% 96% 96%
lower diastereoselectivity due to inability to generate exclusively the Z-enolate (70:30 = Z : E formed) Helmchen Angew. Chem., Int. Ed. Eng. 1981, 20, 207. Tetrahedron Lett. 1980, 21, 1137. 8. Catalytic asymmetric alkylation: Corey Tetrahedron Lett. 1998, 39, 5347. BrPh N Ph O OtBu + RX 1 (10 mol%) CsOHH2O O Ph N Ph H R O OtBu N H N + H O
R= ee (%)
-(CH2)4Cl 99
-(CH2)2CO2CH3 95 99
-(CH2)2COEt 91
Additional examples of asymmetric alkylations may be found in the sections discussing enolate equivalents.
178
G. Aldol Addition (Condensation)

R3CHO R2 + H R1 OM R3 R2 OH O R1 + R3 R2 OH O R1
1. Nomenclature
syn (or threo)
anti (or erythro)
syn/anti erythro/threo Summary IUPAC Others
J. Am. Chem. Soc. 1981, 103, 2106. (supercedes erythro/threo nomenclature) Angew. Chem., Int. Ed. Eng. 1980, 19, 557. Asymm. Synth. Vol. 3, pp. 111-212. (Review of aldol diastereoselection) Pure. Appl. Chem. 1976, 45, 11. Angew. Chem., Int. Ed. Eng. 1966, 5, 385. (based on Cahn, Ingold, Prelog) Angew. Chem., Int. Ed. Eng. 1982, 21, 654. (Seebach, Prelog) J. Org. Chem. 1982, 47, 3811. (Carey, Kuehne)
2. Generalizations R3CHO R2 + R1 Z-enolate OM R3 R2 OH O R1
syn
(or threo)
R3CHO
OM + R2 R1 R3
OH O R1 R2
E-enolate
anti
(or erythro)
1. Z-enolates give predominantly syn (or threo) aldol products (thermodynamic enolates). 2. E-enolates give predominantly anti (or erythro) aldol products (kinetic enolates). and 3. 4. 5. 6. Diastereoselectivity (for syn aldol) of Z-enolates is greater than that of E-enolates (for anti). Correlation for E or Z-enolate is greater when R1 is sterically demanding. Correlation is stronger when R3 is large (most important for boron enolates). Correlation is reversed when R2 is sterically demanding (very large).
- Advances in 1H NMR, 13C NMR permitted detection, quantification and identification. - Issue of equilibration addressed. R. R. Ernst received the 1991 Nobel Prize in Chemistry for the development of the methodology of high resolution NMR spectroscopy.
179
Modern Organic Chemistry The Scripps Research Institute 3. Examples O LDA + EtO CHO E-enolate formation EtO EtO O OH O OH
anti 90-93%
syn 7-10%
- Steric size of R1 affects diastereoselectivity OMg OH O PhCHO Ph
syn:anti >98:2
note: R1 = tBu > iPr
- Z-enolate
OLi PhCHO Ph OLi OH O OH O
syn:anti 90:10
PhCHO Ph
syn:anti 45:55
note: Z > E, stereoselectivity much lower with E-enolate
OLi
PhCHO Ph
OH O Ph
syn:anti 88:12
> 98:2 Z:E OLi CH3 OH O Ph H3C 87:13 Z:E OLi CH3 PhCHO Ph H3C 92:8 E:Z CH3 OH O Ar CH3 Ar
PhCHO
syn:anti 88:12
anti:syn 92:8
note: larger R1 helps maintain high selectivity dictated by enolate geometry and substantially enhances E-enolate diastereoselectivity
Heathcock J. Org. Chem. 1980, 45, 1066.
180
Enolate Chemistry Dale L. Boger 4. Origin of Diastereoselectivity - Zimmerman-Traxler Model (J. Am. Chem. Soc. 1957, 79, 1920) - Chair-like, closed transition state: metal coordination to both carbonyls a. Z-enolates R3 R2 HO H H R1 O O R3 R2 M O H O H R3 R2 M O H R1 R2 HO H R3 R1 O
H H R1 syn (major)
1,3-diaxial interaction (destabilizing) anti is minor diastereomer
OH O R3 R1 R2 Major product (syn)
gauche interaction R2 R3 H O M O H R1 H H
R2 O M O R3 R1 1,3-diaxial interaction R3
OH O R1 R2
1. Diastereoselectivity for Z-enolate (giving syn aldol product) is maximized when R1 and R3 are sterically demanding (R1/R3 interaction is maximized). 2. Diastereoselectivity also increases as metal is changed to boron. This is attritubted to a tighter T.S. (BO bond shorter, so R1/R3 steric interactions are magnified in T.S. for anti product). 3. When R2 is very large the R3/R2 gauche interaction > R1/R3 1,3-diaxial interaction (Why?). LiO MgO ZnO AlO BO TiO ZrO b. E-enolates H HO O R3 2 R R1 H H M 1.922.00 2.012.03 1.922.16 1.92 1.361.47 1.621.73 2.15
Diastereoselection: B > Li > Na > K
O R3
O H
O R R3
2
H M
O H R1
H HO R2 R3 R1
R2 H R1 anti (major)
1,3-diaxial interaction syn (minor)
OH O R3 R1 R2 Major Product (anti) gauche interaction
H R3 R2 O M O H R1 H R2 gauche interaction
H O M O R3 R1 1,3-diaxial interaction R3
OH O R1 R2
syn
1. Diastereoselectivity increases as R1 and R3 become sterically large, and a switch to the boron enolate will increase selectivity. 2. Diastereoselectivity may switch when R2 is very large (Why?).
181
5. Cyclic Ketones - Only E-enolate and therefore anti aldol. - Aldol addition is reversible, can get very different stereoselectivity by allowing reaction products to equilibrate (and equilibration can be very fast). O base + CHO for kinetic aldol product E-enolate O H OH + O H OH
anti anti:syn
>95:5 >95:5 30:70
Dubois:
base LiOH KOH Me4N+OH-
syn (stabilization of adduct via coordinating countercation)
thermodynamic ratio
- Instructive examples: Majewski House Heathcock OLi + PhCHO
Tetrahedron Lett. 1989, 30, 5681. J. Am. Chem. Soc. 1973, 95, 3310. J. Org. Chem. 1980, 45, 1066.
O OH Ph + O OH Ph
anti
52:48
syn
widely quoted - but really is the result of equilibration: Tetrahedron Lett. 1989, 30, 5681. ratio OLi + R O H O OH Ar + O OH Ar
anti
R=H THF DME Et2O THF THF THF THF 84 72 76 73 78 94 74 : : : : : : :
syn
16 28 24 27 28 6 26 75% 50% 84% 68% 68% 67% 80%
THF > DME
R = NMe2 R = OCH3 R = Ph R = CF3
OLi +
tBu
O PhCHO
tBu
OH Ph +
OH Ph axial attack
tBu
anti
1. E-enolate -> anti aldol. 2. Axial attack of enolate (stereoelectronic control). THF 81 Et2O 75 Et2O-HMPA 68 : : :
syn
19 25 32 63% 61% 68%
182
Enolate Chemistry Dale L. Boger 6. Acyclic Enolates - Effect of R1 OLi R1 + PhCHO
syn : anti aldol
syn : anti ratio

R1 OMe OtBu H Et iPr Ph tBu mesityl 7. Refined and Alternative Models - Idealized closed, chair transition state does not account for Z > E diastereoselectivity nor does it explain the switch in diastereoselectivity when R2 is sterically demanding. - Transition state for addition more closely resembles eclipsed conformation. - Dubois, Fellmann Tetrahedron Lett. 1975, 1225; Tetrahedron 1978, 34, 1349. - Heathcock J. Org. Chem. 1980, 45, 1066. - For Z-enolate R2O M O H R1 H H R2O M O R3 R1
Z-enolate 1.0 9.0 9.0 7 70 >50
E-enolate 1.5 1.0 1.5 1.5 1.0 <0.02
typically: Z > E diastereoselection diastereoselection increases as size of R1 increases
syn
R2/R3 gauche
R3 H
anti
R1/R3 interaction even worse than in staggered
interaction is further minimized - For E-enolate HO M O H R1 H R2 HO M
Z>E diastereoselectivity
anti
R3 R2
O R3 1 R
syn
nearly eclipsed much worse than gauche interaction As R2 increases in size, R2/R3 interaction competes with or surpasses R1/R3 interaction
E < Z diastereoselectivity diastereoselectivity reverses when R2 becomes sterically demanding
- Burgi-Dunitz approach angle -skewed approach - R2/R3 come closer together than R1/R3 R2 H R3 H R1 OLi O 109
183
- An additional alternative explanation considers the boat transition states Evans Top. Stereochem. 1982, 13, 1. - In addition to the four idealized closed chair transition states, four closed boat transition states must be considered as well. - Z-enolate R2/R3 eclipsed R2/H eclipsed H O R3 H O R1 R3/H eclipsed R1 R2 M O
2 R3 R M
syn aldol
H H O H/H eclipsed
anti aldol
- E-enolate R3/H eclipsed
- when the R2/R3 gauche interaction is large in chair TS, Z-enolate boat TS might become competitive leading to the anti aldol H/H eclipsed H O R3 R1 R2 O H M
anti aldol
R3 H R2
H O
syn aldol
R2/H eclipsed
R1 R3/R2 eclipsed
- However, the boat transition state alternative does not explain the E-enolate switch from anti to syn aldol when R2 becomes sterically more demanding.
- Examples OMgBr R CH3CHO 0 C O R OH O R OH
E-enolate
Dubois, Fellmann C. R. Hebd. Seances Acad. Sci. Ser. C. 1972, 274, 1307. R = Me = Et = iBu = iPr = tBu
anti
93.5 87.5 80 46 29 : : : : :
syn
6.5 12.5 20 54 71
anti:syn ratio decreases smoothly as R becomes larger (R2 in models above)

O
tBuCHO
OLi
tBu
OH
tBu tBu
OH
tBu
Et2O, 20 C
tBu
Z-enolate
R = Me = Et = nPr = iBu = iPr = tBu
R anti 0 0 2 3 71 100 : : : : : :
R syn 100 100 98 97 29 0
184
Enolate Chemistry Dale L. Boger 8. Boron Enolates - Often much more diastereoselective in their aldol addition reactions - This results from a shorter B-O bond length, tighter transition state
OB(Bu)2 R1
R2CHO R2
OH O R1 R2
OH O R1
Z-enolates (syn aldol) syn

R1 = Me R1 = PhCH2 R1 = Ph R1 = Ph R1 = Ph R2 = Ph R2 = Ph R2 = Ph R2 = Et R2 = iPr
anti
>95:5 for all cases
OB(Bu)2 R1
R2CHO R2
OH O R1 R2
OH O R1
E-enolates (anti aldol)

R1 = Me R2 = Ph 1 = PhCH R2 = Ph R 2 R1 = Ph R2 = Ph
syn
25:75 20:80 25:75
anti
Z > E diastereoselection
Masamune Tetrahedron Lett. 1979, 1665.
E-enolates give lower diastereoselectivity
a. Z-enolate Preparation and Reactions O R1 R2BOTf

iPr NEt 2
OBR2 R1
PhCHO Ph
OH O R1
78 C
Z-enolate
R1 = Et R1 = Et R1 = Ph R1 = Ph Bu2BOTf, 78 C BOTf, 0 C
2
syn aldol
>97:3 syn/anti 84:16 syn/anti >97:3 syn/anti >95:5 syn/anti
>97:3 82:18 >95:5 >99:1
9-BBNOTf, 0 C BOTf, 0 C
2
185
Modern Organic Chemistry The Scripps Research Institute b. E-enolate Preparation and Reactions O Me R1 R2BOTf
iPr NEt 2
OBR2 R1 Me
PhCHO Ph
OH O R1
anti aldol
44:56 syn/anti 18:82 syn/anti
R1 = iPr R1 = iPr
Bu2BOTf, 78 C BOTf, 0 C
2
45:55 Z:E 19:81 Z:E
- originally difficult to control but: O Me StBu R2BOTf

iPr NEt 2
OBR2 StBu Me E-enolate >95:5 >95:5
PhCHO Ph
OH O StBu
Masamune Tetrahedron Lett. 1979, 2225. Bu2BOTf, 0 C BOTf, 0 C

2
anti aldol
10:90 syn/anti 5:95
syn/anti
E-enolates very accessible using tbutylthiol esters

c. Examples of more recent methods to control boron enolate geometry OBBN R R B O H B HR H O H RR OBChx2
Z
iPr NEt 2
E
R
9-BBN-Cl/
(hindered base) Z-enolate thermodynamic enolate E1 elimination mechanism Cl-B(Chx)2
Cl-B-Chx2/Et3N E-enolate kinetic enolate E2 elimination mechanism
BCl
2
OB(Chx)2 i) PhCHO ii) H2O2 workup >99% E OBBN
OH Ph
Et3N, 0 C
>95:5 anti:syn O i) PhCHO ii) H2O2 workup OH Ph
9-BBN-Cl
iPr NEt, 2
0 C >99% Z
98:2 syn:anti
-These results are difficult to achieve with boron triflates Brown J. Am. Chem. Soc. 1989, 111, 3441.
186
Enolate Chemistry Dale L. Boger - Examples BCl O 9-BBN-Cl 99:1 (Z:E) O >99:1 O 98:2 (via equilibration) O 96:4 (via equilibration) O 99:1 (via equilibration) 21:79 <1:99 <1:99 15:85
2
<1:99 (Z:E)
Z-enolate is easy to access: thermodynamic enolate E-enolate is less stable, more difficult to generate without equilibration (also still difficult to prepare unless alkyl groups are bulky).
- see also Brown J. Org. Chem. 1992, 57, 499 and 2716. Brown J. Org. Chem. 1994, 59, 2336. O R OEt Chx2BX
iPr
2NEt
OBChx2 R OEt
OBChx2 OEt R : : : : : :
or Et3N CCl4 X=I X = Br X=I X=I X=I X=I Chx2BI
Z
>97 84 95 <3 <3 <3 OBChx2 OR
E
3 17 5 >97 >97 >97 OBChx2 OR
R = CH3 R = CH3 R = Et R = iPr R = tBu R = Ph O OR
CCl4
Z
R = CH3 R = Et R = iPr R = tBu Et3N iPr NEt 2 Et3N iPr NEt 2 Et3N iPr NEt 2 Et3N iPr NEt 2 >97 >97 >97 >97 86 64 59 3 : : : : : : : :
E
<3 <3 <3 <3 14 36 41 97
187

9. Aldol Condensation with Chiral Aldehydes a. Felkin Addition - Two faces of aldehyde are diastereotopic. - Nucleophilic addition of enolate follows Cram's empirical generalization (Felkin-Ahn addition). H H RL O Felkin model - Example: OM Ph + CHO Ph R OH O R + Ph OH O R RM Nu H H RL RM O Nu major H H RMOH RL RL Nu RM Nu OH
invariant diastereoselectivity with different size of R MO R H H Ph Me O O R H H Ph Me O major
syn 3
O R
anti
: 1
syn
Ph
H H MeOH
Ph H Me MO R O H
H Me R O
Ph O H minor Me H Ph H OH O R
anti
- Can combine all selectivities to give 3 contiguous chiral centers, if the chiral aldehyde and enolate partners are both highly diastereoselective. OLi
tBu
Ph
CHO
Ph OH O
tBu
Ph OH O
tBu
A
tBu
B
tBu
- A & B represent 2,3 syn products (from Z-enolate with large R group)
Ph OH O
Ph OH O
- A & C represent 3,4 syn products (from Cram/ Felkin-Ahn addition to aldehyde)
experimental: A:B:C:D = 86:14:0:0 Heathcock J. Org. Chem. 1980, 45, 1066. - syn aldol reaction proceeds with >98% syn selectivity - Cram/Felkin-Ahn addition proceeds with 86:14 syn selectivity
188
Enolate Chemistry Dale L. Boger b. Chelation Control OLi + R CHO OTBDMS R OH O OTBDMS + R OH O OTBDMS
syn, syn
R = Ph 81 :
syn, anti
19
Z-enolate (with large R group) gives clean syn aldol product for both.
R = CH2OTBDMS
>98% syn aldol, 81:19 Cram addition
21
79
>98% syn aldol, 79:21 chelation-controlled addition to RCHO Explanation of Chelation Control 1. without chelation control OLi Ph H H O Me OTBDMS Me H H Nu Nu Nu H H Ph 2. with chelation control Li O O
+
O Me
OLi
syn, syn aldol condensation

H OTBDMS
Me Me O H H Me OH 3,4 syn Ph Ph
4 3
OTBDMS
OH O
M OTBDMS Me
Li O O
M OTBDMS Me
syn, anti aldol syn, syn aldol

TBDMSO H
TBDMSO H
H H Me
H H Me
nucleophilic addition opposite to larger (Me) substituent -drawn another way H O H Me OR minor Li O OR major
severe Me/Me interaction
backside attack H Me H H RO Me H Li O RO Me Nu
OH 3,4 anti
189
Modern Organic Chemistry The Scripps Research Institute 10. Aldol Condensation with Chiral Enolates Evans' Chiral N-Acyl Oxazolidinones B N O O R R1CHO O O only Z-enolate (independent of conditions) N R O O N R or OH R1 O R Bu2BOTf
iPr NEt 2
OH R1
O O N
O O
1. Experimental results O O N O Me Bu2BOTf R1CHO O O N Me O OH
two possible syn aldol products (relative to chiral center on aux.) O O N Me O
OH R1
R1
R1 = nBu R1 = iPr R1 = Ph
99.3 99.8 >99.8
: : : * no anti adducts
0.7 0.2 <0.2
Evans J. Am. Chem. Soc. 1981, 103, 2876 and 3099.
2. Origin of diastereoselectivity - Z-enolate (boron-enolate/amide) gives syn aldol B O O H N H H O O CH3 R (minor syn aldol product) Xc Me R - H-H interaction - steric interaction with iPr (facial selectivity) - aligned dipoles less favorable O OH H R Me Aldehyde R group equatorial (axial would give anti aldol) O O N H R Me H O O B O O H HN B Chair transition state non-chelated Z-enolate O O
H N O O
B O O CH3 H H R
observed syn aldol product Xc O Me OH
R - chiral auxiliary rotates - non-chelated enolate: opens coordination site on boron required to complex and activate aldehyde
190
Enolate Chemistry Dale L. Boger 3. For the alternative enantiomer O Auxiliary with the opposite absolute configuration or the more accessible O Ph B N Me R= R = iPr R = Ph
nBu
O Me RCHO O Ph
O N
OH R Me
Me
>99.8 >99.8 >99.8
syn : <0.2 : <0.2 : <0.2
: : :
anti : 0 0 : 0 0 : 0 0
O - Note: selectivity not good for Xc - Solution: use removable substituent Xc O SMe H
Evans aldol overrides any chiral aldehyde directing preference: i.e. Felkin-Ahn preference.
As before - two possible transition states for syn aldol product formation B O O CH3 Me R observed syn aldol product
Me Ph O N
Xc
O OH
H R H O - anti carbonyl conformation O O H Ph N H H Me H B O O CH3 R
Xc Me
O OH R
- syn carbonyl conformation - steric interactions between H's
(minor syn aldol product)
Note: Availability of oxazolidinone alternatives Fujita J. Org. Chem. 1986, 51, 2391. Crimmins J. Am. Chem. Soc. 1997, 119, 7883. Advantages: S > O for chelation and more readily cleaved
S X N
O R X=O X=S
191
Modern Organic Chemistry The Scripps Research Institute 4. Ti enolate promoted Evans aldol (non-Evans syn aldol) Ti O O N O R LDA ClTi(OiPr)3 or TiCl4 Et2O vs. THF as solvent O O N O R R1CHO O N R O O OH R1
Z-enolate and chelated enolate higher coordination sphere of Ti
syn : 87
anti : 0
Thornton J. Am. Chem. Soc. 1989, 111, 5722; 1991, 113, 1299. Evans J. Am. Chem. Soc. 1991, 113, 1047. Thornton J. Org. Chem. 1991, 56, 2489.
syn aldol product but opposite absolute stereochemistry (non-Evans syn aldol).
5. Origin of diastereoselectivity - chelated Z-enolate Ti O O H N H H O O CH3 R H R Me O O H N R H Ti O O CH3 H H H Me O H RN O O O H HN O O O
Chelation orients chiral auxiliary in opposite orientation
Ti
syn
Closed, chair transition state with chelated Z-enolate O
anti
Ti
steric interaction 6. Chelated and non-chelated Ti enolates OH O R Me N S
O 1 equiv TiCl4 O 2.5 equiv TMEDA N Bn
iPr NEt 2
OH O N Me
S O
O 2 equiv TiCl4 R RCHO
or sparteine Bn RCHO Evans syn via non-chelated Z-enolate O H N Bn Cl Cl Cl Ti O Cl O S H H Me R
Bn non-Evans syn via chelated Z-enolate
O H +Cl -Cl Bn H N H R Me O O S Cl Ti Cl Cl
Crimmins J. Am. Chem. Soc. 1997, 119, 7883. 7. Anti-selective additions - see also Aldrichchimica Acta 1990, 23, 99; J. Org. Chem. 1991, 56, 5747.
192
Enolate Chemistry Dale L. Boger 11. Asymmetric Aldol Reactions - Review: Paterson Org. React. 1997, 51, 1. Corey J. Am. Chem. Soc. 1990, 112, 4976. Corey J. Am. Chem. Soc. 1989, 111, 5493.
CF3 Ph F3C Ph
F3C CF3 Corey OH O R Me OtBu
N S N S B O O O Br O
O OtBu
Et3N R*2BBr Me
OBR*2 OtBu
RCHO
E-enolate (kinetic enolate)

toluene-hexane CH2Cl2 in plane lone pair oriented away from ester via: Br + O
tBu
anti aldol
93% 90%
R = Ph R = Ph
anti:syn 98:2 96:4
94% ee 89% ee
O Me E2 elimination
E-enolate
H Et3N non-hindered base
O SPh
iPr
2NEt
Me
OBR*2 SPh
RCHO R
OH O SPh Me
CH2Cl2
Z-enolate
R = Ph 93%
syn aldol anti:syn 99:1

97% ee
via: Br
SPh+ B H O Me H Br
B Me O H
SPh+
E1 elimination H
iPr NEt 2
Z-enolate (thermodynamic)
hindered base
193

Facial selectivity: Me R H Ph - Chair transition state - Boron enolate - Z-enolate Ar O O H S Ar SO2 N Orientation determined by the phenyl groups Ph Ph Ph
B N SO2
Ar S N N SO2 B O2 Ar O O Me SPh R H H
Ph
Examples Corey Tetrahedron Lett. 1993, 34, 1737. O X OBR*2 X Yield 82% 78% 82% 94% OH O Ph Config. S S S S X ee 64% 80% 73% 52%
R2*BBr
PhCHO
X = SPh X = OtBu X = StBu X = StBu
CH2Cl2, iPr2NEt CH2Cl2, iPr2NEt CH2Cl2, iPr2NEt toluene, Et3N
OBR*2 O X R2*BBr X OBR*2 X
PhCHO Ph
OH O X 1 Me OH X Ph Me 2a Me 2b ee 97% 95% 94% 94% 97% 97% 81% 94% 50% 46% O X
PhCHO Ph
OH O
Note: Z-enolate E-enolate
X = SPh X = SPh X = OtBu X = OtBu X = OBn X = OBn X = SBn X = SBn X = StBu X = StBu
CH2Cl2, iPr2NEt toluene, Et3N CH2Cl2, iPr2NEt toluene, Et3N CH2Cl2, iPr2NEt toluene, Et3N CH2Cl2, iPr2NEt toluene, Et3N CH2Cl2, iPr2NEt toluene, Et3N
Yield 90% 78% 89% 64% 73% 78% 79% 84% 73% 86%
syn:anti Major Prod. 99:1 1 94:6 1 4:96 2a 2:98 2a 84:16 1 15:85 2a 70:30 1 9:91 2a 71:29 1 6:94 2b (+ 2a)
see also- Corey Tetrahedron Lett. 1992, 33, 6735.
194
Enolate Chemistry Dale L. Boger - Mukaiyama Chem. Lett. 1973, 1011; review Org. React. 1982, 28, 203. - Carreira's catalytic asymmetric aldol O +
tBu
OSiMe3 OMe
R1
1.1 (2-5 mol%) OH O 10 C R1 OMe 2. Bu4NF ee: 97% 95% 97% 94% 95% 96%
Aldehyde N O Ti O O O
tBu
Br O
Me Me Ph
CHO CHO CHO CHO C6H11CHO PhCHO
tBu
Ph
Carreira J. Am. Chem. Soc. 1994, 116, 8837.
- Evans C2-symmetric bisoxazoline catalysts O R1O O N Me3C N Cu 2 O 2 OTf O R1 Me Bn tBu Me Me Et R2 R2 Me Me Me Et iBu iBu + OSiMe3 2 (10 mol%) R2 OH O 78 C R1O StBu StBu 1N HCl O ee: 99% 99% 99% 94% 94% 36%
CMe3
Evans J. Am. Chem. Soc. 1997, 119, 7893.
O EtO O N Bn TfO Sn 3 N OTf Bn O O H + R1
OSiMe3 3 (10 mol%) 78 C EtO SR2 1N HCl O R1 R2 H Me Et iPr iBu iBu iBu Ph Ph Ph Ph Ph tBu Et
OH O SR2 R1 ee 98% 95% 95% 95% 98% 96% 92%
anti:syn 90:10 92:8 93:7 92:8 96:4 92:8
- review of catalyzed enantioselective aldol reaction Tetrahedron Asymm. 1998, 9, 357.
195
Modern Organic Chemistry The Scripps Research Institute 12. Enzyme-Catalyzed Aldol - see: Comprehensive Org. Syn., Vol. 2, 455. - Wong aldolase based synthesis of carbohydrates and aza-sugars
O HO OP = DHAP O FDP aldolase DHAP O H OH Rham-1-P aldolase DHAP PO OH OH H2 / Pd-C R = N3 HO H3C O OH R H N HO OH R PO OH OH OH R 1. Phosphatase 2. H2 / Pd-C R = N3 OH H N HO O
HO HO OH
R = OH
HO
OP HO OH L-Fructose 1-P
- Review: Wong Pure Appl. Chem. 1993, 65, 803.
- Lerner catalytic antibodies - wide range of donors and acceptors utilized - commercially available 38C2 Acceptor O O H Donor Product OH O >99% >99% ee 33F12 ee
O H
OH
O >98% 89%
OH
OH O >95% >95%
O Lerner J. Am. Chem. Soc. 1998, 120, 2768.
196
H. Aldol Equivalents
1. Chiral Organoboranes Brown: B
2
de% 1. CH3CHO, 78 C 2. OH, H2O2 oxidative cleavage gives typical aldol product 1. CH3CHO, 78 C 2. OH, H2O2 CH3 OH 99
ee% yield% 95 78
B
2
OH
99
95
75
CH3 Brown J. Am. Chem. Soc. 1986, 108, 293.
Roush: O
iPrO C 2 iPrO C 2
O OHC O O B Me toluene, 78 C 4A sieves O O OH
de% 80
ee% yield% 84 80
Roush and Halterman J. Am. Chem. Soc. 1986, 108, 294.
A H Me R H O
O O B O
OR
B O H Me R H O B
CO2R
CO2R
O O
OR
- asymmetric induction is a consequence of n/n electronic repulsive interactions disfavoring transition state B relative to transition state A 2. Allylsilanes Reviews: Fleming Org. React. 1989, 37, 57. Panek Chem. Rev. 1995, 95, 1293.
A. Chiral allylsilanes yield E-olefins selectively R3Si H R H H H R H R3Si H

+
Anti-SE'
R
E H
H H R3Si R
H H H R3Si
H
+R
Anti-SE'
H
E E R
A 1,3 -strain
197

- Chiral allylsilanes add to carbonyls in syn fashion (either synclinal or antiperiplanar T.S.) (Unless chelation control is utilized) LA Me H LA H R R OH SiR3 (E)-silane reagent SiR3 R H OH Me H
O Me R
Me
syn-homoallylic alcohol
(Z)-silane reagent
syn-homoallylic alcohol
B. Additions to Aldehydes (Opposite face of silane) O BnO H BF3OEt2 (78 C) Me O F3B H
Antiperiplanar T.S. BnO

CO Me SiMe3 2
OH CO2Me
H BnO Bn
CO2Me SiMe3 O BnO H Br Br H Me3Si
6.5 : 1 syn-homoallylic alcohol
O Mg H O
Me H
Synclinal T.S.
OH BnO CO2Me 12.2 : 1
MgBr2OEt2 (25 C)
MeO2C Panek J. Org. Chem. 1994, 59, 5130.
anti-homoallylic alcohol
oxidative cleavage provides aldehyde, carboxylic acid (R = H) or ketone (R = Me Me, Et) aldol addition products
C. Additions to Chiral Aldehydes - BnO chelation, anti R3SiO no chelation, syn R Me CO2Me SiMe2Ph R Me CO2Me SiMe2Ph R Me CO2Me + SiMe2Ph R Me CO2Me + SiMe2Ph Ph2tBuSiO Me Ph2tBuSiO Me O H TiCl4 78 C R3SiO Me Me + BnO Me O H TiCl4 78 C R3SiO Me Me OH + BnO Me O H O H TiCl4 78 C BnO Me Me OH TiCl4 78 C BnO Me Me OH OH
R R = Me 64%, 10:1 CO2Me R = Et 35%, 15:1
R R=H CO2Me R = Et 85%, >30:1 69%, 10:1
R = H 90%, >30:1 CO2Me R = Me 79%, >30:1 R = Et 74%, 15:1
R R = Me 98%, 8:1 CO2Me R = Et 79%, 10:1
Jain and Panek J. Am. Chem. Soc. 1996, 118, 12475.
198
I. Enolate-imine Addition Reactions

- Review: Hart Chem. Rev. 1989, 89, 1447.
R1 Ph R1 CO2Et R1 H Me Et iPr tBu Hart J. Am. Chem. Soc. 1984, 106, 4819. OH H Ph OH CO2Et 1. LDA 2. PhCH=NPh O Georg Tetrahedron Lett. 1985, 26, 3903. H N Ph 25% + O 1. LDA 2. PhCH=NSiMe3 3. HCl, H2O H O yield 14% 41% 72% 80% 40% H NH + R1 O
H Ph H NH yield 0% 3% 0% 1% 0%
OH H H Ph N Ph 16%
NHBOC CONH2 N + N H 2N CH3 Boger J. Am. Chem. Soc. 1994, 116, 5619. N CO2Et MeS OTf Sn O O THF, 0 C N Me O Ph 85% H2N CH3 Xc MeS N O
NHBOC CONH2 NH N CO2Et + H2N CH3 Xc MeS N O
NHBOC CONH2 NH N CO2Et
7:1 anti:syn (>16:1)
J. Claisen Condensation
O CH3CO2Et + NaOH (or NaOEt) H2C Claisen Chem Ber. 1887, 20, 651. OEt OEt ONa EtO ONa O OEt
reaction driven to completion by forming product which is stable to the reaction conditions.
NaO
O OEt
irreversible
O OEt
pKa = 13
pKa = 13
199
Modern Organic Chemistry The Scripps Research Institute - Weinreb Amide Turner J. Org. Chem. 1989, 54, 4229. O OMe N Me + Li CN 62% OLi + R OLi 47% O NNMe2 + Li 98% NNMe2 OR' 63-89% O + O O OR' R O O CN
- Tetrahedral intermediate is stabilized - Breaks down upon workup, not in reaction - Generality of Weinreb amide - Weinreb Tetrahedron Lett. 1981, 22, 3815.
O R Ph
Li O N Me Me
- Knoevenagel-Doebner and Stobbe Condensation CHO + OMe OMe CO2Et O Ph - Example O (MeO)2P R CO2Et CO2tBu + CO2Et CO2Et CO2H OMe CO2Et NaH Ph Ph CO2Et piperidine OMe CO2Et Knoevenagel-Doebner condensation Knoevenagel Chem. Ber. 1896, 29, 172. Doebner Chem. Ber. 1900, 33, 2140. Review: Org. React. 1967, 15, 204.
Ph
Stobbe condensation Stobbe Chem. Ber. 1893, 26, 2312. Review: Org. React. 1951, 6, 1.
CHO +
CO2Et CO2tBu
NaH 75-100%
1. TFA 2. Ac2O
R = H, Br, OCH3 R CO2Et
N O
Boger J. Org. Chem. 1996, 61, 1710. 1996, 61, 4894.
OH
200
K. Dieckmann Condensation
- Org. React. 1967, 15, 1.
- Examples O EtO O O CO2Et CO2Et NaOEt 64-68% EtO2C O - Org. Syn. Coll. Vol. 2, 288. O CO2Et H2O 180 C OEt ONa NaOEt CO2Et O CO2Et 80%
H+
O 84-89%
KOtBu MeO2C CN THF 70% O H CN
Thorpe-Ziegler condensation Dinitrile is Ziegler condensation Ziegler Chem. Ber. 1934, 67, 139.
Stevens J. Am. Chem. Soc. 1977, 99, 6105.
CO2Et CO2Et
Na EtOH
O CO2Et
Dieckmann Ber. 1894, 27, 965. Fehling Ann. 1844, 49, 192. (1st example - product not identified) R CO2Et CO2Et 2 R O CO2Et 1 R O CO2Et
CO2Et O
- products interconvert under reaction conditions equilibration driven to 1 by formation of enolate.
The analogous intramolecular keto ester condensation may be described as "occurring under Dieckmann conditions" see: Org. React. 1959, 8, 79. CO2Et NNMe2 LiCu 2 conjugate 1,4-addition Boger and Corey Tetrahedron Lett. 1978, 4597. 2. H3O+ 1. CO2Et O NaH benzene cat. MeOH O O
201

OMe MeO MeO MeO2C N CN MeO2C OMe MeO MeO N R OMe MeO Boger and Brotherton J. Org. Chem. 1984, 49, 4090. Boger and Takahashi J. Am. Chem. Soc. 1995, 117, 12452. MeO2C MeO2C N OMe CO2Me Me LDA O N OMe CO2Me OBoger J. Org. Chem. 1992, 57, 3974. Boger J. Am. Chem. Soc. 1995, 117, 11839. - Asymmetric Dieckmann-like condensation Kinetic control: 5 - 7:1 diastereomers NBOC Thermodynamic control: single diastereomer NBOC HN XcOC MeO2C 68-85% O N OMe OH Nat. and ent. Fredericamycin A O R=H rufescine R = OCH3 imeluteine MeO MeO N imerubrine NH2 OMe KOtBu 98% MeO MeO N OMe H+ aq. dioxane 89% MeO MeO N O OMe
TBDMSO
TBDMSO
LDA
NC Me N BOC OBn
LDA
NBOC
N THF O 58% O 78 C, 30 minO
CO2tBu > CHO
Chelated Z-enolate
THF Me N 78% BOC OBn 40 C, 3 h (reversible and equilibration)
(+)-Duocarmycin A
anti-carbonyls
iPr Me O O N N N Li O R
O N iPr N Me
Li O N R iPr
Me NH O N N R O
E = 0.76 Kcal/mol
iPr O
O N O NH N R
Me
202
L. Enolate Dianions
dianion O O OMe NaH ONa O OMe

nBuLi
or LDA
O OMe
78 C
O R Me
1. OH 2. (CO2) O R 1. NaH R' 2. R'X 3. OH 4. dianion useful for slow alkylations (i.e. ketone enolate + epoxide slow but dianion reacts quickly). O OMe H+ R O
R-X
O OMe
R O
Weiler J. Am. Chem. Soc. 1974, 96, 1082. Weiler Tetrahedron Lett. 1983, 24, 253. Harris Org. React. 1969, 17, 155-212. (review)
M. Metalloimines, Enamines and Related Enolate Equivalents

- Corey, Enders Tetrahedron Lett. 1976, 3. (Dimethylhydrazones) O LDA OLi RX O R O via enolate equilibration O OLi R O R R R R R R R O R
OLi
- Simple alkylation of enolates not always straightforward. - Can get polyalkylation mixtures.
203
Modern Organic Chemistry The Scripps Research Institute - Solutions
O NaH EtO O OEt
O NaH OEt RX
O OEt
OH (CO2)
O R
Me2NNH2
NMe2
nBuLi
NMe2 Li
Br
NMe2
pKa = 20
pKa = 30
- Higher pKa so anion is more reactive - Alkylation much faster and polyalkylation is not a problem
Me2NNH2
NMe2
nBuLi
NMe2 Li
Br
NMe2
or LDA pKa = 20 pKa = 30 H3O+ or NaIO4 or CuCl2 O
Advantages: - monoalkylation (more reactive than ketone enolate). - no enolate anion equilibration. - regioselective (deprotonation at least substituted site). - alkylation is in axial mode (diastereoselective).
- Examples: O
tBu
LDA MeI
O
tBu
O +
tBu
Me 45
Me 55 N H N
tBu
90 H3O+ Stork enamine (J. Am. Chem. Soc. 1963, 85, 207) NNMe2 1. LDA 2. MeI
MeI
10
tBu
97
Corey dimethylhydrazone 3. CuCl2 H2O, pH = 7
204
Enolate Chemistry Dale L. Boger -also useful in acyclic cases O C4H9 LDA 78 C C4H9 no problem to make kinetic enolate, but if alkylation is slow, an equilibration may compete in product formation. LDA C4H9 N NMe2 Li MeI C4H9 NMe2 Me OLi
Me2NNH2 N C4H9 NMe2
- very good as aldehyde enolate equivalents R N

nBuLi
Me2NNH2
R O
LDA
H OLi
NMe2 1. LDA 2. R'X
- aldehyde enolates difficult to generate and alkylate cleanly. polycondensation self condensation
R' R CN R N H NMe2
- Enders chiral hydrazones (SAMP and RAMP)
OMe H N NH2 SAMP OMe LDA or

sBuLI
MeO
N NH2 RAMP OMe O3 100%
- alkylation from the least hindered face of chelated anion.
N CH3
N CH3
O CH3
MeI 90% de Review: Asymm. Synth. Vol. 3, 275. - Meyers chiral oxazolines - Phenyl group shields top face to E+ attack O N Ph LDA Me H Li OCH3 R-X OCH3 O N Ph R-X R Me H O N Ph Me H CO2H R
Me
OCH3 95 to 105 C 72-82% de
Z-azaenolate (95:5 Z:E)
S-enantiomer
Review: Asymm. Synth. Vol. 3, 213.
205
N. Alkylation of Extended Enolates

O OCH3 ONa NaH OCH3 R-X -alkylation R O OCH3
two possible sites of alkylation
- For alkylation in the position - can use a dianion O O LDA (2 equiv) OCH3 or 1. NaH, 0 C 2. nBuLi, 78 C O O OCH3 R-X H3 O+ R O O OCH3
- In cyclic systems O LDA (1.05 equiv) 78 C OR R = Me, iPr OR kinetic enolate Danheiser, Stork J. Org. Chem. 1973, 38, 1775. Cargill J. Org. Chem. 1973, 38, 2125. OLi R'X R' O NaBH4 then H3O OR
+
R' O
O LDA or
nBuLi
OLi R'X N
N R'
Yoshimoto, Ishida, Hiraoka Tetrahedron Lett. 1973, 39. Bryson, Gammill Tetrahedron Lett. 1974, 3963.
206
Metalation Reactions Dale L. Boger
IX. Metalation Reactions

A. Directed Metalation
- Kinetic acceleration of deprotonation of a relatively non-acidic site. - Synthesis 1983, 95. - Acc. Chem. Res. 1982, 15, 306. lateral lithiation: Org. React. 1995, 47, 1. - Org. React. 1979, 26, 1. H LB H
nBuLi
H LB or Li
Li
LB
- Usually requires very strong base (nBuLi, sBuLi or tBuLi, sometimes LDA). - Sometimes requires additives (TMEDA, DABCO) to break up Li aggregates (make bases more reactive). NMe2 N TMEDA DABCO N NMe2 - Examples: OCH3 H OCH3
nBuLi
OCH3 Li OCH3
E+
OCH3 E OCH3
- All aromatic H's have approximately the same pKa
OH
nBuLi
nBu
Li (2 equiv) H O
Li
Li
Li
hexane TMEDA 1. CO2 2. H+ - TMEDA breaks up RLi aggregates to form 1:1 complex (makes RLi more reactive) HO2C O Li
- Not limited to aromatic substrates
H H 2C CH3
NR2 O LDA
Li H2C CH3
NR2 O
- Kinetic acceleration of deprotonation even in the presence of a more acidic proton.
207
Modern Organic Chemistry The Scripps Research Institute - Directed Metalation Groups
carbon based Strong: CONR CSNR CONR2 CON(R)CH(Z)TMS, Z = H,TMS CH=NR (CH2)nNR2, n = 1,2 CH(OH)CH2NR2 CN O N Moderate: CF3 O NR2 Weak: C(OTMS)=CH2 CH(OR)2 CC Ph R N N R N N
heteroatom based Strong: NCOR NCO2R OCONR2 OPO(NR)2 OCH2OMe OTHP OPh SO3R SO2N-R SO2NR SO3 SO2tBu SOtBu
Moderate: NR2 NC OMe OCH=CH2 OPO(OR)2 O(CH2)2X, X = OMe, NR2 F Cl PO(NR)2 PS(Ph)NR2
Weak:
O S
Snieckus Chem. Rev. 1990, 90, 879.
- Examples (cooperative effect)
OMOM
nBuLi
OMOM I NBOC H
NBOC H
TMEDA ICH2CH2Cl 25 C, 80%
N O R
Boger and Garbaccio, J. Org. Chem. 1997, 62, 8875.
208
Metalation Reactions Dale L. Boger - Representative Organolithium Compounds by Directed Metalation OCH3 + nBuLi Et2O, 35 C 2h OCH3 Li Li + OCH3
major Shirley J. Org. Chem. 1966, 31, 1221.
minor
NEt2 + nBuLi THF, 78 C TMEDA, 1 h
NEt2 Li
Beak J. Org. Chem. 1977, 42, 1823. Beak J. Org. Chem. 1979, 44, 4463.
CH3
N N CH3 + nBuLi
CH3 ether, 25 C TMEDA, 7 h
N N CH3
Li
Harris J. Org. Chem. 1979, 44, 2004.
+ nBuLi S
THF, 30 C 1h
Li
Jones and Moodie Org. Synth. 1988, 6, 979.
CH2=CHOCH3
+ tBuLi
THF, 0 C
OCH3 H2C Li
Baldwin J. Am. Chem. Soc. 1974, 96, 7125.
CH2=CHCH2OTMS
+ sBuLi
THF, HMPA 78 C, 5 min
H H 2C Li H OTMS
Still J. Org. Chem. 1976, 41, 3620. O Ph3Si
+ nBuLi
THF, 78 C 4h
Ph3Si Li
Eisch J. Am. Chem. Soc. 1976, 98, 4646.
209
B. Organolithium Compounds by Metal-Halogen Exchange

Jones and Gilman Org. React. 1951, 6, 339. 2 equiv tBuLi Br 120 C 1 equiv nBuLi 78 C - configurationally stable - retention of configuration Li Note: 2 equiv of reagent are required Li MeO Li
nBuLi tBuLi
Ph
Ph
Br
MeO
Br
Seebach Tetrahedron Lett. 1976, 4839. Hoye J. Org. Chem. 1982, 47, 331. - Additional examples CH3 H H Br + tBuLi
-> nBuBr - slower elimination but such products may still compete with desired electrophile for reaction with the generated organolithium reagent.
120 C
CH3 H
H Li
Seebach Tetrahedron Lett. 1976, 4839. 70 C
Br
+ nBuLi
Li
Linstrumelle Synthesis 1975, 434.
+ tBuLi CH3O Br Corey Tetrahedron Lett. 1975, 3685. CH3O Li
nBu
TMS Br
+ sBuLi
70 C
nBu
TMS Li
H Miller J. Org. Chem. 1979, 44, 4623.
NC
Br + nBuLi
100 C
NC
Li
Parham J. Org. Chem. 1976, 41, 1187.
note: metalation in presence of reactive groups. Li
O2N Br
Br +
nBuLi
O2N 100 C Br
Parham J. Org. Chem. 1977, 42, 257.
210
Metalation Reactions Dale L. Boger Corey and Boger Tetrahedron Lett. 1978, 5, 9, and 13.
O R R1 CHO R O R Me N Li H O S O O
N S
nBuLi
78
oC
N Li S
O O R
OMe MeO MeO Br Boger N

nBuLi,
OMe 78 C MeO MeO Li N MeO
OMOM Br
nBuLi,
78 C
MeO
OMOM Li
THF, 15 min
Et2O, 15 min OMOM OMOM
J. Org. Chem. 1984, 49, 4050. J. Am. Chem. Soc. 1995, 117, 12452.
Boger J. Org. Chem. 1991, 56, 2115. J. Am. Chem. Soc. 1995, 117, 11839.
C. Organolithium Compounds by Metal-Metal Exchange

- Reactions of organotin reagents with alkyllithium reagents are particularly significant CH2OTHP Bu3Sn
nBuLi
CH2OTHP Li
Corey J. Org. Chem. 1975, 40, 2265. OR R SnBu3

nBuLi
Proceeds in direction of placing the more electropositive metal on the more electronegative (acidic) carbon.
OR R Li Peterson R2NCH2SnBu3
nBuLi
78 C
0 C
R2NCH2Li
Still J. Am. Chem. Soc. 1978, 100, 1481. J. Am. Chem. Soc. 1980, 102, 1201. McGarvey J. Am. Chem. Soc. 1988, 110, 842. Macdonald
J. Am. Chem. Soc. 1971, 93, 4027.
- transmetalation with retention and maintenance of configuration
D. Organolithium Compounds from the Shapiro Reaction

N-NHTs Et Me 2 equiv nBuLi TMEDA Li Et Me
Shapiro Org. React. 1976, 23, 405. Bond J. Org. Chem. 1981, 46, 1315. Chamberlin Org. React. 1990, 39, 1.
211
212
Key Ring Forming Reactions Dale L. Boger
X. Key Ring Forming Reactions

A. Diels-Alder Reaction
1. Reviews 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. General reference: Onischenko, A. S. Diene Synthesis; Daniel Davy: New York, 1964. General reference: Wasserman, A. Diels-Alder Reactions; Elsevier: New York, 1965. General review: Alder, K. Newer Methods of Preparative Organic Chemistry, Vol. 1, Wiley: New York, 1948, pp. 381-511. General review: Huisgen, R.; Grashey, R.; Sauer, J. in Chemistry of Alkenes; S. Patai, Ed.; Wiley: New York, 1964, pp. 878-953. General review: Wollweber, H. in Houben-Weyl, Methoden der Organischen Chemie; E. Muller, Ed.; Georg Thieme: Stuttgart, 1970, pp. 977-1210. General reference: Wollweber, H. Diels-Alder Reaction; Georg Thieme: Stuttgart, 1972. General reference: Fleming, I. Frontier Orbitals and Organic Chemical Reactions; Wiley: New York, 1977. Diels-Alder reactions with maleic anhydride: Kloetzel, M. C. Org. React. 1948, 4, 1. Diels-Alder reactions with ethylenic and acetylenic dienophiles: Holmes, H. L. Org. React. 1948, 4, 60. Diels-Alder reactions with quinones: Butz, L. W.; Rytina, A. W. Org. React. 1949, 5, 136. Diels-Alder reaction: preparative aspects: Sauer, J. Angew. Chem., Int. Ed. Eng. 1966, 5, 211. Diels-Alder reaction: mechanism: Sauer, J. Angew. Chem., Int. Ed. Eng. 1967, 6, 16. Stereochemistry of the Diels-Alder reaction: Martin, J. G.; Hill, R. K. Chem. Rev. 1961, 61, 537. Regiochemistry of the Diels-Alder reaction: Titov, J. A. Russ. Chem. Rev. 1962, 31, 267. Mechanism of the Diels-Alder reaction: Seltzer, S. Adv. Alicycl. Chem. 1968, 2, 1. Diels-Alder reaction of heteroatom-substituted dienes: Petrizilka, M.; Grayson, J. I. Synthesis 1981, 753. Preparation and Synthetic Aspects: Wagner-Jaueggs, T. Synthesis 1976, 349; Synthesis 1980, 165, 769. Diels-Alder reaction of azadienes: Boger, D. L. Tetrahedron 1983, 39, 2869. Review on "Danishefsky's diene" and related dienes in the Diels-Alder reaction: Danishefsky, S.
Acc. Chem. Res. 1981, 14, 400.

Intramolecular Diels-Alder reaction: Carlson, R. G. Ann. Rep. Med. Chem. 1974, 9, 270. Intramolecular Diels-Alder reaction: Oppolzer, W. Angew. Chem., Int. Ed. Eng. 1977, 16, 10. Intramolecular Diels-Alder reaction of o-quinodimethanes: Oppolzer, W. Synthesis 1978, 793. Intramolecular Diels-Alder reaction: Brieger, G.; Bennet, J. N. Chem. Rev. 1980, 80, 63. Intramolecular Diels-Alder reaction: Ciganek, E. Org. React. 1984, 32, 1. Intramolecular Diels-Alder reaction: Fallis, A. G. Can. J. Chem. 1984, 62, 183. Intermolecular Diels-Alder reaction: Oppolzer, W. in Comprehensive Organic Synthesis, Vol. 5; pp. 315-399. Intramolecular Diels-Alder reaction: Roush, W. R. in Comprehensive Organic Synthesis, Vol. 5; pp. 513-550. Retrograde Diels-Alder reactions: Sweger, R. W. in Comprehensive Organic Synthesis, Vol. 5; pp. 551-592. The Retro-Diels-Alder reaction: Rickborn, B. Org. React. 1998, 52, 1. Heterodienophile Diels-Alder reactions: Weinreb, S. M. in Comprehensive Organic Synthesis, Vol. 5; pp. 401-449. Heterodiene Diels-Alder reactions: Boger, D. L. in Comprehensive Organic Synthesis, Vol. 5; pp. 451-512. Hetero Diels-Alder Reaction: Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis; Academic: San Diego, 1987.
213
Modern Organic Chemistry The Scripps Research Institute 2. Discovery Wieland (Ber. 1906, 39, 1492) described the 1:1 dimerization of conjugated dienes in what was probably the first report of a Diels-Alder reaction. Albrecht (Thiele) Reaction: Ann. 1906, 348, 31. O O C5H5 Misassigned structure O Staudinger Structure: Die Ketene, Stuttgart 1912, 59. O O O Structure established by Diels and Alder, and they went on to define scope and mechanism of the reaction. For this, they received the 1950 Nobel Prize in Chemistry.
Diels and Alder Ann. 1928, 460, 98. In fact, von Euler had correctly, but tentatively, identified the 2:1 adduct of isoprene with p-benzoquinone before Diels and Alder's work. von Euler, Josephson Ber. 1920, 53, 822. O O or O O O O
von Euler received the 1929 Nobel Prize in Chemistry for his investigations on fermentations of sugars and the fermentative enzymes. He had trained with Landolt, Nernst, van't Hoff, Arrhenius, Hantzsch, and Thiele and was remarkable in his scientific pursuits. By 1910, he had already initiated his monumental studies of enzyme structure, kinetics, and mechanism and his occasional forays into pure organic chemistry were just as remarkable. For an engaging description of the discovery of the Diels-Alder reaction, the competition for its exploration and applications, and the missed opportunities, see: Berson Tetrahedron 1992, 48, 3. Even in their first disclosure, Diels and Alder recognized the potential the reaction might hold for synthesis: "Thus, it appears to us that the possibility of synthesis of complex compounds related to or identical with natural products such as terpenes, sesquiterpenes, perhaps also alkaloids, has moved to a near prospect." They also felt this could be reserved: "We explicitly reserve for ourselves the application of the reaction discovered by us to the solution of such problems." Fortunately, their claims were ignored and an extraordinary group of investigators helped define the scope and mechanism of the Diels-Alder reaction. The first applications in total synthesis include: Cortisone by Woodward, Sondheimer J. Am. Chem. Soc. 1951, 73, 2403; Sarett (Merck) J. Am. Chem. Soc. 1952, 74, 4974. Cantharidin by Stork, Burgstahler, van Tamelen J. Am. Chem. Soc. 1951, 73, 4501. 3. Mechanism, FMO Treatment [2s + 4s] Cycloaddition HOMOdiene Alternatively: LUMOdiene Dominant interaction in an inverse electron demand Diels-Alder reaction.
LUMOdienophile
This is the dominant interaction in a normal Diels-Alder reaction.
HOMOdienophile
1. Large Ea for the reactions. 2. Driving force is formation of two new bonds accompanying the loss of two bonds.
214
Key Ring Forming Reactions Dale L. Boger 4. Diastereoselectivity a. cis Principle: e.g. CO2CH3 CO2CH3 CO2CH3 CH3O2C Stereospecific R X X R b. Alder's Endo Rule: Stereoselective e.g. CO2CH3 CO2CH3 H H COOCH3 COOCH3 COOCH3 COOCH3 H H R R X X CO2CH3 CO2CH3 CO2CH3 CO2CH3 Geometry of dienophile and diene are maintained in the [4 + 2] cycloadduct.
Endo product and endo transition state predominate even though exo products are usually more stable; endo is the kinetic product.
endo
Major
exo
Minor
Endo, boat transition state
Endo T.S.
Exo T.S.
CH3OOC CH3OOC H
H H
COOCH3 COOCH3
Result: Both cis rule and endo rule
Diels-Alder reaction very useful, diastereoselective
215
Modern Organic Chemistry The Scripps Research Institute c. Factors influencing endo selectivity of the Diels-Alder reaction OAc CHO Me R via AcO OHC H i. ii. iii. R H H H CH3 R OAc CHO Me
Endo transition state is favored by stabilizing secondary orbital interactions. Endo selectivity often increases with the use of Lewis acid catalysis. Endo selectivity often increases with increase in pressure of reaction.
, pressure V = 4 to 8 cm3/mol (endo/exo) Raistrick J. Chem. Soc. 1939. 1761, 1770. Jones Tetrahedron 1962, 18, 267. Dauben demonstrated pressure-promoted reactions are viable: J. Am. Chem. Soc. 1974, 96, 3664. J. Am. Chem. Soc. 1976, 98, 1992. J. Org. Chem. 1977, 42, 282.
Endo selectivity
R OHC H
H H
R CHO
endo T.S.
exo T.S.
-V
is negative (25 to 38 cm3/mol). So increase pressure, increase rate of reaction.
-And endo T.S. is more compact, so V (i.e., diastereoselectivity increases) O Example of O
for endo:exo also negative.
Boger J. Am. Chem. Soc. 1988, 108, 6695 and 6713.
iv. Endo selectivity also increases with decreases in temperature at which the reaction is conducted e.g. COOH COOH COOH COOH COOH COOH
temp. 75 C 90 C
endo
only endo 7 4.5 2 1 : : : :
exo
1 1 1 1
Endo selectivity
, temperature
100 C 110 C 130 C
216
Key Ring Forming Reactions Dale L. Boger CHO + OBn CHO OBn conditions 10 days, 0 C 6 h, 200 C Lewis acid-catalyzed BF3OEt2, 5 min, 20 C + CHO
endo
66 34 90 : : :
OBn exo 34 66 10
Furukawa J. Am. Chem. Soc. 1970, 92, 6548.
Ph O Ph + Ph O temp. 25 C 140 C O O
Ph
Ph H H O
Ph O
+ HH
O O
endo
100 29 : :
exo
0 71
Some Diels-Alder adducts are thermally unstable (reversible) and subject to equilibration via retro Diels-Alder reaction to provide the most stable product: Ripoll Tetrahedron 1978, 34, 19. O O + O O see also: Rickborn Org. React. 1998, 52, 1. HH O O O O 100% exo
5. Regioselectivity a. 1-Substituted dienes react with substituted dienophiles to give the ortho product: X Y + X Y + Y usually around 9:1 X
217
Modern Organic Chemistry The Scripps Research Institute For example: CH3 W + CH3 W + W W = CN = COOR 100 C, 12 h, 30% 200 C, 2 h, 85% 9 6.8 : : 1 1 CH3
higher temperature decreases regioselectivity
regioselectivity lower, because COOR not as strongly electron-withdrawing as CN
-Device for predicting regioselectivity: draw out "zwitterionic" representations (resonance structures) for the reactants.
CN
CN
CN
more stable resonance forms
CH3 CN CN Reaction: 100 C, 12 h 30%, 9:1 regioselectivity
b. 2-Substituted dienes give predominantly the para product: X + Y X = CH3 = OCH3 = CN Y = COOCH3 = COOCH3 = COOCH3 6 10 10 : : : 1 1 1 higher regioselectivity because OCH3 better donating group than CH3. Y X + X Y
218
Key Ring Forming Reactions Dale L. Boger c. Complementary substitution usually provides even greater regioselectivity -1,3-Disubstituted Dienes X Y + X' X' X Y ortho to X group para to X' group
But noncomplementary substitution may cause problems (lower regioselectivity) -1,2-Substituted Dienes X X' + Y X' X Y + Y relative amounts of each depend on electron donating strength of substituents X and X' NHCO2R > SR > OR > alkyl > H SPh CH3O + O CH2Cl2 25 C 85% Cohen J. Org Chem. 1982, 47, 4005. O + PhS toluene , 2 h 75% 100:0 SPh O CH3O X' X
O CH3O PhS : CH3O + PhS O 1
CH3O
>5 Trost J. Am. Chem. Soc. 1980, 102, 3548. NHCO2Bn O + SPh Ph 56 C 26 h, 86% SPh Overman J. Am. Chem. Soc. 1983, 105, 6335.
NHCO2Bn COPh
d. Apparent regioselectivity can be altered by adding a controlling group that is subsequently removed -Dienophile OAc + CO2CH3 CO2CH3 OAc SO2Ph SO2Ph
-endo addition -CO2CH3 is in meta position -SO2Ph > CO2CH3 in controlling regioselectivity Bass J. Chem. Soc., Chem. Commun. 1987, 1836.
219

- Diene O + NO2 In addition to altering regioselectivity, it also serves as an equivalent of an inaccessible cyclic alkyne dienophile.
nBu
3SnH
O 90 C, 40 h
O2N DBN 0 C, 1 h O (86%) O (83%)
Corey Tetrahedron Lett. 1981, 22, 603. Ono J. Chem. Soc., Perkin Trans. 1 1987, 1929. Tanis Syn. Commun. 1986, 16, 251. Rate of reaction generally insensitive to solvent polarity, but...
6. Lewis Acid Catalysis 140 C O + 8-10 h 75% AlCl3 25 C,1 h 75% O
Addition of Lewis Acid Catalysts: O i. Lowers LUMO of dienophile, so increases rate of reaction. ii. Increases the difference in magnitude of coefficients of dienophile -----so increases regioselectivity. iii. Changes coefficient at dienophile substituent, so increases opportunity of secondary orbital interactions .....often increases endo stereoselectivity.
AlCl3 + Al O
Increases: 1. Reaction Rate 2. Reaction Regioselectivity 3. Reaction Endo Diastereoselectivity
220
-Examples O + O Lutz J. Am. Chem. Soc. 1964, 86, 3899. toluene, 120 C, 24 h 71 93 : : 29 7 + O
Yates J. Am. Chem. Soc. 1960, 82, 4436. SnCl4, benzene, 25 C, 1 h
1st example: 100 C, 3 d, dioxane vs AlCl3, 25 C, 5 min Diethyl fumarate EtO2C
CO2Et
+ AlCl3: G
CO2CH3
CO2CH3
9.3 kcal/mol lower than uncatalyzed reaction
Inukai, Kojima J. Org. Chem. 1967, 32, 872.
E endo/exo: CO2CH3 + CO2CH3 CO2CH3 +
uncat. reaction: 0.2 kcal/mol; AlCl3 cat. reaction: 1.8 kcal/mol Spellmeyer , Houk J. Am. Chem. Soc. 1988, 110, 3412. Jensen, Houk J. Am. Chem. Soc. 1987, 109, 3139.
Calculations: s-cis > s-trans
E for: OCH3 O CH3O O
catalyzed reaction: 1.9 kcal/mol for endo 2.7 kcal/mol for exo
uncatalyzed reaction: 0.6 kcal/mol for endo 1.7 kcal/mol for exo
Birney, Houk J. Am. Chem. Soc. 1990, 112, 4127.
221
Modern Organic Chemistry The Scripps Research Institute -Lewis Acid catalysis can also alter regioselectivity O CH3 + CH3O O 100 C BF3OEt2, 16 C cat. SnCl4, 16 C Rationalization: monodentate vs. bidentate coordination CH3O O H 1 4 1 + CH3O O : : : 1 1 20 H 80% >85% >85% O O
most Lewis basic carbonyl
F3B
+ O
versus CH3 bidentate coordination CH3O Sn O CH3
CH3O O
O +
-Hydrophobic effect: H2O solvent acceleration: Breslow J. Am. Chem. Soc. 1980, 102, 7816. Rideout Tetrahedron Lett. 1983, 24, 1901. also: Sternbach J. Am. Chem. Soc. 1982, 104, 5853. Grieco Tetrahedron Lett. 1983, 24, 1897.
Jorgensen - Hydrogen-bonding of H2O serves in the same capacity as a mild Lewis acid.
requires H-bonding carbonyl requires H-bonding solvent
Jorgensen J. Am. Chem. Soc. 1991, 113, 7430. J. Org. Chem. 1994, 59, 803.
222
Key Ring Forming Reactions Dale L. Boger 7. Detailed FMO Analysis -Using simple computational tools now available, one can quickly and easily predict regioselectivity and comparatively assess rate and diastereoselectivity of a Diels-Alder reaction by examining the frontier molecular orbitals (FMO). Each of the calculations that follow took < 1 min to run.
Classification of Diels-Alder Reactions.
NORMAL HOMOdiene-controlled
NEUTRAL
INVERSE LUMOdiene-controlled
EDG EWG
EWG EDG
LUMO
smallest E, dominant molecular orbital interaction
LUMO
LUMO LUMO
HOMO HOMO HOMO HOMO
smallest E, dominant molecular orbital interaction
J. A. Pople (computational methods in quantum chemistry) and W. Kohn (density-functional theory) received the 1998 Nobel Prize in Chemistry for their pioneering contributions to theoretical and computational methods for defining properties and chemical behavior.
Common Computational Tools: Semiempirical MNDO: Dewar J. Am. Chem. Soc. 1977, 99, 4899. AM1: Dewar J. Am. Chem. Soc. 1985, 107, 3902.
Ab Initio
Gaussian: Pople, Carnegie-Mellon Quantum Chem. Pub. Unit, Pittsburgh, PA.
223
Modern Organic Chemistry The Scripps Research Institute AM1 Theoretical Highest Occupied Orbital (HOMO) and Lowest Unoccupied Orbital (LUMO) system E Coefficients
H2C=CH-CH=O E LUMO E HOMO H2C=CH-CH=OH+ E LUMO E HOMO H2C4=CH-C(CH3)=C1H2 E LUMO E HOMO 0.5 eV -9.2 eV LUMO: HOMO: -7.0 eV -16.6 eV LUMO: HOMO: 0.0 eV -10.9 eV LUMO: HOMO:
O-1 0.42 0.35
C-2 -0.50 0.05
C-3 -0.43 -0.68
C-4 0.63 -0.65
0.36 0.36
-0.73 0.23
-0.03 -0.73
0.58 -0.53
C-1 0.57 0.60
C-2 -0.43 0.45
C-3 -0.37 -0.41
C-4 0.51 -0.55
H2C4=CH-C(OCH3)=C1H2 E LUMO E HOMO H2C2=CH-OCH3 E LUMO E HOMO 1.4 eV -9.5 eV LUMO: HOMO: 0.4 eV -9.1 eV LUMO: HOMO: 0.51 0.67 C-1 0.72 0.48 -0.41 0.42 C-2 -0.66 0.69 -0.44 -0.28 OCH3 0.21 -0.51 0.58 -0.41
224
Key Ring Forming Reactions Dale L. Boger AM1 -MO's
Thermal reaction H O
Model for Lewis acid-catalyzed reaction H O H
2.2 eV
1.9 eV
2.2 eV
0.5 eV E
0.5 eV 0.0 eV E
-4.0 eV 9.2 eV 11.4 eV 2.2 eV -7.0 eV
-9.2 eV -10.9 eV
-9.2 eV
-14.3 eV
-14.6 eV
-14.3 eV -16.6 eV
HOMOdiene - LUMOdienophile energy difference is controlling factor for normal Diels-Alder reaction making this E difference smaller will increase rate of reaction. For uncatalyzed reaction, E = 9.2 eV
For catalyzed reaction, E = 2.2 eV
-21.6 eV
Rate: -Lewis acids catalyze reaction by lowering energy of MO's of dienophile. -Importantly, the LUMO of the dienophile becomes much lower in energy. Rate increase by Lewis acid catalysis due to lowering of E of LUMOdieneophile.
225
Modern Organic Chemistry The Scripps Research Institute Regioselectivity: Thermal HOMO 0.51 LUMO 0.43 CHO Lewis acid-catalyzed HOMO 0.51 LUMO 0.03 O H
0.60 = 0.09
0.63 = 0.20
0.60 = 0.09
0.58 = 0.55!
Enhanced polarization of dienophile leads to enhanced regioselectivity.
Diastereoselectivity (endo cycloaddition): Thermal Lewis acid-catalyzed
stabilizing 2 orbital interactions
1 (bonding) orbital interactions HOMOdiene
0.41
H 0.50 O
0.41
H 0.73 O
HOMOdiene LUMOdienophile HOMOdiene LUMOdienophile LUMOdienophile greater endo stereoselectivity gives rise to increase in coefficient at complexed carbonyl carbon
NOTE comparison of MeO
vs.
Me
rate of reaction,
> MeO > MeO
Me
HOMO-LUMO E difference
regioselectivity,
Me
stereoselectivity, MeO
<
Me
due to smaller (relative) coefficient at C3 of diene.
226
AM1 Results
Lewis acid-catalyzed HOMOdiene-controlled Diels-Alder reaction HOMOdiene-controlled Diels-Alder reaction
H CH3O O CH3O 2.2 eV
H O H
2.2 eV
1.9 eV
0.4 eV E
0.4 eV 0.0 eV E
9.1 eV HOMO 11.3 eV -9.1 eV -10.9 eV
17.0 eV -4.0 eV
2.1 eV -9.1 eV
-7.0 eV
-12.7 eV -14.6 eV
-12.7 eV
-16.6 eV
-21.6 eV
Note: 1 eV = 23.06 kcal/mol, so difference of 0.1 eV is 2.3 kcal/mol and is significant in G .
227
E (E LUMOdienophile - E HOMOdiene) = 9.1 eV Rate: versus E (E LUMOdiene - E HOMOdienophile) = 11.3 eV 0.42 MeO -0.28 0.42 O -0.50 stabilizing secondary orbital interaction: endo selectivity -0.43 dominant HOMOdiene-LUMOdienophile orbital interaction: regioselectivity -0.41 0.63 LUMOdienophile 0.67 HOMOdiene
0.42 MeO -0.28 0.36 + H O -0.73 -0.41
0.67 HOMOdiene
0.58 LUMOdienophile
-0.03
E (E LUMOdienophile - E HOMOdiene) = 2.1 eV Rate: versus E (E LUMOdiene - E HOMOdienophile) = 17.0 eV
Thermal and (Lewis) acid-catalyzed HOMOdiene-controlled Diels-Alder reaction of acrolein and 2-methoxybutadiene, AM1 results
228
Key Ring Forming Reactions Dale L. Boger AM1 Results
Lewis acid-catalyzed LUMOdiene-controlled Diels-Alder reaction LUMOdiene-controlled Diels-Alder reaction
H OCH3 O OCH3
H O H
1.9 eV 1.4 eV E 0.0 eV E 1.4 eV
9.5 eV HOMO 12.3 eV -9.5 eV -10.9 eV
18.0 eV -4.0 eV
2.5 eV -9.5 eV
-7.0 eV
-14.6 eV
-16.6 eV
-21.6 eV
229
Rate:
E (E LUMOdienophile - E HOMOdiene) = 12.3 eV versus E (E LUMOdiene - E HOMOdienophile) = 9.5 eV -0.43 0.63 LUMOdiene
-0.50
O 0.42 0.69 HOMOdienophile -0.48 dominant LUMOdiene-HOMOdienophile orbital interaction: regioselectivity
Me
O -0.51
stabilizing secondary orbital interaction: endo selectivity
-0.03 -0.73
0.58 LUMOdiene
O 0.36 + H O
0.69 HOMOdienophile
Me
-0.51
-0.48
Rate:
E (E LUMOdienophile - E HOMOdiene) = 18.0 eV versus E (E LUMOdiene - E HOMOdienophile) = 2.5 eV
Thermal and (Lewis) acid-catalyzed LUMOdiene-controlled Diels-Alder reaction of acrolein and methyl vinyl ether, AM1 results
230
Strained Olefins Participate in Accelerated Normal or Inverse Electron Demand Diels-Alder Reactions: FMO Basis HOMOdiene-controlled Diels-Alder reaction CH3O 2.3eV 1.9 eV 1.0eV 0.5 eV E E = 9.8 eV 0.0 eV -0.5 eV E = 8.8 eV E = 11.0 eV E = 10.8 eV E = 11.4 eV E = 10.9 eV 0.5 eV Neutral Diels-Alder reaction LUMOdiene-controlled Diels-Alder reaction CH3CO2
CH3O
H O 2.3eV 1.4 eV
1.4 eV
1.3 eV 1.0eV
E = 10.3 eV
E = 11.4 eV
E = 9.0 eV
E = 9.3 eV
-8.8 eV HOMO -9.4 eV HOMO -10.9 eV HOMO -10.5 eV HOMO -9.8 eV HOMO -9.5 eV HOMO -9.9 eV HOMO -9.8 eV HOMO Key Ring Forming Reactions Dale L. Boger
-11.4 eV
-12.0 eV -12.4 eV
-14.6 eV
231
Modern Organic Chemistry The Scripps Research Institute 8. Cation-Radical Diels-Alder Reaction Me cat. H H H
Br
N
3
SbCl5
20%
40%
CH2Cl2, 0 C, 0.25 h SPh SPh
SPh
SPh reaction via radical cation
Bauld J. Am. Chem. Soc. 1981, 103, 718; 1982, 104, 2665; 1983, 105, 2378. 9. Ionic Diels-Alder Reaction O O H+ O OH much more reactive, much more electron deficient
O + O
cat. CF3SO3H CH2Cl2 67% O O
Gassman J. Am. Chem. Soc. 1987, 109, 2182. J. Chem. Soc., Chem. Commun. 1989, 837. 10. Dienophiles a. Effect of electron-withdrawing group X X X X = COCl > PhSO2 > PhCO > COCH3 > CN ~ COOCH3 relative rates: 6700 155 18 4 1.1 1.0
232
Key Ring Forming Reactions Dale L. Boger b. Alkyl groups on dienophile can slow Diels-Alder reaction (steric effect) c. Strain in dienophile
>
benzyne
bridgehead olefins Keese, Krebs Angew. Chem., Int. Ed. Eng. 1972, 11, 518.
Wiberg J. Am. Chem. Soc. 1960, 82, 6375.
Corey J. Am. Chem. Soc. 1965, 87, 934.
-Normal and inverse electron demand Diels-Alder reactions of cyclopropenone ketals
O O 25 oC
R O O
exo adduct due to destabilizing steric interactions in preferred endo T.S.
72% R = OMe 69% R = H 65% R = CO2Me Boger Tetrahedron 1986, 42, 2777. Boger J. Am. Chem. Soc. 1986, 108, 6695.
OMe MeO MeO O O N O MeO O MeO
OMe MeO N MeO
OMe MeO N MeO
OMe
OH O Grandirubrine OMe
O O Imerubrine
OMe Isoimerubrine
233
Modern Organic Chemistry The Scripps Research Institute d. Quinones are outstanding dienophiles O
O e. Number and position of electron-withdrawing groups
dienophile
or
Diels-Alder Reaction
Dienophile NC NC NC CN 1.3 x 109 CN CN 5.9 x 105 CN NC CN 1.3 x 104
Relative Rates
4.3 x 107
4.8 x 105
4.5 x 104
CN
0.09
NOTE: large increase in rate by addition of one more complementary EWG NOT as large an increase upon addition of one more noncomplementary EWG
COOCH3 215 CH3OOC CH3OOC COOCH3 140 31 74
f. cis vs. trans Dienophiles -In polar (or radical) processes, cis isomer reacts faster than trans, but in Diels-Alder reaction: COOCH3 CH3OOC Due to E E one additional destabilizing steric interaction -The relative rates of such cis vs. trans reactions are sometimes used to distinguish between concerted cycloadditions vs. nonconcerted stepwise reactions. COOCH3 COOCH3
E E
234
g. Heterodienophiles: typically electron-deficient e.g. CH3OOC O COOCH3 HOMOdiene-controlled Diels-Alder reaction.
2 component h. Heterodienes: typically electron-deficient e.g. H O LUMOdiene-controlled Diels-Alder reaction. 4 component introduction of heteroatom makes diene electron-deficient. Note: Dienophiles can also be generated in situ: OCH3 OCH3 CH3O OCH3 OCH3 CH3O OCH3
Boger J. Org. Chem. 1984, 49, 4050. catalytic amount O N N electron-deficient diene N N N N2, retro Diels-Alder reaction N N
N H
N N H N Catalytic Diels-Alder reaction Boger J. Org. Chem. 1982, 47, 895. i. Dienophiles which are not electron-deficient (1) Participate in inverse electron demand Diels-Alder reactions: Cl Cl Cl Cl Cl Cl O O O O 1 N
krel =
12
McBee J. Am. Chem. Soc. 1954, 77, 3858. Jung J. Am. Chem. Soc. 1977, 99, 5508. (2) Can be used in cation-radical Diels-Alder reactions. (3) Also include the behavior of strained olefins.
235
Modern Organic Chemistry The Scripps Research Institute j. Dienophile equivalents -Many specialized dienophiles have been developed which react well in the Diels-Alder reaction and which serve to indirectly introduce functionality not otherwise directly achievable. inaccessible dienophile OH OH equivalent dienophile O O O OsO4 acetylene AgOAc/I2 acetylene OAc OCH3 OCH2Ph OCH3
J. Am. Chem. Soc. 1958, 80, 209. J. Org. Chem. 1988, 53, 5793. J. Org. Chem. 1984, 49, 4033.
OH HO
m-CPBA; H+, H2O acetylene AcO
OCH2Ph R2B
BR2
Chem. Ber. 1964, 97, 442. J. Org. Chem. 1988, 53, 5793, 3373. Tetrahedron Lett. 1994, 35, 509.
O or CH2
OH
AcO
CN + OH-
Cl
COCl Me3Si + NaN3/ HOAc, H2O
OMe
MeO
OMe
PPh3
BR2
J. Am. Chem. Soc. 1956, 78, 2473. J. Am. Chem. Soc. 1971, 93, 4326. Tetrahedron Lett. 1979, 4438. J. Org. Chem. 1977, 42, 4095. Review: Synthesis 1977, 289.
O or OH OH OH MeO OMe
J. Org. Chem. 1984, 49, 4033.

OMe COCH3 N O N COCH3 R N O OH O R = H, COCH3 O Br CHO + BH4; MeO Br CHO + BH4; TsCl; HO
NH2 NH2
NH2
Tetrahedron Lett. 1977, 3115. Ann. 1976, 1319.
J. Am. Chem. Soc. 1972, 94, 2549.
236
Key Ring Forming Reactions Dale L. Boger inaccessible dienophile O or CH2 O COOR O Cl Cl O O O O MeO O O + m-CPBA O O O O + H2O; Pb(OAc)4 O OR R = Et, Ac NR2 enamines N O SO2Ph SO2Ph SO2Ph S O + (RO)3P O O H Ph + nBuLi OMe Me CO2H MeO OMe O equivalent dienophile RS O O
J. Am. Chem. Soc. 1977, 99, 7079.
J. Am. Chem. Soc. 1977, 99, 7079.
+ PCl5; HO- Chem. Ber. 1964, 97, 442. J. Org. Chem. 1973, 38, 1173.
J. Am. Chem. Soc. 1973, 95, 716, 7161. J. Org. Chem. 1984, 49, 4033.
R R = H, R COR O2N
BR2
SO2Ph
J. Am. Chem. Soc. 1980, 102, 853. J. Am. Chem. Soc. 1990, 112, 7423. J. Am. Chem. Soc. 1978, 100, 2918. Tetrahedron Lett. 1981, 22, 603. J. Org. Chem. 1979, 44, 1180. J. Org. Chem. 1977, 42, 2179. J. Am. Chem. Soc. 1978, 100, 7099.
COR O2N reversed regioselectivity
SO2Ph
COR
PhS
COR
PhO2S
COR
PPh3
CH3
SOPh
J. Org. Chem. 1977, 42, 4095. J. Chem. Soc., Chem. Commun. 1991, 1671.
O EtO2C O O CO2Et
J. Org. Chem. 1977, 42, 4095.
237
Modern Organic Chemistry The Scripps Research Institute 11. Diene -Dienes must adopt an s-cisoid (s-Z) conformation to react. H H H H (~2.3 kcal/mol) s-Z (cisoid) H H
s-E (transoid) Cisoid conformation of diene is favored with: (a) 2- and/or 3-substitution CH3 H CH3 H
CH3 H H CH3 R CH3 CH3 R
(b) 1-Substituted dienes
E-diene
But
R H
not very reactive
Z-diene
105 rate difference for cis and trans R
can be used to separate cis and trans isomers of dienes (c) And, by locking the diene into cisoid conformation
>
>
reaction rates for cyclic dienes are faster
O O O
MeO 110 12 5 3.3 2.2 2 1
Cl 0.1
krel = 1348
238
Key Ring Forming Reactions Dale L. Boger 12. Functionalized Dienes Review: Petrzilka, Grayson Synthesis 1981, 753. -Diels-Alder reaction with introduction of useful functionality O RO 160 oC RO O H3O+ O O
Danishefsky J. Am. Chem. Soc. 1979, 101, 6996. -Danishefsky: OCH3 CHO H OCH3 CHO TMSO Si O H3O+ (-CH3OH) O CHO
So an alternative disconnection for ,-unsaturated enones
looks like a Robinson annulation product
R Y O O
OCH3 Y TMSO Example: OCH3 R TMSO O R = Me i) 200 C 2 h, xylene ii) H3O+ 47% O O R
H compare to O
O Wieland-Miescher Ketone see also: Danishefsky J. Am. Chem. Soc. 1979, 101, 6996, 7001, 7009, 7013.
239
Modern Organic Chemistry The Scripps Research Institute Companion Strategy: Woodward J. Am. Chem. Soc. 1952, 74, 4223; Bloom J. Org. Chem. 1959, 24, 278. regioselectivity: ortho adduct diastereoselectivity: 2o orbital interaction of endo addition O CH3 CH3O O vinylogous ester, not as reactive O NaBH4 CH3O H OH i) MsCl, Et3N, CH2Cl2 ii) Zn/HOAc (reductive elimination) OH CH3O O H CH3 110 oC 5.5 d (endo) 50% CH3O O O
Al2O3 (epimerization) O
vinylogous ester, so this carbonyl not reduced by NaBH4
CH3O
CH3O
H very useful
See also:
Robinson J. Am. Chem. Soc. 1961, 83, 249. Orchin, Butz J. Org. Chem. 1943, 8, 509. Kishi Tetrahedron Lett. 1970, 5127. Kakushima Can. J. Chem. 1976, 54, 3304.
240
Key Ring Forming Reactions Dale L. Boger Can also add nucleophiles (RLi, H) to the "vinylogous ester" carbonyl: H H O R'
i) R'Li (R' = alkyl, H, etc.) H ii) H3O+ R
CH3O
CH3O
as above O CH3 CH3O O -Aromatic Annulation CH3O + O CO2CH3 O CO2CH3 O CO2CH3 R O R'
H3O+
OR any oxygenated aromatic substitution pattern using different electron-rich olefins. OCH3
OCH3 OCH3 OCH3 CH3O OCH3 CH3O
OCH3
Boger J. Org. Chem. 1984, 49, 4033, 4045 and 4050. Use of aromatic annulation in total synthesis:
CH3 OH
OCH3 CH3O CH3O N X Rufuscine, Imelutine Norrufuscine X = H, OR
HO CH3 Juncusol OR
241
Modern Organic Chemistry The Scripps Research Institute Heteroatom Substituted Dienes: CO2CH3 O LICA THF O 90% CO2CH3 Diels-Alder or Michael-Michael Reaction Lee Tetrahedron Lett. 1973, 3333. OLi CO2CH3 60% OR CO2CH3 O
Kraus Tetrahedron Lett. 1977, 3929.
O O CH3O PhS CH3O PhS 5:1 RS > OR Trost J. Am. Chem. Soc. 1980, 102, 3554. HCl H2O [O] PhSO complement to Danishefsky diene Diels-Alder product. O O
Danishefsky Diene: (see summary list) OCH3 W HCl TMSO TMSO H2O-THF O
OCH3
OCH3
CO2CH3 CO2CH3 1) KOH 2) KI3 H Iodolactonization O
O O
TMSO
O O H
OH
O O
Vernolepin Danishefsky J. Am. Chem. Soc. 1977, 99, 6066.
242
Key Ring Forming Reactions Dale L. Boger OSiR3 OR O
OR
Note the dienophile and diene equivalency list O i. 80-140 C OMe Cl OSiR3 O OH ii. HCl, aq. THF O
OH O
OH
Brassard Tetrahedron Lett. 1979, 4911. Danishefsky Applications Reviews: Danishefsky Chemtracts: Org. Chem. 1989, 2, 273. Danishefsky Acc. Chem. Res. 1981, 14, 400. dienes tatettine coriolin prephenate griseofulvin pentalenolactone vernolepin lasiodiplodin papulacandin aglycon vineomycinone methyllincosamide KDO and N-acetylneuraminic acid tunicaminyluracil mevinolin
J. Am. Chem. Soc. 1979, 101, 6996, 7001 and 7008. J. Am. Chem. Soc. 1980, 102, 2838. J. Am. Chem. Soc. 1980, 102, 2097. J. Am. Chem. Soc. 1979, 101, 7013. J. Am. Chem. Soc. 1979, 101, 7018. J. Am. Chem. Soc. 1980, 102, 1974. J. Am. Chem. Soc. 1977, 99, 6066. J. Org. Chem. 1979, 44, 4716. Carbohydr. Res. 1987, 171, 317. J. Am. Chem. Soc. 1985, 107, 1285. J. Am. Chem. Soc. 1985, 107, 1274. J. Am. Chem. Soc. 1988, 110, 3929. J. Am. Chem. Soc. 1985, 107, 7761. J. Am. Chem. Soc. 1989, 111, 2599. Pure App. Chem. 1988, 60, 1555.
compactin avermectin A1a
J. Am. Chem. Soc. 1989, 111, 2596. J. Am. Chem. Soc. 1987, 109, 8119. J. Am. Chem. Soc. 1987, 109, 8117. J. Am. Chem. Soc. 1989, 111, 2967.
octosyl acid -methylperacetylhikosanamide zincophorin 6a-deoxyerythronolide
J. Am. Chem. Soc. 1988, 110, 7434. J. Am. Chem. Soc. 1989, 111, 2193. J. Am. Chem. Soc. 1988, 110, 4368. Silicon Chem. 1988, 25 (Ellis Horwood Ltd.)
243
Modern Organic Chemistry The Scripps Research Institute -Unactivated dienes O CO2CH3 O O HBr CO2CH3
CO2CH3
double activation permits reaction even with deactivated dienes Boger J. Org. Chem. 1985, 50, 1904. RO RO N OR N
intramolecular reaction permits use of unactivated diene or dienophile Boger Tetrahedron Lett. 1991, 32, 7643.
-Deslongchamp: Tetrahedron Lett. 1990, 31, 3969; Synlett 1990, 516. R1 CO2CH3 R2 + O tBu CO2 via [4 + 2] Diels-Alder reaction 1. Cs2CO3, CH2Cl2 2. TsOH H O O R1 R2
E = CO2CH3 R1 R2 OH CO2tBu -Compilation of Representative Functionalized Dienes Review: Petrzilka, Grayson Synthesis 1981, 753. diene R = SiMe3 RO R = Et reference
Tetrahedron Lett. 1976, 2935. J. Chem. Soc., Chem. Commun. 1974, 956. J. Chem. Soc., Chem. Commun. 1966, 1152. J. Am. Chem. Soc. 1980, 102, 3270.
R = Ac R = P(O)(OEt)2
Tetrahedron Lett. 1976, 1967. Helv. Chim. Acta 1979, 62, 442; Synthesis 1981, 756.
244
Key Ring Forming Reactions Dale L. Boger diene R = CH3, Ac R = Ac OR R = CH3, 3-Me R = CH3, 4-Me R = Ac, 3-Me reference
Tetrahedron Lett. 1976, 3869, 3873. J. Am. Chem. Soc. 1977, 99, 8116. Tetrahedron Lett. 1978, 1387. Tetrahedron Lett. 1978, 3869. J. Chem. Soc., Chem. Commun. 1980, 197. Syn. Commun. 1980, 197. J. Org. Chem. 1980, 45, 4825.
OMe Danishefsky's diene Me3SiO
J. Am. Chem. Soc. 1974, 96, 7807. J. Org. Chem. 1975, 40, 538. J. Am. Chem. Soc. 1977, 99, 5810. J. Am. Chem. Soc. 1979, 101, 6996, 7001.
See Danishefsky reference list. see also: J. Chem. Soc., Perkin Trans. 1 1979, 3132.
OR
R = Me R = Et
J. Org. Chem. 1982, 47, 4474. J. Am. Chem. Soc. 1978, 100, 7098. Syn. Commun. 1977, 7, 131. Chem. Lett. 1978, 649. Tetrahedron Lett. 1976, 3169. Chem. Pharm. Bull. 1978, 26, 2442. Synthesis 1981, 30. Tetrahedron Lett. 1979, 159. Tetrahedron Lett. 1980, 21, 3557.
RO
R = SiMe3
OR OMe Me3SiO
R = SiMe3
Tetrahedron Lett. 1979, 4438. Chem. Lett. 1978, 649.
R = Me
J. Chem. Soc., Perkin Trans. 1 1976, 1852. J. Org. Chem. 1978, 43, 379. J. Am. Chem. Soc. 1979, 101, 7001.
OMe
See Danishefsky reference list.
J. Org. Chem. 1977, 42, 1819.

Me3SiO SePh
245
Modern Organic Chemistry The Scripps Research Institute diene OR R = CH3 R = Ac, 2-Me R = SiMe3 OR R = Ac reference
J. Am. Chem. Soc. 1978, 100, 7098. J. Org. Chem. 1976, 41, 2625. J. Org. Chem. 1976, 41, 1799. Tetrahedron Lett. 1980, 21, 3413. J. Org. Chem. 1965, 30, 2414. Org. Syn. 1970, 50, 24. Angew. Chem., Int. Ed. Eng. 1979, 18, 304. J. Chem. Soc., Dalton Trans. 1974, 956. Chem. Ber. 1957, 90, 187. J. Org. Chem. 1976, 41, 1655, 2625. J. Org. Chem. 1978, 43, 4559. J. Chem. Soc., Chem. Commun. 1974, 956.
RO RO
R = SiMe3
J. Org. Chem. 1978, 43, 2726. Chem. Lett. 1977, 1219; 1978, 649. Synthesis 1971, 236. Synthesis 1976, 259. Tetrahedron Lett. 1972, 4593.
Others
J. Org. Chem. 1960, 25, 1279. J. Am. Chem. Soc. 1957, 79, 3878. J. Am. Chem. Soc. 1941, 63, 131. J. Chem. Soc., Perkin Trans. 1 1979, 1893.
OR OMe
R = CH3 R = SiMe3 R = CH3, 3-Me
Recl. Trav. Chim. Pays-Bas 1975, 94, 196. Tetrahedron Lett. 1979, 4911. Tetrahedron Lett. 1979, 4912. J. Org. Chem. 1976, 41, 3018. Can. J. Chem. 1974, 52, 80. J. Org. Chem. 1978, 43, 1435.
OEt EtO
J. Chem. Soc., Perkin Trans. 1 1979, 3132.

Me3SiO
246
Key Ring Forming Reactions Dale L. Boger diene OEt reference
J. Chem. Soc., Perkin Trans. 1 1979, 3132.

Me3SiO OEt OMe OMe R OMe R = H, OSiMe3
J. Chem. Soc., Perkin Trans. 1 1979, 3132. J. Org. Chem. 1978, 43, 1435.
J. Org. Chem. 1976, 41, 3218.

RS
J. Org. Chem. 1978, 43, 1208. Angew. Chem., Int. Ed. Eng. 1966, 5, 668. J. Chem. Soc., Chem. Commun. 1978, 657.
SR (also reports corresponding sulfoxides).
J. Org. Chem. 1978, 43, 1208.

OR R = CH3, R1 = H RO R R R R R1
1
J. Chem. Soc. 1964, 2932, 2941. Tetrahedron Lett. 1976, 3169.
R = SiMe3, R1 = H, Me
R = H, R1 = Me R = H, R1 = Ac R = Me, R1 = SiMe3
Tetrahedron Lett. 1970, 4427. J. Am. Chem. Soc. 1968, 90, 113. Tetrahedron Lett. 1977, 611.
R1O
OR
R = SiMe3
Tetrahedron Lett. 1981, 22, 645. J. Am. Chem. Soc. 1980, 102, 3654 and 5983.
R = CH3
J. Chem. Soc. 1964, 2932 and 2941. J. Chem. Soc., Perkin Trans. 1 1973, 3132; 1976, 2057. Tetrahedron Lett. 1970, 3467 and 4427. Tetrahedron 1967, 23, 87.
247
Modern Organic Chemistry The Scripps Research Institute diene OR reference
SR RO RS
J. Am. Chem. Soc. 1976, 98, 5017. J. Am. Chem. Soc. 1977, 99, 8117. J. Am. Chem. Soc. 1980, 102, 3548 and 3554. J. Org. Chem. 1982, 47, 4005. J. Org. Chem. 1978, 43, 4052.
RO SR SR SR RO SR R SR
J. Org. Chem. 1976, 41, 3218. Org. Syn. 1979, 59, 202.
J. Org. Chem. 1976, 41, 2934.
J. Org. Chem. 1972, 37, 4474.
R R
OSiR3
Tetrahedron Lett. 1980, 21, 3423.

O OSiR3 NR2 = NEt2
J. Chem. Soc., Chem. Commun. 1981, 211.
J. Org. Chem. 1966, 31, 2885. J. Am. Chem. Soc. 1976, 98, 2352 and 2295.
R 2N
NR2 = NHCOX
NR2 = NHCOX NR2 = NHCO2R NR2
Tetrahedron Lett. 1976, 3089. J. Org. Chem. 1979, 44, 4183. Tetrahedron Lett. 1980, 21, 3323. J. Am. Chem. Soc. 1976, 98, 2352. J. Org. Chem. 1978, 443, 2164. Helv. Chim. Acta 1975, 58, 587. Tetrahedron Lett. 1979, 981.
NR2 = NEt2
Chem. Ber. 1957, 90, 238. Chem. Ber. 1942, 75, 233.
NR2 (comparison)
J. Liebigs Ann. Chem. 1969, 728, 64.
248
Key Ring Forming Reactions Dale L. Boger diene reference
Me3Si
J. Org. Chem. 1980, 45, 4810.
CO2Et
J. Org. Chem. 1970, 35, 3851.

EtO SiR3
Tetrahedron 1979, 35, 621.
J. Chem. Soc., Chem. Commun. 1976, 679, 681.

R3Si
R3X X = Si, Sn
13. Heterodienes -Typically, heterodienes are electron-deficient and participate in inverse electron demand Diels-Alder reaction Reviews: Boger Tetrahedron 1983, 34, 2869. Comprehensive Org. Syn., Vol. 5, 451. -Acyclic azadienes, N-sulfonyl-1-azadienes:
R R
SO2Ph N
R R
OR R R
SO2Ph N OR R R R
R * Regiospecific and Diastereospecific R R RO
SO2Ph
endo Boat TS
R R
* Secondary orbital interaction (C-2 diene/OR) * n - * stabilization (T.S. anomeric effect) * Solvent independent rate * Dienophile geometry conserved
* Pressure-induced endo diastereoselectivity * k (trans) > k (cis) * C-3 EWG accelerates reaction (25 C) * And C-2 or C-4 EWG accelerate reaction * C-3 > C-2 or C-4 (25 C)
249
Modern Organic Chemistry The Scripps Research Institute O MeO OH O MeO H2N O O N H OMe Fredericamycin A Boger J. Am. Chem. Soc. 1995, 117, 11839. Streptonigrone Boger J. Am. Chem. Soc. 1993, 115, 10733. N H2N H N O CH3 OH OMe ()-Mappicine Nothapodytine B Boger J. Am. Chem. Soc. 1998, 120, 1218. N X = OH, H X=O O N CH3 X O
OH
O HO
-Representative heteroaromatic azadiene Diels-Alder reactions taken from the work of Boger N N R R N R N N R R=H R = CO2Et R = SCH3 R = CO2CH3 R1 N N R = CO2CH3 R = SCH3 R = OMe R N N R N R R R N R N N O N R2 R=H R = CO2Et R N N R N O R = CO2CH3 R = SCH3 R2 R = SO2CH3 N R N N R = CO2CH3 R = SCH3 O R2 R1 N N R R R CO2CH3 NH CO2CH3 R = CO2CH3 R = H, Cl O N R2 R1 R
EDG
R N N
R = OMe, SMe R = SMe, NHCOR R1
Reviews: Boger Tetrahedron 1983, 34, 2869. Prog. Heterocycl. Chem. 1989, 1, 30. Chem. Rev. 1986, 86, 781. Bull. Chim. Soc. Belg. 1990, 99, 599. Chemtracts: Org. Chem. 1996, 9, 149.
250
Key Ring Forming Reactions Dale L. Boger -Heterocyclic azadiene Diels-Alder reaction total synthesis applications taken from the work of Boger O MeO H2N O N H2N N CO2H CH3 OH OMe OMe Streptonigrin J. Am. Chem. Soc. 1985, 107, 5745. C5H11 N NH CH3 HO OH HO OH Lavendamycin J. Org. Chem. 1985, 50, 5782 and 5790. H2N O HN N N CO2H CH3 O
MeO
NH Prodigiosin J. Org. Chem. 1988, 53, 1405.
O O N H
O O
Ningalin A J. Am. Chem. Soc. 1999, 121, 54.
N H MeO MeO
HO
CO2Me N Me
cis-Trikentrin A J. Am. Chem. Soc. 1991, 113, 4230.
HO MeO2C
N Me
N NH N HN
Isochrysohermidin J. Am. Chem. Soc. 1993, 115, 11418.
OMP J. Org. Chem. 1984, 49, 4405. H. Fischer received the 1930 Nobel Prize in Chemistry on the structure of haemin and chlorophyll and the subsequent synthesis of haemin. By many, this is regarded as a milestone accomplishment for the field of organic synthesis.
O
nBu
OH OH N CO2H
MeO OH O
Phomazarin J. Am. Chem. Soc. 1999, 121, 2471.
251
Modern Organic Chemistry The Scripps Research Institute H2N O N Me HN NH O N O N H N O OH OMe (+)-CC-1065 J. Am. Chem. Soc. 1988, 110, 4796. OH OMe HO2C N H PDE-I PDE-II OH OMe R = NH2 R = CH3 R N O
J. Am. Chem. Soc. 1987, 109, 2717.

Me S
H2N H2N O H N N H2N O N NH2 CONH2 H N O N H N N H CH3 CO2H H2N N
O H N N
Me NH2 CONH2 HO O N H N N H H N O HO
H N N NH N S
H N O O
Me HO
OH O OH
O O OH
OH OH OCONH2
(+)-P-3A J. Am. Chem. Soc. 1994, 116, 82.
Bleomycin A2 J. Am. Chem. Soc. 1994, 116, 5607, 5619, 5631, 5647.
HO
OH
HO
OH
MeO MeO
OMe
OMe
OMe OMe
N O
CO2Me
O O
H N N MeO O
N O
H N OMe
OMe
OH
OMe Permethyl Storniamide A J. Am. Chem. Soc. 1999, 121, 54.
Lamellarin O Lukianol A J. Am. Chem. Soc. 1999, 121, 54.
252
Key Ring Forming Reactions Dale L. Boger 14. Intramolecular Diels-Alder Reactions Review: Ciganek Org. Reac. 1984, 32, 1. Jung Synlett 1990, 186. Thomas Acc. Chem. Res. 1991, 24, 229. Weinreb Acc. Chem. Res. 1985, 18, 16. Oppolzer Comprehensive Organic Synthesis, Vol. 5; 315. A. General Considerations: -less negative S , which accelerates reaction and results in milder reaction conditions. -naturally affects regioselectivity and diastereoselectivity. -extends Diels-Alder reaction to include systems which are normally unreactive. no activating groups 160 C 95% H
Wilson J. Am. Chem. Soc. 1978, 100, 6289. B. Notable applications in synthesis: -tethered intramolecular Diels-Alder reactions Ph + Ph OiPr Me Me 74% (major diastereomer)
B(OiPr)2 OH Me Me
1. BHT, PhCH3, 150 C, 0.5 h 2. H2O2, NaOH
B O
Ph
OH OH Me
Me Me Me
Me
Batey J. Am. Chem. Soc. 1999, 121, 450.
-metal-catalyzed intramolecular Diels-Alder reactions An emerging group of transition-metal mediated [4 + 2] cycloadditions are under development. Ni-catalyzed Ni(COD)2 (0.1 equiv) O TMS TMS 98% Wender J. Am. Chem. Soc. 1989, 111, 6432. Rh-catalyzed [(C8H14)2RhCl]2 (0.013 equiv) TBSO TBSO 98% Livinghouse J. Am. Chem. Soc. 1990, 112, 4965. O
253
Modern Organic Chemistry The Scripps Research Institute -applications in total synthesis CO2Me CO2Me 1,2,4-trichlorobenzene NOMe HN 200 C, 67% NOMe HN Oppolzer Helv. Chim. Acta 1981, 64, 478.
t Me O Bu t Me O Bu t Me O Bu
CO2Me H
NOMe H
HN
o-dichlorobenzene
MeO H 180 C MeO Kametani J. Am. Chem. Soc. 1978, 100, 6218. O toluene, sealed tube NPiv N Ac 140 C, 24 h Merour Synlett 1998, 1051. N H Ac NPiv O H H MeO H
H H
H NHAlloc O TESO O O H O O OTBS CO2

tBu
H O O 0.2 mM in dodecane TESO 70 C H O H O H O O OTBS Kishi J. Am. Chem. Soc. 1998, 120, 7647. OTBS Me
tBu
NHAlloc
CO2tBu
OTBS O O O O Me toluene, BHT 70 C, 20 h 40-45% O O O O

tBu
Me CO2All
Me3Si
OMOM
Me3Si Roush J. Am. Chem. Soc. 1998, 120, 7411.
OMOM
254
Key Ring Forming Reactions Dale L. Boger 15. Asymmetric Diels-Alder Reaction A. General considerations -Unsymmetrically substituted dienes or dienophiles have enantiotopic faces. Even with exclusive cis-endo addition and regioselectivity, products occur as a pair of enantiomers. RO2C H
Si Re
CO2R CO2R
Re
Si
-There are three possible ways to obtain one of the enantiomers in excess: a) using chiral dienes. b) using chiral dienophiles. c) using chiral Lewis acid catalysts. In addition, double stereoselection can be realized in many situations. -Comparison of chiral substrate vs. chiral catalyst use of a chiral substrate (chiral diene or dienophile): a stoichiometric amount of chiral auxiliary R* is needed and its introduction before and removal after the Diels-Alder reaction are neccessary.
R*O2C
TiCl4
Si Re
+ 60 C CO2R*
+ CO2R*
use of a chiral catalyst: usually 0.1 equiv. is enough to introduce chirality and the catalyst can be recovered from the reaction mixture and reused.
CHO
ML*n + CHO + CHO
B. Chiral dienophiles Review: Oppolzer Angew. Chem., Int. Ed. Eng. 1984, 23, 876. Ager and East Asymmetric Synthetic Methodology; CRC Press: New York, 1996. -Chiral dienophiles provide the vast majority of the examples of asymmetric Diels-Alder reactions. Type I O XR* X = O, NR* Type II O R*
255
Modern Organic Chemistry The Scripps Research Institute First example: O OR* R*O O TiCl4 + toluene 25 C COOR* 78% de 80% yield COOR*
R* = ()-menthyl
Walborsky Tetrahedron 1963, 19, 2333.
COOMe O O R + O AlCl4 CH2Cl2 30 C R = CH2Ph, CONHPh 99% de R*OOC
COOMe
Helmchen Angew. Chem., Int. Ed. Eng. 1981, 20, 205.

tBu
OH O
+ O yield 90% 95%

tBu
OH conditions 20 C, 24 h ZnCl2, 43 C, 1 h
endo
89% 94%
de
99% >99%
Masamune J. Org. Chem. 1983, 48, 1139, 4441. O Et2AlCl N O + 100 C O R N
O R
O O >86% de O R N CH3 O Et2AlCl O Ph + 100 C O O N O R CH3 Ph
>98% de Evans J. Am. Chem. Soc. 1984, 106, 4261; 1988, 110, 1238.
256
Key Ring Forming Reactions Dale L. Boger other notable chiral dienophiles:
O OH S O O R N O CH3 R1 Boeckman J. Am. Chem. Soc. 1992, 114, 2258. O TolS O O O N O
Arai J. Org. Chem. 1991, 56, 1983.
O N SO2 R
R O N SO2 Ph H O
Oppolzer Helv. Chim. Acta 1989, 72, 123. Oppolzer Tetrahedron Lett. 1990, 31, 5015. O COOMe
Inverse electron demand Diels-Alder reaction Posner J. Am. Chem. Soc. 1986, 108, 7373.
OR*
R* = l-menthyl
Liu Tetrahedron Lett. 1991, 32, 2005. Boger J. Org. Chem. 1985, 50, 1904. X R O R' X = O, NAc Roush Tetrahedron Lett. 1989, 30, 7305 and 7309. Kneer Synthesis 1990, 599. Me Tol S O CO2Et O
Feringa Tetrahedron: Asymmetry 1991, 2, 1247. O N O Meyers Tetrahedron Lett. 1989, 30, 6977. O O O CH3 H Et CO2Me
O OBn
Koizumi Tetrahedron Lett. 1984, 25, 87. O N R2 Ghosez Tetrahedron Lett. 1989, 30, 5891. R1
Danishefsky J. Am. Chem. Soc. 1982, 104, 6457. Danishefsky J. Am. Chem. Soc. 1984, 106, 2455. Ph3CO R O O
Koga J. Chem. Soc., Perkin Trans. 1 1990, 426.
257
Modern Organic Chemistry The Scripps Research Institute C. Chiral dienes -These have been much less extensively studied. O O (S) O Ph + O H MeO BF3OEt2 Ph H O CHO 64% de
H OMe
Ph O O +
Trost J. Am. Chem. Soc. 1980, 102, 7595.
O 15 kbar 23 h, 20 C 62% O Dauben Tetrahedron Lett. 1982, 23, 4875. O + O O 15 kbar 23 h, 20 C 62% EtO2C
COR* 50% de
EtO2C
O O O
H TMSO Me O OAc OAc OAc OAc + N Ph Me O R*O H Smith Tetrahedron Lett. 1989, 30, 3295.
TMSO
O N Ph 90% de O
Stoodley J. Chem. Soc., Perkin Trans. 1 1990, 1339. OMOM + Me H ( S) OTBS MOMO Toluene N Ph O N Ph 25 C, 48 h H O H Me OTBS MOMO THF N Ph 25 C, 0.5 h O H O H PhS Me O O
OMOM + (R) H SPh Me
O N Ph
McDougal Tetrahedron Lett. 1989, 30, 3897.
258
Key Ring Forming Reactions Dale L. Boger D. Chiral Lewis acid catalysts Review: Oh Org. Prep. Proced. Int. 1994, 26, 129. Age and East Asymmetric Synthetic Methodology; CRC Press: New York, 1996. -Pioneer work CHO + 78 C catalyst: R Cl O ClAl R Et
iBu
catalyst toluene
CHO
yield 56% 57% 67%
ee
57% 35% 23%
Koga J. Chem. Soc., Chem. Commun. 1979, 437. Tetrahedron Lett. 1987, 28, 5687. a. Boron-based Lewis acids O Me Me catalyst: CH3O O O OCH3 O COOH O BH O H catalyst + Me Me CHO endo CHO + Me Me exo
3:97 (endo:exo) 90% yield 91% ee
Yamamoto J. Org. Chem. 1989, 54, 1481.
O BH3, HOAc Ph OH O OH OH Ph Ph O O
O O Ph OCH3
OH O
OCH3
70-90% yield 98% ee
Kelly J. Am. Chem. Soc. 1986, 108, 3510.
259
Modern Organic Chemistry The Scripps Research Institute O B(OMe)3 HO OH O HO NHAr NHAr O O ArHN O O NHAr OSiR3 73% yield 92% ee O O
OH O
OSiR3
Yamamoto Tetrahedron Lett. 1986, 27, 4895.
other boron-based catalysts SO2Ar R N HB O O O O O BB O O O R = Et R = iPr R = 3-indole
C3-symmetric Kaufmann Angew. Chem., Int. Ed. Eng. 1990, 29, 545. See also: Yamamoto J. Am. Chem. Soc. 1998, 120, 6920.
Yamamoto Synlett 1990, 194. Helmchen Synlett 1990, 197. Mukaiyama Chem. Lett. 1991, 1341. Corey J. Am. Chem. Soc. 1991, 113, 8966.
tBuCH 2
BBr2SMe2
CH3 Br B
CH3
Cl2B Hawkins J. Am. Chem. Soc. 1991, 113, 7794. Kaufmann Tetrahedron Lett. 1987, 28, 777. Kaufmann J. Organomet. Chem. 1990, 390, 1.
260
Key Ring Forming Reactions Dale L. Boger b. Aluminum-based Lewis acids BnO O N O O + CH2OBn 78 C CH2Cl2 catalyst O N O O
catalyst: Ph CF3O2SHN Al Ph NHSO2CF3
94% yield 95% ee
CH3
Corey J. Am. Chem. Soc. 1989, 111, 5493. Corey J. Am. Chem. Soc. 1992, 114, 7938.
OMe Me + TMSO Me catalyst: SiAr3 O Al Me O SiAr3 Ar = Ph, 3,5-xylyl H
O 1) (R)-catalyst 2) CF3COOH
Me O
O Ph Me 95 - 97% ee
Yamamoto J. Am. Chem. Soc. 1988, 110, 310.
other chiral ligands used for chiral aluminum-based Lewis acids: CH3 H Ph Ph CH3O OH CH3 H Ph Ph HO OH
Ph Ph
OH OH
Ph Ph
OH OH
Kagan Tetrahedron: Asymmetry 1990, 1, 199.
OH OBn BnO OBn OH Wulff, Rhenigold J. Am. Chem. Soc. 1993, 115, 1814. OBn NH SO2
Chapuis Helv. Chim. Acta 1987, 70, 436.
261
Modern Organic Chemistry The Scripps Research Institute c. Titanium-based Lewis acids Cl Cl R N O + O N O R O +
R*
Ti
O R N O O
endo
catalyst: R* = Ph Ph Me O O Ph Ph OH OH Ph Narasaka J. Am. Chem. Soc. 1989, 111, 5340. Seebach Helv. Chim. Acta 1987, 70, 954. Other Titanium catalysts: O O O O Chapuis Helv. Chim. Acta 1987, 70, 436. O TiCl2 O Ph O R* Ti Cl Cl
exo
endo:exo (90:10) endo 92% ee
Ph
O TiCl2
Oh J. Org. Chem. 1992, 57, 396. CH3
Ph O TiCl2 O O Ph O TiCl2 OH OH
X OH OH X X = Ph, SiPh3, SitBuPh2, SiiPr3, Si(o-tolyl)3
CH3 Mikami Tetrahedron: Asymmetry 1991, 2, 643. Chapuis Helv. Chim. Acta 1987, 70, 436. Yamamoto J. Org. Chem. 1993, 58, 2938.
d. Copper-based Lewis acids R Cu(OTf)2 O + bis(oxazoline) O N O O R = H, CH3, Ph, CO2Me 90 - 97% ee 85 - 92% yield
O R N
262
Key Ring Forming Reactions Dale L. Boger bis(oxazoline): CH3 CH3 O O N R N R R = Ph iPr tBu
Evans J. Am. Chem. Soc. 1993, 115, 6460. Evans Tetrahedron Lett. 1993, 34, 7027.
Me catalyst + (MeO)2P O O OEt (MeO)2P O
Me H+ O OEt MeO2C
Me
CHO
94 - 99% ee
catalyst: CH3 CH3 O O N Me3C Cu N CMe3

2+
or 2 OTf
CH3 CH3 O O N Ph Cu N Ph
2+
2 OTf
Evans J. Am. Chem. Soc. 1998, 120, 4895. e. Iron, Magnesium-based Lewis Acids CH3 CH3 O N Ph I Fe N I Ph
+
CH3 CH3
CH3 CH3 O N Mg N I Ph
CH3 CH3
Ph
Corey J. Am. Chem. Soc. 1991, 113, 728. f. Miscellaneous chiral Lewis acids
Corey Tetrahedron Lett. 1992, 33, 6807.
C3F7 O Yb(OTf) O O Eu(hfc)3 Kobayashi Tetrahedron Lett. 1993, 34, 4535. Danishefsky J. Am. Chem. Soc. 1986, 108, 7060. Eu 3 O
263
Modern Organic Chemistry The Scripps Research Institute E. Biological catalysts COOR + COOR R = Me, Et Rao Tetrahedron Lett. 1990, 31, 5960. Catalytic antibodies (abzymes): O abzyme + O HN O O O O
O
Baker's yeast
COOR COOR 100% exo, against the Alder endo rule
O NHAc O O NH O N NHAc
O Schultz J. Am. Chem. Soc. 1990, 112, 7430. Schultz Science 1998, 279, 1929. Review: Schultz, Lerner Science 1995, 269, 1835. IgG 4D5 + CONMe2 IgG 13D5 CONMe2 (endo) NHCO2R CONMe2 (exo) Houk, Janda, Lerner Science 1993, 262, 204. Janda J. Am. Chem. Soc. 1995, 117, 7041. Houk, Janda, Wilson Science 1998, 279, 1934. O abzyme + N Et O O Cl NHCO2R
NHCO2R R = 4-carboxybenzyl
Cl Cl
Cl SO2 Cl
Cl
O S O Cl O N Et
Cl Cl
O N Et
Cl
Cl Cl O
Hilvert J. Am. Chem. Soc. 1989, 111, 9261. F. Double asymmetric induction O O (S) O Ph + O OH
tBu
MeO BF3OEt2 Ph H
O OH
tBu
H OMe
ds > 130:1
O O (R) O Ph + O OH
tBu
MeO BF3OEt2 H Ph
O OH
tBu
MeO H
ds 35:1
Masamune J. Org. Chem. 1983, 48, 4441.
264
Key Ring Forming Reactions Dale L. Boger S O N Bn O Ph catalyst + 20 C, 36 h O Bn matched S O N Bn catalyst:

2+
H Ph S N O
conversion 72% endo:exo > 97:3 endo1:endo2 97:3
O Ph catalyst + 20 C, 36 h O Bn mismatched H Ph S N O conversion 7% endo:exo 97:3 endo1:endo2 57:43
Cl
H N
H N
Cl
Cu Cl Cl
2 OTf
Evans Tetrahedron Lett. 1993, 34, 7027. G. Intramolecular Diels-Alder reactions CH3 O R O (CH3)2Ph 82 64% ee Roush J. Am. Chem. Soc. 1982, 104, 2269. CH3 O N S S catalyst: Ph Ph Me O O Ph Ph O TiCl2 O Ph O O catalyst S H H : 18 (l-bornyloxy)AlCl2 CO2R* R + R CO2R*
S O N CH3 70% yield 87% ee O O
Narasaka Chem. Lett. 1989, 1947.
265
Modern Organic Chemistry The Scripps Research Institute 16. Some Classic and Favorite Total Synthesis Applications OH MeO N H MeO H O O OMe OMe Reserpine Woodward Tetrahedron 1958, 2, 1. N H O OMe OMe Pyridoxol Harris J. Org. Chem. 1962, 27, 2705. Daktorova Tetrahedron 1969, 25, 3527. CH3 N HO OH
O N O N H H H O Fraxinellone Fukuyama Tetrahedron Lett. 1972, 3401.
Ibogamine Sallay J. Am. Chem. Soc. 1967, 89, 6762. Trost J. Am. Chem. Soc. 1978, 100, 3930. OH OH OH HO OH OH HO OH OH OH OH OH
myo-Inositol allo-Inositol Kowarski J. Org. Chem. 1973, 38, 117.
-Damascone Cookson J. Chem. Soc., Chem. Commun. 1973, 161, 742. HO HO COOH
O O O
HO OH
OH
Cantharidin Stork, Burgstahler J. Am. Chem. Soc. 1953, 75, 384. Dauben J. Am. Chem. Soc. 1980, 102, 6893.
Quinic acid Raphael J. Chem. Soc. 1960, 1560. Smissman J. Am. Chem. Soc. 1963, 85, 2184. Wolinsky J. Org. Chem. 1964, 29, 3596. Raphael Tetrahedron Lett. 1968, 1847. Newkome Tetrahedron Lett. 1968, 1851.
OHO O OH OH OH Patchouli alcohol Naf, Ohloff Helv. Chim. Acta 1974, 57, 1868.
HO HN N OH NH H
Tetrodotoxin Kishi J. Am. Chem. Soc. 1972, 94, 9217.
266
Key Ring Forming Reactions Dale L. Boger COOH O MeO MeO HO OH O OMe Prostaglandins Corey J. Am. Chem. Soc. 1970, 92, 397. Taub Tetrahedron Lett. 1975, 3667. Colchicine Eschenmoser Helv. Chim. Acta 1961, 44, 540. Boger J. Am. Chem. Soc. 1986, 108, 6713. MeO NHAc
O Nootkatone Dastur J. Am. Chem. Soc. 1974, 96, 2605. O O O O O H OH R N H -Copaene Corey J. Am. Chem. Soc. 1973, 95, 2303.
O O
Steroids Sarett J. Am. Chem. Soc. 1952, 74, 4974. Sarett J. Am. Chem. Soc. 1954, 76, 5026. OH HO O O N
Chelidonine Oppolzer J. Am. Chem. Soc. 1971, 93, 3836. Me H O O N Me Me Me
Lycorine Torssell Tetrahedron Lett. 1974, 623.
Dendrobine Kende J. Am. Chem. Soc. 1974, 96, 4332. Roush J. Am. Chem. Soc. 1980, 102, 1390.
HO
N H N CH3 N H CO2CH3
Hasubanan Derivative Evans J. Am. Chem. Soc. 1972, 94, 2891.
Minovine Spitzner J. Am. Chem. Soc. 1973, 95, 7146. Spitzner J. Am. Chem. Soc. 1970, 92, 3492.
267
Modern Organic Chemistry The Scripps Research Institute COOH
HO OH
OH
N H Pumilotoxin Oppolzer Helv. Chim. Acta 1977, 60, 48, 204. Inubushi Chem. Pharm. Bull. 1978, 26, 2442. Inubushi Tetrahedron Lett. 1976, 3169. Overman Tetrahedron Lett. 1977, 1253. Overman J. Am. Chem. Soc. 1978, 100, 5179.
Shikimic acid Raphael J. Chem. Soc., Chem. Commun. 1960, 1560. Raphael Tetrahedron Lett. 1968, 1847. Newkome Tetrahedron Lett. 1968, 1851. Smissman J. Am. Chem. Soc. 1962, 84, 1040. Smissman J. Am. Chem. Soc. 1959, 81, 2910. Wolinsky, Vasileff J. Org. Chem. 1964, 29, 3596.
COOH HO
MeO
N H MeO H
N H O O O OMe OMe OMe
HO
OH
Prostaglandins Sakai, Kobori Tetrahedron Lett. 1981, 115.
OMe Reserpine Wender J. Am. Chem. Soc. 1980, 102, 6157. O OH O CH2R2 OH R1 O OH OR3 R3 =
OH HO HO
O O H
CH3
OH
HO NH2
Illudol Fomannosin Semmelhack J. Am. Chem. Soc. 1980, 102, 7567. Semmelhack J. Am. Chem. Soc. 1981, 103, 2427. Semmelhack J. Am. Chem. Soc. 1982, 104, 747.
Anthraquinone antibiotics (aglycon) Kelly J. Am. Chem. Soc. 1980, 102, 5983. Cava J. Am. Chem. Soc. 1981, 103, 1992. Vogel Tetrahedron Lett. 1979, 4533. Brassard Tetrahedron Lett. 1979, 4911. Gesson Tetrahedron Lett. 1981, 22, 1337. Rapoport Tetrahedron Lett. 1980, 21, 4777. Gesson Tetrahedron Lett. 1980, 21, 3351.
H HO
N H Estrone (orthoquinodimethide) CO2CH3 Grieco J. Org. Chem. 1980, 45, 2247. Saegusa J. Am. Chem. Soc. 1981, 103, 476. Vollhardt J. Am. Chem. Soc. 1980, 102, 5245 and 5253. Vinca alkaloids and related analogs Nicolaou J. Org. Chem. 1980, 45, 1463. Kuehne J. Org. Chem. 1980, 45, 3259.
268
Key Ring Forming Reactions Dale L. Boger CH3 CH3 CH3 H Seychellene Yoshkoshi J. Chem. Soc., Perkin Trans. 1 1973, 1843. Jung Tetrahedron Lett. 1980, 21, 3127. CH3 H Patchouli alcohol Naf Helv. Chim. Acta 1974, 57, 1868. OH CH3
HOOC O OC HO CH3 CO2H Gibberellic acid Corey Tetrahedron Lett. 1973, 4477. Corey J. Am. Chem. Soc. 1978, 100, 8031, 8034. OH CH3O O
O O
Fumagillin Corey J. Am. Chem. Soc. 1972, 94, 2549. O
OMe MeO MeO N
MeO H2N O N H2N H N O CH3 OH OMe OMe Streptonigrone Boger J. Am. Chem. Soc. 1993, 115, 10733. Me S
OMe Rufescine Boger J. Org. Chem. 1984, 49, 4050.
H2N
O H N N N
Me NH2 CONH2 HO O N H N N H H N O HO
H N N NH N S
O H2N S N H2N O O H N N NH2 CONH2 H N O CH3 N COOH H H N N H
H2N Me HO O OH O OH
H N O
O O
OH Bleomycin A2 Boger J. Am. Chem. Soc. 1994, 116, 5607, 5619, 5631, 5647.
OH OH OCONH2
(+)-P-3A Boger J. Am. Chem. Soc. 1994, 116, 82.
269
Modern Organic Chemistry The Scripps Research Institute MeO2C OH MeO MeO N H O MeO2C N HO Me O N Me
cis-Trikentrin A Boger J. Am. Chem. Soc. 1991, 113, 4230.

O MeO
Isochrysohermidin Boger J. Am. Chem. Soc. 1993, 115, 11418. O
H2N O
N H2N HO MeO
CO2H Me H2N O HN N N CO2Me Me
OMe Streptonigrin Boger J. Am. Chem. Soc. 1985, 107, 5745. Weinreb J. Am. Chem. Soc. 1980, 102, 3962.
Lavendamycin methyl ester Boger J. Org. Chem. 1985, 50, 5790.
O N NH N HN H
O OH
Trichodermol Still J. Am. Chem. Soc. 1980, 102, 3654. H2N O N Me C5H11 HN NH Me O N O N H N O OH OMe OH OMe
Octamethylporphin Boger J. Org. Chem. 1984, 49, 4405. MeO NH NH Prodigiosin Boger J. Org. Chem. 1988, 53, 1405. CH3 OH MeO HO CH3 Juncusol Boger J. Org. Chem. 1984, 49, 4045. HO N N
(+)-CC-1065/PDE-I and PDE-II Boger J. Am. Chem. Soc. 1987, 109, 2717. Boger J. Am. Chem. Soc. 1988, 110, 4796.
OMe
Sendaverine Boger J. Org. Chem. 1984, 49, 4033.
270
Key Ring Forming Reactions Dale L. Boger H H Ph H COOH n HOOC H H Ph n H
n = 0: Endiandric acid E n = 1: Endiandric acid F Nicolaou J. Am. Chem. Soc. 1982, 104, 5555, 5557, 5558, 5560.
n = 0: Endiandric acid D n = 1: Endiandric acid G Nicolaou J. Am. Chem. Soc. 1982, 104, 5555, 5557, 5558, 5560. OMe
N N H
O MeO
CO2Me
Catharanthine Trost J. Org. Chem. 1979, 44, 2052. O HO
Quassin and Quassinoids Grieco J. Am. Chem. Soc. 1980, 102, 7586.
HO N O
H O HO H CO2H
Indicine N-oxide Keck J. Am. Chem. Soc. 1980, 102, 3632.
Retigeranic acid Corey J. Am. Chem. Soc. 1985, 107, 4339.
NH O
OH
Dodecahedrane Paquette J. Am. Chem. Soc. 1982, 104, 4503.
Perhydrohistrionicotoxin Keck J. Org. Chem. 1982, 47, 3590.
NC
9-Isocyanopupukeanone 9-Pupukeanone Yamamoto J. Am. Chem. Soc. 1979, 101, 1609. White J. Org. Chem. 1980, 45, 1864.
Sativene Snowden Tetrahedron Lett. 1981, 22, 97, 101.
271
Modern Organic Chemistry The Scripps Research Institute O MeO O MeO2C O OH O Phyllanthocin Burke Tetrahedron Lett. 1986, 27, 4237. OMe O O H Me MeO N OMe MeO MeO N OMe
Grandirubrine Imerubrine Boger J. Am. Chem. Soc. 1995, 117, 12452.
O MeO
OH
O O N N CH3 X
O OH HO O N H
X = OH, H2 X=O
Fredericamycin A Boger J. Am. Chem. Soc. 1995, 117, 11839.
()-Mappicine and Nothapodytine B Boger J. Am. Chem. Soc. 1998, 120, 1218.
272
B. Robinson Annulation
Reviews House pp. 606-613. M. Jung, Tetrahedron 1976, 32, 3. Org. React. 1959, 10, 179. Org. React. 1968, 16, 3. Synthesis 1976, 777. Synthesis 1969, 49. R. Robinson was awarded the 1947 Nobel Prize in Chemistry for his work on the synthesis of natural products, especially steroids and alkaloids. Notably, he was also the first to address the issue of reaction mechanisms with applications of valence theory to reaction mechanisms, and is credited with the first use of the curved arrow to indicate electron movement. His synthesis of tropinone (1917) is viewed by many to represent the first natural product total synthesis from simple precursors (succindialdehyde, acetone, and methylamine). Robinson J. Chem. Soc. 1917, 762. (tropinone) Ph
+ O Ph
NaNH2 NH3-Et2O
43% Robinson J. Chem. Soc. 1935, 1285. Generated a great deal of interest and subsequent work because of relationship to steroid synthesis. 1. Scope - Formally, a [4 + 2] condensation approach 1 2 + O 3 4 O O O O Michael Reaction O
O HO O
H. Wieland received the 1927 Nobel Prize in Chemistry for his work in isolating and deducing the structures of bile acids/steroids including cholic acid. He concluded his Nobel Lecture with the statement that he had a "duty" to synthesize the bile acids even though the task was insurmountable at the time.
Aldol Condensation O O
O Wieland-Miescher ketone
OH
Wieland and Miescher Helv. Chim. Acta 1950, 33, 2215. - Alternative "[3 + 3] Robinson Annulation" + O O O Both the [4 + 2] and [3 + 3] approaches were first generalized by Robinson J. Chem. Soc. 1937, 53.
- Org. Synth., Coll. Vol. 5, 486.

O + O O cat. 0.01 N KOH CH3OH O O O N H benzene reflux O
O 60-65%
273
Modern Organic Chemistry The Scripps Research Institute - With stronger base, other reactions are observed: O CH3O O O irreversible step O O O O OCH3 O OCH3
-O
- Double addition of MVK sometimes a problem, especially at more acidic sites. O O
O O -Solutions O NaH O O CH3O OCH3 O CH3O2C NaH O O R = CO2CH3 R O
- For the preparation of the useful octalone derivative, the low yield is acceptable since it is prepared from readily available materials.
tBuOK
O + O
tBuOH
35%
O But, many variations on the reaction have provided general improvements.
Gaspert J. Chem. Soc. 1958, 624. (CO2H)2, H2O OH O steam distill 86%
MVK, NaOEt EtOH-Et2O 10 C, 54%
Marshall J. Org. Chem. 1964, 25, 2501. At low temperature, MVK polymerization is slow and Michael reaction OK, but not sufficiently vigorous for elimination, so the reaction is conducted in two steps.
MVK, cat. H2SO4 O C6H6, reflux, 16 h 49-55% O
Heathcock and McMurry Tetrahedron Lett. 1971, 4995.
274
Key Ring Forming Reactions Dale L. Boger - Alternatives to methyl vinyl ketone: MVK difficult to employ due to tendency to polymerize
X X = NR2 X = N+R3 X = Cl O
+ CH2O + HNR2
Robinson J. Chem. Soc. 1937, 53. Theobald Tetrahedron 1966, 22, 2869. Halsall J. Chem. Soc. 1964, 1029.
- Other equivalents Julia Bull. Soc. Chim., Fr. 1954, 5, 780. Cl Cl OEt Stork J. Am. Chem. Soc. 1956, 78, 501. I R O N Stork Tetrahedron Lett. 1972, 2755. Wenkert J. Am. Chem. Soc. 1964, 86, 2038. CO2CH3 Fried J. Am. Chem. Soc. 1968, 90, 5926. + O OCH3 O P(OR)2 O P(OR)2 O O (RO)2P O SiMe3 I Stork J. Am. Chem. Soc. 1974, 96, 3682. (allylic alkylation reaction is rapid and yield is high) CO2tBu I TMS O Stork J. Am. Chem. Soc. 1973, 95, 6152. Boeckman J. Am. Chem. Soc. 1973, 95, 6867. Stotter J. Am. Chem. Soc. 1974, 96, 6524. O O + Cl Stork J. Am. Chem. Soc. 1967, 89, 5461 and 5463.
Li
CO2R O O
Li
275
Modern Organic Chemistry The Scripps Research Institute Enamine Annulations
O N + O
O N + H
O N
Stork J. Am. Chem. Soc. 1956, 78, 5129. J. Am. Chem. Soc. 1963, 85, 207. Henderickson J. Am. Chem. Soc. 1971, 93, 1307.
O O +
O O
N Bn
N O Bn Stevens J. Chem. Soc., Chem. Commun. 1970, 1585. Evans Tetrahedron Lett. 1969, 1573. Evans J. Org. Chem. 1970, 35, 4122. O + CHO (Wichterle annulation) CHO
Corey J. Am. Chem. Soc. 1963, 85, 3527. - The bridged annulation
+ O O O
reversible aldol
OH
reversible aldol
irreversible
irreversible O O OH slow, difficult H2O: requires vigorous H+conditions usually kinetic aldol product but formed reversibly elimination especially effective under basic conditions O
276
Key Ring Forming Reactions Dale L. Boger - Helminthosporal synthesis, Corey J. Am. Chem. Soc. 1963, 85, 3527. O 1. HCO2Et 2. MVK, Et3N 3. K2CO3, EtOH-H2O O
BF3OEt2 CH2Cl2
6 steps
OHC CHO H
Aromatic Annulation H O S Ph
PhOS + O O
syn-sulfoxide elimination
HO
O Boger J. Org. Chem. 1980, 45, 5002.
tBuOK
OH OBn HO HO Juncusol
CH3OS + O O
tBuOH
61%
Boger J. Org. Chem. 1984, 49, 4045.
2. Diastereoselectivity
When R = H, also subject to equilibration to most stable isomer.
O Substituents at this position subject to thermodynamic equilibration to most stable product.
R1 R2 General Observations: O R4 R3
277
Modern Organic Chemistry The Scripps Research Institute 3. Tandem Robinson Annulation (Incorporation of more than four carbons from MVK for more convergent syntheses)
- Examples
O CH3O2C Karady Tetrahedron Lett. 1976, 2401. Velluz Angew. Chem., Int. Ed. Eng. 1965, 4, 181.
via Michael addition to vinyl pyridine Birch reduction to dihydropyridine, and hydrolysis to diketone Danishefsky J. Am. Chem. Soc. 1968, 90, 520. Danishefsky J. Am. Chem. Soc. 1975, 97, 380.
Elements of three sequential Robinson annulations O (3) (2) O (1)
CH3O
via Birch reduction of aromatic ring, followed by hydrolysis
MeO
OH
Poirier Tetrahedron 1989, 45, 4191.
Cl O CO2tBu Danishefsky J. Am. Chem. Soc. 1971, 93, 2356.
278
Key Ring Forming Reactions Dale L. Boger 4. Robinson Annulation: Key Synthetic Transformations R R m-CPBA HO O HO H(R') R Claisen Rearrangement CHO NaBH4 (R'Li) R R
2
R CrO3 LiO Li/NH3 HO
reduction Simmons-Smith cyclopropanation
CuLi O
BH3, H2O2 oxidation O
O Key Intermediate Derived From Robinson Annulation R
CHO R NaOH R
R Li/NH3
LiO
cyclopropanation O R Li/NH3 O R RX H R LDA, MeI O R 0.95 equiv Ph3CLi MeI R
O O R
DDQ O R KOtBu, MeI O R R2AlCN O CN R
O R
NH2NH2 base O O R
H2O2, NaOH
R'2CuLi O R' R
Li/NH3 O R R'2CuLi R H R O O [O] H BH3, H2O2 O X X = OH, H X=O O Ph2P(O)O H R HO cat.

tBuOH
H2, Pd-C cat. H+ O H R HO2C
H R Li/NH3 Ph2P(O)Cl O3
O R R OsO4 OH
OH H+ O
Ph3P=CH2
HO
279
Modern Organic Chemistry The Scripps Research Institute R NaBH4 or LiAlH4 H O R LisBu3BH THF equatorial axial OH H HO delivery R
HO
axial delivery equatorial OH - Deconjugation with ketalization or reduction R ethylene glycol O O TsOH, C6H6 O R Ac2O
NaBH4 EtOH HO
AcO
Marshall J. Org. Chem. 1972, 37, 982. - Reductive deoxygenation: - without double bond migration R 1. LiAlH4, Ac2O 2. Li, EtNH2 O R 1. BF3OEt2 ethanedithiol 2. Raney-Ni EtOH R
- with double bond migration R 1. Li, NH3 ClPO(NMe2)2 O R TsHNN via N N H Hydrogenation: McMurry J. Am. Chem. Soc. 1968, 90, 6821; Can. J. Chem. 1972, 50, 336. Birch reduction: For exceptions to generalizations which can exist-see Boger Tetrahedron Lett. 1978, 17. HO2C Pb(OAc)4 O Cu+2 O HO2C Li/NH3 O H2 Pd-C O H trans HO2C Pb(OAc)4 Cu+2 O R NaCNBH3 HCl, DMF R
2. Li, EtNH2 via enol phosphate
H cis 5. Asymmetric Robinson Annulation and Related Reactions
Taber J. Org. Chem. 1989, 54, 3831. H3CO O H O O O O Ar CO2R*
280
Key Ring Forming Reactions Dale L. Boger Asymmetric Michael Revial Tetrahedron Lett. 1989, 30, 4121. d'Angelo J. Am. Chem. Soc. 1985, 107, 273. Guingant Tetrahedron: Asymm. 1993, 4, 25. R EWG EWG N Ph H HN Ph H O 90%, 90% ee
R O
Asymmetric Aldol
O (MeO)2P O O O
HO
64-80% CO2R* 91-98% de Mandai J. Org. Chem. 1994, 59, 5847.
D-proline
DMSO 82% O O 69% ee O O

L-proline
Harada Synthesis 1990, 53.
TsOH, benzene O 69% O 63% ee Swaminathan Tetrahedron: Asymm. 1996, 7, 2189.
L-proline
93% O O 88% ee O O ab 38C2 O O >95% ee Lerner J. Am. Chem. Soc. 1998, 120, 2768. O Hajos J. Org. Chem. 1974, 39, 1615.
281
6. Steroid Synthesis Steroid synthesis: Woodward (Nobel 1965), Robinson (Nobel 1947) Isolation methods: Chromatography Conformational analysis: Barton (Nobel 1969) UV spectroscopy: Woodward, Fieser ORD: Djerassi Biosynthesis theory: Bloch and Lynen (Nobel in Med. 1964), Cornforth (Nobel 1975)
1. Cholesterol Isolation: 1812 Structure, wrong!, Windaus (Nobel 1928) and Wieland (Nobel 1927) 1932, correct planar connectivity (Wieland) 1947, stereochemistry 1952, absolute stereochemistry HO
H H H
2. Sex Hormones OH H H HO Estradiol OH H H O H H
The hormone responsible for female development and maintenance of reproductive organs and secondary sex characteristics. Pure material isolated 1929, E. Doisy (St. Louis Univ.) and A. Butenandt (Gottingen, Nobel 1939) 4 tons of sow ovaries: 25 mg
The male sex hormone 1931, Butenandt isolated androsterone (metabolite of testosterone) 15,000 L of men's urine: 15 mg 1935, testosterone isolated from 100 kg bull testicles: 10 mg, E. Laquer 1939, planar structure elucidated by Butenandt, Ruzicka (Nobel 1939)
Testosterone
O H H O Progesterone H The pregnancy hormone: maintains proper uterine environment for development of fetus, inhibits further ovulation, nature's contraceptive. 1934, isolation and planar structure, Butenandt 50,000 sows to provide 625 kg ovaries: 20 mg
3. Cortisone OH Structure: 1935-38, Kendall, Reidstein, Wintersteiner from adrenal cortex of 1.25 million cattle OH 1952, 36 step synthesis via degradation of bile acids (Sarett, Merck) 1949, Hench and Kendall (Mayo Clinic), 1950 Nobel with Reinstein for anti-arthritic activity 1951, Djerassi (Syntex), synthesis from Mexican yam steroid 1951, Upjohn microbial process for C11 oxidation of progesterone O
O H H O H
282
Key Ring Forming Reactions Dale L. Boger Natural steroid hormones are present in such trace amounts in mammals that it is not a practical source. Synthetic steroids, e.g. 19-nor steroids, became commercially important. Russell E. Marker (Syntex, Penn. State) Degradation of sapogenins and other plant products J. Am. Chem. Soc. 1947, 69, 2167. Diosgenin is obtained from the Mexican diocorea plant (Mexican yams).
H H H HO Diosgenin O O H H O O
(1) Ac2O/C7H11CO2H 2 h, 240 C H (2) KOH, MeOH reflux, 0.5 h 85-90% H HO H
H O OH
(1) Ac2O/pyr 0.5 h, 150 C
(2) CrO3, 90% aq. HOAc 1.5 h, 30 C, 75%
Pseudodiosgenin O
H H AcO
O HOAc, 2 h, reflux 95% H AcO OAc H H
Diosone
16-Dehydropregnen-3()-ol-20-one acetate (> 60% overall)
Dehydropregnenolone is easily transformed to progesterone in 3 steps: (1) H2, Pd-C (2) hydrolysis (3) Oppenauer oxidation: cyclohexanone, Al(OiPr)3 Upjohn avoided attempted monopoly by use of stigmasterol obtained from soybeans:
H H H HO Stigmasterol H
1. Oppenauer oxidation H 2. O3 H O H
CHO
HN benzene, reflux
H H H O H O N O3 H H H
Progesterone
283
Modern Organic Chemistry The Scripps Research Institute O 1. NH2OH, HCl, pyr H 2. SOCl2 H H AcO 16-Dehydropregnenolone acetate (5 steps from diosgenin) O H H O H O H H HO Estrone H MeO Mestranol (16 steps from diosgenin) 1. CH3I 2. acetylene KOtAm H Br2, HOAc Br H O Br H OH H H H H H O AcO Beckmann Rearrangement O collidine H H H H H H NHAc 1. H3O+ 2. NaOH HO Dehydroepiandrosterone O 530 C with mineral oil H H H O 1. H2 2. Jones
CH3I O H H H 1. Li, NH3 2. HOAc, CrO3 O H H H O O HC(OEt)3 HCl H H H H
MeO 2-O-Methyl Estrone 1. acetylene KOtAm
H selective protection of enone carbonyl EtO
more stable isomer OH H 2. HCl O Norethinorone (20 steps from diosgenin) H H
The Total Synthesis Of Steroids Representative strategies employing the Robinson and related annulations The Velluz Approach (Roussel-Uclaf, Paris) Compt. rend. 1960, 250, 1084, 1511. Angew. Chem., Int. Ed. Eng. 1965, 4, 181.
284

Stork isoxazoles, J. Am. Chem. Soc. 1967, 89, 5464. O O S. Danishefsky vinyl pyridines, J. Am. Chem. Soc. 1975, 97, 380. N N O Cl
J. Tsuji via Wacker oxidation of terminal double bonds, J. Am. Chem. Soc. 1979, 101, 5070.
Comparison of strategies employing the intramolecular Diels-Alder reaction: First applications of this strategy were developed independently in laboratories of T. Kametani and W. Oppolzer. Examples T. Kametani, Tetrahedron Lett. 1978, 2425. J. Am. Chem. Soc. 1976, 98, 3378. J. Am. Chem. Soc. 1977, 99, 3461. J. Am. Chem. Soc. 1978, 100, 6218. O OtBu DMF, 1 h, 40 C I O CN NaNH2/NH3 2 h, 33 C 65% OMe OMe optically pure NC 49% OtBu Na/THF/NH3 EtOH, 1 h, 78 oC 85%
17 steps 12%
MeO 3 h, 180 C (o-Cl2C6H4), N2
Br
NaH, DMF 10 min, 25 oC
84% OtBu
exo-transition state
MeO OtBu HCl/H2O HCl, pyr dioxane 45 min, 240 C 7 h, reflux, 84% 81% H HO (+)-Estradiol OH H H
H H MeO H
Oppolzer Helv. Chim. Acta 1977, 60, 2964. Oppolzer Angew. Chem., Int. Ed. Eng. 1977, 16, 10. Oppolzer Helv. Chim. Acta 1980, 63, 1703.
285
Modern Organic Chemistry The Scripps Research Institute O Br CuLi MeO2C O 1. NaBH4, MeOH 2. TBSCl I 3. LiAlH4 4. TsCl, pyr 5. NaI, acetone OTBS
CO2Me 6:1 95%
77%
NaH THF, HMPA 82% SO2 NC
OTBS
1. I2, AgSO4 H2SO4 SO2 2. NaCN, (Ph3P)4Pd toluene NC SO2
1:1 Cl (SO2) 213 oC Cl OH H H H OTBS H H H Cl
1. MeLi 2. CF3CO3H 3. HCl, THF, MeOH NC
HO (+)-Estradiol
80% retro-cheletropic cycloaddition followed by Diels-Alder reaction
T. Saegusa J. Am. Chem. Soc. 1981, 103, 476. O Me3Si CsF >86% H NMe3+I MeO Estrone H H O
MeO
K. P. C. Vollhardt and R. Funk J. Am. Chem. Soc. 1977, 99, 5483. MgBr(CuI) O THF, 45 min 60 to 40 oC TMSCl, Et3N (HMPA) 0.5 h, 40 to 25 oC 89% OSiMe3 1. LiNH2, NH3, THF 0.5 h, 33 oC 2. alkylation, THF 25 oC, 64% I
neat TMSCCTMS CpCo(CO)2 N2, 35 h, 140 oC
286
Key Ring Forming Reactions Dale L. Boger O Me3Si Me3Si O H H H Me3Si 4e- electrocyclic ring opening followed by Diels-Alder reaction Me3Si H O Me3Si H Me3Si Total Synthesis of Cortisone R. B. Woodward received the 1965 Nobel Prize in Chemistry for "Contributions to the Art of Organic Synthesis" and the award preceded the total synthesis of vitamin B12 carried out in collaboration with Eschenmoser, the principles of orbital symmetry conservation (Hoffmann Nobel Prize in 1981), the Wilkinson structure determination of ferrocene (Nobel 1973) carried out with Woodward, and the collaborative delineation of the steroidal biosynthesis involving stereoselective cation-olefin cyclizations in collaboration with Bloch (Nobel 1964). Woodward changed synthesis from application of empirical reactions to a mechanistic foundation for predicting substrate reactivity (rates, stereoselectivity) and designed this rationale into the preplanned synthesis. The results were stunning with unattainable objectives falling one after another: quinine (1944), patulin (1950), cholesterol (1951), cortisone (1951), lanosterol (1954), lysergic acid (1954), strychnine (1954), reserpine (1956), chlorophyll (1960), tetracyclines (1962), colchicine (1963), cephalosporin C (1966), most before the wide spread usage of 1H NMR. Breathtaking natural product structure determinations: penicillin (1945), strychnine (1948), patulin (1949), terramycin (1952), aureomycin (1952), cervine (1954), magnamycin (1956), gliotoxin (1958), oleandomycin (1960), streptonigrin (1963), and tetrodotoxin (1964) also preceded the reliance on 1H NMR. The formal total synthesis of vitamin B12 was completed in 1972 in collaboration with A. Eschenmoser (>100 postdoctoral fellows) and synthetic cobyric acid was converted to vitamin B12 in 1976. R. B. Woodward J. Am. Chem. Soc. 1951, 73, 2403, 3547, 4057. J. Am. Chem. Soc. 1952, 74, 4223. O + MeO O NaOMe HCO2Et O H O H HOHC 1. benzene 100 oC, 96 h 2. NaOH; H+MeO O O 1. LiAlH4 2. 2 N H2SO4 H 1. EVK tBuOK tBuOH 2. KOH O O H OH 1. Ac2O, pyr 2. Zn H H Me3Si 90%, 9:1 regioselectivity TFA, CHCl3, CCl4 30 oC H H H HO Estrone O Pb(OAc)4 H H H H H O TFA, Et2O, CCl4 20 h, 25 oC 100%
()-Estra-1,3,5(10)-trien-17-one K. Vollhardt J. Am. Chem. Soc. 1979, 101, 215. O
H H
1. OsO4 2. acetone, CuSO4
287
Modern Organic Chemistry The Scripps Research Institute O H O H O OsO4 H CH2=CHCN Triton B tBuOH HO2C H O H O O H O H O CO2Me 1. Na2Cr2O72H2O 2. CH2N2 3. H2, Pd-SrCO3 H H O H CO2Me 1. NaOMe 2. Na2Cr2O7 CrO3-H2O O H O HO H CO2Me O Zn-HOAc H O H NC 1. HCN, Et3N 2. POCl3, pyr H HO 1. HBr 2. 2,4-dinitrophenyl hydrazone 3. pyruvic acid 4. hydrolysis O Cortisone H O O H H H CH2OH OH O H H 2. TsOH CH3COCH3 H O H CH2OAc H H 1. NaBH4, 0 oC 2. Ac2O, pyr 3. KOH 4. SOCl2 5. CH2N2; HOAc HO H O 1. KMnO4 CH3COCH3 O H H CH2OAc OH H O H O O H H H CH2OAc HBr O H H H 1. NaBH4, EtOH 2. Ac2O, pyr 3. PhCO3H O H AcO H Br CO2Me O 1. HIO42H2O 2. HOAc piperidine benzene O CHO 1. MeMgBr 2. KOH; H+ H H O CO2Me H O H H2 Pd-SrCO3 O H O 1. NaOMe HCO2Et 2. C6H5NHMe O MeOH O H O H CHNMeC6H5 O H O
Ac2O, NaOAc
288
C. Birch Reduction
Li/NH3 MeO MeO
H3O+ O
Robinson annulationtype product - See the discussion in the sections on the Birch reduction and the Robinson annulation. - Allows an aromatic ring to be incorporated into a synthesis and converted into a useful, nonaromatic ring system.
D. Dieckmann Condensation
- An intramolecular Claisen condensation, see enolate section for a more detailed discussion. O CO2Et CO2Et CO2Et
E. Intramolecular Nucleophilic Alkylation

- Powerful approach to closure of rings
Examples:
- Kinetic enolate generation (Note: O-alkylation may compete). O LDA Br 5566% O - Gem dimethyl effect facilitates cyclization
House J. Org. Chem. 1978, 43, 700.
O LDA Br 5263%
- Versus thermodynamic enolate generation (Note: O-alkylation may compete). O KOtBu Br

tBuOH
O O O
7-19%
58-72%
5-7%
5%
289

- Closure subject to stereoelectronic control. X 180 / SN2 displacement - Note Baldwins Rules Preceded by Eschenmoser Helv. Chim. Acta 1970, 53, 2059. O LDA Br Et2O 25 C O Not possible 70% Not formed O - Examples O O O OMs H X
KOtBu toluene 53%
O O O
Gibberelic Acid, Corey
J. Am. Chem. Soc. 1979, 101, 1038.
Cl
N R N H
NaH N H
N O O
CC-1065, Boger
J. Am. Chem. Soc. 1988, 110, 4796.
OH
OMs O O MeO2C N H N 83% O OH NaH MeO2C N H N O O
Duocarmycin SA, Boger
J. Am. Chem. Soc. 1992, 114, 10056. J. Am. Chem. Soc. 1993, 115, 9025.
Duocarmycin A, Boger
F. Intramolecular Aldol Condensation

- The intramolecular aldol condensation has been used extensively to close or form rings. Representative Examples: - Two aldol closures possible: O O R BF3OEt2 O R Base or H2SO4 R O Robinson Annulation
290
Key Ring Forming Reactions Dale L. Boger OR O NaOCH3 CHO OR RO OR OH OR OR O
Fredericamycin A Boger J. Org. Chem. 1991, 56, 2115.
J. Am. Chem. Soc. 1995, 117, 11839.
G. Intramolecular Michael Reaction
TMS O
EtAlCl2 1 h, 0 C toluene 50% O
Majetich J. Org. Chem. 1985, 50, 3615. Tetrahedron Lett. 1989, 29, 2773.
H House J. Org. Chem. 1965, 30, 2513.
50% O
MeO2C MeO2C O
NaOMe MeOH 100% O
MeO2C MeO2C O
Mander J. Am. Chem. Soc. 1979, 101, 3373.
H. Cation-Olefin Cyclization
1. Reviews Johnson
Acc. Chem. Res. 1968, 1, 1 . Angew. Chem., Int. Ed. Eng. 1976, 15, 9. Bioorg. Chem. 1976, 5, 51.
Harding Goldsmith Lansbury
Bioorg. Chem. 1973, 2, 248. Fortschr. Chem. Org. Nat. 1972, 29, 363. Acc. Chem. Res. 1972, 5, 311.
291
Modern Organic Chemistry The Scripps Research Institute 2. Representative Cation-Olefin Cyclizations COOH SnCl4 Cl Monti J. Org. Chem. 1975, 40, 215. O Cl O
SnCl4 benzene O O Grieco Tetrahedron Lett. 1974, 527.
OAc
H+ BF3 O
Money J. Chem. Soc., Chem. Commun. 1969, 1196. Goldsmith J. Org. Chem. 1970, 35, 3573.
Cl OAc BF3 O
Cl Money J. Chem. Soc., Chem. Commun. 1971, 766.
HCO2H O
Cl Lansbury J. Am. Chem. Soc. 1966, 88, 4290.
J. Am. Chem. Soc. 1970, 92, 5649.
COCl
SnCl4 O
Marvell J. Org. Chem. 1970, 35, 391.
292
OTs
CF3CO2H
OCOCF3 Baldwin Tetrahedron Lett. 1975, 1055.
TsO
HOAc NaOAc
OAc
Bartlett J. Am. Chem. Soc. 1965, 87, 1288. Johnson J. Am. Chem. Soc. 1964, 86, 5593.
OH HCO2H
OR
Marshall J. Am. Chem. Soc. 1965, 87, 2773. J. Am. Chem. Soc. 1966, 88, 3408.
SnCl4 MeNO2, 23 C HO 3 h, 70% Johnson J. Am. Chem. Soc. 1968, 90, 2994. H
H H Progesterone total synthesis
O O O O HO CF3CO2H 70% H H H Progesterone total synthesis H
Johnson J. Am. Chem. Soc. 1970, 92, 4461. J. Am. Chem. Soc. 1980, 102, 7800.
293
Modern Organic Chemistry The Scripps Research Institute O H O
CF3CO2H MeO 70% MeO
Shionone total synthesis
Ireland J. Am. Chem. Soc. 1974, 96, 3333. J. Org. Chem. 1975, 40, 973. J. Am. Chem. Soc. 1970, 92, 2568. OH
HCO2H Cedrene
OH Corey J. Am. Chem. Soc. 1969, 91, 1557. Tetrahedron Lett. 1973, 3153. Stork J. Am. Chem. Soc. 1955, 77, 1072. J. Am. Chem. Soc. 1961, 83, 3114. OH O Cl H
Lansbury J. Am. Chem. Soc. 1966, 88, 4290. J. Chem. Soc., Chem. Commun. 1971, 1107. Tetrahedron Lett. 1973, 5018. O N2 O BF3OEt2 MeO CH2Cl2 MeO
Mander J. Chem. Soc., Chem. Commun. 1971, 1107. Erman J. Am. Chem. Soc. 1971, 93, 2821. O O Nazarov cyclization Hiyama J. Am. Chem. Soc. 1974, 96, 3713. OH CHO SnCl4
MeNO2, 0 C 10 min, 30-40% Ireland J. Am. Chem. Soc. 1974, 96, 3333. J. Org. Chem. 1975, 40, 973. J. Am. Chem. Soc. 1970, 92, 2568.
294
Key Ring Forming Reactions Dale L. Boger H CHO H
OH H
H CHO
PCC
Naves Helv. Chim. Acta 1964, 47, 51. Corey J. Org. Chem. 1976, 41, 380. OH PCC O
OH
PCC
Corey, Boger Tetrahedron Lett. 1978, 2461. H+
O and aldehyde
OMe
Johnson J. Am. Chem. Soc. 1967, 89, 170. J. Am. Chem. Soc. 1973, 95, 2656. SnCl4 OHC CH2Cl2 1.5 min, 90% -Vetivone and Vetispirene total syntheses
HO
McCurry, Jr. Tetrahedron Lett. 1973, 3325. CO2Me CO2Me OPO(OEt)2 Hg(OCOCF3)2 O NaCl ClHg TBDMSO TBDMSO H
Aphidicolin total syntheses
Corey, Tius J. Am. Chem. Soc. 1980, 102, 1742. (Aphidicolin) J. Am. Chem. Soc. 1980, 102, 7612. (Stemodinone) J. Am. Chem. Soc. 1982, 104, 5551. (K-76) OR Tf2O
OR
H HO H Corey J. Am. Chem. Soc. 1987, 109, 6187. (Atractyligenin) J. Am. Chem. Soc. 1987, 109, 4717. (Cafestol)
295
Modern Organic Chemistry The Scripps Research Institute 3. Background Squalene cyclization first suggested as a biosynthetic precursor to cholesterol Heilbrow, Kann, and Owens J. Chem. Soc. 1926, 1630. Robinson Chem. Ind. 1934, 53, 1062. - Robinson's proposal J. L. Goldstein and M. S. Brown received the 1985 Nobel Prize in Medicine for their discoveries concerning the regulation of cholesterol metabolism.
Cholesterol HO - Correct cyclization scheme
Lanosterol HO - Lanosterol was proposed in 1953 by Woodward and Block. - Experimental verification that cholesterol is biosynthesized from squalene was developed independently by Block J. Biol. Chem. 1953, 200, 129. Cornforth Biochem. J. 1954, 58, 403. H
Biochem. J. 1957, 65, 94.

K. Block received the 1964 Nobel Prize in Medicine for his discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism. J. W. Cornforth received the 1975 Nobel Prize in Chemistry jointly with V. Prelog for outstanding intellectual achievement on the stereochemistry of reactions catalyzed by enzymes.
- Stork-Eschenmoser hypothesis: the trans-anti-trans stereochemistry of the steroids and many terpenoids is a consequence of a concerted polyene cyclization.
Cyclization about a trans olefin
Y R H OH H
Y R H R OH Y H OH H H OH
Cyclization about a cis olefin
R Y
- Anti addition of a carbocation and nucleophilic olefin on opposite faces of a -bond analogous to trans electrophilic addition to alkenes. Therefore, cyclization of a trans olefin leads to a trans ring fusion and cyclization of a cis olefin leads to a cis ring fusion.
296
O Squalene
Squalene monooxygenase
H HO O H+ 2,3-Oxidosqualene lanosterol cyclase Squalene-2,3-oxide
H+
H HO HO Dammaradienol 8 chiral centers with 256 possible stereoisomers H
- Two methyl migrations and two hydride transfers
H+
HO
Lanosterol H Twenty enzymatic reactions
Cholesterol
297
Modern Organic Chemistry The Scripps Research Institute 4. Key Publications - Initial experimental demonstrations of multiple cascade cyclizations and the Stork-Eschenmosher steroid-type cyclizations: Stork and Burgstahler J. Am. Chem. Soc. 1955, 77, 5068. Eschenmoser and Arigoni Helv. Chim. Acta 1955, 38, 1890. First disclosed in lectures and proposals as early as 1950, but experimental verification was difficult. - First clear verification of Stork-Eschenmoser hypothesis. Johnson J. Am. Chem. Soc. 1964, 36, 1959. J. Am. Chem. Soc. 1965, 30, 1735.
trans only
HCO2H 12% ONs HCO2H ONs 5. Three Stages of Reaction - Initiation - Cyclization - Termination - Mechanistically all three may take place simultaneously or stepwise paths may be involved. - Depends on the nature of the substrate and the reaction medium. - Without careful control, the formation of many products will result in a complex mixture. - For example: Johnson verification of Stork-Eschenmoser hypothesis. HO 16% H OH Only bicyclic products isolated or generated OH
cis only
HCO2H HCO2Na H2O 75 C, 1 h OH
NaOH H2O to hydrolyze the formates
OH
ONs
51.2%
13.5%
H 6.7% 5.4% OH
OH 3.3%
H 2.9%
H 2.2%
OH 1.6%
total trans = 12% total cis = 0%
- Much effort expended to control the reaction through mild, selective and efficient initiation and termination.
298
Key Ring Forming Reactions Dale L. Boger 8. Synthesis of Progesterone Johnson J. Am. Chem. Soc. 1971, 93, 4332. J. Am. Chem. Soc. 1978, 100, 4274. H O O CF3CO2H 0 C, 2 h O O O H H O O O H H
HO - Tertiary allylic alcohol for initiation - Substituted alkyne for termination - 5-exo-dig vs. 6-endo-dig
Efficient trap of vinyl cation
CF3CO2H, pentane, ClCH2CH2Cl 1 h, 0 C, 78%
10% aq. K2CO3 CH3OH, 70% O
OCOCF3
Ring expansion via diketone and aldol H H
13% cis--epimer
H 1. O3, CH3OHCH2Cl2, 0.5 h, 70 C 2. ZnHOAc, 1 h, 25 C, 84% (2 steps) 3. KOH, CH3OH, 20 h, 25 C, 70%
1. O3, CH3OHCH2Cl2, 2 min, 70 C 2. ZnHOAc, 1 h, 25 C 3. KOH, CH3OH, 20 h, 25 C O 49% overall
H O
O ( )-4-Androstene-3,17-dione
( )-Progesterone
O but also gave
F gave
H 10% only 3.5% - More recent efforts have reduced this to the synthesis of optically active agents. - How would you imagine doing this? - Remember chair-like transition states for the cyclization.
299
I. Free Radical Cyclizations

1. Reviews Acyloin Condensation: Bloomfield, J. J.; Owsley, D. C.; Nelke, J. M. Org. React. 1976, 23, 259. McMurry Coupling: McMurry, J. E. Acc. Chem. Res. 1983, 16, 405. Julia Free Radical Cyclization: Julia, M. Acc. Chem. Res. 1971, 4, 386. Pure App. Chem. 1967, 15, 167. - General Reviews Beckwith, A. L. J.; Ingold, K. U. Rearrangements in Ground State and Excited States, Vol. 1.; de Mayo, P., Ed.; Academic: NY, 1980, pp. 182-220. Beckwith, A. L. J. Tetrahedron 1981, 37, 3037. (Regioselectivity of ring cyclization) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds, Pergamon: Oxford, 1986. Symposium-in-print: Tetrahedron 1985, 41, no. 19. Curran, D. P. Synthesis 1988, 417 and 489. Hart, D. J. Science 1984, 223, 883. Ramaiah, M. Tetrahedron 1987, 43, 3541. Comprehensive Org. Syn., Vol. 4., Chapter 4.1 and 4.2, pp. 715-831. Laird, E. R.; Jorgensen, W. L. J. Org. Chem. 1990, 55, 9. Giese, B. Org. React. 1996, 48, pp. 301-856. 2. Reductive Coupling of Carbonyl Compounds a. Acyloin Condensation CO2CH3 CO2CH3 Na toluene 57% O OH
- Mechanism O 2e O - Alternative O e
Sheehan J. Am. Chem. Soc. 1950, 72, 3376. O O OCH3 O OCH3 O OCH3 O O O O O
OCH3 OCH3
radical coupling
O O OCH3 O
2e
CO2CH3 OCH3 O O
OCH3
2e
O O
b. Rhlmann Modification with Me3SiCl CO2CH3 NaK Et2O, Me3SiCl CO2CH3 OSi(CH3)3 OSi(CH3)3
300
Key Ring Forming Reactions Dale L. Boger 3. Reductive Coupling of Ketones and Aldehydes (Pinacol Coupling and McMurry Reaction) - Low valent Ti reagents used to generate ketyl radicals and chosen to permit generation of either the pinacol or olefin product.
CHO CHO
Ti
n
OH OH
n
CHO CHO
MgHg TiCl4 THF 32%
OH OH
Corey, Danheiser J. Org. Chem. 1976, 41, 260.
MgHg O TiCl4 THF 43% OH OH
O O
ZnCu TiCl3 DME 79%
McMurry J. Org. Chem. 1977, 42, 2655.
LiAlH4 O CO2Et TiCl3 DME 80%
OEt
McMurry J. Am. Chem. Soc. 1983, 105, 1660.
CHO O O H CH3O ZnAg TiCl3 DME CH3O Estrone Synthesis: Ziegler J. Org. Chem. 1982, 47, 5229.
301
Modern Organic Chemistry The Scripps Research Institute - Other Functional Groups: Corey Tetrahedron Lett. 1983, 24, 2821. O Zn CO2CH3 O 75% OH NHOCH3 NOCH3 CO2CH3 84% H (CH3)SiCl 77% OH
CO2CH3 OH O
CN O
4. SmI2 Promoted Reductive Coupling Reactions (Radical Mechanisms) - Lanthanide chemistry reviews Molander Chem. Rev. 1992, 92, 29. Molander in Chemistry of the Carbon Metal Bond, Hartley, F. R.; Patai, S., Eds.; Wiley: NY, 1989, Vol 5 Molander in Comprehensive Org. Syn., Vol. 1, p. 262. Kagan Nouv. J. Chem. 1990, 14, 453. Kagan Tetrahedron 1986, 42, 6573. Soderquist Aldrichim. Acta 1991, 24, 15.
a. Ketyl-Olefin Coupling Reactions - Intermolecular (Only effective for "activated" olefins) 2 SmI2 Ph CHO CO2CH3 Ph O O THFHMPA 1.5 equiv iPrOH 78% e, H+ OCH3
SmI2
O Ph
Sm(III) CO2CH3
(III)Sm Ph
O CO2CH3
Inanaga Tetrahedron Lett. 1986, 27, 5763. Tetrahedron Lett. 1989, 30, 2837. O Ph Si(CH3)3 2 SmI2 THFHMPA tBuOH 93% Ph OH Si(CH3)3
302
Key Ring Forming Reactions Dale L. Boger - Intramolecular O R O 2 SmI2 R' Y THFMeOH 60-80% HO R COY R'
Y = OR", NR2" O R EtO2C O 2 SmI2 R' OEt THFMeOH 90% CO2Et OH O O O 2 SmI2 THFacetone 85% HO HO R
Molander Tetrahedron Lett. 1987, 28, 4367. CO2Et J. Am. Chem. Soc. 1989, 111, 8236. R' J. Org. Chem. 1991, 56, 1439.
J. Org. Chem. 1993, 58, 7216. J. Org. Chem. 1994, 59, 3186.
O O
2 e
Sm(III) O (III)Sm O O O
H+
O O
1. 2 SmI2 THFHMPA 2. (PhSe)2 81% 1. 4 SmI2 THFHMPA OEt 2. H+ 61% O
OH SePh
O I
HO
2 e
H+ 2 e
O I2Sm OEt
CHO TBSO O O 2 SmI2 CO2CH3 73% O TBSO
OH CO2CH3 O
Enholm J. Am. Chem. Soc. 1989, 111, 6463.
303
Modern Organic Chemistry The Scripps Research Institute CHO O O SmI2 THFHMPA 91% H OH H O O ( )-Coriolin
Curran J. Am. Chem. Soc. 1988, 110, 5064. O 8-endo 2 SmI2 OAc THFHMPA 81% OH
Molander J. Org. Chem. 1994, 59, 3186. - Imminium ion generated in situ 2 SmI2 ClO4 N CH3CN N H Ph
Ph Martin Tetrahedron Lett. 1988, 24, 6685.
- Hydrazone (5-exo hydrazone >> 5-exo alkene; 6-exo hydrazone > 5-exo alkene) Ph2N H Ph2N NPh2 H OH n = 1: 72% : 0% n = 2: 4.2 : 1
N n
SmI2 THFHMPA
NH
OH
Ph2N H
N n
Sm(III)
Fallis J. Am. Chem. Soc. 1994, 116, 7447. J. Org. Chem. 1994, 59, 6514. - Fragmentation-cyclization O SmI2 THFHMPA MeOH TMS 79%
e
TMS 5-exo-dig
Sm(III)
(III)Sm
TMS
TMS Motherwall Tetrahedron Lett. 1991, 32, 6649.
304
Key Ring Forming Reactions Dale L. Boger b. Alkyl/Aryl Radical Cyclizations Br O OAc 2 SmI2 O
CH3CN HMPAtBuOH 61% Inanaga Tetrahedron Lett. 1991, 32, 1737.
Br O SmI2 THF HMPAtBuOH 31% Br N Ac O I O SmI2 THF HMPAtBuOH 88% 2 SmI2 THFHMPA 57% O N Ac OH O
Molander J. Org. Chem. 1990, 55, 6171. I O O 2 SmI2 THFHMPA 81% Curran Synlett 1990, 773. c. Pinacol-type Coupling Reactions - Intermolecular 2 R R' aldehydes or ketones O 1. 2 SmI2 2. H3O+ 80-95% HO R' R R' R OH O HO
Kagan Tetrahedron Lett. 1983, 24, 773.
- Intramolecular
iPr
O 2 SmI2 OEt THFtBuOH 73%
HO
iPr
CO2CH3
>200 : 1
HO
OHC
Molander J. Org. Chem. 1988, 53, 2132.
305
Modern Organic Chemistry The Scripps Research Institute O O N CHO O O 2 SmI2 THFtBuOH 52% Molander J. Org. Chem. 1988, 53, 2132. O O N O OH OH
O 2 SmI2 OEt THFtBuOH 45%
HO O
CO2Et >200 : 1
NC
Molander J. Org. Chem. 1988, 53, 2132.
CO2CH3 COCH3 TBSO CHO
CO2CH3 2 SmI2 81% 92% de TBSO OH
OH Hanessian Tetrahedron Lett. 1991, 32, 1125.
OTBS O O CHO CHO OTBS 2 SmI2 THFtBuOH 86% O O
OTBS OH OH OTBS 92 : 8
O O
OTBS OH OH OTBS
Chiara Tetrahedron Lett. 1994, 35, 2969.
306
Key Ring Forming Reactions Dale L. Boger - A recent total synthesis of ()-Grayanotoxin III incorporated two ketyl-olefin cyclization reactions and a pinacol coupling reaction (SmI2-promoted). - Shirahama J. Org. Chem. 1994, 59, 5532.
H HO HO
OH
OH
OH OH ()-Grayanotoxin III
SPh 2 SmI2 THFHMPA 86% CHO O OH O OH TBSO MOMO OMOM
O O O OH
2 SmI2 THFHMPA 78%
H HO O OHC
OMOM TBSO OMOM MOMO

SmI2 THFHMPA 54%
HO MOMO
OMOM
H HO HO
OMOM HO OMOM OH MOMO
OH
HO OH
OH OH
307
Modern Organic Chemistry The Scripps Research Institute 5. Radical-Olefin Cyclizations a. Representative Examples - Concurrent with Johnson's investigation of cation-olefin cyclizations, Julia initiated radical-olefin cyclization studies. CH3O2C NC BzOOBz CH3O2C NC cyclohexane 57% Julia Compt. rend. 1960, 251, 1030. CH3O2C 88% NC 6-endo-trig
Reversible, thermodynamically controlled reactions.
CH3O2C NC
b. Reactivity and Regioselectivity - Relative rates of addition to CH3 PO(OEt)2 : typical electron-deficient olefin. CH3CH2 1 CH3OCH2 2.7 (CH3)2CH 4.8 (CH3)3C 24
krel =
- Alkyl radicals are regarded as nucleophilic.
Steric Effects on Addition Regioselectivity olefin % addition to: Ca Cb >95 <5 >95 a b >95 <5 <5
krel
1.16 18.4 2 x 136
a b a b
a b
50 50
50 50 5 >95
2 x 0.50 2 x 0.63 15 13.9
a b a b
>95 <5
a b
C6H11
CO2CH3 R R=H R = tBu CO2CH3

tBu
krel
1 0.24 5 x 105 -substitution strongly decelerates intermolecular addition with activated acceptors
308

I CN Nucleophilic radical Electrophilic acceptor alkene Bu3SnH 95% CN
Bu
Cl
Ph
CO2CH3
CHO
krel
1.0
8.4
84
3000
8500
CO2CH3
CO2CH3 CO2CH3 CH3O2C 5
CO2CH3
CO2CH3
krel
1.0
150
0.01
EtO2C Cl EtO2C Electrophilic radical OtBu
Bu3SnH 60%
EtO2C CO2Et
OtBu
Nucleophilic acceptor alkene
EtO2C EtO2C
Ph N O
Ph
Ph CO2CH3
krel
23
3.5
309
Modern Organic Chemistry The Scripps Research Institute c. Cyclization Rates, Regioselectivity, and Diastereoselectivity 1 < but 5-exo > 6-endo 98% 2% 2 Stability
Beckwith J. Chem. Soc., Chem. Commun. 1974, 472. Beckwith J. Chem. Soc., Chem. Commun. 1980, 484. 6-exo > 7-endo 90% 10%
- Chair-like transition state subject to stereoelectronic and kinetic control rather than thermodynamic control.
5-exo Stereochemical features of substitution can be rationalized and predicted based on these models.
6-exo
krel exo
krel endo
1.0 1.4
0.02 0.02
(98 : 2) (99 : 1)
2.4
<0.01
(>200:1)
0.022
0.04
(36 : 64) endo predominates
0.16
<0.002
exo >> endo (>80:1)
310
Key Ring Forming Reactions Dale L. Boger - Linker chain effects X R R n n=1 n=2 n=3 R=H R = CH3 X = CH2 X=O
kexo/kendo
0.55 38.6
endo > exo exo >> endo
krel
1 10 gem dimethyl effect
ring size 5 6 7
k
~105 s-1 ~104 s-1 ~102 s-1
krel
1 0.1 0.001
exo >> endo

7-membered ring closure so slow that reduction competes.
- Stabilized radicals participate in reversible cyclizations and the thermodynamic product is observed.
CO2Et CO2Et
CO2Et CO2Et 3:2 only
CO2Et CO2Et
NC
CO2Et
NC
CO2Et
- Alkynyl radicals give 5-exo closure (stereoelectronic) even with stablized radicals. R CN CO2Et R CN CO2Et
- Note effect of additional sp2 centers in the linking chain: 5-exo closure takes precedence over the overall 1 vs 3 stability of the resulting free radical. O O not O more stable 1 vs stabilized 2 not O more stable
O O
311
Modern Organic Chemistry The Scripps Research Institute - Closure onto carbonyls possible CHO Ph - Macrocyclizations are very facile O O n Porter J. Am. Chem. Soc. 1987, 109, 4976. d. Initiator Groups S R OH R O X Bu3Sn R S SnBu3 R O n Ph O OH 6-exo HCO > 5-exo C=C
O X
X = SR, OR, SeR R X Bu3Sn Bu3Sn R SePh R R
Barton deoxygenation reaction Bu3SnX X = Br, I
Bu3SnSePh
Bu3Sn R NO2 Bu3Sn R SO2R Hg(OAc)2 NHCBZ - Different Initiators M-H Bond strength (kcal/mol) 74
nBu Sn 3
N O
OSnBu3
R HgOAc NaBH(OR)3
N N CBZ CBZ Special reagent that increases reactivity of -SiH so it may be used effectively in synthesis. 79 84 90 (Me3Si)3Si H
nBu Ge 3
Et3Si Si-H
< < Sn-H Ge-H More competitive reduction by H abstraction from reagent Giese Tetrahedron Lett. 1989, 30, 681. Ingold Int. J. Chem. Kinet. 1969, 7, 315. e. Rearrangements are possible weakest O O R O Ph
R=H R = Ph
312
Key Ring Forming Reactions Dale L. Boger f. Functionalized Free Radicals Stork, vinyl radicals Br SPh N Me O N Me Hart J. Am. Chem. Soc. 1997, 119, 6226. O
SePh
Boger, acyl radicals J. Org. Chem. 1988, 53, 3377. Intramolecular J. Org. Chem. 1989, 54, 1777. Intermolecular J. Am. Chem. Soc. 1990, 112, 4003. Tandem cyclization - Examples Bu3SnH COX
J. Am. Chem. Soc. 1990, 112, 4008. Macrocyclization J. Org. Chem. 1990, 55, 5442. Ring expansion J. Org. Chem. 1992, 57, 1429. Full description Israel J. Chem. 1997, 37, 119. Review
X = SePH, 84% X = SPh, 0% X = Cl, 59%
COSePh
86% O
COSePh 69% O H 82% O COSePh n X=H X n n=0 n=1 n=2 X = CO2CH3 n=0 n=1 n=2 81% 76% 74% 88% 84% 92% ring size 5 6 7 5 6 7 O X
COSePh
313
Modern Organic Chemistry The Scripps Research Institute COSePh CO2CH3 n n=0 n=1 83% 71% ring size 6 7 O COSePh 58% Note: Alkyl and vinyl radicals are subject to faster reduction. Cyclizations such as the above example or those for the formation of 7-membered rings are not very successful, but acyl radicals are much more stable and not subject to competitive reduction. O R H Strong CH bond R H Weak CH bond n O CO2CH3
- Tandem Cyclizations Ph PhSe O 77% H > 98% cis Ph X O PhSe 72% H O > 97% cis Ph X O3 H O 6 : 4 cis : trans X = CHPh X=O O3 X = CHPh X=O X O O3 X = CHPh X=O
O PhSe
82%
- Cyclization-Addition Reactions
Bu3SnH O SePh CO2CH3 63% CO2CH3 O
314
Key Ring Forming Reactions Dale L. Boger - Addition-Cyclization Reactions O SePh 61% Ph CO2CH3 SePh O Ph - Macrocyclization Reactions O O activated, unsubstituted acceptor alkene n SePh O ring size n = 15 n = 11 n=9 n=7 n=6 20 16 14 12 11 O 57% 68% 55% 46% 47% O O n - decarbonylation very slow - reduction very slow - macrocyclization proceeds exceptionally well O CO2CH3 CO2CH3 CO2CH3 2.4 : 1 diastereomers
Bu3SnH CO2CH3 71% Ph
CO2CH3
- Macrocyclization onto activated acceptor is faster than 6-exo, 7-exo or 6-endo closure. - Competitive with 5-exo closure. O O R O SePh O O O3 O 5-exo-dig cyclization R = H, 30% R R = CH3, 74% O O O
- Rearrangement/Ring-enlargement Cyclization O Br Bu3SnH Ph
Ph
Ph More stable 3 radical
315
H Br N N H SO2Ph Bu3SnH 77% 5-exo-dig N H N SO2Ph BH3THF H2O2 OBn N N N N H SO2Ph N H N O O N H OBn (+)-CC-1065 O OH N H OBn O OH NH2
OBn OH
OBn
H Br NBOC 1. Bu3SnH 2. BH3THF OBn 60% overall
OH
NBOC
OBn 1. NaIO4, OsO4 2. NaBH4
J. Am. Chem. Soc. 1989, 111, 6461. J. Org. Chem. 1989, 54, 1238. J. Am. Chem. Soc. 1990, 112, 5230.
SPh Br NBOC Bu3SnH, 75% self terminating 5-exo-trig cyclization NBOC
OBn
OBn
J. Org. Chem. 1990, 55, 5823.

OTHP Br NBOC Bu3SnH 97% OBn OBn NBOC OTHP
J. Org. Chem. 1992, 57, 2873.
316
N I NBOC Bu3SnH TEMPO 97% OBn
NBOC
OBn
J. Org. Chem. 1995, 60, 1271.

THPO Br NBOC OBn Bu3SnH 5-exo-trig cyclization OBn OBn THPO BnO NBOC
J. Am. Chem. Soc. 1992, 114, 9318.

Cl I NBOC Bu3SnH 90% OBn OBn NBOC Cl

G. Further Notable Examples CO2CH3 HgClOAc C5H11 OOH C5H11 Bu3SnH O2 O O H Biomimetic approach to PGG2 and PGH2 HOO C5H11 Corey Tetrahedron Lett. 1984, 25, 5013. For a more successful alternative see Corey Tetrahedron Lett. 1994, 35, 539. CO2CH3 N N Hirsutene synthesis diyl Little J. Am. Chem. Soc. 1981, 103, 2744. H CO2CH3 CO2CH3 H CO2CH3 O O HgCl CO2CH3
317
J. Anionic Cyclizations
Li stable at 78 C t1/2 = 5.5 min at 25 C Bailey J. Am. Chem. Soc. 1992, 114, 8053. J. Am. Chem. Soc. 1991, 113, 5720. J. Am. Chem. Soc. 1987, 109, 2442. I 1. tBuLi 2. E+ E 63-91% tandem I cyclizations E 65-90% tandem cyclizations I H 65-87% Stereochemistry and comparison with radical cyclizations: Cooke J. Org. Chem. 1992, 57, 1495. Funk J. Am. Chem. Soc. 1993, 115, 7023. OR 5-endo-dig cyclization 120 SO2Ph line of attack OEt OEt SO2Ph R H E Intramolecular carbometalation, review: Comprehensive Org. Syn., Vol. 4, 871. Li
SO2Ph
RX
OEt Li SO2Ph
OEt Li SO2Ph
OEt SO2Ph Li
318
Key Ring Forming Reactions Dale L. Boger Synthetic aspects of magnesium (Grignard) carbometalation have been studied in detail. For a review see: Oppolzer Angew. Chem., Int. Ed. Eng. 1989, 28, 38. 1) Mg powder 2) 60 C, 23 h Cl 3) 76% OH O H 57% SOCl2 Et2O H * * 1) Mg powder 2) 25 C, 20 h OH 3) O2 H Cl 72%
1)
Li
O 2) SOCl2, 25 C
H H
9(12)Capnellene
70% (3 : 2) Oppolzer Tetrahedron Lett. 1982, 23, 4669.
K. 1,3-Dipolar Cycloadditions
Review: 1,3-Dipolar Cycloaddition Chemistry, Padwa, A., Ed., Wiley: New York, 1984. - 2s + 4s Cycloaddition - Subject to FMO control: can predict regioselectivity and reactivity. - FMO Control: (a) Reactivity: E (HOMO/LUMO) and the reactivity of the system is related to the magnitude of the smallest energy gap of the pair of HOMO-LUMO combinations. (b) Regioselectivity: depends on the magnitude of the orbital coefficients and is determined by the orbital coefficients on the predominant HOMO-LUMO interaction. The largest coefficient on the 1,3-dipole binds to the largest coefficient on the dipolarophile. (c) Diastereoselectivity: influenced by stabilizing secondary orbital interactions and subject to an endo effect. (d) Olefin geometry is maintained in the course of the cycloaddition reaction -> concerted reaction. (e) No solvent effect on the reaction rate -> concerted. (f) No rearrangement products from postulated zwitterion or biradical. (g) Trans-1,2-disubstituted olefins react faster than cis-1,2-disubstituted olefins. cis olefins are generally more reactive than trans olefins in ionic or radical addition reactions.
319
Modern Organic Chemistry The Scripps Research Institute 1. Azomethine Ylides R Ar N R' R' R R Ar N + R' R''O2C R' R Ar N + R' R R CO2R'' R''O2C R' Ar N
R R
R' R' CO2R''
H RO2C
H N
H Ar
RO2C
+ N H
H Ar
1,3-dipole 2. Azomethine Imines R H R' N R'' + N
3. Nitrones R' R N OH HgO Oxidation of hydroxylamine R' N R + O R'CHO + RNHOH - Symmetrical precursor or a precusor with one adjacent oxidizable center.
X R' N R + O
X R' N O R X + R R' N O
X = Ph, CO2R, OEt
X = NO2
- The regioselectivity depends on X and the substitution pattern of the nitrone. - Review: Confalone Org. React. 1988, 36, 1.
320
Key Ring Forming Reactions Dale L. Boger 4. Diazoalkanes R N2 R R=H R' R N N R' R or h -N2 R R R'
R R 5. Azides N N +
R R N N +
CO2Me PhN3 25 C 5 days [3 + 2] PhN3 N N R R = Ph (160 C) R = COPh (40 C) Ph OTMS BnO MeO Me OMe N3 SEt O OBn O 110 C toluene MeO Me N N R N N Ph N N N
Ph N N N CO2Me 77% Ph N N N
N R H H R = Ph, 49%
Ph OTMS SEt O O N OMe N N OBn MeO N2 Me OMe
Ph OTMS SEt O O N
Fukuyama J. Am. Chem. Soc. 1989, 111, 8303. 6. Nitrile Oxides R N X OH X=H X = Cl, Br, I O RCH2NO2 R N O H R N C O R HX N O N
Mitomycins
N O
321
Modern Organic Chemistry The Scripps Research Institute R CO2R N O 7. O3 / Carbonyl Oxides O O O + cycloaddition 1,3-dipolar O O O primary ozonide O O R N O CO2R
1,3-dipolar cycloreversion 1,3-dipolar O O O cycloaddition O H + O O
final ozonide
O O
8. Nitrile Ylides Ar N Ar' Ar C N Ar' CN
Ar Cl
Ar'
Et3N (HCl)
Ar
Ar'
Ar
Ar' CN
N Ar
or h
Ar
N H
R' N
O CO2 O R R R' N R R
9. Carbonyl Ylides
R R'
O C
R R'
CO2R O R R' CO2R
- problem: collapse of the carbonyl ylide to the epoxide
322
Key Ring Forming Reactions Dale L. Boger 10. Methylene Cyclopropanone Ketals CN O O O O O O
CN 4 three carbon 1,3-dipole Nakamura J. Am. Chem. Soc. 1989, 111, 7285. J. Am. Chem. Soc. 1991, 113, 3183. Key: reversible ring opening generation of the 4 component 11. Cyclopropenone Ketal (CPK) Diels-Alder/Dipolar Cycloadditions CO2CH3 H OR OR H R CO2CH3 H OCH3 H OR OR O O OR OR
O O R O O 75 oC OCH3 OCH3 OCH3 75 oC Boger, Brotherton-Pleiss: Advances in Cycloaddition Chemistry, Vol. 2, JAI: Greenwich, 1990, 147. Boger: J. Am. Chem. Soc. 1995, 117, 3453. J. Org. Chem. 1994, 59, 3453. J. Org. Chem. 1988, 53, 3408. Org. Syn. 1987, 65, 98. J. Org. Chem. 1985, 50, 3425. J. Am. Chem. Soc. 1986, 108, 6695 and 6713. J. Am. Chem. Soc. 1984, 106, 805. Tetrahedron 1986, 42, 2777. Tetrahedron Lett. 1984, 25, 5611 and 5614.
CH3O
OCH3
CO2CH3 O
CO2CH3
RO2C
CO2R R R
O H (R)
H CO2CH3 O CO RO OR RO2C R
OR CH3O2C OR
CO2R OR OR
OR OR
O R H (R)
OR OR
323
L. 1,3-Sigmatropic Rearrangement
1. Vinylcyclobutane rearrangement 350-600 C Overberger J. Am. Chem. Soc 1960, 82, 1007. H3C KH, THF, NCH3 H H3C 91% CH3 NCH3 H CH3
Bauld J. Am. Chem. Soc. 1988, 110, 8111.
O N OH OH CO2Et
nBu NF, 4
20 C
O N OH CO2Et O
66%
Sano Chem. Pharm. Bull. 1992, 40, 873. 2. Vinylcyclopropane rearrangement Review: Hudlicky Chem. Rev. 1989, 89, 165.
500-600 C
Org. React. 1985 33, 247.

Mechanism:
concerted
diradical
TMS TMS 570 C 80%
Paquette Tetrahedron Lett. 1982, 23, 263.
324
Key Ring Forming Reactions Dale L. Boger R CO2Me RO R Et2AlCl, CH2Cl2 8595% RO CO2Me
Davies Tetrahedron Lett. 1992, 33, 453.
SPh toluene, 250 C 94% MeO MeO Trost J. Am. Chem. Soc. 1976, 98, 248. SPh
hydrolysis 73% MeO O
MeO AlMe3, Et2O, MeO2C

nPr
MeO2C
OMe (MeOH)
MeO2C
48% Prn Harvey Tetrahedron Lett. 1991, 32, 2871. Prn
O h, benzene
O + H Wood, Smith J. Am. Chem. Soc. 192, 114, 10075.
3. Carbonyl/Imine cyclopropane rearrangement OMe OMe aldimine-hydrobromide 76% NMe NMe OMe OMe
Stevens J. Am. Chem. Soc. 1968, 90, 5580.
O h N BOC 100%
N BOC
Boger, Gabaccio J.Org. Chem. 1997, 62, 8875.
325
M. Electrocyclic Reactions
C8H17 Calciferol (Vitamin D) C8H17 HO , <100 C 1,7 H-shift HO Lumisterol h C8H17 h HO Ergosterol C8H17
HO Precalciferol (Previtamin D) C8H17 heat 100-200 C H HO Isopyrocalciferol disrotatory ring closure 6 e HO Pyrocalciferol C8H17
Havinga Tetrahedron 1960, 11, 276. Tetrahedron 1961, 12, 146.
Provided the impetus for the Woodward-Hoffmann rules Ph
H H
CO2R
H H
CO2R 2s + 4s Diels-Alder reaction
Ph
8 e conrotatory closure 6 e disrotatory CO2R closure Ph
Ph
H H CO2R H
Nicolaou J. Am. Chem. Soc. 1982, 104, 5555, 5557, 5558 and 5560.
326
N. Nazarov Cyclization
4 e Conrotatory electrocyclic ring closure Review: Santelli-Rouvier, C.; Santelli, M. Synthesis 1983, 4295. Nazarov Usp. Khim. 1949, 18, 377.; Usp. Khim. 1951, 20, 71. Denmark Org. React. 1994, 45, 1-158. Denmark Comprehensive Org. Syn., Vol. 5, pp. 751-784.
O H+ R1 R2 R1
OH+
OH
4 e conrotatory R2 electrocyclic ring closure
OH
R2
R1
R1
R2 H+
Nazarov Bull. Acad. Sci., USSR 1946, 633. J. Gen. Chim., USSR 1950, 20, 2009, 2079, 2091. Woodward, Hoffmann Angew. Chem. 1969, 81, 797. R1
OH
R2
R1
R2
O HCO2H H3PO4 90 C, 7 h
O 70%
Nazarov Chem. Abstr. 1948, 42, 7731a, 7731h, 7732g, 7733e, 7734a, 7734. O H3PO4 Me Braude J. Chem. Soc. 1953, 2202. - Silicon-directed Nazarov cyclization. O O FeCl3 CH2Cl2 TMS Denmark J. Am. Chem. Soc. 1982, 104, 2642. O under usual Nazarov conditions: isomerization to 95% via: TMS Cl OH Me O
327
Modern Organic Chemistry The Scripps Research Institute CN + Li O 1. Br2 2. LiBr, Li2CO3 O PPA 100 C 62% O
Eaton J. Org. Chem. 1976, 41, 2238.
- Extensions to annulation procedures. OH OH H2SO4 88% Raphael J. Chem. Soc. 1953, 2247. J. Chem. Soc., Perkin Trans. 1 1976, 410. - Stereochemical course of the reaction: via Nazarov cyclization. OH OH O O + O O 70%
OLi Li
conrotatory 4 e electrocyclization
67%
10%
Hiyama J. Am. Chem. Soc. 1979, 101, 1599. Bull. Chem. Soc. Jpn. 1981, 54, 2747. - Lewis acid-catalyzed reactions. O MeO2C MeO2C Also: FeCl3 BF3Et2O GaCl3 MeO2C + MeO2C H 49% MeO2C 40% O MeO2C O
Tsuge Bull. Chim. Soc. Jpn. 1987, 60, 325. - Tin-directed Nazarov cyclization. O R Bu3Sn R' BF3Et2O 44-93% R' O R
Johnson Tetrahedron Lett. 1986, 27, 5947.
328
O. Divinylcyclopropane Rearrangement
Comprehensive Org. Syn., Vol. 5, 971. Org. React. 1992, 41, 1.
(2s + 2s + 2s)
- Mechanism:
H H
H H
H H boat-like transition state
H H
- Synthesis of functionalized 7-membered rings: silyl enol ether O MeO H O H TMSCl, Et3N Et2O 100% MeO H O OTMS O H 210 C benzene 96% KF MeOH Marino J. Org. Chem. 1981, 46, 1912. MeO O O MeO OTMS
- Fused ring systems: ,-unsaturated enone OEt Li 1. H

n
O 170-180 C
n
2. HCl, H2O
benzene H
n=1 n=2
n=1 n=2 Wender J. Org. Chem. 1976, 41, 3490.
n = 1, 72% n = 2, 74%
329
P. Carbene Cycloaddition to Alkenes

1. Halocabenes Parman, Schweizer Org. React. 1963, 13, 55. Moss Acc. Chem. Res. 1989, 22, 15. Acc. Chem. Res. 1980, 13, 58. Kostikov, Molchanov, Khlebnikov Russ. Chem. Rev. 1989, 58, 654.
2s + 2a
cycloaddition
CH2
Addition of a singlet carbene proceeds by a concerted process in a syn fashion. - Methods for generating halocarbenes:
X X
X X
Triplet carbene behaves as a diradical.
For a comprehensive list see: Kirmse Carbene Chemistry, 1971, 313. CHCl3 + KOtBu BrCCl3 + nBuLi CH2Cl2 + RLi N2CHBr Cl3CO2R + RO PhHgCCl2Br - Reaction with alkenes: CBr2 H H H H H CBr2 H H H CCl2 CCl2 CHCl CHBr CCl2 CCl2 Br Br Stereospecific Br Br reactivity of carbenes CH2 > CHCl > CCl2 > CBr2 > CF2
Doering J. Am. Chem. Soc. 1956, 78, 5447. - Reaction with aromatic C=C bonds (cyclopropanation followed by rearrangement): Cl OMe CCl2 Cl OMe Cl O
Parman, Schweizer J. Am. Chem. Soc. 1961, 83, 603. Cl H N
MeLi N H CH2Cl2
N Li Closs, Schwartz J. Org. Chem. 1961, 26, 2609.
330
Key Ring Forming Reactions Dale L. Boger 2. Simmons-Smith Reaction Simmons Org. React. 1973, 20, 1. Simmons, Smith J. Am. Chem. Soc. 1958, 80, 5323. + CH2I2 + Zn(Cu) - Mechanism: C H2C C I C ZnI C C H2 ZnI I C CH2 C + ZnI2 + ZnI2 + Cu
1) concerted mechanism likely (above) 2) reaction is stereospecifically syn 3) alkenes with higher alkyl substitution react faster 4) electron donating substituents accelerate reaction i.e., enol ethers, enamines... - Addition can be directed by a hydroxyl group or ether functionality: OH CH2I2 Zn(Cu) OH H H OMe CH2I2 Zn(Cu) OMe H H Rickborn J. Am. Chem. Soc. 1968, 90, 6406. J. Org. Chem. 1972, 37, 738. - Examples: enone CO2Et MeO N H Shen Chem. Abstr. 1967, 67, 108559m. CH2I2 Zn(Cu) CO2Et MeO N H 70%, 100% cis 60%, 100% cis
HO OMe enol ether
HO OMe 91%
HO O
Wenkert, Berges J. Am. Chem. Soc. 1967, 89, 2507.
331
3. Diazocarbene Addition - Rearrangement Review: Burke and Grieco Org. React. 1979, 26, 361. O Cl Re R
z
O CH2N2 N2 Re R
z
O Cu Re Rz Li/NH3 OLi HCO2H H2 O
OH Rz
regioselective enolate generation Rz Re O O O O 1. NaH CO(OMe)2 2. NaBH4 O O O H HCl THF
Cu C6H6
N2 O O Delongchamps Can. J. Chem. 1970, 48, 3273. Can. J. Chem. 1980, 58, 2460.
MeO2C
OH2+
HO2C
Agarospirol
HO OLi Li + C5H11 O CO2H C5H11 PGA2 H OH PhS sulfoxide [2,3]-sigmatropic rearrangement used to install Nu CO2R CO2R Nu CO2R CO2R CO2Et PhSH dianion alkylation CO2Et O CO2Et TsN3 Et3N N2 C5H11 O CO2Et C5H11 H Taber J. Am. Chem. Soc. 1977, 99, 3513.
t C5H11 KO Bu
CO2Et Cu Toluene
Br O
homoconjugate addition vs. conjugate addition
332
4. Metal-Carbene Cycloaddition Reactions Comprehensive Org. Syn., Vol. 5, pp. 1065. - Three-membered ring [2 + 1] Bookhart, Studabaker Chem. Rev. 1987, 87, 411. Doyle Chem. Rev. 1986, 86, 919.
E. O. Fischer received the 1973 Nobel Prize in Chemistry for his work in organometallic chemistry with transition metal complexes including metallocenes and his stabilized carbene complexes.
Reaction works well for electron-rich, electron-poor and unactivated C=C bonds. OMe + Ph OEt enol ether neat, 50 C 100 atm CO 61% Ph OMe + OEt (76 : 24) OEt Ph OMe
(CO)5Cr
(CO)5Cr
OMe + Ph
Ph OMe CO2Me neat, 90 C 60% enone + CO2Me (29 : 71)
Ph OMe CO2Me
Fischer, Dtz Chem. Ber. 1972, 105, 3966. Chem. Ber. 1972, 105, 1356. - Four-membered rings [2 + 1 + 1] (CO)5Cr h (CO)5Cr O - Fischer carbene addition to alkynes typically leads to 6-membered ring , 4- and 5-membered rings form only under special circumstances.
tBu
OMe +
h R1 R2 CH3CN
O OMe R1 R2
R1 = H, R2 = OEt, 85% R1 = R2 = Me, 61% R1 = H, R2 = Ph, 30%
OMe Hegedus J. Am. Chem. Soc. 1989, 111, 2335.
(CO)5Cr
OMe + Ph
65 C CO2Et
Ph OMe 4-membered ring formation is a result of the large tbutyl group.
Cr leads to 6membered ring (CO)5W OMe +
THF tBu CO2Et 93% Yamashita Tetrahedron Lett. 1986, 27, 3471. Ph Ph 100 C Ph Ph toluene 90% OMe
Ph
Ph OMe
Foly J. Am. Chem. Soc. 1983, 105, 3064. N required for 5-membered ring N (CO)5Cr O Et + Et 100 C DMF 96% N Et Et
O Yamashita Tetrahedron Lett. 1986, 27, 5915.
333

- Six-membered rings [3 + 2 + 1] (Fischer carbene addition to alkynes) Dtz, Fischer Transition Metal Carbene Complexes, VCH: Deerfield Beach, FL, 1983. Dtz Angew. Chem., Int. Ed. Eng. 1984, 23, 587. Casey in Transition Metal Organometallics in Organic Synthesis, Academic Press: New York, 1976, Vol. 1. Dtz Pure Appl. Chem. 1983, 55, 1689. Casey in Reactive Intermediates, Wiley-Interscience: New York, 1982, Vol. 2, and 1985, Vol. 3. Hegedus Principles and Applications of Organotransition Metal Chemistry, University Science Books: Mill Valley, CA, 1987, p. 783. Brown Prog. Inorg. Chem. 1980, 27, 1. Wulff in Advances in Metal-Organic Chemistry, JAI Press: Greenwich, CT, 1989, Vol. 1. - General scheme R
2
R3
RL L + M(CO)4 RS
OH R R2 or R3 = H
2
RL RS OMe
R2 R1
O R3 C RL RS XR
R1
R1
XR
- Most widely studied after cyclopropanation of Fischer carbenes. Extensively applied in natural product synthesis. Examples: OH OH H iPr 1) THF, 45 C OMe + + (CO)4Cr 2) FeCl3-DMF iPr THF, 25 C iPr OMe 99.6 : 0.4 OMe 55% Wulff in Advances in Metal-Organic Chemistry, JAI Press: Greenwich, CT, 1989, Vol. 1. OMe (CO)4Cr + MeO 3. (CF3CO)2O NaOAc CO2tBu 4. TFA 5. aq. NaOH OMe O OH O O 1. PhH, 75 C 2. air, 10 min O
O O 11-Deoxydaunomycinone
Wulff Tetrahedron 1985, 41, 5797. OH OMe (CO)4Cr O CO2Me + 85 C THF O OMe CO2Me Sphondin and Angelicin
Wulff J. Am. Chem. Soc. 1988, 110, 7419. OTBS MOMO MeO OMe Cr(CO)5 + MOMO EtO N EtO N Boger J. Am. Chem. Soc. 1995, 117, 11839. J. Org. Chem. 1991, 56, 2115. J. Org. Chem. 1990, 55, 1919. TBSO MOMO MeO Ac2O heptane MOMO OMe OTBS
Fredericamycin A OH OTBS
334
Q. [2 + 3] Cycloadditions for 5-Membered Ring Formation

Review: Comprehensive Org. Syn., Vol. 5, 239. 1. (2 + 2)
- Noyori reaction: J. Am. Chem. Soc. 1972, 94, 1772. J. Am. Chem. Soc. 1973, 95, 2722. J. Am. Chem. Soc. 1977, 94, 5196. J. Am. Chem. Soc. 1978, 100, 1793. R Br + D Br R O Fe2(CO)4 O benzene D R stepwise process R via OFe2+
OFe D Br O Ph Ph Br Ph O Ph 70%
N O
O n O N O
n = 5, 75% n = 6, 100%
70% Cuparenone Noyori Tetrahedron Lett. 1978, 493.
- Intramolecular version: Yamamoto J. Am. Chem. Soc. 1979, 101, 220.
Br + O Br - Reviews: Acc. Chem. Res. 1979, 12, 61. Org. React. 1983, 29, 163. O 2:1 58% O
335
Modern Organic Chemistry The Scripps Research Institute Cl Cl ZnCl2 + Cl Cl 21%
Miller Tetrahedron Lett. 1980, 577. Cl Cl + Ph Ph Cl Cl ZnCl2, HCl + CH2Cl2 70% 50%
OEt Cl +
OEt
81%
Mayr Angew. Chem., Int. Ed. Eng. 1981, 20, 1027.
2. (2 + 4) + Ph Ph LDA, THF Ph 41%
Ph Ph Ph Kauffman Angew. Chem., Int. Ed. Eng. 1972, 11, 292. CN CN Ph Ph + Ph 25 C, 2 h 65% Martens Angew. Chem., Int. Ed. Eng. 1972, 11, 724. Ph Ph Ph
336
Key Ring Forming Reactions Dale L. Boger - Trost trimethylenemethane equivalent:
EWG + TMS Stepwise mechanism: CO2Me MeO2C MeO2C MeO2C 32% Related equivalents: O + TMS 1,4-addition of allylsilane: Knapp Tetrahedron Lett. 1980, 4557. Cl TiCl4 O Cl KOtBu O CO2Me CO2Me MeO2C MeO2C 60% cis : trans 1 : 1.3 OAc Pd(PPh3)4 EWG
via:
L Pd L
SO2Ph + O
KH TMS Et2O
SO2Ph
TMS Bu4NF THF
SO2Ph
OH
Trost J. Am. Chem. Soc. 1980, 102, 5680.
O O CO2Me MeO2C + O O O Nakamura J. Am. Chem. Soc. 1989, 111, 7285. J. Am. Chem. Soc. 1991, 113, 3183. O
337
R. Cyclopropenone Ketal Cycloadditions

Review: Boger Adv. Cycloaddition Chem., JAI Press: Greenwich, CT, Vol. 2, 1990, pp. 147-219. 1. [2 + 1] Cycloaddition O CO2Me O 80 C [1 + 2] CO2Me H H O O H H CO2Me O O
cis : trans 20 : 1
OH endo diastereoselectivity Boger J. Am. Chem. Soc. 1986, 108, 6895.
- Carbene addition: 2s + 2a
suprafacial H H
antarafacial
H H
H O R H H
OMe OMe H R O H H
OMe
OMe
endo stabilization
H H H O H R H H OMe OMe H O - Carbene angle of attack: Jorgensen J. Am. Chem. Soc. 1989, 111, 1919. O O O O R H H OMe H OMe
117 o
O O
75 oC
OMe OMe
75 oC
MeO
OMe
338
2. [3 + 2] Cycloaddition - Substrates that contain two geminal electron-withdrawing groups. EWG R EWG + O O 70-80 C O O
EWG EWG
[4 + 2] Tetrahedron 1986, 42, 2777. [1 + 2] Tetrahedron Lett. 1984, 25, 5611. [3 + 4] J. Org. Chem. 1985, 50, 3425. J. Am. Chem. Soc. 1986, 108, 6713. O (total synthesis of Colchicine)
R J. Am. Chem. Soc. 1984, 106, 805. J. Am. Chem. Soc. 1986, 108, 6695. J. Org. Chem. 1988, 53, 3408. Advances in Cycloaddition Chemistry Vol. 2, JAI: Greenwich, CT, 1990, pp. 147-219.
single e transfer Note: For substrates that may react via this pathway (e transfer), [3 + 2] > [1 + 2], [4 + 2], or [3 + 4] cycloadditions
EWG R radical anion
EWG +
EWG EWG
radical cation MeO2C
CO2Me
95%
1. Solvent independent rate. MeO 2. No addition-elimination or addition-rearrangement products. 3. No inhibition by free radical traps. 4. Putative carbene addition product (a cyclopropane ketene acetal) does not undergo vinylcyclopropane rearrangement to the product. 5. Little or no loss of olefin stereochemistry and this diastereospecific nature of the reaction increases, not decreases, in polar solvents. Unusual polarity that uniquely stabilized radical anion. NC CN 89%
MeO2C MeO2C
MeO O O
NC NC
Cycloaddition faster than cyclopropylcarbinyl radical rearrangement. NC CO2Me 58% O O
NC MeO2C
- (2s + 2a) Cycloaddition CO2R MeO MeO H H MeO MeO H R H H CO2R'
3 e bond, little loss of stereochemistry due to bond rotation
339

3. [4 + 3] Cycloaddition
O O O O
+
O O
O
+
O O O O
+
O H H O O
MP2/6-31++G(d)//6-31++G(d)
O O O O
+
O O O + O
-
H O
+ -
O H H
H O
+
O H H
-
H H
H H
singlet
anti
-delocalized singlet vinylcarbene

O O H O O + O H -
0.00 kcal
H O O H H
1.40 kcal
H O H O H H
O O O
+
triplet 8.73 kcal
syn
9.22 kcal
Singlet carbene stabilized by two alkoxy electron-donating substituents
- 2s + 4s Cycloaddition or Diels-Alder but via a 2 three carbon dienophile.
MeO 80 C 73% MeO NHCOMe MeO MeO O OMe Colchicine 88% 25 C 6.2 kbar Boger J. Am. Chem. Soc. 1986, 108, 6713. MeO MeO O CO H O MeO MeO O O MeO O O MeO MeO MeO O O CO O
H O
340
Key Ring Forming Reactions Dale L. Boger 4. [4 + 2] Cycloaddition (standard Diels-Alder reaction) O R O 25 C [4 + 2] O R O O O O R O R O
O R O O 25 C 6-13 kbar [4 + 2] R
R O + O
R O O R = CO2CH3, 56-65% R = H, 69% R = OCH3, 56-72%
Participates in normal, neutral, or inverse electron demand Diels-Alder reactions, high lying HOMO and low lying LUMO.
O O
VS
O O
Exclusive exo addition Note: cyclopropene itself is endo selective.
CO2CH3
O O
CO2CH3 O KOtBu, 25 C
CO2CH3 O O 6e disrotatory electrocyclic ring opening referred to as a norcaradiene rearrangement 25 C
CH3O2C X
OCH3
25 C 80%
O OCH3
CH3OH
O X= O X=O
OMe MeO MeO O O N O O MeO MeO
OMe
Grandirubrine Imerubrine Granditropone
O Boger J. Am. Chem. Soc. 1995, 117, 12452.
341
S. [2 + 2] Cycloadditions
1. Ketene [2 + 2] cycloadditions Org. React. 1995, 45, 159. O O H 2s + 2a Cycloaddition
O Et3N hexanes COCl O
Baldwin J. Chem. Soc., Chem. Commun. 1972, 1337. 2. Photochemical [2 + 2] cycloaddition Comprehensive Org. Syn., Vol. 5, 123. Org. React. 1993, 44, 297.
O h 92%
Cargill Tetrahedron Lett. 1978, 4465. OEt 1. LDA, MeI O 2. MgBr Isocomene Pirrung J. Am. Chem. Soc. 1979, 101, 7130. J. Am. Chem. Soc. 1981, 103, 82. O 1. CuI 2. CH2O MgBr O OH 1. TsCl 2. base O h 67% O O h O 1. Ph3P=CH2 2. TsOH
Panasinene
C. R. Johnson J. Am. Chem. Soc. 1981, 103, 7667.
342
Key Ring Forming Reactions Dale L. Boger CHO O EtO O 1. LDA 2. LiAlH4 I O O h O3 O
O O Smith J. Am. Chem. Soc. 1982, 104, 5568. O
Hibiscone C O MeO2C + Note: regioselectivity of cycloaddition in excited state. - Mechanism: CO2Me retro [2 + 2] H CO2Me ene reaction H CHO OH CHO H H Warburganal H Wender Tetrahedron Lett. 1982, 23, 1871. - Note regioselectivity: O + MeO OMe O excited state reversed polarity h OMe OMe O O CO2Me H H 210 C, 2 h h O
CO2Me Ph3P=CH2
CO2Me
H - Ene reaction:
VS.
Corey J. Am. Chem. Soc. 1964, 86, 5570.
343
3. Paterno-Buchi Reaction
Comprehensive Org. Syn., Vol. 5, 151. Dermuth Synthesis 1989, 152. First studied in detail by Buchi J. Am. Chem. Soc. 1954, 76, 4327.
O + R1 R2 h O R1 R2 * R5 R3 R6 R4 R1 R6 R5 O R2 R4 R3 a diradical intermediate has been observed R3 R4 R5 R6 R6 h R
1
O R2 R3
R5 R4
-Addition to enol ether occurs with only moderate selectivity ... O Ph Ph OEt + OEt h Ph Ph OEt (75 : 25) Schroeten J. Org. Chem. 1969, 34, 1181. ... while addition of the carbonyl to a furan occurs with high selectivity. O Ph Ph + O h Ph Ph O O O + Ph Ph O O + O Ph Ph
(1 : 99)
Schenk Chem. Ber. 1963, 96, 498. - Intramolecular variant: O O h cat. Na2CO3 benzene O O Thromboxane A2
Carless J. Chem. Soc., Chem. Commun. 1984, 667. - Diastereoselectivity: R fast R CHO h O H h O O H O O R slow O H O O H R H O H O H R O R H O H O not formed R H
Aoyoma J. Org. Chem. 1984, 49, 396. Pattenden J. Chem. Soc., Chem Commun. 1980, 1195. J. Chem. Soc., Chem Commun. 1979, 235.
344
T. Arene-Olefin Photoadditions
- Discovery in 1966: Wilzbach J. Am. Chem. Soc. 1966, 88, 2066. Bryce-Smith J. Chem. Soc., Chem. Commun. 1966, 512. Comprehensive Org. Syn., Vol. 5, 645.
LiO O + Li OMe
OMe H Li/NH3 H MeO h 65% OMe OMe H + (1 : 1)
KOH, N2H4 diethylene glycol 200 C
H O
1. Br2, CH2Cl2 H 2. Bu3SnH
-Cedrene
Wender J. Am. Chem. Soc. 1981, 103, 688.
h 72% + (1 : 1)
244 C toluene 50-60% Isocomene Wender Tetrahedron 1981, 37, 4455.
OAc h 21%
1. KOH, MeOH H OAc 2. BaMnO4 82%
KOtBu, MeI O THF 68% O
1. Li, Et2NH THF, 0 C Modhephene 2. H2, PtO2 93% Wender J. Am. Chem. Soc. 1982, 104, 5805. OPO(NMe2)2
1. Me2CuLi THF, 78 C 2. then Cl2PO(NMe2) 3. Et2NH 76%
345
U. Intramolecular Ene Reaction

Review: H. M. R. Hoffmann Angew. Chem., Int. Ed. Eng. 1969, 8, 556. Comprehensive Org. Syn., Vol. 5, pp. 9. H H concerted thermal [4 + 2] cycloaddition
ene - First systematic study by Alder:
eneophile O + O O O O
H Ph
Ph O Alder Chem. Ber. 1943, 76, 27.
- First intramolecular versions:
review: Oppolzer Angew. Chem., Int. Ed. Eng. 1978, 17, 476.
O H Treibs, Schmidt Chem. Ber. 1927, 60, 2335. 300 C CO2Me 14 h 65% CO2Me OH
cis
AlCl3, 0 C H BnO O Me 69% BnO OR
Smith J. Am. Chem. Soc. 1991, 113, 2071. R N H CH3 O R AlCl3, 25 C 91% H N OH CH3
Overman Tetrahedron Lett. 1985, 35, 4167. Note the Sharpless mechanism for SeO2 oxidation of olefins: allylic oxidation involves an ene reaction. H Se O O ene reaction Se O [2,3]-sigmatropic rearrangement O Se OH OH
or Nu
OH
Sharpless J. Am. Chem. Soc. 1972, 94, 7154. J. Am. Chem. Soc. 1973, 95, 7917.
346
Key Ring Forming Reactions Dale L. Boger Amine Oxide Elimination (Cope Elimination) Org. React. 1960, 11, 361. Org. Syn. 1963, 4. 612. Cope J. Am. Chem. Soc. 1954, 81, 2799. Zutter J. Am. Chem. Soc. 1986, 108, 1039. H O N + N OH
syn elimination
Sulfoxide Elimination Trost Chem. Rev. 1978, 78, 363. Acc. Chem. Res. 1978, 11, 453. J. Am. Chem. Soc. 1973, 95, 6840. J. Am. Chem. Soc. 1976, 98, 4887. O R S
Ziegler J. Am. Chem. Soc. 1984, 106, 721. Schreiber J. Am. Chem. Soc. 1984, 106, 4038. Agosta J. Am. Chem. Soc. 1986, 108, 3385.
syn elimination
H O S Ph
RSOH
220 C
syn elimination
H O S Me
110 C
H O O S Ph
80 C
syn elimination
syn elimination
O R O O R R
HO
O O PhS O O O SPh O SPh 25 C O O HO O SPh
Boger, Mullican J. Org. Chem. 1980, 45, 5002. J. Org. Chem. 1984, 49, 4045.
347
Modern Organic Chemistry The Scripps Research Institute - Selenoxide Elimination Clive Tetrahedron 1978, 34, 1049. Reich Acc. Chem. Res. 1979, 12, 22. H O Se Ph O 25 C
syn elimination
Selenoxide elimination occurs at lower temperature. O O SeAr
Br
NaSePh R
SeAr
[ox.] R
OH
Bu3P NO2 Se CN
V. Oxy-Ene Reaction: Conia Reaction

Comprehensive Org. Syn., Vol. 5, 20. Review: J. M. Conia Synthesis 1975, 1.
O O H O
350-370 C 30 min
85% Epimerized to more stable trans isomer.
350-370 C 30 min
cis
Conia Bull. Chim. Soc., Fr. 1969, 818.
O O 335 C 60 h 50% tandem Conia reactions: Conia Tetrahedron Lett. 1974, 2931.
348
W. Cyclopentenone Annulation Methodology

1. O 1 Br O OLi 2. O2, PdCl2, CuCl2 3. NaOH, EtOH 2
Wacker oxidation, review:Tsuji Synthesis 1984, 369. Wayner J. Org. Chem. 1990, 55, 2924.
1. 1
Br 2
2. NaIO4, OsO4 3. NaOH, EtOH McMurry J. Am. Chem. Soc. 1979, 101, 1330. Br 1. 1 Br 2
2. H2SO4 3. NaOH, EtOH
1. TMSCl 1 2. SnCl4, CH2=C(Me)NO2 3. NaOH, EtOH 2
1. Br TMS 2. KOH, MeOH (TMS) 1 3. Hg(OAc)2, H+ 4. NaOH, EtOH 2
OMe 1. OLi Br CO2Me O 2. H2SO4, H2O 3. NaOH, EtOH CO2Me
OEt Br PO(OMe)2 + Br
O PPh3
Used in Quadrone total synthesis: Helquist J. Am. Chem. Soc. 1981, 103, 4647.
Piers Tetrahedron Lett. 1979, 3279.
Altenbach Angew. Chem., Int. Ed. Eng. 1979, 18, 940.
349
- Flemming-Greene Annulation: 1. Cl3CCOCl Zn-Cu O Cl 2s + 2a cycloaddition O 2. CH2N2 Cl 3. Zn-HOAc Zn-HOAc O Cl Cl olefin-ketene cycloaddition Cl Cl CH2N2 62% O
O 59%
Loganin: Flemming J. Chem. Soc., Chem. Commun. 1977, 81. Hirsutene: Greene Tetrahedron Lett. 1980, 3059. Hirsutic Acid: Greene J. Am. Chem. Soc. 1983,105, 2435.
O +
SiR3
O TiCl4
R SiR3
Cl3Ti
SiR3
OTiCl3 R
OTiCl3 SiR3 R SiR3
Danheiser J. Am. Chem. Soc. 1981, 103, 1604. Tetrahedron 1983, 39, 935.
- Cyclopropylphosphonium salts: CO2Me
CO2Me + O
PPh3 CO2Et
NaH THF 90%
CO2Et Fuchs J. Am. Chem. Soc. 1974, 96, 1607. PPh3 SPh
Marino Tetrahedron Lett. 1975, 4531.
350
Key Ring Forming Reactions Dale L. Boger - -Vetivone synthesis: O CHO + EtO PPh3 CO2Et NaH HMPA EtO 38% O CO2Et
Dauben J. Am. Chem. Soc. 1975, 97, 1622.
PPh3 O + O
PPh3 Burgstahler, Boger Tetrahedron 1976, 32, 309.
- Benzothiazoles as carbonyl equivalents: N S E+ O Li OEt N S 1. (MeO)2SO2 2. NaBH4 3. H+, Ag(I)
CHO
Corey, Boger Tetrahedron Lett. 1978, 5, 9, 13 and 4557.
I i) LDA, Me2NN
Br I O H BuLi OH PCC O H
ii) CuCl2, H2O
Piers Tetrahedron Lett. 1994, 35, 8573.
- Additional reviews: Denmark Org. React. 1994, 45, 1. Hudlicky Chem. Rev. 1989, 89, 1467. Sehore Chem. Rev. 1988, 88, 1085. Ramarah Synthesis 1984, 529.
351
X. Pauson-Khand Reaction
[2 + 2 + 1] Comprehensive Org. Syn., Vol. 5, pp. 1037-1064. Org. React. 1991, 40, 1. Pauson Tetrahedron 1978, 41, 5855. Schore Chem. Rev. 1988, 88, 1081. First detailed study: Khand J. Chem. Soc., Perkin Trans. 1 1973, 977. Co2(CO)6 CO - Mechanism: OMe H Me MeO H H Me CO Co Co(CO)3 (CO)2 less hindered exo face Co(CO)3 MeO H Co2(CO)6 H H O H H O CO inserted 60% only isomer MeO H Co(CO)3 reductive elimination MeO H MeO H Co (CO)3 Co(CO)3 CO Me large O large H small Me
+ (CO)3Co Co(CO)3 CO H
H O
Co(CO)3 Co (CO)3
1. Regio- and stereochemistry are controlled by steric factors. 2. Complexation of alkene and insertion into Co-C bond occurs from less hindered face. 3. Insertion of the alkene carbon bearing the largest allylic substituent to form the first C-C bond occurs at the alkyne carbon bearing the smallest substituent. 4. Subsequent CO insertion occurs next to the largest alkyne substituent. 5. Reductive elimination followed by decomplexation gives the final product.
- Intermolecular: HO HC CH Co2(CO)6 OMe DME, 65 C 4 days MeO H 65% Schore J. Org. Chem. 1987, 52, 3595. - Intramolecular RO Co2(CO)8 O TMS The dimethyl and alkyne substituents accelerate the reaction. heptane 80-90 C TMS R = H, 18% R = MOM, 69% + O TMS R = H, 7% R = MOM, 0% RO H O HO H 6 steps H OTBDPS O entry into guaianolide and pseudoguaianolide natural products RO H
Magnus J. Am. Chem. Soc. 1983, 105, 2477.
352
Key Ring Forming Reactions Dale L. Boger H O 45% Schore J. Am. Chem. Soc. 1988, 110, 5224. + H O 6%
Co2(CO)8 heptane 110 C, 20 h
TMS OTBDMS Co2(CO)8 O OTBDMS isooctane 160 C H H 76% Serratosa Tetrahedron Lett. 1985, 26, 2475. Tetrahedron 1986, 42, 1831. -Heterosubstituted systems: H O H O 85% Schreiber J. Am. Chem. Soc. 1986, 108, 3128. H OTBDMS TMS OTBDMS Epimerization occurs via the Co-stabilized propargyl cation.
benzene 60 C, 4 h
CO2(CO)6
O Co2(CO)8 hexane 60 C, 4 h
45% Smith Tetrahedron Lett. 1986, 27, 1241.
353
Y. Carbonylation Cyclizations
Comprehensive Org. Syn., Vol. 4, 1015. Alper Acc. Chem. Res. 1995, 28, 414.
- Pd mediated carbonylation O R1 R2 CO2Me PdCl2(PPh3)2 R1 Et3N, CO MeOH (catalytic) I R2 PdCl2(PPh3)2 Et3N, CO 65% O I PdCl2(PPh3)2 Et3N, CO CO2Me Pd(PPh3)4 CO (not catalytic) O CO2Me O R1 R2
66% Negishi J. Am. Chem. Soc. 1985, 107, 8289. - Formation of lactones OH PdCl2, PPh3 SnCl2, CO 93% Norton J. Am. Chem. Soc. 1981, 103, 7520. - Formation of amides Heck J. Org. Chem. 1975, 40, 2667. NHBn Br Pd(OAc)2 PPh3, CO 63% O Mori J. Org. Chem. 1978, 43, 1684. Boc N Pd2(dba)3 PPh3, CO Boc BnO 51% Nakanishi Synlett 1991, 91. - Alternative carbonylation method: Hydroboration/Carbonylation H O OBn Boc N O NBn O O
Pd
BnO
BH2
H B H
1. CO, H2O 1000 psi 2. NaOAc, H2O2
60% Brown, Negishi J. Chem. Soc., Chem. Commun. 1967, 594. J. Am. Chem. Soc. 1967, 89, 5477.
354
Z. Olefin Ring Closing Metathesis

Grubbs Comprehensive Org. Syn., Vol. 5, 1115. Acc. Chem. Res. 1995, 28, 446. Tetrahedron 1998, 54, 4413. Schrock J. Am. Chem. Soc. 1990, 112, 3875 and 8378. J. Am. Chem. Soc. 1991, 113, 6899. -General concept: Ring Opening
K. Ziegler and G. Natta shared the 1963 Nobel Prize in Chemistry for their discovery and development of transition metal catalyzed preparation of polyethylene and stereoregular polymers including polypropylene.
Metathesis Ring Closing X Metathesis Acyclic Cross R1 + R2 Metathesis R1 X
R2
- Mechanism: M
R1 M
R1
R1
R2
The mechanism appears to be the same regardless of transition metal used. R1 M R2 R2 R1 M
Grubbs Comprehensive Organometallic Chem., Vol. 8, 1982, 499. Sehrer J. Sci. Ind. Res. 1983, 42, 250. - Defined Catalysts 1. Early catalysts were poorly defined and incompatible with basic functionality. 2. Development of well-defined catalysts lead to high catalytic activity and compatibility with a wide variety of funtionalities. 3. Catalysts are based on variety of transition metals including: Mo, Ru, W, Re, Ti and Ta. 4. The mechanism appears the same for all transition metals. 5. The most widely used catalysts are:
iPr
iPr
PCy3 Cl Ru Cl PCy3 Ph Ph Cl
PCy3 Cl Ru Ph PCy3
(CF3)2MeCO
N Mo
Ph
(CF3)2MeCO 1 Schrock 2 Grubbs 3 Grubbs
355
Modern Organic Chemistry The Scripps Research Institute - Applications to organic synthesis Ring closing metathesis is rapidly becoming one of the more powerful methods for preparing medium and large rings. Modern use of ring closing metathesis traced back to: M=CHR X
n
X = O, NR, CHR n = 1, 2, 3 Grubbs, R. H.; Fu, G. C. J. Am. Chem. Soc. 1992, 114, 5426, 7324. J. Am. Chem. Soc. 1993, 115, 3800. Recent examples: OH O N O O 3 (1 mol%) CH2Cl2 30 min HO O N O O HO HO Ph 97% carbocyclic nucleosides
Ph
Crimmins J. Org. Chem. 1996, 61, 4192. Jacobsen J. Org. Chem. 1996, 61, 7963.
O
n
R1 1 (13 mol%) C5H12, 25 C O
O
n
R1 R2
R1 = H, n = 1, 2 >90% R1 = Et, n = 1, 2 42-73%
H R2
H O PMP O H
R1
R1 R1 H 1 (25 mol%) C6H6, 60 C PMP O O H

n
n R1 R2 conc(M) Yield 1 2 2 2 H H Et H Et Et H H 0.008 0.003 0.003 0.003 97% 86% 14% 58%
R2
note dependence on conformation between two diastereomers. Clark, Kettle Tetrahedron Lett. 1997, 38, 123 and 127. OAc OAc O NHCOCF3 O 1 (20 mol%) O HN C6H6, 60 C HN O 90% Sch 38516 OAc OAc O NHCOCF3 O
Hoveyda J. Am. Chem. Soc. 1995, 117, 2943. J. Am. Chem. Soc. 1996, 118, 10926.
356

- Danishefsky, Nicolaou and Schinzer have all prepared Epothilone A using ring closing metathesis as the key cyclization step. S N H S N O O X ring closing metathesis H
X Epothilone A
Y OR
Y OR
Danishefsky J. Am. Chem. Soc. 1997, 119, 2733. Nicolaou Angew. Chem., Int. Ed. Eng. 1997, 36, 166. Schinzer Angew. Chem., Int. Ed. Eng. 1997, 36, 523. - Application to ring closing metathesis of enynes:
R H N O
R H N O O O
H H H N
R = Me: 2 (5 mol%), C6H6, 50 C, 73% R = CO2Me: 3 (4 mol%), CH2Cl2, 25 C, 87% Kinoshita, Mori J. Org. Chem. 1996, 61, 8356. - Application to the synthesis of fused nitrogen heterocycles: O
x
()-Stemoamide
O R
n
1, benzene 25 or 50 C
N
n
n = 0, R = Me n = 1, R = H n = 2, R = H n = 3, R = H
a (68%) a (92%); b (91%) a (81%); b (84%) a (47%); b (50%)
a) x = 1 b) x = 2 CO2Me H O O N 1 benzene 50 C 64% BnN
a) x = 1 b) x = 2 CO2Me H O H N
H BnN
Manzamine A O
Martin Tetrahedron 1996, 52, 7251.
357
358
Olefin Synthesis Dale L. Boger
XI. Olefin Synthesis

A. Wittig Reaction
G. Wittig received the 1979 Nobel Prize in Chemistry for "many significant contributions to Organic Chemistry" which included not only the Wittig reaction, but also PhLi prepared by metal-halogen exchange, benzyne, and the Wittig rearrangement. Reviews:
Comprehensive Org. Syn., Vol. 1, 755. Org. React. 1965, 14, 270. Angew. Chem., Int. Ed. Eng. 1964, 3, 250. Top. Stereochem. 1970, 5, 1. Pure. Appl. Chem. 1979, 51, 515. Chem. Rev. 1989, 89, 863.
1. Formation of Ylides Ph3P + X CH2R ether + Ph3P CH2R X PhLi, nBuLi, LDA or MeS(O)CH2Na + Ph3P CHR
strong electron-withdrawing group
pKa ~ 18-20 (R = alkyl, H) Ph3P CHR ylide
- Unstabilized ylides are sensitive to H2O, O2 2. Reaction of Ylides with Ketones O + + Ph3P CHR + PPh3 CH-R
Ylide
Betaine
R + Ph3P O
Ph Ph P Ph O R
Oxaphosphetane Strong bond formation is part of the driving force for the collapse of the oxaphosphetane.
Wittig and Schllkopf Chem. Ber. 1954, 87, 1318.
359

3. Mechanism and Stereoselectivity of the Wittig Reaction
Ph3P CHCH3
RCHO CH3 R
cis olefin from nonstabilized ylides

- Stereoselectivity increases as the size of the R group increases. - Accepted mechanism today: irreversible and concerted [2 + 2] cycloaddition.
P Ph3 slow (- Ph3P O ) CH3 R Ph3P O H H R CH3 O CH3 H H R 2a + 2s cycloaddition suprafacial antarafacial
cis
Orientation such that the R groups on the aldehyde and on the ylide are as far apart as possible.
- The three alternative [2 + 2] cycloaddition transition states suffer destabilizing steric interactions:
Ph Ph Ph P O CH3 H R H
Ph Ph Ph P O H R H CH3
Ph Ph Ph P O H H R CH3
trans
cis
trans
Not bad, probably gives rise to trans product
- So, the mechanism involves fast, irreversible [2 + 2] cycloaddition (usually occurs at 78 C) followed by slow decomposition of oxaphosphetane (frequently requires warming to 0-25 C). - Nonpolar solvents facilitate the initial addition. - Polar solvents facilitate the final elimination reaction.
360
Olefin Synthesis Dale L. Boger 4. Representative Examples + PPh3 1) NaN(SiMe3)2 2) OHC(CH2)8CO2CH3 78 C, THF
CO2CH3 80%, >98% cis
Besterman Chem. Ber. 1976, 109, 1694.
H O
6.5 equiv CH3PPh3Br 5 equiv nBuLi Et2O, 25 C, 1 h reflux, 3 h, 56%
H vitamin D3 OH
OH Inhoffen Chem. Ber. 1958, 91, 2309; J. Am. Chem. Soc. 1957, 79, 5029.
HO
OTs Al2O3
H Ph3P CH2 H 79%
H Bchi J. Am. Chem. Soc. 1966, 88, 4113. NaH DMSO 70 C O S+
O Ph3PCH3Br Na DMSO 25 C Ph3P CH2 50-55 C 73%
Corey J. Org. Chem. 1963, 28, 1128. H N O RO2C H O OH 1) SOCl2 2) Ph3P, iPr2NEt 51% N O RO2C H O PPh3 90 C 48 h, PhMe 89% N O CO2R S
Woodward J. Am. Chem. Soc. 1979, 101, 6301.
- -oxygenated substrates PPh3 O + O OMe 1) addition 2) H3O+ 85%, >99% Z OH - trisubstituted Z-alkene
Still J. Org. Chem. 1980, 45, 4260.
361
Modern Organic Chemistry The Scripps Research Institute - Schlsser modification: allows the preparation of trans vs. cis olefins. + Ph3P CH2R O PPh3 R R CH3 C5H11 C 3H 7 CH3 C 2H 5 R1 C5H11 CH3 C 3H 7 Ph Ph PhLi, Et2O 25 C, 10 min 1 equiv HCl + O PPh3 H R R1 H % yield 70 60 72 69 72 R1CHO 70 C, 5 min KOtBu/tBuOH Et2O, 25 C 2h O PPh3 H R1 R H R1 R PhLi, 30 C 5 min
Ph3P CHR
H R1
trans:cis 99:1 96:4 98:2 99:1 97:3
Schlsser Angew. Chem., Int. Ed. Eng. 1966, 5, 126. .. - -Oxido Phosphonium Ylide Reaction: adaptation of the Schlosser modification for the stereoselective preparation of trisubstituted allylic alcohols. Ph3P R THF + R'CHO 78 C O PPh3 H H R' R
sBuLi
OLi R' R CH2O, 0 C PPh3
78 C
H R'
R OH
H R'
O PPh3 R O
O H R'
+ PPh3 R O
Only 2 alkoxide forms oxaphosphetane that eliminates to form the olefin. Corey, Katzenellenbogen and Posner J. Am. Chem. Soc. 1967, 89, 4245. Corey and Yamamoto J. Am. Chem. Soc. 1970, 92, 226. Corey and Yamamoto J. Am. Chem. Soc. 1970, 92, 6636. Corey and Yamamoto J. Am. Chem. Soc. 1970, 92, 6637. I + Ph3P Ar1 + Ar2CHO 18-crown-6 KOH Ar1 Ar2 > 98:2 Z :E Ar2 Br Cl + Ph2P Ar1 + Ar2CHO 18-crown-6 KOH Ar1 > 96:4 E : Z Chiappe Tetrahedron Lett. 1996, 37, 4225. (E)-alkene (Z)-alkene C. J. Peterson (DuPont) received the 1987 Nobel Prize in Chemistry for his discovery and development of crown ethers.
(I > Cl > Br)
362
Olefin Synthesis Dale L. Boger 5. Stabilized Ylides O Br OR PPh3 ether or benzene + Ph3P O OR Na2CO3 H2O + Ph3P O OR
Has two electron-withdrawing groups so the pKa is very low.
Ph3P CHCOOR
- Stabilized ylides are solid; stable to storage, not particularly sensitive to moisture, and can even be purified by chromatography. - Because they are stabilized, they are much less reactive than alkyl ylides. They react well with aldehydes, but only slowly with ketones. - The first step, involving the addition to the aldehyde, is slow and reversible with stabilized ylides. R'CHO Ph3PCHCOOR Ph3P O H R' ROOC H minor kinetic product Ph3P O H H ROOC R' major kinetic product
rotation available before elimination + Ph3P H ROOC O H R'
faster
slower
R' + ROOC + Ph3P ROOC H O H R' thermodynamically more stable, and is predominant or exclusive product of the reaction. ROOC R'
- It is also possible that elimination occurs in a stepwise manner via stabilized zwitterionic intermediate that may simply afford the more stable product. - -oxygenated substrates - The exception to the generation of E-alkenes with stabilized ylides is their reaction with -alkoxy aldehydes. O O O (EtO)2P O OHC O CHO O MeO2C O CO2Me
CO2Me
Ph3P CHCO2Me CH3OH 78 to 25 C
MeO2C
CO2Me
NaH, DME 78 to 25 C
trans (E)-olefin Krief Tetrahedron Lett. 1988, 29, 1083. - And, this departure is solvent dependent
OHC MeO O O O DMF CHCl3 MeOH Tronchet, Bentzle Helv. Chim. Acta 1979, 62, 2091. Ph3P CHCO2Et
cis (Z)-olefin!
CO2Et O MeO 14 : 86 60 : 40 92 : 9 O O
Z:E Z:E Z:E
trans cis
363
Modern Organic Chemistry The Scripps Research Institute 6. Annulation Applications of the Wittig Reaction OH a) NaH b) O O SH a) NaH b) + PPh3 + PPh3 O + PPh3 O O PPh3 S (SO2) chelotropic extrusion [O] S O2 2 carbon unit O 75% PPh3 O 2 carbon unit
O S
4 carbon unit O + COOEt - Homoconjugate addition: OH + O - Modest yields because one electron-withdrawing group is not sufficient to activate the cyclopropane ring to nucleophilic ring opening. So: BF4 + PPh3 SPh 1) O O N SPh BF4 + PPh3 COOEt + PPh3 NaH O + PPh3 NaH CO2Et
1) ClCOOEt PPh3 2) NaBF4
2) NaBF4
Dauben J. Am. Chem. Soc. 1975, 97, 1622. - Applications: EtOOC NaH + PPh3 COOEt 90% PhS NaH + PPh3 SPh 82%
O COOEt
COOEt
H+ (Hg2+) COOEt
O H COOEt
364
B. Wadsworth-Horner-Emmons Reaction
Horner Chem. Ber. 1958, 91, 61; 1959, 92, 2499. Wadsworth, Emmons J. Am. Chem. Soc. 1961, 83, 1733. Wadsworth, Emmons J. Am. Chem. Soc. 1966, 88, 5654. Reviews:
Org. React. 1977, 25, 73-253. Comprehensive Org. Syn., Vol. 1, 761.
1. Arbuzov Reaction - Preparation of Phosphonate Esters O (EtO)3P: + Cl OEt EtO O OEt P OEt O CH2CH3 EtCl EtO O O P(OEt)2
Cl - The same approach to the preparation of -ketophosphonates is not successful: (RO)3P O Cl R' Perkow reaction O O (RO)2P O R' O P(OR)2 R' - But can use variation on Claisen conditions: OEt EtI P(OEt)3 EtO P+ CH2CH3 O CH3CH2 I Can also use: O (EtO)2P O Cu + Cl R O (EtO)2P LDA or nBuLi, CH3 78 C O (EtO)2P Li O EtO CH3 O R'
CH3
Unstable at higher temperatures or under prolonged reaction times. O (EtO)2P R' O O P(OEt)2 Na+ O (EtO)2P O H R EtOOC H O (EtO)2P H EtOOC O (EtO)2P H EtOOC
Savignac Tetrahedron Lett. 1976, 2829. 2. Mechanism and Stereoselectivity O EtO O P(OEt)2 NaH THF EtO RCHO ONa H R
ONa R H
OH EtO P O EtO
H + EtOOC
R H
O (EtO)2P O H R EtOOC H
E-selective (trans)
Note possibility of C-C bond rotation (may or may not be discrete intermediate)
Water soluble (easily removed through aqueous workup) Good reactions for: EtO EtO P O W W = CN, COOR, C(O)R, CHO, SO2Ph, Ph But not W = alkyl, H
365
Modern Organic Chemistry The Scripps Research Institute 3. Modifications and Scope - LiCl/tertiary amines (DBU, iPr2NEt, Et3N) Masamune, Roush Tetrahedron Lett. 1984, 25, 2183. Can substitute for conventional conditions and is especially good for base sensitive substrates (epimerization, elimination). O CH3 O O + H subject to -elimination CH3CN 80% CH3 O OMTM OMTM LiCl, iPr2NEt O
P(OEt)2 O
Keck J. Org. Chem. 1989, 54, 896. (thioester was also stable to these conditions) -Hindered phosphonates and hindered aldehydes increase E-selectivity (trans). CH3 BnO CHO KOtBu, BnO 7:1 95 : 5 1:3 CH3 CO2R
Ph3P=CHCO2Et, CH2Cl2, 0 C (iPrO)2POCH2CO2Et, THF, 78 C (MeO)2POCH2CO2Me, KOtBu, THF, 78 C Kishi Tetrahedron 1981, 37, 3873.
E:Z E:Z E:Z
- The use of a nonhindered phosphonate, low temperatures, and a strongly dissociating base (KOtBu) can give increased or high Z-selectivity (cis). - Coordinating countercations slow the rate of elimination relative to equilibration. Ph CHO CH3 Stabilized Wittig reagent Ph3P=C(Me)CO2Et, CH2Cl2, 25 C Ph3P=C(Me)CO2Et, MeOH, 25 C (MeO)2POCH(Me)CO2Me, Wadsworth-HornerEmmons reagent (MeO)2POCH(Me)CO2Et, KOtBu, THF, 78 C KOtBu, THF, 78 C Ph CH3 95 85 5 10 40 90 95 CO2R + CH3 : : : : : : : Ph CH3 CH3 CO2R 5 15 95 90 60 10 5
(EtO)2POCH(Me)CO2Et, KOtBu, THF, 78 C (iPrO)2POCH(Me)CO2Et, KOtBu, THF, 78 C (iPrO)2POCH(Me)CO2iPr, KOtBu, THF, 78 C
- Still-Gennari modification selective for Z-alkenes (cis): O (CF3CH2O)2P R R = H, Me Still Tetrahedron Lett. 1983, 24, 4405. CO2Me KHMDS 18-c-6 THF R' R CO2Me
R'CHO
Z - selective Z : E > 10 : 1
366
Olefin Synthesis Dale L. Boger CH3 CO2Me BnO 84% 11 : 1 Z : E Cinquini Tetrahedron 1987, 43, 2369. I I CHO (CF3CH2O)2POCH2CO2Me KHMDS, 18-c-6 78 C, 30 min 97%, >25:1 Z : E O O Combretastatin D-2 Boger J. Org. Chem. 1991, 56, 4204. RCHO R CO2Et (CF3CH2O)2POCH2CO2Me KH, THF BnO CH3 CHO (EtO)2POCH2CO2Et NaH, THF BnO CH3 CO2Me
83% 12 : 1 E : Z OH O
MeO2C
(PhO)2P(O)CH2CO2Et Ando J. Org. Chem. 1997, 62, 1934.
Selected diarylphosphonates provide high (Z)-selectivity as well
C. Peterson Olefination
Peterson J. Org. Chem. 1968, 33, 781. Reviews: Org. React. 1990, 38, 1. 1. Nonstabilized Peterson Reagents
- Me3SiCH2Met, Met = Li, Mg, offer an alternative to Wittig or Tebbe procedures. They are more reactive and sterically less demanding than a Wittig reagent and the volatile byproduct (Me3SiOH/ Me3SiOSiMe3) is simpler to remove than Ph3PO. It does, however, require a second step to promote elimination of the -hydroxysilane. - Example Et3SiO MeO CH3 OMe Danishefsky J. Org. Chem. 1988, 53, 3391. O OMe N NMe 1) LiCH2SiMe3 2) DDQ, THF MeO CH3 O N O OMe NMe
367
Modern Organic Chemistry The Scripps Research Institute - TMS eliminates in preference to Ph3P or P(O)(OR)2: Ph O Ph Peterson. J. Org. Chem. 1968, 33, 780. + Ph3P SiMe3 Ph Ph + PPh3
Note: this is the origin of its discovery
- Modifications include: Me3SiCH2MgBr/ TiCl4 (direct production of olefin), and Me3SiCH2Li/ CeCl3 (enolizable ketones and aldehydes, while esters and acid chlorides give allylsilanes via addition 2x). - The elimination is stereospecific: acid-promoted being anti and base-promoted being syn. Pr Acid (anti) Pr Base (syn)
Me3Si Pr
OH Pr Base (syn) Pr Pr
Me3Si Pr Acid (anti)
OH Pr
Hudrlik, Peterson J. Am. Chem. Soc. 1975, 97, 1464. - Unstabilized Peterson reagents add to ketones and aldehydes irreversibly with little diastereoselectivity. Therefore, mixtures of cis and trans olefins are obtained and the reactions are not yet as useful as the Wittig reaction. 2. Stabilized Peterson Reagents - The stabilized Peterson reagents give predominantly the most stable trans olefins (E) although this has been studied far less than the Wittig or Wadsworth-Horner-Emmons reactions. The origin of this diastereoselection has not been extensively explored with regard to enolate geometry, reversible/ irreversible addition, or mechanism of elimination. In this case, the elimination takes place under the reaction conditions.
368
Olefin Synthesis Dale L. Boger O CH3 OtBu a) LDA, 78 C b) Me3SiCl O OtBu SiMe3 LDA OtBu RCHO CO2
tBu
OSiMe3 OtBu
LiO SiMe3
trans predominates
Rathke Tetrahedron Lett. 1974, 1403. Yamamota J. Am. Chem. Soc. 1974, 96, 1620. - via: Me3Si tBuO C 2 H + Me3Si tBuO C 2 H OLi R H Me3Si tBuO C 2 H O R H
tBuO C 2
OLi H R
Me3Si tBuO C 2 H
O H R
tBuO C 2
major Me3Si H
tBuO C 2
O R H R
tBuO C 2
major
Can be trapped
minor - Both single step and two-step elimination via an equilibration have been proposed. - Additional examples:
Cl CH3O
CH3 NCOCF3 OHC
NtBu CH3 H OMEM S S Li
Cl CH3O CH3 SiMe3
OHC CH3 NCOCF3
CH3 CH3 OMEM S S maytansine
82%
CH3
OMe
CH3
OMe
Corey, Weigel, Chamberlin, Lipshutz J. Am. Chem. Soc. 1980, 102, 1439. Corey, Enders, Bock Tetrahedron Lett. 1976, 3 and 7.
N S
SiMe3 + Li O 92%
N S
Corey and Boger Tetrahedron Lett. 1978, 5.
369
D. The Tebbe Reaction and Related Titanium-stabilized Methylenations

reviews: Org. React. 1993, 43, 1. Comprehensive Org. Syn., Vol. 1, 743. - The Wittig, Wadsworth-Horner-Emmons, and Peterson olefination do not convert esters or amides to the corresponding olefin, but rather fail to react or result in the cleavage of the ester or amide bond. - Schrock discovered that Ta and Nb tert-butyl alkylidene complexes behave analogous to phosphorous ylides and, notably, react with esters and amides to provide the corresponding tbutylalkenes. Schrock J. Am. Chem. Soc. 1976, 98, 5399. - The Tebbe reagent was introduced in 1978 and was shown to react with aldehydes, ketones, esters, and lactones to produce the methylene derivatives. O X X = H, R, OR, NR2 O 65% Tebbe J. Am. Chem. Soc. 1978, 100, 3611. - Tolerates ketal and alkene derivatives. Scope defined by Evans and Grubbs J. Am. Chem. Soc. 1980, 102, 3270. Extended to tertiary amides by Pine J. Org. Chem. 1985, 50, 1212. O Ph OCH3 81% Ph OCH3 Ph O O O O OEt O Ph N 87% O O OEt Ph O 96% Ph O O OEt 90% Ph OEt X Cp2Ti Cl Tebbe reagent AlMe2
80% Ph N
Use of Cp2TiMe2: Petasis J. Am. Chem. Soc. 1990, 112, 6392.
370
E. Representative Other Methods for Terminal Methylene Formation

Reagents R2CO, CH2CI2, Mg R2CO, LiCH2PO(NMe2)2 R2CO, LiCH2SPh; CH3SO2Cl; Li/NH3 R2CO, LiCH2SPh; (RO)2PCl; heat R2CO, LiCH2S(O)Ph - Julia Olefination References Cainelli Tetrahedron Lett. 1967, 5153. Corey J. Am. Chem. Soc. 1966, 88, 5653. Ghatak J. Am. Chem. Soc. 1972, 94, 4758. Kuwajima Tetrahedron Lett. 1972, 737. Kuwajima Tetrahedron Lett. 1972, 649.
Review:

OR'' R R' SO2Ar
1) R'CHO R SO2Ar 2) PhCOCl
Na-Hg
R'
R'' = Ms, Ts, Ac, COPh - Example:
exclusively or predominantly the more stable trans isomer
CHO +
1) addition 2) BzCl BzO H Ts
Na-Hg H MeOH-THF 2 h, 20 C 80% TBSO OTBS
Li
H Ts
TBSO
OTBS TBSO OTBS
Julia Tetrahedron Lett. 1973, 4833.
R2CO, LiCH2S(O)tBu; SOCl2-CH2Cl2 -CH(OH)CH2CO2H, HC(OMe)2NMe2, heat RC CH, RCu R2C=CH2 RCO2CH3, Ph3P=CH2 R(CH3)C=CH2 R2CO, PhS(O)(NCH3)CH2Li RCH2SO2CH2Cl, HO- Ramberg-Backlund reaction R R S O2 Cl
Durst J. Am. Chem. Soc. 1973, 95, 3420. Hara Tetrahedron Lett. 1975, 1545. Normant Tetrahedron Lett. 1971, 2583. van der Gen Tetrahedron Lett. 1975, 1439. Johnson J. Am. Chem. Soc. 1973, 95, 6462. Doomes and Corfield J. Am. Chem. Soc. 1970, 92, 2581.
R S O2 R
R R
Org. React. 1977, 25, 1.
371
Modern Organic Chemistry The Scripps Research Institute Reagents RC CH, H2/ Lindlar catalyst R2CHCH2OAc, (pyrolysis) Also: xanthates R2CHCH2NMe2, H2O2, - Cope Elimination References
Org. Syn. 1969, 46, 89. Org. React. 1961, 12, 57. Chem Rev. 1960, 60, 431. Org. React. 1960, 11, 317.
+ - it is related to the Hofmann elimination reaction (-NMe3) - Both the acetate pyrolysis and the Cope elimination have been superceeded by the related syn elimination reactions of sulfoxides and selenoxides.
R2C(Hal)CH3, tBuOK
J. Chem. Soc., Chem. Commun. 1968, 305.
F. Olefin Inversion Reactions

m-CPBA
Ph Vedejs J. Am. Chem. Soc. 1971, 93, 4070. H OLi O Ph Ph Ph2PLi Ph Ph Ph2P H Li Ph2PCl THF MeI OLi H Ph Ph H PPh2
Ph
Ph
Ph
Ph2MeP O
H H
Ph Ph
OLi H Ph CH3 Ph H + PPh2
99% yield >98% cis -Other examples: Ph Ph
Ph2P O CH3
m-CPBA
1) Ph2PLi 2) MeI
Ph
Ph
95%; > 99% trans
m-CPBA
1) Ph2PLi 2) MeI OTHP 85%; >98% Z
OTHP
m-CPBA
1) Ph2PLi 2) MeI 90%; >99% trans
372
Olefin Synthesis Dale L. Boger -Deoxygenation of epoxides (with retention of geometry) O R -SCN Ph3P S , H+ S S N -SeCN Ph3P Se S Se N -Deoxygenation of epoxides (with inversion of geometry) O R R' R R' Chan Tetrahedron Lett. 1974, 2091. Calo Synthesis 1976, 200. Stojnac Can. J. Chem. 1975, 621. Johnstone J. Chem. Soc., Perkin Trans. 1 1975, 1216. Clive J. Chem. Soc., Chem. Commun. 1973, 253. R' R
R'
van Tamelen J. Am. Chem. Soc. 1951, 73, 3444. Chan J. Am. Chem. Soc. 1972, 94, 2880.
Me3SiK PhMe2SiLi -Diol Alkene HO OH R R' Review: HO OH H H R R' S
Dervan J. Am. Chem. Soc. 1976, 98, 1265. Reetz Synthesis 1976, 199.
R'
Org. React. 1984, 30, 457.

(RO)3P
O H R
O H R'
cis elimination
R'
Corey J. Am. Chem. Soc. 1963, 85, 2677. Corey J. Am. Chem. Soc. 1965, 87, 934. OEt O H R O H R' (-CO2) cis elimination
HO OH H H R R'
H+, EtOH R R'
Eastwood Aust. J. Chem. 1964, 17, 1392. Eastwood Tetrahedron Lett. 1970, 5223.
OH OH RR
HC(OEt)3 RR
O O
H OEt
H+
R R
Burgstahler, Boger Tetrahedron 1976, 32, 309.
373
G. [3,3]-Sigmatropic Rearrangements
1. Claisen and Cope Rearrangement
Org. React. 1975, 22, 1. Synthesis 1977, 589. Acc. Chem. Res. 1977, 10, 227. Comprehensive Org. Syn., Vol. 5, pp. 785. D D
Cope Rearrangement HO HO Oxy-Cope Rearrangement
Claisen Rearrangement Introduction of C=O is the driving force of the reaction
- Originally conducted on aryl allyl ethers. - Most useful variant established when extended to nonaromatic substrates. - First example of an acyclic Claisen rearrangement: CH3 OEt HO cat. Hg(OAc)2 O CH3 200 C 12 h 85% CHO Burgstahler J. Am. Chem. Soc. 1961, 83, 198. 2. Amino-Claisen Rearrangement Me2SO4 N + N + N H2O O CH3
- This reaction occurs best when nitrogen is converted to the ammonium salt. Gilbert Tetrahedron Lett. 1984, 25, 2303. Stille J. Org. Chem. 1991, 56, 5578. 3. Thio-Claisen Rearrangement S S H3O+ O
- This reaction is often run with a reagent that will convert sulfur to oxygen following the reaction. - An advantage of the thio-Claisen rearrangement is that the precursor can be deprotonated and alkylated. 1) nBuLi S 2) RX R S R S R O
trans C=C bond Corey J. Am. Chem. Soc. 1970, 92, 5522. Yamamoto J. Am. Chem. Soc. 1973, 95, 2693 and 4446.
374
Olefin Synthesis Dale L. Boger - Also can be conducted with the corresponding sulfoxide.
Block J. Am. Chem. Soc. 1985, 107, 6731. 4. The Carroll Reaction R R OH esterification HO O O R' O O O R' Base O O R O R'
R R' O Carroll J. Chem. Soc. 1940, 704, 1266. Hartung J. Chem. Soc. 1941, 507. Cope J. Am. Chem. Soc. 1943, 65, 1992. Tanabe J. Am. Chem. Soc. 1980, 102, 862. 5. Ireland Ester Enolate Claisen Rearrangement
H3O+ -CO2
R O O O R'
- The most useful of all Claisen rearrangements. The enolate may be trapped with TMSCl or the enolate may be used directly. - The reaction works well with the free enolate and actually allows for a faster rearrangement that will occur at 25 C (anion accelerated). OSiMe3 R' O R' R OH R R' R Ireland J. Am. Chem. Soc. 1972, 94, 5897. Larock Comprehensive Org. Trans., pp. 935. R O R OSiMe3 O R' O R' R OSiMe3 O OSiMe3 O
375
Modern Organic Chemistry The Scripps Research Institute 6. Oxy-Cope Rearrangement HO relatively slow 250 C HO O H
+ KO
+ KO 1010-1017 rate acceleration, occurs at 25 C H
H3O+
250 C OH (slow)
OH
H KH H 25 C OK H
OK
H H3O+ H
Li N
40 C toluene R
Li N R NBn K
H 60 C THF R H
K NBn
PhS
PhS
Macdonald Tetrahedron Lett. 1993, 34, 247. - For a review of anion accelerated sigmatropic rearrangements: Org. React. 1993, 43, 93.
376

7. Representative [3,3]-Sigmatropic Rearrangement Routes to Olefins X OH O R R Lumbroso-Bader Tetrahedron Lett. 1968, 4139; 1966, 3203. O R OH R Br Katzenellenbogen Tetrahedron Lett. 1975, 3275. O R OH Zn R Br Baldwin J. Chem. Soc., Chem. Commun. 1973, 117. O O SPh Lythgoe Tetrahedron Lett. 1975, 2593. CHO CHO R2NLi, Me3SiCl 60 C SPh O R O OH NaNH2 R
RHC CHCH2COX
O NH2
OH
O OH
Carnduff J. Chem. Soc., Chem. Commun. 1967, 606. O O CH3 H3C
Me3SiO
OSiMe3 O
O OSiMe3 CH3
Me3SiO
CH3
Coates J. Am. Chem. Soc. 1975, 97, 1619.
O S OPh Faulkner J. Am. Chem. Soc. 1973, 95, 553. O S OPh
377
H. [2,3]-Sigmatropic Rearrangements
Review:
Comprehensive Org. Syn., Vol. 6, pp. 834, 873-908. Org. React. 1994, 46, 105-209.
- Analogous to [3,3]-sigmatropic rearrangement except it enlists a localized charge (anion) in place of a double bond. - Often times the reaction is referred to as a Wittig [2,3]-rearrangement in honor of Wittig's discovery of the related 1,2-alkyl shift of oxycarbanions (Wittig Rearrangement). The reacton is simply a [2,3]-sigmatropic version of the Wittig rearrangement. - Examples: R R O Julia Tetrahedron Lett. 1974, 2077. S S + R CN R R R CN O R R R O
more stable anion S S - reaction facilitated by loss of positive charge on sulfur
ylide zwitterion Lythgoe J. Chem. Soc., Chem. Commun. 1972, 757. O S R :PR3 O R S OH
O Cl O S R :PR3 O
Cl Evans Acc. Chem. Res. 1974, 7, 147. - Still's use of the [2,3]-sigmatropic rearrangement: OH R Bu3SnCH2I base R O SnBu3
nBuLi
O R
R [2,3] H CH3 O
Still J. Am. Chem. Soc. 1978, 100, 1927. no 1,3-diaxial interactions CH3 R O Li CH3 H R H O R vs. CH3 H H O H CH3 one isomer, Z R A 1,2-strain O
H Z-transition state
H E-transition state
- R prefers the axial versus equatorial position: - Selectivity is lost when A 1,2-strain is removed H R O H Li H OH R + 40:60 R OH
378
S Ph
+ O S Ph
R H
O S
Ph3P Ph
OH R trans olefin H H
H via the transition state: R Ph H OH R1 R2 (EtO)2PCl O (EtO)2P R1 R2 S H O vs.
H Ph R
S H
Bodalski Synthesis 1990, 799. - Ring expansion: Br S + S + S 65% S
Vedejs J. Am. Chem. Soc. 1975, 97, 6878. Vedejs J. Org. Chem. 1978, 43, 1185. Vedejs Tetrahedron Lett. 1978, 523, 519.
Ph
+ N 90% RO2C Ph
N CO2R N+
83%
Jones J. Org. Chem. 1962, 27, 3572. - Diastereoselectivity:

tBu
Cl
+ S Ph Cl
H2O 53%
tBu
SPh O
97:3
tBu
+ S Ph 59% CO2Et
tBu
SPh CO2Et
91:9
Evans Tetrahedron Lett. 1972, 5121.
379
S Br Ts(H)N Evans Tetrahedron Lett. 1973, 4691. NC Br R NC Mander J. Org. Chem. 1973, 38, 2915. Bchi J. Am. Chem. Soc. 1974, 92, 7573. CH3 R2NLi S Kreiser Tetrahedron Lett. 1975, 1669. Stork J. Am. Chem. Soc. 1974, 96, 6774. R SH R CH3 + N R Base N SMe
S SMe NMe2 R H 3O+
CHO R
o-formylation of anilines:
NH2
Prostaglandin synthesis; sulfenate/sulfoxide rearrangement. note olefin inversion. H N + S NH2 SMe X O OMe CH3 OMe CH3 OH
X RS + N OMe R 2N SR CH3
MeO CH3
MeO CH3
MeO CH3
MeO CH3 Juncusol
Boger J. Org. Chem. 1984, 49, 4045. Me3SiOTf CH3 N CO2CH3 Et3N CH2Cl2, 25 C H CH3 + HN CO2Me CH3 81:19 O CH3 OCH3 CO2Me HN CH3 CH3
Nakai Chem. Lett. 1990, 2069. CH3 H See Also: N+
TMS H H H
Sato J. Am. Chem. Soc. 1990, 112, 1999- 2001. CH3 N+ NaNH2 NH3 di- and trisubstituted olefins N
380
I. Olefin Synthesis Exemplified with Juvenile Hormone

1. Trost Synthesis:
J. Am. Chem. Soc. 1967, 89, 5292.

Me CO2Me
Wadsworth-Horner-Emmons Reaction 2. Syntex Synthesis:
J. Am. Chem. Soc. 1968, 90, 6224.
O Me H
Robinson Annulation Alkylation Diastereoselectivity Fragmentation Reaction Directed Epoxidation Reaction 3. Corey Synthesis:
J. Am. Chem. Soc. 1968, 90, 5618.
Dissolving Metal Reductions: Cyclic Precursors to Trisubstituted Olefins Oxidative Cleavage of Enol Ethers LiAlH4 Reduction of Propargyl Alcohols Cuprate Coupling Reactions Allylic Alcohol Oxidation 4. Johnson Synthesis:
J. Am. Chem. Soc. 1968, 90, 6225.
Julia Olefin Synthesis Cornforth Nucleophilic Addition 5. Corey Synthesis:
J. Am. Chem. Soc. 1970, 92, 6635, 6636, 6637.
Lindlar Catalyst Alkyne Reduction 1,5-Hydrogen Migration -Oxido Ylide Reaction Diimide Reduction 6. Johnson Synthesis:
J. Am. Chem. Soc. 1970, 92, 4463. 3,3-Sigmatropic Rearrangements Claisen Reaction Cope Reaction Oxy-Cope Reaction
7. Stotter-Kondo Synthesis:
J. Am. Chem. Soc. 1973, 95, 4444. J. Chem. Soc., Chem. Commun. 1972, 1311.
Dihydrothiopyran Strategy: Cyclic Precursors to Trisubstituted Olefins Stabilized Allylic Anions, Desulfurization (Benkeser Dissolving Metal Reduction) Sulfur Ylides Cyclopropane Synthesis Epoxide Synthesis 8. Still Synthesis:

2,3-Sigmatropic Rearrangement
9. Other Syntheses: Beltsville Synthesis: Mori Synthesis: MacKay Synthesis: Schering Synthesis: Zoecon Synthesis: van Tamelen Synthesis:
J. Econ. Entomol. 1968, 61, 866. Tetrahedron 1969, 25, 1667. J. Chem. Soc., Chem. Commun. 1969, 733. Angew. Chem., Int. Ed. Eng. 1969, 8, 271. (Farnesol -> C-18 JH) J. Am. Chem. Soc. 1970, 92, 735. J. Am. Chem. Soc. 1970, 92, 737.
381

1. Trost Synthesis:
J. Am. Chem. Soc. 1967, 89, 5292.
Wadsworth-Horner-Emmons Reaction
O (MeO)2P O
CO2Me + CO2Me 37% 17% CO2Me
1. LiAlH4, 86% 2. PBr3, 45% + Br O CO2Et
alkylation NaOH; H+, CO2 73%
spinning-band distillation Wadsworth-HornerEmmons reaction O (MeO)2P O Wadsworth-HornerEmmons reaction O (MeO)2P Me O
CO2Me + 39% CO2Me 30% CO2Me
1. LiAlH4 2. PBr3 3. CH3COCH2CO2Me 4. NaOH 5. H+, CO2
CO2Me Me + Me CO2Me 30%
Wadsworth-HornerEmmons reaction
18%
CO2Me
m-CPBA
Me CO2Me
40% C-18 JH 10% internal epoxide 10% diepoxide
Relative Activity nat. C-18 JH syn. C-18 JH t-t-t (epoxide) c-t-t (triene) t-t-t (triene) c-t-t (epoxide) ethyl ester 1 1 0.4 0.1 0.04 8 Synthesis was relatively non-stereospecific - structural assignment - structure-activity studies - prevents adult development from pupa - more potent analog found
Me H
H H O
HH
Stereoselectivity - not much difference between Me and H (second atom steric effect) - both isomers obtained from the WadsworthHorner-Emmons reaction (Modern improvements now available)
Me CO2Me
Retrosynthetic Analysis - repeating subunits recognized - repeating reactions utilized
382
2. Syntex Synthesis:
J. Am. Chem. Soc. 1968, 90, 6224.
Robinson Annulation Alkylation Diastereoselectivity Fragmentation Reaction Directed Epoxidation Reaction Et OTHP
O Et O + O 1. KOH, MeOH 2. TsOH, C6H6 67% O Et
Et O 1. NaBH4, 5 C 2. DHP, H+ O Et Selective reduction THP protecting group Et OH LiAlH(OtBu)3 74% Et Me
1. KOtBu, MeI 2. H+, H2O 54% (4 steps )(95% d.e.) Thermodynamic enolate: alkylation diastereoselectivty Et OH
Robinson annulation
Et OH
HO
Et Me Reduction diastereoselectivity
m-CPBA CH2Cl2 50%
LiAlH4 HO O Et Me dioxane 65% Reduction regioselectivity
Directed epoxidation Et2O gives exclusively the isomeric epoxide
Et OH TsCl, pyr HO OH Et Me 5 C 89% TsO
Et OH NaH THF, 25 C 50% Fragmentation reaction 100% stereospecific O Et OH 1. DHP, H+ 2. MeLi 3. H+, H2O 57% Stereochemistry of Nu addition
OH Et Me
Selective equatorial OTs formation
Et OH HO Me
TsCl, pyr 25 C 95% 2 vs. 3 TsCl selectivity
Et OTs HO Me
NaH THF, 25 C 80% C-18 JH
Fragmentation reaction
Et O NaBH4 O Et 5 C O Et
Et OH
Selective Reduction - saturated vs. ,-unsaturated carbonyl - ring strain associated with 5-membered ring carbonyl released on reduction - attack from least hindered face
H+ O DHP O
ROH THP O OR
THP Protecting Group - if R group contains chiral centers, diastereomers result - removed by mild acid
383
OTHP OTHP O vs.

O
Thermodynamic Enolate - severe 1,3-diaxial interaction in chair-like T.S. axial alkylation - no steric incumberance to axial alkylation on least hindered face of twist boat T.S.
H OTHP O H H Et OH
Dunitz angle O 109 H
LiAlH(OtBu)3 Reduction - large reagent, usually equatorial H delivery - 1,2-interaction (torsional strain) relatively invariant to Nu size - 1,3-steric interaction highly dependent on Nu size - due to absence of axial C(3)-H, large reagent now gives axial delivery Et OH Epoxidation - in Et2O, coordination of peracid to solvent gives delivery from the least hindered -face - in CH2Cl2, coordination of peracid to OH provides delivery to the less accessible -face - Teranishi J. Am. Chem. Soc. 1979, 101, 159.
Et OH
m-CPBA
HO Et Me HO Solvent CH2Cl2 Et2O O Et Me 50% 0%
+ HO O Et Me 0% 100%
OH TsO OH O H NaH O
1st Fragmentation - utilized to control C=C bond stereochemistry - trans periplanar orientation of breaking bonds - dictates Z olefin geometry in product
OTs O H H R H NaH R H O
2nd Fragmentation - utilized to control C=C bond stereochemistry - trans periplanar orientation of breaking bonds - dictates E olefin geometry in product
Fragmentation Reactions Grob Angew. Chem., Int. Ed. Eng. 1969, 8, 535. Angew. Chem., Int. Ed. Eng. 1967, 6, 1. Interannular
LG P P LG
- Trans periplanar arrangement of participating bond orbital and departing bond orbital
Intraannular
P
LG LG P
Extraannular
LG LG
384
Olefin Synthesis Dale L. Boger - Wharton J. Org. Chem. 1965, 30, 3254. - Fuchs J. Am. Chem. Soc. 1979, 101, 3567. - Case A H OTs KOtBu OH H H KOtBu O OTs E2 elimination, no fragmentation OH H + OH
H - Case B
OTs KOtBu 90%
trans olefin only

O
OH H OTs H KOtBu O
O H - Case C H
OTs KOtBu 90%
trans olefin only

O OTs OH H H less stable conformation and not set up for fragmentation
OH H H O OTs KOtBu
H O
H most stable conformation - Case D H OTs KOtBu 95% OH H TsO H OH KOtBu H O H O
cis olefin only
385
Modern Organic Chemistry The Scripps Research Institute - Other groups at "promoter" site can be used O O H CO2CH3 OTs KOtBu 95% CO2CH3 O O
O O H
Me CO2CH3 OTs H H
KOtBu
O O H
Me CO2CH3
- Many other types of fragmentation reactions CH3 O N OH O O CH3O CO CH 2 3
OCH3
1
CH3O < 5 C oxidative decarboxylation CH3O2C HO N CH3 O
O2
HO2C
CO2CH3 N CH3
[4 + 2] Cycloaddition
Boger J. Org. Chem. 1991, 96, 6942. J. Am. Chem. Soc. 1993, 115, 11418. CO2CH3 CH3O CH3O CH3O2C N CH3 N CH3 CO2H CO2H
1O 2
CH3O CH3O CH3O2C
HO
CO2CH3 N CH3
O O N HO CH3 Isochrysohermidin What is mechanism?
CH3O N N CH3O2C N N CH3O CO2CH3 +
OCH3
CH3O2C CH3O CH3O N N CO2CH3 CO2CH3 N N 1. Zn-HOAc 2. CH3I, NaH
OCH3
CH3O2C
CO2CH3 CH3O CH3O CH3O2C N CH3 N CH3 CO2CH3 CO2CH3 1. LiOH 2. TFAA 3. CH2N2 4. H2O CH3O CH3O CH3O2C N CH3
CO2CH3 N CH3 CO2H CO2H
Intramolecular cyclic anhydride formation utilized to differentiate internal acids of tetraacid.
386

3. Corey Synthesis:
J. Am. Chem. Soc. 1968, 90, 5618.
Cyclic precursor to stereochemically defined trisubstituted olefin
Dissolving Metal Reductions Cyclic Precursors to Trisubstituted Olefins Oxidative Cleavage of Enol Ethers LiAlH4 Reduction of Propargyl Alcohols Cuprate Coupling Reactions Allylic Alcohol Oxidation
MeO
Li, THF/tAmOH NH3, 33 C Birch reduction note regioselectivity 1. TsCl, pyr OH THPO 2. Li
MeO
1. O3 , 78 C Me2S/MeOH 2. NaBH4, 78 C 53% Mechanism OH 1. LiAlH4, NaOMe THF, 2. I2, 60 C 65% Directed hydroalumination of alkyne 1. LiAlH4, NaOMe THF, 2. I2, 60 C OH I HO
CO2Me 1. TsCl, pyr 2. LiAlH4, Et2O 65%
OH
3. TsOH, MeOH 30%
Et2CuLi, Et2O 30 C EtI, 0 C 78% Cuprate substitution
OH
1. PBr3, 0 C TMS 80% 3. AgNO3, KCN 4. nBuLi, (CH2O)n 2. Li
Me2CuLi, 0 C I 53% for 3 steps OH
1. MnO2, hexane 2. MnO2, NaCN OH HOAc, MeOH, 70% MnO2 oxidation MeO O O Me2S: O CO2Me
1. NBS, DME/H2O 2. NaOiPr, iPrOH O CO2Me
Ozonolysis - reacts preferentially with more electron-rich C=C - ring (cleavage) enlisted to control olefin stereochemistry - addition of MeOH gives methyl ester
Stereospecific Synthesis of Trisubstituted Olefins - propargylic alcohols can be reduced with LiAlH4 to give an allylic alcohol R R OH LiAlH4 (1.0) NaOMe (2.0) OH R R LiAlH4 AlCl3 (cat.) H 60:1 ratio Al O R I2 OAl H OH I R'2CuLi H OH R R' H I2 I OH R R'2CuLi R' OH R
387
Modern Organic Chemistry The Scripps Research Institute - Cuprate Mechanism I OH H H I OH Et2CuLi I O + Et2CuLi
O- + Et2CuLi + I H Et Et CuIII O- Posner Org. React. 1975, 22, 253. Org. React. 1972, 19, 1. Et O H CuI Et-Et + H O H EtI competitive reductive elimination product Et O H Cu O origin for requirement for use of EtI + EtCu + H + Li+ + I reductive elimination
MnO2 hexane
OH
MnO2 Oxidation - mild oxidation of allylic alcohols - direct, mild method for oxidation to a methyl ester
MnO2 NaCN MeOH
NC
OH
NC
MeO
1. NBS DME/H2O 2. iPrONa CO2Me O CO2Me
electron deficient and less reactive
Epoxidation - selective - in polar solvent the molecule folds up such that the terminal C=C is more accessible
388
Olefin Synthesis Dale L. Boger 4. Johnson Synthesis:
J. Am. Chem. Soc. 1968, 90, 6225.

R CO2Me O R = CO2Me 1. Ba(OH)2 MeOH 2. H+, H2O
Julia Olefin Synthesis Cornforth Nucleophilic Addition CO2R O CH2N2 65% R=H R = Me
NaH, THF R O NaH (MeO)2CO

Br CO2Me
R=H R = CO2Me
NaBH4 MeOH R PBr3, LiBr collidine Et2O, 0 C 1. NaI, HMPA 25 C 2. LDA, THF 5% HMPA O O O O CuCl2-LiCl DMF, 45%
ZnBr2 CO2Me Et2O, 0 C Cyclopropylcarbinylhomoallylic alcohol rearrangement Br 95%:5% (t,t:t,c) CO2Me
R = OH R = Br
Ba(OH)2 CO2Me R R=H R = Cl EtOH, 0 C O Cl CO2Me
MeMgCl THF, 75 C
Me HO H Cl diastereoselective 92:8
CO2Me
K2CO3 MeOH, 25 C Me
O H
CO2Me
Cornforth nucleophilic addition O O O O Na, EtI O O
HCl Cl O
KOH O
CO2H
1. NBS 2. MeOH cat. H2SO4 Br
CO2Me
Br Et vs. H R
Et Br H R
Br Cl O R Et H
Br
Cyclopropylcarbinyl Bromide Rearrangement - highly stereoselective modification of Julia olefin synthesis - Johnson J. Am. Chem. Soc. 1968, 90, 2882 - Julia Bull. Soc. Chim., Fr. 1960, 1072. - ring opening concomitant with ionization - antiperiplanar arrangement of the C-Br and cleaved cyclopropane bond is necessary
MeMgBr
Cornforth Nucleophilic Addition - J. Chem. Soc. 1959, 112, 2539. - earliest generalization of the Felkin model of nucleophilic addition to a carbonyl group in acyclic systems
389
Modern Organic Chemistry The Scripps Research Institute 5. Corey Synthesis:
J. Am. Chem. Soc. 1970, 92, 6635, 6636.
Lindlar Catalyst Alkyne Reduction 1,5-Hydrogen Migration -Oxido Ylide Reaction Diimide Reduction OH CH2I2, Cu-Ag
H H2SO4
1. nBuLi 2. (CH2O)n 3. Ac2O 4. H2/Pd-BaSO4 5. NaOH
OH H H
OH 350 C 65% OHC
Lindlar catalyst hydrogenation NaBH4 96% HO
Allylic alcohol directed Simmons-Smith
1,5-H Shift dictates olefin stereochemistry
- Alternatively OTHP CHO PPh3 1. nBuLi 2. 3. (CH2O)n OTHP OH PBr3 OTHP Br Me2CuLi or Me3FeLi
-Oxido ylide modification of Wittig reaction OTHP + (50:50) with Cu (100:0) with Fe Me OH 1. H+, DHP 2. O3, Zn, HOAc O Me OTHP H 2. 3. sBuLi 4. (CH2O)n -Oxido ylide 1. H+ 2. [O] (c.f. 1968) Me 3. epoxidation OTHP O Me CO2Me Me OTHP 1. nBuLi
PPh3I
OTHP
1. H3O+ 2. TsCl 3. NaI/acetone 4. Ph3P
PPh3I
HO
1. MnO2 2. Ph3P=CH2 Wittig reaction
HN=NH Me OTHP Diimide reduction

sBuLi
O
Ph3P
+ + R'CHO R' R -Oxido Ylide Modification OH H
O PPh3
H R'
PPh3 (CH2O)n R
H R'
PPh3 R O
H R'
O PPh3 R
O
H R'
HO N N
OH
H H
1,5-H Shift Diimide Reduction - less substituted C=C reduced more rapidly - generated in-situ - no dehalogenation
N N H H R H H R H R
H H
H R
390
Olefin Synthesis Dale L. Boger 6. Johnson Synthesis:
J. Am. Chem. Soc. 1970, 92, 4463.
3,3-Sigmatropic Rearrangements Claisen Reaction Cope Reaction Oxy-Cope Reaction NaBH4 MeOH, 0 C
CO2Me + OH MeO OMe 1
H+, toluene 100 C
CO2Me O 87:13 trans:cis
CO2Me OH 51%
Olefinic ketal Claisen reaction
cis (13%) removed after reduction
1. 1, H+, toluene 100 C 2. NaBH4 MeOH, 0 C 70% Olefinic ketal Claisen reaction OH
CO2Me
SOCl2 hexane, 0 C 85% Cl SN2' reaction and 12% Cl 1. NBS H2O/THF O Me H
CO2Me
NaBH4, DMSO 1,5-hexadiyne 50 C
CO2Me and chlorine impurity
2. K2CO3, MeOH, 35%
CO2Me
CO2Me O
CH3CO2H (CH3CO)2O
CO2Me OAc
K2CO3 MeOH, 0 C 81%
CO2Me OH
H+ MeO OMe OMe
H+, tol CO2Me OH Olefinic Ketal Claisen Reaction - selectivity dependent on 1,3-interaction in chair-like T.S. - second Claisen more selective due to larger R group vs. CO2Me 100 C
CO2Me O OMe H+ -MeOH O
CO2Me
Me O R H H CO2Me vs. R O H H
Me
CO2Me
CO2Me O 87 : O 13 CO2Me
391

7. Stotter-Kondo Synthesis:
S O
1. MeMgBr 2. POCl3, C6H6 Me pyr, 90%
J. Am. Chem. Soc. 1973, 95, 4444. Dihydrothiopyran Strategy: J. Chem. Soc., Chem. Commun. 1972, 1311. Cyclic Precursors to Trisub. Olefins Stabilized Allylic Anions Desulfurization, Benkeser Red. Sulfur Ylides Cyclopropane Synthesis Epoxide Synthesis S
sBuLi
S OH
+ S Me2S (O)CH2 75%
S O
DABCO 20 C, THF Me
SOCl2, pyr 75-90% overall Me
O Sulfur ylide epoxidation
cyclic precursors dictate trisubstituted olefin stereochemistry S Me OR Li/EtNH2 78 C Me SH SH Me OH
sBuLi
S Me
1 or 2 DABCO
R = THP, 60% R = Li, 90% R=H Ra-Ni 55-70% Me Me
Benkeser reduction dissolving metal reduction
[O], see Corey 1968 OH Me
Me CO2Me Trost Intermediate
Me Cl 2 OLi
HOCl
nBuLi
HOCl DHP, H+ Cl
Me OTHP 1
thermodynamic E product
Cl S O Cl O Convergent Route - symmetrical intermediate
N N
DABCO
DABCO - accelerates slow deprotonation - breaks up Li aggregates
** **
S ***
Site of Deprotonation - at carbon activated by both S and vinyl
Sulfur Ylides: Trost, Melvin Sulfur Ylides: Emerging Synthetic Intermediates, Academic Press, 1975. House, pp. 709. Benkeser Reduction Synthesis 1972, 391.
392
Olefin Synthesis Dale L. Boger S Me S Use of Cyclic Precursors - control olefin geometry - insert S, remove with Ra-Ni
S Me
Specific Deprotonation Site - kinetically preferred site due to sterics - the thermodynamic and kinetic product - alkylation occurs cleanly , not , to heteroatom (a well established trend)
- Li/NH3
Birch Reduction (blue solution), 33 C at refluxing NH3 temperatures
- Li/EtNH2 or MeNH2 Benkeser Reduction (more strongly reducing because of higher reaction temperature)
EtNH2
S H H
H 3O +
SH
protonation no protonation, more hindered, olefin geometry maintained restricted rotation of allyl anion -system
- 1,4-Addition of sulfur ylides -> cyclopropanes
Ph2S + EtI
Ph2S-CH2CH3 I AgBF4 AgI + Ph2S-EtBF4 Me Ph2S Me R' = H R' O Me Ph2S Me R' = Me R'
ICH2CH3
O Me Me Me Me R' - In addition, a substituted sulfur ylide increases propensity for epoxide formation over cyclopropane formation - This reaction is sensitive to substitution pattern on the ,-unsaturated carbonyl
393
Modern Organic Chemistry The Scripps Research Institute 8. Still Synthesis:
2,3-Sigmatropic Rearrangement
OHC
Br
THF, 78 C Li 93% OH Br
OHC
Et2O 78 to 0 C OR
OR
tBuLi,
OH
OH
KH, THF Bu3SnCH2Cl 88% O SnBu3 O SnBu3
OR
nBuLi,
OH THF
OH
78 to 20 C 79% 2,3-Sigmatropic rearrangement
OR
OTs TsCl, pyr 0 C, 93%
OTs LiAlH4 OR Et2O, 0 C 98% H2O-HOAc 45 C, 92% OR R = CH(CH3)OCH2CH3 R=H
Me R O Li
Me
J. Am. Chem. Soc. 1978, 100, 1927.

OLi one isomer, Z R
Note: Me substitution on olefin provides Z selectivity.
R H Me vs. H R Me O H H Me R H O O H H Me H R O
severe allylic 1,2-strain
394
Organocuprate and Conjugate Addition Reactions Dale L. Boger
XII. Conjugate Additions: Organocuprate 1,4-Additions

Reviews: House Acc Chem Res., 1976, 9, 59. Ashby Chem Rev., 1975, 75, 521. Comprehensive Org. Syn., Vol. 4, 164. O RMgX or RLi 1,2-addition Review: Lipshutz Org. React. 1992, 41,135. Posner Org. React. 1975, 22, 253. Posner Org. React. 1972, 19, 1. HO R
- But Kharasch observed 1,4-addition with added Cu(I) salt: O RMgX cat. Cu(I) 1,4-addition R R OM O
Kharasch J. Am. Chem. Soc. 1941, 63, 2308. - This led to the development of stoichiometric organocuprate reagents: MeLi + CuI (1 equiv) ether or THF MeLi (1.0 equiv) Me-Cu + LiI insoluble, bright yellow organocopper reagent Me-Cu-Me Li "ate" complex colorless, soluble, stable even at 25 C
House, Whitesides J. Org. Chem. 1966, 31, 3128. - "ate" complexes incorporating Li+ were first described by Gilman (J. Org. Chem. 1952, 17, 1630) and consequently such reagents are often referred to as "Gilman reagents". - Most organometallics, including organocuprates, are susceptible to -elimination: H CH R 40 to 20 C H R Cu H + CH2 R
Cu Li
CH2
- So most organocuprates are best handled at temperatures lower than ca. 40 C.
1. Scope -Relative ease of ligand transfer from Cu follows the order: , Ph > Me > Et > iPr > tBu >> PhS, R2N, RC C Dummy ligands for mixed cuprates
395
Modern Organic Chemistry The Scripps Research Institute - In addition, the size of the migrating group also affects the conversion: R R=H R=H R = CH3 R = CH3 R = CH3 R = CH3 R = CH3 Me2CuLi Ph2CuLi Et2CuLi iPr CuLi 2 tBu CuLi 2 Ph2CuLi CuLi
2
6080% 25% 5565% 58% 40% 0% 0% 1,2-addition observed
- Effect of substrates: O > O OR , CN O >> ORO O OR O
Me2CuLi
tBu
Me
tBu
96%
- Unsaturated esters are less reactive than enones. - ,-Disubstitution slows reaction. O OCH3
tBu
OCH3 Me2CuLi //
tBu
Me
BF3OEt2
BF 3 O OCH3
53%
- unreactive substrates will react if Lewis acids are added to activate substrate toward nucleophilic addition.
tBu
- also note the alternative use of higher order cuprates [R2CuCN]Li2.
Maruyama J. Am. Chem. Soc. 1977, 99, 8068. Yamamoto J. Am. Chem. Soc. 1978, 100, 3240.
396
Organocuprate and Conjugate Addition Reactions Dale L. Boger RCuBF3 Yamamoto J. Am. Chem. Soc. 1980, 102, 2318. Yamamoto J. Org. Chem. 1979, 44, 1745.
MeCuBF3 88% O Me2CuLi // O Review: Yamamoto Angew. Chem., Int. Ed. Eng. 1986, 25, 947.
Me2CuLiBF3 70%
- Conjugate addition to ,-unsaturated aldehydes is typically problematic but successful examples have been reported.
O H
Me3CuLi2 81 %
Me
O H
Still Tetrahedron Lett. 1976, 2659. Meyer Org. Prep. Proceed. 1979, 11, 97. Clive J. Chem. Soc., Chem. Commun. 1981, 643. (Me5Cu3Li2) Clive J. Org. Chem. 1982, 47, 2572. Conjugate Addition/Alkylation (stereochemistry) Posner J. Org. Chem. 1979, 44, 3661. Review: Comprehensive Org. Syn., Vol. 4, pp. 237-268. Conjugate Addition/Aldol Heng Tetrahedron 1979, 35, 425. - Cuprates can also be prepared from other organometallic reagents which have greater compatibility with reactive groups: e.g. activated Cu(o)/RBr, RZnI, RSnBu3/Me2Cu(CN)Li2, RCH=CH2/ Cp2Zr(H)Cl then CuBrSMe2 - Useful in the regiospecific trap and subsequent generation of enolates. R2CuLi O LiO R TMSCl TMSO R
MeLi LiO R
Stork J. Am. Chem. Soc. 1974, 96, 7114. Stork J. Am. Chem. Soc. 1961, 83, 2965. Horiguchi Tetrahedron Lett. 1989, 30, 7087.
397
Modern Organic Chemistry The Scripps Research Institute - Additions to acetylenes R' R' = Et CO2CH3 R = CH3 97:3 92:8 92.5:7.5 24:76 R2CuLi R' R CO2CH3 cis addition of "RCu" Cu
THF at 100 C THF at 78 C toluene (3 h) ether (3 h)
cis:trans
lower stereoselectivity due to configurational instability of alkenyl copper reagent
see also: Alexakis Bull. Chim. Soc., Fr. 1977, 693. Cahiez Synthesis 1976, 245. Alexakis Tetrahedron Lett. 1976, 2313. Truce J. Org. Chem. 1978, 43, 2252. Marfat J. Am. Chem. Soc. 1977, 99, 2513.
R' R
CO2CH3 Cu
30 C to 0 C
R' R
Cu CO2CH3
25 C rapid 0 C slow 30 C observable
Corey, Katzenellenbogen J. Am. Chem. Soc. 1969, 91, 1851. Fried J. Am. Chem. Soc. 1969, 91, 1853. Klein J. Chem. Soc., Perkin Trans. 2 1973, 1971. - Alkenyl copper intermediates can be subsequently trapped: R' R CO2CH3 Cu E+ E+= H+ (H2O), Br+(NBS) R' R CO2CH3 E
- Also, used in displacement of leaving groups (addition/elimination reactions). via -elimination from intermediate enolate R CO2CH3
R2CuLi X CO2CH3
X = SPh, Br, OAc (good leaving group) CO2CH3 X R CO2CH3 net retention of stereochemistry
cis addition
X R CO2CH3 H Cu X R
trans elimination
CO2CH3 H Cu
X = SPh Corey J. Am. Chem. Soc. 1969, 91, 1851. Casey Tetrahedron Lett. 1974, 925. Mukaiyama Chem Lett. 1974, 705.
398
Organocuprate and Conjugate Addition Reactions Dale L. Boger - Examples: CO2CH3 AcO R2CuLi R CO2CH3 Coates J. Org. Chem. 1974, 39, 275. Coates J. Am. Chem. Soc. 1971, 93, 1027. Corey Tetrahedron Lett. 1973, 3817. CO2CH3
AcO
CO2CH3
R2CuLi
O X = SPh, Cl, Br, OAc (but not for OCH3)
O SPh Me2CuLi
OLi Me PhS SPh
O Me
OLi Me Me2CuLi Me RX
Me Me
- Selective preparation of ketones from carboxylic acid derivatives. O R' Cl O

tBu
R2CuLi R' Cl
O // R
tBu
OLi R' R R O
no overaddition to give 3 alcohol
(tBu)2CuLi 60% Et2O, 0 C

tBu
no epimerization of axial carbonyl group
- Additions to terminal alkynes. R'Cu cis addition R Cu R' H+ E+ R R' R E R'
399

- Alkylation reactions Br H Br H H H Br H Me2CuLi 2 Me2CuLi Me H Me H H H Me H substitution reactions proceed with retention of configuration
Me Me2CuLi
O P OR O OR
a) Li/NH3 b) H+
- Mechanism: O P OR O OR OP OR O OR
H e H
- Also can be conducted with aryl and enol triflates
OSO2CF3 Me2CuLi
Me
functional group reactivity~ RCOCl > CHO > tosylates > epoxides > bromides > ketones > esters > nitriles
400
Organocuprate and Conjugate Addition Reactions Dale L. Boger 2. Mechanism reversible -complex a) Me Cu Me
(I)
oxidative addition Me Cu(III) Li Me
Me Cu Me
(I)
Me-Cu(I) + Me
reductive OLi elimination Me Cu(III) Me
OLi
or
b)
Me2CuLi +
electron transfer
Me2Cu + Li
O radical anion
Me2CuLi
-Evidence for mechanism b) i. Isomerization and recovery of substrates without 1,4-addition

tBu
CO2
tBu
tBu
< 1 equiv Me2CuLi via OLi tBu

tBu tBu
CO2tBu vs.
CO2tBu
tBu
MeLi
Me OH
tBu
no isomerization of recovered starting material
evidence for electron transfer mechanism
401
Modern Organic Chemistry The Scripps Research Institute ii. Cation is essential for the reaction Me2Cu Li - if crown ethers are added to reaction mixture, reaction is slowed or prevented - Li+ complexes with carbonyl oxygen and activates substrate to conjugate addition (Ouannes Tetrahedron Lett. 1977, 815.)
iii. Retention of stereochemistry of cuprate alkyl group that is transferred e.g.

tBu
Cu
//
//
retention of configuration
Cu
tBu
O Whitesides J. Org. Chem. 1972, 37, 3718. Whitesides J. Am. Chem. Soc. 1969, 91, 6542.
- So reaction cannot be proceeding through a free-radical
Cu
tBu
O would get mixture
- Retention also observed for alkenyl cuprates: Br CH3 Li CH3 0.5 equiv CuI O CuLi
2
O
CH3 Configurationally stable
Casey Tetrahedron Lett. 1971, 2455.
- Not true for free radical H H H H
402
Organocuprate and Conjugate Addition Reactions Dale L. Boger - Additional evidence for radical anion mechanism: Me Me2CuLi O Marshall Tetrahedron Lett. 1971, 2875. O 55% + O 39% may be formed via intermediate radical anion
Me2CuLi O O 43%
+ O 49%
- but
CO2tBu
Me2CuLi
OtBu OLi
// k = 10-2 s-1
OtBu OLi not observed
Me2CuLi
CO2tBu
tBu
tBu
//
tBu
OLi
LiO - So half-life of intermediate radical anion is very short. - Subsequent coupling with cuprate reagent (after e transfer) is faster than other radical reactions in some cases. - However, competitive single electron reductions with cuprates have been observed and they may be used to effect reductive elimination reactions in manner analogous to dissolving metal or Zn reductions.
403
Modern Organic Chemistry The Scripps Research Institute iv. Trap of intermediate radical anion OTs Me2CuLi, 78 C O MO Ac2O H+ H2O O 96%
AcO
- no conjugate or homo-conjugate addition observed, only intramolecular trap of intermediate radical anion
Hannah Tetrahedron Lett. 1975, 187. OTs OTs
LiO
O e Ac2O
- Key piece of evidence for electron transfer mechanism.
AcO
LiO
v. House J. Am. Chem. Soc. 1972, 94, 5495. - Rate and ease of conjugate addition to the substrate correlate with the polarographic reduction potential while they do not always correlate with propensities for Michael addition. Eo Me2CuLi CuLi
2
Me2CuLi
+ e
2.35 v 2.1 v 2.3 v But these are not experimentally determined Eo values.
CuLi + e
2
Ph2CuLi
Ph2CuLi
+ e
CuLi
CuLi + e
2.4 v
404
Organocuprate and Conjugate Addition Reactions Dale L. Boger - And for conjugate addition with Me2CuLi Ered 1.63 v CO2Et CO2Et MeO2C COMe 2.14 v O OCH3
tBu tBu nPr
O Ph
Ered CO2Me O 2.25 v 2.26 v
2.13 v
2.33 v
2.12 v O
O 2.35 v
2.20 v OCH3 O All can accept an e (undergo reduction) by Me2CuLi. Eo = 2.35 v
- But these substrates do not react with Me2CuLi: OBu 2.43 v

tBu
CO2CH3 2.50 v
O CN 2.54 v
tBu
CO2CH3
tBu
2.55 v
Note that for
the ease of organocuprate conjugate addition decreases in the order: House Acc. Chem. Res. 1976, 9, 59.
E = COR > CO2R > CN
405
Modern Organic Chemistry The Scripps Research Institute -House estimation of O R3 R4 R2 R1 0.1 0.3 +0.4 R2 0.1 0 +0.1 R R R3/R4 0.1 0.3 +0.4 CN R R1 base value = 1.9 v R2 R1 substituent alkyl alkoxy R1 0.1 0.3 R2 0.1 --O
base value = -1.8 v
substituent alkyl alkoxy phenyl
base value = 2.3 v
vi. Kinetic preference for 1,2-addition for standard organometallic (and other) nucleophiles suggests something unique about 1,4-addition of organocuprates
O
//
O
//
R-M
R-CuX
vii.
13C
NMR detection of reaction intermediates
- Mechanism of organocuprate conjugate addition: observation of cuprate-olefin complexes and Li-coordinated intermediates in the reaction of lithium dimethyl cuprate with 10-methyl1,9-2-octalone. Robin and Smith J. Am. Chem. Soc, 1989, 111, 8276. Cu(III) intermediate observed directly O 1 O 3 (CuMe2)nLin Li O
5 CuMe2 The intermediates 1-5 were observed at 78 C in Et2O-d6 by 13C NMR
(CuMe2)nLin 2 4 See also: Corey Tetrahedron Lett. 1990, 31, 1393. LiX
O XLi
O 6
viii. Isolation of the -complex and conversion on to product Corey Tetrahedron Lett. 1985, 26, 6015.
406
Organocuprate and Conjugate Addition Reactions Dale L. Boger 3. Homoconjugate Addition
CO2Et CO2Et
Me2CuLi
Me
CO2Et CO2Et
- Can also use O O O O -These reactions work well with Me2CuLi, and probably vinyl cuprates and aryl cuprates (no problem with elimination) but not as well for simple alkyl cuprates (less stable-must keep < 30 C)
- Application to prostaglandin synthesis: O O CO2CH3 N2 O O CO2CH3

2
O CuLi O CO2CH3
OTHP
OTHP Corey J. Am Chem. Soc. 1972, 94, 4014.
OTHP
and CO2CH3 O N2
CO2CH3 O
Me CO2CH3 O
OSiMe2tBu R R
2Cu
OSiMe2tBu
2
CuLi R O
407
4. Competitive Reduction and Rearrangement a) Interception of radical-anion intermediate OTs Me2CuLi O O
b) Reduction OLi // CH3O Me OCH3 CH3O O
e OLi
OCH3
OCH3
Also observed with -acyloxy enones: OLi R = Ac O Me2CuLi R = CH3 R = THP OLi
OR
OR Note: This is cited as further support of the electron transfer mechanism.
Ruden Tetrahedron Lett. 1975, 2043.
poorer leaving groups
via OLi OLi
OAc
OLi R2CuLi X = Cl reduction
O X R2CuLi X = OCH3 R conjugate addition
OLi X
408
5. Mixed Organocuprates - For dialkylcuprates, one alkyl substituent (ligand) is lost: O R R2CuLi 2RI
O + RCu lost
- Mixed cuprates have been developed in which one ligand will not transfer: Corey J. Org. Chem. 1978, 43, 3419. Cu CH3O - With these reagents, only the non-transferable reagent is lost Cu RS Cu R2N Cu C5H11 Cu
Cu + MeLi CH3O CH3O
Cu Me Li
- Also: addition of Li salts forms cuprate reagents from alkyl copper reagents ("ate" complexes)
MeCu O
No reaction
MeCu LiI (MeCuILi) MeCu LiCN (MeCuCNLi)
1,4-addition
1,4-addition House J. Org. Chem. 1966, 31, 3128.
Higher Order Cuprates
These are more reactive and also very good for sluggish reactions e.g., epoxide openings, alkylations. LiCN R2Cu(CN)Li2 R2Cu(CN)Li2
R2CuLi 2RLi + CuCN
See: Lipshutz Org. React. 1992, 41, 135. Lipshutz Synthesis 1987, 325. Lipshutz Tetrahedron 1984, 40, 5005.
409

- Representative Mixed Cuprates RLi, CuI, R3P (1:1:2) (COD)RCuMgX RCu(SPh)Li, RCu(OtBu)Li, RCu(NMe2)Li RCu(SPh)Li Suzuki Tetrahedron Lett. 1980, 1247. Leyendecker Tetrahedron Lett. 1980, 1311. Posner J. Am. Chem. Soc. 1973, 95, 7788. Alexakis Tetrahedron Lett. 1976, 3461. Org. Prep. Proc. Int. 1976, 8, 13
RCu(C CtBu)Li
and RCu(CN)Li
Boeckman J. Org. Chem. 1977, 42, 1581. Marino J. Org. Chem. 1976, 41, 3213. Acker Tetrahedron Lett. 1977, 3407. Miyaura Tetrahedron Lett. 1977, 3369. Corey J. Am. Chem. Soc. 1972, 94, 7210.
RCu(CN)Li
RCu(C CPr)Li
RCu(C CC(OMe)Me2)Li
Corey J. Org. Chem. 1978, 43, 3418.
6. Functionalized Organocuprate Reagents
- Examples O H O H CuTMEDALiI CO2Et TMSCl, -78 C, 3 h O H O H 92% CO2Et
Configurationally stable (better than higher order cyano cuprate): prepared from the corresponding Bu3Sn reagent/nBuLi then CuI/TMEDA. Linderman J. Org. Chem. 1991, 56, 5491.
410
Organocuprate and Conjugate Addition Reactions Dale L. Boger - Other representative functionalized organocuprate reagents
CuLi )2 O
Kojima, Wakita and Kato Tetrahedron Lett. 1979, 4577.
EtO
CuLi )2
Me3Si
CuLi )2
Doyle and West J. Org. Chem. 1975, 97, 3821. Nordlander and Haky J. Org. Chem. 1979, 45, 4780. Schollkopf and Haenssle Justus Liebigs Ann. Chem. 1972, 763, 208. Baldwin, Hofle and Lever J. Am. Chem. Soc. 1974, 96, 7125. Huynh and LinstrumelleTetrahedron Lett. 1979, 1073.
R2CuLi R = nBu, Ph, CH2=CH, sBu R = tBu, Me, CH2=CHCH2
House and Wilkins J. Org. Chem. 1978, 43, 2443.
N R
N R
X Cu(SPh)Li
) CuLi 2
Corey and Enders Tetrahedron Lett. 1976, 11. Corey and Boger Tetrahedron Lett. 1978, 4597. Gawley, Termine, and Aube Tetrahedron Lett. 1980, 21, 3115.
X = NMe2, OCH3
(RCH=CHCH2)2CuLi
Miginiac, Daviaud and Gerard Tetrahedron Lett. 1979, 1811.
(MeO)2CH
Cu(C CtBu)Li
Depezay and Le Merrer Tetrahedron Lett. 1974, 2751. Boeckman and Rammaiah J. Org. Chem. 1977, 42, 1581. Cyano cuprate: Marino and Farina J. Org. Chem. 1976, 41, 3213. Thiophenyl cuprate: Grieco, Wang, and Majetich J. Org. Chem. 1976, 41, 726.
[(EtO)2P(O)CH2]2CuLi
Savignac and Mathey Tetrahedron Lett. 1976, 2829. Mathey and Savignac Synthesis 1976, 766.
)2CuLi
)2CuLi
Wender and Filosa J. Org. Chem. 1976, 3490. Marino and Browne J. Org. Chem. 1976, 3629. Piers, Lau and Nagakura Tetrahedron Lett. 1976, 3233. Piers and Nagakura Tetrahedron Lett. 1976, 3237. Marino and Browne Tetrahedron Lett. 1976, 3241. Marino and Browne Tetrahedron Lett. 1976, 3245.
PhSCu(Li)CH2(CH2)nCH2Cu(Li)SPh
Wender and Eck Tetrahedron Lett. 1977, 1245.
411
Y ((RO)2PCH2)2CuLi, Y= O, S
Savignac and Mathey Tetrahedron Lett. 1976, 2829.
CuLi )2 Bu3Sn
Fargeas Tetrahedron 1996, 52, 6613; 1994, 35, 7767.
Me2NCH2
CuLi )2
Corey, Cane and Libit J. Am. Chem. Soc. 1971, 93, 7016.
O CuLi
Ireland J. Org. Chem. 1975, 40, 975.
CuLi )2 OEt
Wollenberg J. Am. Chem. Soc. 1977, 99, 7365 Schlosser, M. J. Org. Chem. 1978, 43, 1595.
CuLi )2 Me3Si
Linstrumelle Tetrahedron Lett. 1979, 1073.
OR n
Cu(Li)C CPr
(n = 1, R = THP) Corey J. Am. Chem. Soc. 1976, 98, 222. (n = 3, R = TBDMS) Corey Tetrahedron Lett. 1976, 4701 and 4705 .
Me THPO
Cu(Li)C C(Me)2OMe
Corey Tetrahedron Lett. 1978, 1051. Corey J. Am. Chem. Soc. 1978, 100, 2916.
R(Li)Cu
C5H11 OR
Corey J. Am. Chem. Soc. 1972, 94, 7210. Corey Tetrahedron Lett. 1983, 24, 5571. Corey Tetrahedron Lett. 1986, 27, 2199 and 3556.
412
Organocuprate and Conjugate Addition Reactions Dale L. Boger 7. Stereochemistry of Organocuprate Conjugate Addition Reactions A. Cyclic Substrates Cyclic enones: intraannular diastereoselectivity Ref. 1 2,3-diastereoselectivity O Me Me2CuLi O Me Me O Me2CuLi Me O R2CuLi R R1 3-substituted enones O 3 R R 3,5-diastereoselectivity O 4 R2CuLi R1 R1 R Me CH2Ph O R1 Me R Me R2CuLi R O R
1
condition dependent: cis preferred, but isomerization to trans is facile.
3,4-diastereoselectivity O 2
R1
trans:cis
72:28 78:22 88:12 96:4 (87:13)
R1 Et
trans:cis
77:23 89:11 89:11 92:8
Me Me Et iPr Ph
Me Ph iPr Me Et
trans:cis
98:2 (99:1) (93:7) trans only
3,4-diastereoselectivity vs 3,5-diastereoselectivity O 4 Ph Ph O
2
O Ph2CuLi Ph Ph O CuLi Me Me 80 : 20 CO2Et OSiMe3 Me2CuLi R R Me Ph This will be dependent on the relative size of the C-3 and C-4 substituents.
Me
Me CO2Et
3,6-diastereoselectivity O 5
413
Modern Organic Chemistry The Scripps Research Institute Exocyclic enones and esters Ref. CHCOMe 96% 6
tBu
Me Me2CuLi
CHCOMe
tBu
O Me2CuLi 7
tBu
O Me
tBu
Bicyclic enones and related substrates R Me2CuLi 8 O R = H, Me O R Me2CuLi O Me H N O OTHP Me Me2CuLi O O Me H Me2CuLi O Me OTHP Me H MeMe H N H Me
Me 9 O
H 10 O
CuLi O
Me 11 O R2CuLi O
Me
R1 N O H R2CuLi O
R1 R N H
414
Organocuprate and Conjugate Addition Reactions Dale L. Boger ref. 12 O 1 Me H Me2CuLi O Me O 2 rate: 2 > 1 (>20:1) Me H Me H Me2CuLi O Me Me H
R Me 13 O R2CuLi O R 1,6-addition Me Me Et
iPr tBu
trans:cis
93:7 98:2 100:0 100:0
Medium-sized rings Me 14 O Me2CuLi > 100:1 Me Me O
Me 14 O Me Me2CuLi 96:4 Me O
Me O Me2CuLi 99:1 O Me
Me
BUT Me 14 O Me Me2CuLi 96:4 Me O Me O Me2CuLi 96:4 O Me Me
415
Modern Organic Chemistry The Scripps Research Institute B. Acyclic Substrates O 12 Ph H OMOM Me2CuLi Ph > 30:1 Ph H OMOM O H Me Ph
Bu 15 Ph (Bn)2N H CO2Et H Bu2CuLi > 30:1 Ph (Bn)2N H
H CO2Et H > 95: <5 +
H Ph (Bn)2N H
Bu CO2Et H
Bu 15 Ph (Bn)2N H CO2Et CO2Et Bu2CuLi > 30:1 Ph (Bn)2N H
H CO2Et CO2Et < 5: >95 +
H Ph (Bn)2N H
Bu CO2Et CO2Et
OBOM 16 TBDPSO CO2Me
R2CuLi TMSCl, THF 78 C, 3 h TBDPSO
OBOM CO2Me R
73-93% > 50:1 R = Me R = Et R = Bu
H R'
OR
CO2Et H
- favorable interaction between alkoxy and system. - free of 1,2-allylic strain. - increased stabilization of the ,-unsaturated system via interaction between low-level * orbital and high-level R' - C orbital..
NCO2R O CO2Me
R2CuLi TMSCl, THF 78 C, 3 h O
NCO2R
R R O N H O O H CO2Et H
70-90% yield > 50:1 R = Me CO2Me R = Et R = Bu
- favorable interaction between parallel C - R and *C - Cu orbitals. - possibility of chelation between carbamate and ester may overide 1,2-allylic strain as well as bulk of -substituent.
416
Stereochemistry of Organocuprate Conjugate Addition Reactions (References) Books and Reviews Kozlowski, J. A. in Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 169198. Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135631. Posner, G. H. Org. React. 1972, 19, 1113. March, J. Asymmetric Synthesis, Vol. 4, Academic: New York, New York, 1983. Taylor, R. J. K. Synthesis 1985, 4, 364. Kharasch, M. S.; Reinmuth, O. Grignard Rections of Nonmetallic Substances, Prentice-Hall: Englewood Cliffs, NJ, 1954, pp. 196239. Endocyclic enones 2,3-diastereoselectivity 1. Pesaro, M.; Bozzato, G.; Schradel, P. J. Chem. Soc., Chem. Commun. 1968, 1152. Sisovic, E.; Rao, A. S. Curr. Sci. 1968, 37, 286. Boeckman, R. K. J. Org. Chem. 1973, 38, 4450. Coates, R. M.; Sandefur, L. O. J. Org. Chem. 1974, 39, 275. Posner, G. H.; Sterling, J. J.; Whitten, C. E.; Leutz, C. M.; Brunelle, D. J. J. Am. Chem. Soc. 1975, 97, 107. Posner, G. H. Isr. J. Chem. 1984, 24, 88. Piers, E.; Karunartre, V. J. Chem. Soc., Chem. Commun. 1983, 935.
3,4-diastereoselectivity 2. Luong-Thi, N. T.; Riviere, H. Compt. rend. 1968, 267, 776. Riviere, H.; Tostain, J. Bull. Soc. Chim., Fr. 1959, 568. Zimmerman, H. E.; Morse, R. L. J. Am. Chem. Soc. 1968, 90, 954. Luong-Thi, N. T.; Riviere, H. Tetrahedron Lett. 1971, 587.
3-substituted enones 3. Buchi, G.; Jeger, O.; Ruzicka, L. Helv. Chim. Acta 1948, 31, 241. House, H. O.; Fischer, W. F. J. Org. Chem. 1968, 33, 949. Stotter, P. L.; Hill, K. A. J. Org. Chem. 1973, 38, 2576.
3,5-diastereoselectivity 4. House, H. O.; Fischer, W. F. J. Org. Chem. 1968, 33, 949. Allinger, N. L.; Riew, C. K. Tetrahedron Lett. 1966, 1269. Wheeler, O. H.; de Rodriguez, E. G. J. Org. Chem. 1964, 29, 718. Eliel, E. L.; Biros, F. J. J. Am. Chem. Soc. 1966, 88, 3334. Ellis, J. W. J. Chem. Soc., Chem. Commun. 1970, 406. Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308. House, H. O.; Giese, R. W.; Kronberger, K.; Kaplan, J. P.; Simeone, J. F. J. Am. Chem. Soc. 1970, 92, 2800. Siscovic, E.; Rao, A. S. Curr. Sci. 1968, 37, 286. Cacchi, S.; Caputo, A. Indian J. Chem. 1974, 12, 325. Hoye, T. R.; Magee, A. S.; Rosen, R. E. J. Org. Chem. 1984, 44, 3224. Posner, G. H.; Sterling, J. J.; Whitten, C. E.; Leutz, C. M.; Brunelle, D. J. J. Am. Chem. Soc. 1975, 97, 107.
417
3,6-diastereoselectivity 5. Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462. Stork, G. Pure Appl. Chem. 1968, 17, 383.
Exocyclic enones and esters 6. House, H. O.; Respess, W. L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128. Coates, R. M.; Sowerby, R. L. J. Am. Chem. Soc. 1971, 93, 1027. Foulon, J. P. J. Organometal. Chem. 1982, 228, 321. 7. House, H. O.; Chu, C. Y.; Wilkins, J. M.; Umen, J. J. Org. Chem. 1975, 40, 1460. Corey, E. J.; Boger, D. L. Tetrahedron Lett. 1978, 9 and 13.
Bicyclic enones and polyenones 8. Birch, A. J.; Robinson, R. J. Chem. Soc. 1943, 501. Ireland, R. E.; Pfister, G. Tetrahedron Lett. 1969, 2145. Piers, E.; Keziere, R. J. Tetrahedron Lett. 1968, 583. Marshall, J. A.; Roebke, H. J. Org. Chem. 1968, 33, 840. Birch, A. J.; Smith, M. Proc. Chem. Soc. 1962, 356. Marshall, J. A.; Fanta, W. I.; Roebke, H. J. Org. Chem. 1966, 31, 1016. Filler, R.; Rao, Y. S. J. Org. Chem. 1962, 27, 3348. Settepani, J. A.; Torigoe, M.; Fishman, J. Tetrahedron 1965, 21, 3661. Piers, E.; Britton, R. W.; deWaal, W. J. Chem. Soc., Chem. Commun. 1969, 1069. Piers, E.; deWaal, W.; Britton, R. W. J. Am. Chem. Soc. 1971, 93, 5113. Piers, E.; Keziere, R. J. Can. J. Chem. 1969, 47, 137. Corey, E. J.; Carney, R. L. J. Am. Chem. Soc. 1971, 93, 7318. 11. Marshall, J. A.; Brady, S. F. Tetrahedron Lett. 1969, 1387. Marshall, J. A.; Brady, S. F. J. Org. Chem. 1970, 35, 4068. Wechter, W. J. Tetrahedron 1965, 21, 1625. Marshall, J. A. Tetrahedron Lett. 1971, 3795. Piers, E.; deWaal, W.; Britton, R. W. Can J. Chem. 1969, 47, 4299. Marshall, J. A.; Anderson, N. H. J. Org. Chem. 1966, 31, 667. Piers, E.; deWaal, W.; Britton, R. W. Can J. Chem. 1969, 47, 4307. Wiechert, R.; Kerb, U.; Kieslich, K. Chem. Ber. 1963, 96, 2765. Marshall, J. A.; Warne, T. M. J. Org. Chem. 1971, 36, 178. Slosse, P.; Hootel, C. Tetrahedron Lett. 1979, 4587. Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1990, 1393.
12.
1,6-addition 13. Marshall, J. A.; Roebke, H. J. Org. Chem. 1966, 31, 3109. Campbell, J. A.; Babcock, J. C. J. Am. Chem. Soc. 1959, 81, 4069. Atwater, N. W. J. Org. Chem. 1961, 26, 3077. Birch, A. J.; Smith, M. Proc. Chem. Soc. 1962, 356. Marshall, J. A. Tetrahedron Lett. 1971, 3795. Medium-sized Rings 14. Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981. Acyclic Substrates 15. Reetz, M. T.; Rhrig, D. Angew. Chem., Int. Ed. Eng. 1989, 28, 1706. 16. Hanessian, S.; Sumi, K. Synthesis 1991, 1083.
418
Organocuprate and Conjugate Addition Reactions Dale L. Boger 8. Origin of Diastereoselectivity A. 2,3-Diastereoselection determined by protonation of enolate H+ pseudo equatorial R H R H O Li H R H H+ this is preferred axial protonation, chair-like transition state, trans to C3 R-substituent. O R R' most stable product observed readily epimerizes to more stable product. R R' O Li H pseudo axial R H
Destabilizing 1,3-diaxial interaction developing.
axial protonation, chair-like transition state, cis to C3 R-substituent. O
- Examples: O Me2CuLi O 1:1 H H H O Me2CuLi Me Posner J. Org. Chem. 1973, 38, 4459. O Me H O Li axial, through chair-like transition state
H equatorial, through boat-like transition state
//
419
Modern Organic Chemistry The Scripps Research Institute B. 3,4-Diastereoselection O R'2CuLi R' R R'MgX + cat. CuI R = Me R' Me Et
iPr
O +
R' R minor (cis)
R major (trans) Ratio 72:28 78:22 88:12 87:13 96:4 (75%) (PhCu)
increasing size of R' increasing amount of trans
Ph
R = Et
R' Me Et
Ratio 77:23 89:11 Ratio 89:11 92:8 axial delivery, chair-like transition state; cis to C4 R-substituent H R H increasing size of R increasing amount of trans
R = iPr
R' Me Et
equatorial delivery, boat-like transition state; cis to C4 R-substituent H R H H axial delivery, chair-like transition state; trans to C4 R-substituent
//
vs. O preferred
but remember: reactive intermediate is radical anion

//
H H O
R H H
420
//
H

C. 3,5-Diastereoselectivity O R2CuLi Me Me R O + Me R O
trans (major)
House J. Org. Chem. 1968, 33, 949. R = Me 93 98 99 Posner J. Am. Chem. Soc. 1975, 97, 107. R = CH2Ar : : :
cis (minor)
7 2 1
(MeMgI, cat, CuI) >90% (Me2CuLi) (Me2CuLi + LiI)
trans only
unaffected by C-3 substitution
Posner J. Am. Chem. Soc. 1975, 97, 107. O Me2CuLi Br 4 Me O Me
- equatorial delivery of group, grows into boat conformation of enolate.
H O
two nearly equally populated conformations H
CH3
no destabilizing interactions in the ground state for axial Me group but cannot achieve axial delivery of Nu through chair-like transition state: severe Me/Me1,3-diaxial interaction. O
//
CH3 H
//
~ =
H equatorial delivery but would grow into boat conformation of enolate
axial delivery of group grows into chair form of enolate
Me
enone with alkyl substituent in the equatorial position is the reactive conformation.
421
Modern Organic Chemistry The Scripps Research Institute D. 3,4- vs 3,5-Diastereoselectivity 3,4 > 3,5 O Ph2CuLi Ph Ph equatorial delivery boat-like transition state
//
Ph Ph
Ph
axial delivery, chair-like transition state but destabilizing 1,2-steric interaction H Ph O Ph O H

//
Ph H Ph
1,2-interaction > 1,3-interaction equatorial delivery requires boat-like transition state
axial delivery, 1,3-destabilizing steric interactions but chair-like transition state. preferred again, it is anion radical equatorial
//
axial // H Ph O Li Ph OLi H
Ph H H Ph axial E. 3,6-Diastereoselectivity
equatorial
O R R
R equatorial delivery, boat-like transition state H

//
axial delivery, chair-like transition-state H
H H H
R O more stable ground state
H H
//
R equatorial delivery, boat-like transition-state
axial delivery, chair-like transition-state cis product predominates
422
Organocuprate and Conjugate Addition Reactions Dale L. Boger F. Exocyclic enones O O
tBu
tBu
CH3
equatorial attack would require boat-like transition state O

tBu tBu
O H axial attack proceeds through chair-like transition state axial protonation (observed even when tBu replaced with H, see alkylation section). H OLi
tBu
H+
tBu
H R
//
O R
G. Fused enones
H O H H
relative to B ring this is equatorial delivery of the nucleophile. R decelerates conjugate addition this steric interaction is a CH3 1,2-interaction or torsional strain (eclipsing interaction) H Cuprate behaves as large nucleophile preferring equatorial attack (1,2-interactions) to axial attack (1,3-interactions) on the exocyclic olefin.
H H
-May really want to consider radical-anion conformation 1,2-torsional interaction large reagent (Cuprate) Me H LiO H H small reagent (H+) (e.g., Birch reduction) 1,3-steric interactions
//
axial delivery of nucleophile suffers severe steric interactions (1,3-diaxial interactions)
423
Modern Organic Chemistry The Scripps Research Institute Me Me
Me H
Me Me
- cis ring fusion. - protonation from least hindered face of enolate, also most stable product.
Piers Can. J. Chem. 1969, 47, 137.
O N H OTHP
Me2CuLi
Me
cis fusion
N H OTHP
Me2CuLi O H O Me H
2
CuLi O Corey J. Am Chem. Soc. 1971, 93, 7318.
- but 1,6-addition O R2CuLi O R = Me Et iPr tBu Me2CuLi O 78 oC O R 93:7 98:2 100:0 100:0 H O R
axial delivery of nucleophile
CuLi O 96% H H O 80%
H O
1.
CuLi Me3SiO
1. O3, 1 equiv. 2. BH4 74%
2. Me3SiCl
Clark Tetrahedron Lett. 1974, 1713. [for vernolepin]
424
Organocuprate and Conjugate Addition Reactions Dale L. Boger H. Exocyclic enones 96%
tBu
Me O
tBu
steric 1,3-diaxial interaction
//
H H
tBu
H O H H torsional strain eclipsing 1,2-interaction

tBu
O H Me H H
Cuprate behaves as a large reagent preferring equatorial attack
i) Acyclic systems H Ph NBn2 CO2Et Ph NBn2 > 95:5 H Ph CO2Et NBn2 CO2Et Ph Bn CO2Et NBn2 CO2Et Ph Bn CO2Et
Felkin model NBn2 CO2Et H Bn H
NBn2 CO2Et H CO2Et
425
426
Synthetic Analysis and Design Dale L. Boger
XIII. Synthetic Analysis and Design

Design: Corey The Logic of Chemical Synthesis, Wiley: New York, 1989. Warren Organic Synthesis: The Disconnection Approach, Wiley: New York, 1982. Fuhrhop, Penzlin Organic Synthesis: Concepts, Methods, Starting Materials, VCH: Weinheim, 1994. Total Synthesis: Nicolaou, Sorensen Classics in Total Synthesis, VCH: Weinheim, 1996. Hanessian Total Synthesis of Natural Products: The Chiron Approach, Pergamon: Oxford, 1983. Lindberg Strategies and Tactics in Organic Synthesis, Vol. 1-3; Academic: San Diego. ApSimon The Total Synthesis of Natural Products, Vol. 1-9; Wiley: New York. Turner The Design of Organic Synthesis, Elsevier: Amsterdam, 1976. Fleming Selected Organic Syntheses, Wiley: New York, 1973. Bindra Creativity in Organic Synthesis, Academic: New York, 1975. Bindra Art in Organic Synthesis, Wiley: New York, 1988. Lednicer, Mitscher, Georg The Organic Chemistry of Drug Synthesis, Vol. 1-4; Wiley: New York. Nakanishi Natural Products Chemistry, Vol. 1-3; Academic: New York. Koskinen Asymmetric Synthesis of Natural Products, Wiley: New York, 1993. Danishefsky and Danishefsky Progress in Total Synthesis, Meredith: New York, 1971.
Key Reviews: Corey
Science 1969, 166, 178; 1985, 228, 408. Chem. Soc. Rev. 1988, 17, 111. Pure. App. Chem. 1967, 14, 19; 1971, 18, 45; 1990, 62, 1209. Angew. Chem., Int. Ed. Eng. 1991, 30, 455. (Nobel Prize Lecture)
E. J. Corey received the 1990 Nobel Prize in Chemistry for his development of the theory and methodology of organic synthesis. His development and systemization of retrosynthetic analysis transformed organic synthesis from inspired recognition of a route into a precise and logical science. As the modern techniques of structure determination emerged (NMR, IR, X-ray), Corey applied his retrosynthetic analysis to some of the most challenging syntheses of the time. The application of computer analysis with LHASA (Logic and Heuristics Applied to Synthetic Analysis), the development of practical synthetic methodology for individual transformations based on clear mechanistic rationales, and the more than 100 natural product total syntheses that followed transformed modern organic synthesis. Corey, Cheng The Logic of Chemical Synthesis, Wiley: New York, 1989. Corey, Wipke Science 1969, 166, 178-192.
Protecting Groups: Greene, Wuts Protecting Groups in Organic Synthesis, 3rd Ed., Wiley: New York, 1999. Note: The material in this book was first assembled in conjunction with the LHASA project (Corey) and composed the Ph.D. dissertation for T. W. Greene. Computer Assisted Analysis: Corey, Wipke (LHASA: Logic and Heuristics Applied to Synthetic Analysis), Science 1969, 166, 178. Corey, Long J. Org. Chem. 1978, 43, 2208. Jorgensen (CAMEO: Computer Assisted Mechanistic Evaluation of Organic Reactions): Pure App. Chem. 1990, 62, 1921. Hendrickson J. Chem. Inf. Comput. Sci. 1992, 32, 209. Acc. Chem. Res. 1986, 19, 274.
427
A. Classifications
1. Linear Synthesis - The target compound is made through a series of linear transformations.
5-steps 90%/step 70%/step
overall yield 59% 17%
2. Convergent Synthesis - Individually prepared compounds are convergently brought together to make the target compound. 5-steps overall yield 73% 34%
C E
D F
90%/step 70%/step
Advantages of a convergent synthesis - shorter - simpler to execute - higher overall yields - better material balance and supply - Triply Convergent Synthesis -three major components are brought together in a single step to make the target compound.
C E G
3. Divergent Synthesis
D F H
- For a class of compounds, it is advantageous to prepare a common intermediate and use this common intermediate to prepare all members of the class of agents. - Examples: prostaglandins O O PGF1 PGF2 RO CHO PGF3 HO OH R2 R2
OH Variations lie only in the side chains - Rather than use a linear synthesis for all agents, a divergent synthesis allows the use of a common intermediate to prepare structurally related products. - The divergent synthesis is a very good strategy if structure-activity studies are the ultimate goal.
428
Synthetic Analysis and Design Dale L. Boger Note: Though widely used, the discussion of this strategy was first formally presented in the literature along with a disclosure of a strategy for divergent aromatic annulation in conjunction with the total synthesis of a series of azafluoranthene alkaloids. Today, the divergent introduction of diversity is the basis of most combinatorial chemistry methods. Boger J. Org. Chem. 1984, 49, 4050; see also J. Org. Chem. 1984, 49, 4033 and 4045.
OMe MeO MeO N MeO MeO O OMe Imerubrine Boger J. Am. Chem. Soc. 1995, 117, 12452. 4. Total Synthesis R1 N O MeO OMe MeO
OMe
N R1 OR
R = CH3, =H Rufescine R = H, R1 = H Norrafescine R = CH3, R1 = OCH3 Imeluteine Boger J. Org. Chem. 1984, 49, 4050.
- Start with readily available materials and build up to the target molecule from simple, common materials.
5. Partial Synthesis - This is technically not a total synthesis. - Start with a naturally occurring compound or an advanced intermediate and independently convert that to the target molecule. - Examples
partial synthesis HO HO OH Previtamin D3 - For commercialization, it would be hard to match the synthesis starting with cholesterol. H S N O CO2H partial synthesis O CO2H Cephalosporins - not as accessible through fermentation R O N OAc H N H
H 2N
Penicillins, available by fermentation at Lilly, as an inexpensive bulk chemical
429
Modern Organic Chemistry The Scripps Research Institute 6. Formal Total Synthesis vs. Total Synthesis O O(CH2)8CO2H O O(CH2)8CO2H
HO HO
HO
m-CPBA
known transformation HO O
Pseudomonic Acid
Pseudomonic Acid A
Rogers Tetrahedron Lett. 1980, 881. Kozikowski J. Am. Chem. Soc. 1980, 102, 6577. H OR HO intermediate Formal Total Synthesis HO Me O O CO2H H OH
Gibberellic acid
Independent synthesis of this precursor would constitute a formal total synthesis of gibberellic acid since the conversions have been previously accomplished. In this case, the key intermediate is so far from the final target that most would not "claim" such an accomplishment unless the final conversions were also developed within their own laboratories.
7. Biomimetic (Total) Synthesis - Presumably, nature will not be using a process that is intrinsically difficult or impossible. It is believed that one can effectively mimic the conditions provided by nature, and conduct the same reaction in a flask. - Two important considerations 1 - The reaction must be capable of occurring 2 - The biogenetic process is under a great deal of control (enzymatic) and a similar level of control in lab may be difficult, but necessary - Classic example : Steroid synthesis Extensively studied and many good chemists failed before the experimental parameters were sufficiently defined to mimic the cation-olefin cyclization. R Steroids Biomimetic Synthesis O
430
B. Retrosynthetic Analysis
- Work backwards from the target compound to generate a set of intermediates which can be made from available starting materials. T11 T1 Target Structure T2 T3 These less complicated building blocks in organic synthesis were called synthons in the early years. Now they are referred to as retrons. Objectives: 1. Generate a large number of potential approaches in order to obtain an optimal route. 2. Strive to generate simpler, less complex intermediates which can be obtained from readily available materials. 3. All steps are subject to reevaluation - this allows for design of a better or optimized synthesis. Steps in Design and Execution of a Synthesis 1. Selection of a problem more time is or should be devoted to 2. Selection of goals to be achieved through synthesis steps 1 and 2 than most may realize 3. Simplification 4. Generation of synthetic pathways steps 3 and 4 constitute 5. Evaluation of synthetic pathways --> assignment of merit retrosynthetic analysis 6. Selection of specific reactions and reagents for each step 7. Selection of specific reaction conditions and design of experiments 8. Execution and analysis of results Because of the amount of time and effort involved in the execution, it is important to be meticulous in evaluating the potential synthetic pathways. 1. Selection of a problem - One of the most important considerations. - Should be the first consideration, independent of all others. This assures that it is a problem that you want to address. - Recognize the time and effort involved in the actual conduct of the synthesis. - This will depend on the setting, circumstances and interests of the individual. 2. Selection of goals OH CO2H SR SRS-A (Slow Reacting Substance of Anaphylaxis) T12 T13 antithetic direction working backwards synthetic direction building up materials toward the target
a. Structure determination of SRS-A: the initial intent. The R group on the thiol was not known, so the first synthesis was designed to facilitate the introduction of different R groups permitting a comparison with the endogenous product to confirm the structure. b. Once the structure was determined, objectives included providing sufficient material for biological testing. c. Determination of absolute configuration - the chiral centers were unambiguously established through synthesis. d. Development of a route amenable to analogue preparation: want to inhibit the action of SRS-A (an antagonist development). e. Biomimetic synthesis (follows the biosynthetic generation of materials) - might constitute a simplification.
431

f. g. h. i. j. Development of commercially viable processes. Demonstration of improvements in current methodology. Novel, interesting structures. Common intermediate for a class of structures (divergent synthesis). Mechanism of action of a class of compounds - devise partial structures of the parent . compound to define the mechanism of action. k. Chemistry of a class of compounds. l. Properties of a class of compounds.
The specific goals are established prior to the generation of the retrosynthetic pathway. The goals will play an important role in the assignment of relative merit of each potential pathway in the retrosynthetic analysis.
3. Simplification and Background Chemistry a. Recognition of symmetry elements present in a structure.
i.e, Squalene CHO CHO
- two identical halves - build out from a central core by conducting each of the steps twice and simultaneously - Johnson J. Am. Chem. Soc. 1970, 92, 741.
SO2Ar
Br
OH
- combines two halves prepared from a common intermediate at the end of the synthesis. - Grieco J. Org. Chem. 1974, 39, 2135.
CH3O2C OH CH3O CH3O CH3O2C HO N CH3 N CH3 O O
CO2CH3 CH3O CH3O CH3O2C N CH3 N CH3 CO2H CO2H CH3O2C
N N CO2CH3 N N CH3O OCH3
CH3O Isochrysohermidin Boger J. Am. Chem. Soc. 1993, 115, 11418.
OCH3
432
Synthetic Analysis and Design Dale L. Boger - The recognition of symmetry elements is not always so obvious by initial examination of the agent. e.g., Juncusol Me OH Me OH HO HO Me HO Me Me Kende J. Am. Chem. Soc. 1979, 101, 1057. X
now symmetrical - simplification of the synthetic problem
O O
or start with the central ring and build out in a similar symmetrical fashion Boger J. Org. Chem. 1984, 49, 4045.
e.g., Carpanone Me Me H O O O O Me H O O O O O O O Dimerize O Chapman J. Am. Chem. Soc. 1971, 93, 6696. - biomimetic synthesis of this agent allows for simplification. - this is a very good example where the symmetry elements are not obvious by looking at the agent. O O OH Me Me
e.g., Rifamycin Me AcO OAc OH OH OH O H Me N O O O Me O O - this agent does not contain symmetry in the entire molecule but a subunit is symmetrical. Me Me RO Me OR1 OR2 OR3 S H Me Me Me S Me Me Me RO
Me O H C O O H
Me S S
Corey Tetrahedron Lett. 1979, 335.
433
Modern Organic Chemistry The Scripps Research Institute e.g., Usnic Acid COMe O COMe OH
HO Me
O COMe Oxidative Dimerization
HO Me
OH
Me OH
OH Barton J. Chem. Soc. 1956, 530.
e.g., Porantherine
H Me
H Me
N Me Me
O O Me
O O
H O
H O Me
HN Me N O H Me Me O NH2 O Me
Corey J. Am. Chem. Soc. 1974, 96, 6516. - the symmetry elements are tucked more deeply into the structure b. Background Chemistry - Information available in the literature will provide very important insights required to effectively design a synthesis.
e.g., Quassin O O Me H H Me
OMe Me Me H O Grieco J. Am. Chem. Soc. 1980, 102, 7586. O
MeO
- 7 stereocenters but 3 are epimerizable centers and the natural product possesses the most stable configuration, so a synthesis without stereocontrol of these 3 centers can be used (epimerize later). Need only worry about control of 4 of the 7 stereocenters.
434
Synthetic Analysis and Design Dale L. Boger c. Recognize and Remove Reactive Functionality - Another key to simplification derived from background chemistry e.g., Vernolepin OH O O O OH
O O H
O H
O remove as well - -Methylene lactone in a trans-fused 5-membered ring This is extraordinarily reactive to nucleophiles (Michael). It will not stand up to many synthetic steps/reagents. - the final step should be introduction of the reactive group. Danishefsky J. Am. Chem. Soc. 1976, 98, 3028. Grieco J. Am. Chem. Soc. 1976, 98, 1612. Danishefsky J. Am. Chem. Soc. 1977, 99, 6066. OCH3 CO2CH3 O OHO
e.g., Precursor to aromatic amino acids CO2H O H+ decarboxylation loss of the OH HO H+ H O O
CO2 O
HO
- acid sensitive (derived from background chemistry). - a successful approach must involve generation under basic conditions. Danishefsky J. Am. Chem. Soc. 1977, 99, 7740.
e.g., PGI2 (prostacyclin)
CO2H H H+, H2O
OH CO2H O HO
C5H11 HO OH
C5H11
OH
- enol ether sensitive to acid-catalyzed hydrolysis. Corey J. Am. Chem. Soc. 1977, 99, 2006. S. K. Samuelsson and J. R. Vane shared the 1982 Nobel Prize in Medicine for their discovery of the prostaglandins and related biologically active substances.
U. von Euler received the 1970 Nobel Prize in Medicine for the discovery of hormonal transmitters in the nerve terminals and the mechanism for their storage, release, and inactivation.
435
Modern Organic Chemistry The Scripps Research Institute e.g., Thromboxane A2 (TXA2) CO2H C5H11 OH The strained acetal should be introduced late in the synthesis e.g., PGH2 (R = H) PGG2 (R = OH) O O C5H11 OR CO2H pH = 7.0 t1/2 = 4-5 min pH = 7.0 t1/2 = 32 sec OH CO2H HO O TXB2 C5H11 OH
O O
Still J. Am. Chem. Soc. 1985, 107, 6372.
Reduction / Acid-catalyzed Rearrangement
Reactive cyclic peroxide is sensitive to nucleophilic attack - introduce late in the synthesis Porter J. Am. Chem. Soc. 1980, 102, 1183. Salomon J. Am. Chem. Soc. 1979, 101, 4290. Porter J. Am. Chem. Soc. 1979, 101, 4319. e.g., Mitomycin C - stable as the quinone O H2N CH3 O note vinylogous amide N OH H2 reduction H2N CH3 OH hydroquinone - basic, nucleophilic free amine - intermediate less stable There are only two total syntheses of mitomycin C to date Kishi J. Am. Chem. Soc. 1977, 99, 8115. Fukuyama J. Am. Chem. Soc. 1989, 111, 8303. Absolute configuration established in J. Am. Chem. Soc. 1967, 89, 2905 by a single crystal X-ray structure (INCORRECT). But in the early 1980's, additional X-ray structures on related agents gave the opposite and correct absolute configuration. Take home message: Evaluate the quality of the background chemistry and assess the level of confidence and committment you want to place on it. The earlier X-ray was not on a heavy atom derivative and preceded the advances in direct methods we take for granted today. Hirayama J. Am. Chem. Soc. 1983, 105, 7199. A number of Nobel Prizes have chronicled the achievements of X-ray crystallography including the contributions of: J. Kendrew and M. Perutz (1962, heavy atoms and structure of hemoglobin). D Hodgkin (1964, X-ray structure determinations including vitamin B-12, penicillin and insulin). O. Hassel (1969, chair conformation of cyclohexane reported in 1930). W. N. Lipscomb (1976, borane structures and chemical bonding). A. Klug (1982, elucidation of nucleic acid-protein complexes). H. A. Hauptman and J. Karle (1985, direct methods). N OH H2N CH3 OH steer clear of such synthetic intermediates
CH2OCONH2 OCH3 NH
CH2OCONH2 OCH3 NH
CH2OCONH2 NuN NH
436
Synthetic Analysis and Design Dale L. Boger - The background chemistry can provide keys to the design of a synthetic strategy. O MeO Me O N OCONH2 OMe NH O MeO Me O N N OCONH2 OMe O MeO H Me N H O Isomitomycin was isolated and characterized and provided the basis for Fukuyama's total synthesis. H O H S CO2H NH2 N OCONH2 OMe N H
Mitomycin Rearrangement
e.g., Thienamycin
OH H SR O CO2H OHH H N OH SR CO2H
O H N
trans preferred
A. Fleming and H. W. Florey received the 1945 Nobel Prize in Medicine for the discovery of penicillin and its curative effects in various infectious diseases.
cis less favored must protect the amine throughout the synthesis. unusual trans H-H relationship - easily epimerizable center and fortunately, trans is most stable configuration.
Grieco J. Am. Chem. Soc. 1984, 106, 6414. Georg J. Am. Chem. Soc. 1987, 109, 1129. Yet - almost all the early syntheses went to great length to control this relative stereochemistry and it often, unnecessarily, added to their length.
e.g., Coriolin O O O
OH H Me Me H Me OH O Me
OH H Me Me H Me OH
introduce reactive functionality last
Danishefsky J. Am. Chem. Soc. 1981, 103, 3460.
4. Generation of Synthetic Pathways (Retrosynthesis) (General strategies employed in working backwards) Covered in detail in Corey The Logic of Chemical Synthesis, Wiley: New York, 1989, pp. 1-98. a. Transform-based strategies - powerful, simplifying transformation that reduces complexity. - usually very key reactions in the synthesis that dominate the approach - formation of a key intermediate (i.e., the Diels-Alder transform, the aldol transform). b. Structure-goal strategies - oldest approach. - in working backwards from the target molecule to the various intermediates, an intermediate may actually be located that is already in the literature or commercially available. e.g., Prostaglandins O OH CO2H C5H11 HO OH R'O OR O HO HO abundant O
437
Modern Organic Chemistry The Scripps Research Institute c. Topological strategies - strategic bond disconnections (J. Am. Chem. Soc. 1975, 97, 6116). - recognize strategic bonds and remove them in the retrosynthetic direction. d. Stereochemical strategies - strategies which remove the stereocenters. - simplifying the stereochemistry of the product may be related to: 1. substrate - features of the substrate will permit you to solve the stereochemical problems. 2. mechanism - reaction mechanism will permit relative or absolute stereocontrol. e. Functional group strategies 1. Functional group interconversion (FGI) - don't gain much but it permits you to get from one point to another. 2. Functional group combination (FGC) - combine pairs of functional groups. - usually a ring forming reaction in the retrosynthetic direction to give you one FG rather than two.
O H O X fragmentation O OH OH O O O OH O Baeyer-Villiger H ozonolysis
3. Functional group addition (FGA) - hard to recognize while working in the reverse direction. - introduce a double bond which then may key the recognition of a Diels-Alder reaction.
O O Br O
O OH O Bromo-lactonization
CO2Me CO2Me
CO2Me CO2Me MeO2C
CO2Me Diels-Alder
438
Synthetic Analysis and Design Dale L. Boger i.e., Diels-Alder reaction FGA cat H2 DA + CH2OH CH2OH not optimal neutral unreactive diene CH2OH unreactive dienophile
CH2OH
CH2OH
CH2OH
FGI reduction
O DA O O + optimal neutral unreactive diene
O O O reactive dienophile
O CH2OH CH2OH CO2R O CO2R more reactive due to EWG reevaluation: isomerization may occur about the C=C. O further enhances reactivity assures stereochemistry.
But: There is an alternative and still better Diels-Alder pathway that most would miss without careful consideration. CH2OH CH2OH FGA cat H2 CH2OH CH2OH FGI reduction CO2R CH2OH
FGI hydrolysis O O Intramolecular Diels-Alder O O
439
Modern Organic Chemistry The Scripps Research Institute 5. Evaluation of Pathways and Assignment of Merit a. excellent knowledge of organic chemistry b. suspect reactions must be recognized - only one poor step can ruin the synthesis c. control of stereochemistry is clear d. want opportunity for alternatives - reactions that look good on paper aren't always successful in lab 6. Selection of Specific Reactions and Reagents a. this also requires an excellent knowledge of organic chemistry b. check the literature for alternative reagents - it is wiser to change reagents than to change the entire synthesis if problems arise c. many reference texts are available Larock Fieser and Fieser Paquette Computer Databases
Comprehensive Organic Transformations Reagents for Organic Synthesis Vol. 1-18 Encyclopedia of Reagents for Organic Synthesis CLF, Reaccs, Scifinder, Beilstein, Isis
7. Selection of Reaction Conditions a. reaction temperature b. solvent c. knowledge of reaction mechanism d. consult current and background literature 8. Execution of the synthesis - most difficult and time consuming element of work a. easy: setting up and conducting the reaction b. difficult: interpreting the results from the reaction
C. Strategic Bond Analysis

- For bridged ring systems Corey J. Am. Chem. Soc. 1975, 97, 6116. - Most desirable bond disconnections in the antithetic direction minimize: 1. appendages 2. appendage chiral centers 3. medium or large size rings 4. bridged rings Rule 1: Because it is easy to form common size rings, a strategic bond must be in a 4-7 membered primary ring. A primary ring is one which cannot be expressed as an envelope or two or more smaller rings. This is restricted to primary rings because ring forming reactions are strongly affected by the size of the smallest ring containing the newly forming bond.
The six membered ring is not primary because it contains two smaller rings.
Rule 2a:
A strategic bond must be directly attached to another ring (i.e. exo to another ring). This is because a ring disconnection which produces two functionalized appendages is harder to utilize than one which produces one or no functionalized appendages. c or c or d non-strategic bonds a a or b strategic bonds d b or one ring appendage
two ring appendages - more complicated
440
Synthetic Analysis and Design Dale L. Boger b non-strategic bond a strategic bond
b a
Rule 2b:
A strategic bond may not be exo to a preexisting 3-membered ring.
non-strategic even though exo to a ring
X EWG
anion displacement reactions don't work well on a three membered ring
Rule 3:
Strategic bonds should be in ring(s) which exhibit the greatest degree of bridging. The maximum bridging ring is selected from the set of synthetically significant rings which is defined as the set of all primary rings plus all secondary rings which are less than 8membered. The maximum ring is that which is bridged, not fused at the greatest number of sites. Select the maximum bridging ring and disconnect the strategic bonds within that ring bridge point
fusion point 5R-3B 5R-4B maximum bridging fusion point 4R-2B
fusion point 5R-2B 6R-3B 7R-2B
Rule 4:
To avoid formation of >7-membered rings during the antithetic bond cleavage, any bond common to a pair of rings whose envelope is >7 is not strategic.
non strategic
10-membered ring non-strategic
H * strategic * H
441
Modern Organic Chemistry The Scripps Research Institute Rule 5: Bonds within aryl rings cannot be strategic.
non-strategic
R Rule 6a: If a disconnection leaves chiral atoms on the remaining arc then the disconnections cannot be strategic. * OH H H OH * non-strategic increased difficulty
The stereochemistry is much harder to control on the acyclic precursor than on the cyclic precursor
Rule 6b:
Chiral atoms may be allowed if they appear directly at the point of attachment.
NO2 * * Me OH
b non-strategic b HO
NO2 a Me
a strategic
* * O Me
NO2
Rule 7:
C-X Bonds (X = heteroatom) in rings will be strategic. C-X bonds are easier to form than C-C
442
D. Total Synthesis Exemplified with Longifolene

1. Strategic Bond and Retrosynthetic Analysis
Me
Me
Me fusion point not a fusion point even though it is in a 1,2 relationship b 5R, B2 8R, 3B 8 ring - secondary fusion point 7R, B2
- Ho disconnection (a) - Kuo disconnection (b)
5R, B4
6R, 3B
Fusion vs. bridge points: there must be at least one carbon (not in the ring in question) between the carbon in question and another carbon in the ring for it to be a bridgepoint.
H b * H d H a H * * * H **
a e d b c
* H c H e * Me * * * H * much simpler than longifolene! - Corey and McMurry disconnection - Schultz disconnection non-strategic gives 8-membered ring * *
5R, B4
non-strategic gives 8-membered ring - Oppolzer but via 5-membered ring
- Simultaneous or sequential b/d bond disconnection: Brieger, Fallis (Diels-Alder), Johnson (cation-olefin). - Simultaneous a/e bond disconnection: Schultz (indirect via vinylcyclopropane rearrangement).
443
Modern Organic Chemistry The Scripps Research Institute 2. Corey Synthesis:
J. Am. Chem. Soc. 1961, 83, 1251; 1964, 86, 478.
Intramolecular Michael Addition (Santonin-Santonic Acid) Robinson Annulation Wittig Reaction Pinacol Ring Expansion Dithiane Reduction Chromatographic Resolution through Diastereomeric Derivatization (Product) 3. McMurry Synthesis:
Me
Me
Me
J. Am. Chem. Soc. 1972, 94, 7132.
Intramolecular Enolate-Epoxide Addition (Alkylation) Dibromocarbene Addition, Ring Expansion Ethyl Diazoacetate Ring Expansion Organocuprate 1,4-Additions Intramolecular Aldol Reaction, Transannular Reactions Fragmentation Reaction 4. Brieger Synthesis: (attempted)
J. Am. Chem. Soc. 1963, 85, 3783.
Diels-Alder Reaction Intramolecular Diels-Alder Reaction 1,5-Hydrogen Migration of Cyclopentadienes 5. Johnson Synthesis:
J. Am. Chem. Soc. 1975, 97, 4777.
Organocuprate 1,4-Addition, Regiospecific Enolate Trap Cation-Olefin Cyclization 6. Oppolzer Synthesis:
J. Am. Chem. Soc. 1978, 100, 2583. Helv. Chim. Acta 1984, 67, 1154.
Enamine Acylation Photochemical [2 + 2] Cycloaddition Retro-Aldol Fragmentation Reaction Wittig Reaction Simmons-Smith Cyclopropanation Hydrogenation of Cyclopropanes Classical Resolution via Crystallization of Diastereomeric Salts 7. Schultz Synthesis:
J. Org. Chem. 1985, 50, 916.
Birch Reductive Alkylation Retro Cheletropic Cycloaddition 1,3-Dipolar Cycloaddition Vinylcyclopropane Rearrangement Asymmetric Synthesis via Substrate Chiral Auxiliary 8. Fallis Synthesis:
J. Am. Chem. Soc. 1990, 112, 4609. J. Org. Chem. 1993, 58, 2186.
Intramolecular Diels-Alder Reaction Barton Free Radical Deoxygenation Reaction Acetate Pyrolysis Chromatographic Resolution through Diastereomeric Derivatization (Starting Material) 9. Kuo Synthesis:
Can J. Chem. 1988, 66, 1794.

Intramolecular Aldol Addition Wagner-Meerwein Rearrangement
10. Ho Synthesis:
Can J. Chem. 1992, 70, 1375.

Ethyl Diazoacetate Ring Expansion Alkylative Esterification
444
Synthetic Analysis and Design Dale L. Boger 2. Corey Synthesis:
Wieland-Miescher ketone O Me O Robinson Annulation O H+, O O Me HO OH
Intramolecular Michael Addition Robinson Annulation Wittig Reaction Pinacol Ring Expansion Dithiane Reduction Chromatographic Resolution through Diastereomeric Derivatization (Product) O O MeCH=PPh3 96% O Wittig Reaction
cat 60% C6H6-H2O Ketone Reactivities
O O OsO4 100% Me Dihydroxylation Stereochemistry OH OH
O O
O O
p-TsCl
pyridine OH OTs
LiClO4 CaCO3, THF 50 C, 2.5 d Pinacol Rearrangement
O O O Me 41-48% + Me O
O O 2 N HCl 25 C, 6 h 5% O Me
O Me
2 N HCl 100 C, 24 h
O Me O Me H
Me Et3N ethylene glycol 225 C Intramolecular Michael Addition Me 10-20% O O 0.95 equiv Ph3CLi; CH3I 60% Thermodynamic Enolate
Me Me O O Me
Me
Me
HS SH BF3OEt2 SiO2 separation Diastereomeric Derivatization and Chromatographic Resolution
Me Me Me S O Me S Me Me 1. LiAlH4 O Me 3. RuO4 Desulfurization Wolff-Kishner Reduction Me 2. Na, NH2NH2 Me 1. MeLi, 93% 2. SOCl2, pyr Me Me
445
Modern Organic Chemistry The Scripps Research Institute Osmylation - large reagent reacts preferentially with more accessible double bond and from the least hindered face. Typically, this is from the equatorial direction but one 1,3-diaxial H is removed and axial approach now observed Selective Tosylation - rates: 1 > 2 > 3 - 3 alcohols react very slowly - MsCl and Et3N generates sulfene which will react with 1, 2, 3 OH to give the mesylate
O O OsO4 100% Me OH OH
O O
O O
O O
p-TsCl
pyridine OH OH OH OTs
O H2C S O
- Also note the use of DMAP to acylate 3 alcohols via R O O LiClO4 CaCO3 OH OTs 50 C O Me O O N O Pinacol Rearrangement - LiClO4 used for free Li+ ion to accelerate solvolytic loss of TsO group - migration of unsaturated alkyl group observed preferentially - trans antiperiplanar arrangement N
R TsO R'
O R O O H TsO H O R'
O Me O Me H
Me Et3N HOCH2CH2OH 225 C Me 10-20% Intramolecular Michael Addition - only cis product undergoes Michael - side products include the retro-Michael product A and the OH addition and retro aldol product B O O
Me O O CH3 5% B + A
Me O O Me 5%
446
Synthetic Analysis and Design Dale L. Boger Me Me Me O O Me Me Me Me Me S O Me S Me Thio-ketalization (Derivatization) - other carbonyl much more hindered - diastereomers arise that are separable by conventional chromatography
HS SH BF3OEt2 SiO2 separation
Me Me Me S O Me O H2NNH2 (-H2O) N H NH S Me Me 1. LiAlH4 3. RuO4 Me O Me Desulfurization - direct Wolff-Kishner failed - LiAlH4 protects ketone from reduction - today: Ra-Ni better for desulfurization and would avoid need to protect ketone - Wolff-Kishner reduction of dithiane
2. Na, NH2NH2
N NH
H H
H N N
base
H N NH
Me
Me O 1. MeLi, 93% 2. SOCl2, pyr
Me
Me
Olefination - Wittig reaction unsuccessful, ketone too hindered - two-step procedure adopted
Me
Me
447
Modern Organic Chemistry The Scripps Research Institute 3. McMurry Synthesis:
J. Am. Chem. Soc. 1972, 94, 7132.
Intramolecular Enolate-Epoxide Addition Dibromocarbene Addition, Ring Expansion Ethyl Diazoacetate Ring Expansion Organocuprate 1,4-Additions Intramolecular Aldol Reaction Transannular Reactions Fragmentation Reaction
O O H2, Pd-C 85% O Robinson Annulation Catalytic Hydrogenation O
O O 1. MeMgBr 2. H2SO4 H Me
7 6
O Me
m-CPBA
cis
5 H 69% (31% 6-7 olefin)
Peracid Epoxidation
Me OH O Me MeS(O)CH2Na DMSO, 93% Me O H 5 d, 60 C Me Intramolecular EnolateEpoxide Addition Br Br O H AgClO4 acetone-H2O 100% Me Ring Expansion Methodology Me Dissolving Metal Reduction Me O H2SO4 25 C, 90%
Me
tBuOK
CHBr3 43% Carbene Addition to Olefin
Me
Me Br O Na/NH3 OH MeOH, 62%
Me O Me CrO3 OH pyr
Me O Me Cuprate Reaction Intramolecular Aldol Reaction Me2CuLi O
Me Me 1. LiAlH4 O OH Me 2. TsCl, pyr 97%
Me Me OTs H OH Me base 100%
Fragmentation Reaction
Me Me O Me H2, Pd-C 89%
Me Me O Me steps
Me Me
Me
448
Me H H O O H2, Pd-C 85% O
O O
Hydrogenation - known conditions to give cis stereochemistry - H2 comes in from less hindered face - heteroatoms can also direct H2 to their face
69%
O O Acid-catalyzed Elimination - cis-ring fusion prefers 2,3 double bond - trans-ring fusion prefers 3,4 double bond - known from steroid chemistry
O O 1. MeMgBr 2. H2SO4 O H
Me 31%
H O O
Me
O H Me
O Me
m-CPBA
Me Me O H
Epoxidation - epoxidation from the least hindered face - no competitive Baeyer-Villiger at ketone - trisubstituted olefin more reactive than ketone
NaO H
CH3
O S CH2Na O
Me OH O
Me O Me
Intramolecular Epoxide Addition - very slow epoxide opening due to steric encumbrance of Me group - benefits from irreversible nature of epoxide opening
Me
Alternate route attempted: Me 1. BH3-THF OOH 2. H2Cr2O7 Me Me Ph3CLi MeI Me Me O O CH2N2 AlCl3 failed ring expansion Me Me O O Alternate Route - hydroboration-oxidation gave ketone - methylation conditions specifically employed to avoid over-methylation - ring expansion with CH2N2 did not proceed
449
Modern Organic Chemistry The Scripps Research Institute A O major + minor + CH2 N N O O + O CH2 N N
N N
Diazomethane Ring Expansion - CH2N2 poor nucleophile - AlCl3 added to activate carbonyl - many side reactions possible - CH2N2 explosive, difficult to use - products equally reactive toward additional expansions/epoxidations
A O
+ major HC N N EtO2C O CO2Et OH CO2Et +
EtO2C O
N N Diazoacetate Ring Expansion - improvement over diazomethane - product in enol form and will not further react with reagent - reagent stable, transportable and readily available - ultimately employed in the later Ho synthesis Carbene Addition and Ring Expansion - singlet carbene has electrophilic character, and undergoes stereospecific reaction with olefins (no scrambling as observed with triplet carbene) - Br can donate electrons into the empty p-orbital, thus stabilizing the singlet carbene - cheletropic cycloaddition occurs with olefin geometry maintained via a 2s + 2a cycloaddition Disrotatory Ring Opening of Halocyclopropanes - leaving group will influence direction of ring opening - departure of LG simultaneous with disrotatory ring opening - substituents syn to the departing group will move towards one another while they move away from each other if anti leaving group. Since this system is confined to a 7-membered ring, the R groups must move toward each other to give the compact alkyl cation and it is the syn bromide that is lost
no reaction
CHBr3 +
KOtBu
:CBr2 H
C Br 2a 2s C Br
R + R
R R
R R H H X vs. R R H X H H R + R H H2O or Nuc H H disrotatory ring opening
R H + H R H disrotatory ring opening H H R R H OH R + R compact extended
450
Synthetic Analysis and Design Dale L. Boger H H Br Br Nuc H H Br Br NucH Br H Br H In Fused Bicyclic Systems - imposed geometry of ring controls opening and directs leaving group - nucleophile comes in trans to departing Br - exception: bicyclo[5.1.0]octane can give the trans double bond via outward rotation - Chem. Commun. 1967, 294. - Chem. Commun. 1968, 1593. - J. Am. Chem. Soc. 1970, 92, 2566.
Me
Br Br AgClO4 O H acetone-H2O 100%
Me Br O Me OH H McMurry Application - ring controls geometry of ring opening, thus only one bromine departs - nucleophile (OH2) enters trans to leaving Br - no trap at other end of allyl cation - possible assistance of C=O
Me Me
Br H
Me
Br H
O OH Me
Me
Me Br Na/NH3 O Me Me Me
O
Me OH OH H H Me Me Me Me2CuLi OLi OH Me Cuprate Addition - Intramolecular Aldol Reaction - cuprate adds in Michael fashion to generate enolate - enolate then attacks carbonyl in intramolecular fashion Dissolving Metal Reduction - stereochemistry of reduced OH - most stable product - reduction of the vinyl halide
OH H
Me
Me Me OTs base 100% O Me H
Me Me
O
Fragmentation - reduction occurs from least hindered face - tosylation selective for 2 > 3
Me
451
Modern Organic Chemistry The Scripps Research Institute 4. Brieger Synthesis: (attempted)
J. Am. Chem. Soc. 1963, 85, 3783.
Diels-Alder Reaction Intramolecular Diels-Alder Reaction 1,5-Hydrogen Migration of Cyclopentadienes Me
Me OAc HCl(g)-HOAc 0 C, 50% Me Me Me
Me OAc
MgBr Et2O, 0 C 28% Me Me
OAc 175 C 48 h, 90% Intramolecular Diels-Alder Reaction
Cl
Me CO2Me
Me
Me O OAc Me Me 90% TMSO Snowden Tetrahedron Lett. 1981, 22, 98 and 101. OAc Me but H H Me 94% Me CO2Me
Me 0%
Me Me OAc MgBr Et2O, 0 C 28% Me Me Cl Me Me OAc Grignard Addition - alkylation at 3 center! - nonbasic reagent, E2/E1 elimination not observed
R H R 1,5-H shift H H R H H
1,5 H-Shift - proceeds at 0 C - causes failure of desired [4 + 2] cycloaddition for longifolene above
OAc H H
OAc H H
OAc Intramolecular Diels-Alder - at 175 C, all three 1,5-H shift products present - provide three different possible products - only one product observed
Me
Me Me
Me Me 90%
Me
Me OAc Me
OAc Me Me Me Me Me
Me
OAc
452
Synthetic Analysis and Design Dale L. Boger 5. Johnson Synthesis:
J. Am. Chem. Soc. 1975, 97, 4777.
Organocuprate 1,4-Addition Regiospecific Enolate Trap Cation-Olefin Cyclization Me
Me (Me CuLi
2
2. CH3COCl 84% O Cuprate Conjugate Addition Regiospecific Enolate Trap Me Me OAc
MeLi Br2, 1 equiv O Br
ArCO2NR4 acetone, 76%
LiAlH4 ether, 0C 92% O HO H
CF3CO2H ether, 0 C 75% Cation-Olefin Cyclization
Me HO
Me 2 equiv ZnBr2 NaCNBH3 94%
Me
Me
Me
Me RuO4 (cat.) NaIO4, 72%
Me
Me O LDA MeI
p-TsOH 25 C, 0.5 h 91%
Me
Me O steps
Me
Me
Me Me Me HO
Me
Me Cation-Olefin Cyclization - 2 allylic alcohol for initiation site
CF3CO2H ether, 0 C 75% HO H
Me
Me
Me
Me
Me
Me
453
Modern Organic Chemistry The Scripps Research Institute 6. Oppolzer Synthesis:
J. Am. Chem. Soc. 1978, 100, 2583. Helv. Chim. Acta 1984, 67, 1154.
Enamine Acylation Photochemical [2 + 2] Cycloaddition Retro-Aldol Reaction Wittig Reaction Simmons-Smith Cyclopropanation Hydrogenation of Cyclopropanes Classical Resolution via Crystallization of Diastereomeric Salts
O O N
Cl HO O 87% PhCH2O2CO PhCH2OCOCl pyr O h, pyrex 83% [2 + 2] Photochemical Cycloaddition O Ph3P=CH2 88% Zn-Ag CH2I2, 78% Simmons-Smith Cyclopropanation Me Me O LDA MeI Me Me Me O steps
Enamine Acylation
OCO2CH2Ph O 10% Pd/C , H2 HOAc, 25 C, 18 h Retro-Aldol
H2, PtO2 HOAc, 96% Cyclopropane Hydrogenation
Me
Me
Me
CO2H
optically active starting material
H2N
Me classical resolution recrystallization of diasteromeric salt
454
Synthetic Analysis and Design Dale L. Boger 7. Schultz Synthesis:
J. Org. Chem. 1985, 50, 916.
Birch Reductive Alkylation Retro Cheletropic Cycloaddition 1,3-Dipolar Cycloaddition Vinylcyclopropane Rearrangement Asymmetric Synthesis via Substrate Chiral Auxiliary
Me I OMe CO2Me
Me CH(OMe)2 OMe CO2Me Me Me CH(OMe)2 Ph H 2N N O O CO Me 2 CH3CONHBr MeOH, 95% MeO Br OMe CO2Me Me Me CH(OMe)2 110 C DBN, tol
2.5 equiv K in NH3 1.0 equiv tBuOH 78 C to 25 C 98% Birch Reduction-Alkylation
CO2Me Me Me CH(OMe)2
p-TsOH
acetone, 86%
CO2Me Me Me CHO
Ph toluene, 110 C 43%
Me N N Me
h 366 nm N2
O CO2Me 140 C xylenes Me Me Vinylcyclopropane Rearrangement O Me
Retro-Cheletropic Cycloaddtion 1,3-Dipolar Cycloaddition 40% overall Me H2, Pd/C 92% O CO2Me Me Me KOH, 25 C MeOH-H2O 85% CO2Me 90% from 1,3dipolar cycloadduct Me Me steps O H CH(OMe)2 O N O H HCl/MeOH Me
O CO Me 2
Me
Me 110 C O toluene 86%
Me
Me
CO2H
O N O H
Me I
Me CH(OMe)2
Me Me
Me Me
CHO O O O H HHCl N
from (S)-proline
2.5 equiv K in NH3 1.0 equiv tBuOH 78 C to 25 C 98% Me Me CHO O O O O H N OMe
MeO CO Me 2 1. HCl, CH(OMe)3 2. NaOMe, MeOH Me Me CH(OMe)2
MeOCOCl
455
Modern Organic Chemistry The Scripps Research Institute Ph H2N N O CO2Me Me Me CHO retro cheletropic cycloaddition with loss of stilbene O Ph toluene, 110 C 43% N N Me O CO Me 2 Retro Cheletropic Cycloaddition and Subsequent 1,3-Dipolar Cycloaddition
Me
O CO2Me Me Me N
CO2Me Me Me N N Ph Ph
CO2Me Me Me N
O CO Me 2 h -N2
O CO Me 2 140 C Me Me xylenes
Me
Me O
Vinylcyclopropane Rearrangement - 1,3-sigmatropic rearrangement
Me N N Me
CO2Me
Me O CO2Me
Me O
CO2Me
- This sequence is equivalent to adding the elements of a carbene 1,4 across a diene - Is this 4e + 2e cycloaddition possible? Consider the WoodwardHoffmann rules.
456
Synthetic Analysis and Design Dale L. Boger 8. Fallis Synthesis:
J. Am. Chem. Soc. 1990, 112, 4609. J. Org. Chem. 1993, 58, 2186.
Intramolecular Diels-Alder Reaction Barton Free Radical Deoxygenation Reaction Acetate Pyrolysis Chromatographic Resolution through Diastereomeric Derivatization (Starting Material) OMe H O ClCd 73%
MeLi 65%
OH
MnO2 81%
O O
resolution via diastereomeric derivatization Me MeOH, BF3OEt2 heat. toluene 83 x 97% Intramolecular Diels-Alder Reaction Me Me OMe O O 1. H2, Pd-C, 99% 2. LiAlH4, 96% 3. Ac2O, 74% Me Me Me OMe AcO OH ClC(=S)OPh Bu3SnH, 71%
Barton Free Radical Deoxygenation Me
Me
Me OMe AcO 1. NaI-TMSCl 2. ClC(=S)OPh Bu3SnH, 50%
Me
Me AcO pyrolysis 525 C, 56%
Me
Me
Me Acetate Pyrolysis
Me
Barton Free Radical Deoxygenation
MeLi 65%
O Me
MeLi 65%
OH 3-exo-tet cyclization
OH
O S O
OPh
AIBN Bu3SnH
OPh SSnBu3 H Barton Free Radical Deoxygenation - mild method for removal of alcohols
SnBu3 OPh SSnBu3 Bu3SnH
CH3 O H O + CH3 HO O
Acetate Pyrolysis - a retro ene reaction - comparable to the sulfoxide syn elimination (Trost) which is activated by an adjacent EWG. - comparable to the selenoxide syn elimination (Reich) which is milder, faster and proceeds at lower temperature
457
Modern Organic Chemistry The Scripps Research Institute O O O MeOH BF3OEt2 O
Intramolecular Diels-Alder Reaction - constraints of the 6-membered ring precludes reaction from the other cyclopentadiene isomers and lactone stereochemistry dictates -facial selectivity
OMe
O OMe Me
O OMe Me toluene microwave 2.5 h, 97% Me
Me OMe O O
Me OMe O O
Me
Me
Me OMe O O
Me
Me OMe O O
Me
Me
H OH MnO2 81% O
- MnO2 serves to oxidize cyclopropyl alcohol analogous to allylic alcohol oxidation
H NuO 9:1
Me Me
"conjugated" cyclopropane conformation Nu
- Cadmium reagent for -versus -enolate reaction - Diastereoselective addition OMe O ClCd
R O Me MeI + R O SiMe3 H3O+
SiMe3 R O Me I R O H
NaI-TMSCl deprotection - dealkylative SN2 methyl ether deprotection
458
Synthetic Analysis and Design Dale L. Boger 9. Kuo Synthesis:
Can J. Chem. 1988, 66, 1794.
Intramolecular Aldol Addition Wagner-Meerwein Rearrangement
1. Br2, HBr, HOAc 2. Br2, ClSO3H O
I O NaCN, DMSO 70 C
NC O O TMSO
1. LDA Br
3. Zn, HOAc O 4. KI, DMSO, 110 C 5. TMSCl, HOCH2CH2OH
2. K, HMPA
TMSO O O 1. HCl 2. PDC, CH2Cl2
MeO LDA, 78 C MeO O TMSCl
MeO TiCl4, 78 C MeO TMSO
3. HC(OMe)3, CeCl3
1. Ca/NH3 O MeO 2. Ac2O, DMAP Intramolecular Mukaiyama Aldol MeO H OAc
1. BBr3, NaI 2. PDC, CH2Cl2 3. Ph3P=CHBr, BuLi, 78 C 4. LiAlH4 H OH
Et2Zn CH2I2
H2/Pt H OH HOAc, 2.5 atm H OH
PCC CH2Cl2 O
LiAlH4
Me MeSO2Cl, pyr HO H DMAP, 100 C Wagner-Meerwein Rearrangement Me
Me
Me HO H MeSO2Cl, pyr DMAP, 100 C Me
Me Wagner-Meerwein Rearrangement
Me MsO * H * Me
Me H
459
Modern Organic Chemistry The Scripps Research Institute 10. Ho Synthesis:
Can J. Chem. 1992, 70, 1375.
Ethyl Diazoacetate Ring Expansion Alkylative Esterification
O + benzene O O 80 C, 67% O O H2SO4 53%
O CO2H O
H2SO4 MeOH, 100%
Eaton's Acid O CO2Me O H2, Pd-C 98% NaOMe O CO2Me MeOH, reflux O 93% O O CO2Me P2O5 Me3SO3H 65 C, 82% Acylium ion CationOlefin Cyclization Me2CuLi 0 C, 96% O CO2Me O CO2Me N2CHCO2Et BF3OEt2, 100% Ring Expansion O CO2Me both isomers present Me 1. NaBH4, 82% 2. MsCl, Et3N, 85% O CO2Me both isomers present OMs CO2Me both isomers present Me CO2Et LiI, H2O collidine reflux, 90% O CO2Et NaI, Zn reflux <50% OMs
Me
Me K2CO3 MeI, acetone O CO2H both isomers present 95% O
Me
Me
Me
Me KOH reflux 100% CO2Me
Me
Me 1. MeLi. 87% 2. CF3CO3H. 48% 3. NaOH, 93% 4. PCC, 86% Baeyer-Villiger
Me
Me O longifolene
CO2H
ICO2Et O CO2Me LiI, H2O collidine reflux, 90%
Me
Me K2CO3 MeI, acetone O 95%
Me
Me - SN2 Dealkylative Deesterification followed by decarboxylation of the -keto acid - Alkylative Esterification
HO2C
O CO2Me
460
Combinatorial Chemistry Dale L. Boger
XIV. Combinatorial Chemistry Combinatorial Chemistry Reviews

A Practical Guide to Combinatorial Chemistry; Czarnik, A. W. and DeWitt, S. H., Eds.; ACS: Washington, D. C., 1997. Molecular Diversity and Combinatorial Chemistry: Libraries and Drug Discovery; Chaiken, I. N.; Janda, K. D., Eds.; ACS: Washington, D. C., 1996. Balkenhol, F. et al. Combinatorial Synthesis of Small Organic Molecules. Angew. Chem., Int. Ed. Eng. 1996, 35, 2288. Ellman, J. A. et al. Synthesis of Small Molecule Libraries, Chem. Rev. 1996, 96, 555. Gallop, M. A. et al. Applications of Combinatorial Technologies to Drug Discovery, 1. Background and Peptide Combinatorial Libraries, J. Med. Chem. 1994, 37, 1233. Gordon, E. M. et al. Applications of Combinatorial Technologies to Drug Discovery, 2. Combinatorial Organic Synthesis, Library Screening Strategies, and Future Directions., J. Med. Chem. 1994, 37, 1385. Pavia, M. R., Sawyer, T. K. and Moos, W. H., Eds. The Generation of Molecular Diversity, Bioorg. Med. Chem. Lett. Symposia-in-print no. 4. 1993, 3, 381.
Solid Phase Peptide Synthesis

Cl R1 O O R1 O O O R1 O O O N H R1 O HO O N H H N R2 O H N R2 O N H NHCBz R2 NHCBz
Attach first amino acid to (chloromethylated) polymer bead Deprotect (HBr), Couple (DCC), Cap (acetic anhydride)
R3 O N H R3 O N H NH2 R4 NHCBz R4
Repeat coupling cycle
Deprotect, Saponify, Purify
Allows excess of reagents and reactants to force reaction to completion Removal of reagents, reactants and byproducts by filtration Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149. Nobel Prize, 1984 "for his development of methodology for chemical synthesis on a solid matrix"
461
Tea-Bag Method
.......... .......... .......... .......... .......... .......... .......... .......... XXX
Seal Mesh Opening
10 to 20 mg of 248 different 13-residue peptides Sequence 1. Deprotect 2. Wash 3. Couple 4. Wash 5. HF Cleave
Resin Code
Wash
Houghten, R. A. et al.Proc. Natl. Acad. Sci. USA 1985, 82, 5131.
Multipin Peptide Synthesis

Pin
reagents, reactants in wells
Synthesize on polyacrylategrafted polyethylene rods Utilize conventional solid phase synthesis methods
growing peptide on a pin
Preparation of up to 10,000 spatially separate compounds using inexpensive equipment and readily available automation
Individual pins 96-Well Plate with crowns (1 to 7 mol loading capacity)
Geysen, H. M. et al. Proc. Natl. Acad. Sci. USA 1984, 81, 3998. Zuckermann, R. N. et al. Bioorg. Med. Chem. Lett. 1993, 3, 463.
462
Split and Mix Solid Phase Synthesis (Split-Method, Portioning-Mixing Method)

A1 A
2
A3
A1 B1
A1B1 A2B1 A B
3 1
A2 B2
A1B2 A2B2 A B
3 2
A3 B3
A1B3 A2B3 A B
3 3
Solid support is divided before each coupling cycle - Mix - Split - React Equimolar mixtures of peptides Cannot conduct direct mixture synthesis on solid phase due to differential reaction rates One unique peptide on each bead - Mix - Split - React
N = n1 x n2 x n3 x ..... nm N = number of products after each cycle n = number of reactants in each cycle
C
A1B1C1 A2B1C1 A3B1C1 A1B2C1
C2
A3B3C1
A3B3C2
A3B3C3
Furka, A. et al. Bioorg. Med. Chem. Lett. 1993, 3, 413;
Int. J. Peptide Prot. Res. 1991, 37, 487.
Generation of Combinatorial Antibody Libraries

Use of bacteriophage lambda vector to express in E. coli a combinatorial library of Fab fragments Sequence: First step: Separation of heavy and light chain libraries which are constructed in Hc2 and Lc1 Second Step: Combination of two libraries are combined at the antisymmetric Eco R sites present in each vector This results in a library of clones each of which potentially coexpresses a heavy and a light chain
Lerner, R. A. et al. Science 1989, 246, 1275.
463
Phage Display
Helper Phage
Infection Outer Membrane Periplasmic Space pIII Inner Membrane
Extrusion
The general concept is one in which a library of peptides is presented on the surface of a bacteriophage such that each phage displays a unique peptide and contains within each genome the corresponding DNA sequence Introduction of randomized DNA into gene III of filamentous phage Expression of the corresponding peptides at the N terminus of the absorption peptide (pIII) Very quick and efficient generation of large combinatorial libraries of peptide fragments Screen by panning and enrichment
Peptide-pIII
ssDNA
PeptidepIII Peptide Library pIII
Phage DNA
Identify by DNA sequence Smith, G. P. et al. Science 1990, 249, 386.
Phagemid DNA
Very Large Scale Immobilized Polymer Synthesis (VLSIPS)

Lithographic Mask
h
X NH X NH X X
PhotoDeprotection
NH2 NH2 X X NH NH NH NH
X-A Chemical Coupling
Light-directed spatially addressable parallel chemical synthesis Nitroveratryloxycarbonyl (NVOC) as a photolabile protecting group
h
X A NH X A NH X NH X NH X A NH X A NH X X
X-B Chemical Coupling
OMe O OMe O2N
X=
NH NH
E X A NH X A NH X B NH X C B
F D A NH
E C B NH
F D B NH
Binary masking yields 2n compounds in n chemical steps
Repeat
NH
A NH
Fodor, S. P. A.; Pirrung, M. C. et al. Science 1991, 251, 767.
464
Solid Phase Synthesis of 1,4-Benzodiazepines

Application of solid-phase combinatorial synthesis to non-oligomeric compounds
O R1 Cl
: solid phase attached to linker
Si
SnMe3 NHBoc
1) R1
Pd0
Si
O NH2 O NHFmoc R2
2) TFA, CH2Cl2
"traceless" linker
R1 N R2 N R3 O Si R
1
1) F
2) Piperidine
R1 N R2 N R3 O Si
HF Me2S
1) 5% HOAc, 65 C
2) Ph
O NH O R2 NH2
N O
OLi
3)
R3I,
DMF
Ellman, J. A. et al. J. Am. Chem. Soc. 1992, 114, 10997. DeWitt, S. H. et al. Proc. Natl. Acad. Sci. USA 1993, 90, 6909.
Resin Release Only of Product

R1 R 2 R1 R 2
R1 R2 O O NHBOC
1. TFA 2. R3 NCO
O O HN R3
NH O
HCl,
O N R3
NH O
Hydantoins
The desired heterocycles are formed by acid-catalyzed cyclization with concomitant cleavage from the solid support
R1 O R1 O O NH2 R2 R3 R4 N N R2
NH NHR4 R
3
N O R2 NHR4
TFA,
R3
R1
Benzodiazepines
DeWitt, S. H. et al. Proc. Natl. Acad. Sci. USA 1993, 90, 6909.
465
Split Synthesis ENCODED with Tagging Molecules ( T1T4 )

Separate Beads into 3 Groups OH A+ C+ B+ 1%T1 1% T1 + 1% T2 1% T2 T1 T2 OB T2 OA OC
Tagging Molecules 1. Chemically inert 2. Encoding by attachment to the beads 3. After release, analyzed by Capillary Gas Chromatography using Electron Capture Detection (ECGC) on femtomolar scales from single beads 4. Identity only
(CH2)n N2CHCO O OMe O O HOOC NO2 Linker Cl Ar = Cl Cl Cl Cl Cl H Electrophoric Tag Cl H Cl Cl H Cl H F O ( )n O Ar O Clm n = 211 m = 25
T1
Mix Beads and Divide again into 3 Groups T1 T2 T1 OA OB T2 OC X+ 1% T3 T1 T3 T2 T3 O-AX O-BX Y+ 1% T4 T1 T4 T2 T4 T1 T2 O-AY O-BY O-CY T4 Z+ 1% T3 + 1% T4 T T3 1 O-AZ T4 T T3 2 O-BZ T4 T T2 1 O-CZ T3 T4
T1 O-CX T2 T3
Still, W. C. et al. Proc. Natl. Acad. Sci. USA 1993, 90, 10922; Acc. Chem. Res. 1996, 29, 155.
Nucleotide Encoding
1. A1 2. N1 1. A3 2. N3
1. A2 2. N2 N2 A2 mix
CPG beads Linker Unit
N1
A1
N3 1. A3 2. N3
A3
PCR Primer A1, A2, A3: Amino Acids N1, N2, N3: Encoding Nucleotides
1. A1 2. N1
1. A2 2. N2 N 2N 1 N 2N 2 N 2N 3 A 1A 2 A 2A 2 A 3A 2
Tag attached to molecule, not bead N 1N 1 N 1N 2 N 1N 3 A 1A 1 A 2A 1 A 3A 1 N 3N 1 N 3N 2 N 3N 3 A1A3 PCR enrichment: sensitivity and screening by panning and enrichment A 2A 3 Bonus: nucleotide tagging could be used for identification as well A 3A 3
Janda, K. D. et al. J. Am. Chem. Soc. 1993, 115, 9812. Brenner, S.; Lerner, R. A. Proc. Natl. Acad. Sci. USA. 1992, 89, 5381.
466
Peptide Encoding
Fmoc Ddz B: Fmoc protected, base-labile monomers C: Ddz-protected, acid-labile monomers, which give reproducibly strong signals upon Edman sequencing
=
Distribute resin into n portions Deprotect Fmoc Couple "binding" monomer Bn B1 Ddz B2 Ddz Bn Ddz
FmocHN
O HN MeO O
NHMoz Resin
Deprotect Moz or Ddz Couple "coding" monomer Cn B1 C1 B2 C2 Bn Cn
OMe
Repeat Mix
Identity only
Zuckermann, R. N. et al. J. Am. Chem. Soc. 1993, 115, 2529.
Electronic Encoding
Radiofrequency memory chips allow libraries to be tagged in a machine-readable form The chips (8 x 1 mm) can be incorporated into various reaction platforms (e.g. beads, tubes, bags, pins or cans) Control logic Transmitter and receiver Antenna
Rectifier Memory encoding A B C
Glass Housing
Nova, M.; Nicoloau, K. C. et al. Angew. Chem., Int. Ed. Eng. 1995, 34, 2289. Armstrong, R. W. et al. J. Am. Chem Soc. 1995, 117, 10787.
467
Noncovalent Color-Coding Strategy
A1
A8
A1B1
A1B12
8 different subunits A1A8 are linked to resin each A is then partitioned into 12 Porous Containers (PCs) with different cap colors a small amount of colored bead (one color for each A) is added to each PC the PCs are grouped by cap color and subunit B is attached
A8B1
A8B12
all 96 PCs are combined subunit C is added to each
96-well plate
bead color
compounds are sorted individually by cap and bead color
A1B1C
A2B1C resin is cleaved products are filtered into a separate 96-well plate
cap color
A1B2C
A8B12C
Guiles, J. W. et al. Angew. Chem., Int. Ed. Eng. 1998, 37, 926.
One-Step Mixture Synthesis and Deconvolution "Activated Core Approach"
Core molecules: 3 Tetraacid chlorides
Building blocks: 19 amino acids
Library size: A1: 11,191 A2: 65,341 A3: 1,330
Deconvolution by Omission Resynthesis 1. Libraries A1A3 to find best core molecule 2. Sublibraries B1B6 to find best 9 building block amino acids (AA) 3. Sublibraries C1C7 to check if the selected 9 AA are the best combination 4. Sublibraries D1D9 to find the best 5 AA 5. Sublibraries E1E7 to find the best 3 or 4 groupings of the 5 AA 6. Sublibraries F1F6 to find the best relative position of the 4 AA on the core 7. Single compounds G1G3 synthesized and the best inhibitor of trypsin determined Rebek, J. Jr., et al. Chem. Biol. 1995, 2, 171.
468
Multicomponent One-Step Mixture Synthesis

O NH2 R1 R2 CHO OH CN R3
O N
R1
O N H R3
removal from resin affords pure compounds
O H N
R1
O N H R3
solid support
R2
Libraries of single compounds 4 components 20 structural variants/input 160,000 compounds generated
resin capture excess/unreacted starting materials and byproducts removed by filtration
O H N
R1
O N H
R2
resin capture AcCl

R1 O H N R2 O O
OH
new synthesis
Armstrong, R.W. et al. Acc. Chem. Res. 1996, 29, 123. Ugi, I. et al. Endeavour 1994, 18, 115.
Multistep Solution Phase Synthesis of Combinatorial Libraries Purification via Liquid/Liquid or Liquid/Solid Extraction
O CO2H BOC N CO2H O
EDCI
BOC N
Solvent, reagent byproducts, excess reagents and reactants removed through extraction with acid and/or base Liquid/solid extraction using ion exchange resins Products pure irrespective of yield 2550 mg of products Multistep synthesis in format of: - individual compounds - small mixtures - large mixture synthesis
1st diversification
R1NH2
BOC N
CO2H CONHR1
2nd
diversification
R NH2
BOC N
CONHR2 CONHR1 CONHR2 HClHN CONHR1
PyBOP HCl
3rd diversification
R3CO2H PyBOP
O N R3
CONHR2 CONHR1
Boger, D. L. et al. J. Am. Chem. Soc. 1996, 118, 2567.
469
Multistep Convergent Solution Phase Combinatorial Synthesis

O CO2H BOC N CO2H O
EDCI
BOC N O
R1NH2
CONHR1 BOC N CO2H
R2NH2 PyBOP
CONHR1 BOC N CONHR2
(1) HCl (2) PyBrOP

CO2H BOC N CO2H
The synthesis of large molecules is possible in only a few steps

R1HNOC N R2HNOC N BOC O O N CONHR2 CONHR1
Purification at each step by acid/base extractions or solid/liquid extractions Solution phase only
R1HNOC N R2HNOC
O N X
O N
CONHR1 CONHR2
Multiplication of diversity Final dimerization has been achieved via peptide coupling with diacids or olefin metathesis
3HNOC
N N N O O
CONHR3 CONHR4
R4HNOC
Boger, D. L. et al. Tetrahedron 1998, 54, 3955. Boger, D. L. et al. Bioorg. Med. Chem. 1998, 6, 1347.
Linear, divergent synthesis with mutiplication of diversity (solid or solution phase)
Sequential, linear oligomer synthesis Sequential, linear template functionalization

FG3 FG4 FG3 FG4 FG3 FG4 FG4
FG2
FG1
FG2
FG3
Convergent synthesis with multiplication of diversity (solution phase only) receptor activation FG3 FG3 agonists antagonists
FG1 FG2
FG2
FG3
FG3
FG3
FG2
FG1
FG2
Boger, D. L. et al. Tetrahedron 1998, 54, 3955; J. Am. Chem. Soc. 1998, 120, 7220.
470
Polymer Supported Scavenging Reagents
I. polymer-supported stoichiometric reagents

A XB (>1eq) A-B + X filter A-B
Solve the purification problem in mixture

synthesis
II. polymer-supported catalytic reagents

A + B X (<1eq) A-B + X filter A-B
Entrain impurities upon completion of

solution-phase reactions, either covalently or ionically Covalent scavengers: nucleophile-electrophile Ionic scavengers: a series of anion and cation exchange resins (liquid-solid extraction)
III. polymer-supported scavenging reagents (excess reagents, starting materials)

A + B A-B + Y Side A-B + Products filter A-B X
Boger, D. L. et al. J. Am. Chem. Soc. 1996, 118, 2567. Flynn, D. L. et al. J. Am. Chem. Soc. 1997, 119, 4874. Hodges, J. C. et al. J. Am. Chem. Soc. 1997, 119, 4882. Kaldor, S. W. et al. Tetrahedron Lett. 1996, 37, 7193.
Resin Capture of Product ("Fishing Out" Principle)

Libraries of -amino alcohols are synthesized by parallel synthesis in solution Purification is achieved by "fishing out" the desired products with a PEG-bound dialkylborane Precipitation of the polymer-bound product allows the removal of unreacted starting materials and any byproducts Treatment with HCl releases the product from the polymer support in high purity
Cl R1 O R1 R2 NH2 O R1 OH
phenol or sulfonamide
H B R
1
(Not purified)
1 or 2 amine
N H
R2
Impure mixture
N R2
HCl
R1 OH
N H
R2
(PEG Polymer) purify by precipitation/filtration
Pure product
Janda, K. D. et al. J. Org. Chem. 1997, 63, 889.
471
Resin Release Only of Product

OH O Cl R1 HN R2 O
A wide range of 3 amines can be synthesized on solid support

O
O O
R1 N R2
The product is released via -elimination Only the activated (quaternary) product is released, ensuring purities >95% After cleavage of product, the resin is regenerated and can be reused
R 3X
i-Pr2NEt
O R1 R3 N R2 O
+ R1 N 2 R R3
Morphy, J. R. et al. J. Am. Chem. Soc. 1997, 119, 3288.
Iterative Deconvolution
SURF Deconvolution
(Synthetic Unrandomization of Randomized Fragments)
XXX
Iterative deconvolution was first applied to peptide libraries The SURF procedure was described for nucleotide libraries Libraries are synthesized on solid phase by split synthesis
AXX
BXX
CXX
Repetitive synthesis and screening of increasingly simplified sets. At each step of the deconvolution an additional position is known
AAX
ABX
ACX
Activity increases at each step, enhancing the accuracy of identification Most potent library member guaranteed to be found and multiple hits lead to multiple parallel deconvolutions
ACA
ACB
ACC
Time between synthesis of libraries and hit identity long and cumbersome Houghten, R. A. et al. Nature 1991, 354, 84. Ecker, D. J. et al. Nucleic Acids Res. 1993, 21, 1853.
472
Recursive Deconvolution
The library (XXX) is synthesized by split synthesis At each stage 1/3 of the material is stored and labeled as a partial library These stored partial libraries are used to deconvolute the full library
XXA
XXB
XXC
Test 3 pools for activity Couple A to saved and catalogued XA, XB, and XC
XAA
XBA
XCA
Test 3 pools for activity Couple BA to saved and catalogued A, B and C Test 3 pools for activity Janda, K. D. et al. Proc. Natl. Acad. Sci. USA 1994, 91, 11422.
ABA
BBA
CBA
Positional Scanning of Synthetic Peptide Combinatorial Libraries
Deconvolution libraries produced upfront for testing Identifies most active residue at each position in one round of testing Screen looking for increases in activity This combination is not always the most potent (ca. 2040% of time) Best for identifying multiple hits in a library including weak activities Requires mixture synthesis, not suited for solid phase
O1 X X X X X
X X
X X X
X-NH2 X-NH2 X-NH2 X-NH2
X O2 X X X X
X O3 X X X
X O4 X X
X O5 X-NH2 X O6-NH2
O = individual component X = mixture
Houghten, R. A. et al. Nature 1991, 354, 84.
473
Deletion Synthesis Deconvolution

Deconvolution libraries produced upfront for testing Identifies most active residues at each position in one round of testing Screen library for loss of activity versus full mixture Best at identifying potent hits in a library, poor at identifying weak or multiple hits Requires mixture synthesis, not suited for solid phase Also suited for symmetrical libraries not capable of being addressed by scanning deconvolution
dA1 X X X dA2 X X X dA3 X X X dA4 X X X X dB1 X X X dB2 X X X dB3 X X X dB4 X X dA1 X

= mixture
X X X X X X X X
X dC1 X X dC2 X X dC3 X X dC4 X X X dD1 X X dD2 X X dD3 X X dD4
= mixture minus A1 (delete A1)
Boger, D. L. et al. J. Am. Chem. Soc. 1998, 120, 7220.
Solid Phase or Solution Phase Combinatorial Synthesis? Solid Phase Solution Phase + Simple removal of excess reagents + Chemistry not limited by support or
and reactants linker
+ + +
Automation straightforward Split and mix synthesis Pseudo-dilution effects Adapt chemistry to solid phase and develop linking/cleaving strategies Reaction monitoring difficult No purification possible Linear, cannot conduct convergent synthesis Limited scale Cannot conduct mixture synthesis
+ + + + + + +
Monitor by traditional techniques Purification possible after each step Unlimited amounts (scales) available Avoids extra steps for linking, etc Automation by liquid-liquid techniques Mixture or parallel synthesis Convergent or linear synthesis Removal of excess reagents and reactants limits scope
474
Combinatorial Synthesis Using Soluble Polymers

Reactions were performed in the homogeneous liquid-phase solution using soluble polymer (MeO-PEG: polyethylene glycol monomethyl ether) Homogeneous reaction conditions overcome the difficulties of solid-phase combinatorial synthesis Isolation can be accomplished by precipitation at each stage Intermediates can be purified by conventional means (e.g. chromatography) Analysis of intermediates is possible by conventional means (e.g. NMR)
MeO-PEG-OH +
O C N O O S O Cl
cat. Dibutyltinlaurate CH2Cl2
MeO-PEG-O HN
O S O Cl
R-NH2, pyridine CH2Cl2

O O H2N S O NHR MeO-PEG-O HN O S O NHR
0.5 N NaOH
Janda, K. D. et al. Proc. Natl. Acad. Sci. USA 1995, 92, 6419.
Fluorous Phase Combinatorial Synthesis

Fluorous liquids: Immiscible with both water and organic solvents Simple purification of products by three-phase liquidliquid extraction Accomplishment of a series radical addition by homogeneous fluorous-phase combinatorial synthesis Reagents on fluorous phase Substrates on fluorous phase
(C6F13CH2)3SnH, AIBN R I
+
E CF3 7292%
R E
Fluorinert Fluid F-77 PhCO2C3H7 + PhCH2OH tol/c-C6H11CF3 C6H13CH2CH2CF3)3P Rh(CO)2(acac) PhCO2CH2Ph + C3H7OH C8H17CH(CHO)CH3 + C10H21CHO
C8H17CH=CH2 + CO
Curran, D. P. et al. J. Am. Chem. Soc. 1996, 118, 2531; Chemtracts, Org. Chem. 1996, 9, 75. Angew. Chem., Int. Ed. Eng. 1998, 37, 1175.
475
A Combinatorial Approach to Materials Discovery

Application of the combinatorial approach to the discovery of new solid-state materials with novel physical or chemical properties such as magnetoresistance or high-temperature superconductance. Substrates: polished MgO or LaAlO3 single crystals Sputtering Targets: CuO, Bi2O3, CaO3, PbO, SrCO3, Y2O3, and BaCO3 Generation of a 128-member binary library using 7 deposition-masking steps Superconducting materials: BiSrCaCuOx and YBa2Cu3Ox
(Binary masks used for library synthesis)
Schultz, P. G. et al. Science 1995, 268, 1738.
Comparison of Combinatorial Chemistry Techniques

Technique parallel synthesis mixture synthesis (scanning/deletion deconvolution) parallel arrayed mixture split and mix Single compound /mixture single mixture Speed of synthesis slow fast SAR retrieval fast slow (fast) moderate Utility lead optimization lead identification
mixture
moderate
lead identification
mixture (one compound per bead) mixture (one compound per bead) single
moderate
slow
lead identification lead optimization lead identification lead optimization lead optimization lead identification
chemically encoded mix and split mix and sort (microreactors)
moderate
moderate
moderate
fast
Guiles, J. W. et al. Angew. Chem., Int. Ed. Eng. 1998, 37, 926.
476

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I. II. III.

XIII. Synthetic Analysis and Design XIV. Combinatorial Chemistry

Conformational Analysis Dale L. Boger

fully eclipsed (synperiplanar) 3. Butane H3C H H CH3 H H

gauche (synclinal) H3C H H H CH3

eclipsed (anticlinal) H3C H H

staggered (antiperiplanar) H3C H H

G S 180 240 300 360

Egauche < Estaggered if X = OH, OAc and Y = Cl, F

2.88 kcal/mol (3.0 kcal/mol

3.40 kcal/mol 3.3 kcal/mol

3.90 kcal/mol 3.6 kcal/mol

4.70 kcal/mol 3.9 kcal/mol)

- Experimental - Simple prediction

2.88 kcal/mol (3.0 kcal/mol

1.98 kcal/mol 2.0 kcal/mol

1.07 kcal/mol 1.0 kcal/mol)

- Experimental - Simple prediction

B. Cyclohexane and Substituted Cyclohexanes, A Values (G)

H half chair (rel E = 10 kcal)

H H H twist boat (rel E = 5.3 kcal)

H half chair (rel E = 10 kcal)

- The gauche butane interaction is most often identifiable as 1,3-diaxial interactions.

0 gauche butane interactions

- Note on difference between iPr and tBu A values. H H H CH3 CH3

group can position H toward "inside,"

but tBu group cannot. Very serious interaction, 7.2 kcal.

Conformational Analysis Dale L. Boger

G = (9.0 kcal 3.6 kcal) = 5.4 kcal

CH3 H CH3 H CH3

0.9 kcal each

- Note on interconversion between axial and equatorial positions. H Cl H Cl

t1/2 = 22 years at 160 C

4 x (gauche interaction) 4 x (0.9 kcal) = 3.6 kcal

1 x (gauche interaction) 1 x (0.9 kcal) = 0.9 kcal

3 x (gauche interaction) 3 x (0.9 kcal) = 2.7 kcal

3 x (gauche interaction) 3 x (0.9 kcal) = 2.7 kcal

G = 1.87 kcal/mol (exp) G = 1.80 kcal/mol (calcd)

Modern Organic Chemistry The Scripps Research Institute

2 x (gauche interaction) 2 x (0.9 kcal) = 1.8 kcal

2 x (gauche interaction) 2 x (0.9 kcal) = 1.8 kcal

0 x (gauche interaction) 0 x (0.9 kcal) = 0 kcal

G = 1.80 kcal/mol (exp and calcd)

2 x (gauche interaction) 2 x (0.9 kcal) = 1.8 kcal

G = 3.7 kcal/mol (exp) So, Me-Me 1,3-diaxial interaction = 3.7 kcal/mol.

Conformational Analysis Dale L. Boger

E between cis- and trans-decalin = 2.7 kcal/mol

two conformations equivalent H H H H H H H H H H H CH3 H H H H H H H H H H H H H CH3 H H

4 gauche interactions 4 x 0.9 = 3.6 kcal

5 gauche interactions 5 x 0.9 = 4.5 kcal

E between cis- and trans-9-methyldecalin = 0.9 kcal/mol

Modern Organic Chemistry The Scripps Research Institute

F. Acyclic sp3-sp2 Systems

- Molecular orbital calculations: Repulsion of overlapping filled orbitals: Pitzer

Acc. Chem. Res. 1983, 16, 207.

Butcher, Wilson Allinger, Hickey Allinger Allinger Herschbach Geise

Houk, Hoffmann Hoffmann

2 rel E (kcal) 1 E 0 60 B E 120 180 B E 240 300 360 B

HH alkyl eclipsed relative energies (kcal) Exp 2.5

0.0 0.0 0.0

1.41.8 (2.6) 2.0

B2 B1 E2 60 H C H H 120 180 E2 240 300 B1 E1 360

HH eclipsed (E1) relative energies (kcal) Exp B1, B2 > E1 >> E2