STEREOSELECTIVE

AND TOTAL

SYNTHESIS
123.702

gareth j rowlands
 why d o we n ee d Total Synthesis?

AcO O OH
AcO
BzHN O

Ph O H
OH OH AcO O
taxol OBz
©Wsiegmund@wikimedia commons
 do we need
why
Asymmetric
Synthesis?
O
H
N

O
O N O
H

©Trois Têtes (TT)@Flickr

 pure
synthesis of

enantiomers important

Me
Me
NMe2
Me2N
O Ph
O Ph O
Et O
novrad
cough-suppr Et
essant darvon
painkiller
course outline
6 asymmetric synthesis
lectures

6 total synthesis
lectures

©natashalcd@Flickr
course no
tes
recommended
books
 ume 7 |
ber 9 | 20 Num
09

Number
16 | 2009
www.rs
c.org/obc
s 2053 –2224
ril 20 09 | Page
16 | 28 Ap
Number
ic ations
Volume Commun
Chemical
7 | Num
ber 9 | 7 May
2009 | Pa
ges 1737 comm
–1988 .org/chem
www.rsc

5/2009

ChemCo
D7903 · ASCAF7 · 351 (5) · 661–804 (2009) · ISSN 1615-4150 · No. 5, March 2009

mm
journals Showca si
laborato
ng re search fr
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rn Metho
di st
sor Brent
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Sumerlin
om Profes versity, USA.

ers
’s

c acid bloc
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m
As feature
d in:

Chemical
www.rsc.org
Communication
/chemcomm
s
Number
16 | 28 April
2009 | Pages 2053–2224

e boroni
ip ly-responsiv
Title : Tr e different
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By includi sponsive ntaining
ph re ni c”, triply-re a bo ro nic acid co
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ARTICLE Kita 09)16;1-0

polymeriza
FEATURE Yasuyuki a new
TION et al. Dohi and as 1359-7345(20
ISSN 1359-7345 COMMUNICA Seiji Shinkai Toshifumi reagents
Fujita, control the Hypervalent iodine sts
Norifumi system can to organocataly

capable of
An organogel al course of anthracene entrance

. RAFT co
stereochemiczation
photodimeri

obtained polymers bly being

le d to block co th e self-assem of the Jennifer N.
Cambre
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micelles,
w ith entra n
tio shish Roy, mmun.,
d reverse sugar conc See Deba Sumerlin, Chem. Co
micelles an , pH, and S.
mperature an d Brent
by th e te 06 .
COMMUN governed 2009, 21
Jennifer ICATION onment. FEATURE
ARTICLE suyuki Kita ;1-0
R. local envir ICATION Dohi and
Ya
s as a new 1359-7345
(2009)16
Fluoresce Hiscock et al. ISSN 135
9-7345 et al.
COMMUN jita, Seiji Shinkai rol the Toshifumi t iodine reagent

Pages 20
nt carbaz Fu nt len
receptor olylurea Norifumi gel system can co racene Hyperva catalysts
s to organo
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mcom
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stereochem zation

www.rsc
eri
photodim

53–2224
er 207890
Ch arity Numb
Registered
1477-052
0(2009)7
:9;1-6

Review:
Transition Metal-Catalysed, Direct and
ASC
5-Year Impact Factor 2007
Site-Selective N1-, C2- or C3-Arylation
5.193 of the Indole Nucleus:
The Cutting Edge
that Stays Sharp! 20 Years of Improvements
Lionel Joucla, Laurent Djakovitch
 lecture one
terminology
and
substrate control
 chiral object

©DrStarbuck @ Flickr
non-superposable
 chiral object
non-superposable
chiral compounds

O O

HS OH HO SH
H NH2 H2N H

non-superposable
chiral compounds

O O

HS OH HO SH
H NH2 H2N H

enantiomers
 achiral object

supe r p o sa b l e
achiral compounds

H OH

supe r p o sa b l e
achiral compounds

H OH

Me Me
plane of
symmetry
 O
CH3
HO
H NH2

naming:
see1
23.202
 O
3

2 CH3
HO
H
4
NH
1
2

groups CH3 NH2 H CO2H

1st atom C N H C
naming: 2nd atom H, H, H O, O, O

priorities priority 3 1 4 2
 O O
3 3

HO
2 CH3
≡ H3C 2
OH
H NH2 H2N H
4 1 1 4

naming:
lowest priority
points away
 3 2 2 3

1 1
S R
anticlockwise clockwise
right
naming:
 3 2
O
3
H3C CO2H
2
H3C
OH
1
H2N H 4 NH2
1

S S
naming:
finally... (S)-2-aminopropanoic acid
 O
S
t-Bu N
N
H Ph N N
Ru
non-carbon-based N N
chiral compounds N
O
P
Me OMe
same principals
other forms axia
of chirality
l

O O
O O

O O

O O
©MonkeyBoy69@flickr
 other forms axia
of chirality
l
PPh2
PPh2

Ph2P
Ph2P

©mugley@flickr
other forms helic
of chirality
al

P [8]helicene M [8]helicene
other forms
of chirality Ph Ph
Fe PPh2 Ph2P Fe

lanar
p
compounds with
2 stereocentres
or more

OH OH

NH2 NH2

enantiomers
compounds with
2 stereocentres
or more

OH OH

NH2 NH2

OH OH

NH2 NH2

diastereoisomers
compounds with
2 stereocentres
or more

OH OH

NH2 NH2

enantiomers
2 stereocentres
OH OH

NH2 NH2

OH OH

NH2 NH2
4
compounds
 3 stereocentres

OH OH OH OH
CHO CHO CHO CHO
HO HO HO HO
OH OH OH OH OH OH OH OH

OH OH OH OH
CHO CHO CHO CHO
HO HO HO HO
OH OH OH OH OH OH OH OH

8
compounds
n stereocentres

2n
compounds
this
is
a
!
generalisation!
2 stereocentres
OH OH
HO2C HO2C
CO2H CO2H
OH OH

OH OH
HO2C HO2C
CO2H CO2H
OH OH
3
compounds
2 stereocentres
OH OH
HO2C HO2C
CO2H CO2H
OH OH

OH OH
HO2C HO2C
CO2H CO2H
OH OH
3
diastereoisomers compounds
2 stereocentres
OH OH
HO2C HO2C
CO2H CO2H
OH OH

OH OH
HO2C HO2C
CO2H CO2H
OH OH
3
enantiomers compounds
2 stereocentres
OH OH
HO2C HO2C
CO2H CO2H
OH OH

OH OH
HO2C HO2C
CO2H CO2H

meso
OH OH
3
identical compounds
meso
compounds

OH
HO OH
HO2C
CO2H ≡ HO2C CO2H
OH
meso
compounds

HO OH

HO2C CO2H

achiral
of
plane
symmetry
enantiomers NH2 NH2
NH2 H2N
have identical
properties mp = 41-45°C
mp = 40-43°C
diast e reo isom ers NH2 NH2
NH2 NH2
have different
properties mp = 41-45°C
bp = 221°C
difference between
dia stereoisomers

key
toasymmetric
synthesis
 ow e measure
h do w

purity?

©brittanyculver@flickr
 =
NH2 NH2 NH2
NH2 H2N NH2

80% 20% 60%ee

enantiomeric excess (ee)
 = 4:1
NH2 NH2
NH2 H2N

80% 20%
enantiomeric ratio (er)
 NH2 NH2
NH2 NH2

80% 20%
diastereoisomeric excess 60% de

diastereoisomeric ratio 4 : 1 dr
 ow e measure
h do w

ee?

©brittanyculver@flickr
left and right
handed gloves

arei
d
entical
 you
til
un add a hand
chem istry
thesam
e

need
©David Reeves from Flickr diastereoisomers
chem istry
thesam R S
e

R R R S

need..
R S
diastereoisom ers
 covalent
derivatisation O
Ph
O H
OH DCC, F3C OMe
F3C OMe DMAP
iPr

Ph CO2H O
Ph
O H
F3C OMe
iPr
Mosher’s acid
7 3 J O C 2 1 4 3 & 9 1 J A C S 40 92
73JACS512,
 OTol
HO2C
OH CO2H OH
O O OTol
OTol O2C
NH NH2 CO2H
OTol

S diastereoisomer is insoluble
NaOH

OH
O

ionic (salt) NH

derivatisation
(–)-propranolol
β-blocker
temporary
interactions

O
O O
Si O
Si O H
O
O O Si N
Si O Me
Si O Si NO2
O Me O
O

NO2
silica chiral amine

chiral
©Pere Tubert Juhé@flickr ch rom atography
 asymmetric
©Tony the Misfit@flickr
synthesis
 O

O
H H
n-C4H9 O O
canadensolide3
2, 971 0 06, 6
©simpologist@flickr Tetrahderon, 2
substrate O
O

H H

control n-C4H9 O O

OH O
n-C4H9
OMe
OBn
O
OSiMe3 TiCl4 100%
n-C4H9
H OH O
OMe 77%
OBn n-C4H9
OMe
OBn
0%
100% de
©SarahWynne@flickr
C
ram
helation Cln
ontrol Ti
BnO O

n-C4H9
Me3SiO
H H

MeO
 Bürghi-Dunitz angle
OR
R
Nu RR
Nu Nu
repulsion

R R
C O C O
R R
π π*
C
ram
helation
ontrol
M
O O Nu OH
L M Z L
R R R
Z S S L Z S

Nu
C
ram
helation
ontrol
M
O O Nu OH
L M Z L
R R R
Z S S L Z S

Nu
L Z Z
O O OH L
Nu OH
Nu
Z S Nu S L S L Z S
R R R R
 Me
HO

O OH O

MeO
Me
HO
Me
HO OH OH
Me
Me O
Me

OMe

preswinholide 7
, 943
ron , 1 9 9 5 , 51
Tetra h de
©Ed Bierman@flickr
this isn’t the right sponge!
substrate
control
Me
t-Bu
O H Me
t-Bu Si t-Bu
O
O O
Me t-Bu Si Me
O OH
Me O TiCl4 Me
Me
94% Me O
95% de Me

OMe
OMe
Me3Si Me
why
Felkin-Ahn
model

O M S O

L L
Nu M H Nu
H S Nu
Felkin-Ahn
H OH
model Ph
Et
O Me H
EtMgBr 25%
Ph
H HO H
Me H Ph
Et
Me H
75% (50% de)
Felkin-Ahn
model

O Ph
O
Ph
H
≡
Me H Me H
H

draw
first...
Newman projection
Felkin-Ahn
model

Ph
O Ph O OH Me O
H Ph Ph
Me H Me H H Me HH
H

rotate
group
large
perpendicular
Felkin-Ahn model
Me O Me OH
Ph Ph
HH Et H
Et H

HO H Me OH
Ph
Et ≡ Et Ph
Me H H H
notthe whole
O
story
Ph
SMe
Zn(BH4)2 LiEt3BH

H OH HO H
iPr iPr
Ph Ph
SMe SMe
chelation
control
Zn
MeS O

iPr
H3B H H Ph
no
chelation
O iPr

MeS

Ph H H BEt3

electronegative element
perpendicular
carbonyl
sterics electronics

©Capt Kodak@flickr
substrate
control

O
n-C4H9
H OH O
TiCl4 n-C4H9
OBn
OMe
OSiMe3 OBn

OMe