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Chemistry 215
Second Examination
March 17th , 2015
1.5 hours; 120 points

15

Signature ________________________________
ID No. ________________________________

he

21

Instructors:
Dr. Meg Breen
Professor Anna Mapp
Professor Corey Stephenson

Prob

Pts

Score

GSI

28

\____/

_____

II

25

\____/

_____

III

20

\_____/ _____

IV

29

\_____/ _____

18

\_____/ _____

Total

120

\_____/ _____

Complete structures are required unless you are given other specific instructions. Bond-line notation is acceptable
unless otherwise specified. Do not forget to include important features such as nonbonding electron pairs and non-zero
formal charges unless explicitly excluded. Precision in drawing counts. Check all three-dimensional representations to
ensure you are implying an unequivocal direction of bonding. Individual point values are given in the corner of each
answer space. Include specific chemical formula or drawing for reagents.
The exam has 7 pages total. A pKa/information table is on the last page.

Name _____________________________________
W.15.215
Exam No. 2
Page 1
I. (28 pts)
Complete the following reaction schemes as indicated. Be sure to show stereochemistry where appropriate.
A) J. Org. Chem. 2015, 80, 2397.
O

1)
O

Draw one of the possible

diastereomers

K2CO3, heat

OCH2CH 3 2) H O+
3
workup

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15

C15 H24O4

OCH2CH 3

several reaction
steps

Include stereochemistry

Draw one of the possible

diastereomers

1)

21
5

1) 1 eq

Cl

Cl

O+ workup

OH

MgBr

2) H3

OCH2CH 3
2)

B) J. Med. Chem. 2015, 58, 897-911.

HO

he

Br

H 3C

MgBr
1)

1 eq
O

OCH3
4

Br
2) H3O+ workup

HO

Br

+ enantiomer
4

Name _____________________________________
W.15.215
Exam No. 2
Page 2

II. (25 pts)

A) As part of the synthesis of cis-jasmone, a fragrant component found in jasmine flowers, an
intramolecular aldol condensation was carried out as shown. Provide the structure of the starting
molecule, molecule A, in the box below.
O

KOH

+ H2O

condensation product B

21
5

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15

C11 H18 O2
cis-jasmone
molecule A
6
In addition to cis-jasmone there are three other potential aldol condensation products that could arise from
molecule A. They are consititutional isomers of cis-jasmone In the three boxes below, provide the structures
of each of the other potential aldol condensation products. Note: the order in which you draw the structures
does not matter.

condensation product C

condensation product D

Of the three structures you drew above (B, C and D), which is the closest in stability to cis-jasmone? Write
the letter corresponding to the structure:

2
Circle each of the statement(s) that is true:

he

Cis-jasmone is the most stable aldol condensation product that could be formed in the reaction.
Cis-jasmone is the least stable aldol condensation product that could be formed in the reaction.

The nucleophile in this reaction is an enol.

Elimination to form the conjugated double bond is the final step in the reaction mechanism.

B) From J. Med. Chem. 2015, 58, 1244-1253. Provide the structure of the product.
O

+
O

NaOH

H
HN

CH3CH2OH
4

Name _____________________________________
W.15.215
Exam No. 2
Page 3

III. (20 pts)

A) Pyridine is generally considered a mild base, with the pKa of its conjugate acid measured as 5.

N
H
conjugate acid of pyridine
pKa = 5

N
pyridine

Cl

H 3C

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15

Replacement of C-H bonds on the pyridine ring with other substituents can significantly alter the pKa of the
conjugate acid. In the case of the pyridine derivatives shown below, replacement of the C-H bond at position 2
in the ring leads to molecules with pKas of 6, 0.5, -0.44 and 7. Predict the pKa value that corresponds to each
substituted pyridine and write the value in the space below each structure.

H 2N

21
5

B) Fill in the structures or reagents in the boxes provided.

O

O
O

OCH3

he

NaOCH3 (excess), CH3OH

Br (1 eq)

Br

O
HO

4
+ 2 NaBr

Name _____________________________________
W.15.215
Exam No. 2
Page 4

IV. (29 pts)

A) A research group at Dalian University recently reported the following interesting reaction that proceeds
through a Claisen condensation followed by a retro-Claisen reaction (J. Org. Chem. 2013, 78, 4171):
O

O
+

molecule A

F 3C

1) 1.1 eq NaH
O

molecule B

heat
2) H 3O+
workup

O
+

F 3C
molecule C

O
molecule D

B: F 3C

B-H

F 3C

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15

As you know, the initially formed intermediate, E, shown below, is deprotonated under the reaction conditions
(F, also shown). Under these reaction conditions, however, there is enough of molecule E to continue to
undergo productive reactions. In other words, you may ignore the formation of F in this reaction mechanism.

molecule F

molecule E

Provide a step-wise, curved arrow mechanism for the transformation of A and B to intermediate E (1st box)
and then for the formation of C & D (2 nd box). Use B:- as a generic base and B-H as the conjugate acid; use
H3O+ for the workup step. Make sure to use closed shell resonance structures.

21
5

O
H

molecule A

12

he

F 3C
O
molecule E

F 3C

molecule E

F 3C

O
molecule C

B) J. Med. Chem. 2010, 53, 6681.

O
O

1 eq
HO

O
2

molecule D

12

O
O

OH
N
3

pKa

ACID

(Strongest Acid)

common carbohydrates

H N H

HO

O
HO S OH

9.4

H
OH

O H

O
Cl

O H
C

CH3CH2

CH3

OH

1.3

0.64

OH

3.2

CH3

17

19

Cl

25

C H
Cl

OH

H C C

H2

26

4.2

35

N H

4.6

36

he

H
O
C

CH3

OH

4.8

N H

C
HO

OH

H C N

CH3

H
H

6.5
9.1

H
C

H
H

CH3 9.2

44

O
C

43

H C H

41

5.2

- & -D -glucopyranose

H
H N

H3N

O
R

alanine: R = CH3
arginine: R = CH2CH2CH2 N

proline

15.7

Cl

OH

OH

common amino acids

15.0

CH3CH2

O
Cl3C

HO
HO

10.5
10.6

1.7

O
O

(Weakest Acid)

49

H OH O

H OH H OH
D -glucose

OH

H
O
CH3

HO H

D -ribose

10.2

N H

2.4

D -threose

-4.6

H
O

D -erythrose

HO

H
HO H

H OH H OH

CH3CH2

OCH3

CH3

HO

-7.2

CH3

10.2

OH

21

CH3

HO

H OH

HO

O
H

D -(+)-glyceraldehyde
O

HO

H OH

10.0

O
H

HO
HO

15

-12

H C N H

pKa

ACID

NH2

asparagine: R = CH2CONH2
aspartic acid: R = CH2CO2H
cysteine: R = CH2SH
glutamic acid: R = CH2CH2CO2H
glutamine: R = CH2CH2CONH2
glycine = R = H
H
histidine: R = CH2
N
N

isoleucine: R = CH(CH3)CH2CH3 (S)

leucine: R = CH2CH(CH3)2
lysine: R = CH2CH2CH2CH2NH2
methionine: R = CH2CH2SCH3
phenylalanine: R = CH2Ph
serine: R = CH2OH
threonine: R = CH(OH)CH3 (R)
tryptophan: R = CH2
N
H

tyrosine: R = CH2(C6H4)-OH (para)

valine: R = CH(CH3)2
some common reagents
[(CH 3)2CH]2NLi LDA lithium diisopropylamide
[(CH 3)3Si]2NLi LHMDS lithium hexamethyldisilazide
R-SO2Cl: R = CH3 (MsCl) methanesulfonyl chloride mesyl / mesylate
R = CF3 (TfCl) trifluromethanesulfonyl chloride trifyl / triflate
R = p-CH3(C6H4) (TsCl) para-toluenesulfonyl chloride tosyl / tosylate
(CH3CH2)3N TEA triethylamine
N
p-CH3(C6H4)SO2OH TsOH para-toluenesulfonic acid
DBU
PhCH2OH BnOH benzyl alcohol
N
CH3CH2OH EtOH ethanol
diazabicycloundecane
CH3OH MeOH methanol
(CH3)2CHOH iPrOH or PriOH isopropyl alcohol
N
DBN
(CH3)3COH tBuOH or ButOH tert-butyl alcohol
N
CH3CH2CH2CH2Li BuLi butyllithium
diazabicyclononane
(CH3)2CuLi Me2CuLi lithium dimethylcuprate

Name _____________________________________
W.15.215
Exam No. 2
Page 5

V. (18 pts)

A) 2,6-Disubstituted tetrahydropyran ring systems in which the two substituents are cis to one another are
frequently observed in biologically active molecules. Recently Latif and co-workers described a
straightforward strategy for preparing cis disubstituted tetrahydropyrans (J. Org. Chem. 2015 DOI:
10.1021/acs.joc.5b00046). Provide the reagents and/or structures as necessary in the boxes provided.
OTs

OH
N(CH 3)2

O
O

H 3CO

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15

H 3CO

Li

The nucleophile in this final step is (circle the

correct statement):

21
5

An amine
An enol

Show stereochemistry

An enolate
Lithium diisopropylamide

N(CH 3)2

OH

he

MeO

B) Provide the reagents and/or structures as necessary in the boxes provided (J. Med. Chem. 2013, 56, 10142)
OMe
OMe

Show stereochemistry

O
MeO

Cl
OMe

1)

2) Molecule A

Molecule A

2
MeO

O
N

Ph