N.B.

Some of the following exercises are quite challenging and serve to evaluate your above average
preparation.

1) How are the following compounds in each pair related? Draw and name compounds A and B as a
hexagon with wedges and dashed wedges to show the stereochemistry of the substituents.

2) Write the mechanism with which molecules B and D are formed, highlighting why only one constitutional
isomer is formed in each reaction. Which one between compounds A and C would be more reactive in the
above reaction conditions? Name compounds B and D.

3) Draw a stepwise mechanism for the following intramolecular reaction:

4) Name compound A and determine how is compound A related to compounds B-E (choose from
enantiomers, diastereoisomers, constitutional isomers, or identical molecules).

5) The product C is an intermediate in the synthesis of raloxifene, a drug used to reduce the risk of invasive
breast cancer in postmenopausal women. Determine the structure of compound C and the mechanism of
the reaction between A and B.
6) Concerning the previous reaction, rank the following alcohols from which would require a weaker base
to which would require a stronger base to be reactive: a) compound A; b) para-nitrophenol; c) para
methoxyphenol; d) hexanol; e) meta-nitrophenol. Justify your choice.

7) Concerning the reaction of exercise 2, determine how could you facilitate the reaction by changing the
structure of compound B

8) Draw a stepwise mechanism for the following reaction which forms the four-membered ring in
azelnidipine, a drug used as a calcium channel blocker sold in Japan

9) Prepare each compound from cyclopentanol

10) Identify the product that would be formed by oxidation of the compound represented below

11) Draw the structure of the products formed by the complete hydrolysis under acidic conditions of each
compound
12) Draw a stepwise mechanism for the following reaction, a key step in the synthesis of the anti-
inflammatory drug celecoxib (trade name Celebrex). The regiochemistry (formation of only one isomer)
depends on the different reactivity of the two carbonyl groups in compound A and of the three amino group
in compound B. Determine why there is such difference in the reactivity.

13) Rank the following carboxylic acids in order of increasing acidity:

14) Compound B is the intermediate for the synthesis of Biyouyanagin A, an anti-HIV agent used in traditional
Japanese medicine. Propose a mechanism for the following three-step reaction (Micheal addition – aldolic
reaction – dehydration). How many stereoisomers of B do exist?

15) Methyl ester is a useful protecting group for the synthesize of peptides. Describe how you would use such
protecting group for the synthesis of the following dipeptide. Would you use acid or base condition for the
cleavage step? Justify your answer.
SOLUTIONS

1) A and B are constitutional isomers; A and C are the same molecule; A and D are constitutional isomers;
B and C are constitutional isomers; B and D are diastereoisomers; C and D are constitutional isomers

2)

3)

4) A and B are diastereisomers; A and C are the same molecule; A and D are enantiomers; A and E are
constitutional isomers. A is (R)-trans-5-methylhex-3-en-2-amine

5) SN2 mechanism

6) b) > a) > e) > c) > d). In b) the forming negative charge on the oxygen is more delocalized, thus easier to
form

7) Starting from the corresponding bromide or iodide

8)

9)

10)

11)

12)
The CF3 group is highly electronegative rendering the carbonyl group attacked to it highly electrophilic. In
compound B, the first reaction occurs through the nucleophilic attack of the only amino group which lone
pair is not delocalized.

13) C < D < A < E < B

14)

B exists as four steroisomers since its structure contains two stereocenters

15)