Organic Chemistry of Drug Synthesis. Volume 7

peptide incretin, which stimulates release of insulin by cleaving the
molecule to an inactive form. Inhibition of DPP in effect extends the action
of incretin. This helps prevent the increased levels of blood glucose that
mark diabetes. The protease inhibitorvidagliptin( 7 ), which is modeled
in part on the terminal sequence in DPP, has been found to sustain
levels of insulin in Type 2 diabetics. Inhibition is apparently reversible
in spite of the presence in the structure of the relatively reactive
a-aminonitrile function. Construction of one intermediate in the conver-
gentsynthesis comprises reaction of amino adamantamine ( 1 ) with a mixture
of nitric and sulfuric acid. This reaction affords the product 2 from nitration
of one of the remaining unsubstituted ternary positions. Treatment of this
product with strong base leads to solvolysis of the nitro group to give
aminoalcohol 3. Preparation of the other moiety involves first acylation
of the pyrrolidine ( 4 ) with chloroacetyl chloride to give amide 5.
Reaction of that intermediate with trifluoracetic anhydride (TFAA) con-
verts the amide at the 2 position to the correspounding nitrile. Alkylation
of the adamantamine ( 3 ) with 6 proceeds on nitrogen to afford 7.^1

NH 2

1

HNO 3

H 2 SO 4 NH 2

2

NO 2

KOH

NH2

3

OH

HN

CONH 2

4

Cl COCl N

CONH 2

5

O

Cl TFAA N

CN

6

O

Cl

OH

N

O CN

NH

7

A substituted pyrrolidine, which acts as a DPP inhibitor, comprises
another example in which this ring serves as a surrogate for proline.
This compound is being investigated as an anticancer drug as a result of
the finding that it inhibits growth of tumors in various animal models.
The structure of this compound is notable for the rare occurrence of
boron in the structure; in this case in the form of a covalently bound
boronic acid. The final compound,talabostat ( 18 ), is comprised of a
single enantiomer. This is accomplished in the case at hand by a stereo-
selective synthesis rather than by resolution of the final compound or an
intermediate. The first step in the synthesis comprises protecting the
amine in pyrrolidine ( 8 ) by conversion to its tert-butoxycarbonyl
( 9 ,t-BOC) derivative withtert-butoxycarbonyl anhydride. Reaction of

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