Conversion of five-, six-, and seven-membered lactams to racemic or scalemic 2-substituted heterocycles by amidoalkylation

by Madan, S.; Milano, P.; Eddings, D. B.; Gawley, R. E.

An efficient method for the synthesis of 2-alkyl- and 2-aryl pyrrolidines, piperidines, and azepanes from lactams, in either racemic or enantiopure form, is presented, The lactam nitrogens are acylated with either Boc anhydride or trans-cumylcyclohexyl (TCC) chloroformate. Selective reduction of the lactam carbonyl to the carbinolamide is followed by treatment with benzotriazole. Substitution of the benzotriazole is accomplished by treatment with organometallics, yielding the 2-substituted heterocycles. With TCC, up to 90% diastereoselectivity is achieved. After diastercomer purification, reductive removal of the auxiliary affords enantiopure 2-substituted heterocycles. A mechanistic hypothesis is presented that details the conformational equilibria of the key step.

Journal
Journal of Organic Chemistry
Volume
70
Issue
8
Year
2005
Start Page
3066-3071
URL
https://dx.doi.org/10.1021/jo048484v
ISBN/ISSN
1520-6904; 0022-3263
DOI
10.1021/jo048484v