[3- 7 - STEREOSELECTIVE SYNTHESIS OF EPIBATIDINE AND ANALOGS(2] CYCLOADDITION OF NONSTABILIZED AZOMETHINE YLIDES )

Epibatidine (1) is synthesized by employing a [3 + 2] cycloaddition st rategy as a key step via nonstabilized azomethine ylide 10, generated by one-electron oxidative double desilylation of N-benzyl-2,5-bis(trim ethylsilyl)pyrrolid (12). Cycloaddition of 10 with trans-ethyl-3-(6-ch loro-3-pyridyl)-2-propenoate (22a) gives 26 in which the 6-chloro-3-py ridyl moiety is endo-oriented. Decarboxylation followed by debenzylati on gives unnatural epimer 30 of 1. The required cycloadduct 33, in whi ch 6-chloro-3-pyridyl moiety is exo-oriented, is obtained stereoselect ively utilizing cis-ethyl-(6-chloro-3-pyridyl)-2-propenoate (22b) as d ipolarophile. 30 is also converted to 1 by epimerization reaction usin g (KOBu)-Bu-t. An alternative route involving conjugate addition of 6- chloro-3-iodo pyridine (37) to 36, obtained by cycloaddition of 10 wit h ethyl propiolate, is also suggested for the stereoselective synthesi s of 1. A number of substituted epibatidines (38, 39, 40, 41, and 42) are synthesized through this strategy using appropriate dipolarophiles . Formal synthesis of the N-methyl homoepibatidine 48 and its epimer 4 6 is suggested from the cycloaddition of homologous azomethine ylide 4 4, derived from 43, with 22a and 22b, respectively.