Publication Details:
Title: [3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides. 7. Stereoselective Synthesis of Epibatidine and Analogues
| Author(s) | Ganesh Pandey*, Trusar D. Bagul, and Akhil K. Sahoo : J. Org. Chem. 1998, 63, 3, 760-768 |
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| Journal Name | The Journal of Organic Chemistry |
More Details:
Epibatidine (1) is synthesized by employing a [3 + 2] cycloaddition strategy as a key step via nonstabilized azomethine ylide 10, generated by one-electron oxidative double desilylation of N-benzyl-2,5-bis(trimethylsilyl)pyrrolidine (12). Cycloaddition of 10 with trans-ethyl-3-(6-chloro-3-pyridyl)-2-propenoate (22a) gives 26 in which the 6-chloro-3-pyridyl moiety is endo-oriented. Decarboxylation followed by debenzylation gives unnatural epimer 30 of 1. The required cycloadduct 33, in which 6-chloro-3-pyridyl moiety is exo-oriented, is obtained stereoselectively utilizing cis-ethyl-(6-chloro-3-pyridyl)-2-propenoate (22b) as dipolarophile. 30 is also converted to 1 by epimerization reaction using KOtBu. An alternative route involving conjugate addition of 6-chloro-3-iodo pyridine (37) to 36, obtained by cycloaddition of 10 with ethyl propiolate, is also suggested for the stereoselective synthesis 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 46 is suggested from the cycloaddition of homologous azomethine ylide 44, derived from 43, with 22a and 22b, respectively.