An Asymmetric Route to the Conanine BCDE Ring System. A Formal Total Synthesis of (+)-Conessine

Abstract

The first enantioselective synthesis of the known (+)-conessine precursor (+)-benzohydrindan 23 from the chiral nonracemic bicyclic lactam 1 is described. The key transformation was the highly diastereoselective (3 + 2) cycloaddition of azomethine ylide 11a to lactam 7 in order to construct the pyrrolidine E ring system at any early stage in the synthesis. The requisite pyrrolidine methyl group at C-21 was stereoselectively installed late in the synthesis by lithiation of N-Boc-pyrrolidine intermediate 20 with sec-BuLi/TMEDA followed by quenching at −90 °C with iodomethane, furnishing the tetracyclic pyrrolidine 21. Reduction of t-Boc 21 with lithium aluminum hydride affords (+)-N-methyl tetracycle 23 in a concise 13-step synthesis from 1.