A versatile two-step method for the reductive alkylation and formal [4 + 2] annulation of secondary lactams: step economical syntheses of the ant venom alkaloids (2R,5S)-2-butyl-5-propylpyrrolidine and (+)-monomorine I

Abstract

The reductive alkylation of secondary lactams is an important transformation in the total synthesis of alkaloids and pharmaceuticals. Methods for this transformation are scarce. We report in this paper a versatile two-step approach consisting of N-benzylation and one-pot reductive alkylation–debenzylation. With suitably functionalized Grignard reagents, a formal [4 + 2] annulation reaction has been achieved. Using this method, we have successfully synthesized several N-α-alkyl and N-α,α′-dialkyl heterocycles, including (±)-coniine (7) and the ant venom alkaloids (2R,5S)-cis-2-butyl-5-propylpyrrolidine (8) and (+)-monomorine I (10) each in two steps starting from readily available secondary lactams.