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?

Organic Chemistry Frontiers Pub Date: 2014-02-11 DOI: 10.1039/C3QO00065F

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.

Graphical abstract: 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
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