Divergent total synthesis of the tricyclic marine alkaloids lepadiformine, fasicularin, and isomers of polycitorols by reagent-controlled diastereoselective reductive amination

Abstract

We describe a flexible and divergent route to the pyrrolo-/pyrido[1,2-j]quinoline frameworks of tricyclic marine alkaloids via a common intermediate formed by the ester-enolate Claisen rearrangement of a cyclic amino acid allylic ester. We have synthesized the proposed structure of polycitorols and demonstrated that the structure of these alkaloids requires revision. In addition to asymmetric formal syntheses, stereoselective and concise total syntheses of (-)-lepadiformine and (-)-fasicularin were also accomplished from simple, commercially available starting materials in a completely substrate-controlled manner. The key step in these total syntheses was the reagent-dependent stereoselective reductive amination of the common intermediate to yield either indolizidines 55 a or 55 b. Aziridinium-mediated carbon homologation of the hindered C-10 group to the homoallylic group facilitated the synthesis.

Keywords: aziridinium; diastereoselectivity; reductive amination; substrate and reagent control; total synthesis.