Total Synthesis of the Tricyclic Marine Alkaloids Lepadiformine, Fasicularin, and Isomers of Polycitorols by Diastereoselective Reductive Amination.

Abstract

Due to their bioactivities and interesting structural features, tricyclic marine alkaloids as (–)-lepadiformine and (–)-fasicularine have been the subject of numerous synthetic studies. In this context, The planning and implementation of flexible, divergent total syntheses of pyrrolo-/pyrido[1,2-j]quinoline tricyclic marine alkaloids is presented. A functionally enriched intermediate was readily assembled by employing an ester-enolate Claisen rearrangement of the cyclic amino acid allylic ester possessing an exocyclic N-carbonyl group. This common intermediate was efficiently converted to (–)-lepadiformine A, (–)-fasicularin, and the proposed structure of recently isolated polycitorols A and B in a substrate-controlled manner. In these studies, we also have shown that the configuration of polycitorols requires revision, proposed possible structure of natural polycitorol A. A key step in our synthesis was a reagent-dependent stereoselective intramolecular reductive amination of the common intermediate to yield either indolizidines, for syntheis of (–)-lepadiformine and (–)-fasicularin. In addition, less explored aziridinium-mediated carbon homologation of the hindered C-10 group into a homoallylic group greatly facilitated the synthesis.