Highly stereoselective total syntheses of (+)-allopumiliotoxins 267A and 339A via intramolecular nickel(II)/chromium(II)-mediated cyclization

Abstract

Remarkably high regio- and stereoselective approaches for the syntheses of dendrobatid alkaloids (+)-allopumiliotoxin 267A and 339A have been developed. As a model study for the syntheses of these alkaloids, we initially undertook intramolecular chromium(II)-mediated cyclization of the racemic N-(iodoalkenyl)piperidine 8, which smoothly proceeded by treatment with CrCl 2 (5 equiv) and catalytic NiCl 2 (2.5 mol%) in DMF to form a 1.3:1 epimeric mixture of 2-hydroxy-3(E)-alkylidene-trans-quinolizidines 33a and 33b. When the alternative chiral N-(iodoalkenyl)piperidine 9 was subjected to the identical cyclization conditions, the 3(E)-alkylidene-trans-quinolizidine 35a with the axially oriented 2-hydroxy group was formed as a single isomer. Based on these model studies, we then undertook the enantioselectivie total synthesis of (+)-allopumiliotoxin 267A (1). For the synthesis of (1), coupling of the two segments, (E)-vinyl iodide 45, obtained via stereospecific palladium-catalyzed hydrostannation, and the pyrrolidine derivative 54, gave the N-(iodoalkenyl)pyrrolidine 56, which underwent intramolecular chromium-(II)-mediated cyclization, exclusively providing 58 with complete retention of the required (E)-alkenyl geometry. Subsequent cleavage of the benzyl group furnished 1. Synthesis of allopumiliotoxin 339A (2) was next investigated bu employing the strategy developed for 1. The side-chain segment, (E)-vinyl iodide 74, was prepared via high-degree stereo- and regioselective reactions involving Evans alkylation and palladium-catalyzed hydrostannation. Intramolecular nickel (II)/chromium(II)-mediated cyclization of the N-(iodoalkenyl)pyrrolidine 82, available via coupling 74 with pyrrolidine derivative 79, led to exclusive formation of 83, which was deprotected to afford 2