Enantioselective Total Syntheses of Allopumiliotoxins 267A, 323B‘, and 339A. Application of Iodide-Promoted Iminium Ion−Alkyne Cyclizations for Forming Allopumiliotoxin A Alkaloids

Abstract

A concise, stereocontrolled strategy for the total synthesis of allopumiliotoxin A alkaloids is described. A much improved second generation total synthesis of enantiopure (+)-allopumiliotoxin 267A ( 3 ) was accomplished in 10 steps and 11% overall yield from the commercially available oxazolidinone precursor of alcohol 32 and 17 steps and 4% overall yield from N -[(benzyloxy)carbonyl]- l -proline. The first synthesis of (+)-allopumiliotoxin 323B‘ ( 4 ) rigorously confirms the complete stereostructure of 4 and establishes that the major C(15) epimer isolated from dendrobatid frogs has the 15 S configuration. The total synthesis of 4 was realized in 5 steps and 17% overall yield from alkyne 39 and aldehyde 20; the synthesis proceeded in 13 steps and 6% overall yield from ( S )-2-methyl-1-penten-3-ol and 17 steps and 3.5% overall yield from N -[(benzyloxy)carbonyl]- l -proline, the precursors, respectively, of alkyne 39 and pyrrolidine aldehyde 20 . The first total synthesis of allopumiliotoxin 339A ( 5 ) also confirmed the full stereostructure of this alkaloid. The synthesis of enantiopure 5 was achieved in 5 steps and 32% overall yield from alkyne 45 and pyrrolidine aldehyde 20; the synthesis proceeded in 17 steps and ∼7% overall yield from N -[(benzyloxy)carbonyl]- l -proline and 16 steps and ∼6% overall yield from the commercially available oxazolidinone precursor of 45 . These syntheses provide the best illustrations to date of the substantial utility of iodide-promoted iminium ion−alkyne cyclizations for constructing highly functionalized nitrogen heterocycles.