Enantioselective total syntheses of allopumiliotoxins 267A, 323B', and 339A. Application of iodide-promoted iminium ion alkyne cyclizations for forming allopumiliotoxin A alkaloids

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 15S 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 similar to 7% overall yield from N-[(benzyloxy)carbonyl]-L-proline and 16 steps and similar to 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.