Efficient Total Syntheses of Pumiliotoxins A and B. Applications of Iodide-Promoted Iminium Ion−Alkyne Cyclizations in Alkaloid Construction

• Published in: Journal of the American Chemical Society 1996-09, Vol.118 (38), p.9062-9072
• Main Authors: Lin, Nan-Horng, Overman, Larry E, Rabinowitz, Michael H, Robinson, Leslie A, Sharp, Matthew J, Zablocki, Jeffery
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja961641q

A practical route for the total synthesis of pumiliotoxin A alkaloids is described. The central step is formation of the piperidine ring and establishment of the (Z)-alkylidene side chain by an iodide-promoted iminium ion−alkyne cyclization. The total synthesis of (+)-15(S)-pumiliotoxin A (2) was realized in 5 steps and 32% overall yield from alkyne 36 and epoxide 7. This synthesis of 2 proceeded in 13 steps and 12% overall yield from (S)-2-methyl-1-penten-3-ol (25) and 8 steps and 9% overall yield from N-[(benzyloxy)carbonyl]-l-proline. The synthesis of (+)-pumiliotoxin B (3) was similarly achieved in four steps and 44% overall yield from alkyne 54 and epoxide 7. The overall yield of enantiopure 3 was 8% from N-[(benzyloxy)carbonyl]-l-proline and 10% from (4S,5R)-4-methyl-5-phenyl-2-oxazolidinone. These syntheses represent substantial improvement over previous routes to these important alkaloids.