Progress Toward the Asymmetric Synthesis of (-)-Gephyrotoxin

Abstract

This research has focused on the asymmetric synthesis of the natural product (-)-gephyrotoxin. This product was isolated and characterized by Daly and coworkers in 1977. Kishi and co-workers published the first synthesis of (-)-gephyrotoxin in 1980, and the first synthesis of (+)-gephyrotoxin in 1981. No synthesis of (-)-gephyrotoxin has been published to date.

In exploring the possibilities for the synthesis of (-)-gephyrotoxin, many synthetic transformations were investigated including, Horner-Wadsworth-Emmons, Diels-Alder, orthoester Claisen, and Mukaiyama-Michael addition. Diels-Alder and Horner-Wadsworth-Emmons Chemistry was explored for formation of the 6,6 trans ring system necessary for (-)-gephyrotoxin. Previously synthesis of only cis ring systems had been developed. Orthoester Claisen rearrangement and Mukaiyama-Michael addition were investigated to set the C6 and 5a stereocenters.

Our progress toward the synthesis of (-)-gephyrotoxin yielded other developments as well. The formation of both the cis and trans 4-hydroxy -3,4-dihydro-2H-pyridines was accomplished for the first time, and the formation of 5-iodo, and 5-vinyl-2,3-dihydro-4-pyridones was improved.