Total synthesis and structural elucidation of khafrefungin.

Abstract

Total synthesis and structural elucidation of khafrefungin, a novel antifungal agent isolated from the fermentation culture MF6020, have been achieved. Unlike other inhibitors that inhibit the corresponding enzyme in fungi and mammals to the same extent, khafrefungin does not impair sphingolipid synthesis of mammals. The basic strategy for the structural elucidation is to prepare all stereoisomers of the structurally simplified khafrefungin mimics 1 and 2 that were designed for the elucidation of C10,11,12 and C2',3',4' relative stereochemistry, respectively. The comparison of their spectra with those of natural khafrefungin would result in the identification of eight possible stereoisomers, and the analytical details of these eight stereoisomers have led to the complete stereochemical assignment. On the basis of the structural elucidation, the total synthesis of khafrefungin has been accomplished by using tin(II)-catalyzed asymmetric aldol reactions as key steps.