Exhaustive Synthesis of Strophasterols with a Novel Rearranged Steroidal Skeleton

Abstract

This account describes the synthesis of all members of the strophasterol family of natural products (strophasterols A-F and glaucoposterol A) isolated from mushrooms. They share a common rearranged steroidal skeleton named “straphastane” [15(14→22)-abeoergostane] which was first identified in 2012. Strophasterol A, an inducer of fruiting body formation in mushrooms, and its epimer strophasterol B have been synthesized from ergosterol in 18 steps that features a completely diastereoselective acyl radical cyclization to construct an isolated cyclopentanone ring and hydrogenation of a common cyclopentene intermediate using two types of catalysts to stereodivergently obtain two epimeric cyclopentane derivatives, one of which has been elaborated into strophasterol A and the other into strophasterol B. In the synthesis of strophasterols C, E, and F, which have an oxo or hydroxy group at C23 on the side chain moiety, a 1,3-dipolar cycloaddition of a nitrile oxide intermediate has been employed to simultaneously install the isolated cyclopentanone ring and a C23 oxygen functionality as the key transformation. The proposed structure of glaucoposterol A has also been synthesized, and its NMR analysis has revealed that the proposed stereochemistry of glaucopostrerol A is incorrect and suggested that glaucoposterol A has the same structure as strophasterol F. In addition, the stereochemistry of strophasterol D has been determined through synthesis of two candidate stereoisomers.