Total Synthesis of (±)-Phomactin B2 via an Intramolecular Cyclohexadienone Annulation of a Chromium Carbene Complex

Abstract

A total synthesis of (±)-phomactin B2 is described which has as its key step the intramolecular cyclohexadienone annulation of a Fischer carbene complex. The requisite carbene complex was prepared from geraniol in 11 steps and 12% overall yield. The key cyclohexadienone annulation produced both rings of the [9.3.1] pentadecane ring system of phomactin B2 in a single step in 60% yield and as a 4:1 mixture of diastereomers. The major diastereomer was taken on to the natural product in a series of steps that begins with a Peterson olefination. Initially, the Peterson olefination failed, but X-ray analysis of two intermediates in the diastereomeric series revealed that approach to the hindered carbonyl was blocked by a TIPS protecting group. Replacement of the TIPS group with a MOM group led to a facile Peterson olefination. Other notable steps in the synthesis include a stereoselective methylation of a cyclohexenone and hydroxyl-directed epoxidation of an alkene.