Evolutionary Efforts in the Total Synthesis of Pepluacetal.

Abstract

Pepluacetal is a structurally unique pepluanol family Euphorbia diterpenoid bearing an all-carbon [5-4-7-3] tetracyclic backbone. We describe herein the detailed process of the total synthesis of pepluacetal through the evolution of synthetic strategies. In the final successful strategy, a photoinduced Wolff rearrangement/lactonization cascade reaction gives access to the cyclobutane moiety; a ring-closing metathesis/cyclopropanation sequence rapidly builds up the [7-3] bicycle, and a Rh-catalyzed carbenoid insertion of the cyclobutane methylene C(sp3)-H bond, followed by ring-opening manipulations, introduces the three-carbon branched side chain stereoselectively in a remote traceless stereochemical relay fashion. The synthesis demonstrates excellent control of stereo-, regio-, and chemoselectivities. Moreover, the synthetic route could be performed on a large scale and optimized to a shorter version by running successive reactions in one pot, thus providing a general and practical approach to access pepluacetal.