Synthesis of Bufadienolide Cinobufagin via Late-Stage Singlet Oxygen Oxidation/Rearrangement Approach.

Abstract

This manuscript describes a concise synthesis of cinobufagin, a natural steroid of the bufadienolide family, from readily available dehydroepiandrosterone (DHEA), as well as its α5-epimer derived from 3-epi-andosterone. This synthesis features expedient installation of the 17β-pyrone moiety with the 14β,15β-epoxide and the 16β-acetoxy group using a photochemical regioselective singlet oxygen [4 + 2] cycloaddition followed by CoTPP-promoted in situ endoperoxide rearrangement to provide a 14β,16β-bis-epoxide in 64% yield with a 1.6:1 d.r. This β,β-bis-epoxide intermediate was subsequently subjected to a regioselective scandium(III) trifluoromethanesulfonate catalyzed House-Meinwald rearrangement to establish the 17β-configuration. The synthesis of cinobufagin is achieved in 12 steps (LLS) and 7.6% overall yield, and we demonstrate that it could be used as a platform for the subsequent medicinal chemistry exploration of cinobufagin analogs such as cinobufagin 5α-epimer.