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

This manuscript describes a concise synthesis of cinobufagin, a natural steroid of the bufadienolide family, from readily available dehydro-epiandrosterone (DHEA), as well as its alpha 5-epimer derived from 3-epi-andosterone. This synthesis features expedient installation of the 17 beta-pyrone moiety with the 14 beta,15 beta-epoxide and the 16 beta-acetoxy group using a photochemical regioselective singlet oxygen [4 + 2] cycloaddition followed by CoTPP-promoted in situ endoperoxide rearrangement to provide a 14 beta,16 beta-bis-epoxide in 64% yield with a 1.6:1 d.r. This beta,beta-bis-epoxide intermediate was subsequently subjected to a regioselective scandium(III) trifluoromethane-sulfonate catalyzed House-Meinwald rearrangement to establish the 17 beta-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 5 alpha-epimer.