Concise Synthesis of Bufadienolide Cinobufagin via Late-Stage Sin-glet Oxygen Oxidation/Rearrangement Approach

This manuscript describes a concise synthesis of cinobufagin, a natural steroid of bufadienolide family, from readily available dehydroepiandrosterone (DHEA), as well as its a5-epimer derived from 3-epi-andosterone. This synthesis features expe-dient installation of the b17-pyrone moiety with the b14,b15-epoxide and the b16-acetoxy group using a photochemical re-gioselective singlet oxygen [4+2] cycloaddition followed by CoTPP-promoted in situ endoperoxide rearrangement to provide a b,b-bis-epoxide in 64% yield with a 1.6:1 d.r. This b,b-bis-epoxide intermediate was subsequently subjected to a regioselective scandium(III) trifluoromethanesulfonate catalyzed House-Meinwald rearrangement to establish the b17-configuration. The synthesis of cinobufagin is achieved in 12 steps (LLS) and 7.4% 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 a5-epimer.