Bioinspired Synthesis of Twin abeo ‐Steroids Bufogargarizins A and B via a Divergent Intramolecular Aldol Addition Reaction

Abstract This manuscript describes a concise bioinspired synthesis of twin abeo ‐steroids bufogargarizins A and B with an unusual [7.5.6.5] and [5.7.6.5] skeletons and a highly oxidized D‐ring with an α‐pyrone substituent from (+)‐methyl estrone. The described synthetic approach features ozonolytic cleavage of the Δ 5,10 ‐alkene of an easily available estrone derivative, followed by a bioinspired regio‐ and stereoselective intramolecular aldol addition reaction that produced the desired bufogargarizins A and B precursors with the [7.5.6.5] and [5.7.6.5] skeletons in 27% and 63% yields, correspondingly. This work provides direct evidence that proves the biosynthetic hypothesis for the first time, as prior synthetic studies suggest that only bufogargarizin B could be formed via an intramolecular aldol reaction. The subsequent installation of the β17‐pyrone moiety along with the β14, β15‐epoxide and β16‐acetoxy group was found to be challenging due to the instability of the α‐pyrone moiety to a range of basic, reductive, and oxidative conditions. To address this challenge, we have developed a singlet oxygen‐based oxidation method that results in a streamlined installation of the D‐ring oxidation and stereochemistry from a Δ 14,16 ‐diene precursor. This enabled the completion of the syntheses of bufogargarizins A and B in 19 steps (LLS) and 0.36 and 1.5% overall yields, respectively.