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

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.