Synthesis of Clionastatins A and B through Enhancement of Chlorination and Oxidation Levels of Testosterone.

Comprehensive Summary: A full account of semisyntheses of polychlorinated marine steroids clionastatins A and B is described. We have developed a unique two‐stage chlorination‐oxidation strategy that enabled concise and divergent semisyntheses of clionastatins A and B in 16 steps from inexpensive testosterone. Key transformations in chlorination stage include (a) conformationally controlled, stereospecific dichlorination through an unusual β‐chloronium intermediate to install the diequatorial C1,C2‐dichloride; (b) C4‐OH directed C19–H oxygenation followed by challenging neopentyl chlorination to install the C19–Cl. The high oxidation level was constructed through (a) the desaturation at C6–C7 through one‐pot photochemical dibromination–reductive debromination; (b) regioselective anti‐Markovnikov oxidation of the C6–C7 double bond by photoredox‐metal dual catalysis to forge the B ring enone; (c) late‐stage desaturation with SeO2 to introduce C8–C9 double bond. Wharton transposition was used to forge the D‐ring enone, and thermodynamically driven epimerization secured the cis‐fused C/D ring system. Furthermore, we also provided a 14‐step approach to clionastatin A by optimizing the construction of the D‐ring enone with a dehydration‐oxidation sequence. [ABSTRACT FROM AUTHOR]