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

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 dichlorin-ation through an unusual β-chloronium intermediate to install the diequatorial C1,C2-dichloride;(b)C4-OH directed C19-H oxygena-tion followed by challenging neopentyl chlorination to install the C19-CI.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 opti-mizing the construction of the D-ring enone with a dehydration-oxidation sequence.