Total synthesis of 1,25-dihydroxyvitamin D3 analogs modified at the side chain and D-ring

Herein, we describe a synthetic strategy to access 1,25-dihydroxyvitamin D-3 (calcitriol) analogs with natural or unnatural configuration at C20 and unsaturation at the D-ring. The synthetic approach is exemplified by the synthesis of two potent analogs, namely 1,25-dihydroxy-16-en-23-yne-vitamin D-3 and 1,25-dihydroxy-20-epi-24a-homo-26,27-dimethyl-vitamin D-3. A key feature of the synthetic strategy is the generation of an unnatural configuration at C20 by a catalytic asymmetric reduction of an ,,,-unsaturated ester with the CuH species in a micellar system.