Stereoselective Synthesis of Four Calcitriol Lactone Diastereomers at C23 and C25.

(23S,25R)-Calcitriol lactone is a major metabolite of vitamin D-3, but its synthesis has been far less well investigated than that of 1 alpha,25(OH)(2) vitamin D-3, the active form of vitamin D-3, even though the lactone is present at a significant level in serum. This paper describes stereoselective syntheses of natural calcitriol lactone and its diastereomers at C23 and C25. This work features (i) the diastereoselective Reformatsky-type crotylation of aldehyde 25 in the presence of chiral ligand L2 to construct the stereochemistry at C23 and (ii) the diastereoselective epoxidation of homoallylic-allylic alcohol 31 to control the stereochemistry at C25. These key reactions allowed us to synthesize CD-ring synthon 30 with all four stereoisomers, and these were further converted into calcitriol lactones 3a-3d by reaction with ene-yne-type A-rings 33 in the presence of a palladium (0) catalyst.