Conceptually new 20-epi-22-oxa sulfone analogues of the hormone 1α,25-dihydroxyvitamin D₃: Synthesis and biological evaluation

New C,D-ring side-chain-modified sulfone 4a, with natural 1α,3β-hydroxyl groups but lacking the 25-hydroxyl group characteristic of the natural hormone 1α,25-dihydroxyvitamin D₃ (1), has been prepared and characterized. Novel synthetic features include: (1) chemoselective oxidation of only a primary silyl ether in a primary-secondary bis-silyl ether intermediate and (2) smooth reductive etherification without interference by a neighboring sulfonyl group. Sulfone 4a, but not its 1β,3α-diastereomer 4b, is powerfully antiproliferative and transcriptionally active in vitro but desirably noncalcemic in vivo. Although sulfone 4a, designed to resemble Leo Pharmaceutical. Co.'s KH-1060 (3), is recognized by catabolic enzymes, the selective biological profile of sulfone 4a is likely not due to its metabolites that are formed in only minor amounts.