Conceptually new 20-epi-22-oxa sulfone analogues of the hormone 1 alpha,25-dihydroxyvitamin D-3: Synthesis and biological evaluation

New C,D-ring side-chain-modified sulfone 4a, with natural 1 alpha,3 beta-hy droxyl groups but lacking the 25-hydroxyl group characteristic of the natur al hormone 1 alpha,25-dihydroxyvitamin D-3 (1), has been prepared and chara cterized. Novel synthetic features include: (1) chemoselective oxidation of only a primary silyl ether in a primary-secondary bis-silyl ether intermed iate and (2) smooth reductive etherification without interference by a neig hboring sulfonyl group. Sulfone 4a, but not its 1 beta,3 alpha-diastereomer 4b, is powerfully antiproliferative and transcriptionally active in vitro but desirably noncalcemic in vivo. Although sulfone 4a, designed to resembl e 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 me tabolites that are formed in only minor amounts.