54 1α位に水酸基を有するビタミンD_3代謝物の新しい立体選択的合成

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Recently, much attention has been focused on the action of active metabolite, 1α, 25-dihydroxyvitamin D_3 (2), and other 1α-hydroxylated derivatives in inhibiting proliferation and inducing differentiation of human myeloid leukemia cells (HL-60), in addition to the role of calcium metabolism. While several methods to introduce 1α-hydroxyl group and functionalities on the sterol side chains have been reported, synthetic stratagy and stereocontrolled reaction should be considered from a practical view point of the syntheses of a series of 1α-hydroxylated vitamin D derivatives. In this presentation, facile and stereocontrolled syntheses of 1α, 25-dihydroxyvitamin D_3 (2) and 1α, 24R, 25-trihydroxyvitamin D_3 (3) from 1α-hydroxy-17-oxosteroid (15b), readily available from microbial hydroxylation of dehydroepiandrosterone (15a), is reported. First, we synthesized cholesterol (32a) from dehydroepiandrosterone (15a) via two routes (B & C). In these syntheses, the desired stereochemistries at C(17) and C(20) were introduced by stereoselective catalytic hydrogenation of (Z)-17(20)-dehydro-derivative (28a) which was derived from (Z)-allylsulfone (27a). Compound (27a) was obtained from stereoselective conjugate addition of LiCuMe_2 to allenesulfone (26) (route C) or alkylation of C-22 allylsulfone (20a) obtained from the stereoselective conjugate addition of LiCuMe_2 to allenesulfone (19a) (route B). Applying the method (route C), an intermediate (32c) for the synthesis of the active metabolite (2) was stereoselectively synthesized from the 1α-hydroxysteroid (15b) and acetylene derivative (30b). Finally, an intermediate (32b) for the synthesis of 1α,24R, 25-trihydroxyvitamin D_3 (3) was also stereo-selectively synthesized from 15b and chiral synthon (10) by application of the route B.
1986-09-09

54 1α位に水酸基を有するビタミンD_3代謝物の新しい立体選択的合成

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