An improved synthesis of (20R,22R)-cholest-5-ene-3β,20,22-triol, an intermediate in steroid hormone formation and an activator of nuclear orphan receptor LXRα

Asymmetric dihydroxylation of (20(22)E)-cholesta-5,20(22)-dien-3 beta-ol acetate (2a), prepared from pregnenolone, gave a 1:1 mixture (67% yield) of (20R,22R)-cholest-5-ene-3 beta,20,22-triol 3-acetate (3a) and its 20S,22S isomer 3b. Highly purified 3a and 3b were obtained by semipreparative silver ion high performance liquid chromatography. Saponification of 3a and 3b gave (20R,22R)-cholest-5-ene-3 beta,20,22-triol (4a) and its 20S,22S isomer 4b. This simple approach provided the natural isomer 4a more efficiently than previously described chemical or enzymatic syntheses. Full H-1 and C-13 nuclear magnetic resonance data were presented for triols 4a and 4b and their synthetic precursors. Side-chain conformations of 2a, its 20(22)Z isomer, 4a, and 4b were studied by molecular mechanics and nuclear Overhauser effect difference spectroscopy. (C) 1999 Elsevier Science Inc. All rights reserved.