Convergent synthesis, chiral HPLC, and vitamin D receptor affinity of analogs of 1,25-dihydroxycholecalciferol

A series of analogs of 1,25‐dihydroxycholecalciferol was obtained with an additional chiral center at the terminus of the aliphatic side chain (C‐25). The analogs were obtained from (+)‐(R)‐ and (−)‐(S)‐2‐methylglycidols, by opening of the oxirane ring with the carbanions derived from vitamin D C23a,24‐ or C22‐sulfones. The diastereomeric purity of the analogs was determined by high‐performance liquid chromatography on a chiral stationary phase. The binding affinity of analogs for the calf thymus intracellular vitamin D receptor (VDR) was two orders of magnitude lower than that of the lead compound of this group, 24a,24b‐dihomo‐1,25‐dihydroxycholecalciferol, and it was comparable to the affinity of analogs of 24‐nor‐1,25‐dihydroxycholecalciferol. However, a twofold difference was observed for analogs diastereomeric at C‐25 in their affinity for VDR. The diastereodifferentiation of the binding affinity was found to be specific for vitamin D vicinal 25,26‐diols as it disappears for analogs where 26‐hydroxyl, neighboring the C‐25 chiral center, is replaced with methyl. Chirality 11:249–255, 1999. © 1999 Wiley‐Liss, Inc.