Synthesis and biological evaluations of A-ring isomers of 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D-3

The activated vitamin D-3 derivative 26,27-F-6-1 alpha,25(OH)(2)D-3 (2a), i ts three A-ring diastereomers (2b, 2c, 2d), and 5,6-trans isomer (2e) were prepared. Two analogues (2b, 2c) of these isomers were synthesized by a pal ladium catalyzed coupling reaction using Vinyl bromide 5 and enynes (6a, 6b ), which were derived from readily commercially available 2S-(+)-glycidyl p -toluenesulfonate 7, as a common starting material. Competitive vitamin D r eceptor (VDR) binding affinities of these diastereomers of 2a were evaluate d. Interestingly, the stereochemical effects at C-1,3 of 2a were considerab ly more moderate than those of 1 alpha,25(OH)(2)D-3 (1). In particular, iso merization at the 5,6-double bond of 2a only slightly reduced VDR affinity, whereas 5,6-trans-1 alpha,25(OH)(2)D-3 had a significantly lower binding a ffinity than 1. (C) 2000 Elsevier Science Ltd. All rights reserved.