Synthesis of 1 alpha,25-Dihydroxyvitamin D Analogues Featuring a S-2-symmetric CD-ring Core

Three analogues of 1α,25-dihydroxyvitamin D 3 (calcitriol), featuring a trans- fused decalin C,D-core with local S 2 -symmetry, and possessing identical side-chain and seco-B,A-ring structures, have been synthesized starting from readily available (4a R ,8a S )-octahydronaphthalene-1,5-dione ( 7 ). The very short sequences involve the simultaneous introduction of the side-chain and seco-B,A-ring fragments via Suzuki and Sonogashira coupling reactions. The analogues are devoid of relevant biological activity. Keywords: Suzuki coupling; Sonogashira reaction; Calcitriol analogues. Introduction Since the discovery that the biological action of vitamin D 3 originates from the dihydroxylated metabolite 1α,25-dihydroxyvitamin D 3 ( 1 , calcitriol) and that, next to its classical role in the regulation of calcium homeostasis, these actions also involve immunomodulation, cell differentiation and antiproliferation, there has been an intense search for structural analogues of calcitriol that might show a separation in calcemic and antiproliferative-prodifferentiating activities (Scheme 1) [1]. In this context various successful structural modifications have been introduced in each one of the three parts that one may distinguish in its structure: the rigid central C,D-ring system and the flexible parts of the molecule, comprising the side chain and the seco-B,A-ring [2].