Ontwikkeling van spirocyclische vitamine D3 analoga met potentiële dissociatie van biologische activiteiten

Since the discovery that 1α,25(OH)2D3 (calcitriol), the hormonally active metabolite of vitamin D3, possesses, next to its classical calciotropic activity, also cell differentiating and antiproliferative activities, there has been a search for analogues in which a dissociation of calcemic and other activities is observed (1). In continuation of efforts directed at the development of analogues possessing structural modifications in the central CD‐ring system, the present work describes the synthesis of analogues, featuring next to a spiro[5.4]cyclic core (2), also deletion of C19, so as to preclude isomerisation to previtamin, incorporation of a 22‐oxa and of 20‐epimeric configurations (indicated by cis and trans, cf. relative orientation of the O22 and C14), all features that have been shown to promote dissociation of activities (1). The synthesis of the analogues involves first the enantioselective synthesis of a spirocyclic compound. Next, the nor‐A‐ring and the sidechain are attached. Also a variety of sidechains is tested on their influence on the biological activity. (1) R. Bouillon, W.H. Okamura, Norman, A.W. Endocr. Rev. 1995, 16, 200‐257; (2) W. Schepens et al. Org. Lett. 2006, 8, 4247‐4250; (3) G.‐D. Zhu, W.H. Okamura, Chem. Rev. 1995, 95, 1877‐ 1952; (4) W. Yao, J. Wang Chin. J. Org. Chem 2003, 23, 546‐549