Synthesis of vitamin D-3 and calcitriol dimers as potential chemical inducers of vitamin D receptor dimerization

The design and synthesis of vitamin D-3 dimers 2 and 3 and 1 alpha ,25-dihy droxyvitamin D-3 (calcitriol) dimers 4 and 5 are described. The dimers were designed with a view to doubly binding the vitamin D receptor (VDR) and in ducing the receptor homodimerization. In the dimers the units are linked th rough the C-ll position in ring C by an alkyl side chain of six or 10 carbo n atoms, far from the hydroxy groups responsible for the VDR binding. The l inker is formed by olefin metathesis of an olefinic side chain at the C-11 position introduced by stereoselective cuprate addition. The synthesis, whi ch is both short and convergent, uses the Wittig-Horner approach to constru ct the vitamin D triene system and allows the preparation of dimers with a Linker of modulated length with the purpose of optimizing the vitamin D-3-V DR interaction.