THE SELENO-ACETAL ROUTE TO 1-ALPHA-HYDROXY-VITAMIN-D ANALOGS - SYNTHESIS OF 24-OXA-1-ALPHA-HYDROXY-VITAMIN-D3, A USEFUL VITAMIN-D METABOLISM PROBE

Alkylation of the lithio-demethylseleno-derivative of seleno-acetal 11 with chloromethyl isopropyl ether [shown by NMR to give the (22S)-methylseleno-compound 13a as the major diastereoisomer] is the key reaction in the synthesis of the 24-oxa analogue (MC 1090, 8) of 1alpha-hydroxyvitamin D3 (4). The metabolism of 8 to calcitroic acid (7) is demonstrated in vitro in a hepatocyte cell (Hep 3B) model. This supports the hypothesis that 8 can undergo enzymatic 25-hydroxylation analogous to the activation of 4, or a similar side chain hydroxylation, but then short cuts the target cell side chain cleavage pathway taking 1alpha,25-dihydroxyvitamin D3 to 7.