New Vitamin D₃ Derivatives with Unexpected Antiproliferative Activity: 1-(Hydroxymethyl)-25-hydroxyvitamin D₃ Homologs

Surprisingly, both of the synthetic 1-(hydroxymethyl)-25-hydroxyvitamin D₃ diastereomers (-)-2 and (+)-3 retained the antiproliferative activity of natural calcitriol in murine keratinocytes. Preliminary studies indicated, however, that both of these synthetic diastereomers were less than 0.1% as effective as calcitriol for binding to the 1,25-(OH)₂-D₃ receptor and that they were less them 0.1% as potent as calcitriol for calbindin-D_28K induction in organ-cultured embryonic chick duodenum. 1-(Hydroxymethyl)-25-hydroxyvitamin D₃ homologs (-)-2 and (+)-3 were synthesized in a convergent manner by combining enantiomerically pure C,D-ring ketone 12 with highly enantiomerically enriched A-ring phosphine oxides (-)-11a and (+)-11b. These A-ring chirons were prepared starting from thermal [2 + 4] cycloaddition of 3-bromo-2-pyrone and acrolein.