First Total Syntheses of 1-NH2-and 3-NH2-Vitamin D3 analogs

Abstract

Calcitriol [1,25a-(OH)2-vitamin D3], a metabolite of vitamin D3, is seco-steroid hormone maintaining calcium homeostasis in human. It was also shown to suppress cell proliferation and induce differentiation, that suggested its potential use as an anticancer agent. Therapeutic trials of calcitriol were, however, restricted due to its hypercalcimic activity. Much synthetic work has been conducted, ever since those two activities could be separated by modification of the calcitriol structure. As a study directed toward finding potent analogs with more favorable therapeutic profile, we conducted total syntheses of vitamin D3 analogs containing amino group at A-ring, starting from 2-pyrone-3-carboxylate. Inverse-electron-demand Diels-Alder cycloaddition with benzyl vinyl ether, followed by a series of manipulation provided 1-NH2- and 3-NH2-A-ring phosphine oxides. Lithgoe coupling of A-ring phosphine oxide and CD-ring ketone gave rise to the final 1-NH2- and 3-NH2- vitamin D3 analogs.