Efficient Asymmetric Synthesis of an A-Ring Synthon for Pd-Catalyzed Preparation of 1α-Hydroxyvitamin D Metabolites and Analogs

Abstract

An efficient Lewis acid-assisted asymmetric carbonyl-ene reaction to set the 1α-hydroxyl functionality of enol-triflate, precursor of the A-ring of the hormone calcitriol and its 1α-hydroxyderivatives, is described. The secondary parallel hypercalcemic effects associated with the treatment of several hyperproliferative diseases with the natural hormone 1α,25-dihydroxyvitamin D3 (calcitriol) and/or known active vitamin D metabolites and analogs, demand the development of efficient and rapid methods for the preparation of vitamin D receptor (VDR) ligands as new selective and non-calcemic agonists. Here we describe an efficient and adaptable multigram-scale synthetic sequence to access an A-ring synthon as useful precursor of the vitamin D triene system of 1α-hydroxylated vitamin D derivatives via Pd-catalyzed carbocyclization/Suzuki–Miyaura cross-coupling reactions in a protic medium. The key step is an asymmetric Lewis acid-promoted carbonyl-ene reaction to a chiral glyosylate ester to establish the 1α-hydroxyl group of 1α,25-dihydroxyvitamin D3 and its derivatives