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

Abstract

AbstractThe 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.