Loureiro Martínez, JuliánKattner, LarsMouriño Mosquera, Antonio2022-09-212022-09-212022Eur. J. Org. Chem. 2022, e2022003141434-193Xhttp://hdl.handle.net/10347/29237An 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 derivativeseng© 2022 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are madeAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/A-Ring synthonsCarbonyl-ene reactionChiral β-hydroxy ketones1α-Hydroxyvitamin DPalladiumjournal article10.1002/ejoc.2022003141099-0690open access