Síntesis de 1β,25-dihidroxivitamina D₃ y 1,25-dihidroxivitamina D₃ marcada con ¹³C

Se ha llevado a cabo la síntesis de la 1β,25(OH)₂D₃ para realizar estudios de cristalización con el receptor de la vitamina D, con el fin de profundizar en el mecanismo de acción no genómico. Se ha desarrollado una ruta de síntesis de un sintón del anillo A de la vitamina D a partir de compuestos disponibles comercialmente. Se ha llevado a cabo la síntesis de la 1,25D marcada en seis posiciones de su estructura. La obtención de este metabolito se ha conseguido mediante la utilización de la nueva ruta de acceso al anillo A de la 1,25D. Esta ruta permite la introducción de marcaje isotópico con carbono 13 en el anillo A de la vitamina D en los últimos pasos de síntesis

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

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 derivativesThis research was funded by ENDOTHERM GmbH, Xunta de Galicia (GRC/ED431B/20) and the University of Santiago de Compostela (Spain)S