RESUMEN
A practical synthesis of a highly functionalized tetrahydropyran DPP-4 inhibitor is described. The asymmetric synthesis relies on three back-to-back Ru-catalyzed reactions. A Ru-catalyzed dynamic kinetic resolution (DKR) reduction establishes two contiguous stereogenic centers in one operation. A unique dihydropyran ring is efficiently constructed through a preferred Ru-catalyzed cycloisomerization. Hydroboration followed by a Ru-catalyzed oxidation affords the desired functionalized pyranone core scaffold. Finally, stereoselective reductive amination and subsequent acidic deprotection afford the desired, potent DPP-4 inhibitor in 25% overall yield.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Pironas/síntesis química , Pironas/farmacología , Aminación , Catálisis , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores Enzimáticos , Glicina/análogos & derivados , Glicina/química , Hipoglucemiantes , Cinética , Estructura Molecular , Oxidación-Reducción , Pironas/química , Rutenio/química , EstereoisomerismoRESUMEN
A convergent and enantioselective route to the hNK-1 receptor antagonist (1) is described, which sets all six stereogenic centers with high diastereoselectivity and delivers 1 in only 11 steps and 23% overall yield. The process was enabled by the development of the enantioselective enzymatic reduction of 3-functionalized cyclopentenones and stereospecific Pd-catalyzed etherification coupling of fragments 6 and 7.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Catálisis , Ciclopentanos , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Estructura Molecular , Paladio/química , EstereoisomerismoRESUMEN
The efficient synthesis of optically active trisubstituted 1,2-ethylenediamines is described. Addition of aryl and/or alkyl Grignard reagents to alpha-amino N-diphenylphosphinoyl ketimines derived from alpha-amino acids was demonstrated to afford the desired trisubstituted 1,2-ethylenediamines in good yields and with high diastereoselectivities. Subsequent removal of the diphenyphosphinoyl group from the adduct was smoothly accomplished in reasonable yield without racemization under newly developed reductive conditions.