RESUMO
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.
Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Pironas/síntese química , Pironas/farmacologia , Aminação , Catálise , Inibidores da Dipeptidil Peptidase IV/química , Inibidores Enzimáticos , Glicina/análogos & derivados , Glicina/química , Hipoglicemiantes , Cinética , Estrutura Molecular , Oxirredução , Pironas/química , Rutênio/química , EstereoisomerismoRESUMO
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.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Catálise , Ciclopentanos , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Estrutura Molecular , Paládio/química , EstereoisomerismoRESUMO
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.