ABSTRACT
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.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Pyrones/chemical synthesis , Pyrones/pharmacology , Amination , Catalysis , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Enzyme Inhibitors , Glycine/analogs & derivatives , Glycine/chemistry , Hypoglycemic Agents , Kinetics , Molecular Structure , Oxidation-Reduction , Pyrones/chemistry , Ruthenium/chemistry , StereoisomerismABSTRACT
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.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacology , Neurokinin-1 Receptor Antagonists , Catalysis , Cyclopentanes , Heterocyclic Compounds, 4 or More Rings/chemistry , Humans , Molecular Structure , Palladium/chemistry , StereoisomerismABSTRACT
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.
