Asymmetric synthesis of highly functionalized tetrahydropyran DPP-4 inhibitor.

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.

Enantioselective, biocatalytic reduction of 3-substituted cyclopentenones: application to the asymmetric synthesis of an hNK-1 receptor antagonist.

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.

A highly stereoselective synthesis of optically active trisubstituted 1,2-ethylenediamines: the first example of grignard addition to N-diphenylphosphinoyl ketimines derived from amino acids.

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.