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.
Asymmetrization of racemic dicyclopentadiene derivatives was achieved by enantioselective Kharash-Sosnovsky reaction using chiral Cu(II)-tris-or bis-(oxazoline) complex as a catalyst. Optically active acyloxylated dicyclopentadiene derivatives, useful building blocks bearing multiple asymmetric centers, were obtained directly from racemic starting materials in a highly enantioselective manner (up to 87% ee).
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