title: Asymmetric synthesis of highly functionalized tetrahydropyran DPP-4 inhibitor.
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.
authors.affiliation: Process Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zacuto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kohmura
authors.forename: Jon
authors.initials: J
authors.lastname: Rosen
authors.forename: Andrew
authors.initials: A
authors.lastname: Gibb
authors.forename: Mahbub
authors.initials: M
authors.lastname: Alam
authors.forename: Jeremy
authors.initials: J
authors.lastname: Scott
authors.forename: David
authors.initials: D
authors.lastname: Tschaen
mesh_terms: D000586:Amination; D002384:Catalysis; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry; D007004:Hypoglycemic Agents; D007700:Kinetics; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D011753:Pyrones; D012428:Ruthenium; D005998:Glycine