title: Stereoselective synthesis of a potent thrombin inhibitor by a novel P2-P3 lactone ring opening.
abstract: The concise synthesis of a potent thrombin inhibitor was accomplished by a mild lactone aminolysis between an orthogonally protected bis-benzylic amine and a diastereomerically pure lactone. The lactone was synthesized by the condensation of l-proline methyl ester with an enantiomerically pure hydroxy acid, which in turn was synthesized by a highly stereoselective (>500:1 er) and productive (100,000:1, S/C) enzymatic reduction of an alpha-ketoester. In addition, a second route to the enantiomerically pure lactone was accomplished by a diastereoselective ketoamide reduction.
authors.affiliation: Department of Process Research, Merck Research Laboratories, Merck & Co., 466 Devon Park Drive, Wayne, Pennsylvania 19087, USA. todd_nelson@merck.com
authors.forename: Todd D
authors.initials: TD
authors.lastname: Nelson
authors.forename: Carl R
authors.initials: CR
authors.lastname: LeBlond
authors.forename: Doug E
authors.initials: DE
authors.lastname: Frantz
authors.forename: Louis
authors.initials: L
authors.lastname: Matty
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Mitten
authors.forename: Damian G
authors.initials: DG
authors.lastname: Weaver
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Moore
authors.forename: Jaehon M
authors.initials: JM
authors.lastname: Kim
authors.forename: Russell
authors.initials: R
authors.lastname: Boyd
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Kim
authors.forename: Kodzo
authors.initials: K
authors.lastname: Gbewonyo
authors.forename: Mark
authors.initials: M
authors.lastname: Brower
authors.forename: Michael
authors.initials: M
authors.lastname: Sturr
authors.forename: Kathleen
authors.initials: K
authors.lastname: McLaughlin
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McMasters
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kress
authors.forename: James M
authors.initials: JM
authors.lastname: McNamara
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Dolling
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007783:Lactones / Q000737:chemistry*; D015394:Molecular Structure; D013237:Stereoisomerism; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D007783:Lactones; D013917:Thrombin