Stereoselective synthesis of a potent thrombin inhibitor by a novel P2-P3 lactone ring opening |
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Authors: | Nelson Todd D LeBlond Carl R Frantz Doug E Matty Louis Mitten Jeffrey V Weaver Damian G Moore Jeffrey C Kim Jaehon M Boyd Russell Kim Pei-Yi Gbewonyo Kodzo Brower Mark Sturr Michael McLaughlin Kathleen McMasters Daniel R Kress Michael H McNamara James M Dolling Ulf H |
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Affiliation: | Department of Process Research, Merck Research Laboratories, Merck & Co., 466 Devon Park Drive, Wayne, Pennsylvania 19087, USA. todd_nelson@merck.com |
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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. |
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