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Stereoselective Synthesis of a Potent Thrombin Inhibitor by a Novel P2−P3 Lactone Ring Opening

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journal contribution
posted on 28.05.2004, 00:00 by Todd D. Nelson, Carl R. LeBlond, Doug E. Frantz, Louis Matty, Jeffrey V. Mitten, Damian G. Weaver, Jeffrey C. Moore, Jaehon M. Kim, Russell Boyd, Pei-Yi Kim, Kodzo Gbewonyo, Mark Brower, Michael Sturr, Kathleen McLaughlin, Daniel R. McMasters, Michael H. Kress, James M. McNamara, Ulf H. Dolling
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 (100000:1, S/C) enzymatic reduction of an α-ketoester. In addition, a second route to the enantiomerically pure lactone was accomplished by a diastereoselective ketoamide reduction.