Stereoselective synthesis of a potent thrombin inhibitor by a novel P2-P3 lactone ring opening.
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.
Nelson
Todd D
TD
Department of Process Research, Merck Research Laboratories, Merck & Co., 466 Devon Park Drive, Wayne, Pennsylvania 19087, USA. todd_nelson@merck.com
LeBlond
Carl R
CR
Frantz
Doug E
DE
Matty
Louis
L
Mitten
Jeffrey V
JV
Weaver
Damian G
DG
Moore
Jeffrey C
JC
Kim
Jaehon M
JM
Boyd
Russell
R
Kim
Pei-Yi
PY
Gbewonyo
Kodzo
K
Brower
Mark
M
Sturr
Michael
M
McLaughlin
Kathleen
K
McMasters
Daniel R
DR
Kress
Michael H
MH
McNamara
James M
JM
Dolling
Ulf H
UH
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007783:Lactones / Q000737:chemistry*; D015394:Molecular Structure; D013237:Stereoisomerism; D013917:Thrombin / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D007783:Lactones; D013917:Thrombin