Synthesis and resolution of diethyl (1S,2S)-1-amino-2-vinylcyclopropane-1-phosphonate for HCV NS3 protease inhibitors |
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Authors: | Hyung-Jung Pyun Kleem Chaudhary John R Somoza X Christopher Sheng Choung U Kim |
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Institution: | Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA |
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Abstract: | We herein describe an efficient synthesis of optically active diethyl 1-amino-2-vinylcyclopropane-1-phosphonate (analogous to 1-amino-2-vinylcyclopropane-1-carboxylate). The racemic phosphonate diethyl ester was obtained from an imine derived from aminomethylphosphonate diester and trans-1,4-dibromo-2-butene. Crystallizations of the dibenzoyl-l-tartaric acid salt allowed for separation of enantiomers. The enantiomerically pure material was used to synthesize an extremely potent tripeptide phosphonate inhibitor of HCV NS3 protease. X-ray crystal structure of the inhibitor bound to the HCV NS3 protease confirmed the absolute stereochemistry of the title compound. |
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