Concise asymmetric synthesis of a (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid-derived sulfonamide and ethyl esterElectronic supplementary information (ESI) available: 1H and 13C NMR spectra for compounds 1b, 2, 3, 4a and 8, and chiral HPLC chromatograms for 1b, 2, 3 and 4a. See DOI: 10.1039/c3ob41394b

The development and demonstration of short, robust and chromatography-free sequences for the preparation of a (1 R ,2 S )-1-amino-2-vinylcyclopropane-carboxylic acid-derived sulfonamide and ethyl ester in ≥99% ee are described. Both compounds are common building blocks in multiple preparations of potent HCV NS3 protease inhibitors. The robustness of the asymmetric cyclopropanation of ( E )- N -benzylideneglycine ethyl ester under phase transfer catalysis conditions is significantly improved based on a detailed mechanistic investigation that included an analysis of the catalyst decomposition pathway, a postulated model for the stereo-selectivity that was guided by calculations and rigorous quality control of the starting materials and reagents. Wet milling has been demonstrated to dramatically accelerate this phase transfer reaction. A bench stable benzylidene-protected primary 1-amino-2-vinylcyclopropane amide intermediate was isolated and its reliable enantiomeric enrichment was achieved by a controlled crystallization process. A chemical resolution procedure was identified using di- p -toluoyl-( d )-tartaric acid to access (1 R ,2 S )-1-amino-2-vinyl-cyclopropanecarboxylic ester in high ee. The development and demonstration of short, robust and chromatography-free sequences for the preparation of a (1 R ,2 S )-1-amino-2-vinylcyclopropane-carboxylic acid-derived sulfonamide and ethyl ester in ≥99% ee are described.