title: Concise asymmetric synthesis of a (1R,2S)-1-amino- 2-vinylcyclopropanecarboxylic acid-derived sulfonamide and ethyl ester.
abstract: The development and demonstration of short, robust and chromatography-free sequences for the preparation of a (1R,2S)-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 (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic ester in high ee.
authors.forename: Sha
authors.initials: S
authors.lastname: Lou
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cuniere
authors.forename: Bao-Ning
authors.initials: BN
authors.lastname: Su
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Hobson
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry*; D015394:Molecular Structure; D044367:Phase Transition; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C587841:(1R,2S)-1-amino- 2-vinylcyclopropanecarboxylic acid; D000998:Antiviral Agents; D003521:Cyclopropanes; D004952:Esters; D011480:Protease Inhibitors; D014753:Vinyl Compounds