title: RCM macrocyclization made practical: an efficient synthesis of HCV protease inhibitor BILN 2061.
abstract: We report here that dramatic improvement of the key RCM reaction in the synthesis of HCV protease inhibitor BILN2061 can be achieved by N-substitution of the diene substrate with an electron-withdrawing group. Mechanistic studies using 1H NMR spectroscopy showed an unprecedented switch of the initiation sites and the correlation between such switch and the results of RCM, from the unmodified to the modified substrates. We also provided theoretical evidence that such modification may also increase the thermodynamic preference of the macrocyclic product over the diene substrate.
authors.affiliation: Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield Connecticut 06877, USA. chutian.shu@boehringer-ingelheim.com
authors.forename: Chutian
authors.initials: C
authors.lastname: Shu
authors.forename: Xingzhong
authors.initials: X
authors.lastname: Zeng
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Hao
authors.forename: Xudong
authors.initials: X
authors.lastname: Wei
authors.forename: Nathan K
authors.initials: NK
authors.lastname: Yee
authors.forename: Carl A
authors.initials: CA
authors.lastname: Busacca
authors.forename: Zhengxu
authors.initials: Z
authors.lastname: Han
authors.forename: Vittorio
authors.initials: V
authors.lastname: Farina
authors.forename: Chris H
authors.initials: CH
authors.lastname: Senanayake
mesh_terms: D002219:Carbamates / Q000737:chemistry*; D003500:Cyclization; D016174:Hepacivirus / Q000201:enzymology*; D047028:Macrocyclic Compounds / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry*; D013844:Thiazoles / Q000737:chemistry*
chemical_list: C479555:BILN 2061; D002219:Carbamates; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles