RCM macrocyclization made practical: an efficient synthesis of HCV protease inhibitor BILN 2061.
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.
Shu
Chutian
C
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield Connecticut 06877, USA. chutian.shu@boehringer-ingelheim.com
Zeng
Xingzhong
X
Hao
Ming-Hong
MH
Wei
Xudong
X
Yee
Nathan K
NK
Busacca
Carl A
CA
Han
Zhengxu
Z
Farina
Vittorio
V
Senanayake
Chris H
CH
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*
C479555:BILN 2061; D002219:Carbamates; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles