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References and notes
OH
O
1. (a) Cohen, J. Science 1999, 285, 26; (b) Alter, M. J.; Kruszon-Moran, D.; Nainan,
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Deckman, D.; Fellows, K.; Hussain, M.; Cutler, D.; Zhang, J. Presented at the 56th
Annual Meeting of AASLD, 2005, San Francisco, CA.
H
N
HCl .H2N
CO2H
NH2
CONH2
26
N
N
P1
O
P1
O
O
O
a
O
NH
NH
O
NH
NH
39
40
OH
O
H
N
H
NH2
N
N
F
F
NH
b
O
O
O
O
O
NH
NH
5. Venkatraman, S.; Bogen, S. L.; Arasappan, A.; Bennett, F.; Chen, K.; Jao, E.; Liu,
Y.-T.; Lovey, R. G.; Hendrata, S.; Huang, Y.; Pan, W.; Parekh, T.; Pinto, P.; Popov,
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Prelusky, D.; Korfmacher, W.; White, R.; Bogdanowich-Knipp, S.; Pavlovsky, A.;
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41
42
Scheme 9. Reagents and conditions: (a) i—HATU, DMF, DIPEA, ꢀ20 °C, 24 h; (ii)
Cl2CHCO2H, EDCIꢁHCl, DMSO; (b) Cl2CHCO2H, EDCIꢁHCl, DMSO.
6. Nilov, D.; Reiser, O. Adv. Synth. Catal. 2002, 344, 1169.
7. For a review, see: Schobert, R. In Organophosphorus Reagents; Murphy, P. J., Ed.;
Oxford University Press: Oxford, 2004; pp 129–149.
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Ruff, E. Can. J. Chem. 2001, 79, 114.
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2281.
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Csuk, R.; Eversmann, L. Tetrahedron 1998, 54, 6445.
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Org. Lett. 2000, 2, 563.
12. Kirihara, M.; Takuwa, T.; Takizawa, S.; Momose, T. Tetrahedron Lett. 1997, 38,
2853.
13. Upon treatment with TFA, the hydroxyl group of regioisomer 3a cyclized
readily to form the corresponding lactone. The primary amide moiety was
successfully generated by treatment of the lactone with NH3 in MeOH.
14. Burk, M. J.; Allen, J. G.; Kiesman, W. F. J. Am. Chem. Soc. 1998, 120, 657.
15. Compound 44 (Table 2) was obtained as follows: subsequent to Moffatt
oxidation, the TBS ether was deprotected with formic acid at room
temperature for 2 h. Treatment of the residue after workup with sodium
bicarbonate in methanol/water at room temperature for 1 h afforded
compound 44 in essentially quantitative yield.
16. (a) Boehm, H. J.; Banner, D.; Bendels, S.; Kansy, M.; Khun, B.; Mueller, K.; Obst-
Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637; (b) Rosemblum, S.; Huynh, T.;
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973.
600 nM. Further modifications at the P1 position, via introduction
of difluoro susbstituent at the c-position of nor-Val or nor-Leu (51
and 52) afforded less potent inhibitors.
In summary, we have prepared several HCV NS3 protease inhib-
itors containing hydroxyl or fluoro P1 moieties. Sharpless asym-
metric aminohydroxylation reaction was used as a key step to
efficiently generate the desired hydroxy ester intermediates. Inter-
estingly, we noticed that regioselectivity of the reaction was
greatly influenced by the position of the fluoro or hydroxyl/ether
substituent on the olefin substrate. Incorporation of fluoro or hy-
droxyl functionality on the cyclobutyl or cyclopropyl ring resulted
in diminished inhibitor potency. However, difluoro cyclobutyl P1-
containing inhibitor 46 afforded the best rat PK profile, for the ser-
ies reported here. Fluorination of straight chain alkyl moieties
yielded potent inhibitors but lacked desirable rat PK properties.
Thus, the SAR studies described above clearly demonstrate the
stringent requirements at the P1 position for both, enzyme inhibi-
tion and replicon potency.
17. Zhang, R.; Beyer, B. M.; Durkin, J.; Ingram, R.; Njoroge, F. G.; Windsor, W. T.;
Malcolm, B. A. Anal. Biochem. 1999, 270, 268. For the present study, the
substrate Ac-DTEDVVP(Nva)-O-PAP was employed.
18. Lohmann, V.; Korner, F.; Koch, J.-O.; Herian, U.; Theilmann, L.; Bartenschlager,
R. Science 1999, 285, 110.
Acknowledgments
The authors are grateful to the virology and DMPK groups for in
vitro and in vivo studies, respectively.