inhibitor was developed in our laboratories via a rational
approach involving the use of traditional medicinal chemistry,
parallel synthesis, and structural data for the optimization
of binding properties and downstream biopharmaceutical
properties.7 BILN 2061 is the first compound of its class to
have reached clinical trials. It has shown oral bioavailability
and antiviral effect in humans infected with HCV.8 In the
optimization phase that led to the discovery of BILN 2061,
we developed a synthetic approach to support SAR studies
and to produce several grams of drug substance for preclini-
cal pharmacological studies. The core of BILN 2061 was
built in a convergent manner using four building blocks:
three nonnatural amino acids (P1, P2, and P3, Figure 1)9
and a 4-quinolinol moiety. The preparation and ultimate
assembly of these building blocks are disclosed in this paper.
A retrosynthetic analysis of BILN 2061 suggests that its
15-membered ring can be formed by ring-closing olefin
metathesis of an acyclic tripeptide precursor (Figure 1).10
This acyclic tripeptide precursor can, in turn, be assembled
using standard solution peptide coupling procedures. Intro-
duction of the quinoline moiety onto P2 can be achieved
early or late in the synthetic sequence by an SN2 reaction
with a hydroxyquinoline and an “activated” hydroxyproline
as the electrophile. However, we recognized that a late
introduction renders the sequence more convergent and was
likely better suited for a quinoline bearing potentially
chemically reactive substituents. So, for BILN 2061 we
favored an SN2 coupling strategy between a 4-hydroxyquino-
line fragment and a preassembled macrocyclic ring contain-
ing a cis-(4S)-hydroxyproline residue.
Figure 1. Retrosynthesis of BILN 2061.
The prohibitive cost of cis-hydroxyproline and its pro-
pensity to lactonize during peptide coupling procedures led
us to envisage a double inversion sequence making use of
the more readily available trans isomer. We therefore coupled
(2R,3S)-3-vinyl-2-amino-2-cyclopropylcarboxylic acid (ACCA)
methyl ester 1 (prepared in a racemic form and then resolved
via an enzymatic hydrolysis of the methyl ester11) to
commercially available trans-(2S,4R)-Boc-hydroxyproline 2
using standard peptide coupling reaction procedures with
O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetra-
fluoroborate (TBTU, Scheme 1).12 The resulting suitably
protected P1-P2 dipeptide 3 was then epimerized at the
4-position of proline via a Mitsunobu reaction using p-
nitrobenzoic acid (PNBA).13 Regioselective hydrolysis of the
p-nitrobenzoate group afforded Boc-cis-(2S,4S)-4-hydroxy-
proline-(2R,3S)-vinyl-ACCA methyl ester 4.
(7) (a) Llina`s-Brunet, M.; Bailey, M.; Bolger, G.; Brochu, C.; Faucher,
A.-M.; Ferland, J.-M.; Garneau, M.; Ghiro, E.; Gorys, V.; Grand-Maˆıtre,
C.; Halmos, T.; Lapeyre-Paquette, N.; Liard, F.; Poirier, M.; Rhe´aume, M.;
Tsantrisos, Y.; Lamarre, D. J. Med. Chem. 2004, 47, 1605. (b) Rancourt,
J.; Cameron, D.; Gorys, V.; Lamarre, D.; Poirier, M.; Llina`s-Brunet, M. J.
Med. Chem. 2004, 47, 2511. (c) Goudreau, N.; Cameron, D. R.; Bonneau,
P.; Gorys, V.; Plouffe, C.; Poirier, M.; Lamarre, D.; Llina`s-Brunet, M. J.
Med. Chem. 2004, 47, 123. (d) Bailey, M. D.; Halmos, T.; Goudreua, N.;
Lescop, E.; Llina`s-Brunet, M. J. Med. Chem. 2004, ASAP. (e) Tsantrizos,
Y. S.; Bolger, G.; Bonneau, P.; Cameron, D. R.; Goudreau, N.; Kukolj, G.;
LaPlante, S. R.; Llina`s-Brunet, M.; Nar, H.; Lamarre, D. Angew. Chem.,
Int. Ed. 2003, 42, 1355. (f) Poupart, M. A.; Cameron, D. R.; Chabot, C.;
Ghiro, E.; Goudreau, N.; Goulet, S.; Poirier, M.; Tsantrizos, Y. S. J. Org.
Chem. 2001, 66, 4743. (g) Llina`s-Brunet, M.; Bailey, M.; Fazal, G.; Ghiro,
E.; Gorys, V.; Goulet, S.; Halmos, T.; Maurice, R.; Poirier, M.; Poupart,
M.-A.; Rancourt, J.; Thibeault, D.; Wernic, D.; Lamarre, D. Bioorg. Med.
Chem. Lett. 2000, 10, 2267. (h) LaPlante, S. R.; Aubry, N.; Bonneau, P.
R.; Kukolj, G.; Lamarre, D.; Lefebvre, S.; Li, H.; Llina`s-Brunet, M.; Plouffe,
C.; Cameron, D. R. Bioorg. Med. Chem. Lett. 2000, 10, 2271.
(8) (a) Reiser, M.; Hinrichsen, H.; Benhamou, Y.; Sentjens, R.; Wede-
meyer, H.; Calleja, L.; Forns, X.; Croenlein, J.; Yong, C.; Nehmiz, G.;
Steinmann, G. Hepatology 2003, 38 (Suppl. 1), 221A. (b) Lamarre, D.;
Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Boes,
M.; Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher, A.-M.;
Goudreau, N.; Kawai, S. H.; Kukolj, G.; Lagace, L.; LaPlante, S. R.; Narjes,
H.; Poupart, M.-A.; Rancourt, J.; Sentjens, R. E.; St. George, R.; Simoneau,
B.; Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong,
C.-L.; Llina`s-Brunet, M. Nature 2003, 426, 186. (c) Benhamou, Y.;
Hinrichsen, H.; Sentjens, R.; Reiser, M.; Manns, M. P.; Forns, X.; Avendano,
C.; Cro¨nlein, J.; Nehmiz, G.; Steinmann, G. Hepatology 2002, 36, 304A,
Abst. 563. (d) Hinrichsen, H.; Benhamou, Y.; Reiser, M.; Sentjens, R.;
Wedemeyer, H.; Calleja, J. L.; Forns, X.; Cro¨nlein, J.; Nehmiz, G.;
Steinmann, G.; Hepatology 2002, 36, 297A, Abst. 866.
For the P3 building block, we sought a method suitable
for the preparation of large quantities of material. We favored
a sequence where the key step involves the catalytic
enantioselective hydrogenation of an enamine using the
DUPHOS system developed by Burk et al.14 Commercially
available 7-octene-1,2-diol 5 was cleaved by sodium perio-
(11) The synthesis of P1 is briefly described in: Llina`s-Brunet, M.;
Bailey, M. D.; Cameron, D.; Ghiro, E.; Goudreau, N.; Poupart, M.-A.;
Rancourt, J.; Tsantrizos, Y. S.; Faucher, A.-M.; Halmos, T.; Wernic, D.
M.; Simoneau, B.; Boehringer Ingelheim (Canada) Ltd., U.S. patent
6,323,180 B1, 2000; Chem. Abstr. 132:180871. A more detailed account
of the synthesis of P1 will be reported separately.
(12) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron
Lett. 1989, 30, 1927.
(13) Mitsunobu, O. Synthesis 1981, 1.
(9) Protease subsite nomenclature: Schechter, I.; Berger, A. Biochem.
Biophys. Res. Commun. 1967, 27, 157.
(10) For reviews on olefin metathesis, see: (a) Schrock, R. R.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2003, 42, 4592. (b) Trnka, T. M.; Grubbs, R.
H.; Acc. Chem. Res. 2001, 34, 18. (c) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3012.
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Org. Lett., Vol. 6, No. 17, 2004