Chiral gold(I) vs chiral silver complexes as catalysts for the enantioselective synthesis of the second generation GSK-hepatitis C virus inhibitor

Article abstract of DOI:10.3762/bjoc.7.111

The synthesis of a GSK 2nd generation inhibitor of the hepatitis C virus, by enantioselective 1,3-dipolar cycloaddition between a leucine derived iminoester and tert-butyl acrylate, was studied. The comparison between silver(I) and gold(I) catalysts in th

Full text of DOI:10.3762/bjoc.7.111

Chiral gold(I) vs chiral silver complexes as catalysts
for the enantioselective synthesis of the second
generation GSK-hepatitis C virus inhibitor
María Martín-Rodríguez1, Carmen Nájera*1,§, José M. Sansano*1,§,
Abel de Cózar2 and Fernando P. Cossío*2,¶
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 988–996.
1Departamento de Química Orgánica e Instituto de Síntesis Orgánica,
Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain and
2Departamento de Química Orgánica I, Facultad de Química,
Universidad del País Vasco, Apdo. 1072, E-20018 San Sebastián,
Spain
doi:10.3762/bjoc.7.111
Received: 15 April 2011
Accepted: 14 June 2011
Published: 19 July 2011
Email:
This article is part of the Thematic Series "Gold catalysis for organic
synthesis".
María Martín-Rodríguez - mmartin@ua.es; Carmen Nájera* -
cnajera@ua.es; José M. Sansano* - jmsansano@ua.es;
Fernando P. Cossío* - fp.cossio@ua.es
Guest Editor: F. D. Toste
* Corresponding author
© 2011 Martín-Rodríguez et al; licensee Beilstein-Institut.
License and terms: see end of document.
§ Corresponding author for experimental details
¶ Corresponding author for computational data
Keywords:
BINAP; 1,3-dipolar cycloaddition; gold; HCV; phosphoramidite; silver;
viral inhibitor
Abstract
The synthesis of a GSK 2nd generation inhibitor of the hepatitis C virus, by enantioselective 1,3-dipolar cycloaddition between a
leucine derived iminoester and tert-butyl acrylate, was studied. The comparison between silver(I) and gold(I) catalysts in this reac-
tion was established by working with chiral phosphoramidites or with chiral BINAP. The best reaction conditions were used for the
total synthesis of the hepatitis C virus inhibitor by a four step procedure affording this product in 99% ee and in 63% overall yield.
The origin of the enantioselectivity of the chiral gold(I) catalyst was justified according to DFT calculations, the stabilizing
coulombic interaction between the nitrogen atom of the thiazole moiety and one of the gold atoms being crucial.
Introduction
The prevalence of chronic hepatitis C virus (HCV) infection is virus (belonging to the Flaviviridae family) is present in six
such that it is estimated to be suffered by around 200 million major genotypes in the world’s industrialized nations,
people worldwide [1]. This enveloped single-stranded RNA genotype 1 being the most prevalent, followed by genotype 2
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Beilstein J. Org. Chem. 2011, 7, 988–996.
and 3. Due to the poor toleration of the current therapy, and the
lack of an appropriate vaccine, researchers working on strate-
gies for developing antivirals have tried to attack viruses at
every stage of their life cycles, namely attachment to a host cell,
replication of viral components, assembly of viral components
into complete viral particles and release of viral particles able to
infect new hosts cells. Inside the infected hepatocytes, struc-
tural E1 and E2 and non-structural proteins such as NS2, NS3
(which bear serine proteinase, helicase, and NTPase activities),
NS4A, NS4B, NS5A (regulators of RNA replication), and
NS5B (the RNA-dependent RNA polymerase) are generated
[2,3] and, in fact, constitute the main targets. At the moment,
there are many drugs under clinical trial evaluation, the com-
pounds targeting HCV replication being the most promising
candidates to achieve a sustained virological response [1,4].
Several years ago, a high-throughput screening of the Glaxo-
SmithKline compound collection identified a series of small
pyrrolidine molecules, e.g., 1 (Figure 1), able to inhibit the
RNA-dependent RNA polymerase of the virus responsible for
Figure 1: More active GSK HCV inhibitors.
hepatitis C (genotype 1g) [5]. Thus, their high replication rates and other derivatives including compounds 2, was achieved in
(billions of copies per day) can be drastically suppressed by the several steps using, as the key reaction, the silver(I) or
inhibition of the NS5B RNA-dependent RNA polymerase lithium(I)-metalloazomethine ylide, under basic conditions, and
enzyme, which is the primary target for oral antiviral agents tert-butyl acrylate. The enantiomeric samples were isolated by
[6,7]. In further studies, a second generation of antiviral agents semi-preparative chiral HPLC [9,10]. The first endo-diastereos-
2 and 3 (Figure 1), offering a greater dynamic range even for elective synthesis of the key precursor 5a (HetAr = 2-thienyl),
HCV genotype 1b, was published [5,8,9]. These molecules of the antiviral agent 1 (96% de), was achieved by our group
incorporated a 2-thiazole heterocycle instead of the 2-thienyl from imine 6a (HetAr = 2-thienyl; R1 = Me) in the presence of
group, together with a more hydrophobic environment at the the acrylate derived from (R)-methyl lactate [19]. However, the
amido group [9-12]. However, the design of improved broader most straightforward, and also faster, approach to the enan-
spectrum compounds, capable of effective inhibition of geno- tiomeric formation of this non-nucleosidic antiviral agent 1 is
types 1a and 1b, is desirable. In this sense, GSK625433 (4) based on a catalytic enantioselective 1,3-DC [20-24]. The first
(Figure 1) has exhibited a good pharmacokinetic profile in reported enantioselective overall synthesis of the structure 1
preclinical animal species [13].
was catalyzed by a chiral phosphoramidite and AgClO4 [25,26],
although the synthesis of the five-membered core has also been
The synthesis of the endo-pyrrolidine core of 5 is the key step published using chiral calcium complexes [27,28].
for the preparation of these antiviral agents, and can be effi-
ciently achieved by a 1,3-dipolar cycloaddition (1,3-DC) be- In addition, for the second generation antivirals 2 or 3, the effi-
tween the corresponding azomethine ylide and an alkyl acrylate ciency of the Lewis acid-catalyzed 1,3-DC, following the route
[14-18] (Scheme 1). The first synthesis of racemic product 1, shown in Scheme 1, was combined with hydroquinine as chiral
Scheme 1: Retrosynthetic analysis of antiviral structures.
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Beilstein J. Org. Chem. 2011, 7, 988–996.
base (6 mol %) together with silver acetate (3 mol %), and this
afforded moderate enantioselectivities (70–74%) of 5b, in such
a way that a further 1,1’-binaphthyl-2,2’-dihydrogen phosphate
assisted chiral resolution was required to increase the optical
purity of the target molecule [11]. Chiral calcium(II) complexes
have been used for the synthesis of a similar key molecule 5b
(R1 = t-Bu, 88% ee), but the overall synthesis of the antiviral
drug was not reported [27,28].
In this article, we describe the full study concerning the enantio-
selective synthesis of product 5b using silver(I) or gold(I)
complexes, generated from chiral phosphoramidites or BINAP
as ligands, in order to prepare antiviral agent 2a.
Results and Discussion
The efficiency of the chiral phosphoramidite/silver(I) salts
[25,26,29] and BINAP/Ag(I) salts [30,31] in 1,3-DC, following
the general pattern shown in Scheme 1, has been demonstrated
by our group, establishing a wider scope and sensibly higher
enantioselectivities for the reactions performed in the presence
of chiral phosphoramidite/silver(I) complexes [24]. Concerning
enantioselective gold(I)-catalyzed 1,3-DC, the classical cyclo-
addition starting from iminoesters 6 has not been so extensively
explored. Reports of chiral transformations involving azlac-
tones [32,33] and iminoesters 6 [34], which employed chiral
diphosphines and gold(I) salts, have been published showing
very good endo-diastereoselectivities and moderate to excellent
enantioselectivities. However, the use of acrylates as dipo-
larophiles has only been explored with the 2-thienyliminoesters
6a.
Figure 2: Chiral phosphoramidites tested in this study.
Therefore, based on our experience of silver(I)- and gold(I)-
catalyzed 1,3-DC involving azomethine ylides derived from
α-iminoester 6b and tert-butyl acrylate, we selected a series of when AgClO4 or AgSbF6 were employed as anion interchange
known chiral phosphoramidite ligands (Figure 2), which were agents. Just a small conversion, with some side products, and
prepared according to the literature [35]. The chiral phospho- null enantioselectivity was observed in the crude reaction
ramidite/silver(I) complexes were generated in situ by mixing mixtures obtained when using (Sa)-7/AuTFA (Table 1, entry 4).
equimolar amounts of both components at room temperature for When the reaction was carried out in the presence of chiral
30 min. Chiral phosphoramidite/AuCl complexes were gener- ligand (Ra,R)-8 the enantioselectivities were low or moderate in
ated according to the literature [36] and, finally, underwent the examples concerning AgClO4 and AgTFA (TFA = trifluo-
anion interchange in the presence of the corresponding silver roacetate anion), respectively (Table 1, entries 5 and 7). Surpris-
salt. The precipitate was filtered through a celite pad and used ingly, the reaction involving this chiral ligand 8 combined with
without any other additional treatment.
AgSbF6 afforded a good yield of the enantiomerically pure
cycloadduct 5b (Table 1, entry 6). Attempts to increase the
All of the reactions were performed at room temperature, enantioselectivity, in the example run with AgTFA, by
employing a 5 mol % of both catalyst and base, for 17 h replacing triethylamine by diisopropylethylamine (DIPEA)
(Scheme 1). Reactions between iminoester 6b and tert-butyl were not successful, and only a slight increment of enan-
acrylate, which employed silver complexes derived from tiomeric excess was observed (Table 1, entry 8). Again, the
Monophos (Sa)-7 ligand, afforded racemic endo-cycloadduct 5b gold complex (Ra,R)-8/AuTFA did not give the expected reac-
(Table 1, entries 1–3). The analogous reaction catalyzed by tion product (Table 1, entry 9). The employment of this
chiral phosphoramidite 7/gold(I) complexes did not occur at all matched combination with (Ra,R)-8 was justified by the low
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Beilstein J. Org. Chem. 2011, 7, 988–996.
enantioselectivity achieved through the use of (Ra,S)-8 in the described opportunities provided by chiral phosphoramidite
same transformation (not shown in Table 1). The widely used ligands as a part of gold(I) complexes, their activity (see
chiral ligand (Sa,R,R)-9 has also been similarly studied. In this Table 1) was negligible, until now, when applied in the 1,3-DC
case, the matched combination was determined in previous represented in Scheme 2.
works that investigated the scope of enantioselective silver(I)-
catalyzed 1,3-DC of azomethine ylides and dipolarophiles
Table 1: Optimization of the 1,3-dipolar cycloaddition of 6b and tert-
[25,29]. The enantioselectivities were moderate, even when
using AgSbF6, and the effect of the added base was negligible
(Table 1, entries 10–14). The process catalyzed by the (Sa,R,R)-
9/AuTFA was not suitable (Table 1, entry 15). The more steri-
cally hindered chiral phosphoramidite (Sa,R,R)-10 did not afford
any interesting results because the conversions were extremely
low after 2 days reaction, and the crude reaction mixture was
very complex (1H NMR analysis) (Table 1, entries 16–18).
However, a good result was obtained when phosphoramidite
(Sa,R,R)-11 was tested together with AgClO4. The high enantio-
selectivity achieved for 5b (86% ee) is in contrast to the
racemic samples identified when either AgSbF6 or AgTFA were
employed as co-catalysts (Table 1, entries 19–21). Biphenol
derived ligand (R,R)-12 generally furnished good yields of the
cycloadduct 5b but with a low enantiodiscrimination (Table 1,
entries 22–24). In many examples, although the reactions were
performed at lower temperatures (0 or −20 °C, not shown in Ta-
ble 1) the resulting enantioselectivities did not suffer noticeable
variations. In all of the cases given in Table 1, the endo-
cycloadduct was exclusively generated, and the absolute con-
figuration of 5b was established by extrapolation with the
results previously obtained for each chiral catalyst [25,26,28-
30,33]. According to these results the combination of chiral
phosphoramidite and silver(I) salt is much more appropriate
than the analogous one made with gold(I) salts. Especially
useful is the reaction of (Ra,R)-8/AgSbF6 catalytic complex
affording enantiomerically pure cycloadduct endo-5b. It is
worth mentioning that chiral phosphoramidite/gold(I)
complexes, formed by anion interchange of the corresponding
phosphoramidite/AuCl complex and AgSbF6 [36] or AgBF4
[37,38], have been successfully employed in enantioselective
butyl acrylate using chiral phosphoramidite ligands.
Entry Catalysta
Base
Yieldb (%) eec (%)
___d
1
(Sa)-7/AgClO4
Et3N
rac
___d
2
(Sa)-7/AgSbF6
Et3N
rac
___d
3
(Sa)-7/AgTFA
Et3N
rac
___d
___d
4
(Sa)-7/AuTFA
DIPEA
Et3N
5
(Sa,R)-8/AgClO4
(Sa,R)-8/AgSbF6
(Sa,R)-8/AgTFA
(Sa,R)-8/AgTFA
(Sa,R)-8/AuTFA
(Sa,R,R)-9/AgClO4
(Sa,R,R)-9/AgSbF6
(Sa,R,R)-9/AgSbF6
(Sa,R,R)-9/AgTFA
(Sa,R,R)-9/AgTFA
(Sa,R,R)-9/AuTFA
82
20
6
Et3N
82
99
7
Et3N
82
60
8
DIPEA
DIPEA
DIPEA
Et3N
82
64
___d
___d
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
86
30
40
40
50
40
___d
72
DIPEA
Et3N
82
82
DIPEA
DIPEA
82
___d
___d
___d
___d
(Sa,R,R)-10/AgClO4 Et3N
(Sa,R,R)-10/AgTFA Et3N
(Sa,R,R)-10/AgSbF6 Et3N
(Sa,R,R)-11/AgClO4 Et3N
(Sa,R,R)-11/AgSbF6 Et3N
(Sa,R,R)-11/AgTFA Et3N
rac
rac
rac
86
72
___d
rac
rac
30
___d
(R,R)-12/AgClO4
(R,R)-12/AgTFA
(R,R)-12/AgSbF6
Et3N
Et3N
Et3N
79
87
86
40
30
aThe generation of silver catalysts was achieved by mixing equimolar
amounts of silver(I) or gold(I) salt and the corresponding phospho-
ramidite. bAfter flash chromatography (silica gel). The observed
endo:exo ratio was always >98:2 (1H NMR). cDetermined by using
analytical chiral HPLC columns (Daicel, Chiralpak AS). dNot deter-
mined.
cycloaddition of allenedienes [36,37] or allenenes [38] under The chiral ligand (Sa)-BINAP (13) was also tested in the stan-
very mild reaction conditions (0 ºC to r.t.). Despite these dard reaction to access key molecule endo-5b (Scheme 3).
Scheme 2: Optimization of the reaction conditions for the synthesis of the key intermediate 5b.
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Scheme 3: Preparation of the enantiomerically enriched 5b.
AgClO4 was found to be the most appropriate silver salt to
achieve the highest enantioselectivity (88% ee) compared to the
results obtained when other silver salts were employed (Table 2,
entries 1, 3, and 4). In agreement with the previous results, the
reaction with chiral silver complexes at lower temperatures did
not improve the enantioselectivity. According to our previous
work, dimeric chiral gold(I) catalyst [(Sa)-BINAPAuTFA]2
(Sa,Sa)-14 was very efficient in 1,3-DC compared to other cata-
lysts with different stoichiometry or anion nature. The gold
complex (Sa,Sa)-14 was prepared according to the literature [39]
and immediately used in the cycloaddition in the absence of
base because of its bifunctional behaviour, namely the acti-
vation of the basic character of the dipole [34]. However, no
reaction occurred under these conditions (Table 2, entry 5).
Therefore, the presence of the base was crucial for the evolu-
tion of the reaction, as can be seen in entries 6 and 7 of Table 2.
Triethylamine promoted the reaction affording good yield and
good enantioselectivity (78% ee). However, DIPEA-mediated
Table 2: Optimization of the 1,3-dipolar cycloaddition of 6a and tert-
butyl acrylate using chiral (Sa)-BINAP (13) ligand.
Entry Catalysta
Base
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
(Sa)-13/AgClO4
Et3N
Et3Nd
Et3N
Et3N
___
78
88
(Sa)-13/AgClO4
(Sa)-13/AgSbF6
(Sa)-13/AgTFA
(Sa,Sa)-14
75
85
79
72
82
40
___e
___e
(Sa,Sa)-14
Et3N
90
87
92
78
70
99
(Sa,Sa)-14
DIPEA
Et3Nd,f
(Sa,Sa)-14
aThe generation of silver catalysts was achieved by mixing equimolar
amounts of silver(I) and (Sa)-BINAP. bAfter flash chromatography
(silica gel). The observed endo:exo ratio was always >98:2 (1H NMR).
cDetermined using analytical chiral HPLC columns (Daicel, Chiralpak
AS). dReaction performed at 0 °C. eNot determined. fAfter 3 days reac-
tion.
cycloaddition did not improve the enantioselectivity of the ester hydrolysis. The latter step consisted of a first stage TFA-
resulting endo-cycloadduct 5b. Unlike the results obtained with mediated hydrolysis of the tert-butyl ester followed by a basic
silver(I) catalytic complexes at lower temperatures (0 or stage employing a refluxing solution of KOH/MeOH
−20 °C), the gold(I)-catalyzed cycloaddition could be success- (Scheme 4). The final product 2b was finally isolated in 68%
fully carried out at 0 °C resulting in excellent enantiodiscrimin- overall yield (from pyrrolidine 5b) and with 99% ee, or alter-
ation (99% ee) to the detriment of the reaction time, which had natively in 63% overall yield from iminoester 6b.
to be increased to 3 days (Table 2, entry 8). The result obtained
in this last example was excellent but the enantiomeric excess Although the study of the enantioselectivity exhibited by chiral
achieved at room temperature in the reaction performed with phosphoramidite/silver(I) complexes employing DFT calcula-
(Sa)-13/AgClO4 complex is also valuable.
tions was confirmed by our group [25], an explanation for the
excellent results obtained employing the gold complex (Sa,Sa)-
With the most enantiomerically enriched cycloadduct 5b, the 14 (Table 2, entry 8) was needed. In a previous work, we
synthesis of the antiviral agent 2a could be accomplished in two demonstrated that the stereoselectivity of the 1,3-DC employing
conventional steps involving an amidation reaction and a double chiral metallic Lewis bases arises from the blockage of one of
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Beilstein J. Org. Chem. 2011, 7, 988–996.
Scheme 4: Total synthesis of antiviral agent 2b.
the prochiral faces [40]. In this way, our results (in terms of moiety and minimizes the possible steric hindrance with the
DFT calculations) show that there is only one energetically bulky tert-butyl group of the dipolarophile. When a phenyl
accessible conformation due to the high substitution of the substituent is placed to the imino group this planar con-
leucine-derived ylide (Figure 3). In this reactive complex there formation does not exist and, in consequence, a more steric
is an effective blockage of the (2re,5si) prochiral face of the interaction avoids the approach of the mentioned dipolarophile.
ylide. Therefore, the predicted stereochemical outcome corre-
sponds to the exclusive formation of the (2S,4S,5R)-5b Conclusion
cycloadduct, the same as that obtained experimentally.
In this work the complexity of the 1,3-DC reaction of azome-
thine ylides and dipolarophiles (in this case acrylates) was
As shown in Figure 3, the reaction proceeds to a concerted but demonstrated. There are many parameters to control and a small
highly asynchronous cycloaddition in which the endo-approach variation can cause a dramatic effect in the overall enantiodis-
of the dipolarophile is favoured due to a stabilizing interaction crimination of the process. The temperature does not equally
of the carboxylic group and the metallic centre. The computed affect silver(I) and gold(I) catalysts. The effect of the hetero-
activation Gibbs free energy barrier associated with the forma- cycle remains crucial in these transformations because, origi-
tion of (2S,4S,5R)-5b is 23.4 kcal mol−1, which means that the nally, the enantioselectivity of the reaction between methyl
process is feasible at the reaction temperature. It is worth noting benzylideneiminoglycinate and alkyl acrylates failed in the
that there is a stabilizing coulombic interaction between the presence of the silver(I) or the dimeric gold(I) complexes
nitrogen atom of the thiazole moiety (N7) and one of the gold derived from chiral BINAP. The metal cation and the counter-
atoms of the catalyst, both in the TS and the ylide complex. ion are also important in the final result and, in certain cases,
This interaction fixes the planar conformation of the ylide their position with respect to the reaction centre can modify the
Figure 3: Gibbs activation energy and main geometrical features of the computed ylide and transition structures (TS) corresponding to the 1,3-DC of
the Au(I)–ylide complex and tert-butyl acrylate computed at ONIOM(B3LYP/LanL2DZ:UFF) level of theory. High-level and low-level layers are repre-
sented as ball & stick and wireframe models, respectively. Grey numbers in parentheses represent Mulliken charges. Distances are in Å.
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Beilstein J. Org. Chem. 2011, 7, 988–996.
overall reaction and consequently alter the enantioselectivity of represent atoms included in the low-level layer. In the high-
the process. To date, the best reaction conditions to access GSK level layer, the electron correlation was partially taken into
2nd generation antiviral drugs 2a are: The employment of chiral account by using the hybrid functional B3LYP [45-50]
phosphoramidite (Ra,R)-8/AgSbF6 and Et3N (both in 5 mol % combined with Hay-Wadt small core effective potential (ECP)
amount) at r.t. for 2 h, or chiral (Sa,Sa)-14 gold complex and [51] basis set. UFF [52] molecular mechanics force field was
Et3N (both in 5 mol % amount) at 0 °C for 3 days. Whilst phos- employed in the low-level layer. Thermal corrections of Gibbs
phoramidite complexes operated exclusively in the presence of free energies were computed at the same level of theory and
silver salts, the most versatile chiral BINAP ligand could work were not scaled. All stationary points were characterized by
efficiently with both silver(I) or gold(I) cations. The stabilizing harmonic analysis. Reactant intermediates and cycloadducts
coulombic interaction between the nitrogen atom of the thia- have positive definite Hessian matrices. Transition structures
zole moiety and one of the gold atoms of the catalyst both in the show only one negative eigenvalue in their diagonalized force
TS and the ylide complex is the explanation for the success of constant matrices, and their associated eigenvectors were
the gold-catalyzed cycloaddition, in constrast to the observed confirmed to correspond to the motion along the reaction co-
TS involving methyl benzylideneiminoleucinate.
ordinate under consideration.
Experimental
1,3-Dipolar cycloaddition of iminoester 6b and tert-butyl
General. All reactions were carried out in the absence of light. acrylate. General procedure. To a solution of the in situ
Anhydrous solvents were freshly distilled under an argon prepared chiral gold complex or chiral silver complex
atmosphere. Aldehydes were also distilled prior to use for the (0.05 mmol) in toluene (2 mL) was added, at r.t., a solution of
elaboration of the iminoesters. Melting points were determined the iminoester 6b (120 mg, 0.5 mmol) and tert-butyl acrylate
with a Reichert Thermovar hot plate apparatus and are uncor- (109 μL, 0.75 mmol) in toluene (2 mL). In some cases DIPEA
rected. Only the structurally most important peaks of the IR or triethylamine (0.05 mmol) was added (see Tables) and the
spectra (recorded on a Nicolet 510 P-FT and on a Jasco FTIR mixture stirred at r.t. or 0 °C for 2 or 3 days (see Tables). The
4100) are listed. 1H NMR (300 MHz) and 13C NMR (75 MHz) reaction mixture was filtered off through a celite pad, the
spectra were obtained on a Bruker AC-300 using CDCl3 as organic filtrate was directly evaporated and the residue was
solvent and TMS as internal standard, unless otherwise stated. purified by recrystallization or by flash chromatography,
Optical rotations were measured on a Perkin Elmer 341 yielding pure endo-cycloadduct 5b.
polarimeter. HPLC analyses were performed on a JASCO 2000-
series equipped with a chiral column (detailed for each com- (2S,4S,5R)-4-tert-Butyl-2-methyl-2-isobutyl-5-(thiazol-2-
pound in the main text), using mixtures of n-hexane/isopropyl yl)pyrrolidine-2,4-dicarboxylate (5b): Colourless solid; mp
alcohol as mobile phase, at 25 °C. Low-resolution electron >195 °C dec (n-hexane/ethyl acetate); [α]D20 +43 (c 1.00,
impact (EI) mass spectra were obtained at 70 eV on a Shimadzu CH2Cl2, 99% ee by HPLC); IR (neat) νmax: 3330, 1718 cm−1;
QP-5000 and high-resolution mass spectra were obtained on a 1H NMR (300 MHz, CDCl3) δ 7.70, 7.27 (2 × d, J = 3.4 Hz,
Finnigan VG Platform. HRMS (EI) were recorded on a 2H, CHCHS), 4.83 (d, J = 7.5 Hz, 1H, CHCS), 3.73 (s, 3H,
Finnigan MAT 95S. Microanalyses were performed on a Perkin OCH3), 3.41 (q, J = 7.8 Hz, 1H, CHCHN), 3.25 (br. s, 1H, NH),
Elmer 2400 and a Carlo Erba EA1108. Analytical TLC was 2.79, 2.10 (2 × dd, J = 13.5, 7.9 Hz, 2H, CH2CCO), 1.76–1.69
performed on Schleicher & Schuell F1400/LS silica gel plates (m, 2H, CH2CH), 1.54–1.48 (m, 1H, CH2CH), 1.17 (s, 9H,
and the spots were visualized under UV light (λ = 254 nm). For (CH3)3), 0.94, 0.85 (2 × d, J = 6.2 Hz, 6H, 2 × CH3C); 13C
flash chromatography we employed Merck silica gel 60 NMR (75 MHz, CDCl3) δ 176.2, 170.8, 170.6 (2 × CO and
(0.040–0.063 mm). Ligands 7–12 were prepared according to CSN), 142.4, 118.8 (CHCHS), 80.6 (C(CH3)3), 68.3 (COCN),
the reported procedure (see text). All of the transformations 61.7 (CHCS), 52.2 (OCH3), 49.6 (CHCO), 49.3 (CH2CCO),
performed with silver catalysts were performed in the absence 39.5 (CH2CH), 27.6 ((CH3)3), 25.0 (C(CH3)2), 24.3, 22.9 (2 ×
of light. The synthesis of the already characterized chiral com- CH3C); EIMS m/z (% relative intensity): 368 (M+, 1), 310 (51),
plex (Sa,Sa)-14 was performed according to the published 295 (16), 255 (23), 254 (14), 253 (100); HRMS calcd for
procedure [39].
C18H28N2O4S, 368.1770; found, 368.1761; HPLC (Chiralpak
AD-H), n-hexane:iPrOH 95/5, 1 mL/min, λ = 225 nm, tR,maj =
Computational methods. Hybrid QM/MM calculations for 12 min, tR,min = 18 min.
optimizations of saddle points were performed in terms of
ONIOM [41-43] method implemented in GAUSSIAN09 suite Synthesis of the antiviral agent 2b. Compound (2S,4S,5R)-5b
of programs [44]. Ball & stick model in Figure 3 shows atoms (1.2 mmol, 441 mg) was dissolved in dichloromethane (25 mL),
included in the high-level layer, and a wire model is used to and pyridine (2.4 mmol, 174 μL) and 4-(trifluoromethyl)-
994

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2. Tellinghuisen, T. L.; Evans, M. J.; von Hahn, T.; You, S.; Rice, C. M.
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benzoyl chloride (1.2 mmol, 182 μL) were slowly added at
0 °C. The resulting mixture was refluxed for 1 day and the
solvent was removed under vacuo (15 Torr). Crude compound
(2S,4S,5R)-15, was allowed to react with trifluoroacetic acid/
dichloromethane mixture (9.6 mL/18 mL). The resulting mix-
ture was stirred at r.t. overnight and the solvent evaporated
under vacuo. The residue was dissolved in a 1 M solution of
KOH in a 4/1 MeOH/H2O (50 mL) and refluxed for 16 h.
Methanol was evaporated and aqueous HCl (0.5 M, 20 mL) and
ethyl acetate were added (2 × 20 mL). The combined organic
phases were dried (MgSO4) and evaporated, yielding the crude
compound (2S,4S,5R)-2b, which was recrystallized from a mix-
ture containing n-hexane/ethyl acetate.
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(2S,4S,5R)-2-Isobutyl-5-(thiazol-2-yl)-1-[4-(trifluoromethyl)-
benzoyl]pyrrolidine-2,4-dicarboxylic acid (2b): Pale brown
solid; mp >130 °C dec (n-hexane/ethyl acetate); [α]D20 +35
(c 0.3, toluene, 99% ee); IR (neat) νmax: 3100, 1731,
1693 cm−1; 1H NMR (300 MHz, CD3COCD3) δ 8.15 (d, J =
7.5 Hz, 2H, ArH), 7.80–7.64 (m, 3H, ArH and CHCHS), 7.29
(d, J = 3.4 Hz, 1H, CHCHS), 5.85 (d, J = 8.7 Hz, 1H, CHNS),
4.01–3.81 (m, 1H, CHCO), 2.84 (t, J = 13.3 Hz, 1H, CH2CCO),
2.34 (dd, J = 13.2, 6.5 Hz, 1H, CH2CCO), 1.28 (m, 4H, CH2CH
and 2 × OH), 1.14–1.06 (m, 1H, CH2CH), 0.85 (m, 6H, 2 ×
CH3C); 13C NMR (75 MHz, CDCl3) δ 172.4, 169.1, 168.9,
167.4 (3 × CO and CNS), 141.1, 134.2, 134.1, 130.2, 126.9,
125.4, 120.9, (ArC, CF3, and CHCHS), 69.7 (COCN), 65.3
(NCH), 51.39 (CHCO), 42.3 (CH2CCO), 35.3 (CH2CH), 25.7
(CH(CH3)2), 24.4, 24.2 (CH(CH3)2); ESIMS m/z (% relative
intensity) 470 (M+, 2); HRMS calcd for C21H21F3N2O5S,
470.4620; found, 470,4631; HPLC (Chiralpak AD-H),
n-hexane:iPrOH 85/15, 0.1 mL/min, λ = 250 nm), tR,maj =
12.5 min, tR,min = 15.5 min.
The potent activity of these series of products was correlated with the
binding site identification and genotypic profiling of HCV polymerase
inhibitors.
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Fernandes, S.; Guidetti, R.; Haigh, D.; Hartley, C. D.; Howes, P. D.;
Jackson, D. L.; Jarvest, R. L.; Lovegrove, V. L. H.; Medhurst, K. J.;
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Acknowledgements
This work has been supported by the DGES of the Spanish
Ministerio de Ciencia e Innovación (MICINN) (Consolider
INGENIO 2010 CSD2007-00006, FEDER-CTQ2007-62771/
BQU, CTQ2007/67528, CTQ2010-20387 and by the Hispano-
Brazilian project PHB2008-0037-PC), Generalitat Valenciana
(PROMETEO/ 2009/039), the Basque government (Grant
IT-324-07) and by the University of Alicante. M. M.-R. Also
thanks DGES for a grant. The authors also thank the SGI/IZO-
SGIker of UPV/EHU for allocation of computational resources.
13.Haigh, D.; Amphlett, E. M.; Bravi, G. S.; Bright, H.; Chung, V.;
Chambers, C. L.; Cheasty, A. G.; Convey, M. A.; Maire, A.; Ellis, M. R.;
Fenwick, R.; Gray, D. F.; Hartley, C. D.; Howes, P. D.; Jarvest, R. L.;
Medhurst, K. J.; Mehbob, A.; Mesogiti, D.; Mirzai, F.; Nerozzi, F.; Parry,
N. R.; Roughley, N. R.; Skarynzski, T.; Slater, M. J.; Smith, S. A.;
Stocker, R.; Theobald, C. J.; Thomas, P. J.; Thommes, P. A.; Thorpe,
J. H.; Wilkinson, C. S.; Williams, E. W.
Identification of GSK625433: A novel clinical candidate for the
treatment of hepatitis C.
233rd ACS National Meeting, Chicago, IL, March 25-29, 2007, Division
of Medicinal Chemistry, First Time Disclosure of Clinical Candidates.
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