Toward the Synthesis of Fluorinated Analogues of HCV NS3/4A Serine Protease Inhibitors Using Methyl α-Amino-β-fluoro-β-vinylcyclopropanecarboxylate as Key Intermediate

Article abstract of DOI:10.1021/acs.orglett.5b01216

Synthesis of fluorocyclopropyl building blocks, which constitute the core of various therapeutic agents against the hepatitis C virus, is described. The relevant methyl α-amino-β-fluoro-β-vinylcyclopropanecarboxylate has been used as a key intermediate for the total synthesis of a fluorinated analogue of Simeprevir (TMC 435), a HCV NS3/4A protease inhibitor.

Full text of DOI:10.1021/acs.orglett.5b01216

Letter
pubs.acs.org/OrgLett
Toward the Synthesis of Fluorinated Analogues of HCV NS3/4A
Serine Protease Inhibitors Using Methyl α‑Amino-β-fluoro-β-
vinylcyclopropanecarboxylate as Key Intermediate
Gaelle Milanole,† Floris Andriessen,† Gerald Lemonnier,† Muriel Sebban,† Gael Coadou,†
́
̈
̈
Samuel Couve-Bonnaire,† Jean-Francois Bonfanti,‡ Philippe Jubault,*,† and Xavier Pannecoucke†
̧
†Normandie Universite,
Saint Aignan Cedex, France
́ ́ ̀
COBRA, UMR 6014 & FR 3038, Universite de Rouen, INSA Rouen, CNRS, 1 rue Tesniere, 76821 Mont
‡Janssen Research & Development, Medicinal Chemistry Infectious Diseases, Centre de Recherche Janssen Cilag, Campus de
Maigremont, BP 615, 27106 Val de Reuil Cedex, France
S
* Supporting Information
ABSTRACT: Synthesis of fluorocyclopropyl building blocks, which
constitute the core of various therapeutic agents against the hepatitis C
virus, is described. The relevant methyl α-amino-β-fluoro-β-
vinylcyclopropanecarboxylate has been used as a key intermediate for
the total synthesis of a fluorinated analogue of Simeprevir (TMC 435), a
HCV NS3/4A protease inhibitor.
he hepatitis C virus (HCV) is the leading cause of chronic
Tliver diseases (liver fibrosis, cirrhosis, and hepatocellular
carcinoma), afflicting over 3% of the world population.1 Until
recently, the most effective therapy has been based upon the use
of PEGylated interferon-α in combination with the antiviral drug
ribavirin.2 Unfortunately, approximately 50% of genotype 1
infected patients respond with a sustained virological response,
and the treatment is poorly tolerated.3 Hence, the limited efficacy
of the interferon-based therapy highlights the unmet medical
need for more convenient therapeutics against this emerging
infection.
In the past decades, the NS3/4A protease, which is an essential
protein involved in the virus replication process,4 became an
unavoidable drug target for anti-HCV therapy through the
proven antiviral effect in humans of the macrocyclic noncovalent
inhibitor 1 (BILN 2061). Macrocycle 1, discovered by
Boehringer Ingelheim, displays a nanomolar activity against the
NS3/4A protease (IC50 = 3 nM).5 To date, this class of
macrocylic peptidomimetics has been extensively explored by
medicinal research programs.6 Recent approvals of HCV
protease inhibitors (Boceprevir, Telaprevir, and Simeprevir)
and the NS5B RNA-dependent RNA polymerase inhibitor
Sofosbuvir represent a major step forward. Among them,
numerous new efficient therapeutic agents bear a cyclopropyl
ring in their structural core (Figure 1).7
Indeed, these potent inhibitors are characterized by a 1-amino-
1-carboxyl-2-vinylcyclopropane core, an essential subunit
exhibiting an optimal fit in the hydrophobic S1 pocket of the
NS3 protease.8
As part of our ongoing research program dedicated to the
synthesis of functionalized monofluorocyclopropanes,9 we
decided to explore whether this valuable scaffold could be
incorporated to modulate the pharmaceutical properties of such
Figure 1. Inhibitors of the HCV NS3/4A serine protease.
compounds. Indeed, the replacement of a hydrogen atom by a
fluorine atom is a common and promising strategy in medicinal
chemistry to alter the pharmacological properties of bioactive
compounds such as solubility, lipophilicity, metabolic stability,
and binding properties.10 Moreover, the incorporation of a
fluorine atom in a cyclopropane unit of biomolecules already
proved its relevancy for the design of more powerful therapeutic
agents.9c,e
Received: April 29, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01216
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Organic Letters
Letter
Scheme 1. Synthesis of the Fluorinated Vinylcyclopropane ( )-cis-6
Herein, we report a straightforward synthesis of the fluorinated
analogue of the cyclopropyl core: methyl α-amino-β-fluoro-β-
vinylcyclopropanecarboxylate building block ( )-cis-6. We
report the total synthesis of a fluorinated analogue of 2
(Simeprevir, TMC 435), developed by Janssen Pharmaceutica,
which was recently approved by the FDA (Figure 1),11 from
( )-cis-6.
cyclopropanesulfonamide 14 could be introduced by an
amidation reaction. We envisioned that the introduction of the
quinoline residue 15 onto the cyclopentyl alcohol 16 could be
achieved by a Mitsunobu reaction. Finally, the 14-membered ring
could be fashioned from the fluorinated cyclopropyl amino acid
( )-cis-6 and the building block 16 by a ring-closing metathesis
(RCM) and a peptide coupling (Figure 2).
Total synthesis of compound 13 is depicted in Scheme 2. We
first achieved the peptide coupling reaction between ( )-cis-6
and 1615,16 to obtain the crucial intermediate 17. However,
activation of the acid function of 16 with HBTU and N-
methylmorpholine at 0 °C for 30 min, followed by the
introduction of the amine ( )-cis-6, did not afford the expected
product 17 due to two main side reactions: cyclopropane ring
opening17 from the conjugation of the free amine nitrogen lone
pair in basic conditions with the double bond through the
cyclopropane moiety and intramolecular cyclization in 16
between the alcohol and carboxylic acid functions in cis
configuration, furnishing the corresponding lactone (see
Supporting Information for more details). To prevent these
side reactions, we introduced simultaneous fragments 16 and
( )-cis-6, along with HATU and N-methylmorpholine, at lower
temperature (−15 °C), giving 17 as a mixture of two
diastereoisomers (dr = 1:1) with a good 74% yield. Then,
quinoline 1518 and intermediate 17 were connected via a
Mitsunobu reaction using diisopropylazodicarboxylate and
triphenylphosphine, giving compound 18 in 72% yield (dr =
1:1) (Scheme 2). To construct the macrocycle by RCM of the
olefin, after optimization of reaction parameters, we found out
that the macrocycle 19 could be obtained in 47% yield using
Hoveyda−Grubbs II catalyst in 1,2-dichloroethane at 100 °C.
Interestingly, each diastereoisomer gave rise to only one
configuration of the macrocyclic double bond. These two
diastereoisomeric products were efficiently separated by super-
critical fluid chromatography to provide (7R,9S)-19 and (7S,9R)-
19.19 The methyl ester function of intermediates 19 was
subsequently hydrolyzed using lithium hydroxide at room
temperature to provide the corresponding carboxylic acids
(7R,9S)-20 and (7S,9R)-20 in quantitative and 82% yields,
respectively.
Fluorinated ( )-cis-6 was prepared as outlined in Scheme 1.
Recently, we developed a straightforward cyclopropanation
process from commercially available ethyl dibromofluoroacetate
and electron-deficient alkenes using Zn/LiCl combination.9d
This methodology was successfully applied to the protected
aminoacrylate 7 to generate the cyclopropane diester ( )-8 as a
mixture of diastereoisomers12 (dr cis/trans = 59:41) in 93% yield
on 0.1 mol scale. Subsequently, a diastereoselective and
regioselective hydrolysis of the ethyl ester ( )-8 at low
temperature13 provided after acid/base extraction the carboxylic
acid ( )-cis-9 along with the diester ( )-trans-8 as highly
enriched diastereoisomers. Primary alcohol ( )-cis-10 was
delivered from acid ( )-cis-9 in 68% yield through mixed
anhydride formation and subsequent reduction. Oxidation of
( )-cis-10 with IBX gave quantitatively the corresponding
aldehyde ( )-cis-11.14 Then, ( )-cis-11 was converted to the
corresponding alkene ( )-cis-12 in 86% yield via a Wittig
reaction using triphenylmethylphosphonium bromide. Finally,
removal of the N,N-(di-tert-butyloxycarbonyl) protecting group
upon treatment with 4M HCl in dioxane led to the hydrochloride
salt ( )-cis-6 in a quantitative yield.
With these different fluorocyclopropyl building blocks in hand,
we could have access to numerous fluorinated analogues of
potent inhibitors of NS3/4A protease, as those described in
Figure 1. Among them, in partnership with Janssen Research &
Developement, we turned our attention toward the total
synthesis of fluorinated analogue 13 of the Simeprevir 2 through
a convergent strategy using four key building blocks, including
the highly functionalized fluorinated cyclopropane ( )-cis-6
(Figure 2). To our knowledge, a multistep synthesis based on a
fluorinated vinylcyclopropane scaffold has never been reported
in the literature. The retrosynthetic analysis of the corresponding
fluorinated analogue 13 of Simeprevir 2 suggested that the
To determine the configuration of the macrocyclic double
bond, the two isomers of 20 were analyzed by NMR. The scalar
coupling constant between the olefinic protons H11 and H12
1
(Figure 3) was measured on the H NMR spectrum of each
isomer. The observed values showed that the configuration of the
newly formed double bond differs from one isomer to the other.
Indeed, a large coupling constant of 15.9 Hz, characteristic of a
3Jtrans, was assigned to (11,12E)-cis-20. A smaller one (12 Hz) was
observed for (11,12Z)-cis-20. These conclusions were confirmed
by 1H−1H NOESY. A significantly stronger NOE was observed
between H11 and H12 in (11,12Z)-cis-20 than in (11,12E)-cis-
20, indicating that these two protons are closer in (11,12Z)-cis-
20 than in (11,12E)-cis-20. Finally, 1D 1H−19F HOESY
Figure 2. Retrosynthesis of the fluorinated analogue 13 of Simeprevir 2.
B
DOI: 10.1021/acs.orglett.5b01216
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Organic Letters
Letter
Scheme 2. Synthesis of the Fluoroanalogues 13 of Simeprevir
in DMF at 0 °C for 30 min and subsequent introduction of 14 in
the presence of DMAP and DBU was also unsuccessful even if
this procedure proved to be efficient for the peptide coupling
reaction of a vinylcyclopropyl amino acid.20 Finally, activation of
20a and 20b via a mixed anhydride strategy at 0 °C for 18 h,
followed by reaction with the previously deprotonated cyclo-
propylsulfonamide 14 by a LiHMDS solution,21 afforded the
final targets (7S,9R)-(11,12Z)-cis-13 (13a) and (7R,9S)-
(11,12E)-cis-13 (13b) in 1322 and 83% yield, respectively
(Scheme 2).
Both 13a, which is the exact analogue of Simeprevir, and 13b
were then submitted to biological assay to compare their potency
as anti-HCV agent with Simeprevir 2 (Table 1).11b
Figure 3. NOE/HOE observed for the both isomers of compound 20.
1
1H−1H NOE and H−19F HOE are represented in red and green,
respectively. Bold plain arrows, thin plain arrows, and dashed arrows are
for intense, medium, and weak NOE/HOE, respectively.
Table 1. Antiviral Activity
a
(heteronuclear Overhauser effect spectroscopy) spectra were
recorded for each isomer. In (11,12Z)-cis-20, strong F−H11
HOE and weak F−H12 HOE were observed, which are
consistent with a double bond in Z configuration. On the
contrary, in (11,12E)-cis-20, the strong HOE observed between
F and H12 is in favor of the configuration shown in Figure 3.
Molecular modeling was necessary, in addition to NOESY and
HOESY NMR analysis, to determine the absolute configuration
of C7 and C9 of the fluorinated cyclopropyl. As the chosen
chemical synthesis pathway was expected to lead only to
compounds (11,12E)-cis-20 and (11,12Z)-cis-20, these two
stereoisomers were studied in silico using SYBYL 7.0 (Tripos.
Inc., St. Louis, USA; see Supporting Information for more
details). Our complementary studies of molecular modeling and
NMR experiments allowed us to identify the two products
synthesized as (7S,9R)-(11,12Z)-cis-20 and (7R,9S)-(11,12E)-
cis-20. The 19F chemical shift difference observed in the two
compounds (−163 ppm for (7S,9R)-(11,12Z)-cis-20 and −187
ppm for (7R,9S)-(11,12E)-cis-20) confirms different chemical
environments for the fluorine atom in each compound, probably
linked to the position of the cyclopropyl moiety.
The RCM reaction turned out to be stereoselective, that is,
(7S,9R)-cis-18 giving only the Z geometry of a double bond
(19a) with the (7R,9S)-cis-18 enantiomer leading to the E
stereoisomer 19b (Scheme 2).
To end our synthesis sequence, we activated carboxylic acid
moiety 20 with 1,1′-carbodiimidazole in refluxing THF for 90
min,19 followed by introduction of the cyclopropylsulfonamide
14 in the presence of DBU at 50 °C, but this led to substrate
decomposition. Treatment of 20a or 20b with HATU and DIEA
compound
Huh7-RepEC50
2
8.1 nM
15 μM
>25 μM
13a
13b
a
50% effective concentration (EC50) was determined in the Huh-7
replicon cell line containing the subgenomic bicistronic HCV
genotype 1b replicon clone ET and luciferase readout.
Antiviral activity of fluoroanalogues was low compared to that
of Simeprevir. Analysis of the crystal structure of the TMC435
bound to its NS3/4A protease target8 shows a particular
orientation of the macrocycle to promote the establishment of a
hydrogen bond between the inhibitor and the protease. A
particular orientation of the cyclopropane also allows the
positioning of the acylsulfonamide group in the area S1′. Our
3D models obtained by molecular modeling for compounds 20a
and 20b show a slight rotation of P1−P2 backbone peptide, which
could harm the electrostatic interactions (with Lys136:NZ) and
intermolecular hydrogen bond (with Arg155:O).23 Moreover,
the orientation of the fluorocyclopropane in our two model
compounds seems unfavorable for positioning the acylsulfona-
mide group in the region of the catalytic serine residue (Ser139)
and also causes steric hindrance with the lysine residue (Lys136)
and the possible loss of hydrogen bonding with Gly137:NH.23
These structural changes were only caused by the fluorine atom
in 13a, probably due to orbital interactions between fluorine and
oxygen of the macrocycle. In the case of 13b, the changes were
caused by the fluorine atom and the double bond configuration.
These structural modifications, in both cases, should hamper the
C
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(8) Cummings, M. D.; Lindberg, J.; Lin, T.-I.; de Kock, H.; Lenz, O.;
interactions between inhibitor and target, explaining the loss of
activity of the two fluoroanalogue compounds.24
Lilja, E.; Fellander, S.; Baraznenok, V.; Nystrom, S.; Nilsson, M.; Vrang,
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L.; Edlund, M.; Rosenquist, A.; Samuelsson, B.; Raboisson, P.; Simmen,
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references therein. (d) Ivashkin, P.; Couve-Bonnaire, S.; Jubault, P.;
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Nilsson, M.; Horvath, A.; Kalmeijer, R.; de la Rosa, G.; Beumont-
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(b) Lin, T.-I.; Lenz, O.; Fanning, G.; Verbinnen, T.; Delouvroy, F.;
Scholliers, A.; Vermeiren, K.; Rosenquist, A.; Edlund, M.; Samuelsson,
B.; Vrang, L.; de Kock, H.; Wigerinck, P.; Raboisson, P.; Simmen, K.
Antimicrob. Agents Chemother. 2009, 53, 1377.
In conclusion, we developed an efficient synthesis of versatile
fluorinated cyclopropane amino acid building blocks that can be
used in the synthesis of promising new HCV NS3/4A protease
inhibitors, therapeutic agents against the hepatitis C virus. We
showed that these fluorinated scaffolds could be used efficiently
in the total synthesis of the Simeprevir analogue. The antiviral
activity of the fluoroanalogues was quite low, probably because
the fluorine atom induced some modification in the structure of
the macrocycle.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedure, characterization data, computational
data, and copies of 1H, 13C, and 19F NMR spectra. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01216.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: philippe.jubault@insa-rouen.fr.
Notes
The authors declare no competing financial interest.
(12) See the Supporting Information for the determination of relative
configurations of the substituents of diastereoisomers ( )-cis-8 and
( )-trans-8 by 19F−1H HOESY 2D NMR.
ACKNOWLEDGMENTS
We thank Janssen for financial support (PhD grant to G.M.).
■
(13) Yasuhara, A.; Nakamura, M.; Sakagami, K.; Shimazaki, T.;
Yoshikawa, R.; Chaki, S.; Ohta, H.; Nakazato, A. Bioorg. Med. Chem.
2006, 14, 4193.
MESR (Minister
Recherche), FEDER 32819 (European fund for Regional
development), the Region Haute-Normandie (CRUNCh
program), CNRS, Rouen University, INSA of Rouen, and
Labex SynOrg (ANR-11-LABX-0029) are also thanked for their
support.
̀
e de l’Enseignement Super
́
ieur et de la
(14) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
́
(15) Stokbroekx, S. G. M.; Leys, C.; Swinney, K. A.; Wuyts, S.;
Horvath, A. PCT Int. Appl. WO 2008/092954 A2, 2008.
(16) Relative orientation of the substituents of 16 was confirmed by
NOESY 2D NMR experiment (see the Supporting Information).
(17) For similar ring opening of cyclopropanes in synthesis, see:
(a) Krasnov, V. P.; Korolyova, M. A.; Levit, G. L. Russ. Chem. Rev. 2003,
72, 343. (b) Godier-Marc, E.; Aitken, D. J.; Husson, H.-P. Tetrahedron
Lett. 1997, 38, 4065.
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DOI: 10.1021/acs.orglett.5b01216
Org. Lett. XXXX, XXX, XXX−XXX