A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions

Article abstract of DOI:10.1039/c0cc02823a

A very short and efficient synthesis of the important drug candidate telaprevir, featuring a biocatalytic desymmetrization and two multicomponent reactions as the key steps, is presented. The classical issue of lack of stereoselectivity in Ugi- and Passerini-type reactions is circumvented. The atom economic and convergent nature of the synthetic strategy require only very limited use of protective groups.

Full text of DOI:10.1039/c0cc02823a

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A highly efficient synthesis of telaprevir by strategic use of biocatalysis
and multicomponent reactionsw
a
a
a
a
Anass Znabet, Marloes M. Polak, Elwin Janssen, Frans J. J. de Kanter,
a
b
a
Nicholas J. Turner, Romano V. A. Orru and Eelco Ruijter*
Received 26th July 2010, Accepted 3rd September 2010
DOI: 10.1039/c0cc02823a
A very short and efficient synthesis of the important drug
candidate telaprevir, featuring a biocatalytic desymmetrization
and two multicomponent reactions as the key steps, is presented.
The classical issue of lack of stereoselectivity in Ugi- and
Passerini-type reactions is circumvented. The atom economic
and convergent nature of the synthetic strategy require only very
limited use of protective groups.
Hepatitis C is a viral infectious disease affecting more than
1
00 million people worldwide and is currently treated by a
2
combination of PEGylated interferon and ribavirin. However,
a significant number of patients do not respond to this therapy
2
due to adverse effects or viral rebound due to resistant strains.
Recently, the hepatitis C virus (HCV) NS3 protease has
emerged as a clinically validated target for the treatment of
Scheme 1 Retrosynthetic analysis of telaprevir.
3
hepatitis C infection. Two peptidic HCV NS3 protease
4
5
inhibitors (telaprevir (1, Fig. 1) and boceprevir ) are currently
in Phase III clinical trials for the treatment of HCV infection.
The reported synthesis of 1 involves a lengthy, highly linear
complexity. Although MCRs have been used in medicinal
9
chemistry, issues related to the infamously poor stereo-
6
strategy relying on standard peptide chemistry. For example,
selectivity seriously hamper wider application of this
the central bicyclic proline derivative is synthesized in racemic
promising methodology. The broad repertoire of stereospecific
1
0
form via a nine-step sequence. The desired enantiomer is only
conversions by biocatalysts presents a unique opportunity to
address the stereoselectivity issue of certain MCRs.
6
,7
obtained after chiral HPLC separation. Optimization of the
synthesis of 1 could significantly lower the production costs,
thereby making this promising drug candidate available to an
increased proportion of the world population in the future.
We recently reported the enzymatic desymmetrization of
meso-pyrrolidines by means of a monoamine oxidase N
(MAO-N) from Aspergillus niger optimized by directed
8
11
Multicomponent reactions (MCRs) have become essential
evolution and its combination with a highly diastereo-
1
2
tools in the efficient generation of molecular diversity and
selective Ugi-type three-component reaction (3CR). We
soon realized that this methodology could represent an
efficient approach to the synthesis of telaprevir. A retro-
synthetic analysis of 1 exploiting this biocatalysis/MCR
sequence is presented in Scheme 1.
The required inputs for the key Ugi-type 3CR are carboxylic
1
3
acid 2, cyclic imine 3, and isocyanide 4. The known acid 2 is
readily available by standard peptide chemistry. Imine 3 can
be generated in situ from commercially available 5 by MAO-N
catalyzed oxidation. Isocyanide 4 is accessible via a Passerini
1
4
three-component reaction (P-3CR) of 6, 7, and acetic acid.
Formamido aldehyde 7 can be derived from commercial
Fig. 1 HCV NS3 protease inhibitor telaprevir.
(
S)-2-amino-1-pentanol (8).
a
Department of Chemistry & Pharmaceutical Sciences,
Vrije Universiteit Amsterdam, De Boelelaan 1083,
Thus, coupling of L-cyclohexylglycine methyl ester and
pyrazinecarboxylic acid and subsequent saponification
afforded 10 in excellent yield (Scheme 2). Subsequent coupling
with L-tert-leucine methyl ester and saponification furnished
the required optically pure acid 2.
1081 HV Amsterdam, the Netherlands. E-mail: e.ruijter@few.vu.nl;
Fax: +31 20 59 87488; Tel: +31 20 59 87462
School of Chemistry, University of Manchester,
Manchester Inter-disciplinary Biocentre, 131 Princess Street,
Manchester, UK M1 7DN
b
13
Compared to the reported synthesis of 2, we have
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, characterization data, and copies of
and C NMR spectra. See DOI: 10.1039/c0cc02823a
1
H
significantly increased both the atom and step economy and
13
the overall yield (74% vs. 11% over four steps). The use of
7
918 Chem. Commun., 2010, 46, 7918–7920
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Scheme 2 Synthesis of carboxylic acid fragment 2. Reagents and
conditions: (a) pyrazinecarboxylic acid, BOP, Et N, DMF, 98%;
b) NaOH, THF/H O/MeOH, 95%; (c) H–Tle–OMe, EDC, HOAt,
DMF, 84%; (d) NaOH, THF/H O/MeOH, 95%.
3
(
2
2
Scheme 4 Multicomponent coupling of the fragments and comple-
tion of the synthesis. Reagents and conditions: (a) MAO-N, 100 mM
KPO
4
2 2 2 3
buffer, pH = 8.0, 37 1C; (b) 2, 4, CH Cl , 76%; (c) K CO ,
MeOH; (d) DMP, CH
2
Cl , 80% over 2 steps.
2
advantages compared to other approaches in terms of atom
and step economy. We replaced the carbamate groups
by a formamide that is actually incorporated in the final
product.
The next task at hand was the convergent three-component
Ugi-type coupling (Scheme 4). Thus, commercial amine 5 was
oxidized to imine 3 (94% ee) by MAO-N as described
1
1
previously, and then combined with 2 and 4 to give 14.
Finally, cleavage of the acetate followed by Dess–Martin
1
3
oxidation gave telaprevir (1) as a 83 : 13 : 4 mixture of
diastereomers, with one minor diastereomer derived from the
incomplete stereoinduction of the Ugi-type 3CR, and the other
from the minor enantiomer of imine 3. Flash chromatography
allowed straightforward separation of the diastereomers to
afford pure telaprevir (1) in 80% yield over the last two steps.
We have developed a very short and efficient synthesis of the
important drug candidate telaprevir using a biotransformation
and two multicomponent reactions as the key steps. The
classical issue of lack of stereoselectivity in Ugi- and
Passerini-type reactions is circumvented. The stereogenic
carbon formed in the P-3CR is later oxidized to the corres-
ponding ketone and the stereoselectivity of the Ugi-type 3CR
is controlled by the absolute configuration of the cyclic imine,
which is in turn derived from the highly stereoselective
biotransformation. The use of protective groups is limited to
two intermediate methyl esters and an acetate. The use of
carbamate protective groups is avoided altogether. The
synthesis comprises only eleven steps in total (seven steps in
the longest linear sequence) compared to twenty-four in the
Scheme
conditions: (a) EtOCHO, D, 99%; (b) DMP, CH
c) cyclopropyl isocyanide (6), AcOH, CH Cl , 56%; (d) DMP, 6,
CH Cl , 60%; (e) triphosgene, NMM, CH Cl
, À30 1C, 87%.
3
Synthesis of isocyanide fragment 4. Reagents and
2
2
Cl , 83%;
(
2
2
2
2
2
2
carbamate protective groups is avoided by essentially using the
N-terminal pyrazine carboxylate as an amine protective group.
We then turned our attention to the construction of the
isocyanide fragment 4 (Scheme 3). Commercial (S)-2-amino-1-
pentanol (8) was transformed to aldehyde 7 by N-formylation
and subsequent Dess–Martin oxidation. A P-3CR between 6, 7,
and acetic acid afforded 13 as
a 78 : 22 mixture of
diastereomers. However, aldehyde 7 proved difficult to isolate
due to partial dimerization and the P-3CR proceeded in
disappointing yield. We then realized that these two steps
might be combined in a one-pot process. Ngouansavanh and
Zhu have previously shown that the P-3CR is compatible with
1
5
hypervalent iodine oxidants such as IBX. In our case, both
the Dess–Martin oxidation and the Passerini reaction are
performed in CH Cl , and the acetic acid formed as a
6
,7
originally reported procedure.
The total yield (over the
longest linear sequence) is 45% starting from H–Chg–OMe.
Our approach is general and will be applicable to many other
HCV NS3 protease inhibitors that can be derived from
2
2
by-product in the Dess–Martin oxidation can be used as the
carboxylic acid input in the P-3CR. Thus, one-pot Dess–
Martin oxidation/Passerini reaction of 12 furnished 13
5
17
meso-pyrrolidines, such as e.g. boceprevir and narlaprevir.
(
60% compared to 46% in the two-step procedure). Dehydra-
The combination of synthetic efficiency and convergence
in our approach allows both faster development of second
generation inhibitors and a more economical production of
telaprevir. We strongly believe that biocatalysis and MCRs
will be increasingly important tools for the improvement of
atom and step economy towards the sustainable production of
fine chemicals and pharmaceuticals.
tion then afforded the required isocyanide 4 in very good
yield (87%). No racemization of the C3 stereocenter was
1
observed. This crucial fragment is thus accessible in only
three steps from commercial starting materials.
6
Although the P-3CR has been used to construct telaprevir
1
fragments similar to 13, our approach offers significant
7
This journal is c The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7918–7920 7919

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Notes and references
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¨
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920 Chem. Commun., 2010, 46, 7918–7920
This journal is c The Royal Society of Chemistry 2010