A modular, general and enantiospecific strategy for the synthesis of CVS 1778 analogs: Inhibitors of factor Xa

Article abstract of DOI:10.1016/S0040-4039(02)01924-X

A modular synthetic route has been developed for the synthesis of a series of complex benzalactams which are potent inhibitors of factor Xa. The route produces fused benzalactams of varying ring size via a key-step ring-closing metathesis reaction. The ro

Full text of DOI:10.1016/S0040-4039(02)01924-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8177–8180
A modular, general and enantiospecific strategy for the synthesis
of CVS 1778 analogs: inhibitors of factor Xa
Michael G. Organ,* Juan Xu and Blaise N’Zemba
The Department of Chemistry York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3
Received 1 August 2002; revised 19 August 2002; accepted 23 August 2002
Abstract—A modular synthetic route has been developed for the synthesis of a series of complex benzalactams which are potent
inhibitors of factor Xa. The route produces fused benzalactams of varying ring size via a key-step ring-closing metathesis reaction.
The route also facilitates the synthesis of discrete enantiomers using readily available commercial building blocks. © 2002 Elsevier
Science Ltd. All rights reserved.
The blood clotting cascade mechanism in the body
reacts to both intrinsic and extrinsic stimuli to maintain
a healthy cardiovascular system. This mechanism is
highly complex with a number of factors that play a
role in regulating the depolymerization of fibrinogin to
fibrin that leads to platelet aggregation and blood
clotting. It has been proposed that factor Xa converts
prothrombin to thrombin in response to vascular injury
and in fact this action is the penultimate step of the
extrinsic pathway. In healthy individuals, this extrinsic
pathway poses little concern and in fact it is necessary
to prevent excessive bleeding from injury. However, in
heart attack and stroke patients, who may have suf-
fered vessel damage from the event itself, blood clotting
can prove fatal. Thus, such patients are usually placed
on blood thinners or anticoagulants. At present, com-
pounds used in the treatment and prevention of throm-
boembolic diseases include Coumadin, heparins,
hirudin and Aspirin. Some problems associated with
these agents include parenteral administration (injec-
tion), the need to carefully titrate drug dosage, exces-
sive bleeding and gastrointestinal irritation. These
problems are especially acute when the patients are
elderly and most people requiring these drugs are older.
To combat the oral availability issues, many research
groups utilize peptidomimetics,1 and in particular those
containing lactams and heterocyclic motifs have proven
to be quite efficacious.
One group of peptidomimetics that is attractive for our
purposes is the series of benzalactams (1b) developed
around CVS 1778 (1a) by the research group at Corvas
International Inc. (Fig. 1).2 We are developing a new
screening platform and are using factor Xa as a model
enzyme with which to assess the efficacy of the method.
In order to probe the platform we required a group of
structurally-related compounds with a range of binding
efficiencies, yet, ideally, high selectivity for factor Xa.
With these criteria in mind, 1b served as an ideal
structure to build a library around for a number of
reasons. First, the structure contains a number of chiral
centers which allow for not only the assessment of
differently substituted pharmacophores, but to evaluate
how well the screening platform distinguishes between
Figure 1. Lactam-containing peptidomimetic inhibitors of factor Xa.
* Corresponding author. Tel.: 416-736-5313; fax: 416-736-5936; e-mail: organ@yorku.ca
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01924-X

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M. G. Organ et al. / Tetrahedron Letters 43 (2002) 8177–8180
approach allows for the use of commercially-available
chiral building blocks (e.g. amino acids) to produce the
chiral center in the lactam. Further, this approach can
be used to prepare any medium-sized ring by varying
the length of the tethers (i.e. m and p) on the RCM
precursor 5. In this report we detail the preparation of
2 and how we plan to build a library around this
general structure.
enantiomers and diastereomers. Also, despite the com-
plexity of the core structure, we felt that we could
devise a reasonably modular approach to the library
using solution-phase synthesis with the option of mov-
ing readily to solid phase if a larger number of com-
pounds were required. With these things in mind, we
sought to develop one single strategy to produce a
variety of optically-pure synthetic templates that could
serve as the diversification point from which to build
benzalactams of varying ring size and substitution
pattern.
Construction of the left-hand piece (12) of the RCM
precursor began from commercially-available
(L)
methionine methyl ester (9) (the
D isomer is also avail-
The basic template (2a) used by the group at Corvas
was obtained commercially in racemic form and the
diastereomers of 1b that ultimately were derived from
2a were purified by preparative HPLC. When substi-
tuted benzalactams were prepared, a new synthetic
route was developed and each substituted template (i.e.
2b) was prepared de novo. Each template was individu-
ally resolved to obtain enantiomerically pure 2b that
was then elaborated to optically pure drug candidates
(ignoring the hemiaminal center which is in the open
form when it reacts with the enzyme). Despite these
issues, we still viewed a protected amino acid template
resembling 2 as an ideal diversification point. Thus, we
decided to use this template, but opted to develop a
new and more general synthetic strategy that would
allow for the preparation of all templates in the series
in optically pure form (Fig. 2). Ring-closing metathesis
(RCM) facilitates bond formation that takes place at a
remote position in the lactam ring.3 This chiron-type
able) (Scheme 1).4 Amine protection, oxidation and
sulfoxide elimination proceeded smoothly (70% yield
over three steps) providing the requisite olefin (11).5
The ester was readily modified into the stable acid
chloride 12 in two steps with excellent recovery.
Preparation of the phenyl-containing right-hand piece
(16) began with an aza Claisen rearrangement of 13 to
provide 14 (Scheme 2).6 Alkylation of anilines 14 pre-
sented some unexpected and interesting product stabil-
ity issues. While alkylation of the three compounds
proceeded smoothly, only 15b proved to be stable
enough to handle. Compound 15c decomposed during
silica gel chromatography, although as the crude
product it was effectively carried through amide bond
formation to provide 16c which was a stable com-
pound. Compound 15a appeared to be stable enough to
silica gel, but upon sitting it oxidized to give 15d and by
48 h the oxidation was complete. However, like 15c,
Figure 2. Retrosynthetic analysis of a benzalactam peptidomimetic library of factor Xa inhibitors using RCM as the key step to
provide the intermediate template 2.
Scheme 1.

M. G. Organ et al. / Tetrahedron Letters 43 (2002) 8177–8180
8179
Scheme 2.
Scheme 3.
Scheme 4.
Scheme 5.
As a proof of principle, elaboration of the core tem-
plate to the desired drug candidate structure is dis-
cussed here. Template 17b was further diversified with a
Suzuki coupling at the bromide site before we contin-
ued on with the synthesis (Scheme 4). Although we
have not tested a wide variety of boronic acids to date,
the coupling proceeded cleanly with both an electron-
rich and an electron-poor phenylboronic acid. Under
these reaction conditions, the Fmoc group was also
deprotected which was convenient because the next step
diversifies the primary amine site.
once 15a was converted to the more electron-deficient
amide (i.e. 16a) the methylene group was no longer
readily oxidizable, either in 16 or in any other similar
compounds further along in this synthetic route.
The RCM step,7 which was pivotal in this approach as
a general strategy for making the inhibitor library,
proceeded very cleanly and essentially quantitatively in
all cases (Scheme 3). However, we did discover that
while the reaction was faster at higher temperature
(refluxing benzene), it was accompanied by double
bond isomerization toward the phenyl ring. There was
no observed movement of the olefin under conditions
of refluxing CH2Cl2. Thus, with this step worked out,
we had the desired templates in hand for adding the
diversity elements to the library.
The Fmoc group on templates 17 were removed with
diethylamine to provide 19 and the free amine was
capped as a sulfonamide in very good recovery (20,
Scheme 5). A variety of sulfonyl chlorides will be used
in the final library preparation.8 Carboxylic acids 21

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M. G. Organ et al. / Tetrahedron Letters 43 (2002) 8177–8180
were liberated using trifluoroacetic acid and then they
were condensed with amine 39 to provide 22, once again
in good yield over the two steps. Catalytic hydrogena-
tion of 22 under mild conditions simultaneously
reduced the lactam olefin and deprotected of the nitro-
protected guanidinium moiety. Treatment of the
reduced product (23) with strong acid liberated the
biologically active hemiaminal (24). Although the yield
from the final step is not fully optimized, we have
succeeded in the development of a modular and enan-
tiomerically pure strategy to make compounds possess-
ing the general structure contained in compound 1.
R. F.; Ripka, W. C. Bioorg. Med. Chem. Lett. 2000, 10,
745–749.
2. Tamura, S. Y.; Goldman, E. A.; Bergum, P. W.; Semple,
J. E. Bioorg. Med. Chem. Lett. 1999, 9, 2573–2578.
3. For a review of RCM reactions of nitrogen-containing
compounds, see: Phillips, A. J.; Abell, A. D. Aldrichim.
Acta 1999, 32, 75–89.
4. All compounds were identified by 1H and 13C NMR
spectroscopy, IR, and either elemental analysis or high
resolution mass spectroscopy. Where compounds contain-
ing chiral centers are concerned, optical rotations were
obtained and optical purity was determined by HPLC (UV
detection at 254 nm).
5. (a) Meffre, P.; Vo-Quang, L.; Vo-Quang, Y.; Goffic, F. L.
Synth. Commun. 1989, 19, 3457–3468; (b) Fukuchi, N.;
Isogai, A.; Nakayama, S. T.; Yamashita, S.; Suyama, K.;
Takemoto, J. Y.; Suzuki, A. J. Chem. Soc., Perkin Trans.
1 1992, 1149–1157.
6. (a) Beholz, L. G.; Stille, J. R. J. Org. Chem. 1993, 58,
5095–5100; (b) Nicolaou, K. C.; Roecker, A. J.; Pfeffer-
korn, J. A.; Cao, G. Q. J. Am. Chem. Soc. 2000, 122,
2966–2967.
7. For recent reviews, see: (a) Furstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012–3043; (b) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413–4450; (c) Scholl, M.; Ding, S.;
Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956; (d)
Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1,
1751–1753; (e) Morgan, J. P.; Grubbs, R. H. Org. Lett.
2000, 2, 3153–3155; (f) Sanford, M. S.; Ulman, M.;
Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 749–750; (g)
Boiteau, J.-G.; Weghe, P. V.; Eustache, J. Tetrahedron
Lett. 2001, 42, 239–242; (h) Chattergee, A. K.; Morgan, J.
P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 3783–3784
8. Other sulfonamides prepared include ethyl, tosyl and cam-
phorsulfonyl, all of which coupled in excess of 70% yield.
9. (a) Tamura, S. Y.; Semple, J. E.; Ardecky, R. A.; Leon, P.;
Carpenter, S.; Ge, Y.; Shamblin, B. M.; Weinhouse, M. J.;
Ripka, W. C.; Nutt, R. P. Tetrahedron Lett. 1996, 37,
4109–4112; (b) Siev, D. V.; Semple, J. E.; Robert, C. A.
PCT Int. Appl. (2000), WO 0002508, 64p.
In summary, we have developed a concise and general
strategy for the synthesis of compounds containing a
complex fused benzalactam that have demonstrated
potency against factor Xa. This modular approach
allows for the synthesis of enantiomerically-pure mate-
rials using a key RCM reaction.
Acknowledgements
This work was supported by a research grant from
MDS SCIEX Inc. and NSERC (Canada).
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