Synthesis of 1,5-benzothiazepine dipeptide mimetics via two cul-catalyzed cross coupling reactions

Article abstract of DOI:10.1021/ol900943b

Cul-catalyzed coupling of 4-methylphenyl bromide with amino acids gives N-aryl amino acids, which are converted Into linear dipeptides via lodination and condensation with L-cysteine derived acyl chloride. Cyclization Is achieved via a Cul/N,N-dimethylgly

Full text of DOI:10.1021/ol900943b

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2788-2790
Synthesis of 1,5-Benzothiazepine
Dipeptide Mimetics via Two
CuI-Catalyzed Cross Coupling Reactions
Jiangang Gan and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
Madw@mail.sioc.ac.cn
Received April 30, 2009
ABSTRACT
CuI-catalyzed coupling of 4-methylphenyl bromide with amino acids gives N-aryl amino acids, which are converted into linear dipeptides via
iodination and condensation with L-cysteine derived acyl chloride. Cyclization is achieved via a CuI/N,N-dimethylglycine catalyzed intramolecular
coupling of aryl iodides with the liberated thiol to afford 1,5-benzothiazepine dipeptide mimetics.
Since it was introduced by Slade and co-workers for the
assembly of designed angiotensin converting enzyme inhibi-
tors in 1985,1 1,5-benzothiazepine 1 (Figure 1), a bridging
dipeptide analog, has been frequently employed as a scaffold
for the development of peptidomimetics.2-7 These efforts
have led to the discovery of a considerable number of
pharmaceutically interesting molecules. Recent examples
include CGRP receptor antagonist 3,3 compound 4 that could
be used for treatment of hyperproliferation diseases,4 IAP
(inhibitors of apoptosis proteins) antagonist 5,5 interleukin-1
converting enzyme inhibitor 6,6 as well as selective brady-
kinin agonist JMV1116 (7).7
One problem for 1,5-benzothiazepine 1 as a dipeptide
analog is the lack of substituents at the R-position of its ester
moiety, which limits its potential in drug discovery, because
it cannot fully mimic the most dipeptide backbones. Con-
sidering known synthetic protocols, it looks difficult to
introduce some suitable substituents at this position to
generate substituted 1,5-benzothiazepines 2, particularly in
an enantioselective manner.1 Therefore, an alternative route
is highly required to solve this problem.
(1) Slade, J.; Stanton, J. L.; Ben-David, D.; Mazzenga, G. C. J. Med.
Chem. 1985, 28, 1517.
(2) For a review, see Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33,
1699
.
(3) Gutierrez, C. D.; Termin, A.; Joshi, P.; Hadida Ruah, S.; Bergeron,
D.; Yoo, S.; Cao, J. WO2008011190.
Recently, great progress has been made in the development
of ligand-promoted Ullmann-type coupling reactions, which
has delivered many mild conditions for C-N, C-O, C-S
(4) Goldstein, S. W.; Longo, K. P.; Nagel, A. A.; Lowe, J. A., III
US6319915.
(5) Jaquith, J. WO2007101347.
(6) Golec, J. M. C.; Lauffer, D. J.; Livingston, D. J.; Mullican, M. D.;
Nyce, P. L.; Robidoux, A. L. C.; Wannamaker, M. W. WO9824804.
(7) (a) Amblard, M.; Daffix, I.; Bedos, P.; Berge´, G.; Pruneau, D.;
Paquet, J.-L.; Luccarini, J.-M.; Be´lichard, P.; Dodey, P.; Martinez, J. J. Med.
Chem. 1999, 42, 4185. (b) Amblard, M.; Daffix, I.; Bedos, P.; Berge´, G.;
Calme`s, M.; Dodey, P.; Pruneau, D.; Paquet, J.-L.; Luccarini, J.-M.;
(8) For reviews, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem.
ReV. 2004, 2337. (c) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (d)
Evano, G.; Blanchard, N.; Toumi, M. Chem. ReV. 2008, 108, 3054. (e)
Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096.
Be´lichard, P.; Martinez, J. J. Med. Chem. 1999, 42, 4193
.
10.1021/ol900943b CCC: $40.75
Published on Web 05/29/2009
 2009 American Chemical Society

Scheme 1
L-valine 8a in 83% yield,9a which was treated with methyl
iodide and KHCO3 to afford methyl ester 9. Iodination of 9
with iodine and Ag2SO4 gave 10. Next, we planned to
introduce the required cysteine part into amine 10 via an
amide bond formation. This operation was proven challeng-
ing because of the poor reactivity of the sterically hindered
amine. For example, amine 10 was inert toward EDCI and
HATU-mediated condensation with Boc-L-Cys(Bn)-OH, as
well as toward direct condensation with some L-cysteine
derived mixed anhydrides. Accordingly, we moved our
attention to use the more reactive acyl chloride 11 as a
coupling partner. After having failed in a Et3N-mediated
coupling, we were pleased to find that using K2CO3 as a
base the reaction gave the desired dipeptide 12a in 83% yield.
Changing the N-protecting group in 12a by treatment with
KF/Et3N/(Boc)2O11 afforded 12b, which was reacted with
Hg(O2CCF3)2 to remove the PMB protecting group.12 The
liberated thiol was then subjected to a CuI/N,N-dimethylg-
Figure 1. Structures of substituted 1,5-benzothiazepine derivatives.
and C-C bond formation starting from aryl halides.8 These
new methods have opened new routes for construction of
bioactive compounds and their analogues.8c,d Taking this
advantage, we developed a facile approach to assemble
substituted 1,5-benzothiazepines 2. As depicted in Figure 2,
(9) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459. For other select examples about N-arylation, see: (b)
Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583. (c) Klapars, A.; Antilla, J. C.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. (d)
Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315.
(e) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 11684. (f) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (g)
Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.-Eur. J.
2004, 10, 5607. (h) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70,
5164. (i) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.-Eur. J. 2006,
12, 3636. (j) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128,
8742. (k) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46,
2598. (l) Zou, B.; Yuan, Q.; Ma, D. Org. Lett. 2007, 9, 4291.
Figure 2. Assembly of substituted 1,5-benzothiazepine derivatives
2 via two CuI-catalyzed coupling reactions.
the key elements of this route include a CuI-catalyzed
N-arylation of amino acids,9 and a CuI/N,N-dimethylglycine
catalyzed intramolecular S-arylation.10 Herein, we wish to
disclose our investigations.
As shown in Scheme 1, we started our synthesis by
coupling 4-methylphenyl bromide with L-valine. This CuI-
catalyzed reaction worked well in DMF to give N-toluyl
(10) (a) Zhang, H.; Cao, W.; Ma, D. Synth. Commun. 2007, 37, 25. For
related studies, see: (b) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D.
Org. Lett. 2002, 4, 2803. (c) Kwong, F. Y.; Buchwald, S. L. Org. Lett.
2002, 4, 3517. (d) Deng, W.; Zou, Y.; Wang, Y.-F.; Liu, L.; Guo, Q.-X.
Synlett 2004, 7, 1254. (e) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863.
Org. Lett., Vol. 11, No. 13, 2009
2789

lycine catalyzed intramolecular coupling reaction to furnish
1,5-benzothiazepine 2a in 63% yield.10a With 2a in hand,
we now tried to cleave the methyl ester group to obtain acid
2b. Disappointingly, this transformation was rather difficult
elongation of the side chain at this site impossible, thereby
limiting further applications of 1,5-benzothiazepine 2a.
To solve the above problem, we decided to change the
ester protecting group to phenacyl (Pac),13 because it could
be cleaved via reducing its ketone part. Therefore, it would
allow to avoid attack of the sterically hindered ester moiety.
Accordingly, after coupling of 4-methylphenyl bromide with
four amino acids respectively, resultant N-aryl amino acids
were treated with phenacyl bromide and Et3N in EtOAc to
afford Pac esters 13 in 36-63% yields. Exposure of 13 to
iodine and Ag2SO4 provided the aryl iodides, which were
condensed with acyl chloride 11 to deliver dipeptides 14.
For carrying out the copper-catalyzed intramolecular cou-
pling, the base-sensitive Fmoc was changed to Boc to provide
15. After removal of the PMB protecting group in 15,
intramolecular coupling effected by CuI/N,N-dimethylglycine
produced the cyclization products 2c-2f. Now this is the
stage for the cleavage of the Pac protecting group. We were
pleased to find that treatment of 2e with zinc and 90% acetic
acid at room temperature furnished the desired acid 2g in
55% yield. This result demonstrated that the ester protecting
group in 2c-2f could be removed for the development of
peptidomimetics.
Scheme 2
In conclusion, we have developed a novel protocol to
assemble 1,5-benzothiazepines based on applying two cop-
per-catalyzed coupling reactions. The most important feature
of this method is that it allows for the introduction of various
N-substituents by changing the amino acid coupling partners.
This will enable the development of more diverse peptido-
mimetics for biological investigations. The application of the
presented building blocks in discovery of new enzyme
inhibitors is actively pursued in our group, and the results
will be disclosed in due course.
Acknowledgment. We are grateful to the Chinese Acad-
emy of Sciences and the National Natural Science Foundation
of China (grant 20632050 & 20621062) for their financial
support.
Supporting Information Available: Experimental pro-
cedures and copies of 1H NMR and 13C NMR spectrum for
all new products. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL900943B
under various reaction conditions (such as NaOH/MeOH/
THF/H2O and n-PrSNa/HMPA). The problem might result
from the steric hindrance of the ester group and makes the
(11) Li, W.-R.; Jiang, J.; Joullie, M. J. Tetrahedron Lett. 1993, 34, 1413.
(12) Zhou, B.; Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4, 43.
(13) Schmidt, U.; Kroner, M.; Griesser, H. Synthesis 1991, 294.
2790
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