SCHEME 1
Synthesis of Conformationally Constrained
Cyclic Peptides Using an Intramolecular
Sonogashira Coupling†
V. Balraju,‡,§ D. Srinivasa Reddy,‡
Mariappan Periasamy,§ and Javed Iqbal*,‡
Discovery Research, Dr. Reddy’s Laboratories Ltd.,
Bollaram Road, Miyapur, Hyderabad, 500 049, A.P., India,
and School of Chemistry, University of Hyderabad, Central
University P.O., Gachibowli, Hyderabad 500 046, A.P.,
India
constraint (e.g., double bond, aromatic ring, etc.), which
confers conformational restriction to the peptide leading
to an entropically advantageous mode of binding to the
target protein.7,8 In connection with a project on pepti-
domimetics,9 we are interested in developing novel and
efficient methods for macrocyclizations to furnish cyclic
peptides with various linkers. We envisaged the intro-
duction of a rigid linker with an aryl alkynyl moiety in
macrocycle A from the corresponding precursor B through
sp-sp2 bond formation using a Pd-catalyzed intra-
molecular Sonogashira coupling (Scheme 1).
Received July 8, 2005
The Sonogashira macrocyclization on resin-bound pep-
tide appears to be the only known example for the
synthesis of cyclic peptides using this reaction.10 This
reaction generally is cocatalyzed by copper(I) and uses
an amine as a base and a phosphine as a ligand for
Small peptides having a 3-bromobenzyl group at the C-
termini and n-alkynoyl group at the N-termini undergo a
smooth copper-free intramolecular Sonogashira coupling
reaction to afford the corresponding cyclic peptides in
moderate yields. Scope and limitations of this macrocycliza-
tion is demonstrated with di-, tri-, and tetrapeptides.
(3) (a) Prabhakaran, E. N.; Rajesh, V.; Dubey, S.; Iqbal, J. Tetra-
hedron Lett. 2001, 42, 339. (b) Prabhakaran, E. N.; Rao, I. N.; Boruah,
A.; Iqbal, J. J. Org. Chem. 2002, 67, 8247. (c) Nandy, J. P.; Prabhaka-
ran, E. N.; Kumar, S. K.; Kunwar, A. C.; Iqbal, J. J. Org. Chem. 2003,
68, 1679. (d) Creighton, C. J.; Reitz, A. B. Org. Lett. 2001, 3, 893. (e)
Beal, L. M.; Liu, B.; Chu, W. H.; Moeller, K. D. Tetrahedron 2000, 56,
10113. (f) Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus,
P. J., Jr.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638. (g) Miller,
S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118,
9606.
The enhanced bioavailability, biological specificity, and
reduced conformational flexibility of cyclic peptides make
them attractive leads in modern drug discovery.1 Several
methods are known for cyclic peptide synthesis, including
disulfide bond formation,2 ring-closing metathesis,3 SN-
Ar coupling,4 Heck coupling,5 and free-radical reactions.6
Cyclization of peptides introduces an extra element of
(4) (a) Feng, Y. B.; Pattarawarapan, M.; Wang, Z. C.; Burgess, K.
Org. Lett. 1999, 1, 121. (b) Feng, Y. B.; Wang, Z. C.; Jin, S.; Burgess,
K. J. Am. Chem. Soc. 1998, 120, 10768.
(5) Reddy, P. R.; Balraju, V.; Madhavn, G. R.; Banerji, B.; Iqbal, J.
Tetrahedron Lett. 2003, 44, 353.
(6) Balraju, V.; Reddy, D. S.; Periasamy, M.; Iqbal, J. Tetrahedron
Lett. 2005, 46, 5207.
(7) (a) Davies, J. S. J. Pept. Sci. 2003, 9, 471-501. (b) Li, P.; Roller,
P. P.; Xu, J. Curr. Org. Chem. 2002, 6, 411-440. (c) Wipf, P. Chem.
Rev. 1995, 95, 2115. (d) Humphrey, J. M.; Chamberlin, A. R. Chem.
Rev. 1997, 97, 2243. (e) Webster, K. L.; Maude, A. B.; O’Donnell, M.
E.; Mehrotra, A. P.; Gani, D. J. Chem. Soc., Perkin Trans. 1 2001, 1673.
(f) Dyker, H.; ScherKenbeck, J.; Gondol, D.; Goehrt, A.; Harder, A. J.
Org. Chem. 2001, 66, 3760. (g) Gademann, K.; Ernst, M.; Hoyer, D.;
Seebach, D. Angew. Chem., Int. Ed. 1999, 38, 1223. (h) Wenger, R. M.
Helv. Chim. Acta 1984, 67, 502.
* Corresponding author. Phone: +91-40-2304-5439. Fax: +91-40-
2304-5438.
† DRL Publication No. 497.
‡ Dr. Reddy’s Laboratories Ltd..
§ University of Hyderabad.
(1) (a) Goodman, M.; Seonggu, R. In Burger’s Medicinal Chemistry
and Drug Discovery, 5th ed.; Wolff, M. E., Ed.; Wiley: New York, 1995;
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(c) Ripka, A. S.; Rich, D. H. Curr. Opin. Chem. Biol. 1998, 2, 439. (d)
Wiley, R. A.; Rich, D. H. Med. Res. Rev. 1993, 13, 327. (e) Freidinger,
R. M. Curr. Opin. Chem. Biol. 1999, 3, 395. (f) Aube, J. In Advances
in Amino Acid Mimetics and Peptidomimetics; Abell, A., Ed.; JAI
Press: Greenwich, CT, 1997; Vol. 1, pp 193-232. (g) MacDonald, M.;
Aube, J. Curr. Org. Chem. 2001, 5, 417-438. (h) Hanessian, S.;
McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron
1997, 53, 12789. (i) Burgess, K. Acc. Chem. Res. 2001, 34, 826. (j) Rose,
G. D.; Gierasch, L. M.; Smith, J. A. In Advances in Protein Chemistry;
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FL, 1985; Vol. 37, pp 1-109. (k) Giannis, A.; Kolter, T. Angew. Chem.,
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(8) See references using solid-phase synthesis: (a) Ishida, H.; Qi,
Z.; Sokabe, M.; Donowaki, K.; Inoue, Y. J. Org. Chem. 2001, 66, 2978.
(b) Wittmann, V.; Seeberger, S. Angew. Chem., Int. Ed. 2000, 39, 4348.
(c) Lee, Y.; Silverman, R. B. Org. Lett. 2000, 2, 303. (d) Jensen, K. J.;
Alsina, J.; Songster, M. F.; Vagner, J.; Albericio, F.; Barany, G. J. Am.
Chem. Soc. 1998, 120, 5441 and references therein.
(9) Previous references from our laboratory on peptidomimetics: (a)
Banerji, B.; Mallesham, B.; Kiran kumar, S.; Kunwar, A. C.; Iqbal, J.
Tetrahedron Lett. 2002, 43, 6479. (b) Banerji, B.; Bhattacharya, M.;
Madhu, B. R.; Das, S. K.; Iqbal, J. Tetrahedron Lett. 2002, 43, 6473.
(c) Saha, B.; Das, D.; Banerji, B.; Iqbal, J. Tetrahedron Lett. 2002, 43,
6467. (d) Sastry, T. V. R. S.; Banerji, B.; Kirankumar, S.; Kunwar, A.
C.; Das, J.; Nandy, J. P.; Iqbal, J. Tetrahedron Lett. 2002, 43, 7621.
(e) Saha, B.; Nandy, J. P.; Shukla, S.; Siddiqui, I.; Iqbal, J. J. Org.
Chem. 2002, 67, 7858. (f) Boruah, A.; Rao, I. N.; Nandy, J. P.; Kumar,
S. K.; Kunwar, A. C.; Iqbal, J. J. Org. Chem. 2003, 68, 5006. (g) Rao,
I. N.; Boruah, A.; Kumar, S. K.; Kunwar, A. C.; Devi, A. S.; Vyas, K.;
Ravikumar, K.; Iqbal, J. J. Org. Chem. 2004, 69, 2181.
(2) (a) Janecka, A.; Zubrzycka, M.; Janecki, T. J. Pept. Res. 2001,
58, 91. (b) Eichler, J.; Houghten, R. A. Protein Pept. Lett. 1997, 4, 157-
164. (c) Hargittai, B.; Barany G. Methods Enzymol. 1997, 289, 198-
221.
(10) Spivey, A. C.; McKendrick, J.; Srikaran, R. J. Org. Chem. 2003,
68, 1843-1851.
10.1021/jo051412z CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/08/2005
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J. Org. Chem. 2005, 70, 9626-9628