Synthesis of conformationally constrained cyclic peptides using an intramolecular Sonogashira coupling

Article abstract of DOI:10.1021/jo051412z

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 limitati

Full text of DOI:10.1021/jo051412z

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).
javediqbaldrf@hotmail.com
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;
Vol. 1. (b) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555.
(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;
Anfinsen, C. B., Edsall, J. T., Richards, F. M., Eds.; Academic: Orlando,
FL, 1985; Vol. 37, pp 1-109. (k) Giannis, A.; Kolter, T. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1244. (l) Hruby, V. J. Nat. Rev. Drug Discovery
2002, 1, 847. (m) Suat Kee, K.; Jois, S. D. S. Curr. Pharm. Des. 2003,
9, 1209-1224.
(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-
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10.1021/jo051412z CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/08/2005
9626
J. Org. Chem. 2005, 70, 9626-9628

palladium.11 This Note describes our preliminary studies
on the copper-free Sonogashira reaction on acyclic peptide
B. The synthesis of precursors based on B for Sonogash-
ira coupling are summarized in Scheme 2.
SCHEME 2a
Thus, the N-Boc-Ala-OH 1 was reacted with 3-bro-
mobenzylamine to give compound 2 using standard
solution-phase peptide coupling ((EDC, HOBt, Et3N,
DCM). The Boc deprotection (TFA/DCM) on 2, followed
by coupling with N-Boc-Leu-OH, furnished the peptide
3 in 89% yield. Removal of the Boc on 3, followed by
coupling with N-Boc-Phe-OH, gave tripeptide 4. Finally,
deprotection of 4, followed by coupling with readily
available n-alkynoic acids, gave desired acyclic precursors
5a-c in excellent yields.
Initially, the acyclic peptide 5a was subjected to a
variety of known Sonogashira conditions, which resulted
in the isolation of dimer 6 as the sole product. The
formation of compound 6 can be explained by Glaser-type
oxidative dimerization of the alkyne, which is one of the
side reactions commonly encountered in Sonogashira
reactions.12 However, reacting 5a under the copper-free
Sonogashira coupling conditions12,13 involving a bulky,
electron-rich phosphine ligand [Pd(OAc)2, (o-tolyl)3P, and
EtN(i-Pr)2 ] in acetonitrile at 110 °C resulted in formation
of the desired cyclic peptide 7a in 12% isolated yield. We
then subjected 5b and 5c to copper-free Sonogashira
coupling conditions, and to our delight, both reactions
afforded the corresponding cyclic peptides 7b and 7c,
respectively, in moderate yields (Scheme 3). It is interest-
ing to note that increase in the chain length between the
a Conditions: (a) 3-bromobenzylamine, Et3N, HOBt, EDC, DCM;
(b) i. TFA/DCM, ii. N-Boc-Leu-OH, Et3N, HOBt, EDC, DCM; (c) i.
TFA/DCM, ii. N-Boc-Phe-OH, Et3N, HOBt, EDC, DCM; (d) i. TFA/
DCM, ii. n-alkynoic acid, Et3N, HOBt, EDC, DCM.
SCHEME 3a
a Conditions: (a) (PPh3)2PdCl2, CuI, Et3N, CH3CN + DMF, room temperature, 15 h. (b) Pd(OAc)2, (o-tolyl)3P, EtN(i-Pr)2, CH3CN, 110
°C, 15 h.
J. Org. Chem, Vol. 70, No. 23, 2005 9627

SCHEME 4a
gave the corresponding cyclic peptides 7, we extended the
scope of this reaction to other acyclic peptide precursors
by varying the amino acids and the size of the acyclic
peptide. The change at the i + 1 amino acid residue from
leucine to valine (compound 8) gave desired cyclization
in 36% yield to furnish cyclic peptide 9. Similarly,
dipeptide 10 underwent smooth cylization to furnish 11
in 32% yield. However, the tetrapeptide 12 gave a poor
yield of the corresponding cyclic peptide 13 (Scheme 4).14
These preliminary studies indicate that the yields of the
cyclization of these peptides under the copper-free So-
nogashira conditions used are dependent upon both the
number of amino acid residues and the chain length of
the incorporated n-alkynoic acids.
In conclusion, we have demonstrated that copper-free
Sonogashira coupling conditions can be used for the
macrocyclization of di-, tri-, and tetrapeptides to produce
cyclic peptides with rigid linkers leading to useful pep-
tidomimetics. To the best of our knowledge, this is the
first report of copper-free intramolecular Sonogashira
macrocyclization for the synthesis of cyclic peptides.
These cyclic peptides may prove to be useful in under-
standing the utility of constrained structures in the
search for novel lead molecules.
Experimental Section
Typical Procedure for Sonogashira Macrocyclization
for 7c. Pd(OAc)2 (72 mg, 0.32 mmol) and (o-tolyl)3P (195 mg,
0.64 mmol) were added to warm HPLC-grade acetonitrile (1.2
L) and refluxed at 110 °C for 30 min. Then acylic peptide 5c
(500 mg, 0.80 mmol) was added in single portion, and the
reaction was continued for 15 min at the same temperature.
Finally, N-ethyldiisopropylamine (0.7 mL, 4 mmol) was added.
After 15 h, the reaction mixture was filtered through a pad of
Celite and washed with hot acetonitrile (100 mL). The filtrate
was concentrated, and the product was isolated as a white solid
(243 mg, 35%) after flash column chromatography on (230-400)
silica gel using CH2Cl2/MeOH (98:2) as eluent. mp 289-290 °C;
[R]D +6.80 (c 0.5, DMSO); IR (KBr), 3315, 2929, 1652, 1590,
1524, 1467 cm-1; 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (m, 2H),
a Conditions: (a) Pd(OAc)2, (o-tolyl)3P, EtN(i-Pr)2, CH3CN, 110
°C, 15 h.
alkyne and the amide bond resulted in a higher isolated
yield of the cyclic peptide. Thus, the peptide incorporating
6-heptynoic acid afforded compound 7c in 35% isolated
yield compared to the 12% isolated yield of the cyclic
peptide incorporating 4-pentynoic acid.14 All the cyclic
peptides were purified on silica gel column chromatog-
raphy and characterized using various spectral tech-
niques (see Experimental Section).
8.19 (t, J ) 5.37 Hz, 1H), 7.28-7.14 (m, 10H), 4.50 (dd, J1
)
7.25 Hz, J2 ) 16.12 Hz, 1H), 4.41-4.36 (m, 2H), 4.20-4.16 (m,
1H), 4.05 (dd, J1 ) 4.84 Hz, J2 ) 16.12 Hz, 1H), 3.12 (dd, J1 )
4.57 Hz, J2 ) 13.97 Hz, 1H), 2.80 (dd, J1 ) 10.21 Hz, J2 ) 13.97
Hz, 1H), 2.38 (t, J ) 6.98 Hz, 2H), 2.19-2.14 (m, 1H), 2.03-
1.98 (m, 1H), 1.73-1.44 (m, 7H), 1.26 (d, J ) 7.25 Hz, 3H), 0.84
(dd, J1 ) 6.18 Hz, J2 ) 14.24 Hz, 6H); 13C NMR (DMSO-d6, 50
MHz) 172.5, 172.4, 171.6, 170.6, 139.7, 138.3, 137.9, 134.6, 129.1,
128.9 (2C), 128.8, 128.1 (2C), 127.9, 126.2, 126.1, 123.5, 54.3,
50.2, 49.1, 41.8, 41.0, 35.8, 34.9, 27.9, 24.6, 23.8, 23.2, 21.6, 18.6,
16.9; ESMS m/z 545.5 (M+, 100%); HRMS calcd for C32H41N4O4
545.3127, found 545.3115.
Having demonstrated that reacting the acyclic precur-
sors 5 under the copper-free intramolecular conditions
(11) (a) Sonogashira, K. In Metal-Catalyzed Reactions; Diederich,
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Angew. Chem., Int. Ed. 2003, 42, 1566.
Acknowledgment. We thank Dr. Reddy’s Labora-
tories Ltd. for financial support and the analytical
department for their help in recording spectral data.
V.B. thanks Dr. Santanu Maitra for his help and
cooperation.
(12) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
Ed. 2000, 39, 2632.
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Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) All the new compounds are characterized on the basis of spectral
data. See Supporting Information for details.
JO051412Z
9628 J. Org. Chem., Vol. 70, No. 23, 2005