Synthesis of cyclic peptides constrained with biarylamine linkers using Buchwald-Hartwig C-N coupling

Article abstract of DOI:10.1021/jo061366i

In this paper, we describe the synthesis of conformationally constrained cyclic peptides with biarylamine linkers for peptidomimetics using palladium-catalyzed intramolecular Buchwald-Hartwig C-N coupling. We have prepared a variety of di-, tri-, and tetr

Full text of DOI:10.1021/jo061366i

teicoplanin, and ristocetin A, which are highly effective and
widely used clinical agents for bacterial infections (see Figure
1).6 Here, we are describing the utility of palladium-catalyzed
Buchwald-Hartwig C-N coupling reaction in cyclization of
linear peptides. This is the first report of such cyclization.
Synthesis of Cyclic Peptides Constrained with
Biarylamine Linkers Using Buchwald-Hartwig
C-N Coupling#
V. Balraju†,‡ and Javed Iqbal*,†
Initially, we have prepared an acyclic tripeptide precursor 3
following standard solution chemistry,7 as described in Scheme
1. The bromo compound 1 was prepared from N-Boc-Ala-OH
and 3-bromobenzylamine and was transformed to tripeptide 2
by repeating the sequence of Boc deprotection followed by
peptide coupling using the N-protected amino acids (N-Boc-
Val-OH and N-Boc-Phe-OH). Boc deprotection on compound
2 followed by coupling with the N-Boc-3-aminobenzoic acid
moiety and treatment with TFA in dichloromethane furnished
the acyclic peptide precursor 3 in very good yield. Having the
acyclic precursor 3 in hand, we next attempted the macrocy-
clization to form a cyclic peptide with a biarylamine linker under
various Pd-catalyzed Buchwald-Hartwig reaction conditions
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
jaVediqbaldrf@hotmail.com
ReceiVed July 1, 2006
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In this paper, we describe the synthesis of conformationally
constrained cyclic peptides with biarylamine linkers for
peptidomimetics using palladium-catalyzed intramolecular
Buchwald-Hartwig C-N coupling. We have prepared a
variety of di-, tri-, and tetrapeptides (16-22-membered) in
good yields using this reaction.
(3) (a) Reddy, P. R.; Balraju, V.; Madhavan, G. R.; Banerji, B.; Iqbal,
J. Tetrahedron Lett. 2003, 44, 353-356. (b) Balraju, V.; Reddy, D. S.;
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3571.
Constraining of the linear peptides into more defined con-
formational structures (cyclic peptidomimetics) through cy-
clization is an actively pursued area of research.1 During the
past few decades, great effort has been made to develop more
efficient methods for the synthesis of cyclic peptides and
peptidomimetics, as potential drug leads and/or as models for
conformational analysis.2 As part of the ongoing program in
our laboratory on peptidomimetics, we have developed various
palladium-catalyzed C-C bond forming cyclization strategies,
such as Heck, Sonogashira, and Trost-enyne cycloisomeriza-
tions.3 In continuation to our earlier efforts, we were interested
in studying carbon-nitrogen bond forming reactions, such as
Buchwald-Hartwig coupling,4 during the final cyclization step.
This results in introduction of biarylamine linkers into macro-
cyclic peptides which may be useful as peptidomimetics.5 The
biarylamine moiety also mimics the biaryl ether moiety present
in a variety of naturally occurring cyclic peptides and peptido-
mimetics, such as the glycopeptide antibiotics vancomycin,
(4) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131-
209. (b) Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron
2002, 58, 2041-2075. (c) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem.
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124, 6043-6048. (e) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.;
Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575-
5580. For examples of optimizations of palladium-catalyzed aminations and
amidations, see: (f) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101-
1104. (g) Guari, Y.; van Es, D. S.; Reek, J. N. H.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Tetrahedron Lett. 1999, 40, 3789-3790. (h) Yang,
B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35-38. (i) Browning, R. G.;
Badarinarayana, V.; Mahmud, H.; Lovely, C. J. Tetrahedron 2004, 60, 359-
365. (j) Ferriera, I. C. F. R.; Queiroz, M. J. R. P.; Kirsch, G. Tetrahedron
2003, 59, 3737-3743. (k) Prashad, M.; Mak, X. Y.; Liu, Y.; Repic, O. J.
Org. Chem. 2003, 68, 1163-1164. (l) Harris, M. C.; Huang, X. H.;
Buchwald, S. L. Org. Lett. 2002, 4, 2885-2888. (m) Klapars, A.; Antilla,
J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727-
7729. (n) Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035-2038. (o)
Wang, Z.; Skerlj, R. T.; Bridger, G. J. Tetrahedron Lett. 1999, 40, 3543-
3546. (p) Arterburn, J. B.; Rao, K. V.; Ramdas, R.; Dible, B. R. Org. Lett.
2001, 3, 1351-1354.
(5) Pattarawarappan, M.; Zaccaro, M. C.; Saragovi, U. H.; Burgess, K.
J. Med. Chem. 2002, 45, 4387-4390.
# DRL Publication No. 589.
(6) (a) Blankenstein, J.; Zhu, J. Eur. J. Org. Chem. 2005, 1949-1964.
(b) Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Winssinger, N.; Hughes,
R.; Bando, T. Angew. Chem., Int. Ed. 1999, 38, 240-244. (c) Williams, D.
H.; Bardsley, B. Angew. Chem., Int. Ed. 1999, 38, 1172-1193. (d) Pearson,
A. J.; Bignan, G.; Zhang, P.; Chelliah, M. J. Org. Chem. 1996, 61, 3940-
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* To whom correspondence should be addressed.Tel: +91 40 2304 5439.
Fax: +91 40 2304 5438. E-mail: javediqbaldrf@hotmail.com.
† Dr. Reddy’s Laboratories Ltd.
‡ University of Hyderabad.
(1) (a) Li, P.; Roller, P. P.; Xu, J. Curr. Org. Chem. 2002, 6, 411-440.
(b) Davies, J. S. J. Peptide Sci. 2003, 9, 471-501. (c) Peng, L.; Roller, P.
P. Curr. Top. Med. Chem. 2002, 2, 325-341. (d) Wipf, P. Chem. ReV.
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Chim. Acta 1996, 79, 913-941.
10.1021/jo061366i CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/19/2006
8954
J. Org. Chem. 2006, 71, 8954-8956

FIGURE 1. Biarylamine peptidomimetics of the glycopeptide antibiotic teicoplanin FG ring biaryl ether system.
SCHEME 1a
probably, the size and/or conformation of the peptide are
dictating the possible nucleophilic attack on either side of
benzyne to give compounds 4b and 5b.
To minimize the formation of unwanted cyclic compound
t
5b, we have replaced the BuOK with a milder base, Cs2CO3,
and we found that desired macrocycle 4b is formed exclusively
in good yields in the cyclization of 3b. The scope of this
Buchwald-Hartwig reaction was tested with different acyclic
peptides with varying size and amino acids to give correspond-
ing cyclic peptides (Scheme 3). We also observed that slightly
better yields were obtained in the case of 20/21-membered cyclic
peptides, when compared to that of 19-membered cyclic
peptides.
For the synthesis of smaller-sized 16-membered cyclic
peptides, acyclic peptides 6 and 8 were prepared and subjected
to the above Buchwald-Hartwig reaction conditions using Cs2-
CO3 as base to furnish cyclic peptides 7 and 9, respectively, in
very good yields. We further extended our Buchwald-Hartwig
cyclization method to synthesize 22-membered cyclic tetrapep-
tide 11 successfully in a yield of 20% (Scheme 4).
In conclusion, we have demonstrated that the Buchwald-
Hartwig C-N coupling reaction can be employed for the
macrocyclization of di-, tri-, and tetrapeptides to produce
corresponding cyclic peptides with biarylamine linkers. These
cyclic peptides may prove to be useful in understanding the
utility of constrained structures in the search for novel lead
molecules.
a Conditions: (a) (i) TFA/DCM; (ii) N-Boc-Val-OH, Et3N, HOBt, EDC,
DCM; (iii) TFA/DCM; (iv) N-Boc-Phe-OH, Et3N, HOBt, EDC, DCM; (b)
(i) TFA/DCM; (ii) 3-Boc-aminobenzoic acid, Et3N, HOBt, EDC, DCM;
t
(iii) TFA/DCM; (c) Pd(OAc)2, BINAP, BuOK, CH3CN, 100 °C, 15 h.
reported in the literature. After several attempts, macrocycliza-
tion in refluxing acetonitrile with 30 mol % of Pd(OAc)2, 40
mol % of rac-BINAP ligand, and tBuOK as base was found to
be the optimized conditions to obtain biarylamine containing
cyclic peptides in moderate to good yields.
Experimental Section
Typical Procedure for Intramolecular Buchwald-Hartwig
C-N Coupling for 4a: rac-BINAP (200 mg, 0.32 mmol) was
added to gradient acetonitrile and heated to 80 °C with stirring until
the BINAP dissolved (∼15 min). The mixture was cooled to room
temperature, and Pd(OAc)2 (54 mg, 0.24 mmol) was added. The
mixture was stirred at room temperature for 15 min, and then acyclic
peptide 3a (500 mg, 0.80 mmol) and base (tBuOK, 180 mg, 1.6
mmol or Cs2CO3, 1.04 g, 3.21 mmol) were added. The mixture
was heated at 100 °C (oil bath temperature) for 15-20 h. The
solvent was evaporated under vacuum, and crude product was
Subsequently, these optimized conditions were successfully
employed for the synthesis of 19-21-membered macrocyclic
peptides from their corresponding acyclic peptides 3a-c, and
the results are summarized in Scheme 2. Acyclic peptides 3a
and 3c cyclized smoothly to give cyclic peptides 4a and 4c in
good yields. Surprisingly, under similar conditions (Pd(OAc)2,
t
rac-BINAP, BuOK, CH3CN), compound 3b where n ) 1
produced regioisomeric cyclic peptides 4b and 5b in the ratio
of 1:3 in 54% overall yield. Formation of these regioisomeric
cyclic peptides can be explained via a benzyne intermediate
mechanism as reported by a Chinese group.8 This unusual
behavior observed during the cyclization of compound 3b may
be attributed to the formation of a benzyne intermediate, and
(8) (a) Shi, L.; Wang, M.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q. Org.
Lett. 2003, 5, 3515-3517. (b) March, J. AdVanced Organic Chemistry,
Reactions, Mechanisms and Structure, 4th ed.; John Wiley & Sons: New
York, 1992; p 641.
J. Org. Chem, Vol. 71, No. 23, 2006 8955

SCHEME 2 a
t
a Conditions: (a) Pd(OAc)2, rac-BINAP, BuOK, CH3CN, 100 °C, 15 h.
SCHEME 3 a
SCHEME 4 a
a Conditions: (a) Pd(OAc)2, rac-BINAP, Cs2CO3, CH3CN, 100 °C,
15 h.
(d, J ) 6.98 Hz, 3H); 13C NMR (50 MHz, DMSO-d6) δ 172.3,
171.4, 170.5, 167.9, 143.1, 142.9, 141.1, 137.6, 134.7, 129.4 (2C),
129.0, 128.8, 128.1 (2C), 126.3, 126.1, 121.1, 119.6, 118.3, 117.1,
113.6, 57.5, 55.9, 48.0, 42.5, 36.4, 28.0, 19.1, 18.4, 16.7; ES-MS
m/z calcd for C31H35N5O4 541, found 542 (M+• + 1, 100).
a Conditions: (a) Pd(OAc)2, rac-BINAP, Cs2CO3, CH3CN, 100 °C,
15 h.
subjected to column chromatography on 230-400 mesh silica gel
using CHCl3/CH3OH (98:2) to isolate the desired cyclic peptide
4a as a solid (yield 42%): mp 177-179 °C; [R]20D -50.8° (c 0.25,
DMSO); IR (KBr) ν 3310, 2962, 1654, 1590, 1525 cm-1; 1H NMR
(400 MHz, DMSO-d6) δ 8.70 (d, J ) 6.45 Hz, 1H), 8.33 (s, 1H),
8.27-8.20 (m, 1H), 7.54 (d, J ) 8.06 Hz, 1H), 7.69 (s, 1H), 7.40-
7.12 (m, 10H), 7.02 (dd, J1 ) 1.34 Hz, J2 ) 2.41 Hz, 1H), 6.77
(dd, J1 ) 2.14 Hz, J2 ) 8.06 Hz, 1H), 6.70 (d, J ) 6.71 Hz, 1H),
4.75 (q, J ) 6.71 Hz, 1H), 4.26-4.11 (m, 3H), 3.98 (dd, J1 ) 6.17
Hz, J2 ) 15.23 Hz, 1H), 3.09 (dd, J1 ) 7.79 Hz, J2 ) 13.43 Hz,
1H), 2.96 (dd, J1 ) 7.79 Hz, J2 ) 13.43 Hz, 1H), 2.24-2.20 (m,
1H), 1.25 (d, J ) 7.25 Hz, 3H), 0.67 (d, J ) 6.72 Hz, 3H), 0.58
Acknowledgment. We thank Dr. Reddy’s Laboratories Ltd.
for financial support, and the analytical department for their
help in recording spectral data.
Supporting Information Available: Experimental details of
compounds, 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.
JO061366I
8956 J. Org. Chem., Vol. 71, No. 23, 2006