Click chemistry as a route to cyclic tetrapeptide analogues: Synthesis of cyclo-[Pro-Val-ψ(triazole)-Pro-Tyr]

Article abstract of DOI:10.1021/ol053095o

Despite the plethora of techniques to cyclize small peptides, a synthesis of cyclo-[(L)Pro-(L)Tyr-(L)Pro-(L)Val], a potent tyrosinase inhibitor, remains elusive because of the unfavorable transition state leading to the cyclic product. Herein, we report t

Full text of DOI:10.1021/ol053095o

ORGANIC
LETTERS
2006
Vol. 8, No. 5
919-922
Click Chemistry as a Route to Cyclic
Tetrapeptide Analogues: Synthesis of
cyclo-[Pro-Val-ψ(triazole)-Pro-Tyr]
Victoria D. Bock, Rossana Perciaccante, T. Paul Jansen, Henk Hiemstra, and
Jan H. van Maarseveen*
Van 't Hoff Institute for Molecular Sciences, UniVersity of Amsterdam,
Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands
jVm@science.uVa.nl
Received December 21, 2005
ABSTRACT
Despite the plethora of techniques to cyclize small peptides, a synthesis of cyclo-[(
L
)Pro-(
L
)Tyr-(
L
)Pro-(
L
)Val], a potent tyrosinase inhibitor,
remains elusive because of the unfavorable transition state leading to the cyclic product. Herein, we report the successful synthesis of its
triazole analogue, cyclo-[(L)Pro-(L)Val-ψ(triazole)-(L)Pro-(L)Tyr]. Attempted cyclization via peptide bond formation at room temperature fails to
provide the desired product, but CuI-catalyzed alkyne-azide coupling at 110
utility of “click” chemistry.
°
C affords the triazole tetrapeptide in 70% yield, demonstrating the
Considering the vast number of biologically active cyclic
peptides in nature and their potential as drugs in vivo,1 the
synthesis of cyclic peptides and their analogues remains an
important goal for both academic and industrial laboratories.
Head-to-tail cyclization of tetrapeptides in particular poses
a significant challenge: not only is oligomerization a possible
side reaction, but ring strain in the transition state leading
to the cyclic product may prohibit cyclization altogether.2
A number of strategies to facilitate the cyclization of strained
peptides have been developed,3 but a general, high-yielding
route to cyclotetrapeptides has yet to be reported.
One route that we have chosen to explore involves the
use of a 1,4-disubstituted 1,2,3-triazole as an amide bond
surrogate and cyclization aid. These triazoles have atom
placement and electronic properties similar to those of a
peptide bond (Figure 1)4 and are accessible in one step via
CuI-catalyzed alkyne-azide cycloaddition.5 Further, the in-
creased ring size of triazole analogues and the apparent “ring
contraction” mechanism of CuI-catalyzed alkyne-azide cy-
cloaddition6 may help to promote cyclization.7
(4) (a) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8,
1128-1137. (b) Horne, W. S.; Stout, C. D.; Ghadiri, M. R. J. Am. Chem.
Soc. 2003, 125, 9372-9376. (c) Horne, W. S.; Yadav, M. K.; Stout, C. D.;
Ghadiri, M. R. J. Am. Chem. Soc. 2004, 126, 15366-15367. (d) Brik, A.;
Alexandratos, J.; Lin, Y.-C.; Elder, J. H.; Olson, A. J.; Wlodawer, A.;
Goodsell, D. S.; Wong, C.-H. ChemBioChem 2005, 6, 1167-1169.
(5) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596-2599. (b) Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057-3064. (c) For
a recent review, see: Bock, V. D.; Hiemstra, H.; Van Maarseveen, J. H.
Eur. J. Org. Chem. 2006, 51-68.
(1) Lambert, J. N.; Mitchell, J. P.; Roberts, K. D. J. Chem. Soc., Perkin
Trans. 1 2001, 471-484.
(2) (a) Cavelier-Frontin, F.; Achmad, S.; Verducci, J.; Jacquier, R.; Pe`pe,
G. THEOCHEM 1993, 105, 125-130. (b) Cavelier-Frontin, F.; Pe`pe, G.;
Verducci, J.; Siri, D.; Jacquier, R. J. Am. Chem. Soc. 1992, 114, 8885-
8890.
(3) (a) Meutermans, W. D.; Bourne, G. T.; Golding, S. W.; Horton, D.
A.; Campitelli, M. R.; Craik, D.; Scanlon, M.; Smythe, M. L. Org. Lett.
2003, 5, 2711-2714. (b) Prabhakaran, E. N.; Rao, I. N.; Boruah, A.; Iqbal,
J. J. Org. Chem. 2002, 67, 8247-8250. (c) Schmidt, U.; Langner, J. J.
Pept. Res. 1997, 49, 67-73.
(6) Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Angew. Chem., Int. Ed.
2005, 44, 2210-2215.
10.1021/ol053095o CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/08/2006

Scheme 1. Retrosynthetic Analysis of Triazole Analogue 2
Figure 1. Topological similarities of amides (top) and 1,2,3-
triazoles (bottom).
To demonstrate the cyclization potential of click chemistry
on peptides, we have synthesized cyclo-[Pro-Val-ψ(triazole)-
Pro-Tyr] (2), the triazole analogue of cyclo-[(L)Pro-(L)Val-
(L)Pro-(L)Tyr] (1, Figure 2). First isolated from bacterium
valine 710 with the tert-butyl ester of proline (Scheme 2).
Scheme 2. Synthesis of Dipeptide Coupling Fragments
Figure 2. Tyrosinase inhibitor 1 and its triazole analogue cyclo-
[Pro-Val-ψ(triazole)-Pro-Tyr].
L. helVeticus in 1993,8 cyclotetrapeptide 1 is a potent inhibitor
of tyrosinase, a key enzyme involved in the browning of
plant-derived food products and in various human derma-
tological disorders.9 To date, no synthesis of all-L cyclotet-
rapeptide 1 has been reported; Schmidt and Langner at-
tempted its synthesis in 1997 only to obtain the tyrosine
epimer, cyclo-[(L)Pro-(L)Val-(L)Pro-(D)Tyr], in low yield.3c
We envisioned two pathways to triazole analogue 2
(Scheme 1): disconnecting the lone secondary amide bond
retrosynthetically to give triazole-substituted tetrapeptide 3
and cyclization via CuI-catalyzed alkyne-azide coupling
leading back to azide peptide analogue 4. Conveniently, both
linear precursors disconnect back to the same dipeptide
coupling fragments: azido ester 5 and N-protected amino
alkyne 6.
Synthesis of Val-Pro dipeptide coupling fragment 5 was
achieved via EDC/HOBt-mediated peptide coupling of azido
Tyr-Pro coupling fragment 6 was obtained after HCl depro-
tection of known Boc-protected alkyne 811 and subsequent
peptide coupling with Boc-protected benzyl tyrosine (Scheme
2).
(7) (a) Bodine, K. D.; Gin, D. Y.; Gin, M. S. J. Am. Chem. Soc. 2004,
126, 1638-1639. (b) Roice, M.; Johannsen, I.; Meldal, M. QSAR Comb.
Sci. 2004, 23, 662-673. (c) Punna, S.; Kuzelka, J.; Wang, Q.; Finn, M. G.
Angew. Chem., Int. Ed. 2005, 44, 2215-2220. (d) Billing, J. F.; Nilsson,
U. J. J. Org. Chem. 2005, 70, 4847-4850. (e) Van Maarseveen, J. H.;
Horne, W. S.; Ghadiri, M. R. Org. Lett. 2005, 7, 4503-4506. (f) Angell,
Y.; Burgess, K. J. Org. Chem. 2005, 70, 9595-9598.
Coupling of dipeptides 5 and 6 via CuI-catalyzed alkyne-
azide cycloaddition yielded triazole-substituted tetrapeptide
3 cleanly in 74% yield (Scheme 3). As expected, however,
(8) Kawagishi, H.; Somoto, A.; Kuranari, J.; Kimura, A.; Chiba, S.
Tetrahedron Lett. 1993, 34, 3439-3440.
(9) Kim, Y.-J.; Uyama, H. Cell. Mol. Life Sci. 2005, 62, 1707-1723.
(10) Lundquist, J. T., IV.; Pelletier, J. C. Org. Lett. 2001, 3, 781-783.
Org. Lett., Vol. 8, No. 5, 2006
920

Table 1. Optimization of CuI-Catalyzed Alkyne-Azide Cycloaddition Conditions
a Isolated yield of 10, 13, and 4. b Ratio after column chromatography. c Yield includes 11% (w/w) PPh3 byproducts. d Yield includes 10% (w/w) PyBox
14.
Scheme 3. Synthesis and Attempted Cyclization of
Triazole-Substituted Tetrapeptide 3
Scheme 4. Synthesis of Linear Tetrapeptide Analogue 4
generate 5-substituted iodotriazoles,12 but in our hands, even
high commercial grade CuI13 gave substantial quantities of
the iodotriazole. Conditions utilizing catalytic CuI and DBU
at elevated temperatures failed to go to completion after 7
days and still afforded trace amounts of iodotriazole 13
(Table 1, entry 3).
As a result, we explored the use of sources of CuBr, which
gratifyingly gave no 5-substituted side products (Table 1).
Increasing the temperature succeeded in reducing the reaction
time substantially, even under conditions of catalytic CuI.
Both reaction with Cu(PPh3)3Br, a highly soluble, non-air-
sensitive CuBr source,14 and CuBr stabilized by pybox-type
ligand 1415 went to completion and gave no side products,
but chromatographic removal of both PPh3 byproducts and
ligand 14 proved difficult. Gratifyingly, however, reaction
with CuBr and DBU in refluxing toluene afforded cyclic
peptide 10 in 70% yield (Scheme 5). Subsequent deprotection
yielded triazole analogue 2.
cyclization proved difficult: peptide couplings mediated by
EDC/HOBt, HATU, and PyAOP all failed to provide even
trace quantities of benzyl-protected triazole 10.
We then turned our attention to the cyclization of linear
tetrapeptide analogue 4 (Scheme 1). Following TFA depro-
tection of dipeptides 5 and 6 to yield 11 and 12, respectively
(Scheme 4), EDC/HOBt-mediated coupling proceeded
smoothly in 70% yield to afford linear tetrapeptide analogue
4 as a single diastereomer. Although initial attempts at
cyclization utilizing CuSO4 with sodium ascorbate5a yielded
no product after 8 days at room temperature (Table 1, entry
1), reaction with 2 equiv of CuI proceeded to completion in
3 days. To our surprise, we observed no byproducts from
dimerization, a common side reaction in macrocycle forma-
tion via CuI-catalyzed alkyne-azide cycloaddition.7c,f Instead,
the main side product, comprising more than 40% of the
isolated product, was iodotriazole 13 (Table 1, entry 2).
Recent reports indicate that I2 contamination in CuI can
(11) Dickson, H. D.; Smith, S. C.; Hinkle, K. W. Tetrahedron Lett. 2004,
45, 5597-5599.
(12) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005, 8, 1314-
1318.
(13) Obtained from Aldrich, 99.999% pure, and used immediately.
(14) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett.
2001, 42, 4791-4793.
Org. Lett., Vol. 8, No. 5, 2006
921

transition state may still prevent cyclization under conditions
of peptide coupling. The transition state of CuI-catalyzed
click chemistry, however, involves a binuclear Cu complex
that brings the alkyne and azide moieties in close proximity
before “ring contraction” provides the triazole.6,16 Clearly,
this reaction enables cyclization in a case where other
reactions fail to give the desired product.
Scheme 5. Completion of the Synthesis of
cyclo-[Pro-Val-ψ(triazole)-Pro-Tyr] (2)
In summary, we have demonstrated the potential of click
chemistry as a means of obtaining small peptide analogues
too strained for ring closure via lactamization. While
coupling via peptide methodologies failed to provide the
product, the desired cyclic peptide was isolated in 70% yield
after CuI-catalyzed cycloaddition. Triazole analogue 2 is now
being tested for biological activity, and the synthesis of
additional triazole analogues to biologically active cyclotet-
rapeptides17 is underway.
Overall, the failed cyclization of triazole tetrapeptide 3
with traditional peptide coupling methodologies, in contrast
to the successful CuI-catalyzed click chemistry cyclization,
indicates that the mere presence of a triazole moiety in a
tetrapeptide is not enough to overcome the barriers to
cyclization. Although the triazole increases ring size and
therefore reduces ring strain in the product, strain in the
Acknowledgment. We thank W. Seth Horne for the
modeling work and for helpful conversations. We also
acknowledge the Council for Chemical Sciences of the
Netherlands Organization for Scientific Research (NWO-
CW) for their support of this work.
Supporting Information Available: Experimental meth-
ods and compound characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Meng, J.-c.; Fokin, V. V.; Finn, M. G. Tetrahedron Lett. 2005, 46,
4543-4546.
(16) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210-216.
(17) Loiseau, N.; Gomis, J.-M.; Santolini, J.; Delaforge, M.; Andre´, F.
Biopolymers 2003, 69, 363-385.
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