Published on Web 08/08/2003
A Synthetic Strategy for the Preparation of Cyclic Peptide
Mimetics Based on SET-Promoted Photocyclization
Processes
Ung Chan Yoon,*,† Ying Xue Jin,† Sun Wha Oh,† Chan Hyo Park,†
Jong Hoon Park,† Charles F. Campana,‡ Xiaolu Cai,§ Eileen N. Duesler,§ and
Patrick S. Mariano*,§
Contribution from the Department of Chemistry, College of Natural Sciences, Pusan National
UniVersity, Pusan, 609-735, Korea, Bruker AXS Inc., 5465 East Cheryl Parkway,
Madison, Wisconsin 53711-5373, and Department of Chemistry, UniVersity of New Mexico,
Albuquerque, New Mexico 87131
Received May 16, 2003; E-mail: mariano@unm.edu; ucyoon@pusan.ac.kr
Abstract: A novel method for the synthesis of cyclic peptide analogues has been developed. The general
approach relies on the use of SET-promoted photocyclization reactions of peptides that contain N-terminal
phthalimides as light absorbing electron acceptor moieties and C-terminal R-amidosilane or R-amidocar-
boxylate centers. Prototypical substrates are prepared by coupling preformed peptides with the acid chloride
of N-phthalimidoglycine. Irradiation of these substrates results in the generation of cyclic peptide analogues
in modest to good yields. The chemical efficiencies of these processes are not significantly affected by (1)
the lengths of the peptide chains separating the phthalimide and R-amidosilane or R-amidocarboxylate
centers and (2) the nature of the penultimate cation radical R-heterolytic fragmentation process (i.e.,
desilylation vs decarboxylation). An evaluation of the effects of N-alkyl substitution on the amide residues
in the peptide chain showed that N-alkyl substitution does not have a major impact on the efficiencies of
the photocyclization reactions but that it profoundly increases the stability of the cyclic peptide.
Introduction
ganization of linear precursors by metal cation templation have
found use in routes for the synthesis of crown ethers.3 In the
Substances that possess macrocyclic, polyheteroatom contain-
ing ring systems have played a central role in numerous
investigations aimed at discovering new materials with chemi-
cally and biologically interesting properties. Crown ethers and
their analogues are prime examples of members of this large
family which have attracted great attention as a consequence
of their selective metal and ammonium cation binding proper-
ties.1 In addition, naturally occurring and synthetic cyclic
peptides and their analogues have been the subjects of efforts
aimed at exploring conformationally defined and hydrolytically
more stable polypeptide mimetics.2
area of cyclic peptide synthesis,4 the incorporation of confor-
mationally biasing N-alkyl amino acid and proline units is
known to facilitate macrocyclization processes. Also, several
interesting approaches, including those that employ backbone
cyclizations5 and cyclization-ring contraction sequences,6 have
been used to efficiently generate novel cyclic peptide mimetics.
Owing to the chemical and biological significance of sub-
stances in the crown ether and cyclic peptide families, synthetic
methods, which can be applied to the preparation of new targets,
are still in demand. In recent reports,7 we described a novel,
Several general methods have been developed to construct
the macrocyclic ring systems present in members of the cyclic
peptide and crown ether families. In some of the approaches,
high dilution techniques are required to maximize cyclization
reaction efficiencies. In addition, methods relying on preor-
(3) For representative examples of templation controlled crown ether and
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1793. Vitali, C. A.; Masci, B. Tetrahedron 1989, 45, 2201. Bowsher, B.
R.; Rest, A. J. Inorg. Chim. Acta 1981, 53, L175. (cyclams) Busch, D. H.
Acc. Chem. Res. 1978, 11, 392. Beveridge, K. A.; McAuley, A.; Xu, C.
Inorg. Chem. 1991, 30, 2074. Fortiewr, D. G.; McAuley, A. J. Am. Chem.
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(4) For a review of general approaches to cyclic peptide synthesis, see:
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D.; Bar-Akiva, G.; Seliger, Z.; Byk, G.; Yanaihara, V. J. Peptide Chemistry;
ESCOMA: Leiden, The Netherlands, 1992; p 482. (b) Gilon, C.; Halle,
D.; Choprez, M.; Seliger, Z.; Byk, G. Biopolymers 1991, 31, 745.
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Mentermans, W. D. F.; Golding, S. W.; Bourne, G. T.; Miranda, L. P.;
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† Pusan National University.
‡ Bruker AXS Inc.
§ University of New Mexico.
(1) Gokel, G. W. Crown Ethers and Cryptands; Black Bear Press: Cambridge,
1991.
(2) For representative examples, see: (a) Hruby, V. J. Life Sci. 1982, 31, 189.
(b) Burgess K. Acc. Chem. Res. 2001, 34, 826. (c) Wels, B.; Kruijtzer, J.
A. W.; Liskamp, R. M. J. Org. Lett. 2002, 4, 2173. (d) Fairlie, D. P.;
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H. F.; Timmermans, H. A. M.; Van Unen, M. A.; Ten Hove, G. J.; Vande
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43, 166. (f) Hruby, V. J. Acc. Chem. Res. 2001, 34, 389.
(7) Yoon, U. C.; Oh, S. W.; Lee, J. H.; Park, J. H.; Kang, K. T.; Mariano, P.
S. J. Org. Chem. 2001, 66, 939. Yoon, U. C.; Oh, S. W.; Lee, C. W.
Heterocycles 1995, 41, 2665. Yoon, U. C.; Kim, J. W.; Ryu, J. Y.; Cho, S.
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J. AM. CHEM. SOC. 2003, 125, 10664-10671
10.1021/ja030297b CCC: $25.00 © 2003 American Chemical Society