ORGANIC
LETTERS
2006
Vol. 8, No. 11
2381-2384
Synthesis and Ag(I) Complexation
Studies of Tethered Westiellamide
Peter Wipf* and Chenbo Wang
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
pwipf+@pitt.edu
Received March 18, 2006
ABSTRACT
A new tethered macrocyclic ring system based on the natural product westiellamide was prepared to increase the affinity and ease of complexation
to Ag(I) ions. NMR and fluorescence Ag(I) titrations confirmed that the tethered macrocycles preserve the unique, high-affinity coordination
mode of westiellamide.
The marine genus Lissoclinum has been a rich source of
cyclopeptide alkaloids featuring multiple oxazolines, thia-
zolines, oxazoles, or thiazoles.1 Several of these macrocyclic-
heterocyclic scaffolds have been found to complex to metal
ions,2 in some cases with unique selectivities.2o The direct
biological relevence of these metal ion binding properties,
however, is still unresolved.2k,n,p
Previously, we reported the first example of a silver-ion-
selective Lissoclinum cyclopeptide interaction.2o Westiell-
amide (1) was found to bind to Ag(I) salts in a unique
[(1)2Ag4]4+ complex (Figure 1). An association constant (Ka)
(1) For reviews on the chemistry of Lissoclinum peptides, see: (a) Wipf,
P. In Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W.,
Ed.; Elsevier: Amsterdam, 1998; Vol. 12, p 187. (b) Wipf, P. Chem. ReV.
1995, 95, 2115. (c) Hamada, Y.; Shioiri, T. Chem. ReV. 2005, 105,
4441.
(2) (a) van den Brenk, A. L.; Tyndall, J. D. A.; Cusack, R. M.; Jones,
A.; Fairlie, D. P.; Gahan, L. R.; Hanson, G. R. J. Inorg. Biochem. 2004,
98, 1857. (b) Bernhardt, P. V.; Comba, P.; Fairlie, D. P.; Gahan, L. R.;
Hanson, G. R.; Lotzbeyer, L. Chem.-Eur. J. 2002, 8, 1527. (c) Morris, L.
A.; Milne, B. F.; Thompson, G. S.; Jaspars, M. J. Chem. Soc., Perkin Trans.
2 2002, 1072. (d) Cusack, R. M.; Grøndahl, L.; Fairlie, D. P.; Gahan, L.
R.; Hanson, G. R. J. Chem. Soc., Perkin Trans. 2 2002, 556. (e) Morris, L.
A.; Jaspars, M.; Kettenes-van den Bosch, J. J.; Versluis, K.; Heck, A. J.
R.; Kelly, S. M.; Price, N. C. Tetrahedron 2001, 57, 3185. (f) Cusack, R.
M.; Grøndahl, L.; Abbenante, G.; Fairlie, D. P.; Gahan, L. R.; Hanson, G.
R.; Hambley, T. W. J. Chem. Soc., Perkin Trans. 2 2000, 323. (g) Morris,
L. A.; Jaspars, M. Royal Soc. Chem. 2000 257, 140. (h) Blake, A. J.;
Hannam, J. S.; Jolliffee, K. A.; Pattenden, G. Synlett 2000, 1515. (i)
Grøndahl, L.; Sokolenko, N.; Abbenante, G.; Fairlie, D. P.; Hanson, G. R.;
Gahan, L. R. J. Chem. Soc., Dalton Trans. 1999, 1227. (j) Comba, P.;
Cusack, R.; Fairlie, D. P.; Gahan, L. R.; Hanson, G. R.; Kazmaier, U.;
Ramlow, A. Inorg. Chem. 1998, 37, 6721. (k) Freeman, D. J.; Pattenden,
G.; Drake, A. F.; Siligardi, G. J. Chem. Soc., Perkin Trans. 2 1998, 129.
(l) van den Brenk, A. L.; Fairlie, D. P.; Gahan, L. R.; Hanson, G. R.;
Hambley, T. W. Inorg. Chem. 1996, 35, 1095. (m) van den Brenk, A. L.;
Byriel, K. A.; Fairlie, D. P.; Gahan, L. R.; Hanson, G. R.; Hawkins, C. J.;
Jones, A.; Kennard, C. H. L.; Moubaraki, B.; Murray, K. S. Inorg. Chem.
1994, 33, 3549. (n) van den Brenk, A. L.; Fairlie, D. P.; Hanson, G. R.;
Gahan, L. R.; Hawkins, C. J.; Jones, A. Inorg. Chem. 1994, 33, 2280. (o)
Wipf, P.; Venkatraman, S.; Miller, C.; Geib, S. J. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1516. (p) Michael, J. P.; Pattenden, G. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1. (q) van den Brenk, A. L.; Hanson, G. R.; Hawkins,
C. J. J. Inorg. Biochem. 1989, 36, 165.
Figure 1. Westiellamide (1, left) and the crystal structure of the
[(1)2Ag4][ClO4]4 complex.
of g2.8 × 1013 M-5 was determined by NMR titration.
Tethered cyclopeptides, or “peptide cylinders”, have been
(3) (a) van Maarseveen, J. H.; Horne, W. S.; Ghadiri, M. R. Org. Lett.
2005, 7, 4503. (b) Pattenden, G.; Thompson, T. Chem. Commun. 2001,
717. (c) Clark, T. D.; Ghadiri, M. R. J. Am. Chem. Soc. 1995, 117, 12364.
10.1021/ol060677c CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/04/2006