J. Am. Chem. Soc. 2001, 123, 333-334
333
-(CH2)2CO2H) and L-Lys(Thz) (2b, X ) S, R ) -(CH2)4NH2)
into cyclic hexapeptides (4-6), and their subsequent elaboration
to two new types of highly constrained chiral cavitands, the
peptidic cylinder (7) and cone (8). Both the cylinder and cone
are pentacyclic molecules, featuring two 18-membered macro-
cycles joined by three intercyclic linkages that create three
additional 30-membered rings. These unique peptide cavitands
illustrate new classes of supramolecular peptides for conceivable
further development to catalysts and artificial proteins.
Novel Cylindrical, Conical, and Macrocyclic Peptides
from the Cyclooligomerization of Functionalized
Thiazole Amino Acids
Yogendra Singh,† Nikolai Sokolenko,† Michael J. Kelso,†
Lawrence R. Gahan,§ Giovanni Abbenante,† and
David P. Fairlie†,*
Centre for Drug Design and DeVelopment
Institute for Molecular Bioscience
and Department of Chemistry
UniVersity of Queensland
Brisbane, Qld 4072, Australia
ReceiVed July 21, 2000
Intramolecular condensation of cysteine, serine, or threonine
side chains of dipeptides Aaa-Cys, Aaa-Ser, or Aaa-Thr (1) results
in dipeptide surrogates (2) that incorporate five-membered
heterocyclic ring constraints such as thiazole (X ) S), oxazole
(X ) O) or their reduced analogues. Such dipeptide surrogates
have been found in many natural products, where they often
profoundly influence three-dimensional structures and bioactivi-
ties.1-3 The number and oxidation state of heterocyclic rings can
enforce macro-chair or macro-boat conformations on macrocycles
such as 3,4 and this has been shown to result in very different
5b
affinities for metal ions such as Cu2+ 5a
,
Zn2+
,
and Ca2+ 5c
.
Dipeptide surrogates such as 2 have been exploited as â-turn-
inducing constraints to control cyclooligomerizations6 used to
form macrocycles such as [Ile-Ser-D-Val(Thz)]2-19, with up to
76 amino acids in the cycle.6b
Cyclic hexapeptide 4 was prepared by converting the protected
amino acid BocGlu(OcHx)-OH to the thiazole dipeptide BocGlu-
(OcHx)Thz-OtBu in 86% overall yield by an established method.7
This involved derivatization of BocGlu(OcHx)-OH to the primary
amide, conversion to the corresponding thioamide with Lawes-
son’s reagent, followed by a modified Hantzch synthesis using
tert-butyl bromopyruvate to give the protected thiazole amino acid.
Treatment of the protected thiazole with TFA yielded 9 (R )
-(CH2)2CO2cHx). Cyclooligomerization of 9 (2 × 10-3 M) with
BOP using DIPEA as base and DMF as solvent gave high isolated
yields of cyclic hexapeptide 10a (85%) and cyclic octapeptide
11a (10%) where R ) -(CH2)2CO2cHx), which were separated
by column chromatography.8 This contrasts with poor cyclooli-
gomerization yields reported for similar oxazole-amino acids.9
Removal of the cyclohexyl-protecting group from 10a with HF
produced the cyclic hexapeptide 4. Cyclooligomerization proceeds
equally well at higher concentrations of 9 (85% 10a at 4 × 10-2
M; 83% at 0.1 M).
We now report high-yielding cyclotrimerization reactions of
functionalized dipeptide surrogates L-Glu(Thz) (2a, X) S, R )
* To whom correspondence should be addressed. E-mail: d.fairlie@mailbox.
uq.edu.au. Fax: +61-7-33651990.
† Institute for Molecular Bioscience, University of Queensland.
§ Dept. of Chemistry, University of Queensland.
(1) (a) Faulkner, D. J. Nat. Prod. Rep. 1998, 15, 113-158; 1997, 14, 259-
302; 1996, 13, 75; 1995, 12, 233; 1994, 11, 355. (b) McGeary, R. P.; Fairlie,
D. P. Curr. Opin. Drug DiscoVery DeV. 1998, 1, 208-217. (c) Fate, G. D.;
Benner, C. P.; Grode, S. H.; Gilbertson, T. J. J. Am. Chem. Soc. 1996, 118,
11363-11368.
(2) (a) Wipf, P. Chem. ReV. 1995, 95, 2115. (b) Michael, J. P.; Pattenden,
G. Angew. Chem., Int. Ed. Engl. 1993, 31, 1-23.
(3) Fairlie, D. P.; Abbenante, G.; March, D. R. Curr. Med. Chem. 1995,
95, 654-686.
(7) (a)Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473-2476;
2477-2480. (b) Brendenkamp, M. W.; Holzapfel, C. W.; Snyman, R. M.;
van Zyl, W. J. Synth. Commun. 1992, 22, 3029-3039.
(4) Abbenante, G.; Fairlie, D. P.; Gahan, L. R.; Hanson, G. R.; Pierens,
G.; van den Brenk, A. L., J. Am. Chem. Soc. 1996, 118, 10384-10388.
(5) (a) Van den Brenk, A. L.; Byriel, K. A.; Fairlie, D. P.; Gahan, L. R.;
Hanson, G. R.; Hambley, T.; Hawkins, C. J.; Kennard, C. H. L.; Moubaraki,
B. J.; Murray, K. Inorg. Chem. 1994, 33, 3549-3557. (b) Grøndahl, L.;
Sokolenko, N.; Abbenante, G.; Fairlie, D. P.; Hanson, G. R.; Gahan, L. R. J.
Chem. Soc., Dalton Trans. 1999, 8, 1227-1234. (c) Cusack, R. M.; Grøndahl,
L.; Abbenante, G.; Fairlie, D. P.; Gahan, L. C.; Hanson, G. R.; Hambley, T.
W. J. Chem. Soc., Perkin Trans. 2 2000, 323-331.
(8) Typically: TFA‚H-Glu(OcHX)Thz-OH (3.5 g, 8.2 mmol) and BOP (5.5
g, 12.4 mmol) were dissolved in DMF (200 mL), cooled to 0 °C, DIPEA (10
mL, 57.4 mmol) added, and stirred (0 °C, 5 h). Solvent was evaporated in
vacuo, and the residue was dissolved (150 mL EtOAc), washed with 20%
aqueous citric acid (1 × 50 mL), saturated NaHCO3 (4 × 60 mL), water (1
× 80 mL), and brine (50 mL), dried (anhydrous MgSO4), and concentrated.
Chromatography on Si gel with petroleum ether/EtOAc gave 10a cyclo-[Glu-
(OcHx)Thz]3 (2.0 g, 85%; HRMS: M + H exptl 1177.4253, calcd 1177.4230)
and 11a cyclo-[Glu(OcHx)Thz]4 (241 mg, 10%; HRMS: M + H exptl
883.3201, calcd 883.3192).
(6) (a) Wipf, P.; Miller, C. P. J. Am. Chem. Soc. 1992, 114, 10975-10977.
(b) Sokolenko, N.; Abbenante, G.; Scanlon, M. J.; Jones, A.; Gahan, L. R.;
Hanson, G. R.; Fairlie, D. P. J. Am. Chem. Soc. 1999, 121, 2603-2604. (c)
Bertram, A.; Hannam, J. S.; Jolliffe, K. A.; de Turiso F. G. L.; Pattenden, G.
Synlett 1999, 11, 1723-1726.
(9) Mink, D.; Mecozzi, S.; Rebeck, J., Jr. Tetrahedron Lett. 1998, 39, 5709-
5712.
10.1021/ja002666z CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/19/2000