of more equivalents of reagents to ensure completion of the
reaction, improved yields, purification as a final step, and
suitability for combinatorial chemistry and Fmoc solid-phase
peptide synthesis (Fmoc-SPPS).
Azole-based amino acids are usually prepared in solution
and then used as building blocks in solution or solid-phase
synthesis. Very few solid-phase syntheses of oxazoles and
8
Figure 1. Biosynthesis of azole-containing peptides from serine,
imidazoles have been reported. Commonly used methods
threonine, and cysteine residues.1
c
for the preparation of oxazoles, thiazoles, or imidazoles in
9
solution include (1) a modified Hantzsch’s procedure, (2)
a condensation reaction between N-protected imino ethers
and serine esters, cysteine esters, or 2,3-diaminopropionic
acid esters, respectively,10 and (3) cyclodehydration of
â-hydroxyamides or â-hydroxythioamides, respectively, us-
Oxazole-based peptides can be synthesized from dipeptides
composed of C-terminal threonine by oxidation of the side-
chain followed by a mild Robinson-Gabriel cyclodehydra-
1
3
tion of the resulting â-ketoamide. This very efficient
9
b,11
ing either Mitsunobu conditions or the Burgess reagent.
1
3
method, reported by Wipf and Miller, was chosen because
The freshly synthesized 1,3-azolines are readily converted
into 1,3-azoles by oxidation.12 Alternative methods involve
a Robinson-Gabriel cyclization of â-ketoamide or â-ke-
of its compatibility with Fmoc-SPPS. To apply this method
R
to solid-phase synthesis, N -protected dipeptides composed
of phenylalanine and O-trityl-threonine were synthesized on
1
3
tothioamide to obtain oxazoles and thiazoles, respectively.
1
5
Wang resin using standard Fmoc strategy. After removing
the trityl group with 1% TFA in CH Cl , the resin-bound
Unfortunately, many of these methods are characterized by
long synthetic sequences, harsh reaction conditions, or
extensive purification leading to low overall yields. Our
strategy to overcome this problem was to perform the
heterocyclization directly on solid support from readily
available amino acid derivatives.
2
2
dipeptides 1a-d were subjected to oxidation using the Dess-
16
Martin periodinane to form the â-ketoamide derivatives
2
a-d (Table 1). Oxazole derivatives 3a-d were obtained
by cyclodehydration of the â-ketoamides 2a-d using triph-
enylphosphine in the presence of iodine and diisopropyl-
Most naturally occurring oxazoles and thiazoles are formed
by posttranslational modification of serine, threonine, and
cysteine residues (Figure 1).1c Recently, You and Kelly
reported a biomimetic synthesis of thiazolines and imida-
zolines from N-acylated cysteine or diaminopropionic acid
substrates, respectively, using bis(triphenyl) oxodiphospho-
13
ethylamine. After cleavage from the resin with TFA,
5
-methyloxazole-based dipeptides 4a-d were obtained in
good crude purity (67-78%) and in high yields (80-93%
for six steps) based on the loading of the starting resin after
17
HPLC purification (Table 1).
â-Ketoamides 2a-d were also transformed into thiazole-
1
4
nium salts. Herein, we report the utilization of biomimetic
procedures on solid phase for the synthesis of oxazole-,
thiazole-, and imidazole-containing peptides.
18
based dipeptides 5a-d using the Lawesson’s reagent (Table
6b
1
). Cleavage from the resin with TFA afforded 5-meth-
ylthiazole-based dipeptides 6a-d in good crude purity (70-
9%) and in moderate yields (50-59% for six steps) after
8
1
7
(
8) (a) Pulici, M.; Quartieri, F.; Felder, E. R. J. Comb. Chem. 2005, 7,
63-473. (b) Lee, S. H.; Yoshida, K.; Matsushita, H.; Clapham, B.; Koch,
G.; Zimmermann, J.; Janda, K. D. J. Org. Chem. 2004, 69, 8829-8835.
c) Clapham, B.; Lee, S. H.; Koch, G.; Zimmermann, J.; Janda, K. D.
HPLC purification (Table 1). The evaluated protecting
groups were stable during the synthesis of 4a-d and 6a-d.
The Boc group of 4c and 6c was removed during cleavage
from the resin.
4
(
Tetrahedron Lett. 2002, 43, 5407-5410. (d) Clapham, B.; Spanka, C.; Janda,
K. D. Org. Lett. 2001, 3, 2173-2176. (e) Nishida, A.; Fuwa, M.; Naruto,
S.; Sugano, Y.; Saito, H.; Nakagawa, M. Tetrahedron Lett. 2000, 41, 4791-
Another strategy to obtain oxazoles is to begin with the
4
794.
19
cyclodehydration using the Burgess reagent followed by
(9) (a) Videnov, G.; Kaiser, D.; Kempter, C.; Jung, G. Angew. Chem.,
1
1a,b
Int. Ed. Engl. 1996, 35, 1503-1506. (b) Li, G.; Warner, P. M.; Jebaratnam,
D. J. J. Org. Chem. 1996, 61, 778-780. (c) Bredenkamp, M. W.; Holzapfel,
C. W.; Vanzyl, W. J. Synth. Commun. 1990, 20, 2235-2249. (d) Schmidt,
U.; Utz, R.; Lieberknecht, A.; Griesser, H.; Potzolli, B.; Bahr, J.; Wagner,
K.; Fischer, P. Synthesis 1987, 233-236. (e) Schmidt, U.; Gleich, P. Angew.
Chem., Int. Ed. 1985, 24, 569-571.
the oxidation step.
This strategy applies particularly to
the synthesis of oxazoles from serine residues because the
previously described procedure was unsuccessful in this case.
R
To apply this strategy to the solid phase, N -protected
(10) (a) Stankova, I. G.; Videnov, G. I.; Golovinsky, E. V.; Jung, G. J.
Pept. Sci. 1999, 5, 392-398. (b) Boden, C. D. J.; Pattenden, G.; Ye, T.
(14) (a) You, S. L.; Kelly, J. W. Tetrahedron Lett. 2005, 46, 2567-
2570. (b) You, S. L.; Kelly, J. W. Tetrahedron 2005, 61, 241-249. (c)
You, S. L.; Kelly, J. W. Chem.-Eur. J. 2004, 10, 71-75. (d) You, S. L.;
Kelly, J. W. Org. Lett. 2004, 6, 1681-1683. (e) You, S. L.; Razavi, H.;
Kelly, J. W. Angew. Chem., Int. Ed. 2003, 42, 83-85. (f) You, S. L.; Kelly,
J. W. J. Org. Chem. 2003, 68, 9506-9509.
Synlett 1995, 417-419. (c) North, M.; Pattenden, G. Tetrahedron 1990,
4
2
6, 8267-8290. (d) Jones, R. C. F.; Ward, G. J. Tetrahedron Lett. 1988,
9, 3853-3856.
(
11) (a) Wipf, P.; Fritch, P. C. J. Am. Chem. Soc. 1996, 118, 12358-
1
2367. (b) Wipf, P.; Fritch, P. C. Tetrahedron Lett. 1994, 35, 5397-5400.
(
c) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 1575-1578. (d) Wipf,
(15) Fields, G. B.; Noble, R. L. Int. J. Pept. Protein Res. 1990, 35, 161-
214.
P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907-910. (e) Galeotti, N.;
Montagne, C.; Poncet, J.; Jouin, P. Tetrahedron Lett. 1992, 33, 2807-
(16) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
2
1
810. (f) Wipf, P.; Miller, C. P. J. Am. Chem. Soc. 1992, 114, 10975-
0977.
(17) The yields were calculated based on loading of the first amino acid
on the starting resin. See Supporting Information.
(18) Clausen, K.; Thorsen, M.; Lawesson, S. O.; Spatola, A. F. J. Chem.
Soc., Perkin Trans. 1 1984, 785-798.
(19) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973,
38, 26-31.
(
12) (a) Bertram, A.; Pattenden, G. Heterocycles 2002, 58, 521-561.
b) Bertram, A.; Pattenden, G. Synlett 2000, 1519-1521. (c) Williams, D.
R.; Lowder, P. D.; Gu, Y. G.; Brooks, D. A. Tetrahedron Lett. 1997, 38,
31-334.
13) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604-3606.
(
3
(
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Org. Lett., Vol. 8, No. 11, 2006