6700
J. Am. Chem. Soc. 2001, 123, 6700-6701
Activation of a Terminal Carboxylic Acid by an
Internal Oxazole: A Novel Synthesis of
Macrocyclodepsipeptide
Gang Zhao,† Xiaowen Sun,† Hugues Bienayme´,‡ and
Jieping Zhu*,†
Institut de Chimie des Substances Naturelles
CNRS, 91198 Gif-sur-YVette, France
Rhoˆne-Poulenc Industrialisation
24, AV. Jean Jaures
F-69153 De´cines Cedex, France
Figure 1. Three-component synthesis of 5-amino oxazole.
ReceiVed March 21, 2001
ReVised Manuscript ReceiVed May 15, 2001
Scheme 1
An increasing large number of bioactive cyclopeptides and
cyclodepsipeptides have been found in nature.1 Their reduced
conformational flexibility, bioavailability, and metabolic stability
make them important leads for drug discovery.2 Neither as
completely rigid as small ring heterocycles nor as flexible as
acyclic counterparts, macrocycles provide a unique coverage of
three-dimensional space that is useful for elucidating the bioactive
conformation and for protein surface mimetics in the increasingly
important area of protein-protein interactions.3 Not surprisingly,
they have been for years one of the privileged structures in
medicinal chemistry.4 With the advances in the fields of functional
genomics5 and chemical genetics,6 efficient combinatorial syn-
thesis of natural product-like and drug-like compounds such as
cyclodepsipeptides will be welcomed.7 We report herein a
conceptually novel synthesis of macrocyclodepsipeptide 1 as
outlined in Scheme 1. A three-component synthesis of the
functionalized oxazole followed by an internal activation of the
terminal carboxylate and a controlled macrocyclization are the
keys to the present process. Fleury’s mechanistic study on acidic
hydrolysis of the 5-amino oxazole constitutes the basis of the
projected activation-cyclization sequence.8
Applying our recently developed three-component reaction,9
a range of highly functionalized 5-amino oxazoles (5a-5j, Figure
1) were synthesized in good to excellent yield by simply heating
a methanol solution of an aldehyde (2), an amino alcohol (3),
and a dipeptide isocyanide (4).10 Saponification of methyl ester
(LiOH, THF-H2O) gave the corresponding lithium salt without
affecting the oxazole core.11 Using 8a as a testing compound,
cyclization conditions were surveyed under various conditions.
Some representative results are summarized in Table 1.
Table 1. Survey of Macrolactonization Conditions
As it is seen, the trifluoroacetic acid turned out to be the acid
of choice among those investigated (entries 1, vs 5 and 6).
† Institut de Chimie des Substances Naturelles.
‡ Rhoˆne-Poulenc Industrialisation.
entries
solventa
acid
yield (%)
drb
1/1
(1) (a) Fusetani, N.; Matsunaga, S. Chem. ReV. 1993, 93, 1793-1806. (b)
Tang, Y. Q.; Yuan, J.; Osapay, K.; Tran, D.; Miller, C. J.; Quellete, A. J.;
Selsted, M. E. Science 1999, 286, 498-502.
(2) Fairlie, D. P.; Abbenante, G.; March, D. R. Curr. Med. Chem. 1995, 2,
654-686.
(3) (a) Kessler, H. C. Angew. Chem., Int. Ed. Engl. 1982, 21, 512-513.
(b) Toniolo, Int. J. Pept. Protein Res. 1990, 35, 287-300
(4) (a) Shu, Y. Z. J. Nat. Prod. 1998, 61, 1053-1071. (b) Newman, D. J.;
Gragg, G. M.; Snader, K. M. Nat. Prod. Rep. 2000, 17, 215-234.
(5) Palfreyman, M. G. Expert Opin. InVest. Drugs 1998, 1201-1207.
(6) (a) Mitchison, T. J. Chem. Biol. 1994, 1, 3-6. (b) Schreiber, S. L.
Bioorg. Med. Chem. 1998, 6, 1127-1152.
(7) Schreiber, S. L. Science 2000, 287, 1964-1969. (b) Arya, P.; Chou,
D. T. H.; Baek, M. G. Angew. Chem., Int. Ed. 2001, 40, 339-346.
(8) (a) Clerin, D.; Fleury, J. P. Bull. Soc. Chim. Fr. 1973, 3127-3142. (b)
Clerin, D.; Fleury, J. P. Tetrahedron 1974, 30, 469-474.
(9) Sun, X.; Janvier, P.; Zhao, G.; Bienayme´, H.; Zhu, J. Org. Lett. 2001,
3, 877-880.
(10) Three aldehydes, eight amino alcohols, and three isocyanides were
used in this preliminary study (cf. Supporting Information).
(11) Model studies indicated that methyl ester terminal could not be
activated by oxazole under the acidic conditions.
1
2
3
4
5
6
toluene
MeCN
DMF
THF
toluene
toluene
TFA
TFA
TFA
TFA
TsOH
HClO4
85
81
63
59
9
1/2
1/1.9
1/2.1
1/1.7
1/2.3
7
a Concentration of substrate 5a: 0.001 M, abbreviation: MeCN )
acetonitrile, DMF ) N,N-dimethylformamide, THF ) tetrahydrofuran,
TFA ) trifluoroacetic acid, TsOH ) p-toluenesulfonic acid. b dr )
diastereomeric ratio.
Curiously, the cyclization worked in both nonpolar and aprotic
dipolar solvents, with toluene and acetonitrile being the best
reaction mediums. A moderate asymmetric induction was ob-
served during the protonation step of oxazole, leading to two
diastereomers in a one-to-two ratio.12 Figure 2 lists the cyclodep-
sipeptides synthesized.13 Keeping in mind its potential application
10.1021/ja015854d CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/13/2001