C O M M U N I C A T I O N S
Table 3. Thio Acid/Azide Coupling in Watera
and 4 would resist mild acylation conditions due to significantly
reduced nucleophilic properties, whereas amine analogues of Table
2, entries 2-5, would be expected to undergo facile side reactions.
In addition, many problems in amide synthesis are exacerbated in
methanol and water, where amine nucleophilicity is reduced, and
active esters are rendered susceptible to solvolysis (see Tables 1,
3, and 4). Thus, with this methodology, both simple and complex
amides difficult to access using conVentional methods haVe been
prepared without the use of protecting groups and in aqueous
solution.
These findings complement impressive advances in protein
synthesis,9 engineering,10 as well as unconventional amide synthesis
approaches recently reported.4c,11,12 Considering the ease of prepara-
tion of azides and thio acids in solution and on solid support,13
this method could prove highly useful in the construction of natural
and designed peptides and amide-containing natural products.
Further synthetic, mechanistic, and computational studies will be
reported in due course.
a Conditions: 0.25-0.040 M azide; 1:1.3-5 azide:thio acid; entry 1,
NaHCO3(aq); entry 2, PBS buffer pH 7.4; entry 3, 1.8 equiv of 2,6-lutidine.
(a) Thiobenzoic acid, R ) C6H5. (b) Thioacetic acid, R ) CH3.
Table 4. Preparation of R-Aminoacyl Sulfonamide Derivativesa
Acknowledgment. Financial support by Merck & Co. and
Rutgers, The State University of New Jersey is gratefully acknowl-
edged. The authors would like to thank Prof. Spencer Knapp for
critical reading of the manuscript, and Kavita Joshi and James Huber
for preliminary studies.
yield
(two steps)
entry
8
R
azide
N3-Bs
9
1
2
3
4
5
a
b
c
d
e
i-Bu
9a, N-Ac-Leu-NH-Bs
9b, N-Ac-alle-NH-Ts
9c, N-Ac-lle-NH-Ts
91%
87%
72%
73%
73%
(R)-sec-Bu N3-Ts
(S)-sec-Bu N3-Ts
(R)-sec-Bu N3-dansyl 9d, N-Ac-alle-NH-dansyl
i-Bu N3-dansyl 9e, N-Ac-Leu-NH-dansyl
Supporting Information Available: Synthetic methods and char-
acterization data, including the preparation of 9a-e (PDF). This material
a Conditions: (a) TFA/DCM (40-80% v/v), HSiEt3; (b) CH3OH, 0.16-
0.17 M thio acid; 2-5 equiv of azide, 3-6 equiv of 2,6-lutidine, room
temperature.
References
(1) Rosen, T.; Lico, I. M.; Chu, T. W. J. Org. Chem. 1988, 53, 1580.
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Soc. 2003, 125, ASAP.
dine was converted to the corresponding amides (entry 2), and
N-acyl sulfonamides (entry 3) were smoothly fashioned without
complication in aqueous solution.
The entries in Table 4 illustrate four further advances. N-Acetyl
R-amino acyl sulfonamides were prepared from thioesters 8a-c.5
Liberation of the thio acid, followed by treatment with sulfonyl
azide, gave 9a-e. Hence, sophisticated thio acids participate
predictably in this reaction as well. No epimerization of the thio
acid partner occurred as determined by careful comparison of the
diastereomeric products from entries 2 and 3.5 Entries 1-3 also
demonstrate a new route to highly useful “safety catch” linkers,6
while entries 4 and 5 represent C-terminal fluorescently labeled
peptide derivatives.
Equation 2 presents a new mechanistic framework for this
reaction. Formation of a thiatriazoline intermediate (6), rather than
reduction of the azide to amine, accounts for our observations.7
This intermediate could form via either a 2+3 cycloaddition or a
stepwise diazo transfer-like mechanism. Decomposition of 6,
stepwise or by a retro-[2+3] reaction, would ultimately lead to
amide, nitrogen, and sulfur.8
(5) See Supporting Information for details of preparation and characterization.
(6) Backes, B.; Ellman, J. A. J. Org. Chem. 1999, 64, 2322.
(7) This proposal also accounts for the remarkable observations described in
refs 1-3 as well as those in: (a) Marcaurelle, L. A.; Bertozzi, C. R. J.
Am. Chem. Soc. 2001, 123, 1587. (b) Elofsson, M.; Salvador, L. A.;
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Hsu, C.-H.; Yang, C.; Long, S.-H.; Lin, C.-D. J. Chem. Soc., Perkin Trans.
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R. H. J. Chem. Soc., Chem. Commun. 1993, 94. See also: Paulsen, H.;
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Ed. Engl. 1980, 19, 276.
(9) (a) Tam, J. P.; Xu, J.; Eom, K. D. Biopolymers 2001, 60, 194. (b) Offer,
J.; Dawson, P. E. Org. Lett. 2000, 2, 23. (c) Offer, J.; Boddy, C. N. C.;
Dawson, P. E. J. Am. Chem. Soc. 2002, 124, 4642.
(10) (a) Cornish, V. W.; Mendel, D.; Schultz, P. G. Angew. Chem., Int. Ed.
Engl. 1995, 34, 621. (b) Chin, J. W.; Santoro, S. W.; Martin, A. B.; King,
D. S.; Wang, L.; Schultz, P. G. J. Am. Chem. Soc. 2002, 124, 9026. (c)
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(11) (a) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007. (b) Saxon, E.;
Armstrong, J. I.; Bertozzi, C. R. Org. Lett. 2000, 2, 2141. (c) Nilsson, W.
L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000, 2, 1939. (d) Nilsson,
B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2001, 3, 9. See also: (e)
Humphrey, J. M.; Chamberlin, R. Chem. ReV. 1997, 97, 2243.
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also: Suh, E. M.; Kishi, Y. J. Am. Chem. Soc. 1994, 116, 11205.
(13) For lead references on azide synthesis, see: (a) Scriven, E. F. V.; Turnbull,
K. Chem. ReV. 1988, 88, 297. (b) Rijkers, D. T. S.; Ricardo van Vugt, H.
H.; Jacobs, H. J. F.; Liskamp, R. M. Tetrahedron Lett. 2002, 43, 3657.
For thio acid synthesis, see: (c) Goldstein, A. S.; Gelb, M. Tetrahedron
Lett. 2000, 41, 2797. (d) Rajagopalan, S.; Radke, G.; Tomich, J. Synth.
Commun. 1997, 27, 187. (e) Canne, L.; Walker, S. M.; Kent, S. B. H.
Tetrahedron Lett. 1995, 36, 1217. (f) Schwabacher, A. W.; Maynard, T.
L. Tetrahedron Lett. 1993, 34, 1269.
Thio acid/azide coupling has several advantages over conven-
tional amidation reactions. Amine analogues of azides in Tables 1
JA0294919
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