Indole-3-propionic acid (IPA) is endogenous plant hormone
and its amino acid conjugates are known to interact with serum
albumin.8
Syntheses of IAA- and IPA-Amino Acid
Conjugates
Numerous literature approaches to 3-indoleacetylated amino
acids utilize: (i) mixed-anhydrides,8-11 (ii) active esters,12-16
(iii) acid chlorides,17 and (iv) DCC as a coupling reagent.18-21
Hydroxybenzotriazole (HOBt) has been used to facilitate
acylations but is explosive and can no longer be purchased or
shipped.
Alan R. Katritzky,* Levan Khelashvili, and
Munawar Ali Munawar
Center for Heterocyclic Compounds, Department of
Chemistry, UniVersity of Florida,
GainesVille, Florida 32611-7200
N-Acylbenzotriazoles22 are easily prepared, chirally stable
reagents for N23-, C24- and O-acylation.25 N-(Aminoacyl)ben-
zotriazoles prepared from N-protected alpha-amino acids have
been successfully utilized for synthesis of di-, tri-, and tetrapep-
tides.26
katritzky@chem.ufl.edu
ReceiVed August 13, 2008
I. Preparation of Benzotriazole Derivatives of IAA and
IPA
1-(1H-Benzotriazol-1-yl)-2-(1H-indol-3-yl)ethanone 2a and
1-(1H-benzotriazol-1-yl)-3-(1H-indol-3-yl)propan-1-one 2b were
prepared by a standard method (eq 1).26a Treatment of indole-
3-acetic acid 1a or indole-3-propionic acid 1b with 4 equiv BtH
and 1 equiv SOCl2 at room temperature for 2 h gave products
2a-b in 86-90% yield. Compounds 2a-b are stable indefi-
nitely at 20 °C.
Amino acid derivatives of IAA and IPA are prepared
conveniently and efficiently by coupling of readily available
2a-b with diverse free amino acids 3a-g and (3c+3c′) to
give compounds 4a-j, (4c+4c′) and (4h+4h′) in 38-70%
yields. Similarly, 2a-b afforded IAA and IPA peptide
conjugates 6a-b in 32-40% yields. Complete retention of
chirality was supported by NMR and HPLC analysis.
II. Preparation of Amino Acid Derivatives of Indole-3-
acetic Acid and Indole-3-propionic Acid. IAA-Bt 2a was
Indole-3-acetic acid (IAA) is an indispensable plant hormone
(auxin), which also occurs naturally as numerous ‘conjugates’
linked to amino acid, sugar, or inositol residues.1 Gene
expression, cell division, cell elongation and differentiation in
plant tissue are all regulated by indole-3-acetic acid auxins,1,2
which can also control vascularization, phototropism, geotro-
pism, fruit development, flower development, and apical domi-
nance.3 IAA is a major metabolite of tryptophan in animals,
being formed in body tissues and by intestinal bacteria.4,5
Many plant species convert indole-3-acetic acid (IAA) into
ether-insoluble metabolites, including the amino acid conjugate,
indole-3-acetylaspartic acid (IAA-Asp), as identified by chro-
matography, color tests, and biological activity.6 Indole-3-
acetylysine (IAA-Lys) was isolated from Pseudomonas saVas-
tanoi.7
ˇ
(8) Tomasˇic´, A.; Bertosˇa, B.; Tomic´, S.; Sosˇkic´, M.; Magnus, V. J. Chro-
matogr., A 2007, 1154, 240–249.
(9) Magnus, V.; Nigovic´, B.; Hangarter, R. P.; Good, N. E. J. Plant Growth
Regul. 1992, 11, 19–28.
(10) Wieland, T; Ho¨rlein, G. Liebigs. Ann. Chem. 1955, 591, 192–199.
(11) Amstrong, M. D.; Shaw, K. N. F.; Gortatowski, M. J.; Singer, H. J. Biol.
Chem. 1958, 232, 17–30.
(12) Mollan, R. C.; Donnelly, D. M. X.; Harmey, M. A. Phytochemistry 1972,
11, 1485–1488.
(13) Feung, C.-S.; Hamilton, R. H.; Mumma, R. O. J. Agric. Food Chem.
1975, 23, 1120–1124.
(14) Campanella, J. J.; Olajide, A. F.; Magnus, V.; Ludwig-Mueller, J. Plant
Physiol. 2004, 135, 2230–2240.
(15) Antolic´, S.; Kveder, M.; Klaic´, B; Magnus, V.; Kojic´-Prodic´, B. J. Mol.
Struct. 2001, 560, 223–237.
(16) Park, R. D.; Park, C. K. Plant Physiol. 1987, 84, 826–829.
(17) Weller, L. E.; Sell, H. M. J. Org. Chem. 1958, 23, 1776–1777.
(18) Good, N. E. Can. J. Chem. 1956, 34, 1356–1358.
(19) Napoli, L. D.; Evidente, A.; Piccialli, G.; Santacroce, C.; Iacobellis,
N. S.; Sisto, A. Phytochemistry 1993, 33, 13–16.
(1) Hooykaas, P. J. J., Hall, M. A. , Libbenga, K. R., Eds. Biochemistry and
Molecular Biology of Plant Hormones; Elsevier: Amsterdam,1999; Vol. 115.
(2) Hangarter, R. P.; Peterson, M. D.; Good, N. E. Plant Physiol. 1980, 65,
761–767.
(3) Davies, P. J. The plant hormones: their nature, occurrence, and functions,
In Plant Hormones: Physiology, Biochemistry and Molecular Biology; Davies,
P. J., Ed.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 1995.
(4) Chung, K.-T.; Anderson, G. M.; Fulk, G. E. J. Bacteriol. 1975, 124, 573–
575.
(5) Weissbach, H.; King, W.; Sjoerdsma, A.; Udenfriend, S. J. Biol. Chem.
1959, 234, 81–86.
(6) Andreae, W. A.; Good, N. E. Plant Physiol. 1955, 30, 380–382.
(7) Hutzinger, O.; Kosuge, T. Biochemistry 1968, 7, 601–605.
(20) LeClere, S.; Tellez, R.; Rampey, R. A.; Matsuda, S. R. T.; Bartel, B.
J. Biol. Chem. 2002, 23, 20446–20452.
(21) Ilic, N.; Magnus, V.; Ostin, A.; Sandberg, G. J. Labelled Compd.
Radiopharm. 1997, 39, 433–440.
(22) Katritzky, A. R.; Suzuki, K.; Wang, Z. Synlett 2005, 11, 1656–1665.
(23) Katritzky, A. R.; Khelashvili, L.; Mohapatra, P. P.; Steel, P. J. Synthesis
2007, 23, 3673–3677.
(24) (a) Katritzky, A. R.; Le, K. N. B; Khelashvili, L.; Mohapatra, P. P. J.
Org. Chem. 2006, 71, 9861–9864. (b) Katritzky, A. R.; Abdel-Fattah, A. A. A.;
Akhmedova, R. G. ARKIVOC 2005, 4, 329–338.
(25) (a) Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J. Heterocycl. Chem.
1999, 36, 777–781. (b) Katritzky, A. R.; Angrish, P. Steroids 2006, 71, 660–
669.
10.1021/jo8017796 CCC: $40.75
Published on Web 10/22/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9171–9173 9171