Synthesis of acyl derivatives of L-tryptophan containing residues of anthranilic and oxalic acids

Article abstract of DOI:10.1134/S1070428008050096

Oxamoyl derivatives of dipeptide, N-anthranoyl-L-tryptophan, were synthesized by acylation of L-tryptophan methyl ester hydrochloride with 3,1-benzoxazinone derivatives. A one-stage procedure was developed for the synthesis of esters of N-[2-(N′-R-amidooxalyl)aminobenzoyl]-L-tryptophan.

Full text of DOI:10.1134/S1070428008050096

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 5, pp. 693−696. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © L.A. Shemchuk, V.P. Chernykh, R.G. Red’kin, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 5, pp. 702−705.
Synthesis of Acyl Derivatives of L-Tryptophan Containing
Residues of Anthranilic and Oxalic Acids
L. A. Shemchuk, V. P. Chernykh, and R. G. Red’kin
National Farmaceutical University, Kharkov, 61002 Ukraine
e-mail: alchimik@chuguev.net
Received February 28, 2007
Abstract—Oxamoyl derivatives of dipeptide, N-anthranoyl-L-tryptophan, were synthesized by acylation of
L-tryptophan methyl ester hydrochloride with 3,1-benzoxazinone derivatives.Aone-stage procedure was developed
'
for the synthesis of esters of N-[2-(N -R-amidooxalyl)aminobenzoyl]-L-tryptophan.
DOI: 10.1134/S1070428008050096
Low-molecular peptides and pseudopeptides based
on L-tryptophan possess a versatile pharmacological
activity.Asynthetic pseudopeptide glutaryl-L-tryptophan
(thymogen) exhibits an immunostimulating action
[1], nonpeptide metabolite aspercillin isolated from
Aspergillus alliaceus shows an inhibiting activity with
respect to cholecystokinin receptors [2, 3].Ahigh affinity
to some subtypes of cholecystokinin receptors was
found in a series of pseudopeptides related to aspercillin
and containing C-terminal fragments of anthranoyl-
anthranilic acid linked to L-tryptophan [4]. The residues
of the anthranilic acid and tryptophan are present in the
composition of a number of metabolites: glyantrypine
from Aspergillus clavatus [5], fumiquinazolines F
and G from Aspergillus fumigatus [6], fiscalin Β from
Neosartorya fischeri and Corynascus setosus [7]
exhibiting high antitumor activity.
the presence of an equimolar quantity of triethanolamine
and maintained the reaction mixture at 80°C for 12 h.
Applying thus modified procedure we succeeded in
preparation of N-(2-aminobenzoyl)-L-tryptophan methyl
ester (II) in 95% yield.
The acylation of ester II with ethoxalyl chloride in
ethyl acetate in the presence of triethanolamine led to
the formation of N-[2-(ethoxalylamino)benzoyl]-L-
tryptophan methyl ester (III). The reaction of diester
III with aliphatic amines proceeded regioselectively at
room temperature exclusively at the ethoxalyl fragment
of the molecule, not involving the carbonyl group of
the L-tryptophan residue and resulting in amidoesters
IVa–IVg. At the use of a double excess of aliphatic
amines the reaction gave the same products.
Diester III and amidoesters IVa–IVc, IVe–IVg were
prepared in a single-stage process from L-tryptophan
methyl ester I and the corresponding 3,1-benzoxazinones.
Reacting ester I with ethyl 4-oxo-1,4-dihydro-2H-
3,1-benzoxazine-2-carboxylate (V) or with its amides
VIa–VIc, VIe–VIg by maintaining the initial reagents
in DMF at 80°C resulted in the opening of the oxazine
ring and in the formation of diester III or amidoesters
IVa–IVg respectively. Inasmuch as the synthesis of
the corresponding N-(β-hydroxyethyl)amide of 4-oxo-
1,4-dihydro-2H-3,1-benzoxazine-2-carboxylic acid is
difficult, the most suitable procedure for preparation
of compound IVd is the reaction of diester III with
aminoethanol.
Acyl derivatives of L-tryptophan containing residues
of anthranilic and oxalic acid linked in succession are
unknown. Aiming at preparation of pharmacologically
promising oxamoyl derivatives of N-(2-aminobenzoyl)-
L-tryptophan we carried out their synthesis proceeding
from L-tryptophan methyl ester hydrochloride (I) and
appropriate derivatives of 3,1-benzoxazinone. The
reaction of L-tryptophan alkyl esters with a 3,1-benz-
oxazinedione was previously described [8–10]; however,
boiling in pyridine as solvent for 5 h followed by vacuum
distillation [8, 9] resulted in low yields and tarring. The
application of benzene as solvent [10] required a previous
conversion of hydrochloride I into the base because of
its insolubility in benzene. We used DMF as solvent in
Benzoxazinones V, VIa–VIc, VIe–VIg are strong
electrophiles; at heating in DMF with primary aliphatic
693

SHEMCHUK et al.
694
O
O
MeO
MeO
O
O
O
O
N
_
H
+
NH3
Cl
NH2
HN
N
H
N
H
I
II
O
N
O
N
O
O
OEt
H
N
OEt
R
O
O
O
O
Cl
_
_
V
VIa VIc, VId VIg
R
MeO
MeO
O
O
HN
HN
O
O
EtO
HN
O
O
RNH2
HN
HN
O
O
N
N
H
H
_
IV IVg
III
R = Me (a), Pr (b), CH2CH=CH2 (c), CH2CH2OH (d),
(e),
(f),
(g).
O
and aromatic amines they form N-(R-substituted) amides
of 4-oxo-3,4-dihydroquinazoline-2-carboxylic acid [11].
However the acylation of ester I with 3,1-benzoxazine V
even at boiling the reaction mixture gave only compound
III, most likely because of considerable steric hindrances
at the benzamide moiety of molecule II.
2-carboxylic acid VIa–VIc, VIe–VIg were synthesized
as described in [11].
N-(2-Aminobenzoyl)-L- tryptophan methyl ester
(II). To 0.01 mol (2.54 g) of ester hydrochloride I in 10 ml
of DMF was added 0.02 mol (2.98 g) of triethanolamine.
The reaction mixture was stirred for 30 min, the separated
triethanolamine hydrochloride was filtered off, the filtrate
0.01 mol (1.63 g) of 3,1-benzoxazinedione was added,
and the solution obtained was heated at 80°C for 12 h, then
it was diluted with 20 ml of water, and the precipitated
oily substance was kept till it solidified. Yield 3.16 g
(94%), mp 133–136°C (from ethanol). IR spectrum,
cm–1: 3424, 3330, 3243, 3055, 2951, 1745, 1727, 1644,
1611, 1581, 1512, 1487, 1458, 1344. 1H NMR spectrum,
δ, ppm: 3.25 d (2H, CH2), 3.75 s (3H, OCH3), 4.65 t
(1H, CH), 6.25 br.s (2H, NH2), 6.5 t (1Harom), 6.65 d
(1Harom), 6.9–7.15 m (3Harom), 7.18 d (1H, α-CHindole),
7.35 d (1Harom), 7.55 m (2Harom), 8.5 d (1H, NHCO),
10.58 s (1H, NHindole).
EXPERIMENTAL
1H NMR spectra were registered on a spectrometer
Varian M-200 (200 MHz) from solutions in DMSO-d6,
internal reference TMS. IR spectra were recorded
on a spectrophotometer Specord 75IR from KBr pellets.
Mass spectra were measured on an instrument Varian
1200L with direct probe asmission into the ion source,
ionization energy 70 eV, the temperature of ionization
chamber 50–150°C. The reaction progress was monitored
and the purity of compounds obtained was checked by
TLC on Silufol UV-254 plates in a system ethyl acetate–
hexane, 1:1 (development in iodine vapor).
N-[2-(Ethoxalylamino)benzoyl]-L-tryptophan
methyl ester (III). a. To 0.01 mol (3.37 g) of ester II and
0.01 mol (1.49 g) of triethanolamine in 10 ml of ethyl
acetate was added dropwise 0.01 mol (1.2 ml) of ethoxalyl
L-tryptophan methyl ester hydrochloride (I) was
prepared from L-tryptophan by method [12]. Ethyl 4-oxo-
1,4-dihydro-2H-3,1-benzoxazine-2-carboxylate (V) and
the corresponding amides of 4H-3,1-benzoxazin-4-one-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

SYNTHESIS OF ACYL DERIVATIVES OF L-TRYPTOPHAN
695
chloride, and the mixture was maintained for 12 h. Yield
3.88 g (89%), mp 145–147°C (from ethanol).
(a), 3.69 g (82%) (b), mp 115–117°C. IR spectrum,
cm–1: 3424, 3354, 3057, 1728, 1682, 1634, 1598, 1586,
1
1513, 1450, 1341. H NMR spectrum, δ, ppm: 1.01 t
b. Using as initial compounds 2.54 g (0.01 mol)
of ester hydrochloride I and 2.19 g (0.01 mol) of
2-ethoxycarbonyl-3,1-benzoxazine (V) we carried out
the synthesis by the procedure described for ester II.
Yield 2.92 g (67%), mp 145–147°C (from ethanol). IR
spectrum, cm-1: 3407, 1738, 1646, 1587, 1523, 1453,
1368. 1H NMR spectrum, δ, ppm: 1.25 t (3H, CH2CH3),
3.22 d (2H, CH2), 3.75 s (3H, OCH3), 4.25 q (2H,
CH2CH3), 4.65 t (1H, CH), 7.0 m (2Harom), 7.25 m (3H,
α-CHindole +Harom), 7.75 d (1H, Harom), 8.5 d (1Harom),
9.3 d (1H, CONHCH), 10.95 s (1H, NHindole), 12.5 c (1H,
COCONHAr).
(3H, CH2CH2CH3), 1.10 q (2H, CH2CH2CH3), 1.25
m (2H, CH2CH2CH3), 3.22 d (2H, CH2), 3.25 C (3H,
OCH3), 4,75 q (1H, CH), 7.0 m (2Harom), 7.25 m (3H,
α-CHindole + Harom), 7.6 t (2Harom), 7.75 d (1Harom) 8.5 d
(1Harom), 9.0 m (2H, CHNHCO + CH2NHCOCO), 10.95 s
(1H, NHindole), 12.25 br.s (1H,ArNHCO). Mass spectrum,
m/z (Irel, %): 450 (7.5) [M]+, 304 (3.2) [M − 146]+, 234
(5.9) [M − 216]+, 233 (30.6) [M − 217]+, 216 (11.3)
[M − 234]+, 215 (100) [M − 235]+, 202 (16.1) [M − 248]+,
201 (68.8) [M − 249]+, 170 (10.0) [M − 280]+, 148 (10.0)
[M − 302]+, 147 (3.9) [M − 303]+, 146 (35.9) [M − 304]+,
143 (5.1) [M − 307]+, 131 (6.3) [M − 302]+, 130
(96.8) [M − 302]+, 128 (3.4) [M − 322]+, 120 (4.9)
[M − 330]+.
'
N-[2-(N -R-Amidooxalyl)aminobenzoyl]-L-
tryptophan methyl esters IVa–IVg. a. To 0.01 mol
(4.37 g) of diester III dissolved in 15 ml of ethanol was
added 0.02 mol of an appropriate amine, the mixture was
left standing for 24 h at room temperature, the separated
precipitate was filtered off, recrystallized from ethyl
acetate, and dried in air.
'
N-[2-(N -Allylamidooxalyl)aminobenzoyl]-L-
tryptophan methyl ester (IVc). Yield 3.49 g (78%) (a),
4.12 g (92%) (b), mp 152−155°C. IR spectrum, cm–1: 3427,
3328, 3279, 3060, 2360, 1747, 1672, 1642, 1599, 1586,
1
1509, 1445, 1342. H NMR spectrum, δ, ppm: 3.22 d
b. Using as initial compounds 2.54 g (0.01 mol) of
ester hydrochloride I and 0.01 mol of an appropriate
amide of 4-oxo-1,4-dihydro-2H-3,1-benzoxazine-2-
carboxylic acid VIa–VIc, VIe–VIg the synthesis was
carried out similarly to the preparation of ester II.
(2H, CH2), 3.75 s (3H, OCH3), 3.85 t (2H, =CHCH2NH),
4.75 q (1H, CH), 5.22 m (2H, CH2CH=CH2), 5.80 m (1H,
CH2CH=CH2), 7.0 m (2Harom), 7.25 m (3H, α-CHindole
+
H
arom), 7.75 m (2Harom), 7.80 m (1Harom), 8.5 d (1Harom),
9.2 m (2H, CHNHCO + CH2NHCOCO), 10.95 s (1H,
NHindole), 12.30 br.s (1H, ArNHCO). Mass spectrum,
m/z (Irel, %): 448 (19.5) [M]+, 232 (3.1) [M − 216]+,
231 (18.3) [M − 219]+, 216 (4.5) [M − 232]+, 215
(12.3) [M − 233]+, 202 (17.4) [M − 248]+, 201 (100.0)
[M − 249]+, 170 (10.0) [M − 302]+, 159 (4.8) [M − 302]+,
148 (3.0) [M − 302]+, 146 (14.5) [M − 302]+, 131
(7.9) [M − 302]+, 330 (6.2) [M − 302]+, 120 (3.9)
[M − 302]+.
'
N-[2-(N -Methylamidooxalyl)aminobenzoyl]-L-
tryptophan methyl ester (IVa). Yield 3.45 g (82%) (a),
3.79 g (90%) (b), mp 136–138°C. IR spectrum, cm–1:
3329, 1684, 1632, 1588, 1514, 1450, 1411. H NMR
1
spectrum, δ, ppm: 2.71 d (NHCH3), 3.75 s (3H, OCH3),
3.23 d (2H, CH2), 4.75 q (1H, CH), 7.0 m (2Harom),
7.25 m (3H, α-CHindole + Harom), 7.75 m (2Harom), 8.0 m
(1Harom), 8.5 d (1Harom), 8.8 d (2H, CHNHCO), 9.0 q
(1H, CH3NHCOCO), 10.98 s (1H, NHindole), 12.30 br.s
(1H, ArNHCO). Mass spectrum, m/z (Irel, %): 421
(8.3) [M −1]+, 390 (100) [M − 31]+, 304 (3.6) [M − 117]+,
292 (3.5) [M − 129]+, 243 (3.6) [M − 178]+, 217 (4.0)
[M − 204]+, 216 (16.9) [M − 205]+, 215 (87.9) [M −
206]+, 206 (5.2) [M − 215]+, 205 (44.5) [M − 216]+,
203 (7.7) [M − 218]+, 202 (9.1) [M − 219]+, 201
(35.2) [M − 220]+, 200 (100) [M − 221]+, 199 (4.6)
[M − 222]+, 171 (10.4) [M − 250]+, 170 (55.0) [M −
251] +, 159 (16.0) [M − 262]+, 158 (9.9) [M − 263]+, 148
(16.9) [M − 263] +, 147 (8.9) [M − 262]+, 146 (56.7)
[M − 275]+, 143 (7.5) [M − 278]+, 131 (9.9) [M − 290]+,
130 (98.9) [M − 291]+, 120 (7.5) [M − 301]+.
'
N-[2-(N -β-Hydroxyethylamidooxalyl)aminobe
nzoyl]-L-tryptophan methyl ester (IVd). Yield 3.25
g (72%), mp 119–123°C. IR spectrum, cm–1: 3366,
3296, 2947, 1727, 1683, 1630, 1587, 1515, 1453,
1343. 1H NMR spectrum, δ, ppm: 3.0−3.3 m (6H, CH2
+ CH2CH2), 3.55 s (3H, OCH3), 4.6−4.8 m (2H, CH +
HOCH2), 6.8 m (2Harom), 7.25−7.4 m (3H, α-CHindole.
+
Harom), 7.50−7.75 m (2Harom), 7.80 m (1Harom), 8.40 d
(1Harom), 8.75 d (2H, CHNHCO), 9.0 q (1H, NHCOCO),
10.95 s (1H, NHindole), 12.30 br.s (1H, ArNHCO). Mass
spectrum, m/z (Irel, %): 452 (4.3) [M]+, 235 (9.9) [M −
217]+, 217 (3.5) [M − 235]+, 216 (5.3) [M − 236]+, 215
(31.8) [M − 237]+, 202 (11.9) [M − 250]+, 201 (78.5)
[M − 251]+, 170 (9.3) [M − 282]+, 159 (4.2) [M − 293]+,
'
N-[2-(N -Propylamidooxalyl)aminobenzoyl]-L-
tryptophan methyl ester (IVb). Yield 3.24 g (72%)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

SHEMCHUK et al.
696
148 (4.0) [M − 304]+, 147 (3.7) [M − 305]+, 146 (17.6)
[M − 306]+, 143 (4.0) [M − 309]+, 131 (8.2) [M − 321]+,
130 (100) [M − 322]+, 120 (3.9) [M − 332]+.
CHNHCOCO), 9.2 br.s (1H, ArNHCO), 10.75 s (1H,
NHindole). Mass spectrum, m/z (Irel, %): 490 (7.6) [M]+,
274 (3.4) [M − 216]+, 273 (13.2) [M − 217]+, 216 (10.3)
[M − 274]+, 215 (63.4) [M − 275]+, 202 (20.5) [M − 288]+,
201 (100) [M − 390]+, 191 (8.2) [M − 299]+, 170 (8.5)
[M − 320]+, 159 (6.3) [M − 331]+, 158 (3.3) [M −332]+,
148 (5.2) [M − 342]+, 146 (19.4) [M − 344]+, 143 (5.1)
[M − 347]+, 131 (8.2) [M − 359]+, 130 (81.3) [M − 360]+,
120 (3.3) [M − 370]+.
'
N-[2-(N -Furfurylamidooxalyl)aminobenzoyl]-L-
tryptophan methyl ester (IVe). Yield 3.86 g (79%) (a),
4.00 g (82%) (b), mp 122–125°C. IR spectrum, cm–1:
3344, 2951, 2283, 1738, 1679, 1645, 1598, 1586, 1512,
1450, 1352. 1H NMR spectrum, δ, ppm: 3.10 d (2H, CH2),
3.70 s (3H, OCH3), 4.4 d (2H, CH2NH), 4.7 q (1H, CH),
6.10 d (1H, H3fur), 6.40 t (1H, H4fur), 7.0 m (2Harom), 7.30
m (3H, α-CHindole + Harom), 7.60 m (3H, Harom+ H5fur),
7.80 m (1Harom), 8.5 d (1Harom), 9.1 d (1H, CHNHCO),
9.40 t (1H, CH2NHCOCO), 10.95 s (1H, NHindole), 12.30
br.s (1H, ArNHCO). Mass spectrum, m/z (Irel, %): 488
(5.0) [M]+, 215 (3.4) [M − 273]+, 202 (6.4) [M − 286]+,
201 (100) [M − 287]+, 170 (8.2) [M − 318]+, 146 (11.3)
[M − 342]+, 131 (7.5) [M − 357]+, 130 (60.8) [M − 358]+,
120 (3.3) [M − 368]+.
REFERENCES
1. Okovityi, S.V. and Gaivoronskaya, V.V., Eksp. Farmakol.,
2002, vol. 3, p. 1258.
2. Evans, B.E., Bock, M.G., Rittle, K.E., Pardo, R.M.Di.,
Whitter, W.L., Veber, D.F., Anderson, P.S., and Freidin-
ger, R.M., Proc. Natl. Acad. Sci. USA, 1986, vol. 83,
p. 4918.
3. Varnavas, A., Lassiani, L., Luxich, E., and Zacchigna, M.,
Pharmazie, 1996, vol. 51, p. 697.
'
N-[2-(N -Benzylamidooxalyl)aminobenzoyl]-L-
tryptophan methyl ester (IVf). Yield 4.18 g (84%) (a),
4.53 g (91%) (b), mp 96–98°C. IR spectrum, cm–1: 3351,
3059, 2950, 1738, 1679, 1643, 1598, 1585, 1511, 1451,
4. Antonio, V., Lucia, L., Elena, L., and Valentina, V.,
Farmaco E.N., 2000, vol. 55, no. 4, p. 293.
5. Penn, J., Mantle, P.G., Bilton, J.N., and Sheppard, R.N. J.
Chem. Soc., Perkin Trans. I, 1992, p. 1495.
6. Takahashi, C., Matsushita, T., Doi, M., Minoura, K.,
Shingu, T., Kumeda, Y., and Numata, A., J. Chem. Soc.,
Perkin Trans. I, 1995, p. 2345.
7. Fujimoto, H., Negishi, E., Yamaguchi, K., Nishi, N., and
Yamazaki, M., Chem. Pharm. Bull., 1996, vol. 44,
p. 1843.
8. Verrier, M.B. and Potier, P., Tetrahedron, 1987, vol. 43,
no. 15, p. 3465.
9. Nakagawa, M., Taniguchi, M., Sodeoka, M., Ito, M.,
Yamaguchi, K., and Hino, T., J. Am. Chem. Soc., 1983,
vol. 105, p. 3709.
1
1357. H NMR spectrum, δ, ppm: 3.30 d (2H, CH2),
3.60 s (3H, OCH3), 4.4 d (2H, CH2NH), 4.7 q (1H, CH),
7.0 m (2Harom), 7.1–7.4 m (8H, α-CHindole + Harom),
7.65 m (3Harom), 7.80 d (1Harom), 8.5 d (1H, CHNHCO),
8.9 br.s (1H, CH2NHCOCO), 9.4 br.s (1H, ArNHCO),
10.75 s (1H, NHindole). Mass spectrum, m/z (Irel, %):
498 (11.3) [M]+, 281 (11.8) [M − 217]+, 215 (8.4)
[M − 283]+, 202 (16.3) [M − 296]+, 201 (100) [M − 398]+,
130 (42.9) [M − 368]+.
'
N-[2-(N -Cyclohexylamidooxalyl)aminobenzoyl]-
L-tryptophan methyl ester (IVg). Yield 3.33 g (68%)
(a), 2.84 g (58%) (b), mp 120−122°C. IR spectrum, cm–1:
3339, 2932, 2855, 1737, 1675, 1648, 1585, 1511, 1450,
10. Hart, D.J. and Magomedov, N.A., J. Am. Chem. Soc., 2001,
vol. 123, p. 5892.
1
1350. H NMR spectrum, δ, ppm: 1.10−1.65 m (10H,
CH), 3.20 d (2H, CH2), 3.7 s (3H, OCH3), 4.0 m (1H, CH),
11. Petyunin, P.A., Bulgakov, V.A., and Petyunin, G.A., Khim.
Geterotsikl. Soedin., 1974, vol. 5, p. 609.
12. Kim, D.H., J. Heterocycl. Chem., 1975, vol. 12, p. 1323.
4.7 q (1H, CH), 7.0 m (2Harom), 7.30 m (3H, α-CHindole.
+
Harom), 7.60 m (2Harom), 8.8 d (1H, CHNHCO), 9.0 d (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008