3-Aryl-3,4-Dihydroisocoumarins with Amino-Acid Fragments

Article abstract of DOI:10.1007/s10600-016-1720-6

New amino-acid derivatives of 3-aryl-3,4-dihydroisocoumarins were prepared via acylation of the amine of natural amino acids by phenoxyacetic acids containing 3,4-dihydroisocoumarin substituents on the benzene ring.

Full text of DOI:10.1007/s10600-016-1720-6

DOI 10.1007/s10600-016-1720-6
Chemistry of Natural Compounds, Vol. 52, No. 4, July, 2016
3-ARYL-3,4-DIHYDROISOCOUMARINS WITH
AMINO-ACID FRAGMENTS
*
S. V. Shilin, O. V. Shablykina, V. V. Ishchenko,
Yu. N. Zabolotnaya, and V. P. Khilya
New amino-acid derivatives of 3-aryl-3,4-dihydroisocoumarins were prepared via acylation of the amine of
natural amino acids by phenoxyacetic acids containing 3,4-dihydroisocoumarin substituents on the benzene
ring.
Keywords: isocoumarins, dihydroisocoumarins, 3-aryl-3,4-dihydroisocoumarins, activated esters method,
N-hydroxysuccinimide, amino-acid derivatives.
In continuation of research on new syntheses of isocoumarins modified by natural amino-acid fragments [1], we
focused on 3,4-dihydroisocoumarin derivatives mainly because natural compounds with the 1-oxoisochromane core are
dominated by saturated species [2]. Dihydroisocoumarins in living subjects can be associated with their unsaturated analogs,
e.g., glycosides of dihydrohomalicine and homalicine [3], the aglycons of which are 3-(3-hydroxyphenyl)-3,4-
dihydroisocoumarin and 3-(3-hydroxyphenyl)isocoumarin, respectively. According to recent reports [4, 5], dihydroisocoumarins
are often encountered among compounds produced by fungal microorganisms. Furthermore, ochratoxinA[6] and amicoumacin
B [7], two of few known natural isocoumarins with amino-acid fragments, also contain a 3,4-dihydroisocoumarin ring and are
characterized by high biological activity.
Starting 3-phenyl-3,4-dihydroisocoumarins 10–12 with a hydroxyacetic-acid fragment as a linker for attaching amino
acids were synthesized by known methods [8] using an equivalent amount of ethyl chloroacetate instead of methyl bromoacetate
as indicated in the article (Scheme 1).
O
O
O
COOH
O
a
b
c
O
O
O
R
R
R
R
OH
OCH COOH
OCH COOEt
OCH COOH
2
2
2
1 - 3
4 - 6
7 - 9
10 - 12
1: 4-OH, R = H; 2: 4-OH, R = CH ; 3: 2-OH, R = CH ; 4: 4-OCH COOEt, R = H; 5: 4-OCH COOEt, R = CH
3
3
3
2
2
6: 2-OCH COOEt, R = CH ; 7, 10: 4-OCH COOH, R = H; 8, 11: 4-OCH COOH, R = CH ; 9, 12: 2-OCH COOH, R = CH
2
3
2
2
3
2
3
–
+
+
a. ClCH COOEt, K CO , Me CO; b. 1. OH , 2. H ; c. 1. NaBH , 2. H
2
2
3
2
4
Scheme 1
Activated esters [9, 10] were used as before [1] to attach amino acids to the carboxylic group of 10–12 through an
amide bond. Thus, the acid group to be modified was converted to the N-hydroxysuccinimide (SuOH) ester (Scheme 2).
The resulting esters 13–15 reacted with an optically pure natural L-amino acid to give N-acyl amino-acid derivatives
16–18 (Table 1).
Taras Shevchenko Kiev National University, 64/13 Vladimirskaya St., Kiev, 01601, Ukraine, e-mail:
shablykina@ukr.net. Translated from Khimiya Prirodnykh Soedinenii, No. 4, July–August, 2016, pp. 516–521, original article
submitted September 30, 2015.
©
0009-3130/16/5204-0595 2016 Springer Science+Business Media New York
595

TABLE 1. Yields and Melting Points of 16–18
Yield,
%
Yield,
%
Yield,
%
Amino acid
Ñompound
Ñompound
Ñompound
mp,ꢀÑ
mp,ꢀÑ
mp,ꢀÑ
Glycine
Alanine
Leucine
206–207
176–177
78
57
237–238
44
16a
16b
17a
196–197
177–178
92–93
65
69
74
17c
17d
17e
Norleucine
ꢁ-Alanine
Phenylalanine
Tyrosine
Tryptophan
Methionine
Asparagine
Citrulline
144–145
70
18e
169–170
123–124
178–179
69
40
78
16f
16g
16h
147–148
205–206
88–89
53
69
66
18g
18h
18i
186–187
O
69
17i
169–170
159–160
73
27
16j
16k
157–158
57
18k
O
O
R
1
COOH
R
3'
O
i
ii
3
O
N
H
O
O Su
OCH COOH
2
7
5'
16a, b, f - h, j, k; 17a, c - e, i
5
10, 11
13, 14
O
O
O
O
COOH
i
ii
6'
O
O Su
O
N
H
H C
3
OCH COOH
2
R
2'
15
18g - i, k
12
O
O
O
CH
O
3
3'
O
COOH
O
3
6'
O
N
H
COOH
7
H C
3
O
N
5'
2'
H
5
17e
18e
16a, 17a: R = H; 16b: R = CH ; 17c: R = CH CH(CH ) ; 17d: R = (CH ) CH ; 16f: R = CH Ph; 16g, 18g: R = CH (4-HOC H )
3
2
3 2
2 3
3
2
2
6 4
16h, 18h: R = CH (indol-3-yl); 17i, 18i: R = CH CH SCH ; 16j: R = CH CONH ; 16k, 18k: R = (CH ) NHCONH
2
2
2
3
2
2
2 3
2
10, 13, 16: R = H; 11, 14, 17: R = CH
1
1
3
i. 1. DCC, anhydr. dioxane, RT, 2. SuOH; ii. 1. amino acid, NaHCO , dioxane – H O (1:1), RT, 2. HCl
3
2
Scheme 2
An advantage of the modified activated-ester method used by us was the ability to carry out the two-step synthesis of
the amino-acid derivatives without isolating intermediate succinimide esters 13–15. The completion of their formation was
monitored using TLC. TLC also indicated that the conversion was high and side products did not form during the transformation
of 13–15 into 16–18.
Yields of the derivatives were low in several instances. This was related primarily to specifics of the isolation of these
products. Thus, the dicyclohexylurea formed from dicyclohexylcarbodiimide (DCC) was filtered off before amino-acid
derivatives 16–18 were precipitated according to the procedure in the Experimental section. This led to partial loss of the
target compound for slightly soluble compounds (e.g., tyrosine derivatives) and those precipitating from the reaction mixture
simultaneously with the urea.
Conversely, the main losses of products that were highly soluble in aqueous solutions (in particular, citrulline derivatives)
occurred during their isolation in the last step, i.e., crystallization from weakly acidic aqueous solutions. Of course, the target
compounds could be isolated by extraction from aqueous solutions. However, separation of them from other organic components
was problematical (chromatography of amino-acid derivatives with a free carboxylic acid is extremely difficult). Thus, the
simplicity of the procedure used by us compensated fully in several instances for the slight quantitative losses.
596

Structural changes on going from the (isocoumarinyl)phenoxyacetic acids described by us [1] to the
(3,4-dihydroisocoumarinyl)phenoxyacetic acids presented herein could affect considerably the activity of the carboxylic acid,
which could not lie in the same plane with the phenoxyl fragment because the isochromone 3- and 4-positions were saturated.
The reactivity and, as a result, the time required to form the activated ester of 10, in which the carboxylic acid was distant from
the isochromanone substituent, were practically the same as those for the unsaturated analog. We found that 10, like the
corresponding isocoumarin derivative [1], reacted completely with N-hydroxysuccinimide in 2–3 h and produced activated
ester 13.
A different picture was observed for compounds with an isochromone substituent in the position ortho to the
hydroxyacetic acid on the phenyl ring. [4-Methyl-2-(3,4-dihydroisocoumarin-3-yl)phenoxy]acetic acid (12) was significantly
more active than [4-methyl-2-(isocoumarin-3-yl)phenoxy]acetic acid. The activated ester of dihydroisocoumarin 12 required
3–4 h to form (Experimental section) whereas at least 96 h were required for the conversion into the ester of the corresponding
acid with an isocoumarin fragment [1].
Racemates of dihydroisocoumarins 10–12 were formed from the reactions of 7–9 with NaBH . Therefore, subsequent
4
addition of the optically pure amino acid should produce a mixture of diastereomers. However, as a rule, PMR spectra of
16–18 had only one set of resonances because the chemical shifts (CSs) of the isomers were obviously the same. Instances
where resonances of certain protons were more complicated were explained completely by steric hindrance to rotation around
single bonds because they were observed in spectra of compounds with rather bulky ortho substituents. For example, methylene
resonances of hydroxyacetic acids in PMR spectra of 17c, 18g, i, and k were rather broad multiplets (Experimental section)
13
although this group appeared in spectra of most compounds as a narrow 2H singlet. C NMR spectra of all amino-acid
dihydroisocoumarin derivatives 16–18 also showed one set of resonances. Resonances of C-3 and C-4 of the
3,4-dihydroisocoumarin ring (67 and 34 ppm, respectively) were characteristic of these heterocyclic systems. Resonances of
carboxylic acids fell in the range 165–174 ppm. The hydroxyacetic-acid methylene CS depended on its position on the phenyl
ring and was 78–79 ppm for 16 and 17 with the para-position and 74–75 ppm for ortho derivatives 18. IR spectra given in the
Experimental section were also typical of this class of compounds and confirmed their structures. In particular, a strong broad
–1
carboxylic-acid absorption band (1730–1700 cm with a maximum at 1720 as a rule) and strong absorption bands of single
–1
C–O bonds (~1240 and 1120 cm ) were consistently observed.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Merck 60 F plates using CHCl –MeOH
254
3
(9:1). Melting points were measured on a Kofler apparatus. NMR spectra were recorded on a Varian Mercury-400 spectrometer
vs. TMS (internal standard) (Scheme 2 shows the proton numbering). IR spectra were taken on a PerkinElmer BX II spectrometer.
Elemental analyses were obtained using a Vario Micro Cube instrument and agreed with those calculated.
The method for synthesizing 10–12 was published [8] and also gives the yields, melting points, elemental analyses,
mass spectra, and PMR spectra of 10 and 12 and their synthetic intermediates 7 and 9.
Ethyl 2-[4-(1-Oxo-1H-isochromen-3-yl)phenoxy]acetate (4). Yield 86%, mp 100–101ꢀÑ. IR spectrum (KBr, ꢂ,
cm ): 3433 (br), 3052, 2981, 1747, 1726, 1634, 1604, 1514, 1314, 1299, 1238, 1207, 1184, 1072, 1027, 1013, 845, 825, 753,
–1
1
689. Í NMR spectrum (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 1.31 (3Í, t, J = 7.2, ÑÍ ÑÍ ), 4.22 (2Í, q, J = 7.2,
6
4
2
3
ÑÍ ÑÍ ), 4.75 (2Í, s, 4ꢄ-ÎÑÍ ), 7.02 (2Í, d, J = 8.4, Í-3ꢄ, 5ꢄ), 7.16 (1Í, s, Í-4), 7.49 (1Í, t, J = 7.6, Í-7), 7.59 (1Í, d,
2
3
2
13
J = 7.6, Í-5), 7.75 (1Í, t, J = 7.6, Í-6), 7.85 (2Í, d, J = 8.4, Í-2ꢄ, 6ꢄ), 8.16 (1Í, d, J = 7.6, Í-8). C NMR spectrum (100 MHz,
DMSO-d –CCl 1:1, ꢃ, ppm): 14.7, 33.5, 61.4, 65.4, 101.3, 115.7, 120.1, 125.4, 126.9, 127.2, 128.7, 129.4, 135.9, 138.2,
6
4
153.1, 159.7, 162.0, 169.1.
Ethyl 2-[2-Methyl-4-(1-oxo-1H-isochromen-3-yl)phenoxy]acetate (5). Yield 92%, mp 198–199ꢀÑ. IR spectrum
–1
(KBr, ꢂ, ñm ): 3432 (br), 3080, 3063, 2976, 2924, 2910, 1758, 1730, 1633, 1606, 1564, 1507, 1481, 1430, 1334, 1295, 1267,
1
1243, 1209, 1145, 1081, 1026, 957, 887, 820, 799, 756, 689. Í NMR spectrum (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm,
6
4
J/Hz): 1.30 (3Í, t, J = 8.0, ÑÍ ÑÍ ), 2.33 (3Í, s, ÑÍ -3ꢄ), 4.22 (2Í, q, J = 8.0, ÑÍ ÑÍ ), 4.81 (2Í, s, 4ꢄ-ÎÑÍ ), 6.92 (1Í,
2
3
3
2
3
2
d, J = 7.6, Í-5ꢄ), 7.22 (1Í, s, Í-4), 7.52 (1Í, t, J = 7.6, Í-7), 7.62 (1Í, d, J = 7.6, Í-5), 7.68–7.72 (2Í, m, Í-2ꢄ, 6ꢄ), 7.80 (1Í,
13
t, J = 7.6, Í-6), 8.15 (1Í, d, J = 7.6, Í-8). C NMR spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 14.7, 16.7, 61.4, 65.6,
6
4
101.1, 112.4, 120.0, 124.7, 124.9, 126.9, 127.4, 127.9, 128.7, 129.5, 136.0, 138.3, 153.3, 157.9, 162.1, 169.2.
597

Ethyl 2-[4-Methyl-2-(1-oxo-1H-isochromen-3-yl)phenoxy]acetate (6). Yield 78%, mp 134–135ꢀÑ. IR spectrum
–1
(KBr, ꢂ, cm ): 3422 (br), 3112, 1034, 2986, 2925, 1757, 1720 (br), 1621, 1603, 1563, 1504, 1478, 1448, 1408, 1384, 1339,
1
1323, 1286, 1262, 1244, 1211 (br), 1150, 1083, 1034, 1017, 949, 884, 858, 797, 785, 767, 693. Í NMR spectrum (400 MHz,
DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 1.25 (3Í, t, J = 7.0, ÑÍ ÑÍ ), 2.28 (3Í, s, ÑÍ -5ꢄ), 4.23 (2Í, q, J = 7.0, ÑÍ ÑÍ ), 4.83
6
4
2
3
3
2
3
(2Í, s, 2ꢄ-ÎÑÍ ), 6.94 (1Í, d, J = 8.0, Í-3ꢄ), 7.15 (1Í, br.d, J = 8.0, Í-4ꢄ), 7.52–7.59 (3H, m, Í-5, 7, 6ꢄ), 7.75 (1Í, s, Í-4), 7.80
2
13
(1Í, t, J = 7.8, Í-6), 8.13 (1Í, d, J = 7.8, Í-8). C NMR spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 14.7, 20.7, 61.5,
6
4
66.0, 107.8, 113.6, 120.5, 127.2, 128.6, 129.0, 129.3, 130.8, 131.8, 135.7, 138.3, 150.0, 153.8, 162.0, 169.0.
2-[2-(4-Carboxymethoxy-3-methylphenyl)-2-oxoethyl]benzoic Acid (8). Yield 83%, mp 162–163ꢀÑ. IR spectrum
–1
(KBr, ꢂ, cm ): 3449 (br), 2915, 2563 (br), 1727, 1688, 1602, 1500, 1433, 1379, 1330, 1242, 1217, 1137, 1082, 928, 803, 786,
1
730, 650. Í NMR spectrum (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 2.31 (3Í, s, ÑÍ -3ꢄ), 4.67 (2Í, s, ÑÍ ), 4.75
6
4
3
2
(2Í, s, ÑÍ ), 6.89 (1Í, d, J = 8.0, Í-5ꢄ), 7.25 (1Í, d, J = 7.6, Í-3), 7.36 (1Í, t, J = 7.6, Í-5), 7.49 (1Í, t, J = 7.6, Í-4), 7.82
2
13
(1Í, br.s, Í-2ꢄ), 7.86 (1Í, br.d, J = 8.0, Í-6ꢄ), 7.96 (1Í, d, J = 7.6, Í-6), 12.58 (2Í, br.s, 2 ÑÎÎÍ). C NMR spectrum
(100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 16.7, 44.8, 65.5, 111.5, 126.8, 127.5, 128.6, 130.6, 131.1, 131.2, 131.4, 132.5,
6
4
133.4, 138.0, 160.4, 169.0, 170.6.
2-[2-Methyl-4-(1-oxo-1H-isochroman-3-yl)phenoxy]acetic Acid (11). Yield 87%, mp 153–154ꢀÑ. IR spectrum
–1
(KBr, ꢂ, cm ): 3449 (br), 3120, 3075 (br), 2946, 2907, 1734 (br), 1690 (br), 1607, 1510, 1460, 1423, 1365, 1341, 1275 (br),
1
1231 (br), 1128, 1082, 987, 914, 896, 831, 806, 751, 736, 696, 656, 644. Í NMR spectrum* (400 MHz, DMSO-d –CCl 1:1,
6
4
ꢃ, ppm, J/Hz): 2.23 (3Í, s, ÑÍ -3ꢄ), 3.16 (1Í, dd, J = 16.4, 2.1, Í-4ꢅ), 3.40 (1Í, dd, J = 16.4, 12.0, Í-4ꢁ), 4.74 (2Í, s,
3
ÑÍ Î-4ꢄ), 5.60 (1Í, dd, J = 12.0, 2.1, H-3), 6.90 (1Í, d, J = 7.8, Í-5ꢄ), 7.28 (1Í, br.d, J = 7.8, Í-6ꢄ), 7.34 (1Í, br.s, Í-2ꢄ), 7.43
2
13
(1Í, d, J = 7.6, Í-5), 7.47 (1Í, t, J = 7.6, Í-7), 7.65 (1Í, t, J = 7.6, Í-6), 7.98 (1Í, d, J = 7.6, Í-8). C NMR spectrum
(100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 16.8, 34.6, 65.5, 79.9, 111.8, 125.4, 126.0, 126.8, 128.2, 128.5, 129.7, 130.0, 131.7,
6
4
134.6, 140.4, 156.7, 165.4, 170.9.
General Synthesis of Amino-acid Derivatives 16–18. A solution of the acid (10–12, 2 mmol) and SuOH (0.26 g,
2.2 mmol) in anhydrous dioxane (20 mL) at room temperature was stirred vigorously, treated with DCC (0.46 g, 2.2 mmol),
and stirred at room temperature for 2–3 h (16 and 17) or 3–4 h (18) (course of reactions monitored by TLC). The resulting
activated ester was added to a solution of the appropriate amino acid (2.2 mmol) and NaHCO (0.28 g) in H O (20 mL). The
3
2
mixture was stirred at room temperature for 2 h with TLC monitoring of the reaction. The precipitate of dicyclohexylurea was
filtered off. The filtrate was poured into H O (100 mL). The resulting solution was acidified with dilute HCl until weakly
2
acidic. The resulting precipitate was filtered off and recrystallized from i-PrOH.
–1
N-{2-[4-(1-Oxoisochroman-3-yl)phenoxy]acetyl}glycine (16a). IR spectrum (KBr, ꢂ, cm ): 3393 (br), 3319, 3059
(br), 2937, 2861, 1764, 1708, 1648, 1613, 1557, 1515, 1460, 1450, 1412, 1291, 1249, 1193, 1124, 1077, 1032, 1006, 834, 750,
1
692. Í NMR spectrum* (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 3.16 (1Í, dd, J = 16.4, 2.6, Í-4ꢅ), 3.39 (1Í, dd,
6
4
J = 16.4, 12.0, Í-4ꢁ), 3.83 (2Í, d, J = 4.0, CH ÑÎÎÍ), 4.56 (2Í, s, ÑÍ Î-4ꢄ), 5.56 (1Í, dd, J = 12.0, 2.6, H-3), 7.03 (2Í, d,
2
2
J = 8.4, Í-3ꢄ, 5ꢄ), 7.39–7.51 (4Í, m, Í-5, 7, 2ꢄ, 6ꢄ), 7.64 (1Í, t, J = 7.6, Í-6), 7.97 (1Í, d, J = 7.6, Í-8), 8.41 (1Í, br.t,
13
J = 4.0, NH). C NMR spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 34.6, 41.1, 67.5, 79.8, 115.4, 125.4, 128.3, 128.5,
6
4
128.7, 130.1, 132.4, 134.6, 140.4, 158.4, 165.4, 168.7, 171.7.
–1
N-{2-[4-(1-Oxoisochroman-3-yl)phenoxy]acetyl}alanine (16b). IR spectrum (KBr, ꢂ, cm ): 3389 (br), 3042,
2993, 2928, 2611, 2540, 1728, 1711, 1627, 1546, 1517, 1461, 1438, 1370, 1348, 1278, 1249, 1221, 1183, 1122, 1087, 1011,
1
998, 913, 857, 825, 800, 742, 692. Í NMR spectrum* (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 1.37 (1Í, d, J = 7.2,
6
4
CH[CH ]ÑÎÎÍ), 3.17 (1Í, br.d, J = 16.4, Í-4ꢅ), 3.34 (1Í, dd, J = 16.4, 12.0, Í-4ꢁ), 4.33 (1Í, m, CH[CH ]ÑÎÎÍ), 4.49
3
3
(2Í, s, ÑÍ Î-4ꢄ), 5.56 (1Í, br.d, J = 16.4, H-3), 7.00 (2Í, d, J = 8.0, Í-3ꢄ, 5ꢄ), 7.37 (1Í, d, J = 7.6, Í-5), 7.40–7.45 (3Í, m,
2
13
Í-7, 2ꢄ, 6ꢄ), 7.59 (1Í, t, J = 7.6, Í-6), 7.98 (1Í, d, J = 7.6, Í-8), 8.10 (1Í, br.d, J = 7.6, NH). C NMR spectrum (100 MHz,
DMSO-d –CCl 1:1, ꢃ, ppm): 16.97, 33.8, 47.13, 66.6, 78.9, 124.6, 127.7, 114.6, 127.4, 127.9, 129.2, 131.4, 133.8, 139.6, 157.7,
6
4
164.6, 167.2, 173.64.
–1
N-{2-[4-(1-Oxoisochroman-3-yl)phenoxy]acetyl}phenylalanine (16f). IR spectrum (KBr, ꢂ, cm ): 3420 (br),
3382, 3028, 3068, 2928, 2866, 2531 (br), 1721, 1711, 1630, 1459, 1429, 1348, 1248, 1226, 1184, 1122, 1086, 1070, 1031,
1
1012, 914, 826, 740, 703. Í NMR spectrum* (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 3.02 (1Í, dd, J = 13.6, 8.8,
6
4
CH[CH Ph]ÑÎÎÍ), 3.11–3.20 (2Í, m, CH[CH Ph]ÑÎÎÍ, Í-4ꢅ), 3.34 (1Í, dd, J = 16.0, 12.0, Í-4ꢁ), 4.45 (2Í, s,
ꢅ
ꢁ
ÑÍ Î-4ꢄ), 4.56 (2Í, m, CH[Bn]ÑÎÎÍ), 5.56 (1Í, dd, J = 12.0, 2.4, H-3), 6.91 (2Í, d, J = 8.4, Í-3ꢄ, 5ꢄ), 7.18–7.26 (5Í, m,
2
ꢆꢆꢆꢆꢆꢆ
The amino-acid COOH proton resonance was not observed in PMR spectra because of exchange.
598

13
CH[CH Ph]ÑÎÎÍ), 7.37–7.46 (5Í, m, Í-7, 5, 2ꢄ, 6ꢄ), 7.60 (1Í, t, J = 8.0, Í-6), 7.98–8.03 (2Í, m, NH, Í-8). C NMR
2
spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 33.8, 36.4, 52.9, 66.6, 78.9, 114.5, 124.7, 126.3, 127.4, 127.8, 128.0,
6
4
128.9, 129.2, 131.5, 133.7, 137.3, 139.5, 157.7, 164.5, 167.4, 172.5.
–1
N-{2-[4-(1-Oxoisochroman-3-yl)phenoxy]acetyl}tyrosine (16g). IR spectrum (KBr, ꢂ, cm ): 3430, 3070, 3033,
2934, 2862, 2743, 1719, 1690, 1666, 1613, 1531, 1517, 1461, 1444, 1349, 1298, 1279, 1221, 1179, 1126, 1072, 990, 836, 742.
1
Í NMR spectrum* (400 MHz, DMSO-d , ꢃ, ppm, J/Hz): 2.86 (1Í, dd, J = 13.2, 9.2, CH[CH (4-ÍÎÑ Í )]ÑÎÎÍ), 3.00
6
ꢅ
6 4
(1Í, dd, J = 13.2, 4.4, CH[CH (4-ÍÎÑ Í )]ÑÎÎÍ), 3.18 (1Í, br.d, J = 16.8, Í-4ꢅ), 3.35 (1Í, dd, J = 16.8, 10.8, Í-4ꢁ),
ꢁ
6 4
4.41–4.47 (1Í, m, CH[CH (4-ÍÎÑ Í )]ÑÎÎÍ), 4.50 (2Í, s, ÑÍ Î-4ꢄ), 5.63 (1Í, br.d, J = 10.8, Í-3), 6.65 (2Í, d, J = 8.0,
2
6
4
2
Í-3ꢄꢄ, 5ꢄꢄ (4-ÍÎÑ Í )), 6.91 (2Í, d, J = 7.2, Í-3ꢄ, 5ꢄ), 7.00 (2Í, d, J = 8.0, Í-2ꢄꢄ, 6ꢄꢄ (4-ÍÎÑ Í )), 7.24–7.50 (4Í, m, Í-5, 7,
6
4
6 4
13
2ꢄ, 6ꢄ), 7.67 (1Í, t, J = 7.2, Í-6), 7.98 (1Í, d, J = 7.2, Í-8), 8.21 (1Í, br.d, J = 6.0, NH), 9.25 (1Í, br.s, 4-ÍÎÑ Í ). C NMR
6
4
spectrum (100 MHz, DMSO-d , ꢃ, ppm): 34.6, 36.4, 54.0, 67.2, 79.8, 115.3, 115.7, 125.4, 128.1, 128.3, 128.6, 128.7, 130.1,
6
130.8, 132.2, 134.6, 140.5, 156.6, 158.5, 165.4, 168.1, 173.5.
–1
N-{2-[4-(1-Oxoisochroman-3-yl)phenoxy]acetyl}tryptophan (16h). IR spectrum (KBr, ꢂ, cm ): 3464, 3411 (br),
3382, 3062, 2938, 2910, 2866, 2533 (br), 1719, 1711, 1629, 1612, 1546, 1516, 1460, 1426, 1365, 1355, 1338, 1294, 1278,
1
1249, 1222, 1184, 1122, 1087, 1069, 1011, 824, 755, 745. Í NMR spectrum* (400 MHz, DMSO-d , ꢃ, ppm, J/Hz):
6
3.12–3.19 (2Í, m, Í-4ꢅ, CH[CH (indol-3-yl)]ÑÎÎÍ), 3.25 (1Í, dd, J = 14.0, 4.8, CH[CH (indol-3-yl)]ÑÎÎÍ), 3.42 (1Í,
ꢅ
ꢁ
dd, J = 16.4, 12.0, Í-4ꢁ), 4.51 (2Í, s, ÑÍ Î-4ꢄ), 4.55–4.58 (1Í, m, CH[CH (indol-3-yl)]ÑÎÎÍ), 5.63 (1Í, dd, J = 12.0, 2.0,
2
2
H-3), 6.91 (2Í, d, J = 8.4, Í-3ꢄ, 5ꢄ), 6.98 (1Í, t, J = 7.2, Í-5ꢄꢄ (indol-3-yl)), 7.07 (1Í, t, J = 7.2, Í-6ꢄꢄ (indol-3-yl)), 7.14 (1Í,
br.s, H-2ꢄꢄ), 7.35 (1Í, d, J = 7.6, Í-4ꢄꢄ), 7.40–7.50 (4Í, m, 5, 7, 2ꢄ, 6ꢄ), 7.56 (1Í, d, J = 7.6, Í-7ꢄꢄ), 7.67 (1Í, t, J = 7.6, Í-6),
13
7.99 (1Í, d, J = 7.6, Í-8), 8.20 (1Í, br.d, J = 6.8, NH), 10.89 (1Í, s, NH (indol-3-yl)). C NMR spectrum (100 MHz,
DMSO-d , ꢃ, ppm): 26.7, 33.8, 52.6, 66.5, 78.9, 109.5, 111.3, 114.5, 118.0, 118.3, 120.8, 123.6, 124.6, 127.1, 127.4, 127.7,
6
127.8, 129.2, 131.4, 133.8, 136.0, 139.6, 157.6, 164.6, 167.3, 172.9.
–1
N-{2-[4-(1-Oxoisochroman-3-yl)phenoxy]acetyl}asparagine (16j). IR spectrum (KBr, ꢂ, cm ): 3406 (br), 3076,
2928, 2857, 1720 (br), 1676 (br), 1608, 1534, 1502, 1460, 1438 (br), 1276 (br), 1229 (br), 1117, 1086, 1070, 1032, 996, 807,
1
749, 693. Í NMR spectrum* (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 2.56–2.61 (1Í, m, CH[ÑÍ CONH ]ÑÎÎÍ),
6
4
ꢅ
2
2.67–2.72 (1Í, m, CH[ÑÍ CONH ]ÑÎÎÍ), 3.18 (1Í, br.d, J = 16.8, Í-4ꢅ), 3.34 (1Í, dd, J = 16.8, 12.0, Í-4ꢁ), 4.51 (2Í, m,
ꢁ
2
ÑÍ Î-4ꢄ), 4.58 (1Í, m, CH[ÑÍ CONH ]ÑÎÎÍ), 5.56 (1Í, br.d, J = 12.0, H-3), 5.95 (1Í, br.s, CH[ÑÍ CONH ]ÑÎÎÍ),
2
2
2
2
ꢅ
7.01 (2Í, br.d, J = 7.2, Í-3ꢄ, 5ꢄ), 7.38–7.45 (5Í, m, Í-5, 7, 2ꢄ, 6ꢄ, CH[ÑÍ CONH ]ÑÎÎÍ), 7.59 (1Í, t, J = 7.2, Í-6), 7.98 (1Í,
2
ꢁ
13
d, J = 7.2, Í-8), 8.19 (1Í, br.d, J = 6.8, NH). C NMR spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 34.6, 37.0, 49.2,
6
4
67.6, 79.7, 115.5, 125.4, 128.3, 128.5, 128.7, 130.1, 132.4, 134.6, 140.4, 158.4, 165.4, 168.1, 172.3, 173.1.
–1
N-{2-[4-(1-Oxoisochroman-3-yl)phenoxy]acetyl}citrulline (16k). IR spectrum (KBr, ꢂ, cm ): 3465, 3388,
3333 (br), 3069, 2928, 2878, 2594, 2548, 1721, 1642 (br), 1589, 1552, 1515, 1460, 1432, 1370, 1349, 1278, 1249, 1184, 1122,
1
1087, 1071, 1006, 913, 894, 822, 740, 691. Í NMR spectrum* (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 1.42 (2Í, m,
6
4
CH[ÑÍ ÑÍ ÑÍ NHCONH ]ÑÎÎÍ), 1.68 (1Í, m, CH[ÑÍ (ÑÍ ) NHCONH ]ÑÎÎÍ), 1.80 (1Í, m,
2
2
2
2
ꢅ
2 2
2
CH[ÑÍ (ÑÍ ) NHCONH ]ÑÎÎÍ), 2.99 (2Í, m, CH[(ÑÍ ) ÑÍ NHCONH ]ÑÎÎÍ), 3.19 (1Í, br.d, J = 16.4, Í-4ꢅ), 3.35
ꢁ
2 2
2
2 2
2
2
(1Í, dd, J = 16.4, 10.8, Í-4ꢁ), 4.31 (2Í, br.s, NHCONH ), 4.54 (2Í, m, ÑÍ Î-4ꢄ), 5.57 (1Í, br.d, J = 10.8, H-3), 5.95 (1Í,
2
2
br.s, NHCONH ), 7.01 (2Í, d, J = 7.6, Í-3ꢄ, 5ꢄ), 7.38–7.45 (4Í, m, Í-5, 7, 2ꢄ, 6ꢄ), 7.61 (1Í, t, J = 7.2, Í-6), 7.98 (1Í, d, J = 7.2,
2
13
Í-8), 8.10 (1Í, br.d, J = 6.8, NH). C NMR spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 27.4, 29.1, 34.0, 34.6, 52.3,
6
4
67.4, 79.8, 115.4, 125.4, 128.3, 128.5, 128.7, 130.1, 132.23, 134.6, 140.5, 158.5, 159.5, 165.4, 168.3, 174.1.
–1
N-{2-[2-Methyl-4-(1-oxoisochroman-3-yl)phenoxy]acetyl}glycine (17a). IR spectrum (KBr, ꢂ, cm ): 3397 (br),
2926 (br), 2737, 2624, 2539, 1723 (br), 1630 (br), 1547, 1512, 1460, 1422, 1347, 1267 (br), 1227 (br), 1145, 1120, 1069,
1
1011, 990, 912, 889, 813, 770, 736, 692. Í NMR spectrum* (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 2.27 (3Í, s,
6
4
ÑÍ -3ꢄ), 3.16 (1Í, br.d, J = 16.8, Í-4ꢅ), 3.39 (1Í, m, Í-4ꢁ), 3.84 (2Í, br.d, J = 4.2, CH ÑÎÎÍ), 4.58 (2Í, s, ÑÍ Î-4ꢄ), 5.60
3
2
2
(1Í, br.d, J = 9.6, H-3), 6.92 (1Í, d, J = 7.8, Í-5ꢄ), 7.29 (1Í, br.d, J = 7.8, Í-6ꢄ), 7.35 (1Í, br.s, Í-2ꢄ), 7.42–7.49 (2Í, m,
13
Í-5, 7), 7.65 (1Í, t, J = 7.2, Í-6), 7.97 (1Í, d, J = 7.2, Í-8), 8.23 (1Í, br.t, J = 4.2, NH). C NMR spectrum (100 MHz,
DMSO-d –CCl 1:1, ꢃ, ppm): 16.9, 34.6, 41.2, 67.8, 79.8, 112.2, 125.4, 126.0, 127.0, 128.3, 128.5, 129.7, 130.1, 132.0,
6
4
134.6, 140.4, 156.5, 165.4, 168.9, 171.7.
–1
N-{2-[2-Methyl-4-(1-oxoisochroman-3-yl)phenoxy]acetyl}leucine (17c). IR spectrum (KBr, ꢂ, cm ): 3382 (br),
3070, 2959, 2871, 2733, 2531 (br), 1719 (br), 1624 (br), 1543, 1508, 1460, 1431, 1368, 1346, 1273, 1230, 1138, 1121, 1072,
1
1032, 994, 913, 812, 737, 692. Í NMR spectrum* (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 0.84 (6Í, d, J = 6.0,
6
4
CH[ÑÍ ÑÍ(CH ) ]ÑÎÎÍ), 0.88 (6Í, d, J = 6.0, CH[ÑÍ ÑÍ(CH ) ]ÑÎÎÍ), 1.52–1.63 (3Í, m, CH[ÑÍ ÑÍ(CH ) ]ÑÎÎÍ),
2
3 ꢅ
2
3 ꢁ
2
3 2
599

2.25 (3Í, s, ÑÍ -3ꢄ), 3.16 (1Í, dd, J = 16.4, J = 2.8, Í-4ꢅ), 3.32 (1Í, dd, J = 16.4, 11.6, Í-4ꢁ), 4.28 (1Í, m, CH[i-Bu]ÑÎÎÍ),
3
4.53–4.64 (2H, m, ÑÍ Î-4ꢄ), 5.51 (1Í, dd, J = 11.6, 2.8, H-3), 6.87 (1Í, d, J = 7.6, Í-5ꢄ), 7.26 (1Í, br.d, J = 7.6, Í-6ꢄ), 7.34
2
(1Í, br.s, Í-2ꢄ), 7.42–7.49 (2Í, m, Í-5, 7), 7.65 (1Í, t, J = 7.2, Í-6), 7.97 (1Í, d, J = 7.2, Í-8), 8.19 (1Í, br.d, J = 7.2, NH).
13
C NMR spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 16.9, 22.1, 23.6, 25.1, 34.7, 50.9, 67.7, 79.8, 112.1, 125.4,
6
4
125.9, 126.8, 128.3, 128.5, 129.6, 130.0, 131.9, 134.6, 140.4, 156.7, 165.4, 168.2, 174.7.
–1
N-{2-[2-Methyl-4-(1-oxoisochroman-3-yl)phenoxy]acetyl}norleucine (17d). IR spectrum (KBr, ꢂ, cm ): 3420
(br), 3385, 2958, 2933, 2864, 2539 (br), 1720, 1630, 1542, 1460, 1440, 1370, 1349, 1277, 1230, 1137, 1122, 1087, 812, 740,
1
690. Í NMR spectrum* (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 0.90 (3Í, m, CH[(ÑÍ ) CH ]ÑÎÎÍ), 1.30
6
4
2 3
3
(4Í, m, CH[ÑÍ (ÑÍ ) CH ]ÑÎÎÍ), 1.68 (1Í, m, CH[ÑÍ (ÑÍ ) CH ]ÑÎÎÍ), 1.79 (1Í, m, CH[ÑÍ (ÑÍ ) CH ]ÑÎÎÍ), 2.31
2
2 2
3
ꢅ
2 2
3
ꢁ
2 2
3
(3Í, s, ÑÍ -3ꢄ), 3.16 (1Í, m, Í-4ꢅ), 3.32 (1Í, dd, J = 15.6, 12.0, Í-4ꢁ), 4.29 (1Í, m, CH[n-Bu]ÑÎÎÍ), 4.53 (2Í, s,
3
ÑÍ Î-4ꢄ), 5.51 (1Í, dd, J = 12.0, J = 1.8, H-3), 6.86 (1Í, d, J = 8.0, Í-5ꢄ), 7.24 (1Í, br.d, J = 8.0, Í-6ꢄ), 7.29 (1Í, br.s, Í-2ꢄ),
2
7.37 (1Í, d, J = 7.6, Í-5), 7.43 (1Í, t, J = 7.6, Í-7), 7.60 (1Í, t, J = 7.6, Í-6), 7.89 (1Í, br.d, J = 6.8, NH), 7.97 (1Í, d, J = 7.6,
13
Í-8). C NMR spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 13.6, 16.0, 21.5, 27.2, 30.5, 33.8, 51.4, 66.8, 79.0, 111.3,
6
4
124.6, 125.1, 126.0, 127.4, 127.7, 128.8, 129.2, 131.1, 133.7, 139.6, 155.8, 164.6, 167.5, 173.2.
–1
N-{2-[2-Methyl-4-(1-oxoisochroman-3-yl)phenoxy]acetyl}-ꢁ-alanine (17e). IR spectrum (KBr, ꢂ, cm ): 3481
(br), 3416 (br), 3077, 2924, 2949, 2612 (br), 1728, 1648, 1610, 1546, 1508, 1461, 1439, 1367, 1358, 1271, 1226, 1194, 1135,
1
1122, 1080, 1032, 1000, 955, 910, 887, 821, 780, 736, 692. Í NMR spectrum (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz):
6
4
2.29 (3Í, s, ÑÍ -3ꢄ), 2.42 (2Í, m, NHCH CH COOH), 3.15 (1Í, m, Í-4ꢅ), 3.29–3.41 (3Í, m, Í-4ꢁ, NHCH CH COOH),
3
2
2
2
2
4.45 (2Í, s, ÑÍ Î-4ꢄ), 5.51 (1Í, dd, J = 12.0, 2.4, H-3), 6.83 (1Í, d, J = 8.0, Í-5ꢄ), 7.25 (1Í, br.d, J = 8.0, Í-6ꢄ), 7.29 (1Í,
2
br.s, Í-2ꢄ), 7.37 (1Í, d, J = 7.2, Í-5), 7.43 (1Í, t, J = 7.2, Í-7), 7.60 (1Í, t, J = 7.2, Í-6), 7.85 (1Í, br.t, J = 3.6, NH), 7.97 (1Í,
13
d, J = 7.2, Í-8), 12.45 (1Í, br.s, ÑÎÎÍ). C NMR spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 16.0, 33.6, 33.8, 34.4,
6
4
67.1, 79.0, 111.3, 125.2, 126.13, 127.4, 127.7, 128.8, 129.2, 129.2, 131.2, 133.7, 139.5, 155.7, 164.6, 167.5, 172.9.
–1
N-{2-[2-Methyl-4-(1-oxoisochroman-3-yl)phenoxy]acetyl}methionine (17i). IR spectrum (KBr, ꢂ, cm ): 3425
(br), 3383, 2921, 2529 (br), 1719, 1711, 1630, 1543, 1508, 1461, 1439, 1370, 1348, 1277, 1259, 1229, 1138, 1122, 1088,
1
1064, 1032, 952, 814, 746, 691. Í NMR spectrum* (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 1.90–2.01 (2Í, m,
6
4
CH[ÑÍ ÑÍ SCH ]ÑÎÎÍ), 2.05 (3Í, m, CH[(ÑÍ ) SCH ]ÑÎÎÍ), 2.31 (3Í, s, ÑÍ -3ꢄ), 2.45 (2Í, m,
2
2
3
2 2
3
3
CH[ÑÍ ÑÍ SCH ]ÑÎÎÍ), 3.15 (1Í, br.d, J = 16.4, Í-4ꢅ), 3.33 (1Í, dd, J = 16.4, 12.0, Í-4ꢁ), 4.43 (1Í, m,
2
2
3
CH[(ÑÍ ) SCH ]ÑÎÎÍ), 4.54 (2Í, s, ÑÍ Î-4ꢄ), 5.52 (1Í, br.d, J = 12.0, H-3), 6.86 (1Í, d, J = 8.8, Í-5ꢄ), 7.25 (1Í, br.d,
2 2
3
2
J = 8.8, Í-6ꢄ), 7.29 (1Í, br.s, Í-2ꢄ), 7.37 (1Í, d, J = 7.6, Í-5), 7.43 (1Í, t, J = 7.6, Í-7), 7.60 (1Í, t, J = 7.6, Í-6), 7.98 (1Í,
13
d, J = 7.6, Í-8), 8.03 (1Í, br.d, J = 6.0, NH). C NMR spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 14.4, 16.0, 29.5,
6
4
30.3, 33.8, 50.5, 66.9, 79.0, 111.3, 124.6, 125.1, 126.0, 127.4, 127.7, 128.8, 129.2, 131.1, 133.8, 139.6, 155.9, 164.6, 167.8,
172.8.
–1
N-{2-[4-Methyl-2-(1-oxoisochroman-3-yl)phenoxy]acetyl}-ꢁ-alanine (18e). IR spectrum (KBr, ꢂ, cm ): 3433
(br), 3366, 3077, 3046, 2949, 2918, 1726, 1629, 1610, 1550, 1502, 1466, 1432, 1406, 1350, 1285, 1230, 1167, 1120, 1090,
1
1068, 1001, 915, 816, 753, 721, 694. Í NMR spectrum (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 2.34 (5Í, m, ÑÍ -5ꢄ,
6
4
3
NHCH CH COOH), 3.19 (1Í, dd, J = 16.8, 12.0, Í-4ꢅ), 3.29–3.33 (3Í, m, Í-4ꢁ, NHCH CH COOH), 4.48 (2Í, s, ÑÍ Î-2ꢄ),
2
2
2
2
2
6.02 (1Í, dd, J = 12.0, 2.4, H-3), 6.83 (1Í, d, J = 8.0, Í-3ꢄ), 7.11 (1Í, br.d, J = 8.0, Í-4ꢄ), 7.33 (1Í, br.s, Í-6ꢄ), 7.40 (1Í, d, J = 7.6,
Í-5), 7.46 (1Í, t, J = 7.6, Í-7), 7.62 (1Í, t, J = 7.6, Í-6), 7.93 (1Í, br.t, J = 6.0, NH), 8.01 (1Í, d, J = 7.6, Í-8), 12.09 (1Í, br.s, ÑÎÎÍ).
13
C NMR spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 20.1, 33.1, 33.6, 34.4, 67.3, 74.3, 112.2, 124.5, 126.9, 127.1, 127.5,
6
4
127.7, 129.3, 129.6, 130.0, 133.8, 139.7, 152.2, 164.8, 167.5, 172.7.
–1
N-{2-[4-Methyl-2-(1-oxoisochroman-3-yl)phenoxy]acetyl}tyrosine (18g). IR spectrum (KBr, ꢂ, cm ): 3392 (br),
3038, 2926, 2745, 2540, 1726, 1707, 1637, 1542, 1517, 1502, 1460, 1450, 1345, 1276, 1230 (br), 1120, 1066, 1032, 1011,
1
916, 845, 810, 748, 720, 694, 605. Í NMR spectrum* (400 MHz, DMSO-d , ꢃ, ppm, J/Hz): 2.28 (3Í, s, ÑÍ -5ꢄ), 2.67–2.81
6
3
(1Í, m, CH[CH (4-ÍÎÑ Í )]ÑÎÎÍ), 2.92–2.97 (1Í, m, CH[CH (4-ÍÎÑ Í )]ÑÎÎÍ), 3.17 (1Í, m, Í-4ꢅ), 3.29 (1Í, m,
ꢅ
6
4
ꢁ
6 4
Í-4ꢁ), 4.38 (1Í, m, CH[CH (4-ÍÎÑ Í )]ÑÎÎÍ), 4.47–4.58 (2Í, m, ÑÍ Î-2ꢄ), 5.90–5.99 (1Í, m, H-3), 6.55–6.59 (2Í, m,
2
6
4
2
Í-3ꢄꢄ, 5ꢄꢄ (4-ÍÎÑ Í )), 6.72 (0.4Í, d, J = 8.4, Í-3ꢄ), 6.75 (0.6Í, d, J = 8.4, Í-3ꢄ), 6.87–6.91 (2Í, m, Í-2ꢄꢄ, 6ꢄꢄ (4-ÍÎÑ Í )),
6
4
6 4
7.09 (1Í, br.d, J = 8.4, Í-4ꢄ), 7.33 (1Í, br.s, Í-6ꢄ), 7.40 (1Í, t, Í-5), 7.48 (1Í, t, J = 7.2, Í-7), 7.65 (1Í, t, J = 7.2, Í-6), 8.00
13
(1Í, d, J = 7.2, Í-8), 8.14 (1Í, d, J = 7.2, NH), 9.22 (1Í, br.s, 4-ÍÎÑ Í ). C NMR spectrum (100 MHz, DMSO-d , ꢃ,
6
4
6
ppm): 20.9, 34.0, 36.4, 54.2, 67.8, 75.2, 113.0, 115.7, 125.4, 127.51, 127.8, 128.0, 128.1, 128.3, 128.5, 130.1, 130.4, 130.6,
130.8, 134.6, 140.4, 153.0, 156.6, 165.5, 168.2, 173.4.
600

–1
N-{2-[4-Methyl-2-(1-oxoisochroman-3-yl)phenoxy]acetyl}tryptophan (18h). IR spectrum (KBr, ꢂ, cm ): 3411
(br), 3390, 3044, 2931 (br), 1720, 1711, 1631, 1535, 1502, 1460, 1432, 1349, 1290, 1274, 1233, 1117, 1069, 812, 747, 694.
1
Í NMR spectrum* (400 MHz, DMSO-d , ꢃ, ppm, J/Hz): 2.27 (3Í, s, ÑÍ -5ꢄ), 3.07 (2Í, m, Í-4ꢅ, CH[CH (indol-3-yl)]ÑÎÎÍ),
6
3
ꢅ
3.20–3.22 (2Í, m, Í-4ꢁ, CH[CH (indol-3-yl)]ÑÎÎÍ), 4.43–4.62 (3Í, m, ÑÍ Î-2ꢄ, CH[CH (indol-3-yl)]ÑÎÎÍ), 5.83 (0.4Í,
ꢁ
2
2
m, H-3), 5.54 (0.6Í, br.d, J = 10.6, H-3), 6.70–6.78 (1Í, m, Í-3ꢄ), 6.93 (1Í, br.t, J = 7.4, Í-5ꢄꢄ (indol-3-yl)), 6.99–7.17 (3Í,
m, Í-4ꢄ, 2ꢄꢄ, 6ꢄꢄ), 7.25–7.37 (3Í, m, Í-5, 6ꢄ, 4ꢄꢄ), 7.43–7.53 (2Í, m, Í-7, 7ꢄꢄ), 7.65 (1Í, br.t, J = 7.2, Í-6), 7.98 (1Í, br.s, Í-8),
13
8.14 (1Í, br.s, NH), 10.79 (1Í, s, NH (indol-3-yl)). C NMR spectrum (100 MHz, DMSO-d , ꢃ, ppm): 21.0, 27.6, 33.9, 53.4,
6
67.8, 74.2, 110.4, 112.1, 113.0, 118.8, 119.0, 121.6, 124.2, 125.4, 127.5, 127.7, 127.9, 128.3, 128.5, 130.1, 130.3, 130.7,
134.6, 136.8, 140.4, 153.0, 165.5, 168.2, 173.7.
–1
N-{2-[4-Methyl-2-(1-oxoisochroman-3-yl)phenoxy]acetyl}methionine (18i). IR spectrum (KBr, ꢂ, cm ): 3394
(br), 3068, 3036, 2918 (br), 2560 (br), 1726 (br), 1693, 1606, 1535, 1502, 1461, 1441, 1350, 1277, 1228, 1163, 1117, 1085,
1
1070, 1031, 912, 807, 748, 693. Í NMR spectrum* (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 1.83–2.01 (5Í, m,
6
4
CH[ÑÍ ÑÍ SCH ]ÑÎÎÍ), 2.28–2.34 (5Í, m, ÑÍ -5ꢄ, CH[ÑÍ ÑÍ SCH ]ÑÎÎÍ), 3.15 (1Í, m, Í-4ꢅ), 3.33 (1Í, m,
2
2
3
3
2
2
3
Í-4ꢁ), 4.34 (1Í, m, CH[(ÑÍ ) SCH ]ÑÎÎÍ), 4.52–4.70 (2Í, m, ÑÍ Î-2ꢄ), 5.59–6.05 (1Í, m, H-3), 6.90 (1Í, br.d, J = 8.0,
2 2
3
2
Í-3ꢄ), 7.13 (1Í, br.d, J = 8.0, Í-4ꢄ), 7.35 (1Í, br.s, Í-6ꢄ), 7.40–7.43 (1Í, m, Í-5), 7.48 (1Í, t, J = 7.6, Í-7), 7.66 (1Í, t, J = 7.6,
13
Í-6), 7.99 (1Í, d, J = 7.6, Í-8), 8.24 (1Í, br.t, J = 8.4, NH). C NMR spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 15.2,
6
4
21.0, 30.3, 31.1, 33.8, 34.0, 51.4, 68.0, 75.3, 113.0, 125.4, 127.7, 127.9, 128.3, 128.5, 130.1, 130.3, 130.8, 134.6, 140.5, 153.0,
165.6, 168.6, 173.7.
–1
N-{2-[4-Methyl-2-(1-oxoisochroman-3-yl)phenoxy]acetyl}citrulline (18k). IR spectrum (KBr, ꢂ, cm ): 3503,
3442, 3407, 3356, 3037, 2926 (br), 2863, 1731, 1713, 1669, 1608, 1561, 1530, 1503, 1461, 1444, 1354, 1284, 1230, 1130,
1
1120, 1070, 1016, 806, 752, 692. Í NMR spectrum* (400 MHz, DMSO-d –CCl 1:1, ꢃ, ppm, J/Hz): 1.34 (2Í, m,
6
4
CH[ÑÍ ÑÍ ÑÍ NHCONH ]ÑÎÎÍ), 1.60 (1Í, m, CH[ÑÍ (ÑÍ ) NHCONH ]ÑÎÎÍ), 1.74 (1Í, m,
2
2
2
2
ꢅ
2 2
2
CH[ÑÍ (ÑÍ ) NHCONH ]ÑÎÎÍ), 2.34 (3Í, s, ÑÍ -5ꢄ), 2.91 (2Í, m, CH[(ÑÍ ) ÑÍ NHCONH ]ÑÎÎÍ), 3.18 (1Í, m,
ꢁ
2 2
2
3
2 2
2
2
Í-4ꢅ), 3.32 (2Í, m, Í-4ꢁ), 4.24 (1Í, m, CH[(ÑÍ ) NHCONH ]ÑÎÎÍ), 4.59 (2Í, m, ÑÍ Î-2ꢄ), 5.24 (2Í, br.s, NHCONH ),
2 3
2
2
2
5.85 (1Í, br.s, NHCONH ), 6.00 (1Í, dt, J = 10.4, 1.6, H-3), 6.86 (1Í, d, J = 8.4, Í-3ꢄ), 7.11 (1Í, br.d, J = 8.4, Í-4ꢄ), 7.34 (1Í,
2
br.s, Í-6ꢄ), 7.40 (1Í, d, J = 7.6, Í-5), 7.45 (1Í, t, J = 7.6, Í-7), 7.62 (1Í, t, J = 7.6, Í-6), 8.00 (1Í, d, J = 7.6, Í-8), 8.13 (1Í,
13
br.t, J = 6.0, NH). C NMR spectrum (100 MHz, DMSO-d –CCl 1:1, ꢃ, ppm): 20.1, 26.4, 28.2, 33.0, 33.2, 51.4, 67.1, 74.5,
6
4
112.3, 124.5, 126.8, 127.0, 127.5, 127.7, 129.3, 129.5, 130.0, 133.8, 139.7, 152.3, 158.6, 164.8, 167.5, 173.1.
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