Synthesis of dipeptide derivatives of 3,4-substituted 7-hydroxycoumarins

Article abstract of DOI:10.1007/s10600-008-9047-6

Coumarins modified with dipeptides were prepared by condensation of N-hydroxysuccinimide esters of 2-(3,4,8-substituted-2-oxo-2H-7-chromenyloxy)-and 2-(3,4-substituted-7-methyl-2-oxo-2H-5-chromenyloxy)acetic and-propionic acids with amino acids and dipept

Full text of DOI:10.1007/s10600-008-9047-6

Chemistry of Natural Compounds, Vol. 44, No. 3, 2008
SYNTHESIS OF DIPEPTIDE DERIVATIVES OF
3,4-SUBSTITUTED 7-HYDROXYCOUMARINS
S. V. Shilin,1 M. M. Garazd,2* and V. P. Khilya1
UDC 547.814.5
N
Coumarins modified with dipeptides were prepared by condensation of -hydroxysuccinimide esters of
H
H
2-(3,4,8-substituted-2-oxo-2 -7-chromenyloxy)- and 2-(3,4-substituted-7-methyl-2-oxo-2 -5-
chromenyloxy)acetic and -propionic acids with amino acids and dipeptides.
Key words: coumarins, amino-acid derivatives, dipeptides, activated esters, synthesis.
We have previously reported the preparation of several coumarins and furocoumarins modified with amino acids. In
continuation of this work, we investigated the synthesis of substances in which a dipeptide would be added to the benzopyran
core.
Starting 3,4-disubstituted 7-hydroxycoumarins were synthesized by Pechmann condensation of the corresponding
resorcinols and esters of substituted β-ketoacids in the presence of H SO as condensing agent [3, 4]. PMR spectra of the
2
4
starting coumarins contained resonances typical of the coumarin system and its substituents.
Williamson reaction of the 7-hydroxycoumarins with methylchloroacetate using potash as the base produced the
corresponding esters of substituted 2-oxo-2H-7-chromenyloxyacetic acids. The esters were hydrolyzed by heating with sodium
bicarbonate solution (5%). The structures of the resulting acids were confirmed by PMR spectroscopy. The spectra of the
products (11-20) lacked a resonance for the hydroxyl proton of the starting 7-hydroxycoumarins and contained resonances for
the acetic acid as a very broad singlet for the carboxyl at 12.0-12.5 ppm and a resonance for the α-CH protons at 4.5-5.0 ppm.
2
Dipeptide derivatives of 11-20 could be prepared by two routes, addition of the dipeptide or successive elongation of
the peptide chain. We used activated esters to synthesize the amino-acid derivatives. These are used widelyin peptide synthesis
[5] to activate the carboxyl using the N-hydroxysuccinimide (NHS) ester, which is highly reactive and does not racemize the
products.
Reaction of 11-20 with NHS in absolute dioxane using diisopropylcarbodiimide as the condensing agent produced the
corresponding NHS esters. Compounds 21-36 were synthesized byreaction of the NHS esters with sodium salts ofglycylglycine
(21-30), norleucine (31), leucine (32), and β-alanine (33) in dioxane:water (1:1)with subsequent acidolysisoftheresultingsalts.
The isolated amino-acid derivatives had a free carboxylic acid that could be activated analogouslyfor addition of the next amino
acid. Compounds 34-36 were prepared this way. PMRspectra ofthe isolated compounds contained resonances for the coumarin
ring, the dipeptide, amide bonds at 8.02-8.46 ppm, and the carboxylic acid at 12.11-12.69 ppm.
1) Taras ShevchenkoKievNational University, 01033, Kiev, ul. Vladimirskaya, 64, Ukraine; 2) Institute ofBioorganic
and Petroleum Chemistry, National Academy of Sciences of Ukraine, 02094, Kiev, ul. Murmanskaya, 1, Ukraine, e-mail:
gmm@i.com.ua. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 239-242, May-June, 2008. Original article
submitted February 29, 2008.
0009-3130/08/4403-0301 ©2008 Springer Science+Business Media, Inc.
301

R
O
O
R
O
R
1
1
1
HO
O
R
O
R
Me
O
O
R
O
R
O
O
R
O
R
O
HO
2
2
2
3
3
3
1 - 10
11 - 20
O
R
1
O
R
1
O
O
R
1
H
N
O
O
O
O
O
O
O
O
1.a
2.b
HO
HO
SuO
HO
N
H
O
R
2
R
2
R
2
R
R
3
3
R
3
11 - 20
Me
21 - 30
R
O
Me
O
R
O
Me
O
H
1.a
2.b
1.a
2.b
HO
O
O
O
N
O
O
O
R
O
O
R
O
R
N
HO
N
H
H
O
R
4
O
R
2
2
2
R
3
R
3
3
12, 16, 20
31, 32
34, 35
1.a
2.b
O
O
Me
O
O
Me
O
O
O
1.a
2.b
HO
O
O
O
HO
N
N
N
H
H
H
O
Me
Me
33
36
a. N-hydroxysuccinimide, diisopropylcarbodiimide; b. amino-acid (dipeptide) sodium salt
1, 11, 21:
4, 14, 24:
6, 16, 26:
9, 19, 29:
2, 12, 22:
3, 13, 23:
R1 = CH3, R2 = H, R3 = CH2CH3;
R1 = R2 = H, R3 = CH2CH3;
R1 = R2 = H, R3 = (CH2)2CH3
5, 15, 25:
7, 17, 27:
R1 = CH3, R2 = H, R3 = (CH2)2CH3;
R1 = CH3, R2 = H, R3 = (CH2)3CH3;
R1 = H, R2 = (CH2)5CH3, R3 = CH3;
R1 = R2 = H, R3 = (CH2)3CH3
8, 18, 28:
R1 = H, R2 = R3 = CH3;
R1 = R2 = R3 = CH3
10, 20, 30:
R1 = R3 = CH3, R2 = CH2C6H5
31:
34:
32:
R = CH2CH(CH3)2; R2 = H, R3 = (CH2)3CH3
R = (CH2)3CH3, R2 = H, R3 = CH2CH3;
35:
R = (CH2)3CH3, R2 = H, R3 = CH2CH3, R4 = (CH2)2SCH3;
R = CH2CH(CH3)2, R2 = H, R3 = (CH2)3CH3, R4 = CH(CH3)2
EXPERIMENTAL
The course of reactions and the purity of products were monitored using TLC on Merck 60 F254 plates and
CHCl :CH OH (9:1 and 95:5). Melting points were determined on a Kofler block. PMR spectra were measured on Varian
3
3
VXR-300 and Varian Mercury-400 spectrometers relative to TMS (internal standard). Elemental analyses of all compounds
agreed with those calculated.
General Method for Synthesizing 2-(3,4,8-Substituted-2-oxo-2 -7-chromenyloxy)acetic Acids (11-20).
H
A hot
solution of the starting coumarin (0.05 mol) in absolute acetone (100 mL) was treated with potash (20.7 g, 0.15 mol), stirred
vigorously, heated (50-56°C), treated with methylchloroacetate (4.75 mL, 0.055 mol) and a catalytic amount of KI, and stirred
vigorously for 1-2 h (course of reaction monitored by TLC). The inorganic solid was filtered off. The acetone was evaporated
in vacuo. The solid was dissolved in isopropanol (150 mL), treated with aqueous NaHCO (175 mL, 5%, 0.1 mol), refluxed
3
for 3-4 h (course of reaction monitored by TLC), diluted with water (400 mL), and acidified with HCl until the pH was 4. The
solid was filtered off and crystallized from aqueous isopropanol.
General Methodfor Synthesizing -[7-(Carbonyl- -methoxy)-3,4,8-substituted]coumarinylaminoAcids(31-33)
N
R
and Dipeptides (21-30, 34-36).
A solution of acid (3 mmol) and -hydroxysuccinimide (0.38 g, 3.3 mmol) in absolute dioxane
N
(20 mL) was stirred vigorously, treated with diisopropylcarbodiimide (0.52 mL, 3.3mmol), andstirredfor 2 h (course ofreaction
302

monitored by TLC). The resulting activated ester was treated with the appropriate amino acid or glycylglycine (3.3 mmol) and
NaHCO (0.28 g, 3.3 mmol) in water (20 mL) and stirred vigorously for 2-4 h (course of reaction monitored by TLC). When
3
the reaction was finished the precipitate of diisopropylurea was filtered off. The filtrate was diluted with water (200 mL) and
acidified until the pH was 5-6. The resulting solid was filtered off and crystallized from aqueous ethanol.
4-Butyl-7-hydroxy-2H-2-chromenone (5). Yield 91%, C H O , mp 141-142°C. PMR spectrum (300 MHz,
13 14
3
DMSO-d , δ, ppm, J/Hz): 0.94 (3H, t, J = 7.5, CH CH CH CH -4), 1.41 (2H, m, CH CH CH CH -4), 1.60 (2H, m,
6
3
2
2
2
3
2
2
2
CH CH CH CH -4), 2.68 (2H, t, J = 7.5, CH CH CH CH -4), 5.93 (1H, s, H-3), 6.64 (1H, s, H-8), 6.71 (1H, d, J = 8, H-6),
3
2
2
2
3
2
2
2
7.46 (1H, d, J = 8, H-5), 10.22 (1H, s, OH).
4-Butyl-7-hydroxy-8-methyl-2H-2-chromenone (6). Yield 94%, C H O , mp 152-153°C. PMR spectrum
14 16
3
(300 MHz, DMSO-d , δ, ppm, J/Hz): 0.89 (3H, t, J = 7.5, CH CH CH CH -4), 1.35 (2H, m, CH CH CH CH -4), 1.63 (2H,
6
3
2
2
2
3
2
2
2
m, CH CH CH CH -4), 2.44 (3H, s, CH -8), 2.75 (2H, t, J = 7.5, CH CH CH CH -4), 5.98 (1H, s, H-3), 6.87 (1H, d, J = 8,
3
2
2
2
3
3
2
2
2
H-6), 7.56 (1H, d, J = 8, H-5), 10.35 (1H, s, OH).
2-(4-Ethyl-2-oxo-2H-7-chromenyloxy)acetic Acid (11). Yield 88%, C H O , mp 192-194°C. PMR spectrum
13 12
5
(300 MHz, DMSO-d , δ, ppm, J/Hz): 1.19 (3H, t, J = 7, CH CH -4), 2.81 (2H, q, J = 7, CH CH -4), 4.55 (2H, s, CH O-7), 6.15
6
3
2
3
2
2
(1H, s, H-3), 6.94 (2H, m, H-6, H-8), 7.64 (1H, d, J = 8, H-5), 12.54 (1H, br.s, COOH).
2-(4-Ethyl-8-methyl-2-oxo-2H-7-chromenyloxy)acetic Acid (12). Yield 90%, C H O , mp 237-239°C. PMR
14 14
5
spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.29 (3H, t, J = 7.5, CH CH -4), 2.33 (3H, s, CH -8), 2.80 (2H, q, J = 7.5,
6
3
2
3
CH CH -4), 4.58 (2H, s, CH O-7), 6.07 (1H, s, H-3), 6.88 (1H, d, J = 9, H-6), 7.53 (1H, d, J = 9, H-5), 12.48 (1H, br.s, COOH).
3
2
2
2-(4-Propyl-2-oxo-2H-7-chromenyloxy)acetic Acid (13). Yield 78%, C H O , mp 187-189°C. PMR spectrum
14 14
5
(300 MHz, DMSO-d , δ, ppm, J/Hz): 0.96 (3H, t, J = 7.5, CH CH CH -4), 1.65 (2H, m, CH CH CH -4), 2.75 (2H, t, J = 7.5,
6
3
2
2
3
2
2
CH CH CH -4), 4.66 (2H, s, CH O-7), 6.17 (1H, s, H-3), 7.00 (2H, m, H-6, H-8), 7.76 (1H, d, J = 8, H-5), 12.48 (1H, br.s,
3
2
2
2
COOH).
2-(4-Propyl-8-methyl-2-oxo-2H-7-chromenyloxy)acetic Acid (14). Yield 79%, C H O , mp 220-221°C. PMR
15 16
5
spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.02 (3H, t, J = 8, CH CH CH -4), 1.71 (2H, m, CH CH CH -4), 2.32 (3H, s,
6
3
2
2
3
2
2
8-CH ), 2.73 (2H, t, J = 8, CH CH CH -4), 4.65 (2H, s, CH O-7), 6.07 (1H, s, H-3), 6.91 (1H, d, J = 9, H-6), 7.54 (1H, d,
3
2
2
2
2
J = 9, H-5), 12.51 (1H, br.s, COOH).
2-(4-Butyl-2-oxo-2H-7-chromenyloxy)acetic Acid (15). Yield 81%, C H O , mp 154-156°C. PMR spectrum
15 16
5
(300 MHz, DMSO-d , δ, ppm, J/Hz): 0.90 (3H, t, J = 7.5, CH CH CH CH -4), 1.39 (2H, m, CH CH CH CH -4), 1.60 (2H,
6
3
2
2
2
3
2
2
2
m, CH CH CH CH -4), 2.76 (2H, t, J = 7.5, CH CH CH CH -4), 4.67 (2H, s, CH O-7), 6.18 (1H, s, H-3), 6.99 (2H, m, H-6,
3
2
2
2
3
2
2
2
2
H-8), 7.76 (1H, d, J = 8, H-5), 12.52 (1H, br.s, COOH).
2-(4-Butyl-8-methyl-2-oxo-2H-7-chromenyloxy)acetic Acid (16). Yield 83%, C H O , mp 205-206°C. PMR
16 18
5
spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.92 (3H, t, J = 7.5, CH CH CH CH -4), 1.45 (2H, m, CH CH CH CH -4),
6
3
2
2
2
3
2
2
2
1.67 (2H, m, CH CH CH CH -4), 2.39 (3H, s, CH -8), 2.77 (2H, t, J = 7.5, CH CH CH CH -4), 4.59 (2H, s, CH O-7), 6.01
3
2
2
2
3
3
2
2
2
2
(1H, s, H-3), 6.99 (1H, d, J = 8, H-6), 7.51 (1H, d, J = 8, H-5), 12.50 (1H, br.s, COOH).
2-(3,4-Dimethyl-2-oxo-2H-7-chromenyloxy)acetic Acid(17). Yield92%, C H O , mp175-177°C. PMRspectrum
13 12
5
(400 MHz, DMSO-d , δ, ppm, J/Hz): 2.09 (3H, s, CH -3), 2.38 (3H, s, 4-CH ), 4.63 (2H, s, CH O-7), 6.95 (1H, d, J = 2.5, H-8),
6
3
3
2
6.99 (1H, dd, J = 8.5, 2.5, H-6), 7.66 (1H, d, J = 8.5, H-5), 12.56 (1H, br.s, COOH).
2-(3,4,8-Trimethyl-2-oxo-2H-7-chromenyloxy)acetic Acid (18). Yield 84%, C H O , mp 210-211°C. PMR
14 14
5
spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.09 (3H, s, CH -3), 2.32 (3H, s, CH -8), 2.35 (3H, s, CH -4), 4.61 (2H, s,
6
3
3
3
CH O-7), 6.88 (1H, d, J = 8.5, H-6), 7.47 (1H, d, J = 8.5, H-5), 12.52 (1H, br.s, COOH).
2
2-(H-3-Hexyl-4-methyl-2-oxo-2H-7-chromenyloxy)acetic Acid (19). Yield 68%, C H O , mp 158-160°C. PMR
18 22
5
spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.84 [3H, m, CH (CH ) -3], 1.26-1.41 [8H, m, CH (CH ) CH -3], 2.38 (3H,
6
3
2 5
3
2 4
2
s, CH -4), 2.51 [2H, m, CH (CH ) CH -3], 4.64 (2H, s, CH O-7), 6.94 (1H, d, J = 2, H-8), 6.98 (1H, dd, J = 8, 2, H-6), 7.70
3
3
2 4
2
2
(1H, d, J = 8, H-5), 12.50 (1H, br.s, COOH).
2-(3-Benzyl-4,8-dimethyl-2-oxo-2H-7-chromenyloxy)acetic Acid(20). Yield78%, C H O , mp191-192°C. PMR
20 18
5
spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.27 (3H, s, CH -8), 2.41 (3H, s, CH -4), 3.94 (2H, s, PhCH -3), 4.62 (2H, s,
6
3
3
2
CH O-7), 6.94 (1H, d, J = 8, H-6), 7.14-7.26 (5H, m, PhCH -3), 7.60 (1H, d, J = 8, H-5), 12.53 (1H, br.s, COOH).
2
2
N-[2-(4-Ethyl-8-methyl-2-oxo-2H-7-chromenyloxy)acetyl]norleucine(31). Yield81%, C H NO , mp196-198°C.
20 25
6
PMRspectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.75 [3H, t, J = 8, CH (CH ) CHNHCOCH O-7], 1.24(7H, m, CH CH -4,
6
3
2 3
2
3
2
CH CH CH CH CHNHCOCH O-7), 1.71 (2H, m, CH CH CH CH CHNHCOCH O-7), 2.79 (3H, s, CH -8), 2.79 (2H, q,
3
2
2
2
2
3
2
2
2
2
3
303

J = 7.5, CH CH -4), 4.18 [1H, m, CH (CH ) CHNHCOCH O-7], 4.63 (2H, s, CH O-7), 6.17 (1H, s, H-3), 6.90 (1H, d, J = 9,
3
2
3
2 3
2
2
H-6), 7.58 (1H, d, J = 9, H-5), 8.28 (1H, d, J = 8, NH), 12.66 (1H, br.s, COOH).
N-[2-(4-Butyl-8-methyl-2-oxo-2H-7-chromenyloxy)acetyl]leucine (32). Yield 59%, C H NO , mp 147-148°C.
22 29
6
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.82-0.93 [9H, m, CH CH CH CH -4, (CH ) CHCH NHCOCH O-7],
6
3
2
2
2
3 2
2
2
1.38-1.56 [6H, m, CH CH CH CH -4, (CH ) CH CHNHCOCH O-7], 2.31 (3H, s, 8-CH ), 2.76 (2H, t, J = 7.5,
3
2
2
2
3 2
2
2
3
CH CH CH CH -4), 4.29 [1H, m, (CH ) CH CHNHCOCH O-7], 4.69 (2H, s, CH O-7), 6.18 (1H, s, H-3), 6.95 (1H, d,
3
2
2
2
3 2
2
2
2
J = 8, H-6), 7.73 (1H, d, J = 8, H-5), 8.41 (1H, d, J = 8, NH), 12.66 (1H, br.s, COOH).
N-[2-(3-Benzyl-4,8-dimethyl-2-oxo-2H-7-chromenyloxy)acetyl]-β-alanine (33). Yield 64%, C H NO , mp 208-
23 23
6
210°C. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.27 (3H, s, CH -8), 2.42 (2H, t, J = 7, CH CH NHCOCH O-7),
6
3
2
2
2
2.50 (3H, s, CH -4), 3.39 (2H, t, J = 7, CH CH NHCOCH O-7), 3.96 (2H, s, PhCH -3), 4.62 (2H, s, CH O-7), 6.96 (1H, d,
3
2
2
2
2
2
J = 8, H-6), 7.21-7.26 (5H, m, PhCH -3), 7.61 (1H, d, J = 8, H-5), 8.02 (1H, d, J = 7, NH), 12.13 (1H, br.s, COOH).
2
N-[2-(4-Ethyl-2-oxo-2H-7-chromenyloxy)acetyl]glycylglycine (21). Yield75%, C H N O , mp227-229°C. PMR
17 18
2 7
spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.23 (3H, t, J = 7, CH CH -4), 2.81 (2H, q, J = 7, CH CH -4), 3.77 (2H, d,
6
3
2
3
2
J = 6, CH NHCOCH NHCOCH O-7), 3.82 (2H, d, J = 6, CH NHCOCH NHCOCH O-7), 4.67 (2H, s, CH O-7), 6.17 (1H,
2
2
2
2
2
2
2
s, H-3), 7.01-7.04 (2H, m, H-6, H-8), 7.76 (1H, d, J = 7, H-5), 8.20 (1H, t, J = 6, CH NHCOCH NHCOCH O-7), 8.38 (1H, t,
2
2
2
J = 6, CH NHCOCH NHCOCH O-7), 12.54 (1H, br.s, COOH).
2
2
2
N-[2-(4-Ethyl-8-methyl-2-oxo-2H-7-chromenyloxy)acetyl]glycylglycine (22). Yield 67%, C H N O , mp 197-
18 20
2 7
198°C. PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.29 (3H, t, J = 7.5, CH CH -4), 2.33 (3H, s, CH -8), 2.80 (2H,
6
3
2
3
q, J = 7.5, CH CH -4), 3.78 (2H, d, J = 8, CH NHCOCH NHCOCH O-7), 3.84 (2H, d, J = 8, CH NHCOCH NHCOCH O-7),
3
2
2
2
2
2
2
2
4.65 (2H, s, CH O-7), 6.08 (1H, s, H-3), 6.92 (1H, d, J = 9, H-6), 7.55 (1H, d, J = 9, H-5), 8.12-8.18 (2H, m, 2NH), 12.50 (1H,
2
br.s, COOH).
N-[2-(4-Propyl-2-oxo-2H-7-chromenyloxy)acetyl]glycylglycine (23). Yield64%, C H N O , mp191-192°C. PMR
18 20
2 7
spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.98 (3H, t, J = 7, CH CH CH -4), 1.64 (2H, m, CH CH CH -4), 2.45 (2H, t,
6
3
2
2
3
2
2
J = 7, CH CH CH -4), 3.76-3.80 (4H, m, CH NHCOCH NHCOCH O-7), 4.68 (2H, s, CH O-7), 6.19 (1H, s, H-3), 7.01 (2H,
3
2
2
2
2
2
2
m, H-6, H-8), 7.75 (1H, d, J = 7, H-5), 8.26 (1H, t, J = 6, CH NHCOCH NHCOCH O-7), 8.41 (1H, t, J = 6,
2
2
2
CH NHCOCH NHCOCH O-7), 12.60 (1H, br.s, COOH).
2
2
2
N-[2-(4-Propyl-8-methyl-2-oxo-2H-7-chromenyloxy)acetyl]glycylglycine (24). Yield 78%, C H N O , mp 195-
19 22
2 7
197°C. PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.04 (3H, t, J = 7, CH CH CH -4), 1.71 (2H, m, CH CH CH -4),
6
3
2
2
3
2
2
2.32 (3H, s, CH -8), 2.73 (2H, t, J = 7, CH CH CH -4), 3.78 (4H, m, CH NHCOCH NHCOCH O-7), 4.66 (2H, s, CH O-7),
3
3
2
2
2
2
2
2
6.07 (1H, s, H-3), 6.92 (1H, d, J = 8.5, H-6), 7.55 (1H, t, J = 8.5, H-5), 8.16 (2H, m, 2NH), 12.48 (1H, br.s, COOH).
N-[2-(4-Butyl-2-oxo-2H-7-chromenyloxy)acetyl]glycylglycine (25). Yield73%, C H N O , mp133-135°C. PMR
19 22
2 7
spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.93 (3H, t, J = 7.5, CH CH CH CH -4), 1.39 (2H, t, CH CH CH CH -4), 1.59
6
3
2
2
2
3
2
2
2
(2H, m, CH CH CH CH -4), 2.77 (2H, t, J=7.5, CH CH CH CH -4), 3.74-3.84 (4H, m, CH NHCOCH NHCOCH O-7), 4.68
3
2
2
2
3
2
2
2
2
2
2
(2H, s, CH O-7), 6.19 (1H, s, H-3), 7.01 (2H, m, H-6, H-8), 7.77 (1H, d, J = 8.5, H-5), 8.28 (1H, t, J = 6,
2
CH NHCOCH NHCOCH O-7), 8.46 (1H, t, J = 6, CH NHCOCH NHCOCH O-7), 12.69 (1H, br.s, COOH).
2
2
2
2
2
2
N-[2-(4-Butyl-8-methyl-2-oxo-2H-7-chromenyloxy)acetyl]glycylglycine (26). Yield 81%, C H N O , mp 198-
20 24
2 7
199°C. PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.97 (3H, t, J = 8, CH CH CH CH -4), 1.45 (2H, m,
6
3
2
2
2
CH CH CH CH -4), 1.64 (2H, m, CH CH CH CH -4), 2.29 (3H, s, CH -8), 2.75 (2H, t, J = 7.5, CH CH CH CH -4), 3.77-
3
2
2
2
3
2
2
2
3
3
2
2
2
3.84 (4H, m, CH NHCOCH NHCOCH O-7), 4.65 (2H, s, CH O-7), 6.06 (1H, s, H-3), 6.92 (1H, d, J = 8.5, H-6), 7.54 (1H, d,
2
2
2
2
J = 8.5, H-5), 8.16 (2H, m, 2NH), 12.51 (1H, br.s, COOH).
N-[2-(3,4-Dimethyl-2-oxo-2H-7-chromenyloxy)acetyl]glycylglycine(27). Yield85%, C H N O , mp230-232°C.
17 18
2 7
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.06 (3H, s, CH -3), 2.42 (3H, s, CH -4), 3.82 (4H, m,
6
3
3
CH NHCOCH NHCOCH O-7), 4.66 (2H, s, CH O-7), 6.97-7.03 (2H, m, H-6, H-8), 7.73 (1H, d, J = 8.5, H-5), 8.27 (1H, t,
2
2
2
2
J = 6, CH NHCOCH NHCOCH O-7), 8.44 (1H, m, CH NHCOCH NHCOCH O-7), 12.63 (1H, br.s, COOH).
2
2
2
2
2
2
N-[2-(3,4,8-Trimethyl-2-oxo-2H-7-chromenyloxy)acetyl]glycylglycine (28). Yield 84%, C H N O , mp 203-
18 20
2 7
205°C. PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.10 (3H, s, CH -3), 2.34 (3H, s, CH -8), 2.36 (3H, s, CH -4),
6
3
3
3
3.77-3.85 (4H, m, CH NHCOCH NHCOCH O-7), 4.63 (2H, s, CH O-7), 6.91 (1H, d, J = 8.5, H-6), 7.50 (1H, d, J = 8.5, H-5),
2
2
2
2
8.12-8.19 (2H, m, 2NH), 12.44 (1H, br.s, COOH).
N-[2-(H-3-Hexyl-4-methyl-2-oxo-2H-7-chromenyloxy)acetyl]glycylglycine (29). Yield59%, C H N O , mp186-
22 28
2 7
188°C. PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.85 [3H, t, J = 6.5, CH (CH ) -3], 1.26-1.42 [8H, m,
6
3
2 5
304

CH (CH ) CH -3], 2.43 (3H, s, CH -4), 2.52[2H, t, CH (CH ) CH -3], 3.8-3.84 (4H, m, CH NHCOCH NHCOCH O-7), 4.65
3
2 4
2
3
3
2 4
2
2
2
2
(2H, s, CH O-7), 6.96 (1H, d, J = 2.5, H-8), 7.01 (1H, d, J = 8.5, H-6), 7.71 (1H, d, J = 8.5, H-5), 8.26 (1H, t, J = 6,
2
CH NHCOCH NHCOCH O-7), 8.46 (1H, t, J = 6, CH NHCOCH NHCOCH O-7), 12.57 (1H, br.s, COOH).
2
2
2
2
2
2
N-[2-(3-Benzyl-4,8-dimethyl-2-oxo-2H-7-chromenyloxy)acetyl]glycylglycine (30). Yield 78%, C H N O ,
24 24
2 7
mp 217-219°C. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.29 (3H, s, CH -8), 2.42 (3H, s, CH -4), 3.78-3.82 (4H,
6
3
3
m, CH NHCOCH NHCOCH O-7), 3.96 (2H, s, PhCH -3), 4.71 (2H, s, OCH -7), 7.01 (1H, d, J = 8.5, H-6), 7.19-7.25 (5H,
2
2
2
2
2
m, PhCH -3), 7.65 (1H, d, J = 8.5, H-5), 8.23-8.27 (2H, m, 2NH), 12.54 (1H, br.s, COOH).
2
N-[2-(4-Ethyl-8-methyl-2-oxo-2H-7-chromenyloxy)acetyl]norleucinylmethionine (34). Yield48%, C H N O S,
25 34
2 7
mp 126-128°C. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.82 (3H, t, J = 7, CH CH CH CH ), 1.22 (7H, m,
6
3
2
2
2
CH CH -4, CH CH CH CH ), 1.58 (2H, t, CH CH CH CH ), 1.98 (2H, t, CH SCH CH ), 2.02 (3H, s, CH SCH CH ), 2.26
3
2
3
2
2
2
3
2
2
2
3
2
2
3
2
2
(3H, s, CH -8), 2.40 (2H, t, CH SCH CH ), 2.79 (2H, t,
J
=
7, CH SCH CH ), 4.36 [2H, m,
3
3
2
2
3 2 2
CH(CH CH SCH )NHCOCH((CH ) CH )NHCOCH O-7), 4.74 (2H, s, CH O-7), 6.18 (1H, s, H-3), 6.94 (1H, d, J = 9, H-6),
2
2
3
2 3
3
2
2
7.63 (1H, d, J = 9, H-5), 8.06 [1H, m, CH(CH CH SCH )NHCOCH((CH ) CH )NHCOCH O-7], 8.31 [1H, m,
2
2
3
2 3
3
2
CH(CH CH SCH )NHCOCH((CH ) CH )NHCOCH O-7), 12.69 (1H, br.s, COOH).
2
2
3
2 3
3
2
N-[2-(4-Butyl-8-methyl-2-oxo-2H-7-chromenyloxy)acetyl]leucylvaline (35). Yield 42%, C H N O , mp 169-
27 38
2 7
170°C. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.86 [12H, m, (CH ) CHCH , (CH ) CHCH CH), 1.23 (3H, t,
6
3 2
2
3 2
2
CH CH CH CH -4), 1.40 [3H, m, CH CH CH CH -4, (CH ) CHCH CH], 1.58 [4H, m, CH CH CH CH -4,
3
2
2
2
3
2
2
2
3 2
2
3
2
2
2
(CH ) CHCH CH], 2.05 [1H, m, (CH ) CHCH ], 2.26 (3H, s, CH -8), 2.77 (2H, t, J = 7, CH CH CH CH -4), 4.17 [1H, m,
3 2
2
3 2
2
3
3
2
2
2
CH(CH(CH ) )NHCOCH(CH CH(CH ) )NHCOCH O-7], 4.48[1H, m, CH(CH(CH ) )NHCOCH(CH CH(CH ) )NHCOCH O-
3 2
2
3 2
2
3 2
2
3 2
2
7], 4.73 (2H, br.s, CH O-7), 6.18 (1H, s, H-3), 6.95 (1H, d, J = 8, H-6), 7.63 (1H, d, J = 8, H-5), 8.03 (2H, m, 2NH), 12.66 (1H,
2
br.s, COOH).
N-[2-(3-Benzyl-4,8-dimethyl-2-oxo-2H-7-chromenyloxy)acetyl]-β-alanylglycine (36). Yield 44%, C H N O ,
26 26
2 7
mp 192-194°C. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.40 (3H, s, CH -8), 2.42 (2H, t, J = 7,
6
3
CH NHCH CH NHCOCH O-7), 2.42 (3H, s, CH -4), 3.39 (2H, m, CH NHCH CH NHCOCH O-7), 3.73 (2H, d, J = 7,
2
2
2
2
3
2
2
2
2
CH NHCH CH NHCOCH O-7), 3.96 (2H, s, PhCH -3), 4.62 (2H, m, CH O-7), 6.96 (1H, d, J = 8.5, H-6), 7.22-7.26 (5H, m,
2
2
2
2
2
2
PhCH -3), 7.61 (1H, d, J = 8.5, H-5), 8.02 (1H, d, J = 7, CH NHCH CH NHCOCH O-7), 8.23 (1H, d, J = 7,
2
2
2
2
2
CH NHCH CH NHCOCH O-7), 12.11 (1H, br.s, COOH).
2
2
2
2
REFERENCES
1.
2.
3.
4.
5.
M. M. Garazd, Ya. L. Garazd, S. V. Shilin, and V. P. Khilya, Khim. Prir. Soedin., 338 (2002).
M. V. Veselovskaya, S. V. Shilin, M. M. Garazd, and V. P. Khilya, Khim. Prir. Soedin., 132 (2003).
S. Zafaruddin Ahmad and R. D. Desai, Proc. Indian Acad. Sci. Sect. A, 5, 277 (1937).
P. N. Confalone and D. L. Confalone, Tetrahedron, 39, 1265 (1983).
A. A. Gershkovich and V. K. Kibirev, Chemical Synthesis of Peptides [in Russian], Naukova Dumka, Kiev (1992),
p. 71.
305