Amino-acid derivatives of 2-(4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen- 7-yloxy)acetic acid

Article abstract of DOI:10.1007/s10600-012-0375-1

New amino-acid derivatives of coumarins based on 7-hydroxy-1,2,3,4- tetrahydrocyclopenta[c]chromen-4one were synthesized using the activated ester method.

Full text of DOI:10.1007/s10600-012-0375-1

Chemistry of Natural Compounds, Vol. 48, No. 5, November, 2012 [Russian original No. 5, September–October, 2012]
AMINO-ACID DERIVATIVES OF 2-(4-OXO-1,2,3,4-TETRAHYDRO-
CYCLOPENTA[c]CHROMEN-7-YLOXY)ACETIC ACID
*
M. V. Veselovskaya, S. V. Shilin, and V. P. Khilya
UDC 547.587.51
New amino-acid derivatives of coumarins based on 7-hydroxy-1,2,3,4-tetrahydrocyclopenta[c]chromen-4-
one were synthesized using the activated ester method.
Keywords: coumarins, amino-acid derivatives, activated esters, condensation.
An alternative method for preparing new biologically active compounds is to synthesize analogs of natural bioregulators
in order to increase their pharmacological activity by forming several active centers in the molecule. An advantage of such
compounds is that their structures are similar to the biochemical structures of the living organism and cause significantly less
side effects. Coumarins have traditionally been used as the formative basis for creating pharmacologically active compounds
because of the high biological activity of the naturally occurring examples. On the other hand, considering the significance of
amino acids and their derivatives in the metabolism of all living organisms, it should be expected that combining in a single
molecule coumarin and amino-acid moieties would produce compounds with new physiological properties.
Greater than 30 types of pharmacological activity have been identified for compounds with the coumarin nucleus. In
particular, 7-hydroxy-1,2,3,4-tetrahydrocyclopenta[c]chromen-4-one derivatives include compounds with anti-allergic [1, 2]
and anti-inflammatory [3] activity, CNS stimulants [4], neuroprotectants and anticonvulsives [5], antidepressants, insecticides
[6], depressants, analgesics, and antipyretics [7]. They can also be used to treat hypoxia [8].
The goal of our work was to modify 7-hydroxy-1,2,3,4-tetrahydrocyclopenta[c]chromen-4-one by judicious
introduction into it of amino-acid residues. The starting hydroxycoumarin 1 was prepared in high yield via Pechmann
condensation of resorcinol and ethyl-2-oxocyclopentacarboxylate in the presence of H SO (72%) [9].
2
4
The activated ester method, which is broadly employed in peptide synthesis, was used to introduce the amino-acid
moiety into the coumarin nucleus [10]. Alkylation of 1 in acetone in the presence of potash by ethylbromoacetate gave ethyl
ester 2, saponification of which by NaOH in aqueous propanol-2 with subsequent acidolysis formed the corresponding acid 3
(Scheme 1). The activated esters were N-hydroxysuccinimide esters, which are characteristically highly reactive and do not
lead to racemization [11]. The N-hydroxysuccinimide ester was prepared via reaction of 3 with N-hydroxysuccinimide with
dicyclohexylcarbodiimide (DCC) as the condensing agent.
O
O
5
O
5
O
O
O
O
O
7
O
HO
7
O
O
EtO
HO
a
b
Br
+
O
3
3
9
9
1
1
1
2
3
a. K CO ; b. 1. NaOH, 2. HCl
2
3
Scheme 1
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]amino acids (4–17) were prepared via
condensation of the activated ester of 3 and sodium salts of the amino acids in aqueous dioxane (1:1) at room temperature with
subsequent acidolysis of the resulting salts. The syntheses resulted in the introduction into the coumarin of glycine (4), alanine
(5), valine (6), norvaline (7), ꢀ-phenylglycine (8), phenylalanine (9), aspartic acid (10), glutamic acid (11), citrulline (12), and
arginine (13) and 3-aminopropanoic (14), 4-aminobutanoic (15), 6-aminohexanoic (16), and isonipecotinic (17) acids (Scheme 2).
Kiev National Taras Shevchenko University, Ul. Vladimirskaya 64, 01601, Kiev, Ukraine, e-mail: vesmarvic@mail.ru.
Translated from Khimiya Prirodnykh Soedinenii, No. 5, September–October, 2012, pp. 679–681. Original article submitted
February 21, 2012.
©
0009-3130/12/4805-0757 2012 Springer Science+Business Media New York
757

R
O
O
O
6
4'
HO
O
O
O
O
O
O
O
4'
N
H
N
H
HO
5'
O
O
3
1
14
4 - 13
O
O
O
6'
4'
N
O
O
O
HO
O
O
O
O
O
SuOH
DCC
O
N
H
HO
O
O
O
15
3
O
O
8'
4'
O
O
HO
O
O
O
N
N
H
O
O
OH
17
16
4: R = H; 5: R = CH ; 6: R = CH(CH ) ; 7: R = CH CH CH ; 8: R = Ph; 9: R = CH Ph; 10: R = CH COOH
3
3 2
2
2
3
2
2
11: R = CH CH COOH; 12: R = CH CH CH NHCONH ; 13: R = CH CH CH NHC(NH)NH
2
2
2
2
2
2
2
2
2
2
Scheme 2
PMR spectra of the products contained a resonance for the formed amide in the range 8.20–8.50 ppm and resonances
for the coumarin and amino-acid protons.
EXPERIMENTAL
The course of reactions and purity of products were monitored using TLC on Merck 60 F plates with elution by
254
CHCl :MeOH mixtures (9:1 and 95:5). Melting points were measured on a Kofler block. PMR spectra were measured
3
relative to TMS (internal standard) on Varian VXR-300 and Mercury-400 spectrometers. Elemental analyses of all compounds
agreed with those calculated.
Starting 7-hydroxy-1,2,3,4-tetrahydrocyclopenta[c]chromen-4-one (1) and 2-(4-oxo-1,2,3,4-tetrahydrocyclo-
penta[c]chromen-7-yloxy)acetic acid (3) were prepared as before [9, 12].
General method for preparing N-[2-(4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]amino acids.
A cooled solution of 3 (4 mmol) and N-hydroxysuccinimide (0.51 g, 4.4 mmol) in anhydrous dioxane (20 mL) was treated with
DCC (0.83 g, 4 mmol) and stirred vigorously for 2 h. The course of the reaction was monitored by TLC. The precipitate of
dicyclohexylurea was filtered off. The N-hydroxysuccinimide ester was treated with a solution of the appropriate amino acid
(4.4 mmol) and NaOH (0.18 g, 4.4 mmol) in H O (20 mL) and stirred for 3–4 h. The course of the reaction was monitored by
2
TLC. After the reaction was finished, the mixture was treated with H O (100 mL) and acidified to pH 4. The precipitate was
2
filtered off and crystallized from propanol-2 (50%).
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]glycine (4). Yield 81%, C H NO ,
16 15
6
mp 247–248°C.
PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 2.12 (2H, m, 2H-2), 2.73 (2H, m, 2H-1), 3.03 (2H, m, 2H-3),
6
3.84 (2H, d, 2H-4ꢂ), 4.70 (2H, s, 2H-1ꢂ), 6.93 (1H, s, H-6), 6.98 (1H, d, J = 9, H-8), 7.38 (1H, d, J = 9, H-9), 8.31 (1H, br.t,
J = 6, NH), 12.70 (1H, br.s, COOH).
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]alanine (5). Yield 77%, C H NO ,
17 17
6
mp 225–226.5°C.
PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.36 (3H, d, J = 7, CH -4ꢂ), 2.16 (2H, m, 2H-2), 2.77 (2H, m,
6
3
2H-1), 3.04 (2H, m, 2H-3), 4.32 (1H, m, H-4ꢂ), 4.61 (2H, s, CH O-7), 6.88 (1H, d, J = 9, H-8), 6.92 (1H, s, H-6), 7.32 (1H, d,
2
J = 9, H-9), 8.07 (1H, br.s, NH), 12.60 (1H, br.s, COOH).
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]valine (6). Yield 64%, C H NO , mp 198–
19 21
6
199°C.
758

PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 0.92 [6H, d, J = 7, (CH ) CH-4ꢂ], 2.12–2.20 (3H, m, H-4ꢂ,
6
3 2
2H-2), 2.77 (2H, m, 2H-1), 3.06 (2H, m, 2H-3), 4.25 (1H, m, H-4ꢂ), 4.67 (2H, s, 2H-1ꢂ), 6.93 (2H, m, H-6,8), 7.45 (1H, d,
J = 9, H-9), 8.05 (1H, d, J = 8, NH), 12.59 (1H, br.s, COOH).
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]norvaline (7). Yield 71%, C H NO ,
19 21
6
mp 207–208°C.
PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 0.93 (3H, t, J = 7, CH CH CH -4ꢂ), 1.36 (2H, m,
6
3
2
2
CH CH CH -4ꢂ), 1.76 (2H, m, CH CH CH -4ꢂ), 2.16 (2H, m, 2H-2), 2.78 (2H, m, 2H-1), 3.04 (2H, m, 2H-3), 4.32 (1H, m,
3
2
2
3
2
2
H-4ꢂ), 4.63 (2H, s, 2H-1ꢂ), 6.87 (1H, d, J = 9, H-8), 6.92 (1H, s, H-6), 7.30 (1H, d, J = 9, H-9), 8.01 (1H, d, J = 9, NH), 12.54
(1H, br.s, COOH).
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]phenylglycine (8). Yield 62%, C H NO ,
22 19
6
mp 154.5–156°C.
PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 2.17 (2H, m, 2H-2), 2.78 (2H, m, 2H-1), 3.06 (2H, m, 2H-3),
6
4.63 (2H, s, 2H-1ꢂ), 5.34 (1H, m, H-4ꢂ), 6.82-6.94 (2H, m, H-6,8), 7.26–7.43 (6H, m, Ph-4ꢂ, H-9), 8.72 (1H, m, NH), 12.84
(1H, br.s, COOH).
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]phenylalanine (9). Yield 71%, C H NO ,
23 21
6
mp 199–201°C.
PMR spectrum (300 MHz, DMSO-d , ꢁ, ppm, J/Hz): 2.17 (2H, m, 2H-2), 2.78 (2H, m, 2H-1), 3.02 (4H, m, 2H-3,
6
PhCH -4ꢂ), 4.56 (3H, br.s, 2H-1ꢂ, H-4ꢂ), 6.81 (2H, m, H-6,8), 7.17–7.25 (5H, m, Ph), 7.42 (1H, d, J = 9, H-9), 8.07 (1H, d,
2
J = 7, NH), 12.77 (1H, br.s, COOH).
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]asparticAcid (10). Yield 48%, C H NO ,
18 17
8
mp 158–159.5°C.
PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 2.16 (2H, m, 2H-2), 2.66–2.79 (4H, m, CH -4ꢂ, 2H-1), 3.05 (2H,
6
2
m, 2H-3), 4.55 (1H, m, H-4ꢂ), 4.70 (2H, s, 2H-1ꢂ), 6.88–6.91 (2H, m, H-6,8), 7.43 (1H, 2d, J = 9, H-9), 8.33 (1H, d, J = 8, NH),
12.47 (1H, br.s, COOH).
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]glutamicAcid (11). Yield 48%, C H NO ,
19 19
8
mp 144–144.5°C.
PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.88–2.05 (2H, m, CH CH -4ꢂ), 2.16 (2H, m, 2H-2), 2.27 (2H,
6
2
2
m, CH CH -4ꢂ), 2.77 (2H, m, 2H-1), 3.06 (2H, m, 2H-3), 4.32 (1H, m, H-4ꢂ), 4.62 (2H, s, 2H-1ꢂ), 6.96 (2H, m, H-6,8), 7.44
2
2
(1H, d, J = 8, H-9), 8.27 (1H, d, J = 7, NH), 12.36 (1H, br.s, COOH).
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]citrulline (12). Yield 58%, C H N O ,
20 23
3 7
mp 234–236°C.
PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.41 (2H, m, NH CONHCH CH CH -4ꢂ), 1.66–1.78 (2H, m,
6
2
2
2
2
NH CONHCH CH CH -4ꢂ), 2.15 (2H, m, 2H-2), 2.77 (2H, m, 2H-1), 3.03–3.13 (4H, m, NH CONHCH CH CH -4ꢂ, 2H-3),
2
2
2
2
2
2
2
2
4.28 (1H, m, H-4ꢂ), 4.64 (2H, s, 2H-1ꢂ), 5.25 (2H, s, NH ), 5.88 (1H, t, NH CONHCH CH CH -4ꢂ), 6.87 (2H, m, H-6,8), 7.33
2
2
2
2
2
(1H, d, J = 9, H-9), 8.16 (1H, br.d, J = 7, NH), 12.67 (1H, br.s, COOH).
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]arginine (13). Yield 42%, C H N O ,
21 26
4 6
mp 239–240°C.
PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.47 (2H, m, NH C(NH)NHCH CH CH -4ꢂ), 1.72 (2H, m,
6
2
2
2
2
NH C(NH)NHCH CH CH -4ꢂ), 2.13 (2H, m, 2H-2), 2.74 (2H, m, 2H-1), 3.03 (4H, m, NH C(NH)NHCH CH CH -4ꢂ,
2
2
2
2
2
2
2
2
2H-3), 4.02 (1H, m, H-4ꢂ), 4.54 (2H, s, 2H-1ꢂ), 6.91 (2H, m, H-6,8), 7.40 (1H, d, J = 9, H-9), 7.54–7.74 (3H, br.s,
NH C(NH)NHCH CH CH -4ꢂ), 7.89 (1H, br.d, J = 7, NH), 9.02 (1H, br.s, NH C(NH)NHCH CH CH -4ꢂ).
2
2
2
2
2
2
2
2
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]-ꢃ-alanine (14). Yield 75%, C H NO ,
17 17
6
mp 285–286.5°C.
PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 2.15 (2H, m, 2H-2), 2.42 (2H, t, J = 7, 2H-5ꢂ), 2.76 (2H, m,
6
2H-1), 3.05 (2H, m, 2H-3), 3.36 (2H, m, 2H-4ꢂ), 4.52 (2H, s, 2H-1ꢂ), 6.93 (2H, br.s, H-6,8), 7.44 (1H, d, J = 9, H-9), 8.08 (1H,
br.s, NH), 12.11 (1H, br.s, COOH).
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]aminobutanoic Acid (15). Yield 72%,
C H NO , mp 225–226.5°C.
18 19
6
PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.71 (2H, m, 2H-5ꢂ), 2.13–2.23 (4H, m, 2H-6ꢂ, 2H-2), 2.78 (2H,
6
m, 2H-1), 3.07 (2H, m, 2H-3), 3.20 (2H, m, 2H-4ꢂ), 4.53 (2H, s, 2H-1ꢂ), 6.96 (2H, m, H-6,8), 7.47 (1H, d, J = 9, H-9), 8.11 (1H,
br.t, NH), 11.90 (1H, br.s, COOH).
759

N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]aminohexanoic Acid (16). Yield 62%,
C H NO , mp 171–172.5°C.
20 23
6
PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.21–1.48 (6H, m, 2H-7ꢂ,6ꢂ,5ꢂ), 2.07–2.19 (4H, m, 2H-8ꢂ, 2H-2),
6
2.77 (2H, m, 2H-1), 3.03–3.11 (4H, m, 2H-4ꢂ, 2H-3), 4.71 (2H, s, 2H-1ꢂ), 6.77 (2H, m, H-6,8), 7.28 (1H, d, J = 9, H-9), 7.80
(1H, br.s, NH), 11.82 (1H, br.s, COOH).
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]isonipecotinic Acid (17). Yield 48%,
C H NO , mp 215–216.5°C.
19 19
8
PMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.48, 1.66 (each 1H, m, H-3ꢂa, H-5ꢂa), 1.88 (2H, m, H-3ꢂe,
6
H-5ꢂe), 2.16 (2H, m, 2H-2), 2.77 (2H, m, 2H-1), 2.86 (1H, m, H-4ꢂ), 3.06 (2H, m, 2H-3), 3.18 (2H, m, H-2ꢂa, H-6ꢂa), 3.80, 4.17
(each 1H, m, H-2ꢂe, H-6ꢂe), 4.87 (2H, m, 2H-1ꢂ), 6.90 (1H, d, J = 8, H-8), 6.96 (1H, d, J = 2, H-6), 7.43 (1H, d, J = 8, H-9),
12.14 (1H, br.s, COOH).
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