Synthesis of amino-acid derivatives of chrysin

Article abstract of DOI:10.1007/s10600-009-9194-4

Various conjugates of amino acids with chrysin in which the amino acid was bonded through the C- or N-terminus to the flavone were prepared using peptide chemistry methods (symmetric anhydrides and activated esters).

Full text of DOI:10.1007/s10600-009-9194-4

Chemistry of Natural Compounds, Vol. 44, No. 6, 2008
SYNTHESIS OF AMINO-ACID DERIVATIVES OF CHRYSIN
M. V. Veselovskaya,1* M. M. Garazd,1 A. S. Ogorodniichuk,1
Ya. L. Garazd,2 and V. P. Khilya2
UDC 547.814.5
C
Various conjugates of amino acids with chrysin in which the amino acid was bonded through the - or
N
-terminus to the flavone were prepared using peptide chemistry methods (symmetric anhydrides and
activated esters).
Key words: flavonoids, flavones, chrysin, amino-acid derivatives.
Flavonoids are the most widely distributed compounds of natural origin. They can be found in practically all plant
species. At present, flavonoids comprise about 6500 natural compounds [1]. The study of flavonoids is becoming increasingly
interesting because of the important role that they play in the metabolism of plants and animals and their high and diversified
biological activity [2]. Chrysin (5,7-dihydroxyflavone) is one of the most common flavonoids, has been isolated from various
plant families [3, 4], and possesses, like its derivatives, a broad spectrum ofbiological activity. Thus, chrysin exhibits anticancer
[5, 6], antioxidant [7, 8], anti-inflammatory [9, 10], vasodilating [11, 12], immunomodulating [13, 14], antibacterial [15, 16],
antifungal [16], antiprotozal [17], neuroprotective [18], hypotensive [19], and anti-allergy [20] activity. Chrysin derivatives
possess hypoglycemic [21], anticancer [22-25], anti-inflammatory [26, 27], and antibacterial [15] action.
Considering the importance to the metabolism of all animals of amino acids and their derivatives, our goal was to
synthesize chrysin derivatives with pharmacophores containing amino acids.
The amino-acid derivatives of chrysin were synthesized via two modification pathways. The first was based on
formation of the ester of -protected amino acid and phenolic compounds. The most suitable and convenient method for
N
synthesizing 7- -amino-acid chromone derivatives is the reaction of 7-hydroxychromones and symmetric anhydrides of
O
-substituted amino acids because the reaction proceeds under mild conditions and is not complicated by side reactions [28].
N
It has been used successfully to synthesize similar types of compounds [29, 30].
The hydroxyls of 5,7-dihydroxychromones have different reactivities because of the different influence of electron-
donors, steric factors, and intramolecular H-bonds. Therefore, the 7-hydroxyl of the chromone system is acylated exclusively
under mild conditions [31, 32].
Symmetric anhydrides of -protected amino acids were prepared byreaction of dicyclohexylcarbodiimide (DCC) with
N
two equivalents of the corresponding -protected amino acid in anhydrous dioxane at 0°C. The amines of the amino acids
N
were blocked with -butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and -toluenesulfonic acid (Tos). Chrysin was
t
p
acylated by the resulting amino-acid anhydrides at 0°C in anhydrous dioxane in the presence of catalytic amounts of
4-dimethylaminopyridine (DMAP) to produce -protected 7- -aminoacyl-5-hydroxy-2-phenylchromen-4-ones 2-20. The
N
O
products contained glycine (2, 8), L-alanine (3, 9), L-valine (4, 10), L-leucine (5, 11), L-isoleucine (6, 12), L-methionine (13),
L-phenylalanine (7, 14), β-alanine (15, 17, 19), and 6-aminohexanoic acid (16, 18, 20).
Theselectiveacylation ofthechromone7-hydroxyl wasconfirmedbyPMRspectroscopy. The spectra of2-20contained
resonances for the flavone ring, an amino-acid moiety, and the protecting group. The resonance of the 5-OH, which was
involved in an intramolecular H-bond, appeared in the range 12.72-12.95 ppm. Derivatives 2-20 gave an intense brown color
with alcoholic FeCl due to formation of an intramolecular chelate complex.
3
1) Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine, 02094, Ukraine, Kiev,
ul. Murmanskaya, 1, e-mail: gmm@i.com.ua; 2) Taras Shevchenko Kiev National University, 01033, Ukraine, Kiev, ul.
Vladimirskaya, 64. Translated from KhimiyaPrirodnykh Soedinenii, No. 6, pp. 569-574, November-December, 2008. Original
article submitted January 14, 2008.
0009-3130/08/4406-0704 ©2008 Springer Science+Business Media, Inc.
704

R
Cbz
O
O
O
Ph
R
N
H
Boc
Cbz
O
O
O
Ph
(CH )n
2
O
O
O
Ph
Boc
O
N
H
N
H
O
O
OH
8 - 14
OH
OH
c
2 - 7
(CH )n
15, 16
(CH )n
a
b
HO
O
Ph
O
O
O
Ph
Tos
2
O
O
Ph
2
N
H
d
e
N
O
H
O
OH
O
OH
19, 20
OH
O
1
17, 18
a. (BocNHCHRCO)2O, DMAP; b. (CbzNHCHRCO)2O, DMAP; c. (BocNH(CH2)nCO)2O, DMAP;
d. (CbzNH(CH2)nCO)2O, DMAP; e. (TosNH(CH2)nCO)2O, DMAP
2, 8:
3, 9:
4, 10:
5, 11:
6, 12:
R = CH2CH(CH3)2;
R = H;
R = CH3;
R = CH(CH3)2;
R = CH2CH(CH3)CH2CH3
7, 14:
13:
15, 17, 19:
n = 2;
16, 18, 20:
R = CH2Ph;
R = CH2CH2SCH3;
n = 5
The second approach to modifying chrysin with amino acids was based on the method of activated esters, which is
widely used in peptide chemistry. Selective alkylation of the chrysin 7-hydroxyl under Williamson reaction conditions by
ethylbromoacetate produced ethyl ester 21, saponification of which by NaOH in aqueous propanol-2 and subsequent acidolysis
of the reaction mixture formed [(5-hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetic acid (22).
O
O
Ph
Ph
O
O
O
1. 1N NaOH
HO
O
O
Ph
O
O
EtO
HO
2. 1N H SO
2
4
BrCH COOEt
2
OH
22
OH
R
OH
O
21
1
O
O
O
N
Ph
Ph
HO
O
O
O
O
O
SuOH, DIC
N
H
O
O
O
OH
O
OH
O
23 - 28
O
(CH )n
2
O
O
O
Ph
O
O
Ph
HO
N
H
N
H
HO
O
O
O
OH
OH
O
32
29 - 31
O
O
H
N
O
Ph
HO
N
H
O
33
R = CH2CH2SCH3;
OH
O
23:
24:
25:
26:
27:
28:
30:
31:
n = 2; n = 5
R = H;
R = CH3;
R = CH(CH3)2;
R = CH2Ph;
R = Ph;
The carboxylic acid was activated using -hydroxysuccinimide to form highly reactive esters without racemizing the
N
reaction products [33]. This method was used successfully to synthesize similar types of compounds [30, 34]. The activated
ester was prepared by reacting starting acid 22 and -hydroxysuccinimide (SuOH) in anhydrous DMF with
N
diisopropylcarbodiimide (DIC) as the condensing agent. Reaction of the activated ester and sodium salts of the amino acids in
705

DMF:H O at room temperature with subsequent acidolysis of the resulting salts gave in high yields 23-33 with a free carboxylic
2
acid.
The synthesis gave chrysin derivatives modified with glycine (23), L-alanine (24), L-valine (25), L-methionine (26),
L-phenylalanine (27), L-α-phenylglycine (28), and β-alanine (29) and 4-aminobutanoic (30), 6-aminohexanoic (31), and trans-
4-aminomethylcyclohexanecarboxylic (32) acids in addition to glycylglycine (33). PMR spectra of 23-33 contained resonances
for chrysin, the amino-acid moiety, the amide bond at 8.12-8.93 ppm, and the free carboxylic acid at 11.90-12.65 ppm.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Merck 60 F254 plates with elution by
CHCl :CH OH (9:1). Melting points were determined on a Kofler block. PMR spectra were recorded on Varian VXR-300 and
3
3
Mercury 400 spectrometers at 300 and 400 MHz, respectively, vs. TMS (internal standard). Elemental analyses of all
compounds agreed with those calculated.
5,7-Dihydroxyflavone was prepared as before [35].
N-Substituted7-O-Aminoacyl-5-hydroxy-2-phenylchromen-4-ones2-20. Acooled(0°C)solution oftheappropriate
N-substituted amino acid (9 mmol) in anhydrous dioxane (20 mL) was treated with DCC (0.93 g, 4.5 mmol) and stirred
vigorously for 20-30 min at 0°C. The precipitate of dicyclohexylurea was filtered off. The resulting symmetric anhydride was
treated with chrysin (1.02 g, 4 mmol) in anhydrous dioxane (20 mL) and DMAP (20 mg), held for 1-2 h at room temperature,
and stirred vigorously (finish of the reaction was determined using TLC). Solvent was removed in vacuo. The solid was
dissolved in ethylacetate (50 mL) and washed successively with NaHCO solution (2 × 50 mL), water (50 mL), and saturated
3
NaCl solution (50 mL). The organic phase was dried over anhydrous MgSO . Solvent was removed in vacuo. The solid was
4
crystallized from propanol-2.
7-O-(N-t-Butyloxycarbonylglycyl)-5-hydroxy-2-phenylchromen-4-one (2), yield69%, mp218-219°C, C H NO .
22 21
7
PMR spectrum (300 MHz, CD COCD , δ, ppm, J/Hz): 1.44 [9H, s, (CH ) C], 4.14 (2H, d, J = 5.7, CH -2″), 6.54 (1H,
3 3
2
3
3
br.m, CONH), 6.61 (1H, d, J = 2.1, H-6), 6.92 (1H, s, H-3), 7.01 (1H, d, J = 2.1, H-8), 7.56-7.68 (3H, m, H-3′, H-4′, H-5′), 8.11
(2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.91 (1H, s, OH-5).
7-O-(N-t-Butyloxycarbonyl-L-alanyl)-5-hydroxy-2-phenylchromen-4-one (3), yield 78%, mp 192-193°C,
C H NO .
23 23
7
PMR spectrum (300 MHz, CD COCD , δ, ppm, J/Hz): 1.45 [9H, s, (CH ) C], 1.55 (3H, d, J = 7.5, CH -3″), 4.44 (1H,
3 3
3
3
3
m, H-2″), 6.59 (1H, d, J = 7.2, CONH), 6.61 (1H, d, J = 2.1, H-6), 6.93 (1H, s, H-3), 7.01 (1H, d, J = 2.1, H-8), 7.56-7.68 (3H,
m, H-3′, H-4′, H-5′), 8.12 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.90 (1H, s, OH-5).
7-O-(N-t-Butyloxycarbonyl-L-valyl)-5-hydroxy-2-phenylchromen-4-one (4), yield73%, mp188-189°C, C H NO .
25 27
7
PMR spectrum (300 MHz, CD COCD , δ, ppm, J/Hz): 1.11 (6H, d, J = 6.6, CH -4″, CH -3″), 1.45 [9H, s, (CH ) C],
3
3
3 3
3
3
2.34 (1H, m, H-3″), 4.29 (1H, t, J = 6.0, H-2″), 6.52 (1H, d, J = 7.5, CONH), 6.60 (1H, d, J = 2.1, H-6), 6.95 (1H, s, H-3), 7.02
(1H, d, J = 2.1, H-8), 7.60-7.70 (3H, m, H-3′, H-4′, H-5′), 8.13 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.94 (1H, s, OH-5).
7-O-(N-t-Butyloxycarbonyl-L-leucyl)-5-hydroxy-2-phenylchromen-4-one (5), yield 68%, mp 181-182°C,
C H NO .
26 29
7
PMR spectrum (300 MHz, CD COCD , δ, ppm, J/Hz): 1.03 (6H, d, J = 5.7, CH -5″, CH -4″), 1.45 [9H, s, (CH ) C],
3
3
3 3
3
3
1.82-1.87 (3H, m, CH -3″, H-4″), 4.41 (1H, m, H-2″), 6.61 (1H, d, J = 2.1, H-6), 6.65 (1H, d, J = 7.2, CONH), 6.96 (1H, s, H-3),
2
7.01 (1H, d, J = 2.1, H-8), 7.56-7.69 (3H, m, H-3′, H-4′, H-5′), 8.14 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.95 (1H, s, OH-5).
7-O-(N-t-Butyloxycarbonyl-L-isoleucyl)-5-hydroxy-2-phenylchromen-4-one (6), yield 73%, mp 176-177°C,
C H NO .
26 29
7
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.04 (3H, t, J = 5.7, CH -5″), 1.09 (3H, d, J = 6.9, CH -3″), 1.44 (1H,
3
3
3
m, CH -4″a), 1.45 [9H, s, (CH ) C], 1.66 (1H, m, CH -4″b), 2.10 (1H, m, H-3″), 4.49 (1H, m, H-2″), 5.06 (1H, m, CONH), 6.59
2
3 3
2
(1H, d, J = 2.1, H-6), 6.74 (1H, s, H-3), 6.87 (1H, d, J = 2.1, H-8), 7.50-7.60 (3H, m, H-3′, H-4′, H-5′), 7.95 (2H, dd, J = 2.1,
8.4, H-2′, H-6′), 12.75 (1H, s, OH-5).
7-O-(N-t-Butyloxycarbonyl-L-phenylalanyl)-5-hydroxy-2-phenylchromen-4-one (7), yield 83%, mp 208-209°C,
C H NO .
29 27
7
706

PMR spectrum (300 MHz, CD COCD , δ, ppm, J/Hz): 1.46 [9H, s, (CH ) C], 3.21-3.45 (2H, m, CH -3″), 4.63 (1H,
3 3
2
3
3
q, J = 7.2, H-2″), 6.50 (1H, d, J = 2.1, H-6), 6.62 (1H, d, J = 7.2, CONH), 6.90 (1H, d, J = 2.1, H-8), 6.93 (1H, s, H-3), 7.25-7.45
(5H, m, Ph-3″), 7.58-7.69 (3H, m, H-3′, H-4′, H-5′), 8.12 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.93 (1H, s, OH-5).
7-O-(N-Carbobenzyloxyglycyl)-5-hydroxy-2-phenylchromen-4-one (8), yield 85%, mp 224-225°C, C H NO .
25 19
7
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 4.27 (2H, d, J = 5.7, CH -2″), 5.17 (2H, s, PhCH CO), 5.39 (1H,
2
2
3
m, CONH), 6.59 (1H, d, J = 2.1, H-6), 6.73 (1H, s, H-3), 6.89 (1H, d, J = 2.1, H-8), 7.37 (5H, s, PhCH CO), 7.51-7.62 (3H, m,
2
H-3′, H-4′, H-5′), 7.89 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.74 (1H, s, OH-5).
7-O-(N-Carbobenzyloxy-L-alanyl)-5-hydroxy-2-phenylchromen-4-one (9), yield79%, mp209-210°C, C H NO .
26 21
7
PMR spectrum (300 MHz, CD COCD , δ, ppm, J/Hz): 1.59 (3H, d, J = 7.5, CH -3″), 4.52 (1H, m, H-2″), 5.15 (2H,
3
3
3
s, PhCH CO), 6.59 (1H, d, J = 2.1, H-6), 6.78 (1H, d, J = 7.2, CONH), 6.92 (1H, s, H-3), 6.95 (1H, d, J = 2.1, H-8), 7.28-7.44
2
(5H, m, PhCH CO), 7.55-7.69 (3H, m, H-3′, H-4′, H-5′), 8.11 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.90 (1H, s, OH-5).
2
7-O-(N-Carbobenzyloxy-L-valyl)-5-hydroxy-2-phenylchromen-4-one (10), yield 76%, mp195-196°C, C H NO .
28 25
7
PMRspectrum (300 MHz, CD COCD , δ, ppm, J/Hz): 1.13 (6H, d, J = 6.6, CH -4″, CH -3″), 2.41 (1H, m, H-3″), 4.38
3
3
3
3
(1H, t, J = 6.0, H-2″), 5.14 (2H, s, PhCH CO), 6.60 (1H, d, J = 2.1, H-6), 6.92 (1H, d, J = 7.5, CONH), 6.95 (1H, s, H-3), 7.01
2
(1H, d, J = 2.1, H-8), 7.28-7.44 (5H, m, PhCH CO), 7.58-7.68 (3H, m, H-3′, H-4′, H-5′), 8.14 (2H, dd, J = 2.1, 8.4, H-2′, H-6′),
2
12.95 (1H, s, OH-5).
7-O-(N-Carbobenzyloxy-L-leucyl)-5-hydroxy-2-phenylchromen-4-one (11), yield83%, mp187-188°C, C H NO .
29 27
7
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.03 (6H, d, J = 5.7, CH -5″, CH -4″), 1.68-1.83 (3H, m, CH -3″,
3
3
2
3
H-4″), 4.60 (1H, m, H-2″), 5.16 (2H, s, PhCH CO), 5.26 (1H, d, J = 7.2, CONH), 6.57 (1H, d, J = 2.1, H-6), 6.72 (1H, s, H-3),
2
6.81 (1H, d, J = 2.1, H-8), 7.30-7.44 (5H, m, PhCH CO), 7.54-7.65 (3H, m, H-3′, H-4′, H-5′), 7.91 (2H, dd, J = 2.1, 8.4, H-2′,
2
H-6′), 12.73 (1H, s, OH-5).
7-O-(N-Carbobenzyloxy-L-isoleucyl)-5-hydroxy-2-phenylchromen-4-one (12), yield 77%, mp 184-185°C,
C H NO .
29 27
7
PMR spectrum (300 MHz, CD COCD , δ, ppm, J/Hz): 1.00 (3H, t, J = 5.7, CH -5″), 1.11 (3H, d, J = 6.9, CH -3″),
3
3
3
3
1.48 (1H, m, CH -4″a), 1.69 (1H, m, CH -4″b), 2.12 (1H, m, H-3″), 4.43 (1H, m, H-2″), 5.14 (2H, s, PhCH CO), 6.60 (1H, d,
2
2
2
J = 2.1, H-6), 6.93 (1H, m, CONH), 6.95 (1H, s, H-3), 7.01 (1H, d, J = 2.1, H-8), 7.28-7.45 (5H, m, PhCH CO), 7.58-7.70 (3H,
2
m, H-3′, H-4′, H-5′), 8.15 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.95 (1H, s, OH-5).
7-O-(N-Carbobenzyloxy-L-methionyl)-5-hydroxy-2-phenylchromen-4-one (13), yield 76%, mp 194-195°C,
C H NO S.
28 25
7
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 2.14 (3H, s, SCH ), 2.15-2.42 (2H, m, CH -4″), 2.67 (2H, m,
3
2
3
CH -3″), 4.76 (1H, m, H-2″), 5.16 (2H, s, PhCH CO), 5.54 (1H, d, J = 7.2, CONH), 6.58 (1H, d, J = 2.1, H-6), 6.75 (1H, s, H-3),
2
2
6.86 (1H, d, J = 2.1, H-8), 7.30-7.40 (5H, m, PhCH CO), 7.50-7.60 (3H, m, H-3′, H-4′, H-5′), 7.89 (2H, dd, J = 2.1, 8.4, H-2′,
2
H-6′), 12.76 (1H, s, OH-5).
7-O-(N-Carbobenzyloxy-L-phenylalanyl)-5-hydroxy-2-phenylchromen-4-one (14), yield 86%, mp 228-229°C,
C H NO .
32 25
7
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 3.20-3.35 (2H, m, CH -3″), 4.89 (1H, q, J = 7.2, H-2″), 5.14 (2H,
2
3
s, PhCH CO), 5.32 (1H, d, J = 7.2, CONH), 6.44 (1H, d, J = 2.1, H-6), 6.74 (1H, s, H-3), 6.78 (1H, d, J = 2.1, H-8), 7.18-7.35
2
(5H, m, Ph-3″), 7.50-7.60 (3H, m, H-3′, H-4′, H-5′), 7.91 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.75 (1H, s, OH-5).
7-O-(N-t-Butyloxycarbonyl-β-alanyl)-5-hydroxy-2-phenylchromen-4-one (15), yield 68%, mp 193-194°C,
C H NO .
23 23
7
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.47 [9H, s, (CH ) C], 2.83 (2H, t, J = 7.2, CH -2″), 3.54 (2H, m,
3 3
2
3
CH -3″), 5.01 (1H, m, CONH), 6.59 (1H, d, J = 2.1, H-6), 6.74 (1H, s, H-3), 6.88 (1H, d, J = 2.1, H-8), 7.52-7.61 (3H, m, H-3′,
2
H-4′, H-5′), 7.92 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.74 (1H, s, OH-5).
7-O-(N-t-Butyloxycarbonyl-6-aminohexanoyl)-5-hydroxy-2-phenylchromen-4-one (16), yield64%, mp176-177°C,
C H NO .
26 29
7
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.42-1.78 (6H, m, CH -3″, CH -4″, CH -5″), 1.45 [9H, s, (CH ) C],
2
2
2
3 3
3
2.60 (2H, t, J = 7.2, CH -2″), 3.16 (2H, m, CH -6″), 4.56 (1H, m, CONH), 6.57 (1H, d, J = 2.1, H-6), 6.74 (1H, s, H-3), 6.85
2
2
(1H, d, J = 2.1, H-8), 7.52-7.60 (3H, m, H-3′, H-4′, H-5′), 7.90 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.72 (1H, s, OH-5).
707

7-O-(N-Carbobenzyloxy-β-alanyl)-5-hydroxy-2-phenylchromen-4-one (17), yield76%, mp208-209°C, C H NO .
26 21
7
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 2.86 (2H, t, J = 7.2, CH -2″), 3.60 (2H, m, CH -3″), 5.14 (2H, s,
2
2
3
PhCH CO), 5.30 (1H, m, CONH), 6.57 (1H, d, J = 2.1, H-6), 6.75 (1H, s, H-3), 6.86 (1H, d, J = 2.1, H-8), 7.30-7.40 (5H, m,
2
Ph-3″), 7.50-7.60 (3H, m, H-3′, H-4′, H-5′), 7.89 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.72 (1H, s, OH-5).
7-O-(N-Carbobenzyloxy-6-aminohexanoyl)-5-hydroxy-2-phenylchromen-4-one (18), yield 81%, mp 192-193°C,
C H NO .
29 27
7
PMR spectrum (300 MHz, CD COCD , δ, ppm, J/Hz): 1.42-1.65 (4H, m, CH -3″, CH -4″), 1.72-1.80 (2H, m,
2
2
3
3
CH -5″), 2.66 (2H, t, J = 7.2, CH -2″), 3.21 (2H, m, CH -6″), 5.06 (2H, s, PhCH CO), 6.38 (1H, m, CONH), 6.60 (1H, d,
2
2
2
2
J = 2.1, H-6), 6.93 (1H, s, H-3), 7.02 (1H, d, J = 2.1, H-8), 7.25-7.42 (5H, m, PhCH CO), 7.56-7.68 (3H, m, H-3′, H-4′, H-5′),
2
8.12 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.91 (1H, s, OH-5).
7-O-(N-p-Tosyl-β-alanyl)-5-hydroxy-2-phenylchromen-4-one (19), yield 81%, mp 203-204°C, C H NO S.
25 21
7
PMR spectrum (300 MHz, CD COCD , δ, ppm, J/Hz): 2.43 (3H, s, CH -4′″), 2.89 (2H, t, J = 7.2, CH -2″), 3.35 (2H,
3
2
3
3
m, CH -3″), 6.61 (1H, d, J = 2.1, H-6), 6.68 (1H, t, J = 7.2, SO NH), 6.92 (1H, s, H-3), 7.01 (1H, d, J = 2.1, H-8), 7.42 (2H,
2
2
d, J = 8.1, H-3′″, H-5′″), 7.55-7.65 (3H, m, H-3′, H-4′, H-5′), 7.82 (2H, d, J = 8.1, H-2′″, H-6′″), 8.11 (2H, dd, J = 2.1, 8.4, H-2′,
H-6′), 12.89 (1H, s, OH-5).
7-O-(N-p-Tosyl-6-aminohexanoyl)-5-hydroxy-2-phenylchromen-4-one (20), yield 76%, mp 195-196°C,
C H NO S.
28 27
7
PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.42 (2H, m, CH -4″), 1.55 (2H, m, CH -3″), 1.72 (2H, m, CH -5″),
2
2
2
3
2.43 (3H, s, CH -4′″), 2.56 (2H, t, J = 7.2, CH -2″), 2.99 (2H, m, CH -6″), 4.55 (1H, t, J = 7.2, SO NH), 6.54 (1H, d, J = 2.1,
3
2
2
2
H-6), 6.75 (1H, s, H-3), 6.85 (1H, d, J = 2.1, H-8), 7.32 (2H, d, J = 8.1, H-3′″, H-5′″), 7.50-7.61 (3H, m, H-3′, H-4′, H-5′), 7.76
(2H, d, J = 8.1, H-2′″, H-6′″), 7.89 (2H, dd, J = 2.1, 8.4, H-2′, H-6′), 12.73 (1H, s, OH-5).
Ethyl-[(5-hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetate (21). A hot solution of chrysin (25.42 g, 100 mmol)
in anhydrous acetone (150 mL) was treated with freshlycalcined potash (41.40 g, 0.3 mol), stirred vigorously, heated (50-56°C)
for 1 h, treated dropwise with ethylbromoacetate (12.2 mL, 110 mmol), and heated for 2 h with vigorous stirring (course of
reaction monitored by TLC). When the reaction was finished, the mixture was poured into H SO solution (1 L, 1 N). The
2
4
resulting precipitate was filtered and crystallized from propanol-2. Yield 86%, mp 164-165°C (lit. [36] mp 157°C), C H O .
19 16
6
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.24 (3H, t, J = 7.2, CH -2′), 4.21 (2H, q, CH -1′), 4.96 (2H, s,
6
3
2
OCH -7), 6.44 (1H, d, J = 2.1, H-6), 6.86 (1H, d, J = 2.1, H-8), 7.06 (1H, s, H-3), 7.54-7.68 (3H, m, H-3′, H-4′, H-5′), 8.10 (2H,
2
dd, J = 2.1, 8.4, H-2′, H-6′), 12.82 (1H, s, OH-5).
[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetic Acid (22). A solution of 21 (23.82 g, 70 mmol) in propanol-2
(150 mL) was treated with NaOH solution (150 mL, 1 N), stirred vigorously, and refluxed for 2 h (course of reaction monitored
by TLC). When the reaction was finished, the mixture was treated with H SO solution (400 mL, 1 N). The resulting
2
4
precipitate was filtered and crystallized from propanol-2 (50%). Yield 91%, mp 261-262°C (lit. [37] mp 266-268°C),
C H O .
17 21
6
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 4.84 (2H, s, OCH -7), 6.39 (1H, d, J = 2.0, H-6), 6.79 (1H, d,
6
2
J = 2.0, H-8), 7.01 (1H, s, H-3), 7.52-7.67 (3H, m, H-3′, H-4′, H-5′), 8.07 (2H, dd, J = 2.0, 8.4, H-2′, H-6′), 12.15 (1H, br.s,
OH-5), 12.79 (1H, s, OH-5).
N-[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetylamino Acids 23-33. A cooled solution of acid 22 (1.25 g,
4 mmol) and N-hydroxysuccinimide (0.51 g, 4.4 mmol) in anhydrous DMF (10 mL) was treated with DIC (0.69 mL, 4.4 mmol)
and stirred vigorously for 2 h (course of reaction monitored by TLC). The resulting 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 water (10 mL) and stirred for 3-4
h (course of reaction monitored by TLC). After the reaction was finished, water (100 mL) was added. The pH was adjusted
to 4. The precipitate was filtered and crystallized from propanol-2.
N-[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetylglycine (23), yield 72%, mp 264-265°C, C H NO .
19 15
7
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 3.85 (2H, d, J = 6.0, CH -2″), 4.72 (2H, s, OCH -7), 6.47 (1H,
6
2
2
d, J = 2.0, H-6), 6.85 (1H, d, J = 2.0, H-8), 7.07 (1H, s, H-3), 7.58-7.64 (3H, m, H-3′, H-4′, H-5′), 8.10 (2H, dd, J = 2.0, 8.0,
H-2′, H-6′), 8.53 (1H, d, J = 5.6, CONH), 12.35 (1H, br.s, COOH), 12.82 (1H, s, OH-5).
N-[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetyl-L-alanine (24), yield 81%, mp 249-250°C, C H NO .
20 17
7
708

PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.33 (3H, d, J = 7.2, CH -2″), 4.29 (1H, m, H-2″), 4.80 (2H, q,
6
3
J = 8.0, OCH -7), 6.43 (1H, d, J = 2.0, H-6), 6.79 (1H, d, J = 2.0, H-8), 7.06 (1H, s, H-3), 7.58-7.65 (3H, m, H-3′, H-4′, H-5′),
2
8.09 (2H, dd, J = 2.0, 8.0, H-2′, H-6′), 8.37 (1H, d, J = 7.2, CONH), 12.40 (1H, br.s, COOH), 12.79 (1H, s, OH-5).
N-[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetyl-L-valine (25), yield 77%, mp 254-255°C, C H NO .
22 21
7
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.92 (6H, d, J = 7.2, CH -4″, CH -3″), 2.13 (1H, m, H-3″), 4.24
6
3
3
(1H, m, H-2″), 4.80 (2H, q, J = 8.0, OCH -7), 6.43 (1H, d, J = 2.0, H-6), 6.79 (1H, d, J = 2.0, H-8), 7.06 (1H, s, H-3), 7.58-7.65
2
(3H, m, H-3′, H-4′, H-5′), 8.09 (2H, dd, J = 2.0, 8.0, H-2′, H-6′), 8.33 (1H, d, J = 8.4, CONH), 12.48 (1H, br.s, COOH), 12.79
(1H, s, OH-5).
N-[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetyl-L-methionine (26), yield 74%, mp 232-233°C,
C H NO S.
22 21
7
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.95-2.08 (2H, m, CH -4″), 2.02 (3H, s, SCH ), 2.45 (2H, m,
6
2
3
CH -3″), 4.42 (1H, m, H-2″), 4.74 (2H, q, J = 8.0, OCH -7), 6.45 (1H, d, J = 2.0, H-6), 6.81 (1H, d, J = 2.0, H-8), 7.07 (1H,
2
2
s, H-3), 7.57-7.64 (3H, m, H-3′, H-4′, H-5′), 8.09 (2H, dd, J = 2.0, 8.0, H-2′, H-6′), 8.42 (1H, d, J = 7.6, CONH), 12.64 (1H,
br.s, COOH), 12.81 (1H, s, OH-5).
N-[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetyl-L-phenylalanine (27), yield 88%, mp 268-269°C,
C H NO .
26 21
7
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.99 (1H, dd, J = 12.0, 16.4, CH -3″a), 3.10 (1H, dd, J = 2.8, 16.4,
6
2
CH -3″b), 4.52 (1H, m, H-2″), 4.65 (2H, q, J = 8.8, OCH -7), 6.41 (1H, d, J = 2.0, H-6), 6.72 (1H, d, J = 2.0, H-8), 7.08 (1H,
2
2
s, H-3), 7.13-7.21 (5H, m, Ph-3″), 7.57-7.64 (3H, m, H-3′, H-4′, H-5′), 8.09 (2H, dd, J = 2.0, 8.0, H-2′, H-6′), 8.44 (1H, d,
J = 8.0, CONH), 12.60 (1H, br.s, COOH), 12.82 (1H, s, OH-5).
N-[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetyl-L-phenylglycine (28), yield 78%, mp 276-277°C,
C H NO .
25 19
7
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 4.81 (2H, q, J = 8.8, OCH -7), 5.43 (1H, d, J = 7.2, H-2″), 6.44
6
2
(1H, d, J = 2.0, H-6), 6.79 (1H, d, J = 2.0, H-8), 7.06 (1H, s, H-3), 7.25-7.45 (5H, m, Ph-2″), 7.56-7.64 (3H, m, H-3′, H-4′, H-5′),
8.09 (2H, dd, J = 2.0, 8.0, H-2′, H-6′), 8.93 (1H, d, J = 7.6, CONH), 12.65 (1H, br.s, COOH), 12.81 (1H, s, OH-5).
N-[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetyl-β-alanine (29), yield 83%, mp 252-253°C, C H NO .
20 17
7
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.44 (2H, t, J = 6.8, CH -2″), 3.36 (2H, m, CH -3″), 4.64 (2H,
6
2
2
s, OCH -7), 6.44 (1H, d, J = 2.0, H-6), 6.82 (1H, d, J = 2.0, H-8), 7.06 (1H, s, H-3), 7.58-7.64 (3H, m, H-3′, H-4′, H-5′), 8.11
2
(2H, dd, J = 2.0, 8.0, H-2′, H-6′), 8.23 (1H, d, J = 5.2, CONH), 12.35 (1H, br.s, COOH), 12.82 (1H, s, OH-5).
N-[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetyl-4-aminobutanoic acid (30), yield 76%, mp 248-249°C,
C H NO .
21 19
7
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.69 (2H, m, CH -3″), 2.24 (2H, t, J = 6.8, CH -2″), 3.17 (2H,
6
2
2
m, CH -4″), 4.64 (2H, s, OCH -7), 6.45 (1H, d, J = 2.0, H-6), 6.82 (1H, d, J = 2.0, H-8), 7.05 (1H, s, H-3), 7.57-7.64 (3H, m,
2
2
H-3′, H-4′, H-5′), 8.09 (2H, dd, J = 2.0, 8.0, H-2′, H-6′), 8.22 (1H, d, J = 5.2, CONH), 12.10 (1H, br.s, COOH), 12.81 (1H, s,
OH-5).
N-[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetyl-6-aminohexanoic acid (31), yield 81%, mp 225-226°C,
C H NO .
23 23
7
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.22 (2H, m, CH -4″), 1.44 (4H, m, CH -3″, CH -5″), 2.16 (2H,
6
2
2
2
t, J = 7.2, CH -2″), 3.14 (2H, m, CH -6″), 4.63 (2H, s, OCH -7), 6.45 (1H, d, J = 2.0, H-6), 6.83 (1H, d, J = 2.0, H-8), 7.07 (1H,
2
2
2
s, H-3), 7.57-7.64 (3H, m, H-3′, H-4′, H-5′), 8.10 (2H, dd, J = 2.0, 8.0, H-2′, H-6′), 8.18 (1H, d, J = 5.2, CONH), 11.90 (1H,
br.s, COOH), 12.82 (1H, s, OH-5).
N-[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetyl-trans-4-aminomethylcyclohexane carboxylic acid (32),
yield 86%, mp 264-265°C, C H NO .
25 25
7
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 0.88 and 1.18 (4H, two m, CH -3″, CH -5″), 1.25 (1H, m, H-4″),
6
2
2
1.73 and 1.87 (4H, two m, CH -3″, CH -5″), 2.10 (1H, m, H-1″), 3.00 (2H, t, J = 7.2, CH -1″), 4.66 (2H, s, OCH -7), 6.45 (1H,
2
2
2
2
d, J = 2.0, H-6), 6.81 (1H, d, J = 2.0, H-8), 7.06 (1H, s, H-3), 7.57-7.64 (3H, m, H-3′, H-4′, H-5′), 8.10 (2H, dd, J = 2.0, 8.0,
H-2′, H-6′), 8.15 (1H, d, J = 5.6, CONH), 12.05 (1H, br.s, COOH), 12.81 (1H, s, OH-5).
N-[(5-Hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]acetylglycylglycine (33), yield69%, mp235-236°C, C H N O .
21 18
2 7
709

PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 3.80 and 3.85 (4H, two d, J = 6.0, CH -2″, CH -2′″), 4.72 (2H,
6
2
2
s, OCH -7), 6.48 (1H, d, J = 2.0, H-6), 6.89 (1H, d, J = 2.0, H-8), 7.07 (1H, s, H-3), 7.57-7.64 (3H, m, H-3′, H-4′, H-5′), 8.12
2
(2H, dd, J = 2.0, 8.0, H-2′, H-6′), 8.18, 8.20 (two t, J = 5.6, two CONH), 12.45 (1H, br.s, COOH), 12.82 (1H, s, OH-5).
ACKNOWLEDGMENT
We thank OAO Eksimed (Kiev, Ukraine) for help with performing the work.
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