Amino-acid derivatives of 3-phenoxychromones

Article abstract of DOI:10.1023/A:1017642208068

Peptide-chemistry methods have produced various amino-acid conjugates of 3-phenoxychromones in which 7-hydroxychromone is bound to the amino acid by the C- or N-terminus.

Full text of DOI:10.1023/A:1017642208068

Chemistry of Natural Compounds, Vol. 37, No. 1, 2001
AMINO-ACID DERIVATIVES OF 3-PHENOXYCHROMONES
M. M. Garazd,1 Ya. L. Garazd,2 and V. P. Khilya2
UDC 547.814.5
Peptide-chemistry methods have produced various amino-acid conjugates of 3-phenoxychromones in which
7-hydroxychromone is bound to the amino acid by the C- or N-terminus.
Key words:
flavonoids, 3-phenoxychromones, amino-acid derivatives.
Flavonoids are a large and structurally unique group of compounds that is widely distributed in nature. They occur
in varying quantities in almost all higher plants and are exceedingly rare in microorganisms and insects. In addition to natural
flavonoids, derivatives in which a phenyl substituent is bound to the chromone ring through an O atom are sometimes
encountered. Such compounds are called phenoxychromones. The commonest phenoxychromone in nature is capillarisin,
which was isolated from extracts of Artemisia capillaris Herba [1]. At present, about ten compounds based on the 2-
phenoxychromone moiety have been isolated from natural sources. The roots of Glycyrrhiza aspera, which are widely used in
Chinese folk medicine, yielded glyasperin E, the only 3-phenoxychromone isolated from a natural source [2].
Flavonoids undergo various biochemical transformations and participate in several physiological processes owing to
their high biological activity that is due to the presence of several pharmacophores. Therefore, our goal was to modify 3-
phenoxychromone derivatives by addition to them of amino acids.
The amino-acid derivatives of 3-phenoxychromones were synthesized by two methods. The first is based on formation
of an ester of the amino acids and phenolic compounds. In our opinion, a more suitable and convenient synthesis of 7-O-
aminoacylchromones is the reaction of 7-hydroxychromones and symmetric anhydrides of N-substituted amino acids because
the reaction occurs under mild conditions and has no side reactions [3, 4].
The symmetric anhydrides of N-substituted amino acids are prepared by reaction of dicyclohexylcarbodiimide (DCC)
with two equivalents of an N-substituted amino acid in absolute THF at 0 C. The amino group is blocked using a t-
butyloxycarbonyl (Boc) protecting group. 7-Hydroxy-3-phenoxychromones 1, 2, and 3 were acylated with symmetric anhydrides
(BocNHCHRCO) O in absolute THF in the presence of catalytic amounts of 4-dimethylaminopyridine (DMAP) at low
2
temperature (0oC). The products were N-substituted 7-O-aminoacyl-3-phenoxychromones 4-27, the molecules of which include
glycine (4-6), L-alanine (7-9), L-valine (10-12), L-leucine (13-15), L-isoleucine (16, 17), L-methionine (18-20), L-proline (21,
22), L-phenylalanine (23, 24), L-tyrosine (25, 26), and L-tryptophane (27).
Me
O
R
Me
Me
R
R
1
HO
O
1
O
O
O
O
N
H
HCl, AcOH
(BocNHCHRCO) O, DMAP
2
O
O
OPh
O
R
1: R = H; 2: R = Me; 3: R = CF
3
4 - 27
1
1
1
+
R
1
O
O
O
H N
3
−
O
Cl
OPh
28 - 51
1) Institute of Bioorganic Chemistry and Petroleum Chemistry, National Academy of Sciences of Ukraine, 02094,
Ukraine, Kiev, ul. Murmanskaya, 1; 2) Taras Shevchenko Kiev National University, 01033, Ukraine, Kiev, ul. Vladimirskaya,
64. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 29-34, January-February, 2001. Original article submitted
March 7, 2001.
0009-3130/01/3701-0032$25.00 ©2001 Plenum Publishing Corporation
32

TABLE 1. Physicochemical Constants of N-Substituted 7-O-aminoacyl-3-phenoxychromones 4-27
PMR spectrum, CDCl3, , ppm
Com- Empirical Yield, mp,
Chromone protons
2-R1, 5-H, 6-H,
Phenoxyl protons
pound
formula
%
C
7-O-Amino-acid protons
2-H, 3-H, 4-H, 5-H, 6-H,
8-H, d
s
d
dd
m
m
m
m
m
4
5
C22H21NO7
C23H23NO7
82
89
146 8.02 8.31 7.00 7.08 7.30 7.20 7.20 7.20 7.30
Boc NH CH2
1.48; 5.14; 4.19
Boc NH CH2
(H)
135 2.43 8.24 6.95 7.00 7.30 7.15 7.15 7.15 7.30
(Me)
1.48; 5.15; 4.19
6
C23H20F3NO7 74
121
8.22 6.95 7.00 7.30 7.20 7.20 7.20 7.30
Boc NH CH2
(CF3)
1.49; 5.08; 4.22
7
C23H23NO7
C24H25NO7
86
81
151 8.02 8.30 7.02 7.08 7.30 7.20 7.20 7.20 7.30
Boc NH CH CH3
1.49; 5.06; 4.55; 158
Boc NH CH CH3
1.48; 5.08; 4.55; 158
(H)
8
146 2.43 8.26 6.97 7.06 7.30 7.15 7.15 7.15 7.30
(Me)
9
C24H22F3NO7 79
132
8.21 6.98 7.08 7.30 7.20 7.20 7.20 7.30
Boc NH CH CH3
(CF3)
1.48; 5.04; 4.54; 157
10
11
C25H27NO7
C26H29NO7
81
79
132 8.02 8.28 7.02 7.08 7.35 7.20 7.20 7.20 7.35
Boc NH CH CH (CH3)2
1.48; 5.05; 4.47; 2.32; 1.11; 1.05
Boc NH CH CH (CH3)2
1.48; 5.08; 4.47; 2.32; 1.13; 1.06
Boc NH CH CH (CH3)2
1.49; 5.07; 4.43; 2.31; 1.12; 1.07
Boc NH CH CH2 CH (CH3)2
1.47; 4.96; 4.54; 1.78; 1.78; 1.02
Boc NH CH CH2 CH (CH3)2
1.47; 4.96; 4.54; 1.78; 1.78; 1.02
Boc NH CH CH2 CH (CH3)2
1.48; 4.98; 4.54; 1.77; 1.77; 1.03
(H)
126 2.43 8.26 6.95 7.01 7.30 7.20 7.20 7.20 7.30
(Me)
12 C26H26F3NO7 72
118
8.23 6.98 7.01 7.30 7.20 7.20 7.20 7.30
(CF3)
13
14
C26H29NO7
C27H31NO7
85
78
136 8.02 8.29 7.02 7.08 7.35 7.20 7.20 7.20 7.35
(H)
122 2.43 8.26 6.95 7.01 7.30 7.20 7.20 7.20 7.30
(Me)
15 C27H28F3NO7 73
16 C26H29NO7 75
109
8.23 6.95 7.02 7.30 7.20 7.20 7.20 7.30
(CF3)
125 8.49 8.22 7.05 7.09 7.30 7.20 7.20 7.20 7.30 Boc NH CH CH (CH3) CH2 CH3*
(H)
1.36; 6.57; 4.36; 2.10; 1.10; 1.66; 0.99
8.22 6.95 7.02 7.30 7.20 7.20 7.20 7.30 Boc NH CH CH (CH3) CH2 CH3
1.47; 5.05; 4.48; 2.05; 1.05; 1.35; 1.05
17 C27H28F3NO7 71
18 C25H27NO7S 86
19 C26H29NO7S 81
20 C26H26F3NO7S 79
106
(CF3)
139 8.03 8.28 7.00 7.09 7.30 7.20 7.20 7.20 7.30
Boc NH CH CH2 CH2S CH3
1.48; 5.21; 4.66; 2.68; 2.27; 2.15
Boc NH CH CH2 CH2S CH3
1.48; 5.28; 4.66; 2.67; 2.26; 2.15
Boc NH CH CH2 CH2S CH3
1.48; 5.24; 4.68; 2.68; 2.28; 2.16
Boc N CH2 CH2 CH2 CH COO
1.48; 3.59; 1.6 2.3; 4.51
(H)
131 2.45 8.24 6.95 7.01 7.30 7.20 7.20 7.20 7.30
(Me)
123
8.22 6.95 7.02 7.30 7.20 7.20 7.20 7.30
(CF3)
21
22 C27H24F3NO7 75
23 C29H27NO7 88
C27H27NO7
72
85 2.43 8.23 6.90 7.00 7.30 7.20 7.20 7.20 7.30
(Me)
69
8.23 6.96 7.02 7.30 7.20 7.20 7.20 7.30
Boc N CH2 CH2 CH2 CH COO
1.48; 3.59; 1.6 2.3; 4.55
(CF3)
164 8.01 8.28 7.00 7.10 7.30 7.20 7.20 7.20 7.30
(H)
Boc NH CH CH2 Ph
1.46; 5.08; 4.80; 3.24; 7.35
24 C30H26F3NO7 86
25 C34H35NO10 74
26 C35H34F3NO10 71
153
8.19 7.01 7.11 7.30 7.20 7.20 7.20 7.30
Boc NH CH CH2 Ph
1.45; 5.07; 4.80; 3.23; 7.33
(CF3)
179 8.02 8.27 7.00 7.10 7.30 7.20 7.20 7.20 7.30
Boc NH CH CH2 (4-BocOC6H4)
1.46; 5.06; 4.79; 3.23; 1.57; 7.22
Boc NH CH CH2 (4-BocOC6H4)
1.47; 5.11; 4.75; 3.22; 1.57; 7.25
Boc NH CH CH2 Indol NH
1.46; 5.15; 4.82; 3.44; 7.1 7.6; 8.29
160
8.18 7.00 7.10 7.30 7.20 7.20 7.20 7.30
(CF3)
27 C31H28N2O7
72
172 8.00 8.21 6.90 6.99 7.30 7.20 7.20 7.20 7.30
(H)
33

TABLE 2. Physicochemical Properties of 7-O-Aminoacyl-3-phenoxychromone Hydrochlorides 28-51
PMR spectrum, , ppm, DMSO-d6
Com-
pound
Empirical
formula
Yield, mp,
Chromone protons
Phenoxyl protons
%
C
7-O-Amino-acid protons
2-R1, 5-H, 6-H, 8-H, 2-H, 3-H, 4-H, 5-H, 6-H,
s
d
dd
d
m
m
m
m
m
28
C17H14ClNO5
85 229 8.77 8.19 7.41 7.68 7.30 7.00 7.00 7.00 7.30
Cl H3N CH2
8.90; 4.14
(H)
29 C18H16ClNO5
91 216 2.39 8.10 7.25 7.45 7.20 7.00 7.00 7.00 7.20
(Me)
Cl H3N CH2
8.95; 4.12
30 C19H13F3ClNO5 79 195
8.15 7.45 7.82 7.30 7.15 7.15 7.15 7.30
Cl H3N CH2
(CF3)
8.85; 4.16
31
C18H16ClNO5
88 212 8.78 8.20 7.44 7.76 7.30 7.00 7.00 7.00 7.30
Cl H3N CH CH3
(H)
8.91; 4.43; 1.62
32 C19H18ClNO5
87 205 2.39 8.10 7.25 7.45 7.20 7.00 7.00 7.00 7.20
(Me)
Cl H3N CH CH3
8.99; 4.43; 1.61
33 C19H15F3ClNO5 83 192
8.18 7.49 7.88 7.30 7.15 7.15 7.15 7.30
Cl H3N CH CH3
(CF3)
8.91; 4.42; 1.63
34
C20H20ClNO5
86 209 8.79 8.18 7.44 7.78 7.30 7.10 7.10 7.10 7.30
Cl H3N CH CH (CH3)2
9.00; 4.18; 2.39; 1.14
Cl H3N CH CH (CH3)2
8.98; 4.17; 2.41; 1.14
Cl H3N CH CH (CH3)2
9.04; 4.15; 2.37; 1.14
Cl H3N CH CH2 CH (CH3)2
8.96; 4.25; 2.13; 1.51; 1.09
Cl H3N CH CH2 CH (CH3)2
8.98; 4.24; 2.00; 1.59; 1.05
Cl H3N CH CH2 CH (CH3)2
9.04; 4.26; 1.90; 1.90; 1.00
(H)
35 C21H22ClNO5
88 201 2.40 8.10 7.25 7.45 7.20 7.00 7.00 7.00 7.20
(Me)
36 C21H19F3ClNO5 76 196
8.18 7.50 7.93 7.30 7.15 7.15 7.15 7.30
(CF3)
37 C21H22ClNO5
38 C22H24ClNO5
85 198 8.77 8.18 7.43 7.75 7.30 7.05 7.05 7.05 7.30
(H)
79 189 2.39 8.08 7.25 7.46 7.20 7.00 7.00 7.00 7.20
(Me)
39 C22H21F3ClNO5 83 192
8.19 7.50 7.93 7.30 7.15 7.15 7.15 7.30
(CF3)
40 C21H22ClNO5
82 196 8.78 8.18 7.47 7.79 7.30 7.05 7.05 7.05 7.30 Cl H3N CH CH (CH3) CH2 CH3
(H)
8.98; 4.22; 2.08; 1.03; 1.35; 1.03
8.16 7.48 7.89 7.30 7.15 7.15 7.15 7.30 Cl H3N CH CH (CH3) CH2 CH3
8.92; 4.24; 2.05; 1.05; 1.35; 1.05
41 C22H21F3ClNO5 86 189
(CF3)
42 C20H20ClNO5S 76 218 8.78 8.20 7.46 7.79 7.30 7.05 7.05 7.05 7.30
Cl H3N CH CH2 CH2 S CH3
9.00; 4.46; 2.76; 2.34; 2.11
Cl H3N CH CH2 CH2 S CH3
9.05; 4.47; 2.76; 2.32; 2.12
Cl H3N CH CH2 CH2 S CH3
8.90; 4.46; 2.74; 2.34; 2.12
(H)
43 C21H22ClNO5S 70 209 2.38 8.09 7.25 7.45 7.20 7.00 7.00 7.00 7.20
(Me)
44 C21H19F3ClNO5 78 206
8.10 7.45 7.65 7.30 7.10 7.10 7.10 7.30
S
(CF3)
45
46
47
48
49
50
51
79 215 2.33 7.84 6.95 7.02 7.30 7.05 7.05 7.05 7.30 Cl H3N CH2 CH2 CH2 CH COO
C21H20ClNO5
C21H17F3ClNO5
C24H20ClNO5
C25H19F3ClNO5
C24H20ClNO6
C25H19F3ClNO6
C27H23ClNO5
(Me)
9.10; 3.18; 1.91; 1.91; 4.22
8.10 7.45 7.68 7.30 7.10 7.10 7.10 7.30 Cl H3N CH2 CH2 CH2 CH COO
9.00; 3.19; 1.95; 1.95; 4.28
81 206
(CF3)
90 226 2.39 8.08 7.25 7.46 7.20 7.00 7.00 7.00 7.20
(Me)
Cl H3N CH CH2 Ph
9.11; 4.55; 3.35; 7.39
86 208
8.19 7.42 7.62 7.30 7.10 7.10 7.10 7.30
Cl H3N CH CH2 Ph
(CF3)
9.14; 4.60; 3.35; 7.42
88 206 8.76 8.15 7.32 7.45 7.30 7.10 7.10 7.10 7.30
(H)
Cl H3N CH CH2 (4-HOC6H4)
9.00; 4.46; 3.25; 9.55; 7.20; 6.79
Cl H3N CH CH2 (4-HOC6H4)
8.98; 4.49; 3.35; 9.49; 7.20; 6.76
Cl H3N CH CH2 Indol NH
9.06; 4.50; 3.37; 7.0-7.4; 11.19
79 200
8.13 7.38 7.64 7.30 7.10 7.10 7.10 7.30
(CF3)
62 229 8.76 8.08 7.32 7.64 7.30 7.10 7.10 7.10 7.30
(H)
34

TABLE 3. Physicochemical Properties of N-(3-Phenoxychromonyl-7-hydroxyacetyl)amino Acid Derivatives 58-70
PMR spectrum, , ppm
Com- Empirical Yield mp,
pound formula
Chromone protons
Phenoxyl protons
%
C
Amino-acid protons
CH2 COO CH2 CH3
2-R1, 5-H, 6-H, 7-OCH2CO, 8-H, 2-H, 3-H, 4-H, 5-H, 6-H,
CONH
s
d
dd
s
d
m
m
m
m
m
58 C22H21NO7 73 118 2.37 7.98 7.12
4.76
7.29 7.18 6.98 6.98 6.98 7.18 8.63
7.00 7.30 7.06 7.06 7.06 7.30 7.32
7.00 7.30 7.06 7.06 7.06 7.30 7.32
7.02 7.30 7.05 7.05 7.05 7.30 7.34
6.95 7.30 7.00 7.00 7.00 7.30 7.32
(Me)
3.91;
CH (COOCH3) CH3
4.70; 3.79; 1.49
CH (COOCH3) CH (CH3)2
4.68; 3.77; 2.23; 0.95
CH (COOCH3)CH2 CH (CH3)2
4.68; 3.75; 1.64; 1.64; 0.95
CH (COOCH3)CH2 CH (CH3)2
4.69; 3.75; 1.65; 1.65; 0.93
7.00 7.30 7.05 7.05 7.05 7.30 7.36 CH (COOCH3) CH (CH3) CH2 CH3
4.68; 3.76; 1.98; 0.96; 1.35; 0.93
CH (COOCH3)CH2 CH2 S CH3
4.86; 3.78; 2.52; 2.18; 2.08
CH (COOCH3)CH2 CH2 S CH3
4.82; 3.78; 2.52; 2.18; 2.08
CH (COOCH3) CH2 Ph
5.07; 3.76; 3.16; 7.28
7.05 7.30 7.00 7.00 7.00 7.30 8.56 CH (COOCH3) CH2 (4-HOC6H4)
4.13; 1.19
59 C21H19NO7 69 106 7.99 8.23 6.95
4.62
4.64
4.62
4.61
4.63
4.64
4.63
4.58
4.71
4.88
4.67
4.66
(H)
60 C23H23NO7 66 95 7.99 8.23 6.95
(H)
61 C24H25NO7 64 89 7.98 8.20 6.95
(H)
62 C25H27NO7 61 81 2.41 8.16 6.90
(Me)
63 C24H25NO7 59 86 7.98 8.23 6.95
(H)
64 C23H23NO7S 62 123 7.99 8.23 6.95
7.00 7.30 7.05 7.05 7.05 7.30 7.36
6.97 7.30 7.00 7.00 7.00 7.30 7.32
7.00 7.30 7.00 7.00 7.00 7.30 7.35
(H)
65 C24H25NO7S 68 113 2.41 8.17 6.92
(Me)
66 C27H23NO7 69 126 7.98 8.20 6.90
(H)
67 C27H28NO8 75 132 8.65 7.98 7.00
(H)
4.94;
3.63; 2.93; 9.24; 7.00; 6.66
CH (COOH) CH (CH3)2
68 C23H23NO7 61 145 2.36 7.96 6.95
7.00 7.30 7.00 7.00 7.00 7.30 8.35
7.00 7.30 7.00 7.00 7.00 7.30 8.22
7.00 7.30 7.00 7.00 7.00 7.30 8.20
(Me)
4.78;
12.5; 1.85; 0.97
69 C24H25NO7 66 131 2.35 7.96 6.95
CH2 CH2 CH2 COOH
3.18; 1.68; 2.17; 12.10
CH2 CH2 CH2 CH2 CH2 COOH
3.13; 1.2-1.8; 2.18; 12.00
(Me)
70 C26H29NO7 62 136 2.35 7.98 6.95
(Me)
_______
Solvent: DMSO-d6 58, 67 70; CDCl3 59 66.
The PMR spectra of the synthesized compounds 4-27 contain signals for the chromone ring, the amino acid moiety,
and the protecting group. A strong 9H singlet for the protons of the Boc group appears at 1.4-1.5 ppm. The signal of the amide
appears at 5.0-5.2 ppm (using CDCl solvent) or 6.5-6.7 ppm (acetone-d ). The physicochemical properties and PMR data for
3
6
the N-substituted 7-O-aminoacyl-3-phenoxychromones 4-27 are given in Table 1.
Hydrochlorides of 7-O-aminoacyl-3-phenoxychromones 28-51 were prepared via acidolysis of the corresponding Boc-
derivatives by 3 M dry HCl in glacial acetic acid. The PMR spectra of 28-51 contain signals of the chromone and the amino-
acid moieties. However, in contrast with the spectra of the starting Boc-derivatives, signals of the protecting group are absent.
A signal for the protonated amino group near 9 ppm is observed instead of the amide signals. The physicochemical constants
and PMR data of the hydrochlorides of 7-O-aminoacyl-3-phenoxychromones 28-51 are given in Table 2.
The second method for amino-acid modification of 3-phenoxychromones is based on activated esters. This method
is widely used in peptide synthesis [5]. Alkylation of 7-hydroxy-3-phenoxychromones 1 and 2 by ethylchloroacetate in acetone
in the presence of potash produces 7-ethoxycarbonylmethoxy-3-phenoxychromones 52 and 53. Acidolysis of the ester group
in these compounds by a mixture of glacial acetic and conc. H SO gives the corresponding acids 54 and 55. The carboxyl
2
4
group is activated using N-hydroxysuccinimide esters, which are highly reactive and do not give racemized products [6]. The
N-hydroxysuccinimide esters of 7-carboxymethoxy-3-phenoxychromones 56 and 57 were prepared in high yields by the reaction
of the corresponding acids 54 and 55 with N-hydroxysuccinimide (SuOH) in absolute dioxane using DCC as the condensing
agent [7, 8]. The PMR spectra of the activated esters 56 and 57 contain a 4H singlet at 2.9 ppm that is characteristic of the
35

succinimide.
Condensation of activated esters
56
57
with alkyl esters of the corresponding amino acids (H NCHRCOOAlk) in
and
absolute THF at 0 C forms the amino-acid derivatives
59 60 61 62
2
o
58 67
58
-
. The ethyl esters of glycine (to give ) and methyl esters of L-
63 64 65 66
alanine ( ), L-valine ( ), L-leucine (
67 58 67
contain signals of the amino acid, chromone ring, and amide bond in the range 7.3-
,
), L-isoleucine ( ), L-methionine ( ), L-phenylalanine ( ), and L-tyrosine
,
(
) were used. The PMR spectra of
-
7.4 ppm (in CDCl ) or 8.5-8.6 ppm (DMSO-d ).
3
6
O
R
1
R
1
HO
O
O
O
EtO
ClCH COOEt, K CO
3
2
2
O
OPh
O
O
1: R = H; 2: R = Me
52: R = H; 53: R = Me
1
1
1
1
AcOH, H SO
2
O
4
O
O
R
1
R
O
O
O
1
O
O
N
HO
DCC, SuOH
O
O
OPh
OPh
O
56: R = H; 57: R = Me
54: R = H; 55: R = Me
1 1
1
1
1. H NCHRCOONa
2
H NCHRCOOAlk
2
+
2. H
R
O
R
O
O
R
HO
O
R
1
1
O
O
O
O
O
O
N
N
H
Alk
O
OPh
OPh
58 - 67
68 - 70
57
Reaction of activated ester with sodium salts of amino acids (H NCHRCOONa) in THF—H O at room temperature
2
2
68 70
with a free
followed by acidolysis gives amino-acid derivatives of 7-carboxymethoxy-2-methyl-3-phenoxychromone
-
68
69
carboxyl group. Derivatives of L-valine ( ), L-phenylalanine ( ), and -aminobutyric acids (70) were obtained. The PMR
spectra of 68-70 in DMSO-d contain signals of the chromone, amino acid, and amide bond at 8.2-8.4 ppm and the carboxyl
6
group at 12-13 ppm. The physicochemical constants and PMR data of the amino-acid derivatives of 7-carboxymethoxy-3-
phenoxychromones 58-70 are given in Table 3.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Silufol UV-254 plates using CHCl —CH OH
3
3
mixtures (9:1 and 95:5) as eluent. PMR spectra were measured on a Varian VXR-300 in DMSO-d , acetone-d , and CDCl
6
6
3
(TMS internal standard). Elemental analyses of all compounds corresponded to those calculated.
Starting 7-hydroxy-3-phenoxychromones 1-3 were prepared according to the literature methods [9, 10].
N-Substituted 7-O-Aminoacyl-3-phenoxychromones 4-27. A solution of the appropriate N-Boc-amino acid (9 mmol)
in absolute THF (50 mL) was cooled to 0oC, stirred vigorously, and treated with DCC (0.92 g, 4.5 mmol). The reaction mixture
was cooled for 1 h, treated with the corresponding 7-hydroxychromone (1, 2, or 3, 4 mmol) and DMAP (20 mg), and stirred
and cooled (0oC) for 0.5-1 h (completion of the reaction was determined by TLC). The precipitated dicyclohexylurea was filtered
off. The solvent was removed under vacuum. The oil was dissolved in ethylacetate (50 mL) and treated successively in a
separatory funnel with NaHCO solution (5%, 2×50 mL), water (50 mL), and saturated NaCl solution (50 mL). The organic
3
layer was dried over anhydrous MgSO . The solvent was removed under vacuum. The solid was crystallized from propan-2-ol.
4
Yields and constants of 4-27 appear in Table 1.
36

Hydrochlorides of 7-O-Aminoacyl-3-phenoxychromones 28-51.
A cooled solution of 7-O-(N-Boc-
aminoacyl)chromone (4-27, 2 mmol) in absolute THF (5 mL) was treated with a cooled (0oC) solution (3 M, 10 mL) of dry HCl
in glacial acetic acid. The reaction mixture was stirred for 0.5-1 h (completion of the reaction was determined by TLC), treated
with absolute ether (100 mL), and held at 0oC for 1 h. The precipitate was filtered off and dried under vacuum over NaOH.
Yields and constants of obtained hydrochlorides 28-51 appear in Table 2.
7-Ethoxycarbonylmethoxy-3-phenoxychromones 52 and 53. A hot solution of 7-hydroxychromone (1 or 2, 50 mmol)
in absolute acetone (100 mL) was stirred vigorously, treated with freshly calcined potash (20.7 g, 150 mmol) and
ethylchloroacetate (5.9 mL, 55 mmol), held at 50-60oC with vigorous stirring for 3-4 h (completion of the reaction was
determined by TLC), cooled, transferred into ice water (500 mL), and acidified until the pH was 5-6. The precipitate was
filtered off and crystallized from propan-2-ol (75%).
7-Ethoxycarbonylmethoxy-3-phenoxychromone 52: C19H16O6, yield 88%, mp 175oC. PMR spectrum (300 MHz,
CDCl , , ppm, J/Hz): 1.32 (3H, t, CH ), 4.30 (2H, q, CH ), 4.73 (2H, s, OOCCH O-7), 6.87 (1H, dd, J = 2.0, 8.0, H-6), 7.00
3
3
2
2
(1H, d, J = 2.0, H-8), 7.05 (2H, m, H-2 and H-6 of phenoxyl), 7.27 (3H, m, H-3, H-4, and H-5 of phenoxyl), 7.96 (1H, s, H-2),
8.18 (1H, d, J = 8.0, H-5).
7-Ethoxycarbonylmethoxy-2-methyl-3-phenoxychromone 53: C20H18O6, yield 87%, mp 164oC. PMR spectrum [300
MHz, (CD ) CO, , ppm, J/Hz]: 1.28 (3H, t, CH of ethoxycarbonyl), 2.38 (3H, s, CH -2), 4.25 (2H, q, CH ), 4.93 (2H, s,
3 2
3
3
2
OOCCH O-7), 6.95 (1H, dd, J = 2.0, 8.0, H-6), 7.05 (1H, d, J = 2.0, H-8), 7.15 (2H, m, H-2 and H-6 of phenoxyl), 7.30 (3H,
2
m, H-3, H-4, and H-5 of phenoxyl), 8.01 (1H, d, J = 8.0, H-5).
7-Carboxymethoxy-3-phenoxychromones 54 and 55. A mixture of ester 52 or 53 (40 mmol), glacial acetic acid
(30 mL), and conc. H SO (10 mL) was held at 60-80oC for 2-3 h (completion of the reaction was determined by TLC), cooled,
2
4
and transferred into ice water (300 mL). The precipitate was filtered off and crystallized from aqueous propan-2-ol.
7-Carboxymethoxy-3-phenoxychromone 54: C17H12O6, yield 85%, mp 218oC. PMR spectrum (300 MHz, DMSO-d ,
6
, ppm, J/Hz): 4.90 (2H, s, OOCCH O-7), 6.95 (1H, dd, J = 2.0, 8.0, H-6), 7.00 (2H, m, H-2 and H-6 of phenoxyl), 7.05 (1H,
2
d, J = 2.0, H-8), 7.40 (3H, m, H-3, H-4, and H-5 of phenoxyl), 8.01 (1H, d, J = 8.0, H-5), 8.64 (1H, s, H-2), 13.0 (1H, s, COOH).
7-Carboxymethoxy-2-methyl-3-phenoxychromone 55: C18H14O6, yield 92%, mp 204oC. PMR spectrum (300 MHz,
DMSO-d , , ppm, J/Hz): 2.36 (3H, s, CH -2), 4.88 (2H, s, OOCCH O-7), 6.95 (1H, dd, J = 2.0, 8.0, H-6), 7.05 (1H, d, J = 2.0,
6
3
2
H-8), 7.10 (2H, m, H-2 and H-6 of phenoxyl), 7.30 (3H, m, H-3, H-4, and H-5 of phenoxyl), 7.95 (1H, d, J = 8.0, H-5), 13.0 (1H,
s, COOH).
N-Hydroxysuccinimide Esters of 7-Carboxymethoxy-3-phenoxychromones 56 and 57. A cooled solution of 54 or
55 (20 mmol) and N-hydroxysuccinimide (2.54 g, 22 mmol) in absolute dioxane (50 mL) was treated with DCC (4.12 g,
20 mmol) and held for 1-2 h with vigorous stirring at 0oC (completion of the reaction was determined by TLC). The precipitate
of dicyclohexylurea was filtered off. The solvent was removed under vacuum. The oil was crystallized from propan-2-ol.
N-Hydroxysuccinimide ester of 7-carboxymethoxy-3-phenoxychromone 56: C21H10NO8, yield 79%, mp 159oC.
PMR spectrum (300 MHz, CDCl , , ppm, J/Hz): 2.88 (4H, s, CH CH of N-hydroxysuccinimide), 5.09 (2H, s, OOCCH O-7),
3
2
2
2
6.87 (1H, dd, J = 2.0, 8.0, H-6), 7.00 (1H, d, J = 2.0, H-8), 7.05 (2H, m, H-2 and H-6 of phenoxyl), 7.26 (3H, m, H-3, H-4, and
H-5 of phenoxyl), 7.98 (1H, s, H-2), 8.22 (1H, d, J = 8.0, H-5).
N-Hydroxysuccinimide ester of 7-carboxymethoxy-2-methyl-3-phenoxychromone 57: C22H12NO8, yield 74%, mp
148oC. PMR spectrum (300 MHz, CDCl , , ppm, J/Hz): 2.36 (3H, s, CH -2), 2.85 (4H, s, CH CH of N-hydroxysuccinimide),
3
3
2
2
5.04 (2H, s, OOCCH O-7), 6.95 (1H, dd, J = 2.0, 8.0, H-6), 7.03 (1H, d, J = 2.0, H-8), 7.10 (2H, m, H-2 and H-6 of phenoxyl),
2
7.30 (3H, m, H-3, H-4, and H-5 of phenoxyl), 8.01 (1H, d, J = 8.0, H-5).
Esters of N-(7-Carbonylmethoxy-3-phenoxychromone)-amino Acids 58-67. A suspension of the corresponding
alkylamino-acid hydrochloride (3.5 mmol) in absolute THF (20 mL) was vigorously stirred and cooled to 0oC, treated dropwise
with triethylamine (0.42 mL, 3.5 mmol), and vigorously stirred for 30 min. The precipitate of triethylamine hydrochloride was
filtered off. The filtrate was treated with activated ester 56 or 57 (3 mmol) in absolute THF (10 mL), vigorously stirred for 2
h at 0oC, and held at room temperature for 10-12 h. The solvent was removed under vacuum. The solid was dissolved in
ethylacetate (50 mL) and treated in a separatory funnel successively with H SO (1 N, 50 mL), water (50 mL), NaHCO solution
2
4
3
(5%, 50 mL), water (30 mL), and saturated NaCl solution (50 mL). The organic layer was dried over anhydrous MgSO . The
4
solvent was removed under vacuum. The oil was crystallized by treatment with diethylether. Yields and physicochemical
constants of prepared compounds 58-67 appear in Table 3.
N-(7-Carbonylmethoxy-2-methyl-3-phenoxychromone)amino Acids 68-70. A solution of the appropriate amino
37

acid (3.5 mmol) in NaOH solution (7 mL, 0.5 M, 3.5 mmol) was treated with activated aster 57 (1.27 g, 3 mmol) in THF
(10 mL), vigorously stirred for 1 h at room temperature (completion of the reaction was determined by TLC), treated with
distilled water (100 mL), and acidified until the pH was 5-6. The precipitate was filtered off and crystallized from aqueous
propan-2-ol. Yields and physicochemical constants of compounds 68-70 appear in Table 3.
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