Modified coumarins. 5. Amino-acid derivatives of 3-hydroxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one

Article abstract of DOI:10.1023/A:1022151407961

Peptide-chemistry methods (symmetric anhydrides and activated esters) and the Mannich reaction were used to prepare various conjugates of amino acids with 7,8,9,10-tetrahydrobenzo[c]chromen-6-one in which the amino acids are bound to the coumarin by the C- or N-terminus.

Full text of DOI:10.1023/A:1022151407961

Chemistry of Natural Compounds, Vol. 38, No. 5, 2002
MODIFIED COUMARINS. 5. AMINO-ACID DERIVATIVES OF
3-HYDROXY-7,8,9,10-TETRAHYDROBENZO[c]CHROMEN-6-ONE
M. M. Garazd,1 Ya. L. Garazd,2 S. V. Shilin,2 and V. P. Khilya2
UDC 547.814.5
Peptide-chemistry methods (symmetric anhydrides and activated esters)and the Mannich reaction were used
to prepare various conjugates of amino acids with 7,8,9,10-tetrahydrobenzo[c]chromen-6-one in which the
amino acids are bound to the coumarin by the C- or N-terminus.
Key words: coumarins, 7,8,9,10-tetrahydrobenzo[c]chromen-6-one, amino-acid derivatives, Mannich reaction,
synthesis.
One alternative for constructing new biologically active compounds is to synthesize analogs of natural bioregulators
in order to increase the pharmacological activity, in particular, byforming several active centers in the molecule. An advantage
of such compounds is that their structures are similar to the biochemical structures of a living organism and cause significantly
less side effects. Coumarins are commonlyused as a basis for constructing pharmacologicallyactive compounds because of the
high biological activity of natural coumarins. On the other hand, one can suppose that the combination in one molecule of
coumarin and amino-acid fragments might lead to compounds with new physiological properties in view of the importance of
the latter to the life processes of living organisms.
It is known that more than 30 types ofpharmacological activityhavebeen foundfor compounds with the coumarin core.
In particular, 7,8,9,10-tetrahydrobenzo[ ]chromen-6-one derivatives include compounds that have antiallergic [1] and anti-
c
inflammatory [2] activity; that act as CNS stimulants [3], neuroprotectors and anticonvulsive agent [4],antidepressants and
antiallergens [5], insecticides [6], depressants, anticonvulsants, analgetics, antipyretics, and anti-inflammatoryagents [7]; and
that cure hypoxia [8].
Therefore, our goalwastomodifyderivativesof7,8,9,10-tetrahydrobenzo[ ]chromen-6-one byjudiciouslyintroducing
c
into them amino-acid units. The starting hydroxycoumarin 1 was prepared in high yield by Pechmann condensation of
resorcinol and ethyl-2-hydroxycyclohexanecarboxylate in the presence of H SO (72%) [9].
2
4
The amino-acid unit was introduced into the coumarin by three methods. The first method was based on Mannich
aminomethylation. C-aminomethylation was effected by heating a mixture of 1, the corresponding amino acid, and an
equivalent amount of formalin in aqueous alcohol [10]. The aminomethyl group added to the 4-position of the 7,8,9,10-
tetrahydrobenzo[ ]chromen-6-one. Derivatives of alanine (2), 2-aminobutanoic acid (3), valine (4), norvaline (5), leucine (6),
c
isoleucine (7), norleucine (8), and phenylalanine (9) were prepared this way. The structures of these Mannich bases were
confirmed byquantitative elemental analysis and PMR spectroscopy. The PMR spectra of 2-9 were recorded in CF3CO2H. The
region of coumarin aromatic protons was simplified owing to a lack of coupling by H-4. Aromatic protons in the 1- and 2-
positions resonated as doublets with spin—spin coupling constants (SSCC) 8.8 Hz at 7.8 and 7.2 ppm, respectively. The PMR
spectra also contained signals for the amino-acid protons and 2H signals at 4.9-5.0 ppm for the methylene group.
The second method was based on formation of an ester of the amino acid and phenolic compounds. The most suitable
and convenient method for synthesizing 7-O-aminoacylcoumarins is the reaction of 7-hydroxycoumarins and symmetric
anhydrides of N-substituted amino acids because the reaction proceeds under mild conditions and yields no side products
[11, 12].
1) Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences, the Ukraine, 02094, the Ukraine,
Kiev, ul. Murmanskaya, 1, e-mail: gmm@i.com.ua; 2) Taras Shevchenko Kiev National University, 01033, the Ukraine, Kiev,
ul. Vladimirskaya, 64. Translated from Khimiya Prirodnykh Soedinenii, No. 5, pp. 338-344, September-October, 2002.
Original article submitted July 16, 2002.
0009-3130/02/3805-0416$27.00 ©2002 Plenum Publishing Corporation
416

O
R
HO
NH
HO
O
O
HO
O
O
H N(R)CHCOOH, CH O
2
2
1
2 - 9
(BocNHCHRCO) O, DMAP
2
R
R
_
O
O
O
+
O
O
O
Boc HN
ClH N
3
HCl, AcOH
O
O
10 - 17
18 - 25
2, 11, 19:R = CH ; 3: R = CH CH ; 4, 12, 20:R = CH(CH ) ; 5: R = CH CH CH ;
3 2
3
2
3
2
2
3
6, 13, 21:R = CH CH(CH ) ; 7, 14, 22: R = CH(CH )CH CH ; 8: R = CH CH CH CH ;
3 2
2
3
2
3
2
2
2
3
9, 16, 24:R = CH Ph; 10, 18: R = H; 15, 23: R = CH CH SCH ; 17, 25: R = Ph
2
2
2
3
Symmetric anhydrides of N-substituted amino acids were prepared by reacting dicyclohexylcarbodiimide (DCC) with
twoequivalents ofN-substituted aminoacid in absolute THF at 0°C. The aminogroup was blocked using thet-butyloxycarbonyl
(Boc) protecting group. Acylation of 1 by symmetric anhydrides (BocNHCHRCO) O was carried out in absolute THF in the
2
presence of a catalytic amount of 4-dimethylaminopyridine (DMAP) at 0°C. The reaction yielded N-substituted 7-O-
aminoacylcoumarins 10-17. These molecules included glycine (10), alanine (11), valine (12), leucine (13), isoleucine (14),
methionine (15), phenylalanine (16), and -phenylglycine (17). The PMR spectra of 10-16 contained signals for the coumarin
ring, amino-acid unit, and protecting group. A strong 9H singlet of the Boc group was observed at 1.4-1.5 ppm. The signal
of the amide appeared at 5.0-5.2 ppm.
The protecting group was removed from 10-17 using acidolysis by dry HCl in glacial acetic acid (3 M) at 0°C. The
structures of 18-25 were proved by quantitative elemental analysis and PMR spectroscopy. The PMR spectra of 18-25 in
DMSO-d lacked signals for the protecting group. Signals of the amine hydrochloride appeared at 8.9-9.1 ppm.
6
The third method was based on activated esters. Alkylation of 1 in acetone in the presence of potash by
ethylbromoacetate yielded the ethyl ester 26, saponification of which by NaOH in aqueous propan-2-ol with subsequent
acidolysis gave the corresponding acid 27. N-Hydroxysuccinimide esters were used as the activated esters. These are typically
highly reactive and do not racemize the products [13]. The N-hydroxysuccinimide ester was prepared by reacting 27 and N-
hydroxysuccinimide using DCC as the condensing agent [11, 14].
N-[2-(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yloxy)acetyl]amino acids (28-44) were prepared by
condensation of the activated ester and sodium salts of the amino acids in water:dioxane (1:1) at room temperature with
subsequent acidolysis ofthe resulting salts. These syntheses introduced intothe coumarin glycine (28), alanine(29), valine(30),
norvaline (31), leucine (32), isoleucine (33), norleucine (34), methionine (35), phenylalanine (36), α-phenylglycine (37),
citrulline(39), proline(42), asparagine(38), 3-aminopropanoic(40), 4-aminobutanoic (41), 6-aminohexanoic(43), andtrans-4-
aminomethylcyclohexanecarboxylic (44) acids.
The structures of the amino-acid derivatives 26-37 were proved by quantitative analysis and PMR spectroscopy. The
PMR spectra of 26-37 contained signals for the amide proton at 8.20-8.50 ppm, coumarin protons, and the amino-acid unit.
417

O
HO
O
O
O
O
O
N
H
HO
O
44
1
BrCH COOEt, K CO
3
2
2
O
O
HO
O
O
O
N
H
O
O
O
EtO
O
26
43
1. NaOH
2. HCl
O
O
O
O
N
O
O
O
O
O
O
O
O
O
O
SuOH, DCC
O
HO
N
O
HO
27
42
O
O
R
O
O
HO
O
O
O
HO
O
O
O
O
O
O
HO
N
H
N
H
N
H
O
O
40
41
28 - 39
28: R = H; 29: R = CH ; 30: R = CH(CH ) ; 31: R = CH CH CH ; 32: R = CH CH(CH ) ;
3 2 3 2
3
2
2
3
2
33: R = CH(CH )CH CH ; 34: R = CH CH CH CH ; 35: R = CH CH SCH ; 36: R = CH Ph;
3
2
3
2
2
2
3
2
2
3
2
37: R = Ph; 38: R = CH COOH; 39: R = CH CH CH NHCONH
2
2
2
2
2
EXPERIMENTAL
The course of the reactions and the purity of the products were monitored by TLC on Merck 60 F254 plates using
CHCl —CH OH (9:1 and 95:5). IR spectra were recorded on a Nicolet FTIR Nexus 475 spectrometer; PMR, on Varian VXR-
3
3
300 and Mercury-400 spectrometers at 300 and 400 MHz, respectively, with TMS internal standard. Elemental analyses of all
compounds agreed with those calculated.
1
Starting 7,8,9,10-tetrahydro-3-hydroxy-6H-dibenzo[b,d]pyran-6-one ( ) was prepared by the literature method [9].
Mannich Bases 2-9.
1
A warm solution of hydroxycoumarin ( , 1.08 g, 5 mmole) in EtOH (30 mL) was treated with
a solution of the appropriate amino acid (5 mmole) in water (20 mL) and formalin (5 mmole, 0.45 mL, 35%). The reaction
mixture was held at 80-90°C for 6-8 h. The resulting precipitate was filtered off and crystallized from EtOH (50%).
N-[(7,8,9,10-Tetrahydro-3-hydroxy-6-oxo-6H-dibenzo[ , ]-pyran-4-yl)methyl]-alanine (2).
b d
Yield 28%, mp 255-
256°C, C17H19NO5. IR spectrum (KBr, cm-1): 3150, 2937, 2610, 1704, 1603, 1572, 1473, 1396, 1384, 1363, 1296, 1185, 1090,
1045. PMR spectrum (400 MHz, TFA, δ, ppm, J/Hz): 1.96 (3H, d, J = 6.8, CH -3′), 1.99 (4H, m, CH -8, CH -9), 2.69 (2H,
3
2
2
m, CH -10), 2.97 (2H, m, CH -7), 4.51 (1H, q, H-2′), 4.91 (2H, br.s, CH -4), 7.20 (1H, d, J = 8.8, H-2), 7.87 (1H, d, J = 8.8,
2
2
2
H-1).
2-[[(7,8,9,10-Tetrahydro-3-hydroxy-6-oxo-6H-dibenzo[ , ]pyran-4-yl)methyl]amino]-butanoic Acid (3).
b d
Yield
49%, mp 265-266°C, C18H21NO5. IR spectrum (KBr, cm-1): 3159, 2938, 2535, 1704, 1602, 1581, 1473, 1386, 1342, 1332,
1316, 1293, 1267, 1184, 1091. PMR spectrum (300 MHz, TFA, δ, ppm, J/Hz): 1.25 (3H, t, J = 7.2, CH -4′), 2.02 (4H, m, CH -
3
2
418

8, CH -9), 2.37 (2H, m, CH -3′), 2.69 (2H, m, CH -10), 2.96 (2H, m, CH -7), 4.45 (1H, m, H-2′), 4.98 (2H, br.s, CH -4), 7.18
2
2
2
2
2
(1H, d, J = 9.0, H-2), 7.88 (1H, d, J = 9.0, H-1).
N-[(7,8,9,10-Tetrahydro-3-hydroxy-6-oxo-6H-dibenzo[b,d]pyran-4-yl)methyl]-valine (4). Yield 58%, mp 245-
246°C, C19H23NO5. IR spectrum (KBr, cm-1): 2937, 2541, 1703, 1603, 1562, 1382, 1332, 1323, 1295, 1090. PMR spectrum
(400 MHz, TFA, δ, ppm, J/Hz): 1.22 (3H, d, J = 6.8, CH -4′), 1.29 (3H, d, J = 6.8, CH -3′), 1.99 (4H, m, CH -8, CH -9), 2.65
3
3
2
2
(1H, m, H-3′), 2.69 (2H, m, CH -10), 2.99 (2H, m, CH -7), 4.26 (1H, d, J = 3.6, H-2′), 4.94 (2H, br.s, CH -4), 7.20 (1H, d,
2
2
2
J = 8.8, H-2), 7.87 (1H, d, J = 8.8, H-1).
N-[(7,8,9,10-Tetrahydro-3-hydroxy-6-oxo-6H-dibenzo[b,d]pyran-4-yl)methyl]-norvaline (5). Yield49%, mp260-
261°C, C19H23NO5. IR spectrum (KBr, cm-1): 2967, 2535, 1704, 1603, 1567, 1505, 1469, 1435, 1383, 1365, 1335, 1317, 1302,
1268, 1244, 1184, 1093. PMR spectrum (300 MHz, TFA, δ, ppm, J/Hz): 1.10 (3H, t, J = 7.2, CH -5′), 1.66 (2H, m, CH -4′),
3
2
2.01 (4H, m, CH -8, CH -9), 2.68 (2H, m, CH -10), 2.98 (2H, m, CH -7), 3.07 (2H, m, CH -3′), 4.55 (1H, m, H-2′), 4.97 (2H,
2
2
2
2
2
br.s, CH -4), 7.20 (1H, d, J = 9.0, H-2), 7.86 (1H, d, J = 9.0, H-1).
2
N-[(7,8,9,10-Tetrahydro-3-hydroxy-6-oxo-6H-dibenzo[b,d]pyran-4-yl)methyl]-leucine (6). Yield 43%, mp 246-
247°C, C20H25NO5. IR spectrum (KBr, cm-1): 2938, 2537, 1704, 1604, 1577, 1473, 1376, 1355, 1309, 1292, 1267, 1183, 1092.
PMR spectrum (400 MHz, TFA, δ, ppm, J/Hz): 1.07 (3H, d, J = 6.8, CH -5′), 1.11 (3H, d, J = 6.8, CH -4′), 1.96-2.05 (5H, m,
3
3
CH -8, CH -9, H-4′), 2.09 (2H, m, CH -3′), 2.69 (2H, m, CH -10), 2.99 (2H, m, CH -7), 4.26 (1H, t, J = 6.8, H-2′), 4.94 (2H,
2
2
2
2
2
d, J = 4.0, CH -4), 7.20 (1H, d, J = 8.8, H-2), 7.87 (1H, d, J = 8.8, H-1).
2
N-[(7,8,9,10-Tetrahydro-3-hydroxy-6-oxo-6H-dibenzo[b,d]pyran-4-yl)methyl]-isoleucine (7). Yield52%, mp256-
257°C, C20H25NO5. IR spectrum (KBr, cm-1): 2937, 2533, 1703, 1602, 1561, 1504, 1471, 1451, 1383, 1334, 1319, 1295, 1268,
1245, 1183, 1089. PMR spectrum (300 MHz, TFA, δ, ppm, J/Hz): 1.08 (3H, t, J = 7.2, CH -5′), 1.17 (3H, d, J = 6.9, CH -3′),
3
3
1.5-1.65 (3H, m, H-3′, CH -4′), 1.98 (4H, m, CH -8, CH -9), 2.67 (2H, m, CH -10), 2.99 (2H, m, CH -7), 4.36 (1H, m, H-2′),
3
2
2
2
2
4.95 (2H, br.s, CH -4), 7.20 (1H, d, J = 9.0, H-2), 7.88 (1H, d, J = 9.0, H-1).
2
N-[(7,8,9,10-Tetrahydro-3-hydroxy-6-oxo-6H-dibenzo[b,d]pyran-4-yl)methyl]-norleucine (8). Yield56%, mp247-
248°C, C20H25NO5. IR spectrum (KBr, cm-1): 2934, 2578, 1704, 1604, 1569, 1505, 1470, 1384, 1368, 1335, 1317, 1296, 1267,
1094. PMR spectrum (300 MHz, TFA, δ, ppm, J/Hz): 1.02 (3H, t, J = 7.2, CH -6′), 1.50-1.65 (4H, m, CH -4′, CH -5′), 2.00
3
2
2
(4H, m, CH -8, CH -9), 2.69 (2H, m, CH -10), 2.95 (2H, m, CH -7), 3.02 (2H, m, CH -3′), 4.42 (1H, m, H-2′), 4.95 (2H, br.s,
2
2
2
2
2
CH -4), 7.19 (1H, d, J = 9.0, H-2), 7.87 (1H, d, J = 9.0, H-1).
2
N-[(7,8,9,10-Tetrahydro-3-hydroxy-6-oxo-6H-dibenzo[b,d]pyran-4-yl)methyl]-phenylalanine (9). Yield64%, mp
243-244°C, C23H23NO5. IR spectrum (KBr, cm-1): 2937, 2537, 1705, 1607, 1577, 1474, 1451, 1417, 1390, 1375, 1308, 1291,
1267, 1095, 1082. PMR spectrum (400 MHz, TFA, δ, ppm, J/Hz): 2.01 (4H, m, CH -8, CH -9), 2.68 (2H, m, CH -10), 2.98
2
2
2
(2H, m, CH -7), 3.33 (1H, dd, J = 9.6, J = 10.4, CH -3′a), 3.68 (1H, dd, J = 9.6, J = 10.4, CH -3′b), 4.47 (1H, m, H-2′), 4.87
2
2
2
(2H, dd, J = 13.6, J = 14.0, CH -4), 7.18 (3H, m, H-2, H-2″, H-6″), 7.34 (3H, m, H-3″, H-4″, H-5″), 7.85 (1H, d, J = 8.8, H-1).
2
N-Protected 3-O-Aminoacyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-ones 10-16. A cooled solution (0°C) of
the appropriate N-Boc-amino acid (9 mmole) in absolute THF (20 mL) was treated with DCC (0.93 g, 4.5 mmole). The reaction
mixture was stirred vigorouslyfor 20-30 min at 0°C. The resulting precipitate of dicyclohexylurea was filtered off. The mother
liquor was treated with 7-hydroxycoumarin (1, 0.86 g, 4 mmole) in absolute THF (20 mL) and DMAP (20 mg). The reaction
mixture was held for 30-45 min at room temperature with vigorous stirring (completion ofthe reaction was determined byTLC).
Solvent was evaporated in vacuum. The solid was dissolved in ethylacetate (50 mL) and washed successively with NaHCO
3
(5%, 2×25 mL), water (25 mL), and saturated NaCl (25 mL). The organic layer was dried over anhydrous MgSO . Solvent
4
was removed in vacuum. The solid was crystallized from propan-2-ol.
3-O-(N-t-Butyloxycarbonylglycyl)-7,8,9,10-tetrahydro-6H-benzo[b,d]pyran-6-one (10). Yield73%, mp140-142°C,
C20H23NO6. PMRspectrum (300 MHz, DMSo-d , δ, ppm, J/Hz): 1.40 [9H, s, (CH ) C], 1.73 (4H, m, CH -8, CH -9), 2.42 (2H,
6
3 3
2
2
m, CH -10), 2.78 (2H, m, CH -7), 4.01 (2H, d, J = 5.7, CH -2′), 7.12 (1H, dd, J2,4 = 2.1, J2,1 = 8.4, H-2), 7.18 (1H, d, J = 2.1,
2
2
2
H-4), 7.45 (1H, t, J = 5.4, CONH), 7.75 (1H, d, J = 8.4, H-1).
3-O-(N-t-Butyloxycarbonylalanyl)-7,8,9,10-tetrahydro-6H-benzo[b,d]pyran-6-one (11). Yield82%, mp111-112°C,
C21H25NO6. PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.45 [9H, s, (CH ) C], 1.57 (3H, d, J = 7.5, CH -3′), 1.84 (4H,
3
3 3
3
m , CH -8, CH -9), 2.57 (2H, m, CH -10), 2.74 (2H, m, CH -7), 4.55 (1H, m, H-2′), 5.06 (1H, m, CONH), 7.05 (1H, dd,
2
2
2
2
J2,4 = 2.1, J2,1 = 8.7, H-2), 7.11 (1H, d, J = 2.1, H-4), 7.56 (1H, d, J = 8.4, H-1).
3-O-(N-t-Butyloxycarbonylvalyl)-7,8,9,10-tetrahydro-6H-benzo[b,d]pyran-6-one (12). Yield 71%, mp 88-89°C,
C23H29NO6. PMR spectrum (300 MHz, (CD ) CO, δ, ppm, J/Hz): 1.11 (3H, d, J = 6.6, CH -4′), 1.15 (3H, d, J = 6.6, CH -3′),
3 2
3
3
419

1.45 [9H, s, (CH ) C], 1.77 (4H, m, CH -8, CH -9), 2.36 (1H, m, H-3′), 2.40 (2H, m, CH -10), 2.78 (2H, m, CH -7), 4.31 (1H,
3 3
2
2
2
2
m, H-2′), 6.58 (1H, m, CONH), 6.92 (1H, d, J = 2.4, H-4), 6.98 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.65 (1H, d, J = 9.0, H-1).
3-O-(N-t-Butyloxycarbonylleucyl)-7,8,9,10-tetrahydro-6H-benzo[b,d]pyran-6-one (13). Yield67%, mp84-85°C,
C24H31NO6. PMR spectrum (300 MHz, (CD ) CO, δ, ppm, J/Hz): 1.03 (6H, d, J = 5.7, CH -5′, CH -4′), 1.45 [9H, s, (CH ) C],
3 2
3
3
3 3
1.75 (4H, m, CH -8, CH -9), 1.87 (3H, m, CH -3″, H-4″), 2.41 (2H, m, CH -10), 2.79 (2H, m, CH -7), 4.54 (1H, m, H-2′), 6.51
2
2
2
2
2
(1H, m, CONH), 6.91 (1H, d, J = 2.4, H-4), 6.96 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.64 (1H, d, J = 9.0, H-1).
3-O-(N-t-Butyloxycarbonylisoleucyl)-7,8,9,10-tetrahydro-6H-benzo[b,d]pyran-6-one (14). Yield64%, mp78-80°C,
C24H31NO6. PMR spectrum (300 MHz, (CD ) CO, δ, ppm, J/Hz): 0.99 (3H, t, J = 5.7, CH -5″), 1.10 (3H, d, J = 6.9, CH -3′),
3 2
3
3
1.44 (1H, m, CH -4′a), 1.47 [9H, s, (CH ) C], 1.66 (1H, m, CH -4′b), 1.77 (4H, m, CH -8, CH -9), 2.10 (1H, m, H-3′), 2.40
2
3 3
2
2
2
(2H, m, CH -10), 2.77 (2H, m, CH -7), 4.36 (1H, m, H-2′), 6.57 (1H, m, CONH), 6.92 (1H, d, J = 2.4, H-4), 6.98 (1H, dd,
2
2
J2,4 = 2.4, J2,1 = 9.0, H-2), 7.66 (1H, d, J = 9.0, H-1).
3-O-(N-t-Butyloxycarbonylmethionyl)-7,8,9,10-tetrahydro-6H-benzo[b,d]pyran-6-one (15). Yield 73%, mp 73-
74°C, C23H29NO6S. PMRspectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.47 [9H, s, (CH ) C], 1.86 (4H, m, CH -8, CH -9), 2.15
3
3 3
2
2
(3H, s, SCH ), 2.36 (2H, m, CH -4′), 2.58 (2H, m, CH -10), 2.66 (2H, m, CH -3″), 2.78 (2H, m, CH -7), 4.67 (1H, m, H-2′),
3
2
2
2
2
5.19 (1H, m, CONH), 7.07 (1H, dd, J2,4 = 2.1, J2,1 = 8.7, H-2), 7.12 (1H, d, J = 2.1, H-4), 7.57 (1H, d, J = 8.7, H-1).
3-O-(N-t-Butyloxycarbonylphenylalanyl)-7,8,9,10-tetrahydro-6H-benzo[b,d]pyran-6-one (16). Yield 81%, mp
140-141°C, C27H29NO6. PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.46 [9H, s, (CH ) C], 1.85 (4H, m, CH -8, CH -9),
3
3 3
2
2
2.57 (2H, m, CH -10), 2.77 (2H, m, CH -7), 3.22 (2H, m, CH -3′), 4.81 (1H, m, H-2′), 5.05 (1H, m, CONH), 7.05 (1H, dd,
2
2
2
J
2,4 = 2.1, J2,1 = 8.7, H-2), 7.11 (1H, d, J = 2.1, H-4), 7.26 (2H, m, H-2″, H-6″), 7.34 (3H, m, H-3″, H-4″, H-5″), 7.55 (1H, d,
J = 8.4, H-1).
3-O-(N-t-Butyloxycarbonylphenylglycyl)-7,8,9,10-tetrahydro-6H-benzo[b,d]pyran-6-one (17). Yield75%, mp145-
147°C, C26H27NO6. PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 1.46 [9H, s, (CH ) C], 1.84 (4H, m, CH -8, CH -9), 2.57
3
3 3
2
2
(2H, m, CH -10), 2.75 (2H, m, CH -7), 5.54 (2H, m, H-2′, CONH), 6.95 (1H, dd, J2,4 = 2.1, J2,1 = 8.7, H-2), 6.99 (1H, d,
2
2
J = 2.1, H-4), 7.35-7.50 (5H, m, Ph-2′), 7.56 (1H, d, J = 8.4, H-1).
Hydrochloridesof3-O-Aminoacyl-7,8,9,10-tetrahydro-6H-benzo[b,d]pyran-6-ones18-25. Asolution of7-O-Boc-
aminoacylcoumarin 10-17 (2 mmole) in absolute THF (10 mL) was treated with dry HCl in glacial acetic acid (10 mL, 3 M)
and held for 45-60 min at 0°C. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with
absolute ether (100 mL) and held for 30 min at 0°C. The precipitate was filtered off and dried.
3-O-Glycyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one Hydrochloride (18). Yield 81%, mp 225°C (dec.),
C15H16ClNO4. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.75 (4H, m, CH -8, CH -9), 2.40 (2H, m, CH -10), 2.78
6
2
2
2
(2H, m, CH -7), 4.16 (2H, m, CH -2′), 7.01 (1H, dd, J2,4 = 2.1, J2,1 = 8.4, H-2), 7.12 (1H, d, J = 2.1, H-4), 7.75 (1H, d, J = 8.4,
2
2
+
H-1), 8.80 (3H, br.s, NH ).
3
3-O-Alanyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one Hydrochloride (19). Yield 89%, mp 220°C (dec.),
C16H18ClNO4. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.62 (3H, d, J = 7.2, CH -3′), 1.78 (4H, m, CH -8, CH -9),
6
3
2
2
2.39 (2H, m, CH -10), 2.77 (2H, m, CH -7), 4.43 (1H, m, H-2 ), 6.94 (1H, d, J = 2.4, H-4), 6.99 (1H, dd, J2,4 = 2.4, J2,1 = 9.0,
2
2
+
H-2), 7.68 (1H, d, J = 9.0, H-1), 8.91 (3H, br.s, NH ).
3
3-O-Valyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one Hydrochloride (20). Yield 76%, mp 230°C (dec.),
C18H22ClNO4. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.11 (3H, d, J = 6.9, CH -4′), 1.15 (3H, d, J = 6.9, CH -3′),
6
3
3
1.77 (4H, m, CH -8, CH -9), 2.40 (3H, m, CH -10, H-3 ), 2.78 (2H, m, CH -7), 4.18 (1H, m, H-2 ), 6.93 (1H, d, J = 2.4, H-4),
2
2
2
2
+
6.98 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.67 (1H, d, J = 9.0, H-1), 9.01 (3H, br.s, NH ).
3
3-O-Leucyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one Hydrochloride (21). Yield 73%, mp 235°C (dec.),
C19H24ClNO4. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.88 (3H, d, J = 5.7, CH -5′), 0.94 (3H, d, J = 5.7, CH -4′),
6
3
3
1.59 (2H, m, CH -3′), 1.75 (4H, m, CH -8, CH -9), 1.82 (1H, m, H-4′), 2.38 (2H, m, CH -10), 2.75 (2H, m, CH -7), 4.29 (1H,
2
2
2
2
2
+
m, H-2 ), 6.95 (1H, d, J = 2.4, H-4), 7.00 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.68 (1H, d, J = 9.0, H-1), 8.95 (3H, br.s, NH ).
3
3-O-Isoleucyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one Hydrochloride (22). Yield79%, mp230°C(dec.),
C19H24ClNO4. PMRspectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.00 (3H, t, J = 5.7, CH -5″), 1.12 (3H, d, J = 6.9, CH -3′),
6
3
3
1.44 (1H, m, CH -4′a), 1.69 (1H, m, CH -4′b), 1.75 (4H, m, CH -8, CH -9), 2.13 (1H, m, H-3′), 2.39 (2H, m, CH -10), 2.78
2
2
2
2
2
(2H, m, CH -7), 4.25 (1H, m, H-2′), 6.91 (1H, d, J = 2.4, H-4), 6.97 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.65 (1H, d, J = 9.0,
2
+
H-1), 8.96 (3H, br.s, NH ).
3
3-O-Methionyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one Hydrochloride (23). Yield65%, mp220°C(dec.),
420

C18H22ClNO4S. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.82 (4H, m, CH -8, CH -9), 2.11 (3H, s, SCH ), 2.34
6
2
2
3
(2H, m, CH -4′), 2.58 (2H, m, CH -10), 2.80 (4H, m, CH -7, CH -3″), 4.46 (1H, m, H-2′), 7.07 (1H, dd, J2,4 = 2.4, J2,1 = 8.7,
2
2
2
2
+
H-1), 9.00 (3H, br.s, NH ).
3
3-O-Phenylalanyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one Hydrochloride (24). Yield 87%, mp 245 C
(dec.), C22H22ClNO4. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.75 (4H, m, CH -8, CH -9), 2.40 (2H, m, CH -10),
6
2
2
2
2.77 (2H, m, CH -7), 3.30 (1H, m, CH -3″a), 3.41 (1H, m, CH -3″b), 4.57 (1H, m, H-2′), 6.92 (1H, d, J = 2.4, H-4), 6.99 (1H,
2
2
2
+
dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.32 (5H, m, Ph-3′), 7.69 (1H, d, J = 9.0, H-1), 9.14 (3H, br.s, NH ).
3
3-O-Phenylglycyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one Hydrochloride (25). Yield 79%, mp 250°C
(dec.), C21H20ClNO4. PMRspectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.77 (4H, m, CH -8, CH -9), 2.39 (2H, m, CH -10),
6
2
2
2
2.78 (2H, m, CH -7), 5.58 (1H, m, H-2′), 6.92 (1H, d, J = 2.4, H-4), 6.99 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.37-7.45 (5H,
2
+
m, Ph-2′), 7.69 (1H, d, J = 9.0, H-1), 9.05 (3H, br.s, NH ).
3
Ethyl-2-[(7,8,9,10-tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetate (26). A hot solution of 1 (10.8 g,
50 mmole) in absolute acetone (100 mL) was treated with freshly calcined potash (20.7 g, 150 mmole), stirred vigorously and
heated (50-56°C), and treated with ethylchloroacetate (6.1 mL, 55 mmole). The reaction mixture was held for 2 h with vigorous
stirring (course of the reaction was monitored by TLC). After the reaction was finished, the reaction mixture was poured into
H SO solution (500 mL, 1 N). The resulting precipitate was filtered off and crystallized from propan-2-ol (75%). Yield 92%,
2
4
mp 137-138°C, C17H18O5. IR spectrum (KBr, cm-1): 2947, 1765, 1706, 1612, 1509, 1394, 1267, 1209, 1166, 1101, 1078, 1026,
826. PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.22 (3H, t, J = 7.2, CH -2″), 1.73 (4H, m, CH -8, CH -9), 2.37
6
3
2
2
(2H, m, CH -10), 2.73 (2H, m, CH -7), 4.18 (2H, q, CH -1″), 4.89 (2H, s, CH -2 ), 6.92 (1H, d, J = 2.4, H-4), 6.94 (1H, dd,
2
2
2
2
J2,4 = 2.4, J2,1 = 9.2, H-2), 7.58 (1H, d, J = 9.2, H-1).
2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetic Acid(27). Asolutionof26(11.8g, 40mmole)
in propan-2-ol (100 mL) was treated with NaOH (100 mL, 1 N). The mixture was boiled for 2 h (course of the reaction was
monitored by TLC). After the reaction was finished, the reaction mixture was treated with H SO (200 mL, 1 N). The
2
4
resulting precipitate was filtered off and crystallized from propan-2-ol (50%). Yield 85%, mp 170°C, C15H14O5. IR spectrum
(KBr, cm-1): 2943, 1752, 1705, 1698, 1613, 1510, 1430, 1391, 1297, 1255, 1230, 1168, 1103, 1070, 825. PMR spectrum (400
MHz, DMSO-d , δ, ppm, J/Hz): 1.74 (4H, m, CH -8, CH -9), 2.38 (2H, m, CH -10), 2.73 (2H, m, CH -7), 4.80 (2H, s, CH -2′),
6
2
2
2
2
2
6.91 (1H, d, J = 2.4, H-4), 6.93 (1H, dd, J2,4 = 2.4, J2,1 = 9.2, H-2), 7.59 (1H, d, J = 9.2, H-1), 12.99 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]amino Acids 28-44. A cooled solution
of 27 (1.04 g, 4 mmole) and N-hydroxysuccinimide (0.51 g, 4.4 mmole) in absolute dioxane (20 mL) was treated with DCC
(0.83 g, 4 mmole). The mixture was held for 2 h with vigorous stirring (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 mmole) and NaOH (0.18 g, 4.4 mmole) in water (20 mL). The reaction mixture was stirred for 3-4 h (course
of the reaction was monitored by TLC). After the reaction was finished, the reaction mixture was treated with water (100 mL)
and acidified to pH 4. The precipitate was filtered off and crystallized from propan-2-ol (50%).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]glycine(28). Yield61%, mp229-231°C,
C17H17NO6. IR spectrum (KBr, cm-1): 3346, 2945, 1709, 1621, 1559, 1426, 1296, 1264, 1219, 1165, 1105, 1040. PMR
spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.73 (4H, m, CH -8, CH -9), 2.40 (2H, m, CH -10), 2.76 (2H, m, CH -7), 3.83
6
2
2
2
2
(2H, d, J = 6.0, CH -2″), 4.65 (2H, s, CH -1′), 6.96 (1H, d, J = 2.4, H-4), 7.00 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.64 (1H, d,
2
2
J = 9.0, H-1), 8.45 (1H, t, CONH), 12.40 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]alanine (29). Yield67%, mp212-213°C,
C18H19NO6. IR spectrum (KBr, cm-1): 3391, 2938, 1721, 1714, 1623, 1545, 1511, 1422, 1293, 1161, 1149, 1103, 1030. PMR
spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.33 (3H, d, J = 7.5, CH -3″), 1.73 (4H, m, CH -8, CH -9), 2.40 (2H, m, CH -
6
3
2
2
2
10), 2.77 (2H, m, CH -7), 4.31 (1H, m, H-2″), 4.64 (2H, s, CH -1′), 6.95 (1H, d, J = 2.4, H-4), 7.00 (1H, dd, J2,4 = 2.4,
2
2
J2,1 = 9.0, H-2), 7.63 (1H, d, J = 9.0, H-1), 8.43 (1H, d, J = 7.2, CONH), 12.66 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]valine (30). Yield 54%, mp 177-179°C,
C20H23NO6. IR spectrum (KBr, cm-1): 3375, 2958, 1719, 1711, 1644, 1617, 1513, 1427, 1397, 1283, 1265, 1235, 1170, 1099.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.91 (6H, d, J = 6.9, CH -4″, CH -3″), 1.74 (4H, m, CH -8, CH -9), 2.11
6
3
3
2
2
(1H, m, H-3″), 2.40 (2H, m, CH -10), 2.78 (2H, m, CH -7), 4.21 (1H, m, H-2″), 4.73 (2H, s, CH -1′), 6.90 (1H, d, J = 2.4, H-4),
2
2
2
7.01 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.59 (1H, d, J = 9.0, H-1), 8.43 (1H, d, J = 8.4, CONH), 12.78 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]norvaline (31). Yield 68%, mp 172-
421

174°C, C20H23NO6. IR spectrum (KBr, cm-1): 3381, 2954, 1715, 1621, 1546, 1510, 1428, 1388, 1296, 1265, 1231, 1165, 1104,
1064. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.87 (3H, t, CH -5″), 1.33 (2H, m, CH -4″), 1.73 (6H, CH -8, CH -
6
3
2
2
2
9, CH -3″), 2.39 (2H, m, CH -10), 2.73 (2H, m, CH -7), 4.30 (1H, m, H-2″), 4.67 (2H, s, CH -1′), 6.91 (1H, d, J = 2.4, H-4),
2
2
2
2
6.95 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.58 (1H, d, J = 9.0, H-1), 8.35 (1H, d, J = 8.1, CONH), 12.50 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]leucine (32). Yield 52%, mp 160°C,
C21H25NO6. IR spectrum (KBr, cm-1): 3333, 2944, 1728, 1706, 1614, 1569, 1510, 1431, 1392, 1284, 1264, 1233, 1171, 1158,
1097, 1029. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.82 (3H, d, J = 5.7, C -5″), 0.88 (3H, d, J = 5.7, CH -4″),
6
3
3
1.59 (3H, m, CH -3″, H-4″), 1.73 (4H, m, CH -8, CH -9), 2.40 (2H, m, CH -10), 2.77 (2H, m, CH -7), 4.29 (1H, m, H-2″), 4.66
2
2
2
2
2
(2H, s, CH -1′), 6.92 (1H, d, J = 2.4, H-4), 6.97 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.63 (1H, d, J = 9.0, H-1), 8.37 (1H, d,
2
J = 8.1, CONH), 12.50 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]isoleucine (33). Yield 48%, mp 163°C,
C21H25NO6. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.84 (3H, t, CH -5″), 0.87 (3H, d, J = 5.7, CH -3″), 1.20 (1H,
6
3
3
m, CH -4″a), 1.44 (1H, m, CH -4″b), 1.73 (4H, m, CH -8, CH -9), 1.84 (1H, m, H-3″), 2.40 (2H, m, CH -10), 2.76 (2H, m,
2
2
2
2
2
CH -7), 4.26 (1H, m, H-2″), 4.70 (2H, s, CH -1′), 6.91 (1H, d, J = 2.4, H-4), 6.95 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.62 (1H,
2
2
d, J = 9.0, H-1), 8.17 (1H, d, J = 7.5, CONH), 12.72 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]norleucine (34). Yield 82%, mp 167-
169°C, C21H25NO6. IR spectrum (KBr, cm-1): 3378, 2935, 1716, 1622, 1545, 1510, 1426, 1389, 1295, 1265, 1221, 1165, 1103.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.86 (3H, t, CH -6″), 1.26 (4H, m, CH -5″, CH -4″), 1.74 (6H, m, CH -8,
6
3
2
2
2
CH -9, CH -3″), 2.38 (2H, m, CH -10), 2.73 (2H, m, CH -7), 4.27 (1H, m, H-2″), 4.68 (2H, s, CH -1′), 6.91 (1H, d, J = 2.4,
2
2
2
2
2
H-4), 6.95 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.58 (1H, d, J = 9.0, H-1), 8.35 (1H, d, J = 7.8, CONH), 12.50 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]methionine (35). Yield49%, mp129°C,
C20H23NO6S. IR spectrum (KBr, cm-1): 3322, 2936, 1744, 1719, 1619, 1541, 1510, 1434, 1393, 1281, 1261, 1223, 1168, 1103.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.74 (4H, m, CH -8, CH -9), 1.97 (2H, m, CH -4″), 2.03 (3H, s, SCH ),
6
2
2
2
3
2.40 (2H, m, CH -10), 2.45 (2H, m, CH -3″), 2.76 (2H, m, CH -7), 4.42 (1H, m, H-2″), 4.67 (2H, s, CH -1′), 6.93 (1H, d,
2
2
2
2
J = 2.4, H-4), 6.97 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.62 (1H, d, J = 9.0, H-1), 8.42 (1H, d, J = 7.5, CONH), 12.40 (1H, br.s,
COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]phenylalanine (36). Yield79%, mp192-
194°C, C24H23NO6. IR spectrum (KBr, cm-1): 3411, 2937, 1708, 1667, 1621, 1546, 1509, 1436, 1389, 1297, 1265, 1221, 1192,
1160, 1103, 1031. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.74 (4H, m, CH -8, CH -9), 2.41 (2H, m, CH -10),
6
2
2
2
2.76 (2H, m, CH -7), 2.98 (1H, dd, J = 14.1, J = 14.4, CH -3″a), 3.11 (1H, dd, J = 14.1, J = 14.4, CH -3″b), 4.53 (1H, m, H-2″),
2
2
2
4.59 (2H, s, CH -1′), 6.85 (1H, d, J = 2.4, H-4), 6.91 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.21 (5H, m, Ph-3″), 7.59 (1H, d,
2
J = 9.0, H-1), 8.35 (1H, d, J = 8.4, CONH), 12.40 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]phenylglycine (37). Yield 71%, mp
185°C, C23H21NO6. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.72 (4H, m, CH -8, CH -9), 2.39 (2H, m, CH -10),
6
2
2
2
2.72 (2H, m, CH -7), 4.75 (2H, s, CH -1′), 5.43 (1H, d, J = 7.5, H-2″), 6.92 (1H, d, J = 2.4, H-4), 6.96 (1H, dd, J2,4 = 2.4,
2
2
J2,1 = 9.0, H-2), 7.33-7.42 (5H, m, Ph-2″), 7.58 (1H, d, J = 9.0, H-1), 8.85 (1H, d, J = 7.2, CONH), 12.60 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]aspargicAcid(38). Yield46%, mp198-
199°C, C19H19NO8. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.74 (4H, m, CH -8, CH -9), 2.40 (2H, m, CH -10),
6
2
2
2
2.76 (4H, m, CH -7, CH -3″), 4.64 (1H, m, H-2″), 4.66 (2H, s, CH -1′), 6.92 (1H, d, J = 2.4, H-4), 6.96 (1H, dd, J2,4 = 2.4,
2
2
2
J2,1 = 9.0, H-2), 7.65 (1H, d, J = 9.0, H-1), 8.43 (1H, d, J = 7.5, CONH), 12.40 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]citrulline(39). Yield60%, mp143-146°C,
C21H25N2O7. IR spectrum (KBr, cm-1): 3391, 2949, 1691, 1659, 1613, 1570, 1536, 1512, 1431, 1396, 1355, 1288, 1264, 1244,
1172, 1105. PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.39 (2H, m, CH -4″), 1.76 (6H, m, CH -8, CH -9, CH -3″),
6
2
2
2
2
2.40 (2H, m, CH -10), 2.77 (2H, m, CH -7), 2.95 (2H, m, CH -5″), 4.24 (1H, m, H-2″), 4.66 (2H, s, CH -1′), 5.40 (2H, s, NH ),
2
2
2
2
2
5.96 (1H, t, J = 5.6, NH), 6.94 (1H, d, J = 2.4, H-4), 6.98 (1H, dd, J2,4 = 2.4, J2,1 = 8.8, H-2), 7.64 (1H, d, J = 8.8, H-1), 8.45
(1H, d, J = 8.0, CONH), 12.72 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]-β-alanine (40). Yield 88%, mp 207°C,
C18H19NO6. IR spectrum (KBr, cm-1): 3290, 2944, 1700, 1654, 1610, 1556, 1511, 1435, 1394, 1284, 1262, 1213, 1178, 1101,
1040. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.75 (4H, m, CH -8, CH -9), 2.40 (2H, m, CH -10), 2.44 (2H, m,
6
2
2
2
CH -2″), 2.76 (2H, m, CH -7), 3.36 (2H, m, CH -3″), 4.58 (2H, s, CH -1′), 6.94 (1H, d, J = 2.4, H-4), 6.98 (1H, dd, J2,4 = 2.4,
2
2
2
2
422

J2,1 = 9.0, H-2), 7.63 (1H, d, J = 9.0, H-1), 8.18 (1H, t, J = 4.8, CONH), 12.26 (1H, br.s, COOH).
4-[(2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl)amino]butanoic Acid(41). Yield 68%,
mp 171-172°C, C19H21NO6. IR spectrum (KBr, cm-1): 3379, 2942, 1722, 1704, 1614, 1561, 1509, 1429, 1392, 1283, 1265,
1206, 1171, 1098, 1063. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.72 (6H, m, CH -8, CH -9, CH -3″), 2.22 (2H,
6
2
2
2
t, CH -2″), 2.39 (2H, m, CH -10), 2.74 (2H, m, CH -7), 3.15 (2H, m, CH -4″), 4.58 (2H, s, CH -1′), 6.92 (1H, d, J = 2.4, H-4),
2
2
2
2
2
6.97 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.62 (1H, d, J = 9.0, H-1), 8.19 (1H, t, J = 5.4, CONH), 12.05 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]proline (42). Yield65%, mp105-107°C,
C20H21NO6. IR spectrum (KBr, cm-1): 3434, 2936, 1709, 1612, 1510, 1456, 1430, 1393, 1283, 1262, 1226, 1168, 1101, 1038.
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.72 (4H, m, CH -8, CH -9), 1.83-2.19 (4H, m, CH -3″, CH -4″), 2.39
6
2
2
2
2
(2H, m, CH -10), 2.75 (2H, m, CH -7), 3.43 (1H, m, CH -5″a), 3.61 (1H, m, CH -5″b), 4.92 (2H, s, CH -1′), 6.91 (1H, d,
2
2
2
2
2
J = 2.4, H-4), 6.95 (1H, dd, J2,4 = 2.4, J2,1 = 8.8, H-2), 7.60 (1H, d, J = 8.8, H-1), 12.63 (1H, br.s, COOH).
4-[(2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl)amino]hexanoic Acid(43). Yield63%,
mp 182-183°C, C21H25NO6. IR spectrum (KBr, cm-1): 3368, 2944, 1732, 1714, 1639, 1619, 1565, 1429, 1391, 1287, 1267,
1228, 1166, 1105, 1061. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.22 (2H, m, CH -4″), 1.44 (4H, m, CH -3″,
6
2
2
CH -5″), 1.74 (4H, m, CH -8, CH -9), 2.15 (2H, t, J = 7.5, CH -2″), 2.40 (2H, m, CH -10), 2.77 (2H, m, CH -7), 3.42 (2H,
2
2
2
2
2
2
m, CH -6″), 4.57 (2H, s, CH -1′), 6.94 (1H, d, J = 2.4, H-4), 6.98 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.64 (1H, d, J = 9.0, H-1),
2
2
8.11 (1H, t, J = 5.4, CONH), 11.94 (1H, br.s, COOH).
N-[2-[(7,8,9,10-Tetrahydro-6-oxo-6H-dibenzo[b,d]pyran-3-yl)oxy]acetyl]-trans-4-aminomethylcyclohexane-
carboxylic Acid (44). Yield 71%, mp 219-221°C, C23H27NO6. IR spectrum (KBr, cm-1): 3354, 2930, 1714, 1678, 1646, 1619,
1563, 1510, 1450, 1432, 1392, 1365, 1295, 1266, 1228, 1161, 1105, 1058. PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz):
6
0.88 and 1.18 (4H, two m, CH -3′″, CH -5′″), 1.25 (1H, m, H-4′″), 1.60-1.80 (8H, m, CH -8, CH -9, CH -2′″, CH -6′″), 2.10
2
2
2
2
2
2
(1H, m, H-1′″), 2.41 (2H, m, CH -10), 2.74 (2H, m, CH -7), 2.98 (2H, t, J = 7.2, CH -1″), 4.60 (2H, s, CH -1′), 6.93 (1H, d,
2
2
2
2
J = 2.4, H-4), 6.97 (1H, dd, J2,4 = 2.4, J2,1 = 9.0, H-2), 7.64 (1H, d, J = 9.0, H-1), 8.10 (1H, t, J = 5.7, CONH), 11.90 (1H, br.s,
COOH).
REFERENCES
1.
W. Winter, W. G. Friebe, A. Roesch, and O. H. Wilhelms, Eur. Pat. Appl. EP 43,535, 13 Jan 1982; Chem. Abstr.,
97, 216033p (1982).
2.
3.
M. Miyano, U.S. Pat. No. 3,573,327, 30 Mar 1971; Chem. Abstr., 75, 5707u (1971).
A. M. Andrievskii, M. V. Gorelik, S. V. Avidon, V. Nikonov, G. N. Vorozhtsov, R. V. Linke, O. V. Chelysheva,
A. N. Poplovskii, and K. M. Oyumaev, PCT Int. Appl. WO 90 07,479, 12 Jul 1990; Chem. Abstr., 113, 211867c
(1990).
4.
5.
6.
S. S. Chatterjee, M. Noeldner, and H. Hauer, Ger. Offen. DE 4,111,861, 15 Oct 1992; Chem. Abstr., 118, 124397j
(1993).
R. Schlecker, P. Schmidt, P. C. Thieme, D. Lenke, H.-J. Teschendorf, M. Traut, C. Mueller, H. P. Hofmann, and
H. Kreiskott, Ger. Offen. DE 3,243,158, 23 Nov 1982; Chem. Abstr., 101, 90767m (1984).
"Montecatini" Societa Generale per l'Industrie Mineraria e Chimica, Ital. 598,913, Oct. 19, 1959; Chem. Abstr.,
59, 10057g (1963).
7.
8.
9.
J. W. Bolger, U.S. Pat. No. 3,325,489, June 13, 1967; Chem. Abstr., 68, 68886c (1968).
R. C. Griffith, S. African ZA 84 04,344, 27 Mar 1985; Chem. Abstr., 104, 34005m (1986).
P. N. Confalone and D. L. Confalone, Tetrahedron, 39, 1265 (1983).
10.
11.
M. M. Garazd, Ya. L. Garazd, S. V. Shilin, and V. P. Khilya, Khim. Prir. Soedin., 383 (2000).
A. A. Gershkovich and V. K. Kibirev, Chemical Synthesis of Peptides [in Russian], Naukova Dumka, Kiev (1992),
p. 71.
12.
M. M. Garazd, A. S. Ogorodniichuk, V. V. Shilin, S. A. Vasil ev, A. V. Turov, and V. P. Khilya, Khim. Prir.
Soedin., 466 (1998).
13.
14.
G. W. Anderson, J. E. Zimerman, and F. M. Callahan, J. Am. Chem. Soc., 85, 3039 (1963).
M. M. Garazd, Ya. L. Garazd, M. N. Smirnov, and V. P. Khilya, Khim. Prir. Soedin., 464 (1999).
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