Modified coumarins. 9. Synthesis of amino-acid derivatives of 3-(2,3,5-trimethyl-7-oxofuro-[3,2-g]chromen-6-YL)propanoic acid

Article abstract of DOI:10.1023/A:1024861830143

Furocoumarins modified by amino acids were prepared by condensation of the N-hydroxysuccinimide ester of 3-(2,3,5-trimethyl-7-oxofuro[3,2-g]chromen-6-yl) propanoic acid with amino acids.

Full text of DOI:10.1023/A:1024861830143

Chemistry of Natural Compounds, Vol. 39, No. 2, 2003
MODIFIED COUMARINS. 9. SYNTHESIS OF AMINO-ACID
DERIVATIVES OF 3-(2,3,5-TRIMETHYL-7-OXOFURO-
[3,2-g]CHROMEN-6-YL)PROPANOIC ACID
M. V. Veselovskaya,1 S. V. Shilin,1
M. M. Garazd,2 and V. P. Khilya1
UDC 547.814.5
Furocoumarins modified by amino acids were prepared by condensation of the N-hydroxysuccinimide ester
of 3-(2,3,5-trimethyl-7-oxofuro[3,2-g]chromen-6-yl)propanoic acid with amino acids.
Key words: coumarins, furocoumarins, psoralen, amino-acid derivatives, activated esters, synthesis.
Natural bioregulators with the coumarin and furocoumarin structures have a broad spectrum of physiological activity
and provide a platform for chemical modification. Owing to the important role of aminoacids in life processes, newbiologically
active compounds have been sought for a long time among natural amino acids, their synthetic analogs, and various compounds
containing amino-acid fragments. In our opinion, functionalization of benzopyran bioregulators bypharmacophores of amino-
acid nature is promising. Our goal was to modify the furocouomarin ring with amino-acid substituents.
We prepared ethyl-3-(7-hydroxy-4-methyl-2-oxo-2 -3-chromenyl)propanoate (1), which was necessary for further
H
reactions, in 56% yield by Pechmann condensation of resorcinol and diethyl-2-acetylglutarate in the presence of dry HCl as a
condensing agent. The PMR spectrum of 1 contains signals characteristic of the coumarin system and signals for alkyl
substituents on the coumarin ring. The IR spectrum has a signal at 1735 cm-1 that also proves the coumarin ring was formed.
The MacLeod method was used to fuse the furan ring to the benzopyran-2-one system. This method is based on
cyclization in basic medium of 1-(7-coumarinyloxy)acetone derivatives [1]. The cyclization produces linear furocoumarins
because the 6-position of the coumarin ring is less reactive than the 8-position [1].
Williamson reaction of 1 and 3-chlorobutan-2-one in the presence of potash as the base forms the correspondingly
substituted ketone ethyl-3-[4-methyl-7-(1-methyl-2-oxopropoxy)-2-oxo-2 -3-chromenyl]propanoate (2). The PMR spectrum
H
of 2 contains signals characteristic of a coumarin ring and a 7-alkoxy group.
Heating 2 with NaOH solution (1 N) readily cyclizes it into the corresponding psoralen furocoumarin 3 with
simultaneous hydrolysis of the ester. Fusion of the furan ring to the 6,7-positions of the coumarin was confirmed by PMR
spectroscopy. The PMR spectrum of 3 exhibits a broad splitting pattern for the aromatic protons because H-6 of the coumarin
ring is decoupled, as a result of which H-4 and H-9 of the intact furoocoumarin resonate as singlets at 7.72 and 7.35 ppm,
respectively. The PMR spectrum also has a characteristic signal of the free carboxylic proton as a broad singlet at 12.20 ppm.
The UV spectrum of acid 3, in contrast with that of ketone 2, has a strong absorption at 254 nm that is stronger than the long-
wavelength band at 299 nm. This also proves that the furan ring is fused [2].
The amino-acid derivatives of the furocoumarin were synthesized using the activated-ester method that is commonly
used in peptide synthesis [3]. The carboxylic acids were functionalized using the N-hydroxysuccinimide ester, which is highly
reactive and does not racemize the product [4].
The N-hydroxysuccinimide ester of 3 was prepared by reacting starting 3 and N-hydroxysuccinimide (SuOH) in
absolute dioxane using diisopropylcarbodiimide (DIC) as a condensing agent. Theamino-acidderivativesoffurocoumarin 4-20
with a free carboxylic acid were synthesized in 61-94% yields by reacting the activated ester and the sodium salts of the amino
1) Taras Shevchenko Kiev National University, 01033, Kiev, ul. Vladimirskaya, 64; 2) Institute of Bioorganic and
PetroleumChemistry, National AcademyofSciencesoftheUkraine, 02094, Kiev, ul. Murmanskaya, 1, e-mail:gmm@i.com.ua.
Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 132-136, March-April, 2003. Original article submitted April 14,
2003.
0009-3130/03/3902-0177$25.00 ©2003 Plenum Publishing Corporation
177

acids in dioxane—water at room temperature with subsequent acidolysis of the salts. We prepared furocoumarin derivatives
8
containing glycine ( ), β-alanine (5), L-alanine (9), L-valine (11), DL-norvaline (12), L-leucine (13), L-isoleucine (14),
DL-norleucine (15), L-methionine (16), DL-phenylglycine (17), L-citrulline (18), L-phenylalanine (19), L-tryptophan (20),
DL-2-aminobutanoic(10), 4-aminobutanoic(4), 6-aminohexanoic(6), andtrans-4-aminomethylcyclohexanecarboxylic(7)acids.
The PMR spectra of 4-20 contain signals of the coumarin ring, amino-acid fragment, amide bond at 7.71-8.59 ppm, and free
carboxylic acid at 11.68-12.55 ppm.
1. 1N NaOH
Me
Me
O
O
O
O
O
O
O
O
2. H SO
HO
2 4
O
CH COCHClCH
3
3
Me
K CO
2
3
OEt
OH
OEt
Me
O
O
Me
Me
O
Me
O
1
2
3
O
O
O
O
O
O
O
Me
Me
H
N
SuOH, DIC
O
O
N
OH
Me
Me
Me
O
Me
O
4
O
O
O
O
O
O
O
Me
Me
H
N
Me
H
N
OH
OH
Me
Me
O
Me
O
O
5
6
O
O
O
O
O
O
O
O
Me
H
N
OH
Me
Me
H
N
OH
Me
Me
O
R
Me
O
7
8 - 20
8: R = H; 9: R = CH3; 10: R = CH2CH3; 11: R = CH(CH3)2; 12: R = CH2CH2CH3;
13: R = CH2CH(CH3)2; 14: R = CH(CH3)CH2CH3; 15: R = CH2CH2CH2CH3;
16: R = CH2CH2SCH3; 17: R = Ph; 18: R = CH2CH2CH2NHCONH2; 19: R = CH2Ph;
20: R =
N
H
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). Melting points were determined on a Kofler block. IR and UV spectra were measured on a
3
3
Nicolet FTIRNexus 475 spectrometer and Specord M40spectrophotometer, respectively. PMRspectra wererecordedon Varian
VXR-300 and Mercury-400 spectrometers relative to TMS (internal standard). Elemental analyses of all compounds agreed
with those calculated.
Ethyl-3-(7-hydroxy-4-methyl-2-oxo-2H-3-chromenyl)propanoate (1). A cooled (0°C) solution of resorcinol
(22.0 g, 0.2 mol) and diethyl-2-acetylglutarate (49.4 mL, 0.2 mol) in absolute ethanol (50mL)wasvigorouslystirred and cooled.
Dry HCl was passed through the solution for 3 h. The reaction mixture was left overnight at room temperature and poured into
icewater (500 mL). The precipitate was filtered off and crystallized from ethanol (50%). Yield 30.95 g (56%), empirical
formula C15H16O5, mp 116-117°C. IR spectrum (KBr, cm-1): 3250, 1735, 1675, 1615, 1568, 1513, 1468, 1388, 1360, 1324,
1299, 1237, 1181, 1149, 1095, 853. UV (EtOH, λmax, nm, log ε): 204 (4.65), 222 (4.28), 326 (4.24). PMR spectrum (300 MHz,
DMSO-d , δ, ppm, J/Hz): 1.17 (3H, t, J = 7.2, CH -2′), 2.37 (3H, s, CH -4″), 2.47 (2H, t, J = 7.2, CH -2), 2.80 (2H, t, J = 7.2,
6
3
3
2
178

CH -3), 4.04 (2H, q, CH -1′), 6.68 (1H, d, J = 2.4, H-8″), 6.81 (1H, dd, J = 2.4, J = 8.4, H-6″), 7.58 (1H, d, J = 8.4, H-5″), 10.43
2
2
(1H, s, OH).
Ethyl-3-[4-methyl-7-(1-methyl-2-oxopropoxy)-2-oxo-2H-3-chromenyl]propanoate (2). A hot solution of 1
(27.63 g, 0.1 mol) in absolute acetone (300 mL) was treated with freshly calcined potash (41.4 g, 0.3 mol), stirred vigorously,
heated (50-56°C), treated with 3-chloro-2-butanone (11.1 mL, 0.11 mol), held for 3 h with heating and vigorous stirring (course
of the reaction monitored by TLC), and poured into H SO solution (600 mL, 1 N). The precipitate was filtered off and
2
4
crystallized from aqueous ethanol. Yield 27.36 g (79%), empirical formula C19H22O6, mp 76-77°C. IR spectrum (KBr, cm-1):
1728, 1694, 1614, 1563, 1435, 1377, 1349, 1330, 1298, 1193, 1160, 1123, 1099, 863. UV spectrum (dioxane, λmax, nm,
log ε): 211 (4.55), 223 (4.37), 291 (4.03), 321 (4.24). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.19 (3H, t, J = 7.2,
6
CH -2′), 1.48 (1H, d, J = 7.2, CH -1″′), 2.18 (3H, s, CH -3″′ ), 2.40 (3H, s, CH -4″), 2.47 (2H, t, J = 7.2, CH -2), 2.78 (2H,
3
3
3
3
2
t, J = 7.2, CH -3), 4.06 (2H, q, CH -1′), 5.04 (1H, q, H-1″′), 6.83 (1H, d, J = 2.4, H-8″), 6.88 (1H, dd, J = 2.4, J = 8.4, H-6″),
2
2
7.66 (1H, d, J = 8.4, H-5″).
3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoic Acid (3). A solution of 2 (26.0 g, 75 mmol) in
propan-2-ol (200 mL) was treated with NaOH solution (400 mL, 1 N), heated for 3 h (course of the reaction monitored byTLC),
and poured into H SO solution (100 mL, 1 N). The precipitate was filtered off and crystallized from propan-2-ol. Yield
2
4
17.78 g (79%), empirical formula C17H16O5, mp 219-220°C. IR spectrum (KBr, cm-1): 3506, 2925, 1721, 1707, 1671, 1642,
1627, 1579, 1440, 1400, 1294, 1209, 1177, 1159, 1128, 871. UV spectrum (EtOH, λmax, nm, log ε): 211 (4.12), 254 (4.10),
299 (3.78), 336 (3.64). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.19 (3H, s, CH -3′), 2.39 (3H, s, CH -2′), 2.41
6
3
3
(2H, t, J = 7.2, CH -2), 2.51 (3H, s, CH -5′), 2.81 (2H, t, J = 7.2, CH -3), 7.35 (1H, s, H-9′), 7.72 (1H, s, H-4′), 12.08 (1H, br.s,
2
3
2
COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]amino Acids 4-20. General Method. A
solution of 3 (0.85 g, 3 mmol) and N-hydroxysuccinimide (0.38 g, 3.3 mmol) in absolute dioxane (20 mL) was stirred
vigorously, treated with DIC (0.52 mL, 3.3 mmol), and stirred for 2 h (course of the reaction monitored byTLC). The resulting
activated ester was treated with a solution of the appropriate amino acid (3.3 mmol) and NaHCO (0.28 g, 3.3 mmol) in H O
3
2
(20 mL). The mixture was stirred vigorously for 2-4 h (course of the reaction monitored by TLC). After the reaction was
finished, the diisopropylurea was filtered off. The filtrate was diluted with H O (200 mL) and acidified until the pH was 5-6.
2
The resulting precipitate was filtered off and crystallized from aqueous ethanol.
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-4-aminobutanoic Acid (4). Yield 89%,
empirical formula C21H23NO6, mp 219-220°C. IR spectrum (KBr, cm-1): 3312, 2936, 1704, 1696, 1684, 1660, 1640, 1584,
1552, 1400, 1152. UV spectrum (EtOH, λmax, nm, log ε): 210 (4.33), 254 (4.33), 299 (3.98), 338 (3.83). PMR spectrum
(400 MHz, DMSO-d , δ, ppm, J/Hz): 1.60 (2H, m, CH -3), 2.14 (2H, t, J = 7.2, CH -2), 2.20 (3H, s, CH -3″), 2.26 (2H, t,
6
2
2
3
J = 7.2, CH -1′), 2.40 (3H, s, CH -2″), 2.51 (3H, s, CH -5″), 2.81 (2H, t, J = 7.2, CH -2′), 3.02 (2H, m, CH -4), 7.35 (1H, s,
2
3
3
2
2
H-9″), 7.73 (1H, s, H-4″), 7.81 (1H, t, J = 5.2, CONH), 11.88 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-β-alaninie(5). Yield94%, empiricalformula
C20H21NO6, mp 208-209°C. IR spectrum (KBr, cm-1): 3336, 2920, 1708, 1696, 1684, 1656, 1584, 1552, 1400, 1160.
UV spectrum (EtOH, λmax, nm, log ε): 210 (4.37), 254 (4.36), 299 (4.02), 338 (3.85). PMR spectrum (400 MHz, DMSO-d ,
6
δ, ppm, J/Hz): 2.20 (3H, s, CH -3″), 2.26 (2H, t, J = 7.2, CH -1′), 2.34 (2H, t, J = 7.2, CH -2), 2.40 (3H, s, CH -2″), 2.49 (3H,
3
2
2
3
s, CH -5″), 2.80 (2H, t, J = 7.2, CH -2′), 3.23 (2H, m, CH -3), 7.28 (1H, s, H-9″), 7.65 (1H, s, H-4″), 7.87 (1H, t, J = 5.2,
3
2
2
CONH), 12.01 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-6-aminohexanoic Acid (6). Yield 86%,
empirical formula C23H27NO6, mp 212-213°C. IR spectrum (KBr, cm-1): 3352, 2928, 1688, 1656, 1632, 1584, 1552, 1460,
1400, 1348, 1152, 1128. UV spectrum (EtOH, λmax, nm, log ε): 211 (4.46), 254 (4.47), 299 (4.13), 338 (3.94). PMR spectrum
(400 MHz, DMSO-d , δ, ppm, J/Hz): 1.22 (2H, m, CH -4), 1.34 (2H, m, CH -3), 1.45 (2H, m, CH -5), 2.08 (2H, t, J = 7.2,
6
2
2
2
CH -2), 2.20 (3H, s, CH -3″), 2.26 (2H, t, J = 7.2, CH -1′), 2.40 (3H, s, CH -2″), 2.51 (3H, s, CH -5″), 2.81 (2H, t, J = 7.2,
2
3
2
3
3
CH -2′), 2.99 (2H, m, CH -6), 7.32 (1H, s, H-9″), 7.69 (1H, s, H-4″), 7.71 (1H, t, J = 5.2, CONH), 11.76 (1H, br.s, COOH).
2
2
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-trans-4-aminomethylcyclohexanecarboxylic
Acid (7). Yield 85%, empirical formula C25H29NO6, mp 119-120°C. IR spectrum (KBr, cm-1): 3384, 2928, 1700, 1672, 1652,
1584, 1400, 1152, 1128. UV spectrum (EtOH, λmax, nm, log ε): 210 (4.38), 254 (4.38), 299 (4.03), 338 (3.89). PMR spectrum
(400 MHz, DMSO-d , δ, ppm, J/Hz): 0.82 (2H, m, CH -3α, CH -5α), 1.17 (2H, m, CH -3β, CH -5β), 1.27 (1H, m, H-4), 1.64
6
2
2
2
2
(2H, m, CH -2α, CH -6α), 1.87 (2H, m, CH -2β, CH -6β), 1.96 (1H, m, H-1), 2.20 (3H, s, CH -3″), 2.28 (2H, t, J = 7.2,
2
2
2
2
3
179

CH -1′), 2.40 (3H, s, CH -2″), 2.50 (3H, s, CH -5″), 2.83 (4H, m, CH -4, CH -2′), 7.32 (1H, s, H-9″), 7.69 (1H, s, H-4″), 7.71
2
3
3
2
2
(1H, t, J = 5.6, CONH), 11.68 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-glycine (8). Yield 91%, empirical formula
C19H19NO6, mp 255-256°C. IR spectrum (KBr, cm-1): 3296, 2928, 1688, 1656, 1640, 1584, 1552, 1400, 1160, 1128.
UV spectrum (EtOH, λmax, nm, log ε): 212 (4.37), 255 (4.37), 301 (4.01), 342 (3.87). PMR spectrum (400 MHz, DMSO-d ,
6
δ, ppm, J/Hz): 2.21 (3H, s, CH -3″), 2.34 (2H, t, J = 7.2, CH -1′), 2.41 (3H, s, CH -2″), 2.52 (3H, s, CH -5″), 2.83 (2H, t,
3
2
3
3
J = 7.2, CH -2′), 3.70 (2H, d, J = 5.2, CH -2′), 7.36 (1H, s, H-9″), 7.74 (1H, s, H-4″), 8.14 (1H, t, J = 5.2, CONH), 12.37 (1H,
2
2
br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-L-alanine (9). Yield72%, empirical formula
C20H21NO6, mp 224-225°C. IR spectrum (KBr, cm-1): 3283, 2926, 1734, 1687, 1641, 1622, 1581, 1458, 1400, 1347, 1227,
1154, 1126. UV spectrum (EtOH, λmax, nm, log ε): 210 (4.42), 254 (4.40), 298 (4.06), 338 (3.88). PMR spectrum (400 MHz,
DMSO-d , δ, ppm, J/Hz): 1.23 (3H, d, J = 7.2, CH -2), 2.20 (3H, s, CH -3″), 2.31 (2H, t, J = 7.2, CH -1′), 2.40 (3H, s, CH -2″),
6
3
3
2
3
2.50 (3H, s, CH -5″), 2.82 (2H, t, J = 7.2, CH -2′), 4.16 (1H, m, H-2), 7.52 (1H, s, H-9″), 7.83 (1H, s, H-4″), 8.23 (1H, d,
3
2
J = 7.2, CONH), 12.45 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-DL-2-aminobutanoicAcid(10). Yield94%,
empirical formula C21H23NO6, mp 212-213°C. IR spectrum (KBr, cm-1): 3296, 2968, 1696, 1656, 1644, 1584, 1460, 1400,
1152. UV spectrum (EtOH, λmax, nm, log ε): 210 (4.23), 254 (4.23), 299 (3.88), 338 (3.74). PMR spectrum (400 MHz,
DMSO-d , δ, ppm, J/Hz): 0.84 (3H, t, J = 7.2, CH -4), 1.58 (1H, m, CH -3α), 1.70 (1H, m, CH -3β), 2.20 (3H, s, CH -3″), 2.35
6
3
2
2
3
(2H, t, J = 7.2, CH -1′), 2.40 (3H, s, CH -2″), 2.50 (3H, s, CH -5″), 2.82 (2H, t, J = 7.2, CH -2′), 4.10 (1H, m, H-2), 7.35 (1H,
2
3
3
2
s, H-9″), 7.75 (1H, s, H-4″), 8.05 (1H, d, J = 7.2, CONH), 12.28 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-L-valine (11). Yield89%, empirical formula
C22H25NO6, mp 189-190°C. IR spectrum (KBr, cm-1): 3290, 2962, 2924, 1700, 1641, 1581, 1551, 1460, 1398, 1347, 1271,
1153, 1128. UV spectrum (EtOH, λmax, nm, log ε): 210 (4.40), 254 (4.39), 299 (4.04), 338 (3.88). PMR spectrum (400 MHz,
DMSO-d , δ, ppm, J/Hz): 0.82 (6H, d, J = 6.4, two CH -3), 2.00 (1H, m, H-3), 2.20 (3H, s, CH -3″), 2.40 (3H, s, CH -2″), 2.42
6
3
3
3
(2H, t, J = 7.2, CH -1′), 2.51 (3H, s, CH -5″), 2.81 (2H, t, J = 7.2, CH -2′), 4.11 (1H, dd, J = 6.4, J = 6.4, H-2), 7.52 (1H, s,
2
3
2
H-4″), 7.83 (1H, d, H-9″), 8.06 (1H, d, J = 8.0, CONH), 12.50 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-DL-norvaline (12). Yield 77%, empirical
formula C22H25NO6, mp 101-102°C. IR spectrum (KBr, cm-1): 3320, 2960, 1712, 1696, 1688, 1584, 1548, 1464, 1400, 1152,
1128. UV spectrum (EtOH, λmax, nm, log ε): 211 (4.39), 254 (4.40), 298 (4.05), 338 (3.87). PMR spectrum (400 MHz,
DMSO-d , δ, ppm, J/Hz): 0.81 (3H, t, J = 7.6, CH -5), 1.24 (2H, m, CH -4), 1.56 (1H, m, CH -3α), 1.68 (1H, m, CH -3β), 2.20
6
2
2
2
2
(3H, s, CH -3″), 2.34 (2H, t, J = 7.2, CH -1′), 2.40 (3H, s, CH -2″), 2.50 (3H, s, CH -5″), 2.82 (2H, t, J = 7.2, CH -2′), 4.14
3
2
3
3
2
(1H, m, H-2), 7.33 (1H, s, H-9″), 7.71 (1H, s, H-4″), 8.00 (1H, d, J = 7.6, CONH), 12.22 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-L-leucine (13). Yield75%, empirical formula
C23H27NO6, mp 213-214°C. IR spectrum (KBr, cm-1): 3432, 2960, 1710, 1680, 1656, 1628, 1596, 1580, 1464, 1400, 1348,
1276, 1208, 1156, 1128. UV spectrum (EtOH, λmax, nm, log ε): 210 (4.34), 254 (4.33), 296 (4.00), 338 (3.95). PMR spectrum
(400 MHz, DMSO-d , δ, ppm, J/Hz): 0.72, 0.74 (6H, two d, J = 5.6, two CH -4), 1.41 (3H, m, H-3, CH -3), 2.19 (3H, s,
6
3
2
CH -3″), 2.34 (2H, t, J = 7.2, CH -1′), 2.40 (3H, s, CH -2″), 2.51 (3H, s, CH -5″), 2.81 (2H, t, J = 7.2, CH -2′), 4.17 (1H, m,
3
2
3
3
2
H-2), 7.51 (1H, s, H-4″), 7.83 (1H, s, H-9″), 8.13 (1H, d, J = 8.0, CONH), 12.46 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-L-isoleucine (14). Yield 62%, empirical
formula C23H27NO6, mp 157-158°C. IR spectrum (KBr, cm-1): 3352, 2964, 1704, 1650, 1580, 1544, 1460, 1400, 1348, 1260,
1156. UV spectrum (EtOH, λmax, nm, log ε): 211 (4.35), 253 (4.37), 298 (4.02), 338 (3.86). PMR spectrum (400 MHz,
DMSO-d , δ, ppm, J/Hz): 0.76 (3H, t, J = 7.2, CH -5), 0.79 (3H, d, J = 6.8, CH -3), 1.10 (1H, m, CH -4α), 1.31 (1H, m,
6
3
3
2
CH -4β), 1.70 (1H, m, H-3), 2.19 (3H, s, CH -3″), 2.40 (3H, s, CH -2″), 2.49 (2H, t, J = 7.2, CH -1′), 2.51 (3H, s, CH -5″),
2
3
3
2
3
2.80 (2H, t, J = 7.2, CH -2′), 4.14 (1H, dd, J = 6.4, J = 6.4, H-2), 7.51 (1H, s, H-4″), 7.82 (1H, s, H-9″), 8.08 (1H, d, J = 8.0,
2
CONH), 12.52 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-DL-norleucine (15). Yield 61%, empirical
formula C23H27NO6, mp 127-128°C. IR spectrum (KBr, cm-1): 3344, 2960, 1704, 1596, 1584, 1460, 1400, 1152, 1128.
UV spectrum (EtOH, λmax, nm, log ε): 211 (4.42), 254 (4.42), 299 (4.07), 338 (3.90). PMR spectrum (400 MHz, DMSO-d ,
6
δ, ppm, J/Hz): 0.80 (3H, t, J = 7.2, CH -6), 1.22 (4H, m, CH -4, CH -5), 1.52 (1H, m, CH -3α), 1.63 (1H, m, CH -3β), 2.20
2
2
2
2
2
(3H, s, CH -3″), 2.35 (2H, t, J = 7.2, CH -1′), 2.41 (3H, s, CH -2″), 2.51 (3H, s, CH -5″), 2.83 (2H, t, J = 7.2, CH -2′), 4.12
3
2
3
3
2
180

(1H, m, H-2), 7.32 (1H, s, H-9″), 7.70 (1H, s, H-4″), 7.98 (1H, d, J = 8.0, CONH), 12.20 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-L-methionine (16). Yield 92%, empirical
formula C22H25NO6S, mp 140-141°C. IR spectrum (KBr, cm-1): 3428, 2924, 1700, 1686, 1650, 1625, 1580, 1496, 1400, 1364,
1348, 1252, 1156. UV spectrum (EtOH, λmax, nm, log ε): 210 (4.46), 253 (4.44), 299 (4.09), 338 (3.92). PMR spectrum
(400 MHz, DMSO-d , δ, ppm, J/Hz): 1.81 (1H, m, CH -4α), 1.91 (1H, m, CH -4β), 1.94 (3H, s, CH -6), 2.20 (3H, s, CH -3″),
6
2
2
3
3
2.37 (4H, m, CH -4, CH -1′), 2.40 (3H, s, CH -2″), 2.82 (2H, t, J = 7.2, CH -2′), 4.26 (1H, m, H-2), 7.51 (1H, s, H-4″), 7.82
2
2
3
2
(1H, s, H-9″), 8.20 (1H, d, J = 7.6, CONH), 12.55 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-DL-phenylglycine(17). Yield73%, empirical
formula C25H23NO6, mp 223-224°C. IR spectrum (KBr, cm-1): 3416, 2968, 1700, 1688, 1596, 1584, 1528, 1456, 1400, 1156.
UV spectrum (EtOH, λmax, nm, log ε): 211 (4.52), 254 (4.41), 299 (4.06), 338 (3.89). PMR spectrum (400 MHz, DMSO-d ,
6
δ, ppm, J/Hz): 2.21 (3H, s, CH -3″), 2.39 (2H, t, J = 7.2, CH -1′), 2.40 (3H, s, CH -2″), 2.83 (2H, t, J = 7.2, CH -2′), 5.35 (1H,
3
2
3
2
d, J = 7.2, H-2), 7.24 (3H, m, H-3, H-4, H-5 Ph-2), 7.31 (2H, m, H-2, H-6 Ph-2), 7.33 (1H, s, H-4″), 7.64 (1H, s, H-9″), 8.59
(1H, d, J = 7.6, CONH), 12.10 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-L-citrulline (18). Yield 77%, empirical
formula C23H27N3O7, mp 160-161°C. IR spectrum (KBr, cm-1): 3344, 2936, 1704, 1660, 1596, 1584, 1464, 1400, 1348, 1128.
UV spectrum (EtOH, λmax, nm, log ε): 210 (4.47), 254 (4.46), 299 (4.11), 338 (3.92). PMR spectrum (400 MHz, DMSO-d ,
6
δ, ppm, J/Hz): 1.38 (2H, m, CH -4), 1.55 (1H, m, CH -3α), 1.68 (1H, m, CH -3β), 2.19 (3H, s, CH -3 ), 2.35 (2H, t, J = 7.2,
2
2
2
3
CH -1′), 2.40 (3H, s, CH -2″), 2.50 (3H, s, CH -5″), 2.82 (2H, t, J = 7.2, CH -2′), 2.93 (2H, m, CH -5), 4.16 (1H, m, H-2), 5.23
2
3
3
2
2
(2H, br.s, CONH ), 5.86 (1H, br.s, –NHCO–), 7.31 (1H, s, H-9″), 7.69 (1H, s, H-4″), 8.10 (1H, d, J = 8.0, CONH), 12.20 (1H,
2
br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-L-phenylalanine (19). Yield73%, empirical
formula C26H25NO6, mp 102-104°C. IR spectrum (KBr, cm-1): 3320, 2928, 1708, 1969, 1684, 1640, 1584, 1536, 1456, 1400,
1348, 1272, 1152, 1128. UV spectrum (EtOH, λmax, nm, log ε): 210 (4.62), 254 (4.49), 299 (4.14), 338 (4.02). PMR spectrum
(400 MHz, DMSO-d , δ, ppm, J/Hz): 2.21 (3H, s, CH -3″), 2.30 (2H, t, J = 7.2, CH -1′), 2.41 (3H, s, CH -2″), 2.50 (3H, s,
6
3
2
3
CH -5″), 2.75 (2H, t, J = 7.2, CH -2′), 2.86 (1H, m, CH -3α), 3.03 (1H, m, CH -3β), 4.41 (1H, m, H-2), 7.08-7.22 (5H, m, Ph),
3
2
2
2
7.33 (1H, s, H-9″), 7.68 (1H, s, H-4″), 8.10 (1H, d, J = 8.4, CONH), 12.48 (1H, br.s, COOH).
N-[3-(2,3,5-Trimethyl-7-oxo-7H-furo[3,2-g]chromen-6-yl)propanoyl]-L-tryptophan (20). Yield 68%, empirical
formula C28H26N2O6, mp 200-202°C. IR spectrum (KBr, cm-1): 3312, 3280, 2920, 1700, 1672, 1664, 1580, 1456, 1400, 1344,
1228, 1152, 1128, 1096. UV spectrum (EtOH, λmax, nm, log ε): 214 (4.67), 222 (4.66), 255 (4.47), 284 (4.18), 292 (4.23), 338
(4.00). PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.20 (3H, s, CH -3″), 2.32 (2H, t, J = 7.2, CH -1′), 2.41 (3H, s,
6
3
2
CH -2″), 2.49 (3H, s, CH -5″), 2.77 (2H, t, J = 7.2, CH -2′), 3.02 (1H, m, CH -3α), 3.14 (1H, m, CH -3β), 4.47 (1H, m, H-2),
3
3
2
2
2
6.94 (1H, t, J = 7.2, H-5″′), 7.01 (1H, t, J = 7.2, H-6″′), 7.07 (1H, br.s, H-2″′), 7.27 (1H, d, J = 7.2, H-7″′), 7.33 (1H, s, H-9″),
7.50 (1H, d, J = 7.2, H-4″′), 7.67 (1H, s, H-4″), 8.04 (1H, d, J = 8.0, CONH), 10.67 (1H, br.s, NH-1″′), 12.48 (1H, br.s, COOH).
ACKNOWLEDGMENT
We thank OAO "Eximed" (Kiev, the Ukraine) for assistance with the work.
REFERENCES
1.
2.
J. K. MacLeod, B. R. Worth, and R. J. Wells, Aust. J. Chem., 1533 (1978).
M. E. Perel′son, Yu. N. Sheinker, and A. A. Savina, Spectra and Structure of Coumarins, Chromones, and
Xanthones [in Russian], Meditsina, Moscow (1975).
3.
4.
A. A. Gershkovich and V. K. Kibirev, Chemical Synthesis of Peptides [in Russian], Naukova Dumka, Kiev (1992),
p. 71.
G. W. Anderson, J. Zimmerman, and F. M. Callahan, J. Am. Chem. Soc., 85, No. 19, 3039 (1963).
181