Synthesis of aurones based on usninic acid

Article abstract of DOI:10.1007/s10600-012-0258-5

(+)-Usninic acid was brominated at the acetyl group located on the aromatic ring. Aurones were synthesized based on the intramolecular cyclization of monobrominated (+)-usninic acid.

Full text of DOI:10.1007/s10600-012-0258-5

Chemistry of Natural Compounds, Vol. 48, No. 3, July, 2012 [Russian original No. 3, May-June, 2012]
SYNTHESIS OF AURONES BASED ON USNINIC ACID
*
O. A. Luzina, D. N. Sokolov, A. V. Shernyukov,
UDC 547.992
and N. F. Salakhutdinov
(+)-Usninic acid was brominated at the acetyl group located on the aromatic ring. Aurones were synthesized
based on the intramolecular cyclization of monobrominated (+)-usninic acid.
Keywords: (+)-usninic acid, bromination, aurones.
Chemical modification of natural compounds is one of the leading areas of medicinal chemistry. Apromising compound
for carrying out synthetic transformations is the secondary metabolite of certain lichens, usninic acid (UA, 1), which exhibits
antiviral, antibiotic, analgesic, anti-tuberculosis, and insecticidal activity [1]. Examples of direct introduction into its structure
of halide atoms have not been reported. However, the synthesis of a halo-substituted derivative of usninic acid is a direct
pathway to its further functionalization.
The goal of the present work was direct halogenation (namely, bromination) of usninic acid and a study of possible
further synthetic transformations for the preparation of new potentially biologically active compounds.
Compound (+)-1 was brominated using a two-fold excess of Br in dioxane in the presence of HBr. Of the two
2
acetyls capable of reacting under these conditions, the group on aromatic ring A was brominated. Compound 2 was isolated in
67% yield after column chromatography as a result of the reaction at room temperature for seven days (Scheme 1). Increasing
the content of Br in the reaction mixture to a three-fold excess with respect to (+)-1 facilitated the formation of dibromo-
2
derivative 3 (ratio of 2 to 3, 7:3 according to the PMR spectrum). Compound 3 was characterized by spectral methods from a
mixture with the monobromo-derivative 2 because it could not be isolated pure by chromatographic methods.
12
OH
O
OH
O
OH
O
10
11
O
O
O
9
15
1
a
7
b
A
C
9b
HO
OH
HO
OH
HO
OH
2
+
3
4a
O
O
O
13
14
O
O
O
Br
Br
2
1
3
Br
a. 2Br /HBr, dioxane, 2 d; b. 3Br /HBr, dioxane, 2 d
2
2
Scheme 1
According to the literature, ꢀ-phenacylbromides react rather readily with O,N,S-nucleophiles [2–4]. In fact, 2 reacted
with KOAc. However, the reaction did not stop with the formation of the nucleophilic substitution product of Br for AcO.
Refluxing in acetone with KOAc produced 4 in 90% yield (Scheme 2). This was the product of intramolecular cyclization
that was apparently formed in tandem as a result of two nucleophilic substitution reactions. The first of these was substitution
of Br by AcO to form UA acetoxy derivative 5; the second, intramolecular attack of the C-7 hydroxyl at the C atom containing
the AcO group. According to the literature [5], the reaction of ꢀ-phenacylbromide with KOAc could stop at the formation of
2-acetoxy-2ꢁ-hydroxyacetophenone by varying the pH of the medium. In fact, carrying out the reaction in the presence of
HOAc at room temperature led to the formation of 5 as the main product in a mixture with 4. However, the yield of 5 was only
20% (Scheme 2).
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Russia, 630090, Novosibirsk, Prosp. Akad. Lavrentꢁeva, 9,
e-mail: luzina@nioch.nsc.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2012, pp. 350–355. Original
article submitted October 3, 2011.
©
0009-3130/12/4803-0385 2012 Springer Science+Business Media, Inc.
385

OH
O
OH
O
O
OH
O
O
O
a
b
+
4
HO
OH
OH
O
HO
OH
O
O
O
O
O
O
Br
O
4
2
5
O
16
17
a. AcOK, acetone, reflux, 2h; b. AcOK/AcOH, acetone, RT, 2 d
Scheme 2
Compound 4, which contained an active methylene, was condensed with aldehydes. Substituted benzofuranones are
known to be used as starting compounds for synthesizing aurones (benzylidenebenzofuranones), natural compounds that are
described in the literature as antifungal [6] and antibacterial agents [7]; insect antifeedants [8]; antioxidants [9]; inhibitors of
tyrosinase [10] and acetylcholinesterase [11]; and antitumor [12] and anti-inflammatory agents [8].
The reaction of 4 with a slight excess (1:1.1) of aromatic benzaldehydes was carried out at 60°C for 1–1.5 h in
aqueous MeOH in the presence of KOH. The yields of 6a–d and 6f–i were from 55 to 74% (Scheme 3). Benzaldehyde reacted
with a strong acceptor, with a nitro group in the m-position, at room temperature. However, the aurone yield was the lowest in
the studied series (35%, 6e).
OH
O
OH
O
O
O
a
OH
OH
O
O
14
O
O
R
16
O
O
4
H
6a - l
R = Ph (6a), 4-FC H (6b), 4-ClC H (6c), 4-BrC H (6d), 3-NO -C H (6e),
6
4
6
4
6
4
2
6 4
4-MeOC H (6f), 2-MeOC H (6g), 3,4-MeOC H (6h), 3,4,5-MeOC H (6i),
6
4
6
4
6
3
6 2
furan-2-yl (6j), n-C H (6k), n-C H (6l)
3
7
9 19
a. KOH, MeOH, 1–1.5 h
Scheme 3
Resonances corresponding to a single stereoisomer were observed in PMR spectra of all prepared compounds. The
configuration of the C –C double bond was established for 6g using quantum-chemical calculations and NMR spectra.
14 16
The SSCC between H-16 and C-13 in 6g was 3.2 Hz in the single-resonance spectrum. However, we could not find
literature data for the configuration determination of the double bond in aurones that were based on this constant. Therefore,
conformational analysis and DFT quantum-chemical calculations were carried out in order to establish the configuration of the
C –C double bond in 6g. As a result, it was found that the Z-isomer had a principal conformer in which the aromatic
14 16
substituent was situated in the same plane with the C –C double bond and the MeO group was located on the same side as
14 16
the H-16 proton. Two conformers of energy greater than the ground state by 3.7 and 3.8 kcal/mol corresponded to placement
of the MeO group over and below the molecular plane for the case where it was directed to the opposite side relative to the
H-16 proton. Only one position of the aromatic substituent was possible for the E-isomer. The MeO group in this was directed
toward the side of the H-16 proton. This structure was less stable than that of the principal Z-isomer by 2.6 kcal/mol. A
comparison of the experimental chemical shifts (8.23 ppm) and those calculated for the Z-isomer (8.65) and E-isomer (10.75)
of the C-22 o-proton showed better agreement with the Z-isomer. The same trend was observed for the shifts of C atoms of the
C –C double bond (Table 1).
14 16
Data from NOESY spectra were also in good agreement with the Z-configuration of the C –C bond in 6g and the
14 16
calculated basic conformation for this case. Thus, cross peaks between H-22 and C-10 methyl protons (calculated distance
°
~2.9 A) and between H-16 and the MeO protons were found in the NOE spectrum. Cross peaks between H-22 and H-16 and
between methyl protons C-23 and C-10 were not observed.
386

1
13
TABLE 1. Experimental and Calculated Values of Several H and C Chemical Shifts of 6g
Atom
Atom
ꢂ, ppm,
ꢂ, ppm,
ꢂ, ppm, exp.
ꢂ, ppm,
ꢂ, ppm,
E
ꢂ, ppm, exp.
Z
E
Z
H-16
H-19
H-20
H-21
H-22
H-23
C-13
C-14
7.58
6.84
7.36
7.13
8.65
3.95
174.61
151.50
7.80
6.80
7.46
7.17
10.75
3.93
7.39
6.91
7.35
7.05
8.23
3.89
179.60
147.49
C-16
C-17
C-18
C-19
C-20
C-21
C-22
C-23
102.25
124.08
161.92
107.92
130.54
120.19
132.74
52.24
114.66
124.19
160.05
106.17
133.13
120.70
134.35
52.15
106.26
121.15
158.65
110.63
131.29
120.75
131.56
55.46
173.76
154.08
We assigned the Z-configuration to 6a–6i in analogy with the established structure of 6g and in agreement with
literature data [13] for the configuration of the double bond in aurones.
Thus, the condensation of 4 with substituted benzaldehydes enabled us to produce a series of compounds 6a–i that
were aurones with the Z-configuration of the double bond.
We found that heteroaromatic and aliphatic aldehydes also underwent condensation with 4. Thus, the reaction with
furfurol occurred at room temperature in MeOH:KOH (aqueous) to afford 6j in 65% yield. The condensation with aliphatic
aldehydes occurred at room temperature but not as smoothly. The desired condensation products with butyryl and decyl
aldehydes were isolated in yields of 20 and 13%, respectively. The reaction with acrolein produced a complicated product
mixture.
Thus, bromination of (+)-UA was carried out for the first time. The resulting mono-bromo derivative was converted
readily by KOAc by intramolecular cyclization into the (+)-UA derivative containing an annelated dihydrofuran-3-one fragment.
The furanone derivative was condensed with aldehydes. Aurones were synthesized by the reactions with aromatic aldehydes.
Reactions with aliphatic aldehydes gave the lowest yields of the performed reactions.
EXPERIMENTAL
Analytical and spectral studies were carried out in the Chemical Collective Use Service Center of the SB RAS. PMR
13
1
spectra and C NMR spectra of 6g were recorded on a DRX-500 spectrometer (operating frequencies 500.13 MHz for H and
13
125.76 MHz for C). Spectra of other compounds were recorded on an AV-400 spectrometer (operating frequencies
400.13 MHz for H and 100.61 MHz for C) (Bruker). The internal standards were the CD(H)Cl resonances (ꢂ 7.24 ppm,
ꢂ 76.90 ppm). The structure was established using 1D and 2D spectra (with tuning on J
1
13
3
H
1
= 160 Hz for HSQC and
C
H,C
n
J
= 7 Hz for HMBC).
H,C
The initial set of conformers for both possible isomers at the C –C double bond of 6g was obtained using the
14 16
ChemAxon Marvin (conformers plugin) program [14]. Then, the structures were optimized by the RM1 method [15] in the
MOPAC2009 program [16]. Conformers for structures with the lowest energy were sought using the Confab systematic
generator [17] and then optimized by the DFT method [PBE functional [18], L1 basis set (ꢃ01 [19], an analog of cc-pVDZ) of
the PRIRODA program [20]). Chemical shifts were calculated by the GIAO/DFT/PBE method [L22 basis set ꢃ22, an analog
of cc-pCVTZ) of the PRIRODA program]. Quantum-chemical calculations were carried out on the cluster of the
Information-Calculation Center of Novosibirsk State University.
Mass spectra (ionizing-electron energy 70 eV) were recorded on a DFS high-resolution mass spectrometer (Thermo
Scientific). Melting points were measured on a Kofler stage. Reactions were monitored using TLC. Specific rotation was
–1
–1
expressed in (deg·mL)·(g·dm) ; solution concentrations, g·(100 mL) .
(+)-Usninic acid (1) was isolated from a mixture of lichens of the genus Usnea by the literature method [21],
[ꢀ] +478° (c 0.1, CHCl ). Column chromatography used silica gel (60-200 ꢄm, Merck). TLC was performed on Sorbfil
D
3
plates (UV 254). Atomic numbering in compounds was given for assigning resonances in NMR spectra and did not always
agree with the systematic atomic numbering.
Reaction of (+)-Usninic Acid with a Two-fold Excess of Br . Usninic acid (1 mmol, 344 mg) was treated with the
2
bromine–dioxane complex (2 mmol Br , 0.10 mL, dissolved in dioxane, 14 mL) and several drops of HBr and left for 7 d at
2
387

room temperature. The reaction mixture was concentrated in a rotary evaporator and chromatographed over silica gel
(60–200 ꢄm) with elution by CH Cl .
2
2
(R)-2-Acetyl-6-(2-bromoacetyl)-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one (2). Yield 283 mg
–1
(67%), mp 97–100°C, [ꢀ] +349° (c 0.5, CHCl ). IR spectrum (ꢅ, cm ): 842, 1140, 1292, 1458, 1628, 3013, 3497.
D
3
PMR spectrum (CDCl , ꢂ, ppm, J/Hz): 1.75 (3H, s, H-15), 2.08 (3H, s, H-10), 2.64 (3H, s, H-12), 4.52 (2H, dd,
3
J = 12.4, 14.0, H-14), 6.00 (1H, s, H-4), 11.17 (1H, s, 9-OH), 12.68 (1H, s, 7-OH), 18.81 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.5 (C-10), 27.7 (C-12), 31.9 (C-15), 34.5 (C-14), 61.6 (C-9b), 98.7 (C-4), 99.0
3
(C-6), 104.3 (C-9a), 105.1 (C-2), 109.6 (C-8), 154.3 (C-5a), 158.4 (C-9), 164.1 (C-7), 178.5 (C-4a), 191.5 (C-3), 192.7
(C-13), 197.7 (C-1), 201.7 (C-11).
+
Found: m/z 421.9976 [M] , C H O Br; calcd: MW 421.9996.
18 15
7
Reaction of (+)-Usninic Acid with a Three-fold Excess of Br . Usninic acid (1 mmol, 344 mg) was treated with
2
previously prepared bromine–dioxane complex (3 mmol Br , 0.15 mL, dioxane, 22 mL) and several drops of HBr and left for
2
7 d at room temperature. The reaction mixture was concentrated in a rotary evaporator to afford a mixture of 2 and 3 in a 7:3
ratio according to the PMR spectrum.
(R)-2-Acetyl-6-(2,2-dibromoacetyl)-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one (3). IR
–1
spectrum (ꢅ, cm ): 3499, 3012, 1628, 1458, 1292, 1189, 874.
PMR spectrum (CDCl , ꢂ, ppm): 1.75 (3H, s, H-15), 2.10 (3H, s, H-10), 2.64 (3H, s, H-12), 6.09 (1H, s, H-4), 7.07
3
(1H, s, H-14), 11.33 (1H, s, 9-OH), 12.46 (1H, s, 7-OH), 18.81 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.6 (C-10), 27.7 (C-12), 31.8 (C-15), 41.5 (C-14), 58.8 (C-9b), 95.8 (C-6), 99.1
3
(C-4), 104.3 (C-9a), 104.9 (C-2), 110.2 (C-8), 153.5 (C-5a), 159.1 (C-9), 164.8 (C-7), 177.9 (C-4a), 187.4 (C-13), 191.4
(C-3), 197.6 (C-1), 201.8 (C-11).
+
Found: m/z 499.9096 [M] , C H O Br ; calcd: MW 499.9101.
18 14
7
2
Reaction of 2 with KOAc. A solution of 2 (1 mmol, 423 mg) in acetone (25 mL) was treated with KOAc (150 mg,
1.5 mmol), refluxed for 2 h, diluted with H O (up to ~50–60 mL), acidified with HCl (1:4) to pH 3–4, and extracted with
2
CH Cl (3 ꢆ 10 mL). The extracts were dried over calcined MgSO . The solvent was removed. The residue was
2
2
4
chromatographed over a column of silica gel with elution by CH Cl .
2
2
2,6 10,15
(10R)-8,13-Dihydroxy-7,10-dimethyl-5,16-dioxatetracyclo[7.7.0.0 .0
dione (4). Yield 308 mg (90%), mp 202–203°C, [ꢀ] +397° (c 0.5, CHCl ).
]hexadeca-1,6,8,12,14-pentaen-3,11-
D
3
PMR spectrum (CDCl , ꢂ, ppm): 1.73 (3H, s, H-15), 2.13 (3H, s, H-10), 2.64 (3H, s, H-12), 4.66 (2H, s, H-14), 6.02
3
(1H, s, H-4), 11.27 (1H, s, 9-OH), 18.82 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 6.91 (C-10), 27.80 (C-12), 31.91 (C-15), 58.71 (C-9b), 75.70 (C-14), 99.01
3
(C-4), 100.61 (C-9a), 105.10 (C-6), 105.7 (C-2), 107.10 (C-8), 149.13 (C-5a), 159.80 (C-9), 173.81 (C-7), 179.61 (C-4a),
191.61 (C-3), 194.10 (C-13), 197.90 (C-1), 201.71 (C-11).
+
Found: m/z 342.0736 [M] , C H O ; calcd: MW 342.0734.
18 14
7
Reaction of 2 with KOAc in the Presence of AcOH. A solution of 2 (1 mmol, 423 mg) in acetone (25 mL) was
treated with AcOH (8 mL) and KOAc (150 mg, 1.5 mmol), stirred for 2 d, diluted with H O (up to ~50–60 mL), acidified with
2
HCl (1:4) to pH 3–4, and extracted with CH Cl (3 ꢆ 10 mL). The extracts were dried over calcined MgSO . The solvent was
2
2
4
removed. The residue was chromatographed over a column of silica gel with elution by CH Cl .
2
2
(9aR)-2-(8-Acetyl-1,3,7-trihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-4-yl)-2-oxoethylAcetate
(5). Yield 80 mg (20%), mp 107–110°C.
PMR spectrum (CDCl , ꢂ, ppm, J/Hz): 1.76 (3H, s, H-15), 2.09 (3H, s, H-17), 2.24 (3H, s, H-10), 2.66 (3H, s, H-12),
3
5.26 (2H, dd, J = 17.3, 32.0, H-14), 5.99 (1H, s, H-4), 11.08 (1H, s, 9-OH), 12.61 (1H, s, H-7), 18.84 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.39 (C-10), 20.37 (C-17), 27.69 (C-12), 31.89 (C-15), 58.79 (C-9b), 67.37
3
(C-14), 98.66 (C-9a), 98.75 (C-4), 104.00 (C-6), 105.13 (C-2), 109.58 (C-8), 154.55 (C-5a), 158.04 (C-9), 163.53 (C-7),
170.33 (C-16), 178.56 (C-4a), 191.52 (C-3), 194.09 (C-1), 197.73 (C-13), 201.67 (C-11).
+
Found: m/z 402.0943 [M] , C H O ; calcd: MW 402.0945.
20 18
9
Reaction of 4 with Aldehydes (General Method). A solution of 4 (1 mmol, 342 mg) in MeOH (24 mL) was treated
with the appropriate aldehyde (1.1 mmol) and aqueous KOH (1 mL, 50%), heated (for 6a–d and 6f–i) or stirred at room
temperature for 1.5 h (for 6e and 6j–l), diluted with H O (up to ~50–60 mL), acidified with HCl (1:4) to pH 3–4, and extracted
2
with CH Cl (3 ꢆ 10 mL). The extracts were dried over calcined MgSO . The solvent was removed. The residue was
2
2
4
chromatographed over a column of silica gel with elution by CH Cl .
2
2
388

2,6 10,15
(10R,4Z)-4-(Benzylidene)-8,13-dihydroxy-7,10-dimethyl-5,16-dioxatetracyclo[7.7.0.0 .0
1,6,8,12,14-pentaen-3,11-dione (6a). Yield 262 mg (61%), mp 203°C, [ꢀ] +267° (c 0.45, CHCl ).
]hexadeca-
D
3
PMR spectrum (CDCl , ꢂ, ppm): 1.78 (3H, s, H-15), 2.32 (3H, s, H-10), 2.67 (3H, s, H-12), 6.07 (1H, s, H-4), 6.81
3
(1H, s, H-16), 7.39 (1H, m, H-20), 7.46 (2H, m, H-19,21), 7.87 (2H, m, H-18,22), 11.42 (1H, s, 9-OH), 18.86 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.50 (C-10), 27.86 (C-12), 31.96 (C-15), 58.70 (C-9b), 99.13 (C-4), 100.85
3
(C-6), 105.12 (C-2), 105.77 (C-8), 108.23 (C-9a), 112.12 (C-16), 128.81 (C-18,22), 129.69 (C-20), 131.23 (C-19,21), 132.13
(C-17), 147.44 (C-14), 149.81 (C-5a), 159.36 (C-9), 165.72 (C-7), 179.57 (C-13,4a), 191.62 (C-3), 197.86 (C-1), 201.79
(C-11).
+
Found: m/z 430.1039 [M] , C H O ; calcd: MW 430.1047.
25 18
7
2,6 10,15
(10R,4Z)-8,13-Dihydroxy-7,10-dimethyl-4-(4-fluorobenzylidene)-5,16-dioxatetracyclo[7.7.0.0 .0
1,6,8,12,14-pentaen-3,11-dione (6b). Yield 273 mg (61%), mp 198°C, [ꢀ] +281° (c 0.4, CHCl ).
]hexadeca-
D
3
PMR spectrum (CDCl , ꢂ, ppm): 1.75 (3H, s, H-15), 2.26 (3H, s, H-10), 2.66 (3H, s, H-12), 6.04 (1H, s, H-4), 6.69
3
(1H, s, H-16), 7.10 (2H, m, H-19,21), 7.81 (2H, m, H-18,22), 11.39 (1H, s, 9-OH), 18.84 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm, J/Hz): 7.48 (C-10), 27.82 (C-12), 31.95 (C-15), 58.67 (C-9b), 99.10 (C-4),
3
100.76 (C-6), 105.10 (C-2), 105.69 (C-8), 108.27 (C-9a), 110.67 (C-16), 116.00 (d, J
= 22, C-19,21), 128.43 (d,
C–F
J
J
= 3.18, C-17), 133.10 (d, J
= 252.39, C-20), 165.55 (C-7), 179.22 (C-4a), 179.48 (C-13), 191.60 (C-3), 197.82 (C-1), 201.77 (C-11).
= 8.41, C-18,22), 147.01 (d, J
= 2.64, C-14), 149.76 (C-5a), 159.29 (C-9), 163.00 (d,
C–F
C–F
C–F
C–F
+
Found: m/z 448.0957 [M] , C H O F; calcd: MW 448.0953.
(10R,4Z)-8,13-Dihydroxy-7,10-dimethyl-4-(4-chlorobenzylidene)-5,16-dioxatetracyclo[7.7.0.0 .0
25 17
7
2,6 10,15
]hexadeca-
1,6,8,12,14-pentaen-3,11-dione (6c). Yield 255 mg (55%), mp 217°C, [ꢀ] +262° (c 0.3, CHCl ).
D
3
PMR spectrum (CDCl , ꢂ, ppm): 1.75 (3H, s, H-15), 2.26 (3H, s, H-10), 2.66 (3H, s, H-12), 6.04 (1H, s, H-4), 6.67
3
(1H, s, H-16), 7.36 (2H, m, H-19,21), 7.74 (2H, m, H-18,22), 11.41 (1H, s, 9-OH), 18.84 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.49 (C-10), 27.84 (C-12), 31.96 (C-15), 58.66 (C-9b), 99.14 (C-4), 100.68
3
(C-6), 105.12 (C-2), 105.75 (C-8), 108.35 (C-9a), 110.42 (C-16), 129.06 (C-19,21), 130.64 (C-17), 132.21 (C-18,22), 135.54
(C-14), 147.52 (C-20), 149.80 (C-5a), 159.41 (C-9), 165.53 (C-7), 179.15 (C-4a), 179.43 (C-13), 191.59 (C-3), 197.81 (C-1),
201.77 (C-11).
+
Found: m/z 464.0660 [M] , C H O Cl; calcd: MW 464.0657.
25 17
7
2,6 10,15
(10R,4Z)-8,13-Dihydroxy-7,10-dimethyl-4-(4-bromobenzylidene)-5,16-dioxatetracyclo[7.7.0.0 .0
1,6,8,12,14-pentaen-3,11-dione (6d). Yield 270 mg (53%), mp 218–219°C, [ꢀ] +406° (c 0.3, CHCl ).
]hexadeca-
D
3
PMR spectrum (CDCl , ꢂ, ppm): 1.76 (3H, s, H-15), 2.28 (3H, s, H-10), 2.65 (3H, s, H-12), 6.06 (1H, s, H-4), 6.72
3
(1H, s, H-16), 7.56 (2H, m, H-19,21), 7.70 (2H, m, H-18,22), 11.44 (1H, s, 9-OH), 18.84 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.19 (C-10), 27.53 (C-12), 31.63 (C-15), 58.35 (C-9b), 98.88 (C-4), 100.41
3
(C-6), 104.81 (C-2), 105.49 (C-8), 108.05 (C-9a), 110.23 (C-16), 123.72 (C-20), 130.76 (C-17), 131.75 (C-19,21), 132.10
(C-18,22), 147.36 (C-14), 149.54 (C-5a), 159.18 (C-9), 165.28 (C-7), 178.97 (C-4a), 179.14 (C-13), 191.30 (C-3), 197.51
(C-1), 201.48 (C-11).
+
Found: m/z 508.0161 [M] , C H O Br; calc.: MW 508.0152.
25 17
7
2,6 10,15
(10R,4Z)-8,13-Dihydroxy-7,10-dimethyl-4-(3-nitrobenzylidene)-5,16-dioxatetracyclo[7.7.0.0 .0
1,6,8,12,14-pentaen-3,11-dione (6e). Yield 167 mg (35%), mp 230°C (dec.), [ꢀ] +364° (c 0.2, CH Cl ).
]hexadeca-
D
2
2
PMR spectrum (CD Cl , ꢂ, ppm): 1.80 (3H, s, H-15), 2.34 (3H, s, H-10), 2.66 (3H, s, H-12), 6.09 (1H, s, H-4), 6.77
2
2
(1H, s, H-16), 7.64, 8.12, 8.21 (3H, 3m, H-20,21,22), 8.83 (4H, s, H-18), 11.53 (1H, s, 9-OH), 18.88 (1H, s, 3-OH).
13
C NMR spectrum (CD Cl , ꢂ, ppm): 6.34 (C-10), 27.26 (C-12), 31.34 (C-15), 58.39 (C-9b), 98.81 (C-4), 100.05
2
2
(C-6), 104.89 (C-2), 105.63 (C-8), 107.73 (C-16), 108.49 (C-9a), 123.21, 124.81, 129.43, 136.06 (C-18,19,20,21), 133.60
(C-17), 148.17 (C-14), 148.46 (C-5a), 159.57 (C-9), 165.33 (C-7), 178.45 (C-4a), 179.09 (C-13), 191.38 (C-3), 197.70 (C-1),
201.62 (C-11).
+
Found: m/z 475.0895 [M] , C H O N; calcd: MW 475.0898.
25 17
9
2,6 10,15
(10R,4Z)-8,13-Dihydroxy-7,10-dimethyl-4-(4-methoxybenzylidene)-5,16-dioxatetracyclo[7.7.0.0 .0
1,6,8,12,14-pentaen-3,11-dione (6f). Yield 300 mg (65%), mp 258–260°C, [ꢀ] +300° (c 0.45, CHCl ).
]hexadeca-
D
3
PMR spectrum (CDCl , ꢂ, ppm): 1.75 (3H, s, H-15), 2.29 (3H, s, H-10), 2.65 (3H, s, H-12), 3.84 (3H, s, H-23), 6.04
3
(1H, s, H-4), 6.78 (1H, s, H-16), 6.95 (2H, m, H-19,21), 7.81 (2H, m, H-18,22), 11.34 (1H, s, 9-OH), 18.83 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.54 (C-10), 27.88 (C-12), 32.00 (C-15), 58.28 (C-23), 58.80 (C-9b), 99.06
3
(C-4), 102.93 (C-6), 105.14 (C-2), 105.65 (C-8), 108.06 (C-9a), 112.38 (C-16), 114.43 (C-19,21), 124.92 (C-17), 133.10
389

(C-18,22), 146.42 (C-14), 149.81 (C-5a), 158.99 (C-9), 160.85 (C-20), 165.56 (C-7), 179.42 (C-4a), 179.77 (C-13), 191.65
(C-3), 197.94 (C-1), 201.79 (C-11).
+
Found: m/z 460.1148 [M] , C H O ; calcd: MW 460.1153.
26 20
8
2,6 10,15
(10R,4Z)-8,13-Dihydroxy-7,10-dimethyl-4-(2-methoxybenzylidene)-5,16-dioxatetracyclo[7.7.0.0 .0
1,6,8,12,14-pentaen-3,11-dione (6g). Yield 340 mg (74%), mp 206–208°C, [ꢀ] +362° (c 0.4, CHCl ).
]hexadeca-
D
3
PMR spectrum (CDCl , ꢂ, ppm, J/Hz): 1.76 (3H, s, H-15), 2.29 (3H, s, H-10), 2.65 (3H, s, H-14), 3.89 (3H, s, H-23),
3
6.06 (1H, s, H-4), 6.91 (1H, dd, J
= 8.3, J
= 0.7, H-19), 7.05 (1H, ddd, J
= 7.8, J
= 0.7, H-21), 7.35 (1H, ddd,
= 1.7, H-22), 11.37 (1H, s,
19,20
19,21
21,22
21.20
J
= 8.3, J
= 7.4, J
= 1.7, H-20), 7.39 (1H, s, H-16), 8.23 (1H, dd, J
= 7.8, J
20,19
20,21
20,22
22,21 22.20
9-OH), 18.86 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.54 (C-10), 27.94 (C-12), 31.99 (C-15), 55.46 (C-23), 58.77 (C-9b), 99.08
3
(C-4), 101.14 (C-6), 105.11 (C-2), 105.69 (C-8), 106.26 (C-16), 108.02 (C-9a), 110.63 (C-19), 120.75 (C-21), 121.15 (C-17),
131.29 (C-20), 131.56 (C-22), 147.49 (C-14), 149.74 (C-5a), 158.65 (C-18), 159.06 (C-9), 165.62 (C-7), 179.60 (C-13),
179.76 (C-4a), 191.65 (C-3), 197.91 (C-1), 201.82 (C-11).
+
Found: m/z 460.1154 [M] , C H O ; calcd: MW 460.1153.
26 20
8
2,6 10,15
(10R,4Z)-8,13-Dihydroxy-7,10-dimethyl-4-(3,4-dimethoxybenzylidene)-5,16-dioxatetracyclo[7.7.0.0 .0
]hexadeca-
1,6,8,12,14-pentaen-3,11-dione (6h). Yield 295 mg (60%), mp 230°C (dec.), [ꢀ] +273° (c 0.2, CHCl ).
D
3
PMR spectrum (CDCl , ꢂ, ppm, J/Hz): 1.74 (3H, s, H-15), 2.26 (3H, s, H-10), 2.65 (3H, s, H-12), 3.91, 3.95 (6H, 2s,
3
H-23,24), 6.02 (1H, s, H-4), 6.72 (1H, s, H-6), 6.88 (1H, d, J = 8.5, H-21), 7.30 (1H, m, H-22), 7.54 (1H, d, J = 1.9, H-18),
11.38 (1H, s, 9-OH), 18.84 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.34 (C-10), 27.84 (C-12), 32.02 (C-15), 55.50, 55.79 (C-23,24), 58.72 (C-9b),
3
99.00 (C-4), 101.08 (C-6), 105.08 (C-2), 105.31 (C-8), 108.09 (C-9a), 110.95 (C-18), 112.53 (C-16), 112.85 (C-21), 125.08
(C-17), 125.81 (C-22), 146.36 (C-14), 148.80 (C-20), 149.69 (C-5a), 150.49 (C-19), 158.09 (C-9), 165.34 (C-7), 179.10
(C-13), 179.56 (C-4a), 191.60 (C-3), 197.85 (C-1), 201.79 (C-11).
+
Found: m/z 490.1254 [M] , C H O ; calcd: MW 490.1258.
27 22
9
2,6 10,15
(10R,4Z)-8,13-Dihydroxy-7,10-dimethyl-4-(3,4,5-trimethoxybenzylidene)-5,16-dioxatetracyclo[7.7.0.0 .0
1,6,8,12,14-pentaen-3,11-dione (6i). Yield 385 mg (72%), mp 174–176°C, [ꢀ] +224° (c 0.4, CHCl ).
]hexadeca-
D
3
PMR spectrum (CDCl , ꢂ, ppm): 1.72 (3H, s, H-15), 2.23 (3H, s, H-10), 2.63 (3H, s, H-12), 3.87 (3H, s, H-24), 3.89
3
(6H, s, H-23,25), 6.02 (1H, s, H-4), 6.65 (1H, s, H-16), 7.09 (2H, s, H-18,22), 11.39 (1H, s, 9-OH), 18.82 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.28 (C-10), 27.80 (C-12), 31.98 (C-15), 55.80 (C-24,25), 58.67 (C-9b), 60.83
3
(C-23), 99.11 (C-4), 100.87 (C-6), 105.09 (C-2), 105.32 (C-8), 108.24 (C-9a), 108.30 (C-18,22), 112.23 (C-16), 127.43
(C-17), 139.56 (C-20), 146.95 (C-14), 149.79 (C-5a), 153.04 (C-19,21), 159.15 (C-9), 165.41 (C-7), 179.11 (C-4a), 179.47
(C-13), 191.61 (C-3), 197.80 (C-1), 201.79 (C-11).
+
Found: m/z 520.1374 [M] , C H O ; calcd: MW 520.1364.
28 24 10
2,6 10,15
(10R,4Z)-8,13-Dihydroxy-7,10-dimethyl-4-(furan-2-ylmethylene)-5,16-dioxatetracyclo[7.7.0.0 .0
1,6,8,12,14-pentaen-3,11-dione (6j). Yield 335 mg (65%), mp 188–192°C, [ꢀ] +365° (c 0.3, CHCl ).
] hexadeca-
D
3
PMR spectrum (CDCl , ꢂ, ppm): 1.76 (3H, s, H-15), 2.29 (3H, s, H-10), 2.65 (3H, s, H-12), 6.05 (1H, s, H-4), 6.59
3
(1H, s, H-16), 6.83 (1H, m, H-19), 7.07 (1H, m, H-18), 7.58 (1H, m, H-20), 11.38 (1H, s, 9-OH), 18.83 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.41 (C-10), 27.89 (C-12), 31.96 (C-15), 58.72 (C-9b), 99.13 (C-4), 101.30
3
(C-6), 100.84 (C-19), 105.13 (C-2), 105.80 (C-8), 108.19 (C-9a), 113.01 (C-18), 116.69 (C-16), 145.03 (C-20), 145.70
(C-14), 148.65 (C-17), 149.67 (C-5a), 159.21 (C-9), 165.30 (C-7), 178.78 (C-4a), 179.63 (C-13), 191.64 (C-3), 197.89 (C-1),
201.81 (C-11).
+
Found: m/z 420.0839 [M] , C H O ; calcd: MW 420.0840.
23 16
8
2,6 10,15
(10R)-4-(Butylidene)-8,13-dihydroxy-7,10-dimethyl-5,16-dioxatetracyclo[7.7.0.0 .0
]hexadeca-1,6,8,12,14-
pentaen-3,11-dione (6k). Yield 78 mg (20%), mp 65–70°C, [ꢀ] +242° (c 0.5, CHCl ).
D
3
PMR spectrum (CDCl , ꢂ, ppm, J/Hz): 1.00 (3H, t, J = 7.4, H-19), 1.58 (2H, q, J = 7.4, H-18), 1.75 (3H, s, H-15), 2.21
3
(3H, s, H-10), 2.43 (2H, q, J = 7.4, H-17), 2.66 (3H, s, H-12), 6.04 (1H, s, H-4), 6.10 (1H, t, J = 7.9, H-16), 11.32 (1H, s,
9-OH), 18.84 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.39 (C-10), 13.75 (C-19), 21.76 (C-18), 27.80 (C-12), 29.55 (C-17), 31.98
3
(C-15), 58.74 (C-9b), 99.04 (C-4), 105.03 (C-6), 105.09 (C-2), 106.60 (C-8), 109.20 (C-9a), 116.60 (C-16), 149.50 (C-14),
149.63 (C-5a), 157.42 (C-9), 171.15 (C-7), 179.20 (C-4a), 179.30 (C-13), 191.63 (C-3), 197.92 (C-1), 201.78 (C-11).
+
Found: m/z 396.1207 [M] , C H O ; calcd: MW 396.1204.
22 20
7
390

2,6 10,15
(10R)-8,13-Dihydroxy-7,10-dimethyl-4-(decylidene)-5,16-dioxatetracyclo[7.7.0.0 .0
pentaen-3,11-dione (6l). Yield 66 mg (13%), mp 65–70°C, [ꢀ] +304° (c 0.4, CHCl ).
]hexadeca-1,6,8,12,14-
D
3
PMR spectrum (CDCl , ꢂ, ppm, J/Hz): 0.84 (3H, t, J = 7.4, H-25), 1.24 (H, m, H-19–H-24), 1.53 (2H, m, H-18), 1.74
3
(3H, s, H-15), 2.19 (3H, s, H-10), 2.42 (2H, q, J = 7.4, H-17), 2.64 (3H, s, H-12), 6.03 (1H, s, H-4), 6.08 (1H, t, J = 7.9, H-16),
11.30 (1H, s, 9-OH), 18.82 (1H, s, 3-OH).
13
C NMR spectrum (CDCl , ꢂ, ppm): 7.20 (C-10), 13.97 (C-25), 22.54 (C-24), 25.60, 28.41-29.48 (C-18–C-23),
3
27.87 (C-12), 31.95 (C-17), 58.75 (C-9b), 99.03 (C-4), 101.4 (C-6), 105.10 (C-2), 105.52 (C-8), 107.66 (C-9a), 116.66
(C-16), 149.52 (C-14), 149.77 (C-5a), 159.21 (C-9), 165.84 (C-7), 178.80 (C-4a), 179.77 (C-13), 191.64 (C-3), 197.93 (C-1),
201.77 (C-11).
+
Found: m/z 480.2144 [M] , C H O ; calcd: MW 480.2143.
28 32
7
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