Synthesis of sulfides based on (+)-usninic acid

Article abstract of DOI:10.1007/s10600-014-0928-6

Sulfides containing the pharmacophore (+)-usninic acid and its methyl ether were synthesized from monobrominated precursors.

Full text of DOI:10.1007/s10600-014-0928-6

Chemistry of Natural Compounds, Vol. 50, No. 2, May, 2014 [Russian original No. 2, March–April, 2014]
SYNTHESIS OF SULFIDES BASED ON (+)-USNINIC ACID
*
O. A. Luzina, D. N. Sokolov, N. I. Komarova,
and N. F. Salakhutdinov
Sulfides containing the pharmacophore (+)-usninic acid and its methyl ether were synthesized from
monobrominated precursors.
Keywords: (+)-usninic acid, ꢀ-phenacylbromides, thiols, sulfides.
Synthetic transformations of plant metabolites represent an important area of medicinal chemistry and allow new
effective drugs to be discovered. Research on plant metabolites for which reliable information on the biological activity and
available raw-material base exists is considered to be very promising. Usninic acid is actually one of these compounds and the
major secondary metabolite of several lichens. Both enantiomers of usninic acid have to different extents native antiviral,
antibiotic, analgesic, antituberculosis, and insecticidal activity [1].
Herein were present data on the functionalization of (+)-usninic acid (1, UA) and its methyl ether by various
pharmacophores by the reaction of the corresponding mono-bromo derivatives with S-containing thiol nucleophiles.
We reported earlier [2] on a method for selective preparation of the mono-bromo-substituted derivative at the acetyl
on ring A of UA (Scheme 1). Bromination products of the acetyl on ring C were not observed. It is known that all UA
carbonyls are involved in intramolecular H-bonds [3], the strongest of which is that of the exocyclic carbonyl of ring C. The
H-bond of the carbonyl of ring A is weaker. Apparently, the strengths of these H-bonds differentiated the reactivity of these
groups for electrophilic bromination. The reactions occurred slowly. Sufficient conversion was achieved after 7 d. The yield
of 2 was 67%. Increasing the reaction temperature decreased the yield of the mono-bromo derivative and led to the accumulation
in the reaction mixture of polybromination products.
According to theoretical concepts that the mechanism of bromination occurs through the formation of the enol form
of the acetyl, formation of the enol is facilitated considerably by the destruction of the O–H-7…O=C-13 H-bond, e.g., by
adding a protecting group on the C-7 phenyl hydroxyl. The preparation of usninic acid ethers selectively at the C-7 phenol
hydroxyl was described. However, using the literature method [4] to prepare usninic methyl ether by refluxing with MeI in
Me CO in the presence of K CO , we, like the researchers, were able to isolate only small quantities of it. We proposed a
2
2
3
modified methylation method. The reaction was carried out in DMF at room temperature. First, usninic acid phenolate ion was
generated by stirring in DMF for 2 h in the presence of K CO . A sign of its formation was the gradual color change from
2
3
yellow to green, after which a many-fold excess of MeI was added. The mixture was stirred for 2 d to afford 3 in 82% yield
(Scheme 1).
OH
OH
O
OH
OH
O
O
O
O
O
O
O
a
c
b
7
HO
OH
H CO
OH
HO
OH
H CO
OH
3
3
O
O
O
O
13
O
O
O
O
Br
Br
1
3
4
2
a. Br /HBr, dioxane, 7 days; b. MeI, K CO , DMF; c. Br /HBr, dioxane 20 min
2
2
3
2
Scheme 1
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 630090, Russia, Novosibirsk, Prosp. Akad. Lavrentꢁ,va, 9;
e-mail: luzina@nioch.nsc.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 2, March–April, 2014, pp. 236–240. Original
article submitted November 7, 2013.
©
266
0009-3130/14/5002-0266 2014 Springer Science+Business Media New York

The resulting methyl ether was used in the electrophilic bromination under the aforementioned conditions. Compound
3 showed considerably higher activity in the bromination than starting usninic acid. The reaction occurred in 20 min at room
temperature with a 1:1 mole ratio of reagents. The resulting product (4) was isolated in 73% yield by column chromatography
(Scheme 1).
ꢂ-Phenacylbromides are known to react rather readily with O-, N-, and S-nucleophiles. This type of reaction can
produce hybrid molecules [5] of a substrate with various pharmacophores, leaving the structural backbone of the natural
compound unchanged.
Then, both bromo-derivatives were reacted with several S-nucleophiles such as aromatic, aliphatic, and heterocyclic
thiols (Scheme 2). Thio-compounds containing various pharmacophores were selected for the reaction. Addition of them
favored the discovery of new potentially biologically active compounds. Furthermore, sulfide compounds are important
intermediates in organic synthesis that can be used as universal building blocks for various chemical purposes, e.g., preparation
of sulfones and sulfoxides [6, 7].
12
OH
OH
O
15O
10
11
9
O
O
9a
1
7
3
a
RO
OH
RO
OH
6
5a
4a
O
O
4
13
14
O
O
Br
S
R
1
5a-g, 6a-g
2, 4
2, 5a-g: R = H; 4, 6a-g: R = Me
21 COOH
17
18
21
16
17
17
18
N
17
16
17
22
16
17
22
N
S
N
O
18
R =
1
19
20
18
19
Cl
19
20
19
20
16
18
19
16
16
N
17 COOH
18'
N
N
H
17'
19' a
b
c
d
e21
f
20
18'
g
a. R SH/KOH, MeOH, 1–3 h
1
Scheme 2
The reaction with thiols of UA methyl ether and UA itself occurred smoothly at room temperature. According to
HPLC, the conversion was complete. The main products were the corresponding ꢂ-phenacylsulfides 5a–g and 6a–g (Scheme 2).
Thio-derivatives of the methyl ether (6a–g) were isolated by column chromatography in good (53–90%) yields.
ꢂ-Phenacylsulfides based on UA itself (5a–g) were isolated in lower (16–82%) yields. Apparently, the significant losses
during chromatographic isolation were related to intra- and intermolecular rearrangements that involved the free phenolic
7-OH and the chromatography support.
Thus, preparation of UA methyl ether enhanced considerably electrophilic bromination of the acetyl on UA ring C.
ꢂ-Phenacylsulfides were synthesized from the bromo-derivatives of (+)-UA and its methyl ether. The presence of the methyl
protecting group on the phenolic 7-OH simplified considerably the isolation of the products from the reaction mixture.
EXPERIMENTAL
Analytical and spectral studies were carried out at the Chemical Service, Center for Collective Use, Siberian Branch,
13
Russian Academy of Sciences. PMR and C NMR spectra were recorded in CDCl using solvent resonances (ꢃ 7.24 ppm,
3
H
1
13
ꢃ 76.90 ppm) as standards on a BrukerAV-400 spectrometer (operating frequencies 400.13 MHz for H and 100.61, for C).
C
Mass spectra (ionizing-electron energy 70 eV) were measured in a DFS Thermo Scientific high-resolution mass spectrometer.
Melting points were measured on a Kofler block. The reaction was monitored by TLC. Specific rotation was expressed in
–1
–1
(deg4mL)4(g4dm) ; solution concentration, in g4(100 mL) .
(+)-UA {1, [ꢂ] +478° (c 0.1, CHCl )} was isolated from a mixture of Usnea lichen species using the literature
D
3
method [8]. Column chromatography used Merck silica gel (60–200 ꢄm). TLC was performed on Sorbfil plates (UV 254).
The course of reactions and analysis of fractions were monitored during purification of the compounds by column
chromatography using HPLC on a MilikhromA-02 microcolumn chromatograph (ZAO EkoNova, Novosibirsk) with a standard
267

chromatography column (2 ꢅ 75 mm) packed with reversed-phase sorbent (ProntoSIL 120-5-C18, 5 ꢄm, Bischoff, Germany).
Gradient elution used trifluoroacetic acid (0.1%) in MeOH (from 0 to 100% MeOH in 25 min) with simultaneous multi-
wavelength detection at eight wavelengths (210, 230, 250, 260, 280, 300, 340, and 360 nm). The temperature was 35°C;
pressure, 30–36 atm; flow rate, 150 ꢄL/min. The resulting chromatograms were processed using the MultiKhrom 1.5x-E
program (ZAO Ampersand, Moscow).
We used commercially available thiols (95–99% pure, Acros Organics) in the reactions.
The atomic numbering in the compounds was given in order to assign the NMR spectra and did not always agree with
the nomenclature atomic numbering.
Reaction of UA with MeI. UA (1 mmol, 344 mg) in DMF (20 mL) (distilled over BaO and passed immediately
before the reaction over a column of calcined Al O ) was stirred with calcined K CO (828 mg) for 2 h at room temperature
2
3
2
3
until the solution became dark-green. Then, MeI (0.5 mL) was added. The mixture was stirred for 2 d at room temperature and
diluted with H O. The resulting resinous precipitate was filtered off on filter paper, washed with H O, dried, rinsed off with
2
2
CHCl , and concentrated in a rotary evaporator. The resulting precipitate was chromatographed over silica gel using CH Cl
3
2
2
eluent.
(R)-1,1ꢁ-(3,9-Dihydroxy-7-methoxy-8,9b-dimethyl-1-oxo-1,9b-dihydrodibenzo[b,d]furan-2,6-diyl)diethanone (3).
27
1
C H O . Viscous yellow amorphous substance, yield 293 mg (82%), [ꢂ] +460ꢆ (c 0.48; CHCl ). Í NMR spectrum
19 18
7
D
3
(CDCl , ꢃ, ppm, J/Hz): 1.71 (3Í, s, Í-15), 2.12 (3Í, s, Í-10), 2.55 (3Í, s, Í-12), 2.59 (3Í, s, Í-14), 3.71 (3Í, s, Í-16), 5.88
3
13
(1H, s, H-4), 10.76 (1H, s, ÎÍ-9), 18.76 (1H, s, ÎÍ-3). Ñ NMR spectrum (CDCl , ꢃ, ppm): 8.60 (Ñ-10), 27.84 (Ñ-12), 31.79
3
(Ñ-15), 31.81 (Ñ-14), 50.04 (Ñ-9b), 62.20 (Ñ-16), 97.87 (Ñ-4), 108.32 (Ñ-9à), 112.30 (Ñ-6), 104.99 (Ñ-2), 116.30 (Ñ-8),
152.68 (C-5a), 154.81 (Ñ-9), 159.35 (Ñ-7), 179.97 (Ñ-4à), 191.58 (Ñ-13), 196.61 (Ñ-3), 197.78 (Ñ-1), 201.58 (Ñ-11). Found:
+
m/z 358.1046 [M] . Calcd: Ì 358.1046.
Reaction of 3 with Br . Compound 3 (358 mg, 1 mmol) in dioxane (20 mL) was added to the previously prepared
2
Br :dioxane complex [Br (0.05 mL, 1 mmol) dissolved in dioxane (10 mL)] and several drops of HBr, stirred for 20 min at
2
2
room temperature, and concentrated in a rotary evaporator. The solid was chromatographed over silica gel using CH Cl
2
2
eluent.
(R)-2-Acetyl-6-(2-bromoacetyl)-3,9-dihydroxy-7-methoxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one (4).
79
29
1
C H O Br. Viscous yellow amorphous substance, yield 319 mg (73%), [ꢂ] +202ꢆ (c 0.2; CHCl ). Í NMR spectrum
19 17
7
D
3
(CDCl , ꢃ, ppm, J/Hz): 1.73 (3Í, s, Í-15), 2.13 (3Í, s, Í-10), 2.60 (3Í, s, Í-12), 3.75 (3Í, s, Í-16), 4.43 (2Í, dd, J = 13.1,
3
13
14, Í-14), 5.91 (1H, s, H-4), 10.91 (1H, s, ÎÍ-9), 18.78 (1H, s, ÎÍ-3). Ñ NMR spectrum (CDCl , ꢃ, ppm): 8.64 (Ñ-10),
3
27.75 (Ñ-12), 31.74 (Ñ-15), 36.07 (Ñ-14), 58.9 (Ñ-9b), 62.3 (Ñ-16), 98.16 (Ñ-4), 108.45 (Ñ-9à), 108.53 (Ñ-6), 104.99 (Ñ-2),
116.49 (Ñ-8), 153.07 (C-5a), 155.75 (Ñ-9), 159.60 (Ñ-7), 179.32 (Ñ-4à), 189.25 (Ñ-13), 191.48 (Ñ-3), 197.56 (Ñ-1), 201.57
+
(Ñ-11). Found: m/z 436.0159 [M] . Calcd: Ì 436.0152.
Reaction of 2 and 4 with Thiols (general method). A weighed portion of KOH (1.1 mmol), MeOH (6 mL), and the
appropriate thiol (1.1 mmol) were placed into a flask, stirred at room temperature for 10–15 min, treated with a solution of 2
(or 4) (1 mmol) in CH Cl (2 mL), stirred at room temperature for 2–3 h until the reaction was finished (TLC monitoring),
2
2
washed with distilled H O (two times the volume), dried over MgSO , and concentrated. The solid was chromatographed
2
4
over silica gel using CH Cl eluent.
2
2
(R)-2-Acetyl-6-[2-(benzylthio)acetyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one (5a).
27
1
C H O S. Yellow amorphous powder, yield 238 mg (51%), mp. 124–125ꢆC, [ꢂ] +353ꢆ (c 0.45; CHCl ). Í NMR spectrum
25 22
7
D
3
(CDCl , ꢃ, ppm, J/Hz): 1.72 (3Í, s, Í-15), 2.10 (3Í, s, Í-10), 2.63 (3Í, s, Í-12), 3.66 (2H, dd, J = 14.0, 18.0, H-16), 3.73
3
(2H, s, H-14), 5.88 (1H, s, H-4), 7.23 (1H, m, H-20), 7.31 (4Í, m, H-arom.), 11.06 (1H, s, ÎÍ-9), 13.01 (1H, s, ÎÍ-7), 18.79
13
(1H, s, ÎÍ-3). Ñ NMR spectrum (CDCl , ꢃ, ppm): 7.45 (Ñ-10), 27.72 (Ñ-12), 31.88 (Ñ-15), 35.68 (Ñ-16), 39.60 (Ñ-14), 58.82
3
(Ñ-9b), 98.27 (Ñ-4), 99.66 (Ñ-9a), 104.05 (Ñ-6), 105.10 (Ñ-2), 109.47 (Ñ-8), 127.12 (Ñ-20), 128.39 (Ñ-19, 19ꢁ), 129.11 (Ñ-18,
18ꢁ), 137.18 (Ñ-17), 154.39 (Ñ-5a), 157.64 (Ñ-9), 164.37 (Ñ-7), 178.81 (Ñ-4a), 191.48 (Ñ-13), 196.64 (Ñ-3), 197.83 (Ñ-1),
+
201.62 (Ñ-11). Found: m/z 466.1077 [M] . Calcd: Ì 466.1081.
(R)-6-[2-(1H-1,2,4-Triazol-3-ylthio)acetyl]-2-acetyl-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-
27
one (5b). C H N O S. Yellow amorphous powder, yield 142 mg (32%), mp 176–178ꢆC, [ꢂ] +324ꢆ (c 0.21; CHCl ).
20 17
3
7
D
3
1
Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 1.72 (3Í, s, Í-15), 2.06 (3Í, s, Í-10), 2.63 (3Í, s, Í-12), 4.62 (2H, dd, J = 16.9,
3
18.4, H-14), 6.00 (1H, s, H-4), 7.56 (1H, br.s, N-H), 8.37 (1Í, s, H-17), 11.15 (1H, s, 9-ÎÍ), 12.54 (1H, s, 7-ÎÍ), 18.80 (1H,
13
s, 3-ÎÍ). Ñ NMR spectrum (CDCl , ꢃ, ppm): 7.41 (Ñ-10), 27.71 (Ñ-12), 31.86 (Ñ-15), 42.56 (Ñ-14), 58.68 (Ñ-9b), 98.83
3
(Ñ-4), 99.81 (Ñ-9a), 104.37 (Ñ-6), 105.05 (Ñ-2), 109.45 (Ñ-8), 128.16 (Ñ-17), 154.59 (Ñ-9), 155.60 (Ñ-5a), 158.25 (Ñ-16),
268

+
163.65 (Ñ-7), 178.32 (Ñ-4a), 191.47 (Ñ-13), 194.82 (Ñ-3), 197.67 (Ñ-1), 201.69 (Ñ-11). Found: m/z 443.0775 [M] .
Calcd: Ì 443.0782.
(R)-2-[2-(8-Acetyl-1,3,7-trihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-4-yl)-2-
oxoethylthio]nicotinic Acid (5c). C H NO S. Yellow amorphous powder, yield 303 mg (61%), mp 195–197ꢆC,
24 19
9
25
1
[ꢂ] +307ꢆ (c 0.23; acetone). Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 1.83 (3Í, s, Í-15), 2.04 (3Í, s, Í-10), 2.63 (3Í, s,
D
3
Í-12), 3.23 (1H, br.s, ÑÎÎÍ), 4.74 (2H, dd, J = 17.1, 45.7, H-14), 6.17 (1H, s, H-4), 7.18 (1H, dd, J = 7.7, 4.7, H-19), 8.30
(1H, dd, J = 1.8, 7.7, H-18), 8.43 (2H, dd, J = 1.8, 4.7, H-17), 11.23 (1H, s, ÎÍ-9), 13.05 (1H, s, 7-ÎÍ), 18.94 (1H, s, 3-ÎÍ).
13
Ñ NMR spectrum (CDCl , ꢃ, ppm): 6.62 (Ñ-10), 26.84 (Ñ-12), 31.12 (Ñ-15), 40.27 (Ñ-14), 58.90 (Ñ-9b), 97.90 (Ñ-4),
3
100.82 (Ñ-9a), 104.49 (Ñ-6), 105.09 (Ñ-2), 108.00 (Ñ-8), 118.58 (Ñ-18), 122.67 (Ñ-20), 138.87 (Ñ-19), 151.49 (Ñ-17), 155.04
(Ñ-5a), 157.10 (Ñ-9), 160.46 (Ñ-7), 163.17 (Ñ-16), 165.42 (Ñ-21), 179.34 (Ñ-4a), 191.83 (Ñ-13), 197.12 (Ñ-3), 198.35 (Ñ-1),
+
201.74 (Ñ-11). Found: m/z 497.0770 [M] . Calcd: Ì 497.0775.
(R)-2-Acetyl-6-[2-(4-chlorophenylthio)acetyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one
27
1
(5d). C H O SCl. Yellow amorphous powder, yield 398 mg (82%), mp 147–148ꢆC, [ꢂ] +365ꢆ (c 0.34; CHCl ). Í NMR
24 19
7
D
3
spectrum (CDCl , ꢃ, ppm, J/Hz): 1.72 (3Í, s, Í-15), 2.06 (3Í, s, Í-10), 2.63 (3Í, s, Í-12), 4.17 (2H, dd, J = 14.5, 25.6,
3
H-14), 5.92 (1H, s, H-4), 7.20 (2H, d, J = 8.4, H-17, 17ꢁ), 7.28 (2Í, d, J = 8.4, H-18, 18ꢁ), 11.07 (1H, s, 9-ÎÍ), 12.74 (1H, s,
13
7-ÎÍ), 18.79 (1H, s, 3-ÎÍ). Ñ NMR spectrum (CDCl , ꢃ, ppm): 7.46 (Ñ-10), 27.72 (Ñ-12), 31.88 (Ñ-15), 44.46 (Ñ-14),
3
58.79 (Ñ-9b), 98.47 (Ñ-4), 99.75 (Ñ-9a), 104.15 (Ñ-6), 105.14 (Ñ-2), 109.60 (Ñ-8), 129.08 (Ñ-18, 18ꢁ), 132.19 (Ñ-17, 17ꢁ),
132.81 (Ñ-19), 133.47 (Ñ-16), 154.36 (Ñ-5a), 157.97 (Ñ-9), 164.19 (Ñ-7), 178.63 (Ñ-4a), 191.48 (Ñ-13), 195.87 (Ñ-3), 197.77
+
(Ñ-1), 201.68 (Ñ-11). Found: m/z 486.0529 [M] . Calcd: Ì 486.0535.
(R)-2-Acetyl-6-[2-(benzo[d]oxazole-2-ylthio)acetyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-
27
one (5e). C H O NS. Yellow amorphous powder, yield 79 mg (16%), mp 155–156ꢆC, [ꢂ] +217ꢆ (c 0.32; CHCl ).
25 19
8
D
3
1
Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 1.80 (3Í, s, Í-15), 2.12 (3Í, s, Í-10), 2.68 (3Í, s, Í-12), 4.90 (2H, dd, J = 17.3,
3
16.7, H-14), 6.06 (1H, s, H-4), 7.27 (2H, m, H-arom.), 7.44 (1Í, m, H-arom.), 7.57 (1Í, m, H-arom.), 11.17 (1H, s, 9-ÎÍ),
13
12.63 (1H, s, 7-ÎÍ), 18.84 (1H, s, 3-ÎÍ). Ñ NMR spectrum (CDCl , ꢇꢃ, ppm): 7.44 (Ñ-10), 27.67 (Ñ-12), 31.90 (Ñ-15),
3
43.07 (Ñ-14), 58.80 (Ñ-9b), 98.84 (Ñ-4), 100.09 (Ñ-9a), 104.30 (Ñ-6), 105.14 (Ñ-2), 109.60 (Ñ-8), 109.86, 118.42, 124.01,
124.27 (Ñ-18, 19, 20, 21), 141.55, 151.89 (Ñ-17, 22), 154.67 (Ñ-5a), 158.23 (Ñ-9), 163.41 (Ñ-7), 163.68 (Ñ-16), 178.50
+
(Ñ-4a), 191.50 (Ñ-13), 193.43 (Ñ-3), 197.76 (Ñ-1), 201.66 (Ñ-11). Found: m/z 493.0830 [M] . Calcd: Ì 493.0826.
(R)-2-Acetyl-6-[2-(benzo[d]thiazol-2-ylthio)acetyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-
27
one (5f). C H O NS . Yellow amorphous powder, yield 81 mg (16%), mp 159–160ꢆC, [ꢂ] +207ꢆ (c 0.32; CHCl ).
25 19
7
2
D
3
1
Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 1.76 (3Í, s, Í-15), 2.08 (3Í, s, Í-10), 2.65 (3Í, s, Í-12), 4.91 (2H, dd, J = 16.8, 19.0,
3
H-14), 5.98 (1H, s, H-4), 7.27 (1H, m, H-arom), 7.37 (1Í, m, H-arom), 7.72 (1Í, m, H-arom), 7.80 (1Í, m, H-arom), 11.12
13
(1H, s, 9-ÎÍ), 12.64 (1H, s, 7-ÎÍ), 18.79 (1H, s, 3-ÎÍ). Ñ NMR spectrum (CDCl , ꢃ, ppm): 7.46 (Ñ-10), 27.74 (Ñ-12),
3
31.90 (Ñ-15), 43.76 (Ñ-14), 58.75 (Ñ-9b), 98.66 (Ñ-4), 100.07 (Ñ-9a), 104.20 (Ñ-6), 105.05 (Ñ-2), 109.46 (Ñ-8), 120.90,
121.38, 124.40, 126.00 (Ñ-18, Ñ-19, Ñ-20, Ñ-21), 135.17 (Ñ-22), 152.48 (Ñ-17), 154.57 (Ñ-5a), 158.02 (Ñ-9), 163.63 (Ñ-7),
+
164.91 (Ñ-16), 178.52 (Ñ-4a), 191.46 (Ñ-13), 193.87 (Ñ-3), 197.69 (Ñ-1), 201.64 (Ñ-11). Found: m/z 509.0593 [M] . Calcd:
Ì 509.0598.
(R)-3-[2-(8-Acetyl-1,3,7-trihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-4-yl)-2-
oxoethylthio]propanoic Acid (5g). C H O S. Yellow amorphous powder, yield 278 mg (62%), mp 165–166ꢆC,
21 20
9
27
1
[ꢂ] +413ꢆ (c 0.34; CHCl ). Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 1.726 (3Í, s, Í-15), 2.06 (3Í, s, Í-10), 2.62 (3Í, s,
D
3
3
Í-12), 2.67 (2H, t, J = 7, H-17), 2.81 (2H, t, J = 7, H-16), 3.80 (2H, dd, J = 14.1, 17.0, H-14), 5.95 (1H, s, H-4), 9.28 (1H, br.s,
13
ÑÎÎÍ), 11.09 (1H, s, 9-ÎÍ), 12.92 (1H, s, 7-ÎÍ), 18.80 (1H, s, 3-ÎÍ). Ñ NMR spectrum (CDCl , ꢃ, ppm): 7.44 (Ñ-10),
3
26.19 (Ñ-16), 27.77 (Ñ-12), 31.89 (Ñ-15), 33.81 (Ñ-17), 40.66 (Ñ-14), 58.76 (Ñ-9b), 98.36 (Ñ-4), 99.37 (Ñ-9a), 104.11 (Ñ-6),
105.04 (Ñ-2), 109.44 (Ñ-8), 154.34 (Ñ-5a), 157.71 (Ñ-9), 164.28 (Ñ-7), 177.50, 178.70 (Ñ-4a, 18), 191.46 (Ñ-13), 196.50
+
(Ñ-3), 197.76 (Ñ-1), 201.67 (Ñ-11). Found: m/z 448.0822 [M] . Calcd: Ì 448.0823.
(R)-2-Acetyl-6-[2-(benzylthio)acetyl]-3,9-dihydroxy-7-methoxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one
29
1
(6a). C H O S. Viscous amorphous yellow substance, yield 432 mg (90%), [ꢂ] +292ꢆ (c 0.29; CHCl ). Í NMR spectrum
26 24
7
D
3
(CDCl , ꢃ, ppm, J/Hz): 1.75 (3Í, s, Í-15), 2.17 (3Í, s, Í-10), 2.64 (3Í, s, Í-12), 3.65 (2Í, dd, J = 14.3, 16.5, Í-17), 3.73
3
(3H, s, H-14), 3.76 (3H, s, OMe), 5.91 (1H, s, H-4), 7.21 (1H, m, H-21), 7.26–7.32 (4H, m, H-19, 19ꢁ, 20, 20ꢁ), 10.86 (1H, s,
13
9-ÎÍ), 18.83 (1H, s, 3-ÎÍ). Ñ NMR spectrum (CDCl , ꢃ, ppm): 8.39 (Ñ-10), 27.52 (Ñ-12), 31.51 (Ñ-15), 35.49 (Ñ-16),
3
40.40 (Ñ-14), 58.74 (Ñ-9b), 62.04 (OMe), 97.66 (Ñ-4), 104.73 (Ñ-9à), 108.06 (Ñ-6), 109.92 (Ñ-2), 116.08 (Ñ-8), 126.70 (Ñ-20),
128.02 (Ñ-18, 18ꢁ), 128.77 (Ñ-19, 19ꢁ), 136.91 (Ñ-17), 152.79 (Ñ-5a), 154.77 (Ñ-9), 159.02 (Ñ-7), 179.39 (Ñ-4a), 191.22 (Ñ-13),
+
192.99 (Ñ-3), 197.37 (Ñ-1), 201.27 (Ñ-11). Found: m/z 480.1242 [M] . Calcd: Ì 480.1237.
269

(R)-6-[2-(1H-1,2,4-Triazol-5-ylthio)acetyl]-2-acetyl-3,9-dihydroxy-7-methoxy-8,9b-dimethyldibenzo[b,d]furan-
29
1(9bH)-one (6b). C H N O S. Yellow amorphous powder, yield 306 mg (67%), mp 151–153ꢆC, [ꢂ] +176ꢆ (c 0.23;
21 19
3
7
D
1
CHCl ). Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 1.66 (3Í, s, Í-15), 2.15 (3Í, s, Í-10), 2.62 (3Í, s, Í-12), 3.75 (3H, s,
3
3
OMe), 4.52 (2Í, dd, J = 16.8, 29.4, Í-14), 5.97 (1H, s, H-4), 8.12 (1H, s, H-17), 9.74 (1Í, br.s, NÍ), 10.84 (1H, s, 9-ÎÍ),
13
18.65 (1H, s, 3-ÎÍ). Ñ NMR spectrum (CDCl , ꢃ, ppm): 8.72 (Ñ-10), 27.69 (Ñ-12), 31.81 (Ñ-15), 43.18 (Ñ-14), 58.68
3
(Ñ-9b), 62.16 (OMe), 98.21 (Ñ-4), 104.73 (Ñ-9a), 108.44 (Ñ-6), 109.73 (Ñ-2), 116.48 (Ñ-8), 145.49 (Ñ-5a), 153.25 (Ñ-5a),
155.71 (Ñ-9), 156.22 (Ñ-16), 159.75 (Ñ-7), 178.97 (Ñ-4a), 191.31 (Ñ-13), 192.87 (Ñ-1), 197.39 (Ñ-3), 201.58 (Ñ-11). Found:
+
m/z 457.0944 [M] . Calcd: Ì 457.0938.
(R)-2-[2-(8-Acetyl-1,7-dihydroxy-3-methoxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-4-yl)-2-
oxoethylthio]nicotinic Acid (6c). C H NO S. Yellow amorphous powder, yield 460 mg (90%), mp 79–81ꢆC, [ꢂ] +222ꢆ
25 21
9
D
1
(c 0.26; CHCl ). Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 1.71 (3Í, s, Í-15), 2.15 (3Í, s, Í-10), 2.60 (3Í, s, Í-12), 3.75
3
3
(3H, s, OMe), 4.41 (2Í, s, Í-14), 5.85 (1H, s, H-4), 7.03 (1H, dd, J = 4.7, 7.8, H-19), 8.23 (1H, dd, J = 1.7, 7.8, H-18), 8.34 (1H,
13
dd, J = 1.7, 4.7, H-20), 10.76 (1H, s, 9-ÎÍ), 10.91 (1H, br.s, ÑOÎÍ), 18.74 (1H, s, 3-ÎÍ). Ñ NMR spectrum (CDCl , ꢃ,
3
ppm): 8.61 (Ñ-10), 27.72 (Ñ-12), 31.73 (Ñ-15), 41.89 (Ñ-14), 59.02 (Ñ-9b), 62.20 (OMe), 97.62 (Ñ-4), 104.90 (Ñ-9a), 108.24
(Ñ-6), 111.26 (Ñ-2), 116.09 (Ñ-8), 118.51 (Ñ-19), 121.74 (Ñ-17), 139.64 (Ñ-18), 151.83 (Ñ-20), 152.50 (Ñ-5a), 154.63 (Ñ-9),
159.12 (Ñ-7), 161.15 (Ñ-16), 169.71 (Ñ-21), 179.85 (Ñ-4a), 191.45 (Ñ-3), 197.61 (Ñ-1), 201.45 (Ñ-11). Found: m/z 511.0929
+
[M] . Calcd: Ì 511.0932.
(R)-2-Acetyl-6-[2-(4-chlorophenylthio)acetyl]-3,9-dihydroxy-7-methoxy-8,9b-dimethyldibenzo[b,d]furan-
27
1(9bH)-one (6d). C H ClO S. Viscous yellow amorphous substance, yield 330 mg (66%), [ꢂ] +272ꢆ (c 0.5; CHCl ).
25 21
7
D
3
1
Í NMR spectrum (CDCl , ꢃ, ppm): 1.68 (3Í, s, Í-15), 2.12 (3Í, s, Í-10), 2.60 (3Í, s, Í-12), 3.68 (3H, s, OMe), 4.13 (2Í,
s, Í-14), 5.82 (1H, s, H-4), 7.14 (4H, m, H-17, 17ꢁ, 18, 18ꢁ), 10.80 (1H, s, 9-ÎÍ), 18.76 (1H, s, 3-ÎÍ). Ñ NMR spectrum
3
13
(CDCl , ꢃ, ppm): 8.56 (Ñ-10), 27.69 (Ñ-12), 31.63 (Ñ-15), 45.20 (Ñ-14), 58.85 (Ñ-9b), 62.20 (OMe), 97.86 (Ñ-4), 104.94
3
(Ñ-9a), 108.22 (Ñ-6), 109.90 (Ñ-2), 116.31 (Ñ-8), 128.71 (Ñ-18, 18ꢁ), 131.55 (Ñ-17, 17ꢁ), 132.76 (Ñ-19), 133.20 (Ñ-16), 152.80
(Ñ-5a), 155.20 (Ñ-9), 159.29 (Ñ-7), 179.39 (Ñ-4a), 191.41 (Ñ-13), 192.64 (Ñ-3), 197.52 (Ñ-1), 201.49 (Ñ-11). Found: m/z
+
500.0682 [M] . Calcd: Ì 500.0691.
(R)-2-Acetyl-6-[2-(benzo[d]oxazol-2-ylthio)acetyl]-3,9-dihydroxy-7-methoxy-8,9b-dimethyldibenzo[b,d]furan-
27
1(9bH)-one (6e). C H NO S. Yellow amorphous powder, yield 319 mg (63%), mp 64–66ꢆC, [ꢂ] +190ꢆ (c 0.36; CHCl ).
26 21
8
D
3
1
Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 1.71 (3Í, s, Í-15), 2.18 (3Í, s, Í-10), 2.63 (3Í, s, Í-12), 3.80 (3H, s, OMe), 4.74
3
(2Í, dd, J = 17.0, 17.8, Í-14), 5.88 (1H, s, H-4), 7.22 (2H, m, H-arom.), 7.39 (1Í, m, H-arom.), 7.49 (1Í, m, H-arom.), 10.95
13
(1H, s, 9-ÎÍ), 18.81 (1H, s, 3-ÎÍ). Ñ NMR spectrum (CDCl , ꢃ, ppm): 8.69 (Ñ-10), 27.84 (Ñ-12), 31.71 (Ñ-15), 43.83
3
(Ñ-14), 58.89 (Ñ-9b), 62.35 (OMe), 98.14 (Ñ-4), 104.96 (Ñ-9a), 108.60 (Ñ-6), 109.65 (Ñ-2), 109.77 (Ñ-21), 116.47 (Ñ-8),
118.27 (Ñ-18), 123.85 (Ñ-20), 124.17 (Ñ-19), 141.59 (Ñ-17), 151.81 (Ñ-22), 153.19 (Ñ-5a), 155.77 (Ñ-9), 159.66 (Ñ-7),
+
163.60 (Ñ-16), 179.50 (Ñ-4a), 190.83 (Ñ-13), 191.51 (Ñ-3), 197.61 (Ñ-1), 201.62 (Ñ-11). Found: m/z 507.0979 [M] . Calcd:
Ì 507.0982.
(R)-2-Acetyl-6-[2-(benzo[d]thiazol-2-ylthio)acetyl]-3,9-dihydroxy-7-methoxy-8,9b-dimethyldibenzo[b,d]furan-
27
1
1(9bH)-one (6f). C H NO S . Yield 277 mg (53%), mp 63–65ꢆC, [ꢂ] +279ꢆ (c 0.39; CHCl ). Í NMR spectrum
26 21
7
2
D
3
(CDCl , ꢃ, ppm): 1.68 (3Í, s, Í-15), 2.17 (3Í, s, Í-10), 2.62 (3Í, s, Í-12), 3.78 (3H, s, OMe), 4.73 (2Í, s, Í-14), 5.80 (1H,
3
s, H-4), 7.23 (1H, m, H-arom.), 7.32 (1Í, m, H-arom.), 7.69 (2Í, m, H-arom.), 10.87 (1H, s, 9-ÎÍ), 18.76 (1H, s, 3-ÎÍ).
13
Ñ NMR spectrum (CDCl , ꢃ, ppm): 8.68 (Ñ-10), 27.80 (Ñ-12), 31.69 (Ñ-15), 44.48 (Ñ-14), 58.94 (Ñ-9b), 62.34 (OMe),
3
98.02 (Ñ-4), 104.98 (Ñ-9a), 108.49 (Ñ-6), 110.03 (Ñ-2), 116.37 (Ñ-8), 120.87, 121.33 (Ñ-21, 22), 124.25 (Ñ-20), 125.85
(Ñ-19), 135.40 (Ñ-22), 152.67 (Ñ-17), 153.06 (Ñ-5a), 155.53 (Ñ-9), 159.60 (Ñ-7), 165.04 (Ñ-16), 179.590 (Ñ-4a), 191.38
+
(Ñ-13), 191.50 (Ñ-3), 197.64 (Ñ-1), 201.56 (Ñ-11). Found: m/z 523.0752 [M] . Calcd: Ì 523.0754.
(R)-3-[2-(8-Acetyl-1,7-dihydroxy-3-methoxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-4-yl)-2-
27
oxoethylthio]propanoic Acid (6g). C H O S. Viscous yellow amorphous substance, yield 272 mg (58%), [ꢂ] +296ꢆ
22 22
9
D
1
(c 0.32; CHCl ). Í NMR spectrum (CDCl , ꢃ, ppm, J/Hz): 1.75 (3Í, s, Í-15), 2.15 (3Í, s, Í-10), 2.62 (3Í, s, Í-12), 2.65
3
3
(2H, t, J = 6.9, H-16), 2.79 (2H, t, J = 6.9, H-17), 3.75 (3H, s, OMe), 3.79 (2Í, dd, J = 14.0, 23.0, Í-14), 5.92 (1H, s, H-4), 7.95
13
(1H, br.s, ÑÎÎH), 7.32 (1Í, m, H-arom.), 10.84 (1H, s, 9-ÎÍ), 18.76 (1H, s, 3-ÎÍ). Ñ NMR spectrum (CDCl , ꢃ, ppm):
3
8.68 (Ñ-10), 26.56 (Ñ-16), 27.80 (Ñ-12), 31.78 (Ñ-15), 33.87 (Ñ-17), 41.94 (Ñ-14), 59.04 (Ñ-9b), 62.36 (OMe), 98.05 (Ñ-4),
105.06 (Ñ-9a), 108.46 (Ñ-6), 109.92 (Ñ-2), 116.45 (Ñ-8), 153.19 (Ñ-5a), 155.23 (Ñ-9), 159.37 (Ñ-7), 177.06 (Ñ-18), 179.67
+
(Ñ-4a), 191.56 (Ñ-13), 193.33 (Ñ-3), 197.72 (Ñ-1), 201.60 (Ñ-11). Found: m/z 462.0978 [M] . Calcd: Ì 462.0979.
270

ACKNOWLEDGMENT
The work was supported financially by RFBR project 13-03-00810-a.
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