Total synthesis of thelephantin O, vialinin A/Terrestrin A, and terrestrins B-D

Article abstract of DOI:10.1021/jo300565s

The first total synthesis of natural, unsymmetrical 2′,3′- diacyloxy-p-terphenyls, thelephantin O (1) and terrestrins C and D (2 and 3, respectively), was achieved via a practical route which was also applicable to the synthesis of the symmetrical diesters vialinin A/terrestrin A (4) and terrestrin B (5). Compounds 1-5 exhibited cytotoxicity against cancer cells (HepG2 and Caco2) with IC₅₀ values of 13.6-26.7 μmol/L.

Full text of DOI:10.1021/jo300565s

Note
pubs.acs.org/joc
Total Synthesis of Thelephantin O, Vialinin A/Terrestrin A, and
Terrestrins B−D
Kenshu Fujiwara,*,† Takuto Sato,† Yusuke Sano,† Toshio Norikura,‡ Ryo Katoono,† Takanori Suzuki,†
and Hajime Matsue‡
†Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
‡Department of Nutrition, Faculty of Health Science, Aomori University of Health and Welfare, Mase 58-1, Hamadate, Aomori
030-8505, Japan
S
* Supporting Information
ABSTRACT: The first total synthesis of natural, unsym-
metrical 2′,3′-diacyloxy-p-terphenyls, thelephantin O (1) and
terrestrins C and D (2 and 3, respectively), was achieved via a
practical route which was also applicable to the synthesis of the
symmetrical diesters vialinin A/terrestrin A (4) and terrestrin
B (5). Compounds 1−5 exhibited cytotoxicity against cancer
cells (HepG2 and Caco2) with IC50 values of 13.6−26.7
μmol/L.
skeleton,7 the steps were modified to obtain a reasonable
amount of 4.8 Furthermore, we explored more efficient routes
to related compounds, particularly to unsymmetrical diesters
1−3. Here, the first total synthesis of 1−3 via a new practical
route, which is also applicable to symmetrical diesters 4 and 5,
is described along with the cytotoxicity of synthetic 1−5 against
HepG2 and Caco2 cells.
helephantin O (1)1 (Figure 1) was recently isolated by
Norikura as a novel, naturally occurring 2′,3′-diacyloxy-p-
T
Our synthesis of 2′,3′-diacyloxy-p-terphenyl compounds 1−5,
outlined in Scheme 1, employed an isopropylidene acetal
Scheme 1. Outline of Synthesis Method for 1−5
Figure 1. Thelephantin O (1), vialinin A/terrestrin A (4), and
terrestrins B, C, and D (5, 2, and 3, respectively).
terphenyl compound from the fungus Thelephora aurantiotincta,
collected in Aomori Prefecture, Japan, along with vialinin A/
terrestrin A (4), previously isolated from other fungi of
Thelephora genus, T. vialis,2 and T. terrestris.3 Compounds 1
and 4 were also reported to show cytotoxicity against human
hepatocellular carcinoma cells (HepG2) and human colonic
carcinoma cells (Caco2).1 We are interested in the biological
properties of other members of the 2′,3′-diacyloxy-p-terphenyl
family, such as terrestrins B, C, and D (5, 2, and 3,
respectively),3,4 of which the bioactivity has not been
investigated so far. Therefore, we aimed to synthesize all of
these compounds for biological evaluation.
Vialinin A/terrestrin A (4) and terrestrin B (5) were first
synthesized by Takahashi et al.5,6 The synthetic path was
followed later by Fujiwara to prepare a reference compound for
identification of 4 isolated from T. aurantiotincta.1 Because the
path included some technical and poorly reproducible steps due
to the oxidation-sensitive middle ring of the p-terphenyl
group, instead of the methylene acetal group in the previous
synthesis,1,5 for protection of the 1,2-diol of the central benzene
ring, with the aim of simultaneously removing it and the TBS
Received: March 21, 2012
© XXXX American Chemical Society
A
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Note
ethers of the terminal benzene rings under acidic conditions at
the final stage. The installation of unsymmetrical or sym-
metrical diester was scheduled after the construction of the p-
terphenyl skeleton by Suzuki-Miyaura coupling9 of triarylbor-
oxine 710 and dibromide 8, derived concisely from
commercially available benzene-1,2,4-triol (9). Our synthesis
also relied on careful selection of reaction conditions for the
steps generating an unstable intermediate. In such cases, a
clean, catalytic reaction with no byproduct was employed, and
the unstable product was used immediately, without isolation,
in the next step.
Treatment of 10 with Frem
́
y’s salt produced water-soluble o-
quinone 11,13 which was isolated quantitatively in an almost
pure form by continuous extraction with EtOAc. The o-
quinone was reduced in THF by catalytic hydrogenation with
PtO2 to give air-sensitive 12,14 which was used immediately
without purification in the next reaction with MOMBr to
produce 13 in 77% yield over three steps. The ortho-lithiation
of 13 with BuLi, followed by reaction with 1,2-dibromo-1,1,2,2-
tetrafluoroethane, afforded 8 in 94% yield.
The p-terphenyl skeleton was constructed from 8 by Suzuki−
Miyaura cross-coupling under standard conditions (Scheme 3).
The reaction of 8 with 7 in the presence of (Ph3P)4Pd and
K2CO3 in refluxing aqueous 1,4-dioxane successfully afforded p-
terphenyl 6 (92%), of which the MOM groups were oxidatively
removed with DDQ in the presence of TsOH·H2O, according
to the Takahashi procedure,5,15 to give o-quinone 14 (98%).
Next, the formation of unsymmetrical diester was examined.
As benzo[d][1,3]dioxole-5,6-diol derivative 15, derived from 14
by hydrogenation with PtO2 catalyst in THF,14 was extremely
unstable in air, it was used in situ for the subsequent
esterification reaction. Our first attempt at unsymmetrical
diesterification via a dianion, generated from 15 with 2 equiv of
BuLi, by one-pot sequential addition of phenylacetyl chloride
and benzoyl chloride resulted in moderate yield of diester 17
(up to 51%) with significant byproduction of symmetrical
diesters. This may be attributable to a small difference in
reactivity between the dianion of 15 and the monoanion
generated by monoesterification of the dianion during the
reaction. Therefore, we explored a stepwise route for diesters.
Monodeprotonation of diol 15, generated in situ, with 1.2 equiv
of BuLi followed by reaction with phenylacetyl chloride
selectively afforded monoester 16 as a fairly stable compound
in 85% yield over two steps from 14.16 Monoester 16 was
deprotonated with NaH, and the resulting phenoxide was
treated with benzoyl chloride to successfully produce unsym-
metrical diester 17 in 96% yield. The esterification of 16 with
Dibromide 8 was synthesized from 9 in five steps (Scheme
2). Purified 911 was reacted with 2,2-dimethoxypropane, which
Scheme 2. Synthesis of Compound 8
was added portionwise to the reaction system in the presence
of a catalytic amount of PPTS in refluxing toluene with
azeotropic removal of methanol to produce 10 in 80% yield.12
When a strong acid catalyst, such as TsOH, or an increased
amount of PPTS was used in the reaction, significant amounts
of byproduct were obtained due to aromatic substitution.
Scheme 3. Total Synthesis of Thelephantin O (1), Vialinin A/Terrestrin A (4), and Terrestrins B, C, and D (5, 2, and 3,
respectively)
B
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NMR (100 MHz, CDCl3) δ 25.7 (CH3 × 2), 98.1 (CH), 106.0 (CH),
107.9 (CH), 118.2 (C), 141.5 (C), 148.0 (C), 150.1 (C); EI-HRMS
(m/z) calcd for C9H10O3 [M+] 166.0630, found 166.0657.
butanoyl chloride and acetyl chloride under the same
conditions also gave diesters 18 (69%) and 19 (78%),
respectively.
5,6-Bis(methoxymethoxy)-2,2-dimethylbenzo[d][1,3]dioxole
(13). To an ice-cooled, vigorously stirred suspension of KH2PO4
(1.552 g, 11.40 mmol) and potassium nitrosodisulfonate (6.067 g, 70%
purity, 15.82 mmol) in H2O (45 mL) was added dropwise a solution
of 10 (1.246 g, 7.498 mmol) in MeOH (3 mL), and the mixture was
stirred for 60 min at the same temperature. Then, the mixture was
saturated with NaCl (24 g) and subjected to continuous extraction
with EtOAc overnight. The extract was concentrated under reduced
pressure to give 2,2-dimethylbenzo[d][1,3]dioxole-5,6-dione (11)
(yellow needles, 1.360 g) in an almost pure form. 11: mp 180 °C
(sublimed); IR (KBr) ν 3088, 3027, 3001, 2926, 2853, 1659, 1633,
1403, 1390, 1284, 1229, 1214, 1146, 1083, 985, 870, 837, 661 cm−1;
1H NMR (400 MHz, CDCl3) δ 1.80 (6H, s), 5.94 (2H, s); 13C NMR
(100 MHz, CDCl3) δ 26.1 (CH3 × 2), 101.1 (CH × 2), 124.0 (C),
161.0 (C × 2), 177.8 (C × 2); EI-HRMS (m/z) calcd for C9H8O4
[M+] 180.0423, found 180.0454. To a suspension of the above 11
(1.360 g) in THF (50 mL) was added PtO2 (17.7 mg, 0.0779 mmol),
and the mixture was stirred under H2 atmosphere at 24 °C. After being
stirred for 2 h, the reaction mixture turned to a clear pale yellow
solution. Then, the solvent was removed under the reduced pressure,
and the residue (crude 2,2-dimethylbenzo[d][1,3]dioxole-5,6-diol, 12)
was immediately dissolved in DMF (38 mL). To the solution was
added NaH (60% in mineral oil, 1.267 g, 31.68 mmol) at 0 °C, and the
mixture was stirred for 1 h. To the resulting dark blue solution was
added dropwise bromomethyl methyl ether (2.5 mL, 31 mmol) at 0
°C, and the mixture was stirred at 24 °C for 20 h. The reaction was
quenched with H2O, and the mixture was extracted with EtOAc
several times. The combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, hexane/EtOAc = 12) to give 13 (1.557 g, 5.760
mmol, 77% over three steps) as a colorless oil. 13: IR (neat) ν 3122,
3086, 3062, 2991, 2953, 2936, 2903, 2827, 1494, 1386, 1377, 1244,
1215, 1151, 1083, 1045, 980, 922, 877, 844, 787 cm−1; 1H NMR (400
MHz, CDCl3) δ 1.64 (6H, s), 3.52 (6H, s), 5.09 (4H, s), 6.66 (2H, s);
13C NMR (100 MHz, CDCl3) δ 25.7 (CH3 × 2), 56.1 (CH3 × 2), 96.8
(CH2 × 2), 100.7 (CH × 2), 118.3 (C), 141.4 (C × 2), 142.4 (C × 2);
EI-HRMS (m/z) calcd for C13H18O6 [M+] 270.1103, found 270.1137.
4,7-Dibromo-5,6-bis(methoxymethoxy)-2,2-dimethylbenzo-
[d][1,3]dioxole (8). To a solution of 13 (141.9 mg, 0.5250 mmol) in
THF (2.1 mL) was added dropwise BuLi (1.65 mol/L in hexane, 0.95
mL, 1.6 mmol) at 0 °C, and the mixture was stirred for 1 h. To the
resulting suspension was added dropwise 1,2-dibromo-1,1,2,2-tetra-
fluoroethane (0.20 mL, 1.7 mmol) at 0 °C, and the mixture was stirred
for 1 h. To the mixture was added H2O, and the mixture was extracted
with EtOAc several times. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 15) to give 8 (211.0
mg, 0.4929 mmol, 94%) as a colorless solid. 8: mp 149−151 °C; IR
(KBr) ν 2992, 2963, 2935, 2923, 2831, 1452, 1377, 1362, 1309, 1251,
1222, 1162, 1088, 1054, 1018, 987, 965, 934, 922, 855, 806, 749, 719
cm−1; 1H NMR (400 MHz, CDCl3) δ 1.76 (6H, s), 3.66 (6H, s), 5.10
(4H, s); 13C NMR (100 MHz, CDCl3) δ 26.0 (CH3 × 2), 58.3 (CH3
× 2), 96.9 (C × 2), 99.7 (CH2 × 2), 120.6 (C), 142.0 (C × 2), 142.6
(C × 2); EI-HRMS (m/z) calcd for C13H16O679Br2 [M+] 425.9314,
found 425.9322.
4,7-Bis[4-(tert-butyldimethylsilyloxy)phenyl]-5,6-bis-
(methoxymethoxy)-2,2-dimethylbenzo[d][1,3]dioxole (6). To a
mixture of 8 (1.193 g, 2.787 mmol), tris[4-(tert-butyldimethylsilyloxy)-
phenyl]boroxine (7) (2.947 g, 4.195 mmol), K2CO3 (2.319 g, 16.80
mmol), Pd(PPh3)4 (163.8 mg, 0.1417 mmol) was added a 3:1 mixture
of 1,4-dioxane and H2O (30 mL) at 24 °C, and the mixture was
refluxed for 2 h. The mixture was cooled to 24 °C, and satd aq NH4Cl
(30 mL) was added to the mixture. The mixture was extracted with
EtOAc several times. The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated under
Symmetrical diesters 20 and 21 were synthesized via
diesterification of the dianion of 15, in line with Takahashi’s
method,5 in good yield (81% and 98%, respectively, over two
steps).
Finally, the optimal conditions for removal of TBS and the
isopropylidene acetal groups were determined after intensive
exploration. As the treatment of 17 with methanolic HCl at 50
°C removed only the TBS groups, and the isopropylidene
acetal remained intact, the combination of a Lewis acid and
ethane-1,2-dithiol was employed for deprotection. Among
several Lewis acids examined, SnCl4 and AlCl3 were found to
cleave both the isopropylidene acetal and TBS groups of 17.
However, SnCl4 formed firm a chelate complex with product 1,
and hence the desired 1 was isolated at low yield. On the other
hand, AlCl3 cleanly produced 1. Thus, after optimization of the
reaction conditions, deprotection of 17 was achieved on
treatment with ethane-1,2-dithiol and AlCl3 in nitromethane at
−20 °C to give 1 at 88% yield. Compounds 18, 19, 20, and 21
were also deprotected under the same conditions to produce 2
(88%), 3 (95%), 4 (73%), and 5 (93%), respectively, in good
yield.
The spectral data for synthetic 1, 2, 3, 4, and 5 were identical
to those for natural thelephantin O,1 terrestrin C,3 terrestrin
D,3 vialinin A/terrestrin A,2,3 and terrestrin B,3,5b respectively.
The cytotoxicity of the synthetic compounds against HepG2
and Caco2 was then investigated. Compounds 1,17,18 2, 3, 4,17
and 5 exhibited inhibitory activity against HepG2/Caco2
growth, with IC50 values of 16.3/24.1, 13.6/24.1, 15.5/26.5,
14.1/23.7, and 20.7/26.7 μmol/L, respectively. Thus, the
cytotoxic effects of terrestrins B−D on cancer cells were
confirmed.
In conclusion, the first total synthesis of natural, unsym-
metrical 2′,3′-diacyloxy-p-terphenyls, thelephantin O (1), and
terrestrins C and D (2 and 3, respectively), was achieved via a
practical route, which was also applicable to the synthesis of
symmetrical diesters, vialinin A/terrestrin A (4) and terrestrin
B (5). p-Terphenyl compounds 1−5 exhibited cytotoxicity
against cancer cells (HepG2 and Caco2) with IC50 values of
13.6−26.7 μmol/L.
EXPERIMENTAL SECTION
General experimental methods are provided in the Supporting
Information.
■
2,2-Dimethylbenzo[d][1,3]dioxol-5-ol (10). In a two-necked
flask, equipped with a distillation apparatus in one neck and a stopcock
in the other, were added benzene-1,2,4-triol (9) (purified by silica gel
column chromatography, 629.2 mg, 4.989 mmol), pyridinium p-
toluenesulfonate (1.0 mg, 0.004 mmol), and anhydrous toluene (50
mL), and the mixture was stirred and heated to reflux with slow
distillation of the solvent (ca. 0.7 mL/min). To the mixture was added
2,2-dimethoxypropane portionwise through the stopcock every 15 min
(0.15 mL × 4 and 0.10 mL × 3: total 0.90 mL, 7.3 mmol). During the
reaction, toluene (10 mL) was also added every 15 min to compensate
for the loss of solvent. After 110 min from the start of the reaction, the
reaction mixture was cooled to 24 °C and was directly subjected to
column chromatography (silica gel, hexane/EtOAc = 10 → 1) to give
10 (664.4 mg, 3.998 mmol, 80%) as a colorless oil along with
recovered 9 (97.2 mg, 7.71 mmol, 15%). 10: IR (neat) ν 3369, 3073,
3054, 2991, 2937, 1636, 1618, 1496, 1476, 1386, 1377, 1275, 1221,
1152, 1116, 1074, 980, 946, 835, 787, 764 cm−1; 1H NMR (400 MHz,
CDCl3) δ 1.65 (6H, s), 4.70−4.99 (1H, brs, OH), 6.21 (1H, dd, J =
2.6, 8.3 Hz), 6.34 (1H, d, J = 2.6 Hz), 6.55 (1H, d, J = 8.3 Hz); 13C
C
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reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, hexane/EtOAc = 100 → 50) to give 6 (1.756 g, 2.571
mmol, 92%) as a colorless solid. 6: mp 166−169 °C; IR (KBr) ν 3040,
2992, 2956, 2930, 2896, 2858, 2826, 1608, 1517, 1472, 1463, 1438,
1398, 1376, 1363, 1298, 1262, 1217, 1170, 1160, 1102, 1080, 1043,
1013, 973, 950, 915, 838, 804, 781 cm−1; 1H NMR (400 MHz,
CDCl3) δ 0.22 (12H, s), 1.00 (18H, s), 1.66 (6H, s), 3.01 (6H, s), 4.84
(4H, s), 6.88 (4H, d, J = 8.6 Hz), 7.45 (4H, d, J = 8.6 Hz); 13C NMR
(100 MHz, CDCl3) δ −4.4 (CH3 × 4), 18.2 (C × 2), 25.7 (CH3 × 6),
26.0 (CH3 × 2), 57.0 (CH3 × 2), 99.2 (CH2 × 2), 117.3 (C × 2),
117.8 (C), 119.6 (CH × 4), 125.7 (C × 2), 131.6 (CH × 4), 141.1 (C
× 2), 141.3 (C × 2), 154.9 (C × 2); FD-HRMS (m/z) calcd for
C37H54O8Si2 [M+] 682.3357, found 682.3378.
mixture was stirred for 1 h. To the mixture was added benzoyl chloride
(0.024 mL, 0.21 mmol) at 0 °C, and the mixture was stirred at 24 °C
for 22 h. The reaction was quenched with satd aq NH4Cl, and the
mixture was extracted with EtOAc several times. The combined
organic layers were washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, hexane/EtOAc = 50 →
20) to give 17 (80.6 mg, 0.0986 mmol, 96%) as a colorless solid. 17:
mp 78−79 °C; IR (KBr) ν 3089, 3064, 3034, 2956, 2930, 2896, 2887,
2858, 1768, 1748, 1609, 1520, 1463, 1440, 1392, 1377, 1258, 1219,
1173, 1112, 1080, 1066, 1046, 1025, 1006, 914, 841, 805, 782, 709
cm−1; 1H NMR (400 MHz, CDCl3) δ 0.11 (6H, s), 0.24 (6H, s), 0.91
(9H, s), 1.01 (9H, s), 1.71 (6H, s), 3.42 (2H, s), 6.74 (2H, d, J = 8.6
Hz), 6.80 (2H, d, J = 8.6 Hz), 6.92 (2H, brd, J = 8.0 Hz), 6.99−7.08
(3H, m), 7.32 (2H, d, J = 8.6 Hz), 7.37 (2H, d, J = 8.6 Hz), 7.39 (2H,
brt, J = 7.8 Hz), 7.56 (1H, brt, J = 7.5 Hz), 7.92 (2H, brd, J = 8.0 Hz);
13C NMR (100 MHz, CDCl3) δ −4.5 (CH3 × 2), −4.4 (CH3 × 2),
18.1 (C), 18.2 (C), 25.58 (CH3 × 3), 25.64 (CH3 × 3), 26.0 (CH3 ×
2), 40.7 (CH2), 116.3 (C), 116.4 (C), 118.9 (C), 119.6 (CH × 2),
119.7 (CH × 2), 124.1 (C), 124.2 (C), 126.9 (CH), 128.3 (CH × 2),
128.4 (CH × 2), 128.8 (C), 129.1 (CH × 2), 130.1 (CH × 2), 130.7
(CH × 2), 130.8 (CH × 2), 132.7 (C), 133.4 (C), 134.36 (C), 134.40
(C), 142.8 (C), 142.9 (C), 155.2 (C), 155.3 (C), 164.3 (C), 169.1
(C); FD-HRMS (m/z) calcd for C48H56O8Si2 [M+] 816.3514, found
816.3477.
4,7-Bis[4-(tert-butyldimethylsilyloxy)phenyl]-2,2-dimethyl-
6-(phenylacetoxy)benzo[d][1,3]dioxol-5-yl Butanoate (18). In
the same manner as 17, compound 18 was synthesized as a colorless
solid (57.6 mg, 0.0736 mmol, 69%) from 16 (75.4 mg, 0.106 mmol),
NaH (60% in mineral oil, 10.3 mg, 0.258 mmol), and butanoyl
chloride (0.0221 mL, 0.212 mmol). 18: mp 157−159 °C; IR (KBr) ν
3088, 3067, 3035, 2959, 2932, 2899, 2888, 2861, 1770, 1605, 1518,
1468, 1441, 1396, 1264, 1176, 1126, 1110, 1011, 917, 841, 807, 785,
730 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.20 (6H, s), 0.24 (6H, s),
0.74 (3H, t, J = 7.4 Hz), 0.98 (9H, s), 1.01 (9H, s), 1.37 (2H, sx, J =
7.4 Hz), 1.68 (6H, s), 1.91 (2H, t, J = 7.4 Hz), 3.57 (2H, s), 6.80 (2H,
d, J = 8.6 Hz), 6.82 (2H, d, J = 8.6 Hz), 7.19 (2H, brd, J = 8.0 Hz),
7.21−7.31 (3H, m), 7.30 (4H, d, J = 8.6 Hz); 13C NMR (100 MHz,
CDCl3) δ −4.4 (CH3 × 2), −4.3 (CH3 × 2), 13.5 (CH3), 18.0 (CH2),
18.2 (C × 2), 25.7 (CH3 × 6), 26.0 (CH3 × 2), 35.2 (CH2), 40.9
(CH2), 116.2 (C), 116.4 (C), 118.9 (C), 119.7 (CH × 4), 124.2 (C),
124.3 (C), 127.2 (CH), 128.6 (CH × 2), 129.4 (CH × 2), 130.8 (CH
× 2), 130.9 (CH × 2), 133.0 (C), 134.2 (C × 2), 142.7 (C), 142.9
(C), 155.3 (C × 2), 168.9 (C), 171.0 (C); FD-HRMS (m/z) calcd for
C45H58O8Si2 [M+] 782.3670, found 782.3658.
6-Acetoxy-4,7-bis[4-(tert-butyldimethylsilyloxy)phenyl]-2,2-
dimethylbenzo[d][1,3]dioxol-5-yl Phenylacetate (19). In the
same manner as 17, compound 19 was synthesized as a colorless solid
(23.9 mg, 0.0317 mmol, 78%) from 16 (29.0 mg, 0.0407 mmol), NaH
(60% in mineral oil, 12.0 mg, 0.300 mmol), and AcCl (0.007 mL, 0.1
mmol). 19: mp 157−160 °C; IR (KBr) ν 3088, 3067, 3035, 2955,
2930, 2895, 2858, 1772, 1609, 1520, 1472, 1464, 1440, 1394, 1376,
1368, 1300, 1263, 1217, 1196, 1172, 1110, 1020, 914, 839, 805, 782
cm−1; 1H NMR (400 MHz, CDCl3) δ 0.21 (6H, s), 0.24 (6H, s), 0.98
(9H, s), 1.01 (9H, s), 1.65 (3H, s), 1.68 (6H, s), 3.58 (2H, s), 6.82
(2H, d, J = 8.6 Hz), 6.83 (2H, d, J = 8.6 Hz), 7.20−7.32 (5H, m),
7.307 (2H, d, J = 8.6 Hz), 7.315 (2H, d, J = 8.6 Hz); 13C NMR (100
MHz, CDCl3) δ −4.4 (CH3 × 2), −4.3 (CH3 × 2), 18.2 (C × 2), 19.9
(CH3), 25.6 (CH3 × 6), 26.1 (CH3 × 2), 41.0 (CH2), 116.22 (C),
116.25 (C), 118.9 (C), 119.7 (CH × 4), 124.1 (C), 124.2 (C), 127.2
(CH), 128.7 (CH × 2), 129.4 (CH × 2), 130.74 (CH × 2), 130.78
(CH × 2), 133.1 (C), 134.1 (C), 134.2 (C), 142.81 (C), 142.84 (C),
155.3 (C × 2), 168.5 (C), 168.9 (C); FD-HRMS (m/z) calcd for
C43H54O8Si2 [M+] 754.3357, found 754.3337.
4,7-Bis[4-(tert-butyldimethylsilyloxy)phenyl]-2,2-
dimethylbenzo[d][1,3]dioxole-5,6-dione (14). To a solution of 6
(1.756 g, 2.571 mmol) in benzene (30 mL) were added 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (883.5 mg, 3.892 mmol) and TsOH·-
H2O (253.4 mg, 1.318 mmol) at 24 °C, and the mixture was heated to
50 °C for 24 min with stirring. The reaction was quenched with satd
aq NaHCO3, and the mixture was extracted with CHCl3 several times.
The combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, hexane/EtOAc = 5) to
give 14 (1.497 g, 2.524 mmol, 98%) as red needles. 14: mp 258−261
°C; IR (KBr) ν 3072, 3043, 2994, 2956, 2930, 2895, 2886, 2858, 1672,
1636, 1603, 1511, 1472, 1463, 1389, 1381, 1342, 1299, 1277, 1268,
1225, 1178, 1153, 1075, 1034, 1011, 918, 843, 823, 811, 784, 715
1
cm−1; H NMR (400 MHz, CDCl3) δ 0.23 (12H, s), 1.00 (18H, s),
1.83 (6H, s), 6.88 (4H, d, J = 8.7 Hz), 7.53 (4H, d, J = 8.7 Hz); 13C
NMR (100 MHz, CDCl3) δ −4.4 (CH3 × 4), 18.1 (C × 2), 25.6 (CH3
× 6), 26.3 (CH3 × 2), 112.7 (C × 2), 119.6 (CH × 4), 121.6 (C),
122.2 (C × 2), 130.9 (CH × 4), 155.6 (C × 2), 156.0 (C × 2), 176.8
(C × 2); FD-HRMS (m/z) calcd for C33H44O6Si2 [M+] 592.2676,
found 592.2682.
4,7-Bis[4-(tert-butyldimethylsilyloxy)phenyl]-6-hydroxy-2,2-
dimethylbenzo[d][1,3]dioxol-5-yl Phenylacetate (16). To a
solution of 14 (253.2 mg, 0.4271 mmol) in THF (4.2 mL) was
added PtO2 (4.8 mg, 0.021 mmol), and the mixture was stirred under
H2 atmosphere at 24 °C. After being stirred for 1 h, the red reaction
solution turned to a clear pale yellow solution. Then, the solution
(including 4,7-bis[4-(tert-butyldimethylsilyloxy)phenyl]-2,2-
dimethylbenzo[d][1,3]dioxole-5,6-diol (15)) was placed under Ar
atmosphere, and cooled to −78 °C. To the solution were added BuLi
(1.62 mol/L in hexane, 0.316 mL, 0.512 mmol) and the mixture was
stirred at −78 °C for 1 h. Then, to the mixture was added phenylacetyl
chloride (0.0678 mL, 0.512 mmol) at −78 °C, and the mixture was
warmed to 0 °C and stirred for 21 h. Then, the mixture was filtered
through a Celite pad, and the filtrate was concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel, hexane/toluene/EtOAc = 50/50/1) followed by recrystallization
(EtOH, several times) to give 16 (257.5 mg, 0.3611 mmol, 85%) as a
colorless solid. 16: mp 189−191 °C; IR (KBr) ν 3429, 3089, 3063,
3034, 2984, 2956, 2930, 2896, 2886, 2858, 1766, 1736, 1609, 1521,
1472, 1442, 1392, 1376, 1329, 1262, 1215, 1173, 1128, 1058, 1009,
1
916, 840, 805, 781, 730 cm−1; H NMR (400 MHz, CDCl3) δ 0.23
(6H, s), 0.24 (6H, s), 1.00 (9H, s), 1.02 (9H, s), 1.64 (6H, s), 3.67
(2H, s), 4.72 (1H, s, OH), 6.80 (2H, d, J = 8.5 Hz), 6.91 (2H, d, J =
8.5 Hz), 7.18 (2H, brd, J = 7.8 Hz), 7.21−7.28 (3H, m), 7.29 (2H, d, J
= 8.5 Hz), 7.41 (2H, d, J = 8.5 Hz); 13C NMR (100 MHz, CDCl3) δ
−4.4 (CH3 × 2), −4.3 (CH3 × 2), 18.1 (C), 18.2 (C), 25.62 (CH3 ×
3), 25.63 (CH3 × 3), 25.8 (CH3 × 2), 40.9 (CH2), 110.9 (C), 116.2
(C), 118.0 (C), 119.6 (CH × 2), 120.2 (CH × 2), 123.8 (C), 124.6
(C), 127.2 (CH), 128.6 (CH × 2), 129.1 (C), 129.3 (CH × 2), 130.7
(CH × 2), 131.1 (CH × 2), 133.3 (C), 138.4 (C), 139.1 (C), 142.7
(C), 155.1 (C), 155.5 (C), 169.6 (C); FD-HRMS (m/z) calcd for
C41H52O7Si2 [M+] 712.3252, found 712.3219.
4,7-Bis[4-(tert-butyldimethylsilyloxy)phenyl]-2,2-
dimethylbenzo[d][1,3]dioxole-5,6-diyl Bis(phenylacetate) (20).
To a solution of 14 (100.0 mg, 0.1687 mmol) in THF (3.4 mL) was
added PtO2 (1.9 mg, 0.0084 mmol), and the mixture was stirred under
H2 atmosphere at 24 °C. After being stirred for 1 h, the red reaction
solution turned to a clear pale yellow solution. Then, the solution
4,7-Bis[4-(tert-butyldimethylsilyloxy)phenyl]-2,2-dimethyl-
6-(phenylacetoxy)benzo[d][1,3]dioxol-5-yl Benzoate (17). To a
solution of 16 (73.1 mg, 0.103 mmol) in THF (2.0 mL) was added
NaH (60% in mineral oil, 15.4 mg, 0.385 mmol) at 0 °C, and the
D
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The Journal of Organic Chemistry
Note
(including 15) was placed under Ar atmosphere, and cooled to −78
°C. To the solution were added BuLi (1.65 mol/L in hexane, 0.307
mL, 0.506 mmol) and the mixture was stirred at −78 °C for 1 h. Then,
to the mixture was added phenylacetyl chloride (0.067 mL, 0.51
mmol) at −78 °C, and the mixture was warmed to 0 °C and stirred for
17 h. Then, the mixture was filtered through a Celite pad, and the
filtrate was concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, hexane/EtOAc = 50 →
15) to give 20 (113.9 mg, 0.1370 mmol, 81% over two steps) as a
colorless solid. 20: mp 174−175 °C; IR (KBr) ν 3088, 3064, 3033,
2955, 2930, 2887, 2858, 1772, 1609, 1520, 1471, 1463, 1440, 1391,
1376, 1263, 1219, 1172, 1125, 1106, 1011, 915, 841, 806, 782, 730,
1077, 983, 834, 730, 697 cm−1; 1H NMR (400 MHz, CD3OD) δ 0.70
(3H, t, J = 7.4 Hz), 1.30 (2H, brsx, J = 7.4 Hz), 1.86 (2H, t, J = 7.3
Hz), 3.48 (2H, s), 6.796 (2H, d, J = 8.7 Hz), 6.800 (2H, d, J = 8.7 Hz),
7.06 (2H, dd, J = 1.8, 7.6 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.13 (2H, d, J
= 8.7 Hz), 7.18−7.27 (3H, m); 13C NMR (100 MHz, CD3OD) δ 13.7
(CH3), 19.0 (CH2), 36.1 (CH2), 41.5 (CH2), 115.97 (CH × 2),
116.10 (CH × 2), 123.86 (C), 123.93 (C), 124.91 (C), 124.98 (C),
128.1 (CH), 129.6 (CH × 2), 130.4 (CH × 2), 132.62 (CH × 2),
132.67 (CH × 2), 134.71 (C), 134.76 (C), 134.80 (C), 142.49 (C),
142.61 (C), 158.2 (C × 2), 171.2 (C), 173.1 (C); UV−vis (MeOH) λ
(log ε) 204 (4.76, shoulder), 227 (4.38), 262 (4.30) nm; FD-HRMS
(m/z) calcd for C30H26O8 [M+] 514.1628, found 514.1617.
1
696 cm−1; H NMR (400 MHz, CDCl3) δ 0.23 (12H, s), 1.00 (18H,
Terrestrin D (3). In the same manner as 1, compound 3 was
synthesized as a pale brown solid (15.9 mg, 0.0327 mmol, 95%) from
19 (25.9 mg, 0.0343 mmol), ethane-1,2-dithiol (0.029 mL, 0.35
mmol), and AlCl3 (37.4 mg, 0.280 mmol). 3: mp 118−120 °C; IR
(KBr) ν 3425, 3061, 3031, 2958, 2924, 2855, 1757, 1701, 1613, 1526,
1457, 1426, 1369, 1340, 1214, 1173, 1106, 1014, 980, 903, 834, 730,
s), 1.67 (6H, s), 3.29 (4H, s), 6.75 (4H, d, J = 8.5 Hz), 7.09 (4H, brd, J
= 8.0 Hz), 7.20−7.29 (10H, m); 13C NMR (100 MHz, CDCl3) δ −4.3
(CH3 × 4), 18.1 (C × 2), 25.6 (CH3 × 6), 26.0 (CH3 × 2), 40.4 (CH2
× 2), 116.3 (C × 2), 118.8 (C), 119.6 (CH × 4), 124.0 (C × 2), 127.2
(CH × 2), 128.5 (CH × 4), 129.4 (CH × 4), 130.7 (CH × 4), 133.1
(C × 2), 134.1 (C × 2), 142.8 (C × 2), 155.2 (C × 2), 168.8 (C × 2);
FD-HRMS (m/z) calcd for C49H58O8Si2 [M+] 830.3670, found
830.3690.
1
696, 592, 536 cm−1; H NMR (400 MHz, CD3OD) δ 1.61 (3H, s),
3.50 (2H, s), 6.80 (4H, d, J = 8.7 Hz), 7.08 (2H, dd, J = 1.6, 7.7 Hz),
7.12 (2H, d, J = 8.7 Hz), 7.14 (2H, d, J = 8.7 Hz), 7.19−7.28 (3H, m);
13C NMR (100 MHz, CD3OD) δ 20.0 (CH3), 41.5 (CH2), 115.96
(CH × 2), 116.10 (CH × 2), 123.80 (C), 123.86 (C), 124.89 (C),
124.96 (C), 128.2 (CH), 129.6 (CH × 2), 130.4 (CH × 2), 132.56
(CH × 2), 132.62 (CH × 2), 134.71 (C), 134.80 (C), 134.82 (C),
142.55 (C), 142.57 (C), 158.12 (C), 158.18 (C), 170.5 (C), 171.2
(C); UV−vis (MeOH) λ (log ε) 204 (4.80), 224 (4.42), 263 (4.39)
nm; FD-HRMS (m/z) calcd for C28H22O8 [M+] 486.1315, found
486.1331.
4,7-Bis[4-(tert-butyldimethylsilyloxy)phenyl]-2,2-
dimethylbenzo[d][1,3]dioxole-5,6-diyl Bis(butanoate) (21). In
the same manner as 20, compound 21 was synthesized as a colorless
solid (116.8 mg, 0.1589 mmol, 98% over two steps) from 14 (96.1 mg,
0.162 mmol), PtO2 (≤1.0 mg, ≤ 0.0044 mmol), H2, BuLi (1.62 mol/L
in hexane, 0.30 mL, 0.49 mmol), and butanoyl chloride (0.0508 mL,
0.486 mmol). 21: mp 164−168 °C; IR (KBr) ν 3066, 3041, 2958,
2930, 2898, 2885, 2859, 1771, 1608, 1520, 1471, 1464, 1440, 1394,
1377, 1362, 1299, 1263, 1221, 1169, 1141, 1109, 1094, 1077, 1017,
Vialinin A/Terrestrin A (4). In the same manner as 1, compound
4 was synthesized as a colorless solid (11.3 mg, 0.0201 mmol, 73%)
from 20 (22.9 mg, 0.0276 mmol), ethane-1,2-dithiol (0.0236 mL,
0.283 mmol), and AlCl3 (36.7 mg, 0.275 mmol). 4: mp 211−213 °C;
IR (KBr) ν 3427, 3088, 3064, 3033, 2925, 2853, 1760, 1613, 1525,
1496, 1455, 1428, 1384, 1343, 1229, 1173, 1126, 985, 835, 731, 696,
588, 538, 513 cm−1; 1H NMR (400 MHz, acetone-d6) δ 3.36 (4H, s),
6.83 (4H, d, J = 8.7 Hz), 7.02 (4H, brd, J = 8.1 Hz), 7.12 (4H, d, J =
1
1010, 916, 837, 805, 782 cm−1; H NMR (300 MHz, CDCl3) δ 0.22
(12H, s), 0.82 (6H, t, J = 7.4 Hz), 0.99 (18H, s), 1.53 (4H, sx, J = 7.4
Hz), 1.68 (6H, s), 2.26 (4H, t, J = 7.4 Hz), 6.84 (4H, d, J = 8.6 Hz),
7.33 (4H, d, J = 8.6 Hz); 13C NMR (75 MHz, CDCl3) δ −4.4 (CH3 ×
4), 13.5 (CH3 × 2), 18.17 (C × 2), 18.21 (CH2 × 2), 25.6 (CH3 × 6),
26.0 (CH3 × 2), 35.7 (CH2 × 2), 116.4 (C × 2), 118.8 (C), 119.7
(CH × 4), 124.4 (C × 2), 130.9 (CH × 4), 134.3 (C × 2), 142.8 (C ×
2), 155.3 (C × 2), 171.1 (C × 2); FD-HRMS (m/z) calcd for
C41H58O8Si2 [M+] 734.3670, found 734.3683.
1
8.7 Hz), 7.19−7.28 (6H, m); H NMR (400 MHz, CD3OD) δ 3.25
(4H, s), 6.77 (4H, d, J = 8.7 Hz), 6.96 (4H, brd, J = 8.1 Hz), 7.09 (4H,
d, J = 8.7 Hz), 7.17−7.26 (6H, m); 13C NMR (100 MHz, acetone-d6)
δ 40.6 (CH2 × 2), 115.9 (CH × 4), 123.1 (C × 2), 124.4 (C × 2),
127.7 (CH × 2), 129.2 (CH × 4), 130.2 (CH × 4), 132.3 (CH × 4),
134.6 (C × 2), 134.7 (C × 2), 141.7 (C × 2), 157.8 (C × 2), 169.6 (C
× 2); 13C NMR (100 MHz, CD3OD) δ 41.1 (CH2 × 2), 116.1 (CH ×
4), 123.9 (C × 2), 124.8 (C × 2), 128.1 (CH × 2), 129.6 (CH × 4),
130.4 (CH × 4), 132.6 (CH × 4), 134.68 (C × 2), 134.72 (C × 2),
142.6 (C × 2), 158.1 (C × 2), 171.2 (C × 2); UV−vis (MeOH) λ (log
ε) 209 (4.68, shoulder), 230 (4.31), 261 (4.20) nm; FD-HRMS (m/z)
calcd for C34H26O8 [M+] 562.1628, found 562.1607.
Thelephantin O (1). To a solution of 17 (28.2 mg, 0.0345 mmol)
and ethane-1,2-dithiol (0.0322 mL, 0.345 mmol) in MeNO2 (0.7 mL)
was added AlCl3 (40.0 mg, 0.300 mmol) at −20 °C, and the mixture
was stirred for 30 min. To the solution were added satd aq potassium
sodium tartrate, H2O, and EtOAc, and the mixture was stirred at 24 °C
for 1 h. Then, the mixture was extracted with EtOAc several times.
The combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel,
CHCl3/MeOH = 20) to give 1 (16.7 mg, 0.0304 mmol, 88%) as a
colorless solid. 1: mp 246−247 °C; IR (KBr) ν 3432, 3036, 2919,
2850, 1738, 1632, 1613, 1526, 1452, 1429, 1263, 1173, 1107, 1059,
1024, 973, 833, 711, 699, 544 cm−1; 1H NMR (400 MHz, CD3OD) δ
3.32 (2H, s), 6.70 (2H, d, J = 8.8 Hz), 6.79 (2H, brd, J = 7.9 Hz), 6.81
(2H, d, J = 8.8 Hz), 6.94−7.03 (3H, m), 7.16 (2H, d, J = 8.8 Hz), 7.20
(2H, d, J = 8.8 Hz), 7.41 (2H, brdd, J = 7.5, 8.4 Hz), 7.59 (1H, brtt, J =
1.3, 7.5 Hz), 7.80 (2H, brdd, J = 1.3, 8.4 Hz); 13C NMR (100 MHz,
CD3OD) δ 41.3 (CH2), 115.9 (CH × 2), 116.1 (CH × 2), 123.88
(C), 123.95 (C), 124.82 (C), 124.84 (C), 127.9 (CH), 129.3 (CH ×
2), 129.6 (CH × 2), 130.04 (CH × 2), 130.08 (C), 130.9 (CH × 2),
132.55 (CH × 2), 132.61 (CH × 2), 134.2 (C), 134.7 (CH), 134.83
(C), 134.92 (C), 142.6 (C × 2), 157.9 (C), 158.1 (C), 166.1 (C),
171.3 (C); UV−vis (MeOH) λ (log ε) 208 (4.83), 231 (4.66), 261
(4.44) nm; FD-HRMS (m/z) calcd for C33H24O8 [M+] 548.1471,
found 548.1463.
Terrestrin B (5). In the same manner as 1, compound 5 was
synthesized as a pale yellow solid (6.0 mg, 0.013 mmol, 93%) from 21
(10.2 mg, 0.0139 mmol), ethane-1,2-dithiol (0.012 mL, 0.14 mmol),
and AlCl3 (28.2 mg, 0.211 mmol). 5: mp 182−184 °C; IR (KBr) ν
3425, 2968, 2934, 2875, 1745, 1639, 1632, 1614, 1598, 1526, 1461,
1385, 1250, 1172, 1104, 978, 832 cm−1; 1H NMR (400 MHz,
CD3OD) δ 0.76 (6H, t, J = 7.4 Hz), 1.43 (4H, brsx, J = 7.3 Hz), 2.16
(4H, t, J = 7.1 Hz), 6.82 (4H, d, J = 8.6 Hz), 7.15 (4H, d, J = 8.6 Hz);
13C NMR (100 MHz, CD3OD) δ 13.8 (CH3 × 2), 19.2 (CH2 × 2),
36.4 (CH2 × 2), 116.0 (CH × 4), 123.9 (C × 2), 125.0 (C × 2), 132.7
(CH × 4), 134.8 (C × 2), 142.5 (C × 2), 158.2 (C × 2), 173.1 (C ×
2); UV−vis (MeOH) λ (log ε) 204 (4.71), 226 (4.38), 263 (4.35) nm;
FD-HRMS (m/z) calcd for C26H26O8 [M+] 466.1628, found 466.1629.
ASSOCIATED CONTENT
* Supporting Information
General experimental methods, the assay method for
■
Terrestrin C (2). In the same manner as 1, compound 2 was
synthesized as a pale brown solid (8.5 mg, 0.017 mmol, 88%) from 18
(14.7 mg, 0.0188 mmol), ethane-1,2-dithiol (0.016 mL, 0.19 mmol),
and AlCl3 (21.2 mg, 0.159 mmol). 2: mp 91−93 °C; IR (neat) ν 3414,
3090, 3065, 3033, 2976, 2935, 2876, 1767, 1751, 1703, 1613, 1592,
1526, 1496, 1456, 1429, 1384, 1365, 1269, 1230, 1173, 1147, 1108,
S
1
cytotoxicity against HepG2 and Caco2 cells, and copies of H
and 13C NMR spectra of all new compounds as well as
synthetic thelephantin O, vialinin A/terrestrin A, and terrestrins
E
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The Journal of Organic Chemistry
Note
of monoester 16 and diester 20 (total 77% yield) along with a small
amount of recovered 14. However, the separation of the mixture of 16
and 20 proved to be difficult. Therefore, esterification of a monoanion
of diol 15, which gave monoester 16 almost exclusively, was employed.
(17) In the previous report,1 the inhibition rate of cell viability in
HepG2/Caco2 by natural thelephantin O and vialinin A (terrestrin A)
at 8 μmol/L concentration showed 53.91 3.34%/67.74 2.34% and
38.85 5.14%/55.41 0.92%, respectively. Synthetic vialinin A also
B−D. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: fjwkn@sci.hokudai.ac.jp.
■
Notes
exhibited 44.23
concentration.
3.54% inhibition against HepG2 at 8 μmol/L
The authors declare no competing financial interest.
(18) In this work, the inhibitory activity of natural thelephantin O
against HepG2 and Caco2 was remeasured, and the IC50 values were
determined to be 15.8 (HepG2) and 15.2 μmol/L (Caco2).
ACKNOWLEDGMENTS
■
We thank Dr. Eri Fukushi (GC−MS & NMR Laboratory,
Faculty of Agriculture, Hokkaido University) for assistance with
mass spectroscopy. This work was supported by the Global
COE Program (B01: Catalysis as the Basis for Innovation in
Materials Science) and a Grant-in-Aid for Scientific Research
from MEXT, Japan (23650463).
REFERENCES
■
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(11) When 9 was used as obtained from commercial sources, we
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absence of acid catalyst.
(12) Niimura, K.; Katohno, M.; Sagawa, K. Process for preparation of
esculetin compounds, esculetin coumounds and intermediates thereof,
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of related o-quinones to catechols, often produces sulfur during
workup, and it makes isolation/purification of catechols difficult.
Hydrogenation of 11 and 14 with a small amount of PtO2 catalyst
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(16) The monoacylation step was also examined with pyridine (2
equiv) and phenylacetyl chloride (1.1 equiv) in CH2Cl2 after in situ
hydrogenation of o-quinone 14: the reaction produced a 12:1 mixture
F
dx.doi.org/10.1021/jo300565s | J. Org. Chem. XXXX, XXX, XXX−XXX