Structural revision of thelephantin G by total synthesis and the inhibitory activity against TNF-α production

Article abstract of DOI:10.1021/jo900638b

(Chemical Equation Presented) This paper describes the total synthesis of thelephantin G, thus revising the proposed structure 1 to 2. The key steps involved a double Suzuki-Miyaura coupling and an esteri-fication reaction. By a similar strategy, ganbajun

Full text of DOI:10.1021/jo900638b

focused on positional isomers of aromatic substituents including
phenolic hydroxyl groups.1 Thelephantin G is a natural terphenyl
that was isolated from the mushroom Thelephora aurantiotincta
by Asakawa et al. in 2003, and the structure was assigned as 1
having a unique p-hydroquinone moiety by spectroscopic
analyses.2 A natural terphenyl with a similar structure, ganba-
junin E (4), has been reported in the literature.3 However, the
natural product was isolated as an inseparable mixture with
ganbajunin D (3). This result suggested that rearrangement of
the hydroxybenzoyl group did not proceed easily. In general,
the tendency for benzoate migration to adjacent hydroxyls, in
contrast to acetates, is known to be modest.4 In connection with
our studies on natural terphenyls,5 we were interested in the
unique reactivity hidden in 1 and its inhibitory activity against
tumor necrosis factor (TNF)-R production in rat basophilic
leukemia cells. TNF-R is a potent multifunctional cytokine that
mediates a variety of biological actions with a central role in
the pathogenesis of many inflammatory diseases.6 Thus, inhibi-
tors of TNF-R production in activated mast cells and basophils
are promising candidates for a new type of antiallergic agent.
Described herein is the total synthesis of thelephantin G that
dictates revision of the formula to 2. In addition, biological
activities of 1 and 2, as well as synthesis of a mixture of
ganbajunins D and E (3 and 4) from the key intermediate, are
also discussed.
Structural Revision of Thelephantin G by Total
Synthesis and the Inhibitory Activity against
TNF-r Production
Yue Qi Ye,†,‡ Hiroyuki Koshino,† Jun-ichi Onose,‡
Chiemi Negishi,‡ Kunie Yoshikawa,‡ Naoki Abe,‡ and
Shunya Takahashi*,†
RIKEN, Wako, Saitama 351-0198, Japan, and Department of
Nutritional Science, Faculty of Applied Bio-Science, Tokyo
UniVersity of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku,
Tokyo 156-8502, Japan
shunyat@riken.jp
ReceiVed March 26, 2009
Our synthetic strategy toward 1 involved reduction of 11
followed by benzoylation and debenzylation to install the
p-hydroquinone diester moiety. To construct the p-terphenyl
skeleton of these molecules, we planned to utilize the
Suzuki-Miyaura coupling reaction7 using the highly function-
alized aryl halide 6 and benzyl boronic acid 7 as shown in
Scheme 1.8 Bromanilic acid (5) was reduced with sodium
dithionite and the resulting compound was immediately sub-
jected to O-alkylation, giving tetramethoxymethyl (MOM)
derivative 6. Suzuki-Miyaura coupling of 6 with 7 was
performed under several conditions (Table 1). The best result
was obtained by the use of palladium acetate (0.05 mol equiv)
and triphenylphosphine (0.15 mol equiv) in the presence of
sodium carbonate in aqueous 1-propanol9 at 100 °C to afford
p-terphenyl derivative 8 in high yield (Table 1, entry 4).
This paper describes the total synthesis of thelephantin G,
thus revising the proposed structure 1 to 2. The key steps
involved a double Suzuki-Miyaura coupling and an esteri-
fication reaction. By a similar strategy, ganbajunins D and
E (3 and 4) were also prepared. Compound 2 strongly
inhibited TNF (tumor necrosis factor)-R production in rat
basophilic leukemia (RBL-2H3) cells: IC50 ) 3.5 nM, while
a mixture of 1 and its regioisomer 15 showed no such
activity.
Highly substituted phenolic compounds such as certain
antibiotics and pigments contain many quaternary carbon atoms,
and they lack hydrogens suitable for long-range correlation
HMBC experiments if hydroxyl proton does not give a sharp
(3) Hu, L.; Gao, J.-M.; Liu, J.-K. HelV. Chim. Acta 2001, 84, 3342–3349.
(4) Haines, A. H. In AdVances in Carbohydrate Chemistry and Biochemistry;
Tipson, S.; Horton, D., Ed.; Academic Press, New York, 1976; Vol. 33, pp 11-
110.
(5) (a) Xie, C.; Koshino, H.; Esumi, Y.; Takahashi, S.; Yoshikawa, K.; Abe,
N. Biosci. Biotechnol. Biochem. 2005, 69, 2326–2332. (b) Ye, Y.-Q.; Koshino,
H.; Onose, J.; Yoshikawa, K.; Abe, N.; Takahashi, S. Org. Lett. 2007, 9, 4131–
4134. (c) Onose, J.; Xie, C.; Ye, Y.-Q.; Takahashi, S.; Koshino, H.; Yasunaga,
K.; Abe, N.; Yoshikawa, K. Biol. Pharm. Bull. 2008, 31, 831–833.
(6) (a) Vassalli, P. Annu. ReV. Immunol. 1992, 10, 411–452. (b) Sieper, J.;
Braun, J. Expert Opin. Emerging Drugs 2002, 2, 235–246. (c) Holgate, S. T.
Cytokine 2004, 28, 152–157.
(7) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(8) For examples of the coupling of electron-rich arylbromide, see: (a)
Narayan, S.; Roush, W. R. Org. Lett. 2004, 6, 3789–3792. (b) Takase, M.;
Nakajima, A.; Takeuchi, T. Tetrahedron Lett. 2005, 46, 1739–1742. (c)
Yonezawa, S.; Komurasaki, T.; Kawada, K.; Tsuri, T.; Fuji, M.; Kugimiya, A.;
Haga, N.; Mitsumori, S.; Inagaki, M.; Nakatani, T.; Tamura, Y.; Takechi, S.;
Taishi, T.; Ohtani, M. J. Org. Chem. 1998, 63, 5831–5837.
1
signal in the H NMR spectrum. Therefore it is not easy to
determine the hydroxyl group position and connectivity in these
molecules. Actually, there are several reports on structural
revision of aromatic compounds in the past few years, especially
† RIKEN.
‡ Tokyo University of Agriculture.
(1) (a) Williamson, R. T.; McDonald, L. A.; Barbieri, L. R.; Carter, G. T.
Org. Lett. 2002, 4, 4659–4662. (b) Bergeron, R. J.; Huang, G.; Smith, R. E.;
Bharti, N.; McManis, J. S.; Butler, A. Tetrahedron 2003, 59, 2007–2014. (c)
Srikrishna, A.; Ravikumar, P. C. Tetrahedron Lett. 2005, 46, 6105–6109. (d)
Ye, Y. H.; Zhu, H. L.; Song, Y. C.; Liu, J. Y.; Tan, R. X. J. Nat. Prod. 2005,
68, 1106–1108. (e) Chud´ık, S.; Marek, R.; Secˇeka´ˇrova´, P.; Necˇeas, M.; Dosta´l,
J.; Slav´ık, J. J. Nat. Prod. 2006, 69, 954–956. (f) Siddaiah, V.; Maheswara, M.;
Rao, C. V.; Venkateswarlu, S.; Subbaraju, G. V. Bioorg. Med. Chem. Lett. 2007,
17, 1288–1290.
(2) Quang, D. N.; Hashimoto, T.; Hitaka, Y.; Tanaka, M.; Nukada, M.;
Yamamoto, I.; Asakawa, Y. Phytochemistry 2003, 63, 919–924.
(9) Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, M. A. Organic
Syntheses; Wiley & Sons: NewYork, 2004; Collect. Vol. X, pp 102-107.
4642 J. Org. Chem. 2009, 74, 4642–4645
10.1021/jo900638b CCC: $40.75 2009 American Chemical Society
Published on Web 05/19/2009

SCHEME 1. Suzuki-Miyaura Coupling of 6 with 7
SCHEME 3. Synthesis of the Proposed Structure 1 of
Thelephantin G
TABLE 1. Suzuki-Miyaura Coupling of Bromide 6 with Benzyl
Boronic Acid 7
entry
1
conditions
terphenyl biphenyl
TABLE 2. 1H NMR (600 MHz) Data (δ) for Natural Thelephantin
G, 1, and 2 in MeOH-d4
7 (2.3 mol equiv), Pd(PPh3)4 (0.05 mol
equiv), K3PO4, DMF, 100 °C, 8 h
7 (2.3 mol equiv), Pd(PPh3)4 (0.05 mol equiv), 8 (27%)
Cs2CO3, toluene, 100 °C, 8 h
8 (15%)
9 (40%)
2
3
4
9 (61%)
position
thelephantin Gab
1b
2b
7 (2.3 mol equiv), Pd(PPh3)4 (0.05 mol equiv), 8 (75%)
Na2CO3, DME-EtOH-H2O, 100 °C, 8 h
7 (2.3 mol equiv), Pd(OAc)2 (0.05 mol equiv), 8 (91%)
Ph3P (0.15 mol equiv), Na2CO3,
2 (2′′)
3 (3′′)
5 (5′′)
6 (6′′)
2′′′
3′′′
5′′′
6′′′
7.26 d (8.8)
6.75 d (8.8)
6.75 d (8.8)
7.26 d (8.8)
7.62 d (8.8)
6.62 d (8.8)
6.62 d (8.8)
7.62 d (8.8)
7.22 d (8.8)
6.73 d (8.8)
6.73 d (8.8)
7.22 d (8.8)
7.80 d (8.8)
6.77 d (8.8)
6.77 d (8.8)
7.80 d (8.8)
7.26 d (8.8)
6.75 d (8.8)
6.75 d (8.8)
7.26 d (8.8)
7.62 d (8.8)
6.62 d (8.8)
6.62 d (8.8)
7.62 d (8.8)
aq 1-propanol, 100 °C, 4 h
SCHEME 2. Synthesis of Ganbajunins D and E (3 and 4)
a Reference 2 b Numbers in parentheses are J values.
TABLE 3. 13C NMR (150 MHz) Data (δ) for Natural
Thelephantin G, 1, and 2 in MeOH-d4
position
thelephantin Ga
1
2
1 (1′′)
2, 6 (2′′, 6′′)
3, 5 (3′′, 5′′)
4 (4′′)
1′ (4′)
2′
3′
5′
6′
1′′′
2′′′, 6′′′
3′′′, 5′′′
4′′′
125.1
132.6
115.9
157.9
124.1
135.3
142.5
135.3
142.5
120.9
133.2
116.0
163.8
166.6
125.3
132.7
115.9
157.9
125.7
137.2
141.3
137.2
141.3
121.6
133.4
116.0
163.8
166.6
125.1
132.6
115.9
157.9
124.1
135.3
142.4
135.3
142.4
120.9
133.1
116.0
163.8
166.5
7′′′
a Reference 2.
The structural difference between 1 and 4 lies in the ester
moiety of the central ring. Therefore, acylation of 11 was done
with 1311 instead of phenylacetyl chloride (Scheme 3). The fully
protected terphenyl 14 thus obtained was subjected to hydro-
genolysis, giving a single product as judged by TLC analysis.
However, 1H NMR analyses revealed it as an inseparable
mixture of 1 and 15 not a single isomer 1.10 The result suggested
that the benzoyl groups also migrated during hydrogenolysis.
The NMR data of 1 did not match with that of natural
thelephantin G reported, showing that the proposed structure 1
was incorrect (Tables 2 and 3). Compound 15 also showed
different NMR spectra compared with that of natural thele-
phantin G.
Prior to the synthesis of 1, ganbajunins D and E (3 and 4)
were prepared for confirmation of a facile rearrangement of the
phenylacetyl groups. Acidic hydrolysis of 8, followed by air
oxidation provided p-quinone 10 (Scheme 2). Benzylation of
10 proceeded cleanly by heating it in DMF at 80 °C, furnishing
tetrabenzyl p-quinone 11. After reduction of 11 with sodium
dithionite, the resulting compound was treated successively with
n-butyllithium at -78 °C and then phenylacetyl chloride, giving
12 in good yield. As anticipated, hydrogenolysis of 12 was
accompanied by acyl migration, resulting in an inseparable
mixture of 3 and 4.10
(10) These structures were determined by extensive 2D-NMR analyses.
(11) Cavallito, C. J.; Buck, J. S. J. Am. Chem. Soc. 1943, 65, 2140–2142.
J. Org. Chem. Vol. 74, No. 12, 2009 4643

SCHEME 4. Synthesis of the Revised Structure 2 of
Thelephantin G
In conclusion, p-terphenyl 1 and its regioisomer 2 were
synthesized from 5 and 16, respectively, thus revising the
originally proposed structure of thelephantin G to 2. Compound
2 was shown to be a potent inhibitor of TNF-R production from
RBL-2H3 cells (IC50 ) 3.5 nM).
Experimental Section
3,6-Di(p-(benzyloxy)phenyl)-1,2,4,5-tetrakis((methoxy)methoxy)-
benzene (8). A mixture of 6 (299 mg, 0.63 mmol) and 7 (329 mg,
1.44 mmol) in 1-propanol (6.0 mL) was stirred at rt for 30 min,
allowing the solids to dissolve. The resulting solution was treated
with palladium acetate (7.1 mg, 31.6 µmol), triphenylphosphine
(24.8 mg, 94.5 µmol), 2 M sodium carbonate (0.95 mL), and water
(0.55 mL) then heated at 100 °C with stirring for 4 h and cooled
to rt. After addition of water, the resulting mixture was stirred at rt
for 1 h, and then extracted with ethyl acetate. The extracts were
washed successively with water and brine, dried, and concentrated.
The residue was chromatographed on silica gel (n-hexane-ethyl
acetate ) 100:1 f 25:1) to give 8 (390 mg, 91%) as a colorless
solid: mp 146.5-147 °C (ethanol); IR (ZnSe) 2901, 2826, 1518,
1430, 1376, 1244, 1156, 1044, 993, 917 cm-1; UV λmax (CH3CN)
nm (log ꢀ) 214 (4.43), 228 (4.44), 265 (4.42); 1H NMR (400 MHz,
CDCl3) δ 7.31-7.45 (14H, m), 7.03 (4H, d, J ) 8.3 Hz), 5.13
(4H, s), 4.81 (8H, s), 2.87 (12H, s); 13C NMR (100 MHz, CDCl3)
δ 157.6, 144.3, 136.9, 132.5, 130.9, 128.5, 127.9, 127.4, 126.8,
114.3, 98.9, 69.9, 56.8; HRMS (ESI) calcd for C40H42O10Na [M +
Na]+ 705.2676, found 705.2690. Anal. Found: C, 70.39; H, 6.22.
Calcd for C40H42O10: C, 70.37; H, 6.20.
In re-examining the NMR data reported, we considered that
natural thelephantin G should have a symmetrical structure, and
proposed two possible structures: one was the originally
proposed ganbajunin C type3,12 with tetrahydroxy groups on
the central ring and the other vialinin A type 2. But the former
was precluded because of instability toward oxygen.5b Conse-
quently, we proposed 2 as the real structure of natural thele-
phantin G. The synthesis began from a key intermediate 165b
in our total synthesis of vialinin A (Scheme 4). Acylation of
the catechol obtained from 16 with 13 afforded the correspond-
ing benzoate 17. This underwent oxidation with lead tetraacetate,
giving 18 in good yield. Finally, acid treatment of 18 followed
by hydrogenolysis under the same conditions that were used
3,6-Di(p-(benzyloxy)phenyl)-2,5-dibenzyloxy-1,4-di(p-(benzyloxy)-
benzoyloxy)benzene (14). To a stirred solution of 11 (101 mg, 0.15
mmol) in ethyl acetate-methanol (15:1, 32 mL) was added
dropwise a solution of sodium dithionite (105 mg, 0.60 mmol) in
water (4.0 mL) at rt. The resulting mixture was stirred for 4 h, and
then extracted with ethyl acetate. The extracts were washed
successively with cold aqueous HCl, water, and brine, dried, then
concentrated to give hydroquinone (106 mg), which was employed
in the next step without further purification. To a stirred solution
of the above hydroquinone (106 mg, ca. 0.15 mmol) in THF (8.0
mL) was added dropwise 1.59 M n-butyllithium (0.20 mL, 0.32
mmol) in hexane at -78 °C. After 15 min, 13 (86.7 mg, 0.33 mmol)
in THF (1.5 mL) was added, and the mixture was stirred at -78
°C for 30 min and at 0 °C f rt for 13 h. After being quenched
with the addition of saturated aqueous NH4Cl, the resulting mixture
was extracted with ethyl acetate. The extracts were washed
successively with water, saturated aqueous NaHCO3, water, and
brine, dried, and concentrated. The residue was treated with ether
to afford 14 (126 mg, 78% from 11) as a colorless solid: IR (ZnSe)
13
1
on 14 afforded 2. The H and 13C NMR data of 2 were
identical with those of natural thelephantin G, establishing the
structure of the natural product as 2.14
The inhibitory activities of 2 and the mixture of 1 and 15
against TNF-R production from RBL-2H3 cells were evalu-
ated.15 Compound 2 showed potent inhibition of TNF-R
production (IC50 ) 3.5 nM vs. 0.25 nM for FK-506) while the
regioisomeric mixture was not effective. These results are similar
to those of vialinin A and ganbajunins D and E (3 and 4).16
The fact that displacement of the phenylacetyl group in vialinin
A by a hydroxybenzoyl group retained most of the inhibitory
activity is of interest. These results would be useful for designing
new antiallergic drugs.
1
3030, 2926, 1725, 1604, 1508, 1438, 1233, 1161, 1074 cm-1; H
NMR (500 MHz, CDCl3) δ 7.93 (4H, d, J ) 8.8 Hz), 7.30-7.46
(24H, m), 7.08 (2H, t, J ) 7.4 Hz), 6.99 (4H, t, J ) 7.7 Hz), 6.95
(4H, d, J ) 8.8 Hz), 6.94 (4H, d, J ) 8.8 Hz), 6.75 (4H, d, J ) 7.1
Hz), 5.13 (4H, s), 5.04 (4H, s), 4.44 (4H, s); 13C NMR (100 MHz,
CDCl3) δ 164.6, 162.8, 158.3, 145.6, 140.6, 136.9, 136.5, 136.2,
132.3, 131.4, 129.6, 128.7, 128.52, 128.46, 128.2, 127.9, 127.7,
127.5, 127.4, 125.1, 121.7, 114.5, 114.4, 75.2, 70.1, 69.9; HRMS
(ESI) calcd for C74H58O10Na [M + Na]+ 1129.3928, found
1129.3938.
3,6-Di(p-(hydroxy)phenyl)-2,5-dihydroxy-1,4-di(p-(hydroxy)ben-
zoyloxy)benzene (1) and 3,6-Di(p-(hydroxy)phenyl)-2,4-dihydroxy-
1,5-di(p-(hydroxy)benzoyloxy) benzene (15). To a stirred solution
of 14 (40.0 mg, 36.1 µmol) in THF-methanol (4:1, 2.5 mL) was
(12) Hu, L.; Liu, J.-K. Z. Naturforsch. 2003, 58c, 452–454.
(13) As shown in Scheme 4, a numbering system different from that of 1 in
Scheme 3 was used for comparison of NMR data.
(14) Many natural p-terphenyls with a p-hydroquinone diester moiety like
ganbajunin E (4) have been described. However, terphenyls such as thelephorin
A,17 thelephantins A-C,18 D-F,2 and J and N19 curtisian M-Q20 were reported
to be isolated as a single isomer although the reported 13C NMR data of their
central ring were similar to those of the revised thelephantin G (2). We would
like to suggest that reinvestigation of the structures of such terphenyls are
necessary. Actually, reported NMR data of thelephantin D and terrestrin C were
almost identical and the true structure should be terrestrin C.21
(15) The bioassay was performed by the method5c previously reported.
(16) Vialinin A is an extremely potent inhibitor of TNF-R production from
RBL-2H3 cells (IC50 ) 90 pM vs. 0.25 nM for FK-506).5c On the other hand,
the positional isomers 3 and 4 showed no such activity.
(19) Quang, D. N.; Hashimoto, T.; Hitaka, Y.; Tanaka, M.; Nukada, M.;
Yamamoto, I.; Asakawa, Y. Phytochemistry 2004, 65, 1179–1184.
(20) Quang, D. N.; Hashimoto, T.; Nukada, M.; Yamamoto, I.; Tanaka, M.;
Asakawa, Y. Chem. Pharm. Bull. 2003, 51, 1064–1067.
(17) Tsukamoto, S.; Macabalang, A. D.; Abe, T.; Hirota, H.; Ohta, T.
Tetrahedron 2002, 58, 1103–1105.
(18) Quang, D. N.; Hashimoto, T.; Nukada, M.; Yamamoto, I.; Hitaka, Y.;
Tanaka, M.; Asakawa, Y. Phytochemistry 2003, 62, 109–113.
(21) Radulovic, N.; Quang, D. N.; Hashimoto, T.; Nukada, M.; Asakawa,
Y. Phytochemistry 2005, 66, 1052–1059.
4644 J. Org. Chem. Vol. 74, No. 12, 2009

added palladium hydroxide (10.0 mg). The mixture was stirred
vigorously under a hydrogen atmosphere at rt for 1 d, filtered
through a filter paper under N2 atmosphere, and then concentrated.
The residue was treated with n-hexane-THF to give a ca. 2:1
mixture of 1 and 15 (17.6 mg, 86%) as a powder: IR (ZnSe) 3390,
8.8 Hz), 7.81 (1H, s), 7.45 (4H, d, J ) 8.6 Hz), 7.32-7.38 (10H,
m), 6.82 (4H, d, J ) 8.8 Hz), 6.78 (4H, d, J ) 8.6 Hz), 5.03 (4H,
s), 2.14 (3H, s), 0.94 (18H, s), 0.15 (12H, s); 13C NMR (125 MHz,
CD2Cl2) δ 169.2, 164.2, 163.4, 156.2, 140.5, 136.7, 136.5, 132.4,
131.1, 128.9, 128.5, 127.9, 123.7, 121.2, 120.3, 118.1, 114.8, 113.5,
70.5, 25.7, 21.3, 18.4, -4.4; HRMS (ESI) calcd for C61H64O12Si2Na
[M + Na]+ 1067.3834, found 1067.3859.
1
1702, 1604, 1589, 1511, 1257, 1218, 1161, 1075 cm-1; H NMR
for 15 (600 MHz, CD3OD) δ 7.78 (4H, d, J ) 8.8 Hz), 7.32 (2H,
d, J ) 8.8 Hz), 7.13 (2H, d, J ) 8.8 Hz), 6.88 (2H, d, J ) 8.8 Hz),
6.75 (4H, d, J ) 8.8 Hz), 6.59 (2H, d, J ) 8.8 Hz); 13C NMR for
15 (150 MHz, CD3OD) δ 166.9, 163.7, 158.0, 157.7, 146.3, 133.44,
133.41, 132.0, 131.6, 130.1, 125.3, 125.2, 121.6, 119.9, 116.3,
116.0, 115.7; 1H NMR for 1 (600 MHz, CD3OD) δ 7.80 (4H, d, J
) 8.8 Hz), 7.22, (4H, d, J ) 8.8 Hz), 6.77 (4H, d, J ) 8.8 Hz),
6.73 (4H, d, J ) 8.8 Hz); 13C NMR for 1 (150 MHz, CD3OD) δ
166.6, 163.8, 157.9, 141.3, 137.2, 133.4, 132.7, 125.7, 125.3, 121.6,
116.0, 115.9; HRMS (ESI) calcd for C32H22O10Na [M + Na]+
589.1111, found 589.1129.
Thelephantin G (2). To a stirred solution of 18 (38.1 mg, 36.4
µmol) in dichloromethane (2.0 mL) was added a 10% HCl solution
in methanol (0.5 mL), and the mixture was stirred at rt for 14 h,
then concentrated. The residue was passed through a short column
of silica gel (n-hexane-ethyl acetate ) 10:1 f 0:1) to give a solid
(25.8 mg), which was dissolved in ethyl acetate (2.0 mL). Palladium
hydroxide (10.0 mg) was added and the resulting mixture was stirred
vigorously under a hydrogen atmosphere at rt for 15 h, filtered
through a filter paper under N2 atmosphere, and then concentrated.
The residue was chromatographed on silica gel (n-hexane-ethyl
acetate ) 10:1f 1:2) under N2 atmosphere to give 2 (16 mg, 76%)
as a white solid: mp 192.5-195 °C; IR (ZnSe) 3307, 1701, 1604,
5,6-Bis-p-(benzyloxy)benzoyloxy-4,7-di(p-(tert-butyldimethylsi-
lyloxy)phenyl)benzo[d][1,3]dioxole (17). According to the method
for the preparation of 14, 16 (90 mg, 0.16 mmol) was transformed
into 17 (112 mg, 71%) as needles: mp 174-175 °C; IR (ZnSe)
1
1588, 1511, 1217, 1161, 1073, 1043 cm-1; H NMR (500 MHz,
CD3OD) δ 7.62 (4H, d, J ) 8.8 Hz), 7.26 (4H, d, J ) 8.8 Hz),
6.75 (4H, d, J ) 8.8 Hz), 6.62 (4H, d, J ) 8.8 Hz); 13C NMR (125
MHz, CD3OD) δ 166.6, 163.8, 157.9, 142.5, 135.3, 133.2, 132.6,
125.1, 124.1, 120.9, 116.0, 115.9; HRMS (ESI) calcd for
C32H22O10Na [M + Na]+ 589.1111, found 589.1111.
1
2927, 2886, 2855, 1731, 1604, 1508, 1245, 1165, 1074 cm-1; H
NMR (400 MHz, CDCl3) δ 7.83 (4H, d, J ) 9.0 Hz), 7.43 (4H, d,
J ) 8.6 Hz), 7.32-7.38 (10H, m), 6.81 (4H, d, J ) 9.0 Hz), 6.78
(4H, d, J ) 8.6 Hz), 6.06 (2H, s), 5.02 (4H, s), 0.93 (18H, s), 0.13
(12H, s); 13C NMR (125 MHz, CDCl3) δ 164.3, 162.8, 155.4, 142.8,
136.0, 135.4, 132.2, 130.7, 128.7, 128.2, 127.4, 124.0, 121.2, 119.8,
117.1, 114.2, 101.5, 70.1, 25.6, 18.1, -4.5; HRMS (ESI) calcd for
C59H62O10Si2Na [M + Na]+ 1009.3779, found 1009.3792.
5,6-Bis-p-(benzyloxy)benzoyloxy-4,7-di(p-(tert-butyldimethylsi-
lyloxy)phenyl)benzo[d][1,3]dioxole-2-yl Acetate (18). A mixture of
17 (42.4 mg, 42.9 µmol) and lead tetraacetate (38.1 mg, 85.9 µmol)
in benzene (2.0 mL) was stirred at 80 °C for 10 h. Then more lead
tetraacetate (8.3 mg, 18.7 µmol) was added and stirring was
continued for a further 10 h. After being cooled to rt, the reaction
mixture was filtered through a pad of Celite, and then concentrated.
The residue was chromatographed on silica gel (n-hexane-ethyl
acetate ) 50:1f 20:1) to give 18 (38.1 mg, 85%) as an amorphous
solid: IR (ZnSe) 2953, 2930, 2856, 1780, 1735, 1603, 1508, 1249,
1166, 1003 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.84 (4H, d, J )
Acknowledgment. We are grateful to Ms. K. Yamada in
RIKEN for the elemental analyses. This work was supported
by a Grant-in-Aid for Scientific Research from MEXT and by
the Chemical Genomics Project (RIKEN). N.A. acknowledges
the Advanced Research Project of Tokyo University of Agri-
culture, and a Grant-in-Aid for Pursuing the Sophistication of
Education Research in Private Universities from MEXT.
Supporting Information Available: Experimental proce-
dures, NMR spectra of 1-4, 6, 8-12, 14, 15, 17, and 18. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO900638B
J. Org. Chem. Vol. 74, No. 12, 2009 4645