Facile preparation of dehydrodigallic acid and its derivative for the synthesis of ellagitannins

Article abstract of DOI:10.1248/cpb.c13-00458

A facile method for the synthesis of dehydrodigallic acid, which is a fundamental structure of ellagitannins, was developed. A classical Ullmann condition was effective for the formation of the highly hindered biaryl ether structure, and we clarified that the suitable protection of the phenolic hydroxy groups was crucial in this reaction. In this way, the synthesis of dehydrodigallic acid and its derivative was successfully performed. The described method would provide a synthetic utility toward ellagitannins.

Full text of DOI:10.1248/cpb.c13-00458

1308
Note
Chem. Pharm. Bull. 61(12) 1308–1314 (2013)
Vol. 61, No. 12
Facile Preparation of Dehydrodigallic Acid and Its Derivative for the
Synthesis of Ellagitannins
Kazuma Shioe, Shingo Ishikura, Yoshikazu Horino, and Hitoshi Abe*
Graduate School of Science and Engineering, University of Toyama; Toyama 930–8555, Japan.
Received June 10, 2013; accepted September 17, 2013
A facile method for the synthesis of dehydrodigallic acid, which is a fundamental structure of ellagitan-
nins, was developed. A classical Ullmann condition was effective for the formation of the highly hindered
biaryl ether structure, and we clarified that the suitable protection of the phenolic hydroxy groups was
crucial in this reaction. In this way, the synthesis of dehydrodigallic acid and its derivative was successfully
performed. The described method would provide a synthetic utility toward ellagitannins.
Key words ellagitannin; Ullmann reaction; biaryl ether
Ellagitannins are representative polyphenolic secondary synthesize a diverse set of ellagitannins.
metabolites of higher plants and possess a wide range of bio-
The synthesis of 3 was already accomplished by the clas-
logical activities (e.g., antioxidant, antivirus, and antitumor ac- sical Ullmann reaction of phenol and an aryl halide that was
tivities).1) Although this class of compounds is composed only derived from 1.8) In the C–O bond formation step, however,
of gallic acid (1), oxidized gallic acid, and sugar, a few hun- the yield was very low. In 1996, Feldman and co-workers
dred congeners have been discovered in nature as the mono- overcame the difficulty of the construction of the highly func-
or oligomeric form (Fig. 1). Based on their multifunctional tionalized biaryl ether structure of 3 in a completely differ-
property and structural diversity, these compounds have at- ent way.9) They investigated the reactivity of galloyl-derived
tracted a great deal of attention from many synthetic chemists. orthoquinones, such as 4, and applied it to the hetero Diels–
One of the most outstanding features of the ellagitannnins is Alder reaction (Chart 1). The four-step sequence involving the
furnishing an axially chiral biaryl unit which is formed by the Diels–Alder dimerization/reductive rearrangement was moder-
C–C oxidative phenolic coupling of gallic acid (1), hence they ately effective for the synthesis of 5a that was the benzylated
produce ellagic acid (2) upon hydrolysis. From this point of derivative of 3, which was the key synthetic intermediate of
view, synthetic studies of the ellagitannnins have focused on coriariin A.10–12) Although their strategy is very effective for
the construction of the biaryl part with an axial chirality2–5)
;
the ellagitannin synthesis, it might be difficult that the two
however, gallic acid (1) also provides dehydrodigallic acid (3)6) ester groups of 5a would be distinguished.13) This concern
as a skeletal motif of the ellagitannins via the biogenetic C–O must be solved in order to synthesize coriariin B and other el-
oxidative coupling reaction in plants. In fact, numerous ella- lagitannins. In this context, we thus reinvestigated the synthe-
gitannnins incorporate this compound as the dehydrodigalloyl sis of 3 and its derivative using the Ullmann condensation14)
(DHDG) group in their structure, such as coriariin B.7) There- that seemed to be convergent, flexible, and efficient, as shown
fore, a convenient method for preparing 3 has been required to in Chart 1.15–18)
Fig. 1. Structure of Ellagitannin-Related Compounds
The authors declare no conflict of interest.
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: abeh@eng.u-toyama.ac.jp

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Chart 1. Two Different Approaches for Highly Functionalized Biaryl Ether
Chart 2. Ullmann Reaction of 6a–e with 7
For our initial explorations, the reaction of phenol 6a19)
and an aryl bromide 720) was carried out as a model system.
Although a small amount of 5a was detected in the pres-
ence of excess copper dust21) and N,N-dimethylformamide
(DMF), a serious amount of unavoidable byproducts, such as
a dehalogenated compound of 7 and a homocoupling product
Chart 3. Synthesis of Dehydrodigallic Acid (3)
of 7 were produced while the starting material 6a remained. part of 6. When 6b24) was subjected to the reaction, 5b was
This is a typical drawback of the classical Ullmann reaction. obtained in a slightly better yield. It was suggested that the
Thus, we examined another reagent system using copper(I) steric hindrance of the phenol side was related to the reactiv-
species.22) However, the desired 5a was not obtained and de- ity.2) We postulated that an acetal type protective group, which
benzylation of the substrates was observed. This complexity can be easily attached to the phenolic hydroxyl groups, would
might be due to the steric hindrance of the ortho-substituted be effective to decrease the steric hindrance. From this stand-
7. In this regard, we thought that there would be a possibil- point, phenols 6c–e were prepared25–27) and underwent the
ity only using a less sterically-hindered compound as the same reaction. It was found that benzylidene acetal 6d seemed
coupling partner under the Cu(0)-mediated classical Ullmann to be the most suitable for this reaction than the orthoester
reaction to construct the sterically-hindered biaryl ether.
6c and p-methoxybenzylidene acetal 6e. We thought that the
In order to consume phenol 6a and complete the reaction, lower yields of both 5c and 5e were due to the unstability of
we needed 3eq of the aryl bromide 7 with an excess amount the acetal moiety under the reaction conditions. Consequently,
of copper dust in a refluxing solvent.23) When we used N,N- the biaryl ether 5d, which is an equivalent of 5a, was obtained
dimethylacetamide (DMA) as the solvent, 5a was successfully in a satisfactory yield (91%), and thus, the reaction was car-
obtained in an acceptable yield (Chart 2). In this case, the de- ried out on a gram-scale basis.
halogenated byproduct produced from 7 was easily separated
With the biaryl ether 5d in hand, we attempted the synthe-
by standard silica gel column chromatography and 5a was sis of 3 (Chart 3). The transformation of 5d to Feldman’s in-
isolated in an almost pure form. In order to improve the yield, termediate 5a was performed by a simple operation including
we attempted to modify the protective group on the catechol hydrogenolysis and benzylation. Additionally, the synthesis

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Vol. 61, No. 12
Chart 4. Functionalization of Gallic Acid (1)
Chart 5. Synthesis of 15
of 3 was also accomplished from 5d by a two-step sequence nent of coriariin B.
that involved the hydrolysis of the methyl ester and reductive
cleavage of the benzyl and benzylidene groups. The spectral functionalized biaryl ether derived from 1 via the classical
data of the synthetic 3 was matched the reported data.28)
Ullmann reaction. By using the benzylidene group, the biaryl
In conclusion, we investigated the formation of a highly
When we plan to synthesize the natural ellagitannin, cori- ether 5d was sufficiently obtained, and dehydrodigallic acid
ariin B, the two carboxy groups of 3 should be distinguished (3) was readily synthesized. Additionally, we demonstrated the
for the construction of the dehydrodigalloyl part. In order to construction of the DHDG part of coriariin B. We believe that
mask the carboxylic acid, we selected the benzyl and tert- compound 15, which is derivative of 3, must be a common
butyl esters, which can be cleaved in a different deprotective building block toward the synthesis of the ellagitannins.
manner. Chart 4 shows the preparation of the bromide 9 and
phenol 11. Benzylation of an inexpensive starting material 1
Experimental
Melting points were measured using a Yanagimoto micro
(monohydrate) afforded 8,29) which was smoothly brominated
to give 9. On the other hand, the tert-butylation of 1 was ac- melting point hot-plate and are uncorrected. The IR spectra
complished using Ohta’s system.30) It was noted that although were recorded using a SHIMADZU FTIR-8400 spectropho-
the yield of 1031) was quite low, this method was the best way tometer. The NMR spectra were obtained using a JEOL α-400
for our intensive examination because the production of any (400MHz) or a JEOL JNX-ECX500 (500MHz) instrument.
undesired byproducts was suppressed and the unreacted 1 was The chemical shifts are given in δ ppm with tetramethylsilane
easily removed. For the protection of the catechol moiety, the (TMS) as an internal standard. The elemental analyses were
reaction of 10 with benzalchloride in pyridine was carried out performed using a Thermo Scientific FlashEA1112 analyzer.
to provide 11.
FAB-MS was obtained using a JEOL JMS-AX505HAD in-
The phenol 11 and bromide 9 were reacted by heating at strument with m-nitrobenzyl alcohol as the matrix. Electron
160°C to afford the biaryl ether 12, which was successively ionization-mass spectra (EI-MS) was obtained using a JMS-
deprotected without rigorous purification (Chart 5). Selective GCmate II instrument. Silica gel column chromatography was
removal of the benzylidene group was achieved by use of the carried out using a wakogel® C-200 (Wako). TLC analysis was
SnCl2–EtSH combination system32) to give 13 in 76% yield. performed on Kieselgel 60F254 (Merck) plates. Copper dust
Compound 14 could be obtained by the reprotection of the was activated by the reported method.21) Solvents were dried
catechol part of 13. Finally, the tert-butyl group of 14 was by the standard procedure.
removed by SnCl2, which afforded the desired carboxylic acid
General Procedure for Ullmann Reaction A mixture
15. Thus, we succeeded in constructing the synthetic compo- of ArOH (6a–e) (1.00mmol), ArBr (7) (1.60g, 3.00mmol),

December 2013
1311
and activated Cu (381mg, 6.00mmol) in DMA (2.5mL) was with EtOAc (400mL), and filtered using celite. The filtrate
refluxed under N2 in a pre-heated oil bath at 200°C. After was poured into H2O (400mL) and extracted with EtOAc
stirring for 15–30min, the reaction mixture was cooled to (400 mL×3). The combined organic layer was washed with
ambient temperature, diluted with EtOAc, and filtered. The brine (300mL), dried over MgSO4, and filtered. The filtrate
filtrate was poured into H2O and extracted with EtOAc. The was evaporated and the resulting residue (17.6g) was purified
combined organic layer was washed with brine, dried over by silica gel column chromatography (1:4; EtOAc–hexane),
MgSO4, and filtered. The filtrate was evaporated and the re- providing 5d (6.60g, 91%) as a yellow oil; 1H-NMR (500MHz,
sulting residue was purified by silica gel column chromatog- CDCl3) δ: 3.74 (3H, s, OMe), 3.81 (3H, s, OMe), 4.96 (2H, s,
raphy (1:4–1:3; EtOAc–hexane), providing the biaryl ether CH2), 5.09 (2H, s, CH2), 5.12 (2H, s, CH2), 6.95 (1H, s, PhCH),
product (5a–e).
7.03 (1H, d, J=2.0Hz, ArH), 7.24 (1H, d, J=2.0Hz, ArH),
Methyl 3,4,5-Tribenzyloxy-2-(2,3-dibenzyloxy-5-methoxy- 7.13–7.53 (21H, m, ArH); 13C-NMR (125MHz, CDCl3) δ: 52.2,
carbonylphenoxy)benzoate10) (5a): From 6a (455mg, 52.4, 71.5, 75.7, 75.8, 104.3, 110.9, 112.0, 112.5, 119.9, 124.3,
1.00mmol), 5a (547mg, ca. 67%, yellow oil) was obtained by 126.5, 127.9, 128.0, 128.2, 128.3, 128.4, 128.4, 128.7, 128.8,
the same procedure mentioned above. The reaction was car- 130.5, 135.6, 136.4, 136.9, 137.0, 139.7, 142.1, 142.8, 146.7,
1
ried out for 30min; H-NMR (500MHz, CDCl3) δ: 3.72 (3H, s, 146.8, 149.3, 150.2, 165.3, 166.3; IR (CHCl3) νmax 3030, 3011,
OMe), 3.80 (3H, s, OMe), 4.97 (2H, s, CH2), 5.13 (4H, s, CH2), 2953, 1712, 1635, 1499, 1437, 1363, 1226, 1201, 1087, 1018,
5.14 (2H, s, CH2), 5.15 (2H, s, CH2), 6.91 (1H, d, J=1.5Hz, 909, 747, 697cm−1; HR-MS (EI) Calcd for C44H36O10 [M]+:
ArH), 7.11–7.47 (27H, m, ArH); IR (CHCl3) νmax 3033, 3015, 724.2308; Found: 724.2283 [M]+.
2953, 2357, 1717, 1539, 1435, 1338, 1224, 1206, 1093, 1011,
Methyl
3,4,5-Tribenzyloxy-2-(2,3-p-methoxybenzaloxy-5-
770, 697, 666cm−1.
methoxycarbonylphenoxy)benzoate (5e): From 6e (302mg,
Methyl 3,4,5-Tribenzyloxy-2-(2,3-dimethoxy-5-methoxycar- 1.00mmol), 5e (346mg, 46%, yellow amorphous) was ob-
bonylphenoxy)benzoate (5b): From 6b (212mg, 1.00mmol), tained by the same procedure mentioned above. The reaction
1
5b (527mg, 79%, pale yellow solid) was obtained by the was carried out for 15min; H-NMR (400MHz, DMSO-d6) δ:
same procedure mentioned above. The reaction was carried 3.70 (3H, s, OMe), 3.75 (3H, s, OMe), 3.77 (3H, s, OMe), 4.85
1
out for 30min; mp 142–144°C; H-NMR (500MHz, CDCl3) (1H, d, A of AB, J=10.8Hz, CHAHB), 4.92 (1H, d, B of AB,
δ: 3.73 (3H, s, OMe), 3.81 (3H, s, OMe), 3.94 (3H, s, OMe), J=10.8Hz, CHAHB), 5.09 (2H, s, CH2), 5.21 (2H, s, CH2), 6.82
3.94 (3H, s, OMe), 4.96 (2H, s, CH2), 5.13 (2H, s, CH2), 5.14 (1H, s, PhCH), 6.98–7.51 (22H, m, ArH); 13C-NMR (125MHz,
(2H, s, CH2), 6.84 (1H, d, J=1.5Hz, ArH), 7.10–7.48 (17H, m, acetone-d6) δ: 52.3, 52.4, 55.6, 71.4, 75.9, 76.1, 104.1, 111.2,
ArH). 13C-NMR (125MHz, CDCl3) δ: 52.3, 52.4, 56.4, 61.1, 112.8, 112.9, 114.8, 120.7, 124.8, 128.5, 128.7, 128.7, 128.7,
71.5, 75.7, 75.8, 107.3, 108.8, 111.0, 119.9, 125.0, 127.9, 128.1, 128.8, 128.9, 129.0, 129.0, 129.3, 137.5, 137.9, 137.9, 140.4,
128.3, 128.3, 128.4, 128.4, 128.5, 128.8, 128.8, 136.4, 136.9, 142.9, 142.9, 147.2, 147.2, 150.3, 150.9, 162.3, 165.3, 166.2; IR
136.9, 142.0, 142.6, 146.7, 146.9, 150.1, 152.4, 153.4, 165.3, (CHCl3) νmax 3031, 3013, 2953, 2357, 1714, 1635, 1499, 1436,
166.6; IR (KBr) νmax 2948, 2360, 2334, 1721, 1595, 1467, 1437, 1306, 1252, 1223, 1214, 1172, 1086, 1024, 773, 668cm−1;
1417, 1337, 1224, 1097, 1012, 748, 697, 668, 420cm−1; high HR-MS (EI) Calcd for C45H38O11 [M]+: 754.2415; Found:
resolution (HR)-MS (EI) Calcd for C39H36O10 [M]+: 664.2308; 754.2378 [M]+.
Found: 664.2277 [M]+. Anal. Calcd for C39H36O10: C, 70.47; H,
Conversion of 5d to 5a To a solution of 5d (643mg,
5.46. Found: C, 70.74; H, 5.41.
0.887mmol) in MeOH (8mL) and EtOAc (8mL), 10% Pd–C
Methyl 3,4,5-Tribenzyloxy-2-(2,3-ethoxymethylenedioxy-5- (64mg) was added at room temperature. After stirring for
methoxycarbonylphenoxy)benzoate (5c): From 6c (240mg, 30min under H2, the reaction mixture was filtered and con-
1.00mmol), 5c (494mg, 71%, colorless oil) was obtained centrated in vacuo to give a yellow amorphous (371mg)
by the same procedure mentioned above. The reaction was powder, which was used in the next reaction without further
carried out for 15min; 1H-NMR (500MHz, acetone-d6) δ: purification. A mixture of the above residue (371mg) and
1.19 (3H, t, J=6.5Hz, OCH2CH3) 3.72 (2H, q, J=6.5Hz, K2CO3 (1.23g, 8.90mmol) in DMF (20mL) was stirred at
OCH2CH3), 3.73 (3H, s, OMe), 3.78 (3H, s, OMe), 5.01 (1H, room temperature. BnBr (1.06mL, 8.92mol) was added to the
d, A of AB, J=11.0Hz, CHAHB), 5.03 (1H, d, B of AB, solution and the mixture was heated at 80°C with stirring.
J=11.0Hz, CHAHB), 5.21 (2H, s, CH2), 5.25 (2H, s, CH2), 7.03 After 1h, the reaction mixture was poured into H2O (100mL)
(1H, d, J=1.5Hz, ArH), 7.09 (1H, s), 7.48 (1H, s), 7.20–7.59 and extracted with EtOAc (50mL×3). The combined organic
(16H, m, ArH); 13C-NMR (125MHz, acetone-d6) δ: 15.1, layer was washed with brine (50mL), dried over MgSO4, and
52.4, 52.4, 60.3, 71.8, 76.0, 76.2, 103.9, 111.3, 112.5, 120.8, filtered. The filtrate was evaporated and the resulting residue
121.3, 124.9, 128.7, 128.8, 128.8, 128.9, 129.0, 129.1, 129.3, (1.63g) was purified by silica gel column chromatography
129.4, 137.6, 137.9, 138.0, 138.6, 142.7, 142.8, 147.3, 147.3, (1:4; EtOAc–hexane), providing 5a (661mg, 91%) as a pale
148.5, 151.1, 165.3, 166.2; IR (CHCl3) νmax 3030, 3015, 2953, yellow solid.
1714, 1635, 1438, 1372, 1313, 1212, 1085, 769, 697, 666cm−1;
HR-MS (EI) Calcd for C40H36O11 [M]+: 692.2258; Found: 2.00mmol) in THF (10mL), 10% KOH aq. (10mL) was added
692.2225 [M]+.
and the mixture was stirred at room temperature. After
Dehydrodigallic Acid (3) To a solution of 5d (1.45g,
Methyl 2-(2,3-Benzaloxy-5-methoxycarbonylphenoxy)-3,4,5- 18h, MeOH (5mL) was added and the mixture was heated
tribenzyloxybenzoate (5d): The mixture of 6d (2.72g, at 60°C with stirring for 24h. The reaction mixture was
10.0mmol), 7 (16.0g, 30.0mmol), and activated Cu (3.81g, quenched with 10% HCl aq. (10mL) and extracted with EtOAc
60.0mmol) in DMA (25mL) was refluxed under N2 in a (50 mL×3). The combined organic layer was washed with
pre-heated oil bath at 200°C. After stirring for 15min, the brine (50mL), dried over MgSO4, and filtered. The filtrate
reaction mixture was cooled to ambient temperature, diluted was evaporated and the obtained pale yellow solid (1.45g)

1312
Vol. 61, No. 12
was recrystallized from EtOAc–hexane, providing the dicar- 165.9; IR (KBr) νmax 3030, 2362, 2333, 1700, 1577, 1454, 1369,
boxylic acid (1.29g, 93%) as a colorless solid; mp 215–217°C 1329, 1216, 1159, 1100, 955, 909, 740, 698cm−1; HR-MS (EI)
(EtOAc–hexane); 1H-NMR (500MHz, acetone-d6) δ: 4.99 Calcd for C35H29O5Br [M]+: 608.1198; Found: 608.1241 [M]+.
(1H, d, A of AB, J=11.0Hz, CHAHB), 5.03 (1H, d, B of AB, Anal. Calcd for C35H29O5Br: C, 68.97; H, 4.80. Found: C,
J=11.0Hz, CHAHB), 5.18 (2H, s, CH2), 5.26 (2H, s, CH2), 7.08 68.74; H, 4.75.
(1H, d, J=1.0Hz, ArH), 7.13 (1H, s, PhCH), 7.19–7.61 (22H,
tert-Butyl Gallate31) (10) A mixture of gallic acid mono-
m, ArH); 13C-NMR (125MHz, acetone-d6) δ: 71.8, 75.9, 76.1, hydrate (1) (47.0g, 250mmol), t-BuOH (300mL), and t-BuOAc
104.3, 111.6, 112.7, 113.1, 121.2, 125.3, 127.3, 128.7, 128.8, (300mL) was stirred at 0°C under N2. Conc. H2SO4 (25mL)
128.8, 128.9, 129.0, 129.1, 129.3, 129.4, 129.5, 131.3, 136.7, was carefully added to the solution with maintaining the
137.7, 138.0, 138.0, 140.4, 143.1, 147.2, 147.3, 150.1, 151.0, temperature at 0°C. After stirring for 1h at the same tempera-
165.7, 166.7; IR (KBr) νmax 3033, 2945, 2362, 1685, 1631, 1498, ture, the resulting mixture was warmed to room temperature
1438, 1367, 1305, 1218, 1089, 1016, 737, 695cm−1; HR-MS and stirred for 5d. The reaction mixture was quenched with
(EI) Calcd for C42H32O10 [M]+: 696.1995; Found: 696.2034 sat. NaHCO3 aq., poured into H2O (500mL), and extracted
[M]+. The resulting product (139mg, 0.200mmol) was dis- with Et2O (500mL×3). The combined organic layer was
solved in MeOH (6mL), 10% Pd–C (14.0mg) was added to washed with brine (300mL), dried over MgSO4, and filtered.
the solution and the mixture was stirred at room tempera- The filtrate was evaporated and the resulting yellow residue
ture under H2. After 2h, the reaction mixture was filtered (64.5g) was dissolved in CHCl3 (100mL). After removal of
and concentrated in vacuo, providing 3 (66.7mg, 99%) as a the insoluble precipitate by filtration, the filtrate was concen-
1
brown solid; H-NMR (500MHz, DMSO-d6) δ: 6.46 (1H, d, trated in vacuo and the yellow residue (29.5g) was separated
J=1.5Hz, ArH), 6.90 (1H, s, ArH), 7.00 (1H, d, J=1.5Hz, by silica gel column chromatography (1:4; EtOAc–hexane).
ArH); 13C-NMR (125MHz, DMSO-d6) δ: 106.6, 108.2, 110.5, The obtained pale yellow solid (24.5g) was recrystallized
115.2, 119.9, 136.0, 139.0, 139.2, 139.7, 142.5, 145.6, 147.5, from CHCl3, providing 10 (21.7g, 38%) as a colorless solid.
166.3, 167.5; IR (KBr) νmax 3498, 2357, 2342, 1685, 1611, 1522, Analytical sample of 10 was obtained by further recrystal-
1440, 1329, 1244, 1190, 1101, 1034, 668cm−1; HR-MS (EI) lization from CHCl3–hexane; mp 146–147°C (CHCl3–hexane);
Calcd for C14H10O10 [M]+: 338.0274; Found: 338.0289 [M]+. IR (KBr) νmax 3377, 3314, 3227, 2980, 1697, 1670, 1624, 1445,
1
The spectral data of the synthetic 3 matched the data provided 1371, 1348, 1256, 1157, 1026, 771cm−1; H-NMR (500MHz,
in the literature.26)
acetone-d6) δ: 1.53 (9H, s, Ot-Bu), 7.07 (2H, s, ArH);
Benzyl 3,4,5-Tribenzyloxybenzoate29) (8) A mixture of 13C-NMR (125MHz, acetone-d6) δ: 28.3, 80.3, 109.7, 123.6,
gallic acid monohydrate (1) (100g, 0.532mol), K2CO3 (587g, 138.2, 145.8, 166.0; Anal. Calcd for C11H14O5: C, 58.40; H,
4.25mol), and nBu4NI (9.9g, 26.8mmol) in DMF (1L) was 6.24. Found: C, 58.35; H, 6.40.
stirred using a mechanical stirrer at room temperature. BnCl
tert-Butyl 3,4-Benzaloxy-5-hydroxybenzoate (11) To a
(501mL, 4.25mol) was added to the suspention and the mix- solution of 10 (10.0g, 44.2mmol) in pyridine (25.0mL), benzal
ture was heated at 100°C with stirring for 4.5h. The reaction chloride (8.54mL, 66.3mmol) was added and the mixture
mixture was cooled to ambient temperature, poured into the was heated at 110°C under N2. After stirring for 8h, toluene
mixed solution of H2O (5L) and hexane (0.5L), and stirred. was added to the reaction mixture and the solvent was re-
The precipitate was then collected on a glass filter and washed moved in vacuo. The resulting purple residue was dissolved
with H2O and hexane. The obtained white solid (497.2g) was in CHCl3 and filtered with SiO2 pad. After concentration of
recrystallized from acetone, providing 8 (243g, 86%) as color- the filtrate, pale yellow solid (16.2g) was recrystallized from
1
less needles; mp 101.3–102.8°C (acetone); H-NMR (500MHz, CHCl3–hexane, providing 11 (9.71g, 70%) as a colorless
CDCl3) δ: 5.10 (4H, s, CH2), 5.15 (2H, s, CH2), 5.33 (2H, s, solid; mp 167.5–169.8°C (CHCl3–hexane); IR (KBr) νmax 3369,
CH2), 7.26–7.44 (22H, m, ArH); 13C-NMR (125MHz, CDCl3) 2976, 1684, 1645, 1614, 1512, 1447, 1398, 1337, 1335, 1305,
1
δ 66.8, 71.2, 75.1, 109.2, 125.2, 127.6, 128.0, 128.0, 128.1, 1259, 1219, 1163, 1076, 1076, 1016, 766, 696cm−1; H-NMR
128.2, 128.2, 128.6, 128.6, 136.1, 136.7, 137.5, 142.5, 152.6, (400MHz, CDCl3) δ: 1.57 (9H, s, Ot-Bu), 7.04 (1H, s, PhCH),
165.9; IR (KBr) νmax 3064, 3032, 2945, 2866, 1710, 1594, 1500, 7.13 (1H, d, J=1.6Hz, ArH), 7.33 (1H, d, J=1.6Hz, ArH),
1454, 1428, 1385, 1366, 1338, 1204, 1128, 1029, 971, 862, 753, 7.44–7.57 (5H, m, ArH); 13C-NMR (125MHz, acetone-d6) δ:
730, 695, 604cm−1; HR-MS (EI) Calcd for C35H30O5 [M]+: 28.2, 81.0, 102.4, 111.9, 114.5, 127.1, 127.2, 129.5, 131.2, 137.0,
530.2093; Found: 530.2115 [M]+.
Benzyl 3,4,5-Tribenzyloxy-2-bromobenzoate (9) To a H, 5.77. Found: C, 68.50; H, 5.86.
139.0, 140.9, 149.7, 165.3; Anal. Calcd for C18H18O5: C, 68.78;
stirring solution of 8 (79.6g, 150mmol) in DMF (350mL), a
Benzyl 2-(2,3-Benzaloxy-5-tert-butoxycarbonylphenoxy)-
solution of N-bromosuccinimide (NBS) (30.7g, 172.5mmol) 3,4,5-tribenzyloxybenzoate
(12) Two
round-bottomed
in DMF (70mL) was dropwise added at room temperature. flasks (200mL) were equipped with 11 (3.15g, 10.0mmol),
After stirring for 24h, H2O was added to the solution and the 9 (18.3g, 30.0mmol), activated Cu (3.81g, 60.0mmol), and
resulting mixture was then stirred. The precipitate was col- DMA (25mL), respectively. The each mixture was heated
lected on a glass filter and washed with H2O and hexane. The at 160°C under N2. After stirring for 30min, the each reac-
obtained solid (112.4g) was recrystallized from acetone, pro- tion mixture was cooled to ambient temperature, diluted
viding 9 (78.5g, 86%) as colorless needles; mp 123.8–124.4°C with EtOAc (250mL), and filtered. The filtrate were com-
1
(acetone); H-NMR (500MHz, CDCl3) δ: 5.03 (2H, s, CH2), bined, poured into H2O (500mL), and extracted with EtOAc
5.10 (4H, s, CH2), 5.37 (2H, s, CH2), 7.29–7.51 (21H, m, ArH); (500 mL×3). The combined organic layer was washed with
13C-NMR (125MHz, CDCl3) δ: 67.6, 71.4, 75.6, 75.9, 110.6, brine (300mL), dried over MgSO4, and filtered. The filtrate
112.4, 127.7, 128.4, 128.4, 128.5, 128.5, 128.6, 128.6, 128.8, was evaporated and the resulting residue (46.3g) was purified
128.8, 128.8, 135.6, 136.1, 136.7, 136.9, 146.0, 151.1, 151.8, by silica gel column chromatography (1:4; EtOAc–hexane) to

December 2013
1313
give a colorless residue (39.9g) as a mixture containing 12, tive ion mode) Calcd for C60H55O10 [M+H]+: 935.3795; Found:
which was used in the next reaction without further purifi- 935.3816 [M+H]+. Anal. Calcd for C60H54O10: C, 77.07; H,
cation. Analytical sample of 12 was separately obtained by 5.82. Found: C, 76.87; H, 5.87.
1
silica gel column chromatography as a colorless oil; H-NMR
3,4-Dibenzyloxy-5-(2,3,4-tribenzyloxy-6-benzyloxycar-
(500MHz, acetone-d6) δ: 1.52 (9H, s, Ot-Bu), 4.98 (1H, d, A bonylphenoxy)benzoic Acid (15) To a stirring solution of
of AB, J=10.5Hz, CHAHB), 5.01 (1H, d, B of AB, J=10.5Hz, 14 (935mg, 1.00mmol) in CH2Cl2 (10mL), AcOH (286µL,
CHAHB), 5.17 (2H, s, CH2), 5.19 (1H, d, A of AB, J=12.5Hz, 5.00mmol) and SnCl2 (457mg, 2.50mmol) were subsequently
CHAHB), 5.24 (1H, d, B of AB, J=12.5Hz, CHAHB), 5.25 (2H, added. After stirring for 22h at room temperature, AcOH
s, CH2), 6.98 (1H, d, J=1.5Hz, ArH), 7.04 (1H, s, PhCH), 7.10 (286 µL, 5.00mmol) and SnCl2 (457mg, 2.50mmol) were
(1H, d, J=1.5Hz, ArH), 7.50 (1H, s, ArH), 7.19–7.56 (25H, added to the mixture and the resulting mixture was stirred.
m, ArH); 13C-NMR (125MHz, acetone-d6) δ: 28.2, 67.4, After 32h, the reaction mixture was filtered and concentrated
71.8, 76.0, 76.2, 81.2, 104.0, 111.5, 112.5, 112.7, 120.9, 126.9, in vacuo. The obtained yellow amorphous (1.02g) was purified
127.2, 128.6, 128.8, 128.9, 129.0, 129.1, 129.3, 129.5, 131.2, by silica gel column chromatography (1:1; EtOAc–hexane),
136.7, 136.8, 137.5, 137.8, 137.9, 139.7, 142.8, 142.8, 147.3, providing 15 (777mg, 88%) as a colorless solid. Analytical
147.4, 150.0, 151.0, 164.9, 165.0; IR (CHCl3) νmax 3034, 3013, sample of 15 was obtained by recrystallization from acetone–
1
2490, 1704, 1635, 1498, 1436, 1367, 1217, 1159, 1087, 1017, hexane; mp 137–139°C (acetone–hexane); H-NMR (500MHz,
770, 697cm−1; HR-MS (FAB, positive ion mode) Calcd for acetone-d6) δ: 4.93 (2H, s, CH2), 5.01 (2H, s, CH2), 5.21 (2H,
C53H47O10 [M+H]+: 843.3169; Found: 843.3148 [M+H]+.
s, CH2), 5.22 (2H, s, CH2), 5.25 (2H, s, CH2), 5.26 (2H, s,
Benzyl 3,4,5-Tribenzyloxy-2-(5-tert-butoxycarbonyl-2,3- CH2), 6.94 (1H, d, J=2.0Hz, ArH), 7.16–7.58 (32H, m, ArH);
dihydroxyphenoxy)benzoate (13) To a stirring solution of 13C-NMR (125MHz, acetone-d6) δ: 67.4, 71.5, 71.6, 75.3, 75.8,
the above residue (39.9g) in CH2Cl2 (500mL), EtSH (14.8mL, 76.0, 109.7, 111.4, 120.8, 126.0, 128.3, 128.5, 128.6, 128.6,
200mmol) and SnCl2 (9.13g, 50.0mmol) were added at 0°C. 128.8, 128.8, 128.9, 129.0, 129.0, 129.1, 129.2, 129.3, 136.6,
After stirring for 22h at room temperature, the reaction mix- 137.3, 137.6, 137.7, 137.7, 138.8, 142.3, 142.7, 147.1, 147.4,
ture was filtered and concentrated in vacuo. The resulting resi- 150.7, 153.5, 153.6, 165.0, 167.3; IR (KBr) νmax 3064, 3032,
due (52.7g) was purified by silica gel column chromatography 2947, 2874, 2360, 2342, 1704, 1684, 1591, 1497, 1426, 1375,
(1:3–1:2; EtOAc–hexane), providing 13 (11.4g, 76%) as a col- 1217, 1092, 972, 909, 749, 736, 696cm−1; HR-MS (FAB, posi-
1
orless amorphous powder; H-NMR (500MHz, acetone-d6) δ: tive ion mode) Calcd for C56H47O10 [M+H]+: 879.3169; Found:
1.46 (9H, s, Ot-Bu), 4.99 (2H, s, CH2), 5.20 (2H, s, CH2), 5.21 879.3190 [M+H]+.
(2H, s, CH2), 5.25 (2H, s, CH2), 6.75 (1H, d, J=1.5Hz, ArH),
7.18 (1H, d, J=1.5Hz, ArH), 7.49 (1H, s, ArH), 7.23–7.56
Acknowledgments This work was financially supported
(20H, m, ArH); 13C-NMR (125MHz, acetone-d6) δ: 28.2, 67.3, by the JSPS KAKENHI Grant No. 22590003 and the Tamura
71.8, 76.0, 76.2, 80.5, 107.9, 111.6, 111.8, 121.0, 123.2, 128.6, Science and Technology Foundation.
128.7, 128.9, 128.9, 129.1, 129.1, 129.1, 129.3, 129.3, 136.9,
137.6, 137.9, 138.0, 139.3, 143.4, 146.3, 147.5, 147.6, 147.9,
150.8, 165.1, 165.6; IR (CHCl3) νmax 3551, 3034, 3014, 1703,
1615, 1455, 1436, 1367, 1339, 1311, 1207, 1178, 11186, 1068,
966, 788, 697cm−1; HR-MS (EI) Calcd for C46H42O10 [M]+:
754.2778; Found: 754.2744 [M]+.
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