Notes
Facile Preparation of Dehydrodigallic Acid and Its Derivative for the Synthesis of Ellagitannins
2013 Volume 61 Issue 12 Pages 1308-1314
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2013 Volume 61 Issue 12 Pages 1308-1314
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.
Ellagitannins are representative polyphenolic secondary metabolites of higher plants and possess a wide range of biological activities (e.g., antioxidant, antivirus, and antitumor activities).1) Although this class of compounds is composed only of gallic acid (1), oxidized gallic acid, and sugar, a few hundred congeners have been discovered in nature as the mono- or oligomeric form (Fig. 1). Based on their multifunctional property and structural diversity, these compounds have attracted a great deal of attention from many synthetic chemists. One of the most outstanding features of the ellagitannnins is furnishing an axially chiral biaryl unit which is formed by the C–C oxidative phenolic coupling of gallic acid (1), hence they produce ellagic acid (2) upon hydrolysis. From this point of view, synthetic studies of the ellagitannnins have focused on the construction of the biaryl part with an axial chirality2–5); however, gallic acid (1) also provides dehydrodigallic acid (3)6) as a skeletal motif of the ellagitannins via the biogenetic C–O oxidative coupling reaction in plants. In fact, numerous ellagitannnins incorporate this compound as the dehydrodigalloyl (DHDG) group in their structure, such as coriariin B.7) Therefore, a convenient method for preparing 3 has been required to synthesize a diverse set of ellagitannins.
The synthesis of 3 was already accomplished by the classical Ullmann reaction of phenol and an aryl halide that was derived from 1.8) In the C–O bond formation step, however, the yield was very low. In 1996, Feldman and co-workers overcame the difficulty of the construction of the highly functionalized biaryl ether structure of 3 in a completely different way.9) They investigated the reactivity of galloyl-derived orthoquinones, such as 4, and applied it to the hetero Diels–Alder reaction (Chart 1). The four-step sequence involving the Diels–Alder dimerization/reductive rearrangement was moderately effective for the synthesis of 5a that was the benzylated derivative of 3, which was the key synthetic intermediate of coriariin A.10–12) Although their strategy is very effective for the ellagitannin synthesis, it might be difficult that the two ester groups of 5a would be distinguished.13) This concern must be solved in order to synthesize coriariin B and other ellagitannins. In this context, we thus reinvestigated the synthesis of 3 and its derivative using the Ullmann condensation14) that seemed to be convergent, flexible, and efficient, as shown in Chart 1.15–18)
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 presence 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 of 7 were produced while the starting material 6a remained. This is a typical drawback of the classical Ullmann reaction. Thus, we examined another reagent system using copper(I) species.22) However, the desired 5a was not obtained and debenzylation of the substrates was observed. This complexity might be due to the steric hindrance of the ortho-substituted 7. In this regard, we thought that there would be a possibility only using a less sterically-hindered compound as the coupling partner under the Cu(0)-mediated classical Ullmann reaction to construct the sterically-hindered biaryl ether.
In order to consume phenol 6a and complete the reaction, we needed 3 eq of the aryl bromide 7 with an excess amount of copper dust in a refluxing solvent.23) When we used N,N-dimethylacetamide (DMA) as the solvent, 5a was successfully obtained in an acceptable yield (Chart 2). In this case, the dehalogenated byproduct produced from 7 was easily separated by standard silica gel column chromatography and 5a was isolated in an almost pure form. In order to improve the yield, we attempted to modify the protective group on the catechol part of 6. When 6b24) was subjected to the reaction, 5b was obtained in a slightly better yield. It was suggested that the steric hindrance of the phenol side was related to the reactivity.2) We postulated that an acetal type protective group, which can be easily attached to the phenolic hydroxyl groups, would be effective to decrease the steric hindrance. From this standpoint, phenols 6c–e were prepared25–27) and underwent the same reaction. It was found that benzylidene acetal 6d seemed to be the most suitable for this reaction than the orthoester 6c and p-methoxybenzylidene acetal 6e. We thought that the lower yields of both 5c and 5e were due to the unstability of the acetal moiety under the reaction conditions. Consequently, the biaryl ether 5d, which is an equivalent of 5a, was obtained in a satisfactory yield (91%), and thus, the reaction was carried out on a gram-scale basis.
With the biaryl ether 5d in hand, we attempted the synthesis of 3 (Chart 3). The transformation of 5d to Feldman’s intermediate 5a was performed by a simple operation including hydrogenolysis and benzylation. Additionally, the synthesis of 3 was also accomplished from 5d by a two-step sequence that involved the hydrolysis of the methyl ester and reductive cleavage of the benzyl and benzylidene groups. The spectral data of the synthetic 3 was matched the reported data.28)
When we plan to synthesize the natural ellagitannin, coriariin B, the two carboxy groups of 3 should be distinguished for the construction of the dehydrodigalloyl part. In order to mask the carboxylic acid, we selected the benzyl and tert-butyl esters, which can be cleaved in a different deprotective manner. Chart 4 shows the preparation of the bromide 9 and phenol 11. Benzylation of an inexpensive starting material 1 (monohydrate) afforded 8,29) which was smoothly brominated to give 9. On the other hand, the tert-butylation of 1 was accomplished using Ohta’s system.30) It was noted that although the yield of 1031) was quite low, this method was the best way for our intensive examination because the production of any undesired byproducts was suppressed and the unreacted 1 was easily removed. For the protection of the catechol moiety, the reaction of 10 with benzalchloride in pyridine was carried out to provide 11.
The phenol 11 and bromide 9 were reacted by heating at 160°C to afford the biaryl ether 12, which was successively deprotected without rigorous purification (Chart 5). Selective removal of the benzylidene group was achieved by use of the SnCl2–EtSH combination system32) to give 13 in 76% yield. Compound 14 could be obtained by the reprotection of the catechol part of 13. Finally, the tert-butyl group of 14 was removed by SnCl2, which afforded the desired carboxylic acid 15. Thus, we succeeded in constructing the synthetic component of coriariin B.
In conclusion, we investigated the formation of a highly functionalized biaryl ether derived from 1 via the classical Ullmann reaction. By using the benzylidene group, the biaryl ether 5d was sufficiently obtained, and dehydrodigallic acid (3) was readily synthesized. Additionally, we demonstrated the construction of the DHDG part of coriariin B. We believe that compound 15, which is derivative of 3, must be a common building block toward the synthesis of the ellagitannins.
Melting points were measured using a Yanagimoto micro melting point hot-plate and are uncorrected. The IR spectra were recorded using a SHIMADZU FTIR-8400 spectrophotometer. The NMR spectra were obtained using a JEOL α-400 (400 MHz) or a JEOL JNX-ECX500 (500 MHz) instrument. The chemical shifts are given in δ ppm with tetramethylsilane (TMS) as an internal standard. The elemental analyses were performed using a Thermo Scientific FlashEA1112 analyzer. FAB-MS was obtained using a JEOL JMS-AX505HAD instrument with m-nitrobenzyl alcohol as the matrix. Electron ionization-mass spectra (EI-MS) was obtained using a JMS-GCmate II instrument. Silica gel column chromatography was carried out using a wakogel® C-200 (Wako). TLC analysis was performed on Kieselgel 60 F254 (Merck) plates. Copper dust was activated by the reported method.21) Solvents were dried by the standard procedure.
General Procedure for Ullmann ReactionA mixture of ArOH (6a–e) (1.00 mmol), ArBr (7) (1.60 g, 3.00 mmol), and activated Cu (381 mg, 6.00 mmol) in DMA (2.5 mL) was refluxed under N2 in a pre-heated oil bath at 200°C. After stirring for 15–30 min, the reaction mixture was cooled to ambient temperature, diluted with EtOAc, and filtered. The filtrate was poured into H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was evaporated and the resulting residue was purified by silica gel column chromatography (1 : 4–1 : 3; EtOAc–hexane), providing the biaryl ether product (5a–e).
Methyl 3,4,5-Tribenzyloxy-2-(2,3-dibenzyloxy-5-methoxycarbonylphenoxy)benzoate10) (5a): From 6a (455 mg, 1.00 mmol), 5a (547 mg, ca. 67%, yellow oil) was obtained by the same procedure mentioned above. The reaction was carried out for 30 min; 1H-NMR (500 MHz, CDCl3) δ: 3.72 (3H, s, OMe), 3.80 (3H, s, OMe), 4.97 (2H, s, CH2), 5.13 (4H, s, CH2), 5.14 (2H, s, CH2), 5.15 (2H, s, CH2), 6.91 (1H, d, J=1.5 Hz, ArH), 7.11–7.47 (27H, m, ArH); IR (CHCl3) νmax 3033, 3015, 2953, 2357, 1717, 1539, 1435, 1338, 1224, 1206, 1093, 1011, 770, 697, 666 cm−1.
Methyl 3,4,5-Tribenzyloxy-2-(2,3-dimethoxy-5-methoxycarbonylphenoxy)benzoate (5b): From 6b (212 mg, 1.00 mmol), 5b (527 mg, 79%, pale yellow solid) was obtained by the same procedure mentioned above. The reaction was carried out for 30 min; mp 142–144°C; 1H-NMR (500 MHz, CDCl3) δ: 3.73 (3H, s, OMe), 3.81 (3H, s, OMe), 3.94 (3H, s, OMe), 3.94 (3H, s, OMe), 4.96 (2H, s, CH2), 5.13 (2H, s, CH2), 5.14 (2H, s, CH2), 6.84 (1H, d, J=1.5 Hz, ArH), 7.10–7.48 (17H, m, ArH). 13C-NMR (125 MHz, CDCl3) δ: 52.3, 52.4, 56.4, 61.1, 71.5, 75.7, 75.8, 107.3, 108.8, 111.0, 119.9, 125.0, 127.9, 128.1, 128.3, 128.3, 128.4, 128.4, 128.5, 128.8, 128.8, 136.4, 136.9, 136.9, 142.0, 142.6, 146.7, 146.9, 150.1, 152.4, 153.4, 165.3, 166.6; IR (KBr) νmax 2948, 2360, 2334, 1721, 1595, 1467, 1437, 1417, 1337, 1224, 1097, 1012, 748, 697, 668, 420 cm−1; high resolution (HR)-MS (EI) Calcd for C39H36O10 [M]+: 664.2308; Found: 664.2277 [M]+. Anal. Calcd for C39H36O10: C, 70.47; H, 5.46. Found: C, 70.74; H, 5.41.
Methyl 3,4,5-Tribenzyloxy-2-(2,3-ethoxymethylenedioxy-5-methoxycarbonylphenoxy)benzoate (5c): From 6c (240 mg, 1.00 mmol), 5c (494 mg, 71%, colorless oil) was obtained by the same procedure mentioned above. The reaction was carried out for 15 min; 1H-NMR (500 MHz, acetone-d6) δ: 1.19 (3H, t, J=6.5 Hz, OCH2CH3) 3.72 (2H, q, J=6.5 Hz, OCH2CH3), 3.73 (3H, s, OMe), 3.78 (3H, s, OMe), 5.01 (1H, d, A of AB, J=11.0 Hz, CHAHB), 5.03 (1H, d, B of AB, J=11.0 Hz, CHAHB), 5.21 (2H, s, CH2), 5.25 (2H, s, CH2), 7.03 (1H, d, J=1.5 Hz, ArH), 7.09 (1H, s), 7.48 (1H, s), 7.20–7.59 (16H, m, ArH); 13C-NMR (125 MHz, acetone-d6) δ: 15.1, 52.4, 52.4, 60.3, 71.8, 76.0, 76.2, 103.9, 111.3, 112.5, 120.8, 121.3, 124.9, 128.7, 128.8, 128.8, 128.9, 129.0, 129.1, 129.3, 129.4, 137.6, 137.9, 138.0, 138.6, 142.7, 142.8, 147.3, 147.3, 148.5, 151.1, 165.3, 166.2; IR (CHCl3) νmax 3030, 3015, 2953, 1714, 1635, 1438, 1372, 1313, 1212, 1085, 769, 697, 666 cm−1; HR-MS (EI) Calcd for C40H36O11 [M]+: 692.2258; Found: 692.2225 [M]+.
Methyl 2-(2,3-Benzaloxy-5-methoxycarbonylphenoxy)-3,4,5-tribenzyloxybenzoate (5d): The mixture of 6d (2.72 g, 10.0 mmol), 7 (16.0 g, 30.0 mmol), and activated Cu (3.81 g, 60.0 mmol) in DMA (25 mL) was refluxed under N2 in a pre-heated oil bath at 200°C. After stirring for 15 min, the reaction mixture was cooled to ambient temperature, diluted with EtOAc (400 mL), and filtered using celite. The filtrate was poured into H2O (400 mL) and extracted with EtOAc (400 mL×3). The combined organic layer was washed with brine (300 mL), dried over MgSO4, and filtered. The filtrate was evaporated and the resulting residue (17.6 g) was purified by silica gel column chromatography (1 : 4; EtOAc–hexane), providing 5d (6.60 g, 91%) as a yellow oil; 1H-NMR (500 MHz, CDCl3) δ: 3.74 (3H, s, OMe), 3.81 (3H, s, OMe), 4.96 (2H, s, CH2), 5.09 (2H, s, CH2), 5.12 (2H, s, CH2), 6.95 (1H, s, PhCH), 7.03 (1H, d, J=2.0 Hz, ArH), 7.24 (1H, d, J=2.0 Hz, ArH), 7.13–7.53 (21H, m, ArH); 13C-NMR (125 MHz, CDCl3) δ: 52.2, 52.4, 71.5, 75.7, 75.8, 104.3, 110.9, 112.0, 112.5, 119.9, 124.3, 126.5, 127.9, 128.0, 128.2, 128.3, 128.4, 128.4, 128.7, 128.8, 130.5, 135.6, 136.4, 136.9, 137.0, 139.7, 142.1, 142.8, 146.7, 146.8, 149.3, 150.2, 165.3, 166.3; IR (CHCl3) νmax 3030, 3011, 2953, 1712, 1635, 1499, 1437, 1363, 1226, 1201, 1087, 1018, 909, 747, 697 cm−1; HR-MS (EI) Calcd for C44H36O10 [M]+: 724.2308; Found: 724.2283 [M]+.
Methyl 3,4,5-Tribenzyloxy-2-(2,3-p-methoxybenzaloxy-5-methoxycarbonylphenoxy)benzoate (5e): From 6e (302 mg, 1.00 mmol), 5e (346 mg, 46%, yellow amorphous) was obtained by the same procedure mentioned above. The reaction was carried out for 15 min; 1H-NMR (400 MHz, DMSO-d6) δ: 3.70 (3H, s, OMe), 3.75 (3H, s, OMe), 3.77 (3H, s, OMe), 4.85 (1H, d, A of AB, J=10.8 Hz, CHAHB), 4.92 (1H, d, B of AB, J=10.8 Hz, CHAHB), 5.09 (2H, s, CH2), 5.21 (2H, s, CH2), 6.82 (1H, s, PhCH), 6.98–7.51 (22H, m, ArH); 13C-NMR (125 MHz, acetone-d6) δ: 52.3, 52.4, 55.6, 71.4, 75.9, 76.1, 104.1, 111.2, 112.8, 112.9, 114.8, 120.7, 124.8, 128.5, 128.7, 128.7, 128.7, 128.8, 128.9, 129.0, 129.0, 129.3, 137.5, 137.9, 137.9, 140.4, 142.9, 142.9, 147.2, 147.2, 150.3, 150.9, 162.3, 165.3, 166.2; IR (CHCl3) νmax 3031, 3013, 2953, 2357, 1714, 1635, 1499, 1436, 1306, 1252, 1223, 1214, 1172, 1086, 1024, 773, 668 cm−1; HR-MS (EI) Calcd for C45H38O11 [M]+: 754.2415; Found: 754.2378 [M]+.
Conversion of 5d to 5aTo a solution of 5d (643 mg, 0.887 mmol) in MeOH (8 mL) and EtOAc (8 mL), 10% Pd–C (64 mg) was added at room temperature. After stirring for 30 min under H2, the reaction mixture was filtered and concentrated in vacuo to give a yellow amorphous (371 mg) powder, which was used in the next reaction without further purification. A mixture of the above residue (371 mg) and K2CO3 (1.23 g, 8.90 mmol) in DMF (20 mL) was stirred at room temperature. BnBr (1.06 mL, 8.92 mol) was added to the solution and the mixture was heated at 80°C with stirring. After 1 h, the reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over MgSO4, and filtered. The filtrate was evaporated and the resulting residue (1.63 g) was purified by silica gel column chromatography (1 : 4; EtOAc–hexane), providing 5a (661 mg, 91%) as a pale yellow solid.
Dehydrodigallic Acid (3)To a solution of 5d (1.45 g, 2.00 mmol) in THF (10 mL), 10% KOH aq. (10 mL) was added and the mixture was stirred at room temperature. After 18 h, MeOH (5 mL) was added and the mixture was heated at 60°C with stirring for 24 h. The reaction mixture was quenched with 10% HCl aq. (10 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over MgSO4, and filtered. The filtrate was evaporated and the obtained pale yellow solid (1.45 g) was recrystallized from EtOAc–hexane, providing the dicarboxylic acid (1.29 g, 93%) as a colorless solid; mp 215–217°C (EtOAc–hexane); 1H-NMR (500 MHz, acetone-d6) δ: 4.99 (1H, d, A of AB, J=11.0 Hz, CHAHB), 5.03 (1H, d, B of AB, J=11.0 Hz, CHAHB), 5.18 (2H, s, CH2), 5.26 (2H, s, CH2), 7.08 (1H, d, J=1.0 Hz, ArH), 7.13 (1H, s, PhCH), 7.19–7.61 (22H, m, ArH); 13C-NMR (125 MHz, acetone-d6) δ: 71.8, 75.9, 76.1, 104.3, 111.6, 112.7, 113.1, 121.2, 125.3, 127.3, 128.7, 128.8, 128.8, 128.9, 129.0, 129.1, 129.3, 129.4, 129.5, 131.3, 136.7, 137.7, 138.0, 138.0, 140.4, 143.1, 147.2, 147.3, 150.1, 151.0, 165.7, 166.7; IR (KBr) νmax 3033, 2945, 2362, 1685, 1631, 1498, 1438, 1367, 1305, 1218, 1089, 1016, 737, 695 cm−1; HR-MS (EI) Calcd for C42H32O10 [M]+: 696.1995; Found: 696.2034 [M]+. The resulting product (139 mg, 0.200 mmol) was dissolved in MeOH (6 mL), 10% Pd–C (14.0 mg) was added to the solution and the mixture was stirred at room temperature under H2. After 2 h, the reaction mixture was filtered and concentrated in vacuo, providing 3 (66.7 mg, 99%) as a brown solid; 1H-NMR (500 MHz, DMSO-d6) δ: 6.46 (1H, d, J=1.5 Hz, ArH), 6.90 (1H, s, ArH), 7.00 (1H, d, J=1.5 Hz, ArH); 13C-NMR (125 MHz, DMSO-d6) δ: 106.6, 108.2, 110.5, 115.2, 119.9, 136.0, 139.0, 139.2, 139.7, 142.5, 145.6, 147.5, 166.3, 167.5; IR (KBr) νmax 3498, 2357, 2342, 1685, 1611, 1522, 1440, 1329, 1244, 1190, 1101, 1034, 668 cm−1; HR-MS (EI) Calcd for C14H10O10 [M]+: 338.0274; Found: 338.0289 [M]+. The spectral data of the synthetic 3 matched the data provided in the literature.26)
Benzyl 3,4,5-Tribenzyloxybenzoate29) (8)A mixture of gallic acid monohydrate (1) (100 g, 0.532 mol), K2CO3 (587 g, 4.25 mol), and nBu4NI (9.9 g, 26.8 mmol) in DMF (1 L) was stirred using a mechanical stirrer at room temperature. BnCl (501 mL, 4.25 mol) was added to the suspention and the mixture was heated at 100°C with stirring for 4.5 h. The reaction mixture was cooled to ambient temperature, poured into the mixed solution of H2O (5 L) and hexane (0.5 L), and stirred. The precipitate was then collected on a glass filter and washed with H2O and hexane. The obtained white solid (497.2 g) was recrystallized from acetone, providing 8 (243 g, 86%) as colorless needles; mp 101.3–102.8°C (acetone); 1H-NMR (500 MHz, CDCl3) δ: 5.10 (4H, s, CH2), 5.15 (2H, s, CH2), 5.33 (2H, s, CH2), 7.26–7.44 (22H, m, ArH); 13C-NMR (125 MHz, CDCl3) δ 66.8, 71.2, 75.1, 109.2, 125.2, 127.6, 128.0, 128.0, 128.1, 128.2, 128.2, 128.6, 128.6, 136.1, 136.7, 137.5, 142.5, 152.6, 165.9; IR (KBr) νmax 3064, 3032, 2945, 2866, 1710, 1594, 1500, 1454, 1428, 1385, 1366, 1338, 1204, 1128, 1029, 971, 862, 753, 730, 695, 604 cm−1; HR-MS (EI) Calcd for C35H30O5 [M]+: 530.2093; Found: 530.2115 [M]+.
Benzyl 3,4,5-Tribenzyloxy-2-bromobenzoate (9)To a stirring solution of 8 (79.6 g, 150 mmol) in DMF (350 mL), a solution of N-bromosuccinimide (NBS) (30.7 g, 172.5 mmol) in DMF (70 mL) was dropwise added at room temperature. After stirring for 24 h, H2O was added to the solution and the resulting mixture was then stirred. The precipitate was collected on a glass filter and washed with H2O and hexane. The obtained solid (112.4 g) was recrystallized from acetone, providing 9 (78.5 g, 86%) as colorless needles; mp 123.8–124.4°C (acetone); 1H-NMR (500 MHz, CDCl3) δ: 5.03 (2H, s, CH2), 5.10 (4H, s, CH2), 5.37 (2H, s, CH2), 7.29–7.51 (21H, m, ArH); 13C-NMR (125 MHz, CDCl3) δ: 67.6, 71.4, 75.6, 75.9, 110.6, 112.4, 127.7, 128.4, 128.4, 128.5, 128.5, 128.6, 128.6, 128.8, 128.8, 128.8, 135.6, 136.1, 136.7, 136.9, 146.0, 151.1, 151.8, 165.9; IR (KBr) νmax 3030, 2362, 2333, 1700, 1577, 1454, 1369, 1329, 1216, 1159, 1100, 955, 909, 740, 698 cm−1; HR-MS (EI) Calcd for C35H29O5Br [M]+: 608.1198; Found: 608.1241 [M]+. Anal. Calcd for C35H29O5Br: C, 68.97; H, 4.80. Found: C, 68.74; H, 4.75.
tert-Butyl Gallate31) (10)A mixture of gallic acid monohydrate (1) (47.0 g, 250 mmol), t-BuOH (300 mL), and t-BuOAc (300 mL) was stirred at 0°C under N2. Conc. H2SO4 (25 mL) was carefully added to the solution with maintaining the temperature at 0°C. After stirring for 1 h at the same temperature, the resulting mixture was warmed to room temperature and stirred for 5 d. The reaction mixture was quenched with sat. NaHCO3 aq., poured into H2O (500 mL), and extracted with Et2O (500 mL×3). The combined organic layer was washed with brine (300 mL), dried over MgSO4, and filtered. The filtrate was evaporated and the resulting yellow residue (64.5 g) was dissolved in CHCl3 (100 mL). After removal of the insoluble precipitate by filtration, the filtrate was concentrated in vacuo and the yellow residue (29.5 g) was separated by silica gel column chromatography (1 : 4; EtOAc–hexane). The obtained pale yellow solid (24.5 g) was recrystallized from CHCl3, providing 10 (21.7 g, 38%) as a colorless solid. Analytical sample of 10 was obtained by further recrystallization from CHCl3–hexane; mp 146–147°C (CHCl3–hexane); IR (KBr) νmax 3377, 3314, 3227, 2980, 1697, 1670, 1624, 1445, 1371, 1348, 1256, 1157, 1026, 771 cm−1; 1H-NMR (500 MHz, acetone-d6) δ: 1.53 (9H, s, Ot-Bu), 7.07 (2H, s, ArH); 13C-NMR (125 MHz, acetone-d6) δ: 28.3, 80.3, 109.7, 123.6, 138.2, 145.8, 166.0; Anal. Calcd for C11H14O5: C, 58.40; H, 6.24. Found: C, 58.35; H, 6.40.
tert-Butyl 3,4-Benzaloxy-5-hydroxybenzoate (11)To a solution of 10 (10.0 g, 44.2 mmol) in pyridine (25.0 mL), benzal chloride (8.54 mL, 66.3 mmol) was added and the mixture was heated at 110°C under N2. After stirring for 8 h, toluene was added to the reaction mixture and the solvent was removed in vacuo. The resulting purple residue was dissolved in CHCl3 and filtered with SiO2 pad. After concentration of the filtrate, pale yellow solid (16.2 g) was recrystallized from CHCl3–hexane, providing 11 (9.71 g, 70%) as a colorless solid; mp 167.5–169.8°C (CHCl3–hexane); IR (KBr) νmax 3369, 2976, 1684, 1645, 1614, 1512, 1447, 1398, 1337, 1335, 1305, 1259, 1219, 1163, 1076, 1076, 1016, 766, 696 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 1.57 (9H, s, Ot-Bu), 7.04 (1H, s, PhCH), 7.13 (1H, d, J=1.6 Hz, ArH), 7.33 (1H, d, J=1.6 Hz, ArH), 7.44–7.57 (5H, m, ArH); 13C-NMR (125 MHz, acetone-d6) δ: 28.2, 81.0, 102.4, 111.9, 114.5, 127.1, 127.2, 129.5, 131.2, 137.0, 139.0, 140.9, 149.7, 165.3; Anal. Calcd for C18H18O5: C, 68.78; H, 5.77. Found: C, 68.50; H, 5.86.
Benzyl 2-(2,3-Benzaloxy-5-tert-butoxycarbonylphenoxy)-3,4,5-tribenzyloxybenzoate (12)Two round-bottomed flasks (200 mL) were equipped with 11 (3.15 g, 10.0 mmol), 9 (18.3 g, 30.0 mmol), activated Cu (3.81 g, 60.0 mmol), and DMA (25 mL), respectively. The each mixture was heated at 160°C under N2. After stirring for 30 min, the each reaction mixture was cooled to ambient temperature, diluted with EtOAc (250 mL), and filtered. The filtrate were combined, poured into H2O (500 mL), and extracted with EtOAc (500 mL×3). The combined organic layer was washed with brine (300 mL), dried over MgSO4, and filtered. The filtrate was evaporated and the resulting residue (46.3 g) was purified by silica gel column chromatography (1 : 4; EtOAc–hexane) to give a colorless residue (39.9 g) as a mixture containing 12, which was used in the next reaction without further purification. Analytical sample of 12 was separately obtained by silica gel column chromatography as a colorless oil; 1H-NMR (500 MHz, acetone-d6) δ: 1.52 (9H, s, Ot-Bu), 4.98 (1H, d, A of AB, J=10.5 Hz, CHAHB), 5.01 (1H, d, B of AB, J=10.5 Hz, CHAHB), 5.17 (2H, s, CH2), 5.19 (1H, d, A of AB, J=12.5 Hz, CHAHB), 5.24 (1H, d, B of AB, J=12.5 Hz, CHAHB), 5.25 (2H, s, CH2), 6.98 (1H, d, J=1.5 Hz, ArH), 7.04 (1H, s, PhCH), 7.10 (1H, d, J=1.5 Hz, ArH), 7.50 (1H, s, ArH), 7.19–7.56 (25H, m, ArH); 13C-NMR (125 MHz, acetone-d6) δ: 28.2, 67.4, 71.8, 76.0, 76.2, 81.2, 104.0, 111.5, 112.5, 112.7, 120.9, 126.9, 127.2, 128.6, 128.8, 128.9, 129.0, 129.1, 129.3, 129.5, 131.2, 136.7, 136.8, 137.5, 137.8, 137.9, 139.7, 142.8, 142.8, 147.3, 147.4, 150.0, 151.0, 164.9, 165.0; IR (CHCl3) νmax 3034, 3013, 2490, 1704, 1635, 1498, 1436, 1367, 1217, 1159, 1087, 1017, 770, 697 cm−1; HR-MS (FAB, positive ion mode) Calcd for C53H47O10 [M+H]+: 843.3169; Found: 843.3148 [M+H]+.
Benzyl 3,4,5-Tribenzyloxy-2-(5-tert-butoxycarbonyl-2,3-dihydroxyphenoxy)benzoate (13)To a stirring solution of the above residue (39.9 g) in CH2Cl2 (500 mL), EtSH (14.8 mL, 200 mmol) and SnCl2 (9.13 g, 50.0 mmol) were added at 0°C. After stirring for 22 h at room temperature, the reaction mixture was filtered and concentrated in vacuo. The resulting residue (52.7 g) was purified by silica gel column chromatography (1 : 3–1 : 2; EtOAc–hexane), providing 13 (11.4 g, 76%) as a colorless amorphous powder; 1H-NMR (500 MHz, acetone-d6) δ: 1.46 (9H, s, Ot-Bu), 4.99 (2H, s, CH2), 5.20 (2H, s, CH2), 5.21 (2H, s, CH2), 5.25 (2H, s, CH2), 6.75 (1H, d, J=1.5 Hz, ArH), 7.18 (1H, d, J=1.5 Hz, ArH), 7.49 (1H, s, ArH), 7.23–7.56 (20H, m, ArH); 13C-NMR (125 MHz, acetone-d6) δ: 28.2, 67.3, 71.8, 76.0, 76.2, 80.5, 107.9, 111.6, 111.8, 121.0, 123.2, 128.6, 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, 697 cm−1; HR-MS (EI) Calcd for C46H42O10 [M]+: 754.2778; Found: 754.2744 [M]+.
Benzyl 3,4,5-Tribenzyloxy-2-(2,3-dibenzyloxy-5-tert-butoxycarbonylphenoxy)benzoate (14)To a stirring solution of 13 (1.51 g, 2.00 mmol) and K2CO3 (691 mg, 5.00 mmol) in DMF (10 mL), BnBr (0.52 mL, 4.38 mmol) was added and the mixture was heated at 40°C. After 2 h, the reaction mixture was cooled to ambient temperature, poured into H2O (100 mL), and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over MgSO4, and filtered. The filtrate was evaporated and the resulting yellow residue (2.20 g) was purified by silica gel column chromatography (1 : 4; EtOAc–hexane), providing 14 (1.71 g, 91%) as a colorless solid. Analytical sample of 14 was obtained by recrystallization from acetone; mp 129–131°C (acetone); 1H-NMR (500 MHz, acetone-d6) δ: 1.49 (9H, s, Ot-Bu), 4.97 (2H, s, CH2), 5.01 (2H, s, CH2), 5.20 (4H, s, CH2), 5.22 (2H, s, CH2), 5.27 (2H, s, CH2), 6.86 (1H, d, J=2.0 Hz, ArH), 7.17–7.57 (32H, m, ArH); 13C-NMR (125 MHz, acetone-d6) δ: 28.2, 67.4, 71.7, 71.8, 75.3, 76.0, 76.1, 81.2, 109.5, 109.6, 111.6, 121.0, 127.8, 128.4, 128.5, 128.6, 128.7, 128.7, 128.8, 128.9, 129.0, 129.1, 129.2, 129.3, 136.8, 137.6, 137.8, 138.0, 138.0, 139.0, 142.1, 142.9, 147.2, 147.6, 150.8, 153.5, 165.0, 165.2; IR (KBr) νmax 3031, 2952, 2357, 1716, 1594, 1423, 1371, 1343, 1222, 1095, 1000, 967, 859, 753, 697 cm−1; HR-MS (FAB, positive ion mode) Calcd for C60H55O10 [M+H]+: 935.3795; Found: 935.3816 [M+H]+. Anal. Calcd for C60H54O10: C, 77.07; H, 5.82. Found: C, 76.87; H, 5.87.
3,4-Dibenzyloxy-5-(2,3,4-tribenzyloxy-6-benzyloxycarbonylphenoxy)benzoic Acid (15)To a stirring solution of 14 (935 mg, 1.00 mmol) in CH2Cl2 (10 mL), AcOH (286 µL, 5.00 mmol) and SnCl2 (457 mg, 2.50 mmol) were subsequently added. After stirring for 22 h at room temperature, AcOH (286 µL, 5.00 mmol) and SnCl2 (457 mg, 2.50 mmol) were added to the mixture and the resulting mixture was stirred. After 32 h, the reaction mixture was filtered and concentrated in vacuo. The obtained yellow amorphous (1.02 g) was purified by silica gel column chromatography (1 : 1; EtOAc–hexane), providing 15 (777 mg, 88%) as a colorless solid. Analytical sample of 15 was obtained by recrystallization from acetone–hexane; mp 137–139°C (acetone–hexane); 1H-NMR (500 MHz, acetone-d6) δ: 4.93 (2H, s, CH2), 5.01 (2H, s, CH2), 5.21 (2H, s, CH2), 5.22 (2H, s, CH2), 5.25 (2H, s, CH2), 5.26 (2H, s, CH2), 6.94 (1H, d, J=2.0 Hz, ArH), 7.16–7.58 (32H, m, ArH); 13C-NMR (125 MHz, acetone-d6) δ: 67.4, 71.5, 71.6, 75.3, 75.8, 76.0, 109.7, 111.4, 120.8, 126.0, 128.3, 128.5, 128.6, 128.6, 128.8, 128.8, 128.9, 129.0, 129.0, 129.1, 129.2, 129.3, 136.6, 137.3, 137.6, 137.7, 137.7, 138.8, 142.3, 142.7, 147.1, 147.4, 150.7, 153.5, 153.6, 165.0, 167.3; IR (KBr) νmax 3064, 3032, 2947, 2874, 2360, 2342, 1704, 1684, 1591, 1497, 1426, 1375, 1217, 1092, 972, 909, 749, 736, 696 cm−1; HR-MS (FAB, positive ion mode) Calcd for C56H47O10 [M+H]+: 879.3169; Found: 879.3190 [M+H]+.
This work was financially supported by the JSPS KAKENHI Grant No. 22590003 and the Tamura Science and Technology Foundation.
