HETEROCYCLES

Paper | Regular issue | Vol. 87, No. 12, 2013, pp. 2555-2565
Received, 19th September, 2013, Accepted, 30th October, 2013, Published online, 8th November, 2013.
DOI: 10.3987/COM-13-12847

■ Synthesis of Nigricanin via Intramolecular Biaryl Coupling Reaction of Functionalized Phenol Benzoate

Takuya Matsukihira, Tatsuya Kida, Kei Hidaka, Shumpei Saga, Mami Takemura, Atsuro Yonoki, Tsuyoshi Nishimori, Yoshikazu Horino, Takashi Harayama, Yasuo Takeuchi, and Hitoshi Abe*

Department of Environmental Applied Chemistry, Faculty of Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan

Abstract

A tetracyclic natural product, nigricanin (1), was synthesized through an intramolecular biaryl coupling reaction of the phenyl benzoate derivative which was derived from the corresponding phenol and benzoic acid.

INTRODUCTION
Ellagic acid and its family are well known to exhibit a wide range of biological activities, such as antioxidant1 and anti-cancer properties.2 Because of their polyphenolic structures, ellagic acid and its derivatives act as free radical scavengers and thus are utilized in anti-aging supplements.3 Nigricanin (1) is one of the ellagic acid congeners, which was isolated from Russula nigricans, and its chemical structure was determined in 2004 (Figure 1).4 Although there are several methods for the synthesis of ellagic acid,5 the synthesis of 1 has never been reported in spite of its unique structure and suspected biological interest.

In this article, we report the first synthesis of 1 via the intramolecular biaryl coupling reaction of a phenyl benzoate derivative.6

RESULTS AND DISCUSSION
Based on the retrosynthesis depicted in Scheme 1, we planned to prepare the lactone compound 2 as the precursor of the target molecule, nigricanin 1. The lactone 2 should be realized by the intramolecular biaryl coupling reaction of the functionalized phenyl benzoate 3, which can be simply prepared from the corresponding benzoic acid 4 and phenol 5.

Synthesis of 1 commenced with the preparation of the phenol part by a two-step conversion from 3,4-dihydroxybenzaldehyde (6), involving the selective benzylation of 6 into 7, followed by the protection of the formyl group with ethylene glycol to afford 8 (Scheme 2). The monobenzyl compound 7 was also regioselectively iodinated with ICl into 9, which was benzylated again, to generate 10. The aldehyde 10 was oxidized with NaClO2 for the generation of the desired benzoic acid 11, and then the coupling precursor 12 was prepared by a simple esterification between 8 and 11.

To construct the lactone ring, we examined the palladium-mediated intramolecular coupling reaction with 12 (Pd(OAc)2, NaOAc, PPh3, DMF, 120 °C) (Scheme 3). During the work-up stage, the ethylenedioxy group was deprotected, thus the tricyclic formyl compound 13 was produced in 39% yield. However, a byproduct 14 (44%) was also generated in this step. The undesired 14 was a chemo-isomer of 13, namely, the protecting benzyloxy group at the position ortho to the iodo function reacted under the employed reaction conditions.7 In spite of the moderate yield of 13, the catalytic hydrogenation of 13 in methanol successfully produced the target molecule, nigricanin 1.

In order to avoid the participation of the protecting group during the key coupling reaction, we postulated that the MOM protection would be suitable at the 3-position of the benzoyl moiety (Scheme 4). Thus, 9 was protected with the MOM group to form 15 followed by the oxidation of the formyl group, then the esterification between 16 and 8 furnished the coupling precursor 17. The coupling reaction of 17 proceeded under conditions as illustrated in Scheme 4 (Pd(OAc)2, Ag2CO3, PPh3, DMA, 120 °C), then the acidic work-up removed the two acetal functions to afford a tetracyclic product 18. The final deprotection of the benzyl group by conventional hydrogenolysis afforded nigricanin (1). The comparison of the NMR data of both the synthetic and reported4 ones is listed in Table 1. Consequently, these NMR data are identical, therefore, the synthesis of nigricanin was completed.

CONCLUSION
The synthesis of nigricanin (1) was achieved through the palladium-mediated biaryl coupling reaction of the phenyl benzoates as the key step. Progress toward the synthesis of these types of natural products will be reported in due course.

EXPERIMENTAL
General Information
Melting points were measured using a Yanagimoto micro-melting point hot-plate and are uncorrected. The IR spectra were recoded using a Jasco FTIR-350 or FTIR-4100 spectrophotometer. The NMR spectra were obtained using a Varian VXR-500 (500 MHz), or JEOL α-400 (400 MHz) instrument. The chemical shifts are given in δ parts per million with TMS as an internal standard. The elemental analyses were performed using a Yanaco MT-5 or Elementar vario MICRO cube analyzer. The FABMS was obtained using a VG-70SE or JEOL JMS-AX505HAD instrument with m-nitrobenzyl alcohol as the matrix. The EIMS was obtained using a JEOL JMS-700 or JMS-GCmate II instrument. Silica gel column chromatography was carried out using wakogel® C-200 (Wako) or 9385 Kieselgel 60 (Merck). TLC analysis was performed on Kieselgel 60 F254 (Merck) plates. Solvents were dried with a standard procedure.

4-Benzyloxy-3-hydroxybenzaldehyde (7)8
To a mixture of 6 (8.21 g, 59.4 mmol), K2CO3 (9.04 g, 65.4 mmol), KI (0.496 g, 2.99 mmol), and DMF (10 mL), benzyl bromide (7.60 mL, 64.0 mmol) was dropwise added at 0 °C. The mixture was stirred for 22 h at the same temperature, then acidified with 10% HCl aq. After extraction with ether, the organic layer was washed with brine and dried over MgSO4. The organic solvent was removed in vacuo to give a residue which was purified by silica gel column chromatography (15/1 to 4/1: AcOEt/hexane). The obtained solid was recrystallized from AcOEt/hexane to provide colorless prisms of 7 (8.48 g, 63%): mp 120.1-121.0 ºC (AcOEt−hexane) [lit.,8 mp 118-120 ºC]. 1H-NMR (400 MHz, CDCl3) δ 9.84 (s, 1H, ArCHO), 7.46 (d, J = 2.0 Hz, 1H, ArH), 7.44-7.37 (m, 6H, ArH), 7.04 (d, J = 8.8 Hz, 1H, ArH), 5.80 (s, 1H, ArOH), 5.21 (s, 2H, ArCH2-).

5-(1,3-Dioxolan-2-yl)-2-benzyloxyphenol (8)9
Using a Dean-Stark apparatus, a mixture of 7 (1.51 g, 6.60 mmol), ethylene glycol (1.82 mL, 32.8 mmol), p-TsOH (monohydrate, 119 mg, 0.69 mmol), MgSO4 (4.03 g, 33.5 mmol), and dry benzene (30 mL) was heated under reflux for 18 h. The mixture was poured into 10% NaHCO3 aq. and extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and evaporated to give a residue, which was recrystallized from CH2Cl2-Et2O. Colorless needles of 8 (1.66 g, 92%) were obtained: mp 84.5-86.5 °C (CH2Cl2-Et2O). 1H-NMR (400 MHz, CDCl3) δ 7.43-7.34 (m, 5H, ArH), 7.08 (d, J = 2.0 Hz, 1H, ArH), 6.96 (dd, J = 8.2, 2.0 Hz, 1H, ArH), 6.91 (d, J = 8.2 Hz, 1H, ArH), 5.73 (s, 1H, ArOH), 5.68 (s, 1H, ArCH-), 5.22 (s, 2H, ArCH2-), 4.16-3.97 (m, 4H, -OCH2CH2O-).

4-Benzyloxy-3-hydroxy-2-iodobenzaldehyde (9)
To a solution of 7 (8.45 g, 37.0 mmol) in pyridine (80 mL), ICl (2.3 mL, 44.0 mmol) was added at 0 °C, then the mixture was stirred for 4 days at the same temperature. After it was warmed to room temperature, the mixture was stirred for 4 h at rt, then 10% HCl aq. was added to acidify the mixture, which was then extracted with AcOEt. The organic layer was washed with 10% Na2S2O3 aq. and brine, then dried over MgSO4 and evaporated to give a crude residue. After silica gel column chromatography (20/1/2 to 5/1/4: AcOEt/hexane/CHCl3), the obtained solid material was recrystallized from AcOEt to provide light yellow needles of 9 (9.66 g, 74%): mp 126.2-127.2 °C (AcOEt). IR (KBr) υmax 3062-2789, 2640, 2568, 1685, 1577, 1476, 1421, 1382, 1308, 1274, 1162, 1082, 1012, 997, 977, 921, 900, 828, 778, 743, 698, 676 cm-1. 1H-NMR (400 MHz, CDCl3) δ 10.03 (s, 1H, ArCHO), 7.53 (d, J = 8.2 Hz, 1H, ArH), 7.46-7.37 (m, 5H, ArH), 6.98 (d, J = 8.2 Hz, 1H, ArH), 6.36 (s, 1H, ArOH), 5.22 (s, 2H, ArCH2-). 13C-NMR (150 MHz, CDCl3) δ 195.0, 149.9, 146.0, 134.9, 129.0, 129.0, 128.9, 128.0, 123.7, 111.4, 88.5, 71.7. Anal. Calcd for C14H11IO3: C, 47.48; H, 3.13. Found: C, 47.31; H, 3.33.

3,4-Benzyloxy-2-iodobenzaldehyde (10)
A solution of 9 (4.01 g, 11.3 mmol), K2CO3 (1.76 g, 12.7 mmol), DMF (45mL), and a portion of KI was stirred for 30 min at 0 °C. Benzyl bromide (1.34 mL, 11.3 mmol) was added to the solution, and stirred for 6 h at 0 °C. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4, and evaporated to give a residue which was recrystallized from AcOEt. Flesh-colored crystals of 10 (3.81 g, 76%) were provided. For an analytical sample, further recrystallization was carried out from Et2O-hexane: mp 129.8-130.8 °C (Et2O-hexane). IR (KBr) υmax 2934, 2893, 2845, 1739, 1620, 1577, 1517, 1477, 1442, 1389, 1304, 1272, 1222, 1211, 1160, 1125, 1084, 1017, 917, 825, 819, 770, 761, 737 cm-1. 1H-NMR (400 MHz, CDCl3) δ 10.03 (s, 1H, ArCHO), 7.72 (d, J = 8.6 Hz, 1H, ArH), 7.50-7.28 (m, 10H, ArH), 7.07 (d, J = 8.6 Hz, 1H, ArH), 5.23 (s, 2H, ArCH2-), 5.05 (s, 2H, ArCH2-). 13C-NMR (150 MHz, CDCl3) δ 195.1, 157.0, 148.0, 136.6, 135.6, 129.4, 128.90, 128.88, 128.6, 128.5, 128.4, 127.7, 127.5, 113.4, 101.2, 74.7, 71.3. Anal. Calcd for C21H17IO3: C, 56.77; H, 3.86. Found: C, 56.55 ; H, 4.09.

3,4-Dibenzyloxy-2-iodobenzoic acid (11)
To a solution of 10 (511 mg, 1.15 mmol) and 2-methyl-2-butene (5.0 mL, 42.3 mmol) in a mixed solvent of t-BuOH, THF, and H2O (13:12:1, 65 mL), a solution of NaH2PO4∙2H2O (1.24 g, 7.92 mmol) and NaClO2 (1.20 g, 10.5 mmol) in water (20 mL) was dropwise added and allowed to stand for 3 h. After evaporation of the organic solvent, the mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and evaporated to give a yellow solid. Recrystallization from AcOEt-hexane produced pure 11 (520 mg, 98%) as colorless prisms, mp 214.1-215.4 °C (hexane-AcOEt). IR (KBr) υmax 3031, 2940, 2886, 1695, 1576, 1418, 1361, 1268, 1148, 1014, 978, 901, 773, 750, 734, 695, 671 cm-1. 1H-NMR (500 MHz, d6-DMSO) δ 7.56-7.33 (m, 12H, ArH), 7.27 (d, J = 9.0 Hz, 1H, ArH), 5.26 (s, 2H, ArCH2Ph), 4.93 (s, 2H, ArCH2Ph). 13C-NMR (125 MHz, d6-DMSO) δ 167.6, 153.4, 147.7, 136.8, 136.2, 129.6, 128.5, 128.4, 128.2, 128.1, 127.9, 127.2, 113.4, 94.8, 73.5, 70.3. Anal. Calcd for C21H17IO4: C, 54.80; H, 3.72. Found: C, 54.76; H, 3.68.

2-Benzyloxy-5-(1,3-dioxolan-2-yl)phenyl 3,4-dibenzyloxy-2-iodobenzoate (12)
Under an N2 atmosphere, to a solution of 11 (1.40 g, 3.03 mmol) in CH2Cl2 (50 mL), DMAP (0.19 g, 1.54 mmol), EDC (0.87 g, 4.54 mmol), and 8 (0.83 g, 3.05 mmol) were successively added. The mixture was stirred for 3 h at room temperature, poured into ice water, neutralized with sat. NaHCO3 aq., then extracted with CH2Cl2. The extract was washed with brine, dried over MgSO4, and evaporated to give a residue which was recrystallized from Et2O. Colorless needles of 12 (1.78 g, 82%) were then obtained: mp 135.2-136.3 °C; IR (KBr) υmax 3056, 3033, 2880, 1733, 1579, 1510, 1455, 1390, 1372, 1272, 1124, 1012, 997, 807, 747, 699 cm-1. 1H-NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.8 Hz, 1H, ArH), 7.54-7.23 (m, 17H, ArH), 7.03 (d, J = 8.4 Hz, 1H, ArH), 6.96 (d, J = 8.8 Hz, 1H, ArH), 5.81 (s, 1H, ArCH-), 5.20 (s, 2H, ArCH2-), 5.13 (s, 2H, ArCH2-), 5.03 (s, 2H, ArCH2-), 4.13-4.00 (m, 4H, -OCH2CH2O-). 13C-NMR (100 MHz, CDCl3) δ 163.9, 154.8, 151.1, 149.1, 140.3, 136.8, 136.6, 135.9, 131.3, 129.0, 128.9, 128.8, 128.5, 128.45, 128.43, 128.3, 127.9, 127.6, 127.4, 127.2, 125.2, 121.4, 113.7, 113.0, 103.1, 96.0, 74.5, 71.1, 70.8, 65.3. Anal. Calcd for C37H31IO7: C, 62.19; H, 4.37. Found: C, 62.36; H, 4.52.

Intramolecular coupling reaction of 12
A mixture of 12 (50.8 mg, 0.0711 mmol), Pd(OAc)2 (4.0 mg, 0.0178 mmol), NaOAc (11.7 mg, 0.143 mmol), PPh3 (9.3 mg, 0.0355 mmol), and DMF (1.5 mL) was stirred for 1.5 h at 120 °C, then cooled to room temperature. To the mixture, 10% HCl aq. (1.5 mL) was added and stirred for 10 min. After the mixture was filtered, the filtrate was extracted with CH2Cl2. The extract was washed with brine, dried over MgSO4, and evaporated to give a residue which was subjected to silica gel column chromatography (benzene). Colorless prisms of 13 (14.9 mg, 39%) from the more polar fraction and an amorphous powder of 14 (16.9 mg, 44%) from the less polar fraction were obtained.

4,9,10-Ttribenzyloxy-1-formyl-6H-dibenzo[b,d]pyran-6-one (13): mp 171.8-172.8 °C (AcOEt). IR (KBr) υmax 1728, 1676, 1591, 1562, 1497, 1445, 1379, 1281, 1242, 1200, 1132, 1105, 1003, 791, 733, 694, 411 cm-1. 1H-NMR (400 MHz, CDCl3) δ 9.68 (s, 1H, ArCHO), 8.11 (d, J = 8.8 Hz, 1H, ArH), 7.58 (d, J = 8.4 Hz, 1H, ArH), 7.45-6.76 (m, 17H, ArH), 5.22 (s, 2H, ArOCH2), 5.17 (s, 2H, ArOCH2), 4.63 (s, 2H, ArOCH2). 13C-NMR (100 MHz, CDCl3) δ 187.8, 160.1, 157.5, 149.8, 143.2, 141.1, 136.0, 135.5, 134.7, 129.6, 129.0, 128.9, 128.7, 128.5, 128.4, 128.2, 127.9, 127.7, 127.4, 127.2, 124.9, 117.6, 116.5, 115.5, 113.3, 75.8, 71.4, 71.2. Anal. Calcd for C35H26O6: C, 77.48; H, 4.83. Found: C, 77.11; H, 4.88.

2-Benzyloxy-5-formylphenyl 4-benzyloxy-6H-benzo[c]chromen-1-carboxylate (14): IR (CHCl3) υmax 3028, 3012, 2928, 2855, 1738, 1692, 1607, 1566, 1506, 1479, 1454, 1437, 1421, 1381, 1277, 1259, 1186, 1117, 1088, 1013, 918, 812, 781, 770, 762, 743, 719, 696, 671, 652, 465, 449, 422, 407cm-1. 1H-NMR (400 MHz, CDCl3) δ 9.88 (s, 1H, ArCHO), 7.73 (dd, J = 8.4, 2.0 Hz, 1H, ArH), 7.70 (d, J = 2.0 Hz, 1H, ArH), 7.60 (d, J = 7.6 Hz, 1H, ArH), 7.54 (d, J = 8.4 Hz, 1H, ArH), 7.47-7.15 (m, 13H, ArH), 7.12 (d, J = 8.4 Hz, 1H, ArH), 6.84 (d, J = 8.4 Hz, 1H, ArH), 5.27 (s, 2H, ArOCH2), 5.24 (s, 2H, ArOCH2), 5.14 (s, 2H, ArOCH2). 13C-NMR (100 MHz, CDCl3) δ 190.2, 166.4, 155.9, 151.3, 146.3, 140.9, 136.4, 135.6, 132.1, 130.4, 130.3, 128.9, 128.8, 128.7, 128.5, 128.4, 128.3, 128.1, 127.5, 127.4, 127.3, 125.9, 125.1, 124.9, 123.3, 120.2, 113.4, 112.2, 71.1, 71.0, 69.6. EI-MS m/z: 542 [M]+. HRMS (EI) Calcd for C35H26O6 [M]+: 542.1729; Found: 542.1728.

Nigricanin (1) from 13
A suspension of 13 (17.2 mg, 0.0317 mmol), Pd/C (6.2 mg), and MeOH (20 mL) was vigorously stirred for 30 min under an H2 atmosphere. The solid materials were removed by filtration, and the solvent was evaporated to give a residue which was subjected to silica gel column chromatography with AcOEt/hexane (1:1). Colorless prisms of 1 (5.0 mg, 55%) were obtained: mp 218 °C (acetone, decomp.) [lit.,4 mp 224 °C (acetone, decomp.)]; 1H-NMR (400 MHz, (CD3)2CO) δ 7.80 (d, J = 8.8 Hz, 1H, ArH), 7.22 (d, J = 8.8 Hz, 1H, ArH), 7.20 (d, J = 8.4 Hz, 1H, ArH), 7.14 (d, J = 8.4 Hz, 1H, ArH), 6.35 (s, 1H, ArCH), 3.58 (s, 3H, OCH3). 13C-NMR (125 MHz, (CD3)2CO) δ 160.0, 151.8, 145.6, 138.2, 135.9, 124.8, 123.0, 121.8, 120.4, 119.0, 118.3, 112.9, 112.0, 99.7, 56.0.

4-Benzyloxy-2-iodo-3-methoxymethoxybenzaldehyde (15)
Under an N2 atmosphere, i-Pr2NEt (2.7 mL, 15.9 mmol) and MOMCl (1.50 mL, 19.9 mmol) were added to a solution of 9 (4.91 g, 13.9 mmol) in DMF (30 mL) at 0 °C. After stirring for 18 h at 0 °C, 10% HCl aq. (30 mL) was added to acidify the reaction mixture. Water (150 mL) was added to the mixture and extracted with AcOEt. The organic layer was washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated. The resulting yellow residue was subjected to silica gel column chromatography with hexane/AcOEt/CHCl3 (35:1:2 to 5:1:2) to give a yellow solid which was recrystallized from hexane-AcOEt. Colorless needles of 15 (5.40 g, 98%) were obtained: mp 72.8-73.8 °C. IR (KBr) υmax 1275, 1254, 1213, 1200, 1178, 1148, 1126, 1107, 991, 934, 899, 824, 802, 791, 743, 694, 662, 610 cm-1. 1H-NMR (400 MHz, CDCl3) δ 10.04 (d, 1H, ArCHO), 7.69 (d, J = 8.8 Hz, 1H, ArH), 7.43-7.34 (m, 5H, ArH), 7.03 (d, J = 8.8 Hz, 1H, ArH), 5.22 (s, 2H, ArCH2Ph), 5.18 (s, 2H, ArOCH2OMe), 3.61 (s, 3H, OCH3). 13C-NMR (100 MHz, CDCl3) δ 195.3, 156.4, 146.2, 135.4, 129.5, 128.9, 128.7, 127.7, 127.4, 113.3, 100.9, 99.1, 71.3, 58.7. Anal. Calcd for C16H15IO4: C, 48.26; H, 3.80. Found: C, 48.11; H, 3.93.an N2 atmosphere, i-Pr2NEt (2.7 mL, 15.9 mmol) and MOMCl (1.50 mL, 19.9 mmol) were added to a solution of 9 (4.91 g, 13.9 mmol) in DMF (30 mL) at 0 °C. After stirring for 18 h at 0 °C, 10% HCl aq. (30 mL) was added to acidify the reaction mixture. Water (150 mL) was added to the mixture and extracted with AcOEt. The organic layer was washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated. The resulting yellow residue was subjected to silica gel column chromatography with hexane/AcOEt/CHCl3 (35:1:2 to 5:1:2) to give a yellow solid which was recrystallized from hexane-AcOEt. Colorless needles of 15 (5.40 g, 98%) were obtained: mp 72.8-73.8 °C. IR (KBr) υmax 1275, 1254, 1213, 1200, 1178, 1148, 1126, 1107, 991, 934, 899, 824, 802, 791, 743, 694, 662, 610 cm-1. 1H-NMR (400 MHz, CDCl3) δ 10.04 (d, 1H, ArCHO), 7.69 (d, J = 8.8 Hz, 1H, ArH), 7.43-7.34 (m, 5H, ArH), 7.03 (d, J = 8.8 Hz, 1H, ArH), 5.22 (s, 2H, ArCH2Ph), 5.18 (s, 2H, ArOCH2OMe), 3.61 (s, 3H, OCH3). 13C-NMR (100 MHz, CDCl3) δ 195.3, 156.4, 146.2, 135.4, 129.5, 128.9, 128.7, 127.7, 127.4, 113.3, 100.9, 99.1, 71.3, 58.7. Anal. Calcd for C16H15IO4: C, 48.26; H, 3.80. Found: C, 48.11; H, 3.93.

4-Benzyloxy-2-iodo-3-methoxymethoxybenzoic acid (16)
To a solution of 15 (1.01 g, 2.53 mmol) and 2-methyl-2-butene (11.1 mL, 94.0 mmol) in a mixed solvent of t-BuOH, THF, and H2O (7:6:1, 70 mL), a solution of NaH2PO4∙2H2O (2.75 g, 17.6 mmol) and NaClO2 (2.65 g, 23.1 mmol) in water (20 mL) was dropwise added and allowed to stand for 3 h. After evaporation of the organic solvent, the mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and evaporated to give a yellow solid. Recrystallization from AcOEt-hexane produced pure 16 (1.02 g, 97%) as colorless prisms, mp 129.2-131.4 °C. IR (KBr) υmax 3062-2789 (br), 2640, 2568, 1685, 1577, 1476, 1462, 1453, 1421, 1404, 1382, 1308, 1274, 1195, 1162, 1082, 1012, 997, 977, 921, 900, 849, 828, 778, 758, 743, 698, 676 cm-1. 1H-NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.8 Hz, 1H, ArH), 7.44-7.33 (m, 5H, ArH), 6.98 (d, J = 8.8 Hz, 1H, ArH), 5.20 (s, 2H, ArCH2Ph), 5.16 (s, 2H, ArOCH2OMe), 3.61 (s, 3H, OMe). 13C-NMR (100 MHz, CDCl3) δ 155.1, 147.6, 136.0, 129.6, 129.2, 128.9, 128.0, 113.1, 99.4, 96.1, 71.5, 59.0, 71.5, 59.0. Anal. Calcd for C16H15IO5: C, 46.40; H, 3.65. Found: C, 46.29; H, 3.78.

2-Benzyloxy-5-(1,3-dioxolan-2-yl)phenyl 4-benzyloxy-2-iodo-3-methoxymethoxybenzoate (17)
Under an N2 atmosphere, to a solution of 16 (2.01 g, 4.85 mmol) in CH2Cl2 (60 mL), DMAP (151.7 mg, 1.24 mmol), EDC (1.17 g, 6.12 mmol), and 8 (1.10 g, 4.04 mmol) were successively added. The mixture was stirred for 5.5 h at room temperature, poured into ice water, neutralized with sat. NaHCO3 aq., then extracted with CH2Cl2. The extract was washed with brine, dried over MgSO4, and evaporated to give a residue which was subjected to silica gel column chromatography with hexane/AcOEt (6:1 to 2:1) to give a white amorphous solid of 17 (2.69 g, 100%). IR (CHCl3) υmax 3013, 1746, 1580, 1508, 1454, 1381, 1267, 1231, 1202, 1161, 1124, 1082, 966, 793, 770, 750, 712, 698, 675, 467, 449, 434, 411 cm-1. 1H-NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.8 Hz, 1H, ArH), 7.44-7.23 (m, 12H, ArH), 7.02 (d, J = 8.8 Hz, 1H, ArH), 6.91 (d, J = 8.4 Hz, 1H, ArH), 5.80 (s, 1H), 5.22 (s, 2H), 5.14 (s, 2H), 5.11 (s, 2H), 4.13-3.97 (m, 4H, -OCH2CH2O-), 3.62 (s, 3H, OMe). 13C-NMR (100 MHz, CDCl3) δ 164.0, 154.2, 151.0, 147.1, 140.2, 136.5, 135.7, 131.2, 128.8, 128.7, 128.51, 128.46, 127.9, 127.6, 127.3, 125.2, 121.4, 113.6, 112.8, 103.1, 99.0, 71.1, 70.7, 65.3, 58.6. EI-MS m/z: 668 [M]+; HRMS (EI) Calcd for C26H29IO8 [M]+: 668.0907; Found: 668.0910.

3,8-Dibenzyloxy-10-hydroxychromeno[5,4,3-cde]chromen-5(10H)-one (18)
A mixture of 17 (113.8 mg, 0.17 mmol), Pd(OAc)2 (9.9 mg, 0.0441 mmol), Ag2CO3 (91.4 mg, 0.331 mmol), PPh3 (21.5 mg, 0.0820 mmol), and DMA (3 mL) was stirred for 6 h at 120 °C, then cooled to room temperature. To the mixture, PPTS (384.0 mg, 1.52 mmol) and water (1 mL) was added, and then stirred for 18 h at rt and for 2.5 h at 80 °C. After the mixture was filtered, the filtrate was extracted with CH2Cl2. The extract was washed with brine, dried over MgSO4, and evaporated to give a residue which was subjected to silica gel column chromatography with benzene/hexane/AcOEt (10:10:1 to 10:3:1) Colorless prisms of 18 (62.3 mg, 81%) was obtained. When this reaction was carried out using 1.78 g of 17, the chemical yield was 73%, mp 210.4-212.9 °C (CHCl3). 1H-NMR (400 MHz, CDCl3) δ 7.94 (1H, d, J = 8.5 Hz), 7.49-7.30 (10H, m, ArH), 7.19 (2H, t, J = 6.0 Hz, ArH), 7.11 (1H, d, J = 7.0 Hz, ArH), 6.73 (1H, d, J = 5.0 Hz), 5.33 (2H, s, ArCH2Ph), 5.29 (2H, s, ArCH2Ph), 3.48 (1H, d, J = 5.0 Hz, OH). HRMS (EI) Calcd for C28H20O6 [M]+: 452.1260; Found: 452.1283. This compound was gradually decomposed

Nigricanin (1) from 18
A suspension of 18 (50.9 mg, 0.112 mmol), 10% Pd/C (13.5 mg), and MeOH (40 mL) was heated at 90 °C with vigorous stirring for 90 min under an H2 atmosphere. The solid materials were removed by filtration, and the solvent was evaporated to give a residue which was subjected to silica gel column chromatography using AcOEt/hexane (1:10 to 1:1). Colorless prisms of 1 (29.8 mg, 93%) were obtained. When this reaction was carried out using 365.5 mg of 18, the chemical yield was 86%.

ACKNOWLEDGMENT
A part of this work was financially supported by JSPS KAKENHI Grant No. 22590003 to H. A. We also thank the SC-NMR Laboratory of Okayama University for use of their facilities.

References

1. (a) Atta-ur-Rahman, F. N. Ngounou, M. I. Choudhary, S. Malik, T. Makhmoor, M. Nur-e-Alam, S. Zareen, D. Lontsi, J. F. Ayafor, and B. L. Sondengam, Planta Med., 2001, 67, 335; CrossRef (b) D. Bagchi, E. A. Hassoun, M. Bagchi, and S. J. Stohs, Free Radic. Biol. Med., 1993, 15, 217. CrossRef
2. (a) Y. H. Choi, J. M. Pezzuto, A. D. Kinghorn, and N. R. Fornsworth, Planta Med., 1988, 54, 511; CrossRef (b) A. Constantinou, G. D. Stoner, R. Mehta, K. Rao, C. Runyan, and R. Moon, Nutr. Cancer, 1995, 23, 121. CrossRef
3. (a) J.-H. Lee and S. T.Talcott, J. Agric. Food Chem., 2004, 52, 361; CrossRef (b) D. A. Vattem and K. Shetty, Proc. Biochem., 2003, 39, 367. CrossRef
4. J.-W. Tan, J.-B. Xu, Z.-J. Dong, D.-Q. Luo, and J.-K. Liu, Helv. Chim. Acta, 2004, 87, 1025. CrossRef
5. (a) J. Takahara and R. Hans, Jpn. Kokai Tokkyo Koho, 2004, JP2004168688; (b) A. Alam, Y. Takaguchi, and S. Tsuboi, J. Fac. Environ. Sci. Tech., Okayama Univ., 2005, 10, 111.
6. We have reported the Pd-mediated biaryl coupling reaction of the phenyl benzoate derivatives for natural product synthesis: (a) H. Abe, T. Matsukihira, T. Fukumoto, Y. Horino, Y. Takeuchi, and T. Harayama, Heterocycles, 2012, 84, 323; CrossRef (b) K. Shioe, Y. Sahara, Y. Horino, T. Harayama, Y. Takeuchi, and H. Abe, Tetrahedron, 2011, 67, 1960; CrossRef (c) K. Shioe, Y. Takeuchi, T. Harayama, and H. Abe, Chem. Pharm. Bull., 2010, 58, 435; CrossRef (d) H. Abe, T. Fukumoto, Y. Horino, T. Harayama, and Y. Takeuchi, Heterocycles, 2010, 82, 851; CrossRef (e) H. Abe, M. Arai, Y. Takeuchi, and T. Harayama, Heterocycles, 2009, 77, 1409; CrossRef (f) H. Abe, M. Arai, K. Nishioka, T. Kida, K. Shioe, Y. Takeuchi, and T. Harayama, Heterocycles, 2008, 76, 291; CrossRef (g) H. Abe and T. Harayama, Heterocycles, 2008, 75, 1305; CrossRef (h) H. Abe, Y. Sahara, Y. Matsuzaki, Y. Takeuchi, and T. Harayama, Tetrahedron Lett., 2008, 49, 605; CrossRef (i) S. Takeda, H. Abe, Y. Takeuchi, and T. Harayama, Tetrahedron, 2007, 63, 396; CrossRef (j) H. Abe, T. Fukumoto, Y. Takeuchi, and T. Harayama, Heterocycles, 2007, 74, 265; CrossRef (k) H. Abe, K. Nishioka, S. Takeda, M. Arai, Y. Takeuchi, and T. Harayama, Tetrahedron Lett., 2005, 46, 3197; CrossRef (l) H. Abe, S. Takeda, T. Fujita, K. Nishioka, Y. Takeuchi, and T. Harayama, Tetrahedron Lett., 2004, 45, 2327; CrossRef (m) T. Harayama, H. Yasuda, T. Akiyama, Y. Takeuchi, and H. Abe, Chem. Pharm. Bull., 2000, 48, 861. CrossRef
7. Chemoselectivity of this type of coupling reaction using phenyl 3-benzyloxy-2-iodobenzoate derivetives is under investigation in our laboratory.
8. D. Pez, I. Leal, F. Zuccotto, C. Boussard, R. Brun, S. L. Croft, V. Yardley, L. M. R. Perez, D. G. Pacanowska, and I. H. Gilbert, Bioorg. Med. Chem., 2003, 11, 4693. CrossRef
9. H. Ohnota, M. Hayashi, J. Kuroda, Y. Komatsu, and T. Nishimura, PCT Int. Appl., 2002, WO 02094319.