An ellagic acid-related natural product, nigricanin (1), was synthesized via the Ullmann coupling reaction of 2-bromo-3,4-dialkoxybenzaldehyde (4) followed by the Cannizzaro reaction for desymmetrization of the symmetric biaryl compound (5). Compared to our previously reported study, the presented synthesis improved the sequence step number.

Nigricanin (1) was isolated from fruiting bodies of Russula nigricans (Russulaceae), and its chemical structure was determined by Liu and colleagues in 2004.¹⁾ The structural feature of 1 is possessing a highly oxygenated tetracyclic skeleton which is an ellagic acid-like heterocyclic system with partially-reduced aromatic rings. This class of compounds often exhibits interesting biological activities,^2–7) thus their total synthesis would be an attractive subject. Recently, we achieved the synthesis of 1, in which a palladium-mediated biaryl coupling reaction of the phenyl benzoate derivative⁸⁾ was used in the key step⁹⁾ (Chart 1).

Chart 1. Previous Synthesis of Nigricanin (1) via Palladium-Mediated Biaryl Coupling Reaction

In Chart 1, nine steps were necessary for completion of the synthesis of 1, and the expensive palladium reagent was essential for the key coupling process. In order to improve the efficiency of the synthesis, we planned an alternative synthetic route as shown in Chart 2, involving the Ullmann coupling reaction^10,11) and the Cannizzaro reaction.¹²⁾ This sequential method for forming non-symmetrical biaryl compounds via the Ullmann coupling and the Cannizzaro reaction has been reported by Kobayashi et al.,¹³⁾ Moore et al.,¹⁴⁾ Bringmann et al.,¹⁵⁾ and Seitz and colleagues.¹⁶⁾

Chart 2. Synthesis Plan for Nigricanin (1)

According to the retrosynthesis scheme, we selected isovanillin (2) as the starting material for the synthesis of nigricanin (1), which was transformed into 3 by the ortho-selective bromination with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (Chart 3). The phenolic hydroxyl group of 3 was protected with the benzyl group to afford 4,¹⁷⁾ then the coupling precursor 4 was subjected to the Ullmann conditions using an excess amount of copper dust to perform the dimerization reaction for producing 5. The intramolecular Cannizzaro reaction was effective for desymmetrization of the symmetric structure of 5 under alkaline conditions.¹⁸⁾ Transformation of the generated carboxylic acid into a methyl ester 6 using trimethylsilyl (TMS) diazomethane was necessary, otherwise, the oxidation reaction in the next step did not cleanly proceed. The pyridinium dichromate (PDC) oxidation of the benzylic alcohol of 6 was conducted to form the aldehyde 7. Finally, treatment of 7 with BBr₃ followed by the addition of methanol was successful for forming the target nigricanin (1) in a one-pot operation. The obtained material was identical to the sample in hand which we previously prepared.

Chart 3. Synthesis of Nigricanin (1) via Ullmann Coupling and Cannizzaro Reaction

Consequently, we completed the synthesis of nigricanin (1) via a different route from the previously reported way. In the presented scheme, the sequence step number was improved (seven steps), and the synthesis without using of an expensive palladium reagent was accomplished, compared to our previous work.

Melting points (mp) were measured using a Yanagimoto micro-melting point hot-plate apparatus and are uncorrected. The IR spectra were recorded using a Shimadzu FTIR-8400 spectrophotometer. The NMR spectra were obtained using a JEOL α-400 instrument with the chemical shifts being reported as δ ppm and the couplings expressed in Hertz (Hz). The elemental analysis was performed using a Thermo Scientific FlashEA1112 analyzer. Electron ionization mass spectra (EI-MS) was obtained using a JEOL JMS-700 instrument. Silica gel column chromatography was carried out using Wako-gel C-200. Copper was treated by the reported method before use.¹⁹⁾

To a solution of isovanillin (2) (5.0 g, 32.9 mmol) in CHCl₃ (1000 mL), DBDMH (5.2 g, 18.2 mmol) was portionwise added, and the mixture was stirred for 9 h at ambient temperature. After the addition of water (300 mL), the organic layer was separated, washed with brine, and dried over MgSO₄. The organic solvent was removed in vacuo to give a crude material which was purified by recrystallization from AcOEt. The title compound (3, 5.8 g, 25.1 mmol, 77%) was obtained as a pale orange powder, mp 200.2–201.0°C (AcOEt) [lit.¹⁵⁾ mp 206–207°C (EtOH)]. ¹H-NMR (400 MHz, CDCl₃) δ: 10.26 (d, 1H, CHO), 7.58 (d, J=8.8 Hz, 1H, ArH), 6.93 (d, J=8.8 Hz, 1H, ArH), 6.07 (s, 1H, OH), 4.01 (s, 3H, OMe).

To a solution of 3 (7.65 g, 33.1 mmol) and K₂CO₃ (13.7 g, 99.4 mmol) in N,N-dimethylformamide (DMF) (100 mL), BnBr (3.7 mL, 33.6 mmol) was added at room temperature (r.t.), and the mixture was stirred for 1 h at 75°C. After cooling, the mixture was acidified to pH 1, then extracted with AcOEt. The organic layer was washed with brine, dried over MgSO₄, and evaporated to give the title compound (4, 9.94 g, 30.9 mmol, 94%) as a pale orange solid, mp 78.1–78.9°C [lit.²⁰⁾ mp 79–81°C]. ¹H-NMR (400 MHz, CDCl₃) δ: 10.27 (s, 1H, CHO), 7.76 (d, J=8.8 Hz, 1H, ArH), 7.35–7.54 (m, 5H, ArH), 6.98 (d, J=8.8 Hz, 1H, ArH), 5.05 (s, 2H, ArCH₂), 3.96 (s, 3H, OMe). This material was used for the next step without further purification.

Under an N₂ atmosphere, a mixture of 4 (2.20 g, 6.85 mmol), Cu (2.61 g, 41.1 mmol), and DMF (10 mL) was stirred for 1 h at 160°C. After cooling, any undissolved materials were removed by filtration, and AcOEt and 10% HCl aq. were added to the mixture for adjusting the pH to 1. The mixture was then extracted with AcOEt, and the organic layer was washed with brine, dried over MgSO₄, and evaporated to give a crude solid. Recrystallization from AcOEt–hexane gave colorless prisms of 5 (960 mg), and the mother liquid was further purified by silica gel column chromatography with hexane–AcOEt (8 : 1 to 3 : 1) to give 5 (322 mg). Compound 5 (total: 1.28 g, 2.65 mmol, 78%) was obtained in a pure form, mp 126.0–126.5°C (AcOEt/hexane) [lit.²¹⁾ mp 123–125°C (MeOH–H₂O 9 : 1)]. ¹H-NMR (400 MHz, CDCl₃) δ: 9.51 (s, 2H, CHO), 7.82 (d, J=8.4 Hz, 2H, ArH), 7.21–6.92 (m, 12H, ArH), 4.77 (s, 4H, ArCH₂), 3.99 (s, 6H, OMe). ¹³C-NMR (100 MHz, CDCl₃) δ: 56.2, 74.4, 112.0, 126.0, 127.6, 127.8, 128.2, 128.9, 131.9, 137.4, 145.8, 157.8, 190.1.

A mixture of 5 (100 mg, 0.208 mmol), KOH (411 mg, 7.32 mmol), and EtOH (10 mL) was heated at 100°C for 1 h. After cooling to r.t., the mixture was acidified with 10% HCl aq. and extracted with CH₂Cl₂. The organic layer was washed with brine, dried over MgSO₄, and evaporated to give an amorphous solid (111 mg) which was dissolved in MeOH (1.8 mL). TMSCHN₂ (0.34 mL, 0.68 mmol) was added to the solution and the mixture was stirred for 12.5 h at r.t. After concentration to form a residue, silica gel column chromatography with hexane–AcOEt (8 : 1 to 3 : 2) was carried out. The pale yellow oil of 6 (99.0 mg, 0.192 mmol, 93%) was obtained. IR (CHCl₃) ν_max 3481, 3028, 3009, 2947, 2359, 1720, 1709, 1593, 1570, 1454, 1435, 1271, 1148, 1078, 1026, 752, 698 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 7.84 (d, J=9.2 Hz, 1H, ArH), 7.29 (d, J=8.8 Hz, 1H, ArH), 6.86–7.19 (m, 12H, ArH), 4.92 (d, J=11.6 Hz, 1H, ArCH₂), 4.83 (d, J=10.6 Hz, 1H, ArCH₂), 4.67 (d, J=11.6 Hz, 1H, ArCH₂), 4.60 (d, J=10.6 Hz, 1H, ArCH₂), 4.29 (dd, A of AB, J=5.6, 11.6 Hz, 1H, ArCH₂OH), 4.23 (dd, B of AB, J=5.6, 11.6 Hz, 1H, ArCH₂OH), 3.93 (s, 3H, OMe), 3.88 (s, 3H, OMe), 3.64 (s, 3H, CO₂Me), 2.59 (t, J=5.6 Hz, 1H, OH). ¹³C-NMR (100 MHz, CDCl₃) δ: 167.3, 156.4, 152.3, 145.6, 144.7, 138.1, 137.2, 133.3, 132.4, 131.2, 128.0 (2C), 127.9 (2C), 127.7 (2C), 127.5 (2C), 127.2 (3C), 125.1, 123.4, 111.8, 110.8, 74.5, 74.0, 63.9, 55.82, 55.76, 51.9. Anal. Calcd for C₃₁H₃₀O₇: C, 72.36; H, 5.88. Found: C, 72.01; H, 5.82.

Under an N₂ atmosphere, to a mixture of PDC (2.09 g, 5.55 mmol) and CH₂Cl₂ (4 mL), a solution of 6 (952.5 mg, 1.85 mmol) in CH₂Cl₂ (18.6 mL) was added at 0°C, and the mixture was stirred at r.t. for 38 h. After Celite™ filtration, the filtrate was concentrated to give a crude solid which was subjected to silica gel column chromatography with hexane–AcOEt (8 : 1 to 3 : 2). The colorless powder of 7 (822.7 mg, 1.61 mmol, 87%) was obtained. mp 134.7–135.5°C (AcOEt/hexane). IR (KBr) ν_max 3028, 2945, 2841, 1717, 1684, 1587, 1570, 1431, 1275, 1146, 1020, 741 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 9.53 (s, 1H, CHO), 7.90 (d, J=8.8 Hz, 1H, ArH), 7.80 (d, J=8.8 Hz, 1H, ArH), 6.90–7.19 (m, 12H, ArH), 4.70–4.87 (m, 4H, ArCH₂), 3.952 (s, 3H, OMe), 3.947 (s, 3H, OMe), 3.58 (s, 3H, CO₂Me). ¹³C-NMR (100 MHz, CDCl₃) δ: 190.4, 166.1, 157.4, 156.3, 146.0, 144.9, 137.8, 137.3, 135.9, 130.9, 128.2, 127.92 (2C), 127.90 (2C), 127.5, 127.44 (2C), 127.42, 127.36 (2C), 127.3, 125.2, 123.2, 111.2, 111.0, 74.12, 74.09, 55.9, 55.8, 51.7. Anal. Calcd for C₃₁H₂₈O₇: C, 72.64; H, 5.51. Found: C, 72.76; H, 5.39.

Under an N₂ atmosphere, to a solution of 7 (257 mg, 0.501 mmol) in CH₂Cl₂ (25 mL) was added BBr₃ (1 M solution in CH₂Cl₂, 6.0 mL, 6.0 mmol) at 0°C, and the mixture was stirred for 3.5 h at r.t. After cooling to 0°C, the mixture was poured into MeOH and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO₄, and evaporated. To the resulting residue, MeOH (25 mL) was added and the mixture was stirred for 16 h at r.t. Concentration in vacuo gave a pale orange solid which was recrystallized from CH₂Cl₂–MeOH to afford the colorless needles of 1 (92.7 mg, 0.324 mmol, 65%), mp 217.4°C (CH₂Cl₂/MeOH, decomp.) [lit.¹⁾ mp 224°C (acetone, decomp.)]. IR (KBr) ν_max 3427–3009 (br), 1701, 1603, 1589, 1273, 1236, 1184, 1103, 1080, 953, 910, 818, 721 cm⁻¹. ¹H-NMR (400 MHz, acetone-d₆) δ: 7.80 (d, J=8.8 Hz, 1H, ArH), 7.22 (d, J=8.4 Hz, 1H, ArH), 7.20 (d, J=8.8 Hz, 1H, ArH), 7.14 (d, J=8.4 Hz, 1H, ArH), 6.35 (s, 1H, ArCH), 3.58 (s, 3H, OMe). ¹³C-NMR (100 MHz, acetone-d₆) δ: 160.0, 151.8, 145.6, 138.2, 135.9, 124.8, 123.0, 121.8, 120.3, 119.0, 118.3, 112.9, 112.0, 99.7, 56.0. Anal. Calcd for C₁₅H₁₀O₆: C, 62.95; H, 3.53. Found: C, 62.87; H, 3.46.

A part of this study was financially supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant Number 15K07854 for H. A.).

The authors declare no conflict of interest.

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