Synthesis of 3-Methylobovatol

Abstract

Biphenyl lignans are rare compounds that exhibit a broad range of biological activities. The first total synthesis of natural biphenyl ether lignan, 3-methylobovatol, has been achieved in four steps. This synthesis allows for modification of the C-2 phenol and in doing so, will facilitate various structure–activity relationship studies into these bioactive compounds.

Key words

synthesis - lignin - biphenyl ether - obovatol - Ullmann condensation

• References and Notes

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• 16 4-Bromoeugenol (8) ²⁸ To a solution of eugenol (7, 1.00 g, 6.09 mmol) in dry THF (20 mL) at –78 °C was added i-PrMgCl (2.0 M in THF, 3.05 mL, 6.09 mmol), and the mixture was stirred for 30 min at –78 °C. A solution of DBDMH (1.39 g, 4.87 mmol) in dry THF (10 mL) was then added, and the mixture stirred at –78 °C for 3 h. Sat. aq NH₄Cl (25 mL) was then added along with EtOAc (20 mL) and the two layers separated. The aqueous layer was further extracted with EtOAc (2 × 20 mL), and the combined organic extracts were washed with brine (20 mL), dried (MgSO₄), and the solvent removed in vacuo. The crude product was purified by flash chromatography (n-hexanes–EtOAc, 9:1) to yield the title product 8 (0.360 g, 31%) as a yellow oil. R_f = 0.42 (n-hexanes–EtOAc, 4:1). ¹H NMR (400 MHz, CDCl₃, Me₄Si): δ = 3.29 (2 H, d, J = 6.4 Hz, H-7), 3.87 (3 H, s, OMe), 5.07–5.10 (2 H, m, H-9), 5.80 (1 H, br s, OH), 5.86–5.97 (1 H, m, H-8), 6.63 (1 H, s, H-5), 6.92 (1 H, s, H-3). ¹³C NMR (100 MHz, CDCl₃): δ = 39.5 (C-7), 56.2 (OMe), 109.8 (C-2), 110.4 (C-5), 116.2 (C-9), 124.3 (C-3), 132.7 (C-4), 136.9 (C-8), 141.3 (C-1), 147.1 (C-6). The ¹H NMR and ¹³C NMR data were in agreement with the literature values.
• 17 5-Allyl-1-bromo-3-methoxy-2-(methoxymethoxy)benzene (9) To phenol 8 (0.200 g, 0.82 mmol) in CH₂Cl₂ (5 mL) at r.t., under an atmosphere of nitrogen, was added DIPEA (0.18 mL, 1.03 mmol) followed by MOMCl (0.18 mL, 1.65 mmol), and the mixture was stirred at r.t. for 22 h. Sat. aq NH₄Cl (5 mL) was added and the organic layer separated. The aqueous layer was further extracted with CH₂Cl₂ (3 × 5 mL), and the combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo. The crude product was purified by flash chromatography (n-hexanes–EtOAc, 9:1) to yield the title product 9 (0.176 g, 73%) as a pale yellow oil. R_f = 0.61 (n-hexanes–EtOAc, 4:1). IR (film): ν_max = 3078, 2939, 2842, 1596, 1567, 1487, 1464, 1414, 1269, 1159, 1078, 1046, 959, 843, 815, 684 cm^–1. ¹H NMR (400 MHz, CDCl₃, Me₄Si): δ = 3.30 (2 H, d, J = 6.4 Hz, H-7), 3.65 (3 H, s, OCH₂OCH ₃), 3.83 (3 H, s, OMe), 5.08–5.13 (2 H, m, H-9), 5.14 (2 H, s, OCH ₂OCH₃), 5.86–5.96 (1 H, m, H-8), 6.67 (1 H, s, H-4), 6.98 (1 H, s, H-6). ¹³C NMR (100 MHz, CDCl₃): δ = 39.6 (C-7), 56.0 (OCH₂OCH₃), 57.9 (OMe), 98.6 (OCH₂OCH₃), 112.1 (C-4), 116.5 (C-9), 117.6 (C-1), 124.8 (C-6), 136.5 (C-8), 137.4 (C-5), 153.0 (C-2), 162.3 (C-3). MS (ESI⁺): m/z (%) = 311 (100) [⁸¹BrMNa⁺], 309 (98) [⁷⁹BrMNa⁺], 233 (10) and 199 (5). HRMS (ESI⁺): m/z calcd for C₁₂H₁₅ ⁸¹BrNaO₃: 311.0077; found [MNa⁺]: 311.0076; m/z calcd for C₁₂H₁₅ ⁷⁹BrNaO₃: 309.0097; found [MNa⁺]: 309.0094.
• 18 Lin JM, Prakasha Gowda AS, Sharma AK, Amin S. Bioorg. Med. Chem. 2012; 20: 3202
• 19 4-(2-Bromopropyl)phenol (12) To a solution of methyl ether 11 (100 mg, 0.674 mmol) in CH₂Cl₂ (5 mL) under an atmosphere of nitrogen and cooled to 0 °C was added dropwise a solution of BBr₃ (0.190 mL, 2.0 mmol) in CH₂Cl₂ (1 mL). The resulting solution was stirred at 0 °C for 15 min and then let warm to r.t. and stirred for 3.5 h. The mixture was then cooled to 0 °C and quenched with H₂O (10 mL). The aqueous mixture was extracted with CH₂Cl₂ (10 mL), and then the combined organic extracts were washed with brine (10 mL), dried (MgSO₄), and the solvent removed in vacuo. The crude product was purified by flash chromatography (n-hexanes–EtOAc, 9:1) to yield the title product 12 (44.4 mg, 31%) as a colorless oil. R_f = 0.39 (n-hexanes–EtOAc, 4:1). IR (film): ν_max = 3316, 2969, 2921, 1612, 1598, 1512, 1443, 1377, 1223, 1171, 1057, 999, 847, 820, 772 cm^–1. ¹H NMR (400 MHz, CDCl₃, Me₄Si): δ = 1.67 (3 H, d, J = 6.4 Hz, CH₃), 2.97 (1 H, q, J = 3.2 Hz, ArCH _aH_b), 3.12 (1 H, q, J = 3.2 Hz, ArCH_a H _b), 4.21 (1 H, sext, J = 6.4 Hz, CHBr), 5.40 (1 H, br s, OH), 6.78 (2 H, d, J = 8.4 Hz, H-2), 7.06 (2 H, d, J = 8.4 Hz, H-3). ¹³C NMR (100 MHz, CDCl₃): δ = 25.5 (CH₃), 46.6 (CH₂), 51.1 (CHBr), 115.3 (C-2), 130.4 (C-3), 130.8 (C-4), 154.4 (C-1). MS (ESI⁺): m/z (%) = 215 (50) [⁸¹BrM – H]⁺, 213 (50) [⁷⁹BrM – H]⁺, 181 (100). HRMS (ESI⁺): m/z calcd for C₉H₁₀ ⁸¹BrO: 214.9900; found [M – H]⁺: 214.9894. m/z calcd for C₉H₁₀ ⁷⁹BrO: 212.9921; found [M – H]⁺: 212.9922. In a separate fraction, 4-allylphenol (10, 43.8 mg, 49%) was isolated as a colorless oil.
• 20 4-Allylphenol (10) ²⁹ To a solution of methyl ether 11 (1.00 g, 6.74 mmol) in CH₂Cl₂ (18 mL) under an atmosphere of nitrogen and cooled to 0 °C was added dropwise a solution of BBr₃ (0.96 mL, 10 mmol) in CH₂Cl₂ (18 mL). The resulting solution was stirred at 0 °C for 15 min and then let warm to r.t. and stirred for 1 h. The mixture was then cooled to 0 °C and quenched with H₂O (20 mL). The aqueous mixture was extracted with CH₂Cl₂ (20 mL), and then the combined organic extracts were washed with brine (20 mL), dried (MgSO₄), and the solvent removed in vacuo. The crude product was purified by flash chromatography (n-hexanes–EtOAc, 9:1) to yield the title product 10 (0.66 g, 73%) as a colorless oil. R_f = 0.45 (n-hexanes–EtOAc, 4:1). ¹H NMR (400 MHz, CDCl₃, Me₄Si): δ = 3.33 (2 H, d, J = 6.8 Hz, ArCH₂), 5.05–5.10 (2 H, m, CH=CH ₂), 5.53 (1 H, br s, OH), 5.92–6.02 (1 H, m, CH=CH₂), 6.78 (1 H, dd, J = 2.0, 6.4 Hz, H-2), 7.06 (1 H, dd, J = 2.0, 6.4 Hz, H-3). ¹³C NMR (100 MHz, CDCl₃): δ = 39.3 (ArCH₂), 115.3 (C-2), 115.4 (CH=CH₂), 129.7 (C-3), 132.2 (C-4), 137.8 (CH=CH₂), 153.7 (C-1). The ¹H NMR and ¹³C NMR data were in agreement with the literature values.
• 21 Kwak J.-H, In J.-K, Lee M.-S, Choi E.-H, Lee H, Hong JT, Yun Y.-P, Lee SJ, Seo S.-Y, Suh Y.-G, Jung J.-K. Arch. Pharm. Res. 2008; 31: 1559
• 22 5-Allyl-1-(4′-allylphenoxy)-3-methoxy-2-(methoxymethoxy)benzene (13) A mixture of bromide 9 (189 mg, 0.658 mmol), phenol 10 (132 mg, 0.987 mmol), Cs₂CO₃ (429 mg, 1.32 mmol), CuI (12.5 mg, 0.066 mmol), and N,N-dimethylglycine hydrochloride (28.0 mg, 0.197 mmol) in dioxane (3 mL) in a sealed tube under an atmosphere of nitrogen was heated at 90 °C for 4 d. The solution was removed from the heat and allowed to cool to r.t. The cooled mixture was partitioned between EtOAc (2 mL) and H₂O (2 mL), and the organic layer was separated. The aqueous layer was further extracted with EtOAc (2 × 2 mL). The combined organic extracts were dried (MgSO₄), and the solvent was removed in vacuo. The crude product was purified by flash chromatography (n-hexanes–EtOAc, 9:1) with silver impregnated silica to yield the title product 13 (80.0 mg, 36%) as a pale yellow oil. R_f = 0.61 (n-hexanes–EtOAc, 4:1) 0.61. IR (film): ν_max = 2967, 2839, 1565, 1504, 1487, 1463, 1269, 1216, 1156, 1078, 1045, 952, 815, 774 682 cm^–1. ¹H NMR (400 MHz, CDCl₃, Me₄Si): δ = 3.26 (2 H, d, J = 6.8 Hz, H-7), 3.34 (2 H, d, J = 6.8 Hz, H-7′), 3.51 (3 H, s, OCH₂OCH ₃), 3.86 (3 H, s, OMe), 5.03–5.08 (4 H, m, H-9 and H-9′), 5.09 (2 H, s, OCH ₂OCH₃), 5.86–5.99 (2 H, m, H-8 and H-8′), 6.41 (1 H, d, J = 2.0 Hz, H-6), 6.54 (1 H, d, J = 2.0 Hz, H-4), 6.88 (2 H, d, J = 8.0 Hz, H-2′ and H-6′), 7.09 (2 H, d, J = 8.0 Hz, H-3′ and H-5′). ¹³C NMR (100 MHz, CDCl₃): δ = 39.4 (C-7′), 40.0 (C-7), 55.9 (OMe), 56.9 (OCH₂OCH₃), 98.2 (OCH₂OCH₃), 108.0 (C-4), 113.1 (C-6), 115.6 (C-9′), 116.0 (C-9), 117.4 (C-2′ and C-6′), 129.5 (C-3′ and C-5′), 134.2 (C-4′), 135.6 (C-2), 136.4 (C-5), 136.8 (C-8), 137.5 (C-8′), 149.8 (C-1), 153.7 (C-3) and 155.9 (C-1′). MS (ESI⁺): m/z (%) = 363 (100) [MNa⁺], 265 (5), 207 (5). HRMS (ESI+): m/z calcd for C₂₁H₂₄NaO₄: 363.1567; found: [MNa⁺]: 363.1578. In a separate fraction, bromide 9 (98 mg, 0.381 mmol) was isolated as a colorless oil.
• 23 Kobayashi S, Hirano T, Iwakiri K, Miyamoto H, Nakazaki A. Heterocycles 2009; 79: 805
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• 26 5-Allyl-1-(4′-allylphenoxy)-3-methoxyphenol (6) or 3-Methylobovatol (6) To a solution of methoxymethyl ether 13 (50.0 mg, 0.15 mmol) in MeOH (5 mL) was added 2 M HCl (0.5 mL), and the resultant mixture was stirred at r.t. for 18 h. 1 M NaOH was added until the solution was pH 5, and then the solution was extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo. The crude product was purified by flash chromatography (n-hexanes–EtOAc, 9:1) to give the title product 6 (32.0 mg, 74%) as a yellow oil. R_f = 0.42 (n-hexanes–EtOAc, 4:1). IR (film): ν_max: 3507, 2976, 2915, 2844, 1600, 1504, 1453, 1433, 1312, 1220, 1168, 1058, 994, 914, 823 cm^–1. ¹H NMR (400 MHz, CDCl₃, Me₄Si): δ = 3.25 (2 H, d, J = 6.8 Hz, H-7), 3.34 (2 H, d, J = 6.8 Hz, H-7′), 3.90 (3 H, s, OMe), 5.02–5.09 (4 H, m, H-9 and H-9′), 5.45 (1 H, br s, OH), 5.81–6.01 (2 H, m, H-8 and H-8′), 6.43 (1 H, d, J = 2.0 Hz, H-6), 6.53 (1 H, d, J = 2.0 Hz, H-4), 6.90 (2 H, d, J = 8.0 Hz, H-2′ and H-6′), 7.10 (2 H, d, J = 8.0 Hz, H-3′ and H-5′). ¹³C NMR (100 MHz, CDCl₃): δ = 39.4 (C-7′), 39.9 (C-7), 56.2 (OMe), 107.3 (C-4), 113.0 (C-6), 115.7 (C-9′), 115.8 (C-9), 117.3 (C-2′ and C-6′), 129.6 (C-3′ and C-5′), 131.4 (C-5), 134.4 (C-4′), 135.6 (C-2), 137.3 (C-8), 137.5 (C-8′), 143.0 (C-1), 147.8 (C-3), 155.8 (C-1′). MS (ESI⁺): m/z (%) = 319 (100) [MNa⁺], 227 (80), 158 (20). HRMS (ESI⁺): m/z calcd for C₁₉H₂₀NaO₃ [MNa⁺]: 319.1305; found: 319.1304. The ¹H NMR data were in agreement with the literature values.⁹
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