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Synlett 2015; 26(17): 2425-2428
DOI: 10.1055/s-0035-1560262
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 3-Methylobovatol

Lisa I. Pilkington
School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland 1142, New Zealand   eMail: d.barker@auckland.ac.nz
,
David Barker*
School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland 1142, New Zealand   eMail: d.barker@auckland.ac.nz
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Publikationsverlauf

Received: 09. Juli 2015

Accepted after revision: 11. August 2015

Publikationsdatum:
07. September 2015 (online)

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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. Rf = 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. Rf = 0.61 (n-hexanes–EtOAc, 4:1). IR (film): νmax = 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
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  • 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. Rf = 0.39 (n-hexanes–EtOAc, 4:1). IR (film): νmax = 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 aHb), 3.12 (1 H, q, J = 3.2 Hz, ArCHa 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. Rf = 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
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  • 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. Rf = 0.61 (n-hexanes–EtOAc, 4:1) 0.61. IR (film): νmax = 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. Rf = 0.42 (n-hexanes–EtOAc, 4:1). IR (film): νmax: 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
  • 27 Kwon B.-M, Han DC, Lee S.-K, Kim H.-Y, Han Y.-M, Shin D.-S. US 20090239955 A1, 2009
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