Efficient Total Synthesis of (±)-Isoguaiacin and (±)-Isogalbulin

Abstract

1-Arylnaphthalene lignans such as (–)-isoguaiacin and (–)-isogalbulin have been reported to exhibit notable biological properties. While (–)-isoguaiacin has not been previously synthesized, syntheses of (–)-isogalbulin are generally long and produce a mixture of stereoisomers. We herein present the efficient total synthesis of (±)-isoguaiacin and (±)-isogalbulin in seven and eight steps with an overall yield of 46% and 36%, respectively. The reported approach harnesses a hydrogenolysis reaction in acidic conditions, to convert a furan into an arylnaphthalen structure.

Key words

lignan - 1-arylnaphthalene - synthesis - Paal–Knorr - cyclization

• References and Notes

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• 39 (±)-2′,3′-Bis(4-benzyloxy-3-methoxybenzoyl)butane (8) To liquid NH₃ (20 mL) at –78 °C was added FeCl₃ (0.002 g) and Na (0.092 g, 3.95 mmol) and the mixture stirred for 2.5 h. To the dark-grey suspension of sodamide was added a solution of 6 (0.464 g, 1.72 mmol) in THF (6 mL), dropwise over 10 min and stirred for 40 min. A solution of 7 (0.600 g, 1.72 mmol) in THF (18 mL) was then added dropwise over 30 min. After the mixture was stirred for a further 2.5 h, NH₄Cl (0.500 g) was added, and the mixture warmed to r.t. to remove the NH₃. The mixture was then filtered, washed with EtOAc, and concentrated in vacuo to give the crude product which was then purified using flash chromatography (9:1 n-hexanes–EtOAc) to give the title product (0.742 g, 80%) as a colorless semisolid. ¹H NMR (400 MHz, CDCl₃): δ = 1.27 (6 H, d, J = 6.6 Hz, 2′-CH₃ and 3′-CH₃), 3.87–3.96 (8 H, m, 2 × OCH₃, H-2′ and H-3′), 5.23 (4 H, s, 2 × ArCH₂), 6.91 (2 H, d, J = 8.4 Hz, H-5, H-5′′′), 7.31 (2 H, tt, J = 1.2, 7.2 Hz, H-4, H-4′′′), 7.35–7.40 (4 H, m, H-3′′, H-5′′, H-3′′′′, H-5′′′′), 7.42–7.44 (4 H, m, H-2′′, H-6′′, H-2′′′′, H-6′′′′), 7.50 (2 H, d, J = 2.0 Hz, H-2, H-2′′′), 7.61 (2 H, dd, J = 2.0, 8.4 Hz, H-6, H-6′′′). ¹³C NMR (100 MHz, CDCl₃): δ = 16.0 (2′-CH₃ and 3′-CH₃), 43.3 (C-2′ and C-3′), 56.0 (2 × OCH₃), 70.8 (2 × OCH₂), 111.2 (C-2 and C-2′′′), 112.3 (C-5 and C-5′′′), 122.9 (C-6 and C-6′′′), 127.2 (C-2′′, C-6′′, C-2′′′′ and C-6′′′′), 128.1 (C-4′′ and C-4′′′′), 128.7 (C-3′′, C-5′′, C-3′′′′, and C-5′′′′), 129.5 (C-1 and C-1′′′), 136.4 (C-1′′, C-1′′′′), 149.5 (C-3 and C-3′′′), 152.4 (C-4 and C-4′′′), 203.0 (C-1′ and C-4′). The ¹H NMR and ¹³C NMR data were consistent with those reported in literature.⁴⁶
• 40 3,4-Dimethyl-2,5-bis(4′-benzyloxy-3′-methylphenyl)furan (9) To a solution of diketone 8 (0.300 g, 0.557 mmol) in CH₂Cl₂ (5.5 mL) was added a solution of aq methanolic HCl (9.45 mL, 4.8% HCl in MeOH) and stirred at 80 °C at reflux for 2.75 h. The mixture was then cooled to r.t. to give the title product (0.29 g, quant.) as a white solid; mp 155 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.20 (6 H, s, 3-CH₃ and 4-CH₃), 3.95 (6 H, m, 2 × OCH₃), 5.20 (4 H, s, 2 × ArCH₂), 6.94 (2 H, d, J = 8.4 Hz, H-5, H-5′′′), 7.14 (2 H, dd, J = 1.6, 8.4 Hz, H-6′, H-6′′′), 7.24 (2 H, d, J = 1.6 Hz, H-2′, H-2′′′), 7.31 (2 H, t, J = 7.2 Hz, H-4′′, H-4′′′′), 7.38 (4 H, t, J = 7.2 Hz, H-3′′, H-5′′, H-3′′′′, H-5′′′′), 7.46 (4 H, d, J = 7.2 Hz, H-2′′, H-6′′, H-2′′′′, H-6′′′′). ¹³C NMR (100 MHz, CDCl₃): δ = 9.9 (3-CH₃ and 4-CH₃), 56.1 (2 × OCH₃), 71.2 (2 × OCH₂), 109.8 (C-2 and C-2′′′), 114.2 (C-5 and C-5′′′), 118.1 (C-3 and C-4), 118.4 (C-6′ and C-6′′′), 125.7 (C-1 and C-1′′′), 127.3 (C-2′′, C-6′′, C-2′′′′, and C-6′′′′), 127.9 (C-4′′ and C-4′′′′), 128.6 (C-3′′, C-5′′, C-3′′′′, and C-5′′′′), 137.2 (C-1′′ and C-1′′′′), 146.9 (C-2 and C-5), 147.2 (C-4′ and C-4′′′′), 149.7 (C-3′, C-3′′′).
• 41 Stevenson R. Williams JR. Org. Prep. Proc. Int. 1976; 8: 179
• 42 (±)-Isoguaiacin (1) To furan 9 (0.100 g, 0.192 mmol) in a solution of THF (5.5 mL) and AcOH (2.3 mL) was added p-toluenesulfonic acid monohydrate (0.010 g, 10 % w/w) and Pd/C (0.100 g, 100 % w/w). The mixture was stirred under and atmosphere of hydrogen for 15 h and was then filtered through Celite. To the filtrate was added water (4 mL), and the mixture was extracted with water (2 mL), followed by brine (2 mL), dried (MgSO₄), and concentrated in vacuo to afford the title product (0.065 g, quant.) as an orange-brown solid; mp 147–149 °C (lit. 149 °C). ¹H NMR (400 MHz, CDCl₃): δ = 0.89–0.90 (6 H, m, H-9 and H-9′), 1.92–1.95 (1 H, m, H-8′), 2.02–2.04 (1 H, m, H-8), 2.46 (1 H, dd, J = 7.2, 16.0 Hz, H-7_b), 2.90 (1 H, dd, J = 5.6, 16.0 Hz, H-7_a), 3.59 (1 H, d, J = 6.4 Hz, H-7′), 3.81 (3 H, s, OCH₃), 3.86 (3 H, s, OCH₃), 5.35 (br s, OH), 5.47 (br s, OH), 6.41 (1 H, s, H-5), 6.49 (1 H, dd, J = 2.0, 8.1 Hz, H-6′), 6.55 (1 H, d, J = 2.0 Hz, H-2′), 6.57 (1 H, s, H-2), 6.78 (1 H, d, J = 8.1 Hz, H-5′). ¹³C NMR (100 MHz, CDCl₃): δ = 15.8 and 15.9 (C-9 and C-9′), 29.3 (C-8), 35.3 (C-7), 40.6 (C-8′), 50.5 (C-7′), 55.9 (3-OCH₃ and 3′-OCH₃), 110.6 (C-2), 111.5 (C-2′), 113.8 (C-5′), 116.1 (C-5), 122.0 (C-6′), 127.6 (C-6), 130.9 (C-1), 139.0 (C-1′), 143.5 (C-4), 143.7 (C-4′), 145.0 (C-3), 146.2 (C-3′). The ¹H NMR and ¹³C NMR data were consistent with that reported in literature.⁴⁴
• 43 Hydrogenation of 9 for one hour leads to complete removal of the benzyl groups to give 10 only; an extended reaction time is required to transform 10 into (±)-1.
• 44 Wang B.-G. Hong X. Li L. Zhou J. Hhao X.-J. Planta Med. 2000; 66: 511
• 45 (±)-Isogalbulin (2) To a stirred solution of 1 (0.025 g, 0.076 mmol) in acetone (3 mL) was added K₂CO₃ (0.053 g, 0.38 mmol), followed by MeI (0.024 mL, 0.38 mmol) and the mixture stirred at 40 °C for 3 d. The reaction mixture was then filtered and the to give the title product (0.0205 g, 78%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.90–0.93 (6 H, m, H-9 and H-9′), 1.92–1.96 (1 H, m, H-8′), 2.00–2.05 (1 H, m, H-8), 2.46 (1 H, dd, J = 8.0, 16.0 Hz, H-7_b), 2.87 (1 H, dd, J = 5.6, 16.0 Hz, H-7_a), 3.67 (3 H, s, OCH₃), 3.67–3.69 (1 H, m, H-7′), 3.80 (3 H, s, OCH₃), 3.86 (3 H, s, OCH₃), 3.87 (3 H, s, OCH₃), 6.35 (1 H, s, H-5), 6.50 (1 H, dd, J = 2.0, 8.0 Hz, H-6′), 6.57 (1 H, d, J = 2.0 Hz, H-2′), 6.60 (1 H, s, H-2), 6.74 (1 H, d, J = 8.0 Hz, H-5′). ¹³C NMR (100 MHz, CDCl₃): δ = 16.2 and 16.5 (C-9 and C-9′), 28.6 (C-8), 34.7 (C-7), 40.8 (C-8′), 50.9 (C-7′), 55.69 (OCH₃), 55.74 (OCH₃), 55.78 (OCH₃), 55.83 (OCH₃), 110.6 (C-5′), 111.0 (C-2), 112.2 (C-2′), 113.3 (C-5), 121.3 (C-6′), 128.4 (C-6), 129.5 (C-1), 139.8 (C-1′), 147.1 and 147.2 (C-3, C-4, C-4′), 148.6 (C-3′). The ¹H NMR and ¹³C NMR data were consistent with those reported in literature.¹⁷
• 46 Yamauchi S. Masuda T. Sugahara T. Kawaguchi Y. Ohuchi M. Someya T. Akiyama J. Tominaga S. Yamawaki M. Kishida T. Akiyama K. Maruyuma M. Biosci. Biotechnol. Biochem. 2008; 72: 2981