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Synlett 2017; 28(12): 1449-1452
DOI: 10.1055/s-0036-1588788
DOI: 10.1055/s-0036-1588788
letter
Efficient Total Synthesis of (±)-Isoguaiacin and (±)-Isogalbulin
Weitere Informationen
Publikationsverlauf
Received: 06. März 2017
Accepted after revision: 21. März 2017
Publikationsdatum:
19. April 2017 (online)
![](https://www.thieme-connect.de/media/synlett/201712/lookinside/thumbnails/st-2017-d0162-l_10-1055_s-0036-1588788-1.jpg)
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.
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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-7b), 2.90 (1 H, dd, J = 5.6, 16.0 Hz, H-7a), 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.
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- 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-7b), 2.87 (1 H, dd, J = 5.6, 16.0 Hz, H-7a), 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
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