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Synlett 2017; 28(12): 1449-1452
DOI: 10.1055/s-0036-1588788
letter
© Georg Thieme Verlag Stuttgart · New York

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

Lisa I. Pilkington
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand   Email: d.barker@auckland.ac.nz
,
Soo Min Song
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand   Email: d.barker@auckland.ac.nz
,
Bruno Fedrizzi
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand   Email: d.barker@auckland.ac.nz
,
David Barker  *
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand   Email: d.barker@auckland.ac.nz
› Author Affiliations
Further Information

Publication History

Received: 06 March 2017

Accepted after revision: 21 March 2017

Publication Date:
19 April 2017 (online)

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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
 

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  • 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′′′).
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  • 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
  • 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
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