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

Publication History

Received: 06 March 2017

Accepted after revision: 21 March 2017

Publication Date:
19 April 2017 (eFirst)

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.

 
  • References and Notes

  • 1 Ayres DC. Loike JD. Lignans: Chemical, Biological and Clinical Properties. 1990
  • 2 Ma CJ. Kim SR. Kim J. Kim YC. Br. J. Pharmacol. 2005; 146: 752
  • 3 King FE. Wilson JG. J. Chem. Soc. 1964; 4011
  • 4 Konno C. Lu Z.-Z. Xue H.-Z. Erdelmeier CA. J. Meksuriyen D. Che CT. Cordell GA. Soejarto DD. Waller DP. Fong HH. S. J. Nat. Prod. 1990; 53: 396
  • 5 Yu YU. Kang SK. Park HY. Sung SH. Lee EJ. Kim SY. Kim YC. J. Pharm. Pharmacol. 2000; 52: 1163
  • 6 Ma CJ. Sung SH. Kim YC. Planta Med. 2004; 70: 79
  • 7 Lee JS. Kim J. Yu YU. Kim YC. Arch. Pharm. Res. 2004; 27: 1043
  • 8 Lee MK. Yang H. Ma CJ. Kim YC. Biol. Pharm. Bull. 2007; 30: 814
  • 9 Lobo-Echeverri T. Rivero-Cruz JF. Su B.-N. Chai H.-B. Cordell GA. Pezzuto JM. Swanson SM. Soejarto DD. Kinghorn AD. J. Nat. Prod. 2005; 68: 577
  • 10 Lopes LM. X. Yoshida M. Gottlieb OR. Phytochemistry 1984; 23: 2647
  • 11 Messiano GB. Wijeratne EM. K. Lopes LM. X. Gunatilaka AA. L. J. Nat. Prod. 2010; 73: 1933
  • 12 Landais Y. Lebrun A. Lenain V. Robin J.-P. Tetrahedron Lett. 1987; 28: 5161
  • 13 Perry CW. Kalmins MV. Deitcher KH. J. Org. Chem. 1972; 37: 4371
  • 14 Landais Y. Robin J.-P. Lebrun A. Lenain V. Tetrahedron Lett. 1987; 28: 5161
  • 15 Kastatkin AN. Checksfield G. Whitby RJ. J. Org. Chem. 2000; 65: 3236
  • 16 Peng Y. Luo Z.-B. Zhang J.-J. Luo L. Wang Y.-W. Org. Biomol. Chem. 2013; 11: 7574
  • 17 Li X. Jiao X. Liu X. Tian C. Dong L. Yao Y. Xie P. Tetrahedron Lett. 2014; 55: 6324
  • 18 Pilkington LI. Barker D. J. Org. Chem. 2012; 77: 8156
  • 19 Pilkington LI. Barker D. Eur. J. Org. Chem. 2014; 1037
  • 20 Pilkington LI. Wagoner J. Polyak SJ. Barker D. Org. Lett. 2015; 17: 1046
  • 21 Jung E. Pilkington LI. Barker D. J. Org. Chem. 2016; 81: 12012
  • 22 Jung E. Dittrich N. Pilkington LI. Rye CE. Leung E. Barker D. Tetrahedron 2015; 71: 9439
  • 23 Rye C. Barker D. Synlett 2009; 3315
  • 24 Barker D. Dickson B. Dittrich N. Rye CE. Pure Appl. Chem. 2012; 84: 1557
  • 25 Dickson BD. Dittrich N. Barker D. Tetrahedron Lett. 2012; 53: 4464
  • 26 Duhamel N. Rye CE. Barker D. Asian J. Org. Chem. 2013; 2: 491
  • 27 Paterson DL. Barker D. Beilstein J. Org. Chem. 2015; 11: 265
  • 28 Davidson SJ. Barker D. Tetrahedron Lett. 2015; 56: 4549
  • 29 Pilkington LI. Barker D. Synlett 2015; 26: 2425
  • 30 Rye CE. Barker D. Eur. J. Med. Chem. 2013; 60: 240
  • 31 Tran H. Dickson B. Barker D. Tetrahedron Lett. 2013; 54: 2093
  • 32 Rye CE. Barker D. J. Org. Chem. 2011; 76: 6636
  • 33 Crossley NS. Djerassi C. J. Chem. Soc. 1962; 1459
  • 34 Wu A. Zhao Y. Yang W. Wang M. Pan X. Synth. Commun. 1997; 27: 2087
  • 35 Kuwano M. Ono M. Tomita M. Watanabe J. Takeda M. WO 9415594A1, 1994
  • 36 Adler E. Delin S. Miksche GE. Acta Chem. Scand. 1996; 20: 1035
  • 37 Perry CW. Kalnis MV. Deitcher KH. J. Org. Chem. 1972; 37: 4371
  • 38 Schneiders GE. Stevenson R. J. Org. Chem. 1981; 46: 2969
  • 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.
  • 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-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