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Synlett 2013; 24(6): 723-726
DOI: 10.1055/s-0032-1318333
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© Georg Thieme Verlag Stuttgart · New York

Total Synthesis of Chaetoquadrins H and I

U Bin Kim
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand   Fax: +64(9)3737422   Email: m.brimble@auckland.ac.nz
,
Andrew F. Dalebrook
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand   Fax: +64(9)3737422   Email: m.brimble@auckland.ac.nz
,
Daniel P. Furkert
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand   Fax: +64(9)3737422   Email: m.brimble@auckland.ac.nz
,
Margaret A. Brimble*
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand   Fax: +64(9)3737422   Email: m.brimble@auckland.ac.nz
› Author Affiliations
Further Information

Publication History

Received: 04 February 2013

Accepted: 12 February 2013

Publication Date:
06 March 2013 (online)

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Abstract

The first total syntheses of the chromone-containing natural products chaetoquadrins H and I are reported, using an aldol reaction and an acid-catalyzed deprotection/cyclization/elimination sequence. Chaetoquadrin H was isolated from the ascomycete Chaetomium quadrangulatum and exhibits potent mouse liver monoamine oxidase (MAO) inhibitory activity. Chaetoquadrin I was not isolated in sufficient quantity to enable biological evaluation. The synthesis of the title compounds provides a useful starting point for a medicinal chemistry program focused on chaetoquadrin natural products.

Key words

monoamine oxidase inhibitors - natural products - spiroketal compounds - aldol reaction
 

  • References and Notes

  • 1 Fujimoto H, Nozawa M, Okuyama E, Ishibashi M. Chem. Pharm. Bull. 2002; 50: 330
    Crossref
  • 2 Fujimoto H, Nozawa M, Okuyama E, Ishibashi M. Chem. Pharm. Bull. 2003; 51: 247
    Crossref
  • 3 For selected examples, see: Yuen T.-Y, Brimble MA. Org. Lett. 2012; 14: 5154 ; and references within
    Crossref
  • 4 Kim UB, Furkert DP, Brimble MA. Org. Lett. 2013; 15: 658
    Crossref
  • 5 Wuts PG. M, Greene TW. Greene’s Protective Groups in Organic Synthesis . 4th ed. Wiley; Hoboken: 2007: 383
    Google Scholar
  • 6 Frigerio M, Santagostino M, Sputore S. J. Org. Chem. 1999; 64: 4537
    Crossref
  • 7 Tsuji J, Nagashima H, Nemoto H. Org. Synth. 1984; 62: 9
  • 8 Cergol KM, Coster MJ. Nat. Protoc. 2007; 2: 2568
    Crossref
  • 9 Aldol reaction between 7 and 8: A two-necked, round-bottom flask was charged with (+)-Ipc2BCl (210 mg, 0.66 mmol) and placed under high vacuum for 1 h to remove traces of HCl. Et2O (2 mL) was added and the mixture was cooled to –78 °C. NEt3 (0.1 mL, 0.72 mmol) was added followed by a solution of ketone 8 (100 mg, 0.63 mmol) in Et2O (1 mL). The resultant white suspension was warmed to 0 °C and stirred for 40 min. The reaction mixture was cooled to –78 °C and aldehyde 7 (100 mg, 0.31 mmol) in Et2O (2 mL) was added. The reaction mixture was stirred at –78 °C for 4 h then quenched by addition of aqueous pH 7 buffer solution (1 mL), MeOH (0.5 mL) and 30% H2O2 solution (0.5 mL), warmed to r.t. and stirred for 1 h. The mixture was then diluted with H2O (10 mL) and EtOAc (10 mL), the layers separated, and the aqueous layer was further extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (5 mL), brine (5 mL), dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc–hexanes, 2:1) to yield β-hydroxy ketone 15 (44 mg, 30%) as an inseparable mixture of diastereoisomers (1:1) and as a colourless oil. 1H NMR (300 MHz, CDCl3): δ = 1.13–1.30 (m, 9 H), 1.60–1.78 (m, 2 H), 2.29 (s, 3 H), 2.40–2.63 (m, 3 H), 2.69–2.98 (m, 3 H), 3.55 (q, J = 7.24 Hz, 2 H), 3.81–3.92 (m, 2 H), 3.89 (s, 3 H), 3.93–4.04 (m, 1 H), 4.11–4.28 (m, 1 H), 4.63–4.72 (m, 2 H), 5.12–5.23 (m, 2 H), 5.99 (s, 1 H), 6.63 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 15.0 (CH3), 15.2 (CH3), 19.6 (CH2), 19.9 (CH3), 20.6 (CH3), 35.9 (CH2), 36.0 (CH2*), 50.4 (CH2), 50.5 (CH2*), 50.9 (CH2), 51.0 (CH2*), 56.0 (CH3), 63.3 (CH2), 65.7 (CH2), 67.2 (CH), 67.3 (CH*), 69.6 (CH), 69.7 (CH*), 93.7 (CH2), 93.8 (CH2*), 95.3 (CH), 100.5 (CH2), 111.2 (C), 111.5 (CH), 122.0 (C), 155.2 (C), 158.1 (C), 161.8 (C), 163.5 (C), 177.0 (C), 209.6 (C), 209.7 (C*). IR (film): 2974, 1709, 1655, 1600, 1446, 1388, 1341, 1260, 1177, 1107, 1046, 990 cm–1. HRMS (ESI): m/z [M + H]+ calcd for C25H37O9 +: 481.2432; found: 481.2417
  • 10 Bartlett SL, Beaudry CM. J. Org. Chem. 2011; 76: 9852
    CrossrefPubMed
  • 11 Breton GW. J. Org. Chem. 1997; 62: 8952
    Crossref
  • 12 Synthesis of Chaetoquadrin I (5): To a solution of β-hydroxyketone 15 (19 mg, 0.04 mmol) in EtOAc (2 mL) was added 2-iodoxybenzoic acid (100 mg, 0.36 mmol) and the reaction mixture was heated to reflux for 5 h. The reaction mixture was then allowed to cool to r.t. and filtered through a plug of cotton wool. The solvent was removed in vacuo to give 1,3-diketone 6, which was dissolved in CHCl3 (1 mL). NaHSO4·SiO2 11 (20 mg) was added and the reaction mixture was stirred for 1 h. The reaction mixture was filtered through cotton wool and the filtrate loaded directly on a preparative TLC plate (EtOAc–hexanes, 2:1) to yield chaetoquadrin I (5; 5.5 mg, 40% over two steps). [α]D 20 –10.8 (c 0.05, CHCl3) {lit.2 [α]D 20 –40.8 (c 0.05, CHCl3)}. 1H NMR (300 MHz, CDCl3): δ = 1.44 (d, J = 6.1 Hz, 3 H), 2.33–2.39 (m, 2 H), 2.36 (s, 3 H), 2.43–2.50 (m, 2 H), 2.83–3.02 (m, 2 H), 3.88 (s, 3 H), 4.38–4.53 (m, 1 H), 5.22 (s, 1 H), 6.05 (s, 1 H), 6.36 (s, 1 H), 12.8 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 19.6 (CH2), 20.6 (CH3), 20.6 (CH3), 33.8 (CH2), 42.8 (CH2), 56.0 (CH3), 75.8 (CH), 89.5 (CH), 104.2 (CH), 105.2 (C), 109.1 (CH), 111.3 (C), 157.0 (C), 159.0 (C), 163.2 (C), 166.6 (C), 177.8 (C), 182.6 (C), 193.5 (C). IR (film): 2928, 1660, 1493, 1448, 1343, 1174 cm–1. HRMS (ESI): m/z [M + H]+ calcd for C19H21O6 +: 345.1333; found: 345.1341
  • 13 Aldol reaction between 16 and 8: A solution of diisopropylamine (0.04 mL, 0.25 mmol) in THF (1 mL) was cooled to –78 °C. n-BuLi (1.6 M in hexanes, 0.24 mmol, 0.15 mL) was carefully added by using a syringe and the mixture was stirred for 1 h at the same temperature. The reaction mixture was then warmed to 0 °C for 10 min, then cooled to –78 °C. A solution of ketone 8 (39 mg, 0.24 mmol) in THF (1 mL) was cooled to –78 °C and added to the LDA mixture by using a cannula, maintaining the temperature of all of the reactants at –78 °C. The solution of aldehyde 16 (36 mg, 0.11 mmol) in THF (1 mL) was then cooled to –78 °C and added to the mixture dropwise by using a cannula. The reaction mixture was stirred at this temperature for 2 h, then NH4Cl (4 mL) was added and reaction mixture was allowed to warm to r.t. The reaction mixture was extracted with EtOAc (3 × 4 mL) and the combined organic extracts were washed with brine (6 mL), dried over MgSO4, and purified by flash column chromatography (EtOAc–hexanes, 1.5:1) to yield β-hydroxy ketone 17 (22 mg, 43%) as an inseparable mixture of diastereomers (1:1) as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 0.78 (d, J = 7.14 Hz, 1.5 H), 0.84 (d, J = 6.76 Hz*, 1.5 H), 1.14–1.22 (m, 6 H), 1.73–1.98 (m, 2 H), 2.23–2.71 (m, 6 H), 2.31 (s, 1.5 H), 2.32 (s*, 1.5 H), 3.47–3.59 (m, 2 H), 3.76–3.87 (m, 1 H), 3.88 (s, 1.5 H), 3.90 (s*, 1.5 H), 4.07–4.19 (m, 1 H), 4.59–4.69 (m, 2 H), 4.87–4.95 (m, 1 H), 4.99–5.09 (m, 1 H), 6.04 (s, 0.5 H), 6.05 (s*, 0.5 H), 6.65 (s, 0.5 H), 6.67 (s*, 0.5 H), 7.29–7.44 (m, 3 H), 7.56–7.66 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 13.7 (CH3), 15.1 (CH3), 15.2 (CH3*), 15.4 (CH3), 20.0 (CH3), 20.7 (CH3*), 25.9 (CH2), 27.3 (CH2*), 38.1 (CH), 38.6 (CH*), 46.6 (CH2), 48.1 (CH2*), 50.8 (CH2), 50.9 (CH2*), 56.0 (CH3), 56.1 (CH3*), 63.3 (CH2), 63.4 (CH2*), 69.0 (CH), 69.6 (CH), 69.7 (CH*), 71.2 (CH*), 77.0 (CH2), 93.8 (CH2), 93.9 (CH2*), 95.4 (CH), 95.7 (CH*), 111.9 (CH), 112.2 (C), 121.0 (C), 121.4 (C*), 128.2 (CH), 128.3 (CH*), 128.5 (CH), 128.6 (CH*), 129.0 (CH), 129.1 (CH*), 137.2 (C), 137.5 (C*), 156.7 (C), 156.8 (C*), 158.3 (C), 158.4 (C*), 162.2 (C), 162.3 (C*), 163.4 (C), 163.5 (C*), 176.9 (C), 177.0 (C*), 209.6 (C), 210.7 (C*). IR (film): 2971, 2932, 1709, 1655, 1600, 1444, 1389, 1341, 1202, 1129, 1034 cm–1. HRMS (ESI): m/z [M + H]+ calcd for C30H39O8 +: 527.2639; found: 527.2622
  • 14 Synthesis of chaetoquadrin H (4): 1,3-diketone 18 (10 mg, 0.02 mmol) was taken up in EtOAc (1 mL), 10% Pd/C (16 mg) was added, and the reaction mixture was stirred under an atmosphere of hydrogen for 30 min. The mixture was filtered through cotton wool and the solvent was removed in vacuo. The crude product was dissolved in CHCl3 (1 mL), NaHSO4·SiO2 11 (15 mg) was added, and the mixture was stirred for 2 h. The reaction mixture was filtered through cotton wool and the filtrate was loaded directly on a preparative TLC plate (EtOAc–hexanes, 3:1) to yield chaetoquadrin H (4; 3 mg, 44% over two steps). [α]D 20 –41.3 (c 0.15, CHCl3) {lit.2 [α]D 20 –57.2 (c 0.2, CHCl3)}. 1H NMR (300 MHz, CDCl3): δ = 1.17 (d, J = 6.7 Hz, 3 H), 1.44 (d, J = 6.5 Hz, 3 H), 2.24–2.42 (m, 2 H), 2.35 (s, 3 H), 2.63–2.81 (m, 2 H), 2.89–3.05 (m, 1 H), 3.87 (s, 3 H), 4.29–4.45 (m, 1 H), 5.11 (s, 1 H), 6.04 (s, 1 H), 6.34 (s, 1 H), 12.85 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 17.6 (CH3), 20.5 (CH3), 20.6 (CH3), 27.3 (CH2), 39.1 (CH), 42.9 (CH2), 56.0 (CH3), 75.8 (CH), 89.5 (CH), 103.3 (CH), 105.2 (C), 109.1 (CH), 110.8 (C), 157.0 (C), 159.2 (C), 163.4 (C), 166.6 (C), 181.3 (C), 182.7 (C), 193.7 (C). IR (film): 2935, 1661, 1598, 1494, 1449, 1343, 1127 cm–1. HRMS (ESI): m/z [M + H]+ calcd for C20H23O6 +: 359.1489; found: 359.1487