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Synlett 2014; 25(14): 2059-2063
DOI: 10.1055/s-0034-1378342
letter
© Georg Thieme Verlag Stuttgart · New York

New Synthetic Procedure for 2-Aryl-1,4-naphthoquinone-1-oxime Methyl Ethers with Potent Antitumor Activity

Scebi Mkhize
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan   Fax: +81(43)2262919   Email: n-suzuki@chiba-u.jp
,
Noriyuki Suzuki*
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan   Fax: +81(43)2262919   Email: n-suzuki@chiba-u.jp
,
Ayako Kurosawa
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan   Fax: +81(43)2262919   Email: n-suzuki@chiba-u.jp
,
Makiko Fujinami
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan   Fax: +81(43)2262919   Email: n-suzuki@chiba-u.jp
,
Chanya Chaicharoenpong
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan   Fax: +81(43)2262919   Email: n-suzuki@chiba-u.jp
,
Tsutomu Ishikawa*
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan   Fax: +81(43)2262919   Email: n-suzuki@chiba-u.jp
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Further Information

Publication History

Received: 09 May 2014

Accepted after revision: 26 May 2014

Publication Date:
01 July 2014 (online)

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Abstract

1,4-Naphthoquinone 1-oxime methyl ethers carrying an ester-substituted aryl pendant at 2-position were concisely prepared as seed compounds with structural flexibility for structure–activity relationship studies on antitumor activity. The key synthetic intermediate was a phthalide–tetralone spiro compound, which was provided by palladium-coupling reaction between 2-bromobenzoate and 1-tetralone followed by OsO4–NMO oxidation.

Key words

coupling reaction - oxidation - oxime - quinone - spiro compound

Supporting Information

    for this article is available online at http://www.thieme-connect.com/products/ejournals/journal/ 10.1055/s-00000083.
  • Supporting Information
 

  • References and Notes

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    • 1b Watanabe T, Ohashi Y, Yoshino R, Komano N, Eguchi M, Maruyama S, Ishikawa T. Org. Biomol. Chem. 2003; 1: 3024
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    • 2b Sato H, Yamada R, Yanagihara M, Okuzawa H, Iwata H, Kurosawa A, Ichinomiya S, Suzuki R, Okabe H, Yano T, Kumamoto T, Suzuki N, Ishikawa T, Ueno K. J. Pharmacol. Sci. 2012; 118: 467
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  • 5 Watanabe T, Oku Y, Ishii H, Ishikawa T. Synlett 1997; 161
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  • 6 Ishikawa T, Murota M, Watanabe T, Harayama T, Ishii H. Tetrahedron Lett. 1995; 36: 4269
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  • 7 Ishii H, Ishikawa T, Murota M, Aoki Y, Harayama T. J. Chem. Soc., Perkin Trans. 1 1993; 1019
  • 8 Konno F, Ishikawa T, Kawahata M, Yamaguchi K. J. Org. Chem. 2005; 71: 9818
  • 9 Synthetic procedures for compounds shown in Schemes 1 and 2, except those described in Note, are given in Supporting Information.
  • 10 4-Hydroxy-6,7-methylenedioxy-1-tetralone-2-spiro-3′-(6,7-dimethoxyphthalide) (10a) A mixture of 8a (82 mg, 0.223 mmol), NBS (43 mg, 0.243 mmol), and AIBN (5 mg, 0.029 mmol) in dry benzene (8 mL) was stirred at 85 °C for 1.5 h under argon. After addition of EtOAc (30 mL) the solution was washed with H2O (20 mL) and brine (10 mL), dried over Na2SO4, and evaporated. The residual oil was dissolved in THF (10 mL) and H2O (8 mL). The mixture was stirred at r.t. for 16 h and extracted with CHCl3 (3 × 20 mL). The combined organic solutions were washed with brine (10 mL), dried over Na2SO4, and evaporated. Column chromatography of the residue (SiO2, toluene–EtOAc = 10:1 → 1:1) afforded trans-10a (24 mg, 28%) as colorless solid, mp 212–213 °C, and cis-10a (27 mg, 31%) as colorless solid, mp 209–211 °C. trans-10a: IR (ATR): 1767, 1682 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.35 (d, J = 7.1 Hz, 1 H, exchangeable), 2.63 (dd, J = 13.7, 9.4 Hz, 1 H), 2.71 (dd, J = 13.7, 4.9 Hz, 1 H), 3.93 (s, 3 H), 4.14 (s, 3 H), 5.36 (ddd, J = 9.4, 7.1, 4.9 Hz, 1 H), 6.09 (s, 2 H), 7.03 (d, J = 8.3 Hz, 1 H), 7.21 (s, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 7.41 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 43.6, 56.8, 62.4, 64.4, 85.3, 102.2, 106.2, 106.6, 117.1, 117.9, 119.7, 124.2, 141.8, 144.5, 147.9, 148.3, 153.2, 153.7, 167.3, 187.9. MS–FAB: m/z = 407 [M + Na]+, 385 [M + H]+. Anal. calcd for C20H18O8: C, 62.50; H, 4.20. Found: C, 62.21; H, 3.96. cis-10a: IR (ATR): 1769, 1684 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.59 (d, J = 9.7 Hz, 1 H, exchangeable), 2.71 (dd, J = 13.6, 7.1 Hz, 1 H), 2.83 (dd, J = 13.6, 5.1 Hz, 1 H), 3.90 (s, 3 H), 4.14 (s, 3 H), 5.16 (ddd, J = 9.7, 7.1, 5.1 Hz, 1 H), 6.11 (s, 2 H), 6.82 (d, J = 8.2 Hz, 1 H), 7.14 (d, J = 8.2 Hz, 1 H), 7.18 (s, 1 H), 7.43 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 42.2, 56.8, 62.4, 65.5, 84.7, 102.4, 106.7, 107.5, 116.5, 117.9, 119.1, 124.2, 140.2, 142.3, 148.8, 148.9, 153.4, 153.9, 166.5, 188.1. MS–FAB: m/z = 407 [M + Na]+, 385 [M + H]+. Anal. calcd for C20H18O8·1/3H2O: C, 61.54; H, 4.30. Found: C, 61.79; H, 4.11.
  • 11 The same orientation of oxygen functions at the 2- and 4-positions of the tetralone unit is assigned to be cis configuration.
  • 12 2,3-Dimethoxy-6-[2-(1-methoxyimino-6,7-methylene-dioxy-4-oxo-1,4-dihydronaphthyl)]benzoic Acid (1d) A mixture of 11a (230 mg, 0.556 mmol) and IBX (260 mg, 0.929 mmol) in DMSO (4 mL) was stirred at 60 °C for 2 h. After addition of H2O (10 mL) insoluble precipitate was removed by filtration, and the filtrate was extracted with EtOAc (3 × 20 mL). The combined organic solutions were washed with H2O (3 × 1 mL) and brine (10 mL), dried over Na2SO4, and evaporated. The residue was dissolved in CH2Cl2 (20 mL), stirred with Et3N (0.2 mL, 1.42 mmol) at r.t. for 1 h, and extracted with H2O (3 × 20 mL). The combined aqueous solutions were acidified with 10% HCl aqueous solution (pH ca. 3) and extracted with CHCl3 (3 × 20 mL). The combined organic solutions were washed with brine (10 mL), dried over Na2SO4, and evaporated. Column chromatography of the residue (SiO2, acetone–toluene = 1:20) afforded 1d (211 mg, 92%) as pale yellow solid, mp 207–209 °C. IR (ATR): 1725, 1624 cm–1. 1H NMR (400 MHz, CDCl3): δ (Z-isomer) = 3.98 (s, 3 H), 3.99 (s, 3 H), 4.03 (s, 3 H), 6.10 (s, 2 H), 6.54 (s, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 7.68 (s, 1 H), 8.33 (s, 1 H). 13C NMR (100 MHz, DMSO-d 6): δ (Z-isomer) = 55.9, 61.0, 64.4, 102.8, 105.0, 109.2, 113.1, 123.7, 125.8, 127.5, 127.8 (2 C), 130.2, 144.8, 145.2, 149.4, 151.3, 151.4, 153.0, 167.8, 182.1. MS–FAB: m/z = 434 [M + Na]+, 412 [M + H]+. Anal. calcd for C21H17NO8: C, 61.31; H, 4.17; N, 3.40. Found: C, 61.14; H, 3.98; N, 3.28.
  • 13 Methyl 2,3-Dimethoxy-6-[2-(1-methoxyimino-6,7-methylenedioxy-4-oxo-1,4-dihydronaphthyl)]benzoate (1c) A mixture of 1d (211 mg, 0.512 mmol), MeI (0.07 mL, 1.10 mmol), and K2CO3 (140 mg, 1.01 mmol) in DMF (5 mL) was stirred at r.t. for 2 h, diluted with H2O (10 mL), and extracted with EtOAc (3 × 20 mL). The combined organic solutions were washed with H2O (2 × 10 mL), sat. NaHCO3 aqueous solution (5 mL), and brine (10 mL), dried over Na2SO4, and evaporated. Column chromatography of the residue (SiO2, EtOAc–hexane = 1:6 → 1:3) afforded 1c (201 mg, 92%) as pale yellow solid, mp 172–173 °C (lit.1b mp 171–173 °C). IR (ATR): 1715, 1638 cm–1. 1H NMR (400 MHz, CDCl3): δ (Z-isomer) = 3.66 (s, 3 H), 3.93 (s, 2 × 3 H), 4.08 (s, 3 H), 6.12 (s, 2 H), 6.57 (s, 1 H), 7.01 (d, J = 8.3 Hz, 1 H), 7.11 (d, J = 8.3 Hz, 1 H), 7.69 (s, 1 H), 8.33 (s, 1 H). ESI–HRMS: m/z calcd for C22H19NNaO8: 448.10084; found: 448.10020.
  • 14 Methyl 2-Hydroxy-3-methoxy-6-[2-(1-methoxyimino-6,7-methylenedioxy-4-oxo-1,4-dihydronaphthyl)]benz-oate (1f) To a stirred solution of 1c (29 mg, 6.8·10–2 mmol) in CH2Cl2 (7 mL) was added a 1 mol solution of BCl3 in CH2Cl2 (0.14 mL, 7.0·10–2 mmol) at –78 °C under argon, and the mixture was stirred at the same temperature for 2 h. After addition of H2O (5 mL) the mixture was extracted with CHCl3 (3 × 10 mL). The combined organic solutions were washed with brine (5 mL), dried over Na2SO4, and evaporated. Purification of the residue by PTLC (CHCl3) afforded 1f (26 mg, 92%) as yellow solid, mp 154–156 °C. IR (ATR): 2919, 1667, 1634 cm–1. 1H NMR (400 MHz, CDCl3): δ (Z-isomer) = 3.60 (s, 3 H), 3.96 (s, 3 H), 3.97 (s, 3 H), 6.13 (s, 2 H), 6.54 (s, 1 H), 6.82 (d, J = 8.3 Hz, 1 H), 7.02 (d, J = 8.3 Hz, 1 H), 7.72 (s, 1 H), 8.34 (s, 1 H), 10.8 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ (Z-isomer) = 52.4, 56.1, 64.5, 102.2, 106.2, 109.8, 113.6, 114.2, 120.7, 124.1, 126.8, 128.7, 130.3, 146.3, 148.9, 149.4, 150.0, 151.4, 153.7, 170.7, 183.6. ESI-HRMS: m/z calcd for C21H17NNaO8: 434.08519; found: 434.08440.
  • 15 Chen J, Zhang Y, Yang L, Zhang X, Liu J, Li L, Zhang H. Tetrahedron 2007; 63: 4266
    Crossref
  • 16 Methyl 4-Hydroxy-5-methoxy-2-[2-(1-methoxyimino-6,7-methylenedioxy-4-oxo-1,4-dihydronaphthyl)]benz-oate (1g) A mixture of 16 (7 mg, 1.3·10–3 mmol), Pd(OAc)2 (0.15 mg, 7·10–5 mmol), and Ph3P (0.7 mg, 2.6·10–4 mmol) in n-BuOH (3 mL) was stirred at 100 °C for 2 h under nitrogen, diluted with EtOAc (6 mL), and filtered through Celite pad. The filtrate was washed with H2O (2 × 3 mL) and brine (3 mL), dried over Na2SO4, and evaporated. Column chromatography of the residue (SiO2, EtOAc–hexane = 1:1) afforded 1g (5 mg, 93%) as pale yellow solid, mp 89–91 °C. IR (ATR): 3437, 1771 cm–1. 1H NMR (400 MHz, CDCl3): δ (Z-isomer) = 3.64 (s, 3 H), 3.97 (s, 3 H), 4.00 (s, 3 H), 6.12 (s, 2 H), 6.49 (s, 1 H), 6.91 (s, 1 H), 7.49 (s, 1 H), 7.70 (s, 1 H), 8.35 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ (Z-isomer) = 52.2, 56.4, 64.5, 102.3, 106.4, 110.2, 112.4, 116.6, 123.1, 124.6, 127.3, 129.0, 133.2, 146.1, 146.5, 148.7, 149.5, 151.5, 153.4, 167.1, 183.6. ESI-HRMS: m/z calcd for C21H17NNaO8: 434.08519; found: 434.08329.
  • 17 Results on the cytotoxic activity of these naphthoquinone oximes will be reported elsewhere.