Synthesis of Thia-Analogues of Calothrixin B Involving FeCl₃-Mediated Domino Reaction

Abstract

The total synthesis of thiacalothrixins, an isostere of the biologically important carbazoloquinone alkaloid calothrixin B, was achieved from ethyl benzo[b]thiophene-2-carboxylate. Alternatively, the multi-step synthesis of thiaisocalothrixins could be achieved from 3-methylbenzo[b]thiophene. A preliminary in vitro cytotoxicity evaluation of the synthesized thia analogues of calothrixins displayed promising potential against cancer cell cultures.

Key words

carbazole alkaloids - calothrixin B - electrocyclization - Lewis acid - quinones

• References and Notes

• 1 Goodwin S, Smith AF, Horning EC. J. Am. Chem. Soc. 1959; 81: 1903
• 2a Miki Y, Hachiken H, Yanase N. J. Chem. Soc., Perkin Trans. 1 2001; 2213
• 2b Knölker H.-J, Reddy KR. Chem. Rev. 2002; 102: 4303
• 2c Knölker H.-J, Reddy KR In The Alkaloids . Vol. 65. Cordell GA. Elsevier Science; New York: 2008: 1-430
• 2d Miller CM, McCarthy FO. RSC Adv. 2012; 2: 8883
• 2e Schmidt AW, Reddy KR, Knölker H.-J. Chem. Rev. 2012; 112: 3193
• 2f O’Sullivan EC, Miller CM, Deane FM, McCarthy FO. Studies in Natural Product Chemistry 2013; 189-232
• 3a Buzdar AU, Hortobagyi GN, Esparza LT, Holmes FA, Ro JS, Fraschini G, Lichtiger B. Oncology 1990; 47: 101
• 3b Rouesse J, Spielmann M, Turpin F, Le Chavelier T, Azab M, Mondesir JM. Eur. J. Cancer 1993; 6: 856
• 3c Ohashi M, Oki T. Expert Opin. Ther. Pat. 1996; 6: 1285
• 3d Kattan J, Durand M, Droz JP, Mahjoubi M, Marino JP, Azab M. Am. J. Clin. Oncol. 1994; 17: 242
• 4 Rickards RW, Rothschild JM, Willis AC, de Chazal NM, Kirk J, Kirk K, Saliba KJ, Smith GD. Tetrahedron 1999; 55: 13513
• 5a Bernardo PH, Chai CL. L, Heath GA, Mahon PJ, Smith GD, Waring P, Wilkes BA. J. Med. Chem. 2004; 47: 4958
• 5b Bernardo PH, Chai CL. L, Le Guen M, Smith GD, Waring P. Bioorg. Med. Chem. Lett. 2007; 17: 82
• 5c Matsumoto K, Choshi T, Hourai M, Zamami Y, Sasaki K, Abe T, Ishikura M, Hatae N, Iwamura N, Tohyama S, Nobuhiro J, Hibino S. Bioorg. Med. Chem. Lett. 2012; 22: 4762
• 6 Doan NT, Stewart PR, Smith GD. FEMS Microbiol. Lett. 2001; 196: 135
• 7 Khan QA, Lu J, Hecht SM. J. Nat. Prod. 2009; 72: 438
• 8 Chen X, Smith GD, Waring P. J. Appl. Phycol. 2003; 15: 269
• 9a Kelly TR, Zhao Y, Cavero M, Torneiro M. Org. Lett. 2000; 2: 3735
• 9b Bernardo PH, Chai CL. L, Elix JA. Tetrahedron Lett. 2002; 43: 2939
• 9c Bernardo PH, Chai CL. L. J. Org. Chem. 2003; 68: 8906
• 9d Tohyama S, Choshi T, Matsumoto K, Yamabuki A, Ikegata K, Nobuhiro J, Hibino S. Tetrahedron Lett. 2005; 46: 5263
• 9e Yamabuki A, Fujinawa H, Choshi T, Tohyama S, Matsumoto K, Ohmura K, Nobuhiro J, Hibino S. Tetrahedron Lett. 2006; 47: 5859
• 9f Sissouma D, Maingot L, Collet S, Guingant A. J. Org. Chem. 2006; 71: 8434
• 9g Bernardo PH, Fitriyanto W, Chai CL. L. Synlett 2007; 1935
• 9h Bennasar M.-L, Roca T, Ferrando F. Org. Lett. 2006; 8: 561
• 9i McErlean CS. P, Sperry J, Blake AJ, Moody CJ. Tetrahedron 2007; 63: 10963
• 9j Abe T, Ikeda T, Yanada R, Ishikura M. Org. Lett. 2011; 13: 3356
• 9k Sissouma D, Collet CS, Guingant AY. Synlett 2004; 2612
• 9l Abe T, Ikeda T, Choshi T, Hibino S, Hatae N, Toyata E, Yanada R, Ishikura M. Eur. J. Org. Chem. 2012; 5018
• 9m Ramkumar N, Nagarajan R. J. Org. Chem. 2013; 78: 2802
• 9n Ramkumar N, Nagarajan R. J. Org. Chem. 2014; 79: 736
• 9o Bhosale SM, Gawade RL, Puranik VG, Kusurkar RS. Tetrahedron Lett. 2012; 53: 2894
• 9p Mal DR, Roy J, Biradha K. Org. Biomol. Chem. 2014; 12: 8196
• 9q Xu S, Ngugen T, Pomilio I, Vitale MC, Velu SE. Tetrahedron 2014; 70: 5928
• 9r Kaliyaperumal SA, Banerjee S, Kumar SU. K. Org. Biomol. Chem. 2014; 12: 6105
• 9s Dethe DM, Murhade GM. Eur. J. Org. Chem. 2014; 6953
• 9t Ramkumar N, Nagarajan R. RSC Adv. 2015; 5: 87838
• 10a Ramalingam BM, Saravanan V, Mohanakrishnan AK. Org. Lett. 2013; 15: 3726
• 10b Saravanan V, Ramalingam BM, Mohanakrishnan AK. Eur. J. Org. Chem. 2014; 1266
• 11a Fujiwara AN, Acton EM, Goodman LJ. J. Heterocycl. Chem. 1968; 5: 853
• 11b Elmes BC, Swan JM. Aust. J. Chem. 1969; 22: 1963
• 11c Kano S, Mochizuki N, Hibino S, Shibuya S. J. Org. Chem. 1982; 47: 3566
• 12 Shi LM, Myers TG, Fan Y, OʼConnor PM, Paul KD, Friend SH, Weinstein SH. Mol. Parmacol. 1998; 53: 241
• 13a Romagnoli R, Baraldi PG, Carrion MD, Lopez-Cara C, Preti D, Fruttarolo F, Pavani MG, Tabrizi MA, Tolomeo M, Grimaudo S, Cristina AD, Balzarini J, Hadfield JA, Brancale A, Hamle E. J. Med. Chem. 2007; 50: 2273
• 13b Romagnoli R, Baraldi PG, Lopez-Cara C, Preti D, Tabrizi MA, Balzarini J, Basseetto M, Brancale A, Fu X.-H, Gao Y, Li J, Zhang S.-Z, Hamel E, Bortolozzi R, Basso G, Viola G. J. Med. Chem. 2013; 56: 9296
• 14a Jarak I, Kralj M, Šuman L, Pavlolić G, Dogan J, Piantanida I, Žinić M, Pavelić K, Karminski-Zamola G. J. Med. Chem. 2005; 48: 2346
• 14b Ester K, Hranjec M, Piantanida I, Ćaleta I, Jarak I, Pavelić K, Kralji M, Karminski-Zamola G. J. Med. Chem. 2009; 52: 2482
• 15 Kutsunugi Y, Kawai S, Nakashima T, Kawai T. New J. Chem. 2009; 33: 1368
• 16 Matsunaga N, Kaku T, Itoh F, Tanaka T, Hara T, Miki H, Iwasaki M, Aono T, Yamaoka M, Kusaka M, Tasaka A. Bioorg. Med. Chem. Lett. 2004; 12: 2251
• 17 Bauer I, Knölker H.-J. Chem. Rev. 2015; 115: 3170
• 18 Representative Procedure for the Preparation of Thiacalothrixin B (23a) To a solution of enamine 22a (300 mg, 0.8 mmol) in dry DMF (20 mL), FeCl₃ (520 mg, 3.2 mmol) was added. The reaction mixture was refluxed for 3 h under N₂ atmosphere. It was then poured over crushed ice (50 g) containing concd HCl (1 mL). The crude product was filtered and dried. It was then purified by flash column chromatography on silica gel (230–420 mesh, n-hexane–CH₂Cl₂ = 9:1 to 1:1) to afford thiacalothrixin B (23a) as a red-orange solid (160 mg, 65%); mp 260–262 °C. IR (film): 1651, 1519, 1258, 1092 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 9.81 (s, 1 H), 9.60 (d, J = 8.7 Hz, 1 H), 8.87 (d, J = 7.8 Hz, 1 H), 8.22 (d, J = 8.1 Hz, 1 H), 7.98 (d, J = 7.5 Hz, 1 H), 7.90 (t, J = 7.5 Hz, 1 H), 7.81 (t, J = 7.8 Hz, 1 H), 7.66–7.57 (m, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 182.9, 180.3, 152.1, 148.7, 148.2, 142.4, 135.8, 133.6, 132.9, 132.1, 130.7, 130.4, 128.8, 127.7, 127.5, 127.3, 124.7, 123.0, 122.7 ppm. DEPT 135: δ = 148.2, 132.1, 130.7, 130.4, 128.8, 127.7, 127.5, 127.3, 123.0 ppm. HRMS (EI): m/z cacld for C₁₉H₉NO₂S [M⁺]: 315.0354; found: 315.0354.