Total Synthesis of 4-Azaeudistomin Y₁ and Analogues by Inverse-Electron­Demand Diels–Alder Reactions of 3-Aminoindoles with 1,3,5-Triazines

Abstract

A new inverse-electron-demand Diels–Alder (IDA) reaction of 3-aminoindoles as dienophiles was developed for the efficient preparation of 4-aza-β-carbolines in high yields. Because N¹-unprotected 3-aminoindoles show poor thermal stability, a one-pot protocol was developed that combines the removal of tert-butoxycarbonyl protecting groups with the IDA reaction. This protocol, using tert-butyl 1H-indol-3-ylcarbamates as reactants, gave the corresponding IDA products in excellent yields. The new IDA methodology was used in a total synthesis of 4-azaeudistomin Y₁, which was obtained in 57% overall yield in four steps. Moreover, the chemistry is suitable for the rapid preparation, through either Friedel–Crafts acylation or amide-formation reactions, of analogues that are useful for exploring structure–activity relationships at the C₁-position.

Key words

indoles - Diels–Alder reactions - heterocycles - total synthesis

• References

• 1 Wang WH, Nam SJ, Lee BC, Kang H. J. Nat. Prod. 2008; 71: 163
• 2 Gul W, Hamann MT. Life Sci. 2005; 78: 442
• 3 Won TH, Jeon J.-e, Lee S.-H, Rho BJ, Oh K.-B, Shin J. Bioorg. Med. Chem. 2012; 20: 4082
• 4 Yamagishi H, Matsumoto K, Iwasaki K, Miyazaki T, Yokoshima S, Tokuyama H, Fukuyama T. Org. Lett. 2008; 10: 2369
• 5 Yamashita T, Kawai N, Tokuyama H, Fukuyama T. J. Am. Chem. Soc. 2005; 127: 15038
• 6 Dong XC, Miao YP, Lin ZG, Yu F, Wen R. Yaoxue Xuebao 2003; 38: 876
• 7 Bracher F, Hildebrand D, Ernst L. Arch. Pharm. (Weinheim, Ger.) 1994; 327: 121
• 8 Panarese JD, Waters SP. Org. Lett. 2010; 12: 4086
• 9 Nissen F, Richard V, Alayrac C, Witulski B. Chem. Commun. 2011; 47: 6656
• 10 Balunas MJ, Kinghorn AD. Life Sci. 2005; 78: 431
• 11 Haefner B. Drug Discovery Today 2003; 8: 536
• 12 Vuorela P, Leinonen M, Saikku P, Tammela P, Rauha JP, Wennberg T, Vuorela H. Curr. Med. Chem. 2004; 11: 1375
• 13 Boger DL. Chem. Rev. 1986; 86: 781
• 14 Boger DL, Weinreb SM. Hetero Diels–Alder Methodology in Organic Synthesis . Academic Press; San Diego: 1987
• 15 Seitz G, Kämpchen T. Arch. Pharm. (Weinheim, Ger.) 1976; 309: 679
• 16 Haider N. Heterocycles 1995; 41: 2519
• 17 Dang Q, Brown BS, Erion MD. J. Org. Chem. 1996; 61: 5204
• 18 Dang Q, Liu Y, Erion MD. J. Am. Chem. Soc. 1999; 121: 5833
• 19 Lee L, Snyder JK In Advances in Cycloadditions . Vol. 6. Harmata M. JAI Press; Stamford: 1999: 119
• 20 Dang Q, Liu Y, Sun ZL. Tetrahedron Lett. 2001; 42: 8419
• 21 Dang Q, Gomez-Galeno JE. J. Org. Chem. 2002; 67: 8703
• 22 Lahue BR, Wan Z.-K, Snyder JK. J. Org. Chem. 2003; 68: 4345
• 23 Dang Q, Carruli E, Tian F, Dang FW, Gibson T, Li WY, Bai HC, Chung M, Hecker SJ. Tetrahedron Lett. 2009; 50: 2874
• 24 Dang Q, Liu Y. Tetrahedron Lett. 2009; 50: 6758
• 25 Yu ZX, Dang Q, Wu YD. J. Org. Chem. 2001; 66: 6029
• 26 Yu ZX, Dang Q, Wu YD. J. Org. Chem. 2005; 70: 998
• 27 Xu G, Zheng L, Wang S, Dang Q, Bai X. Synlett 2009; 3206
• 28 Salvati ME, Balog JA, Shan W, Giese S, Harikrishnan LS. US 2004077606, 2004
• 29 Beccalli EM, Broggini G, Martinelli M, Sottocornola S. Synthesis 2008; 136
• 30 The solubilities of 1a and 1b in DMF were 1.53 and 0.06 mmol/mL, respectively; see: Xu G, Zheng L, Wang S, Dang Q, Bai X. Synth. Commun. 2010; 40: 361
• 31 Dess DB, Martin JC. J. Am. Chem. Soc. 1991; 113: 7277
• 32 More JD, Finney NS. Org. Lett. 2002; 4: 3001
• 33 Studer M, Blaser H.-U. J. Mol. Catal. A: Chem. 1996; 112: 437
• 34 Fletcher S, Gunning PT. Tetrahedron Lett. 2008; 49: 4817
• 35 Murakami Y, Watanabe T, Kobayashi A, Yokoyama Y. Synthesis 1984; 738
• 36 Cusack NJ, Shaw G, Litchfield GJ. J. Chem. Soc. C 1971; 1501
• 37 Crystallographic data for compound 14 have been deposited with the accession number CCDC 907559 and can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: [phone]; E-mail: [e-mail]; Web site: www.ccdc.cam.ac.uk/conts/retrieving.html.
• 38 Glennon RA, Von Strandtmann M. J. Heterocycl. Chem. 1975; 12: 135
• 39 Kitano M, Kojima A, Nakano K, Miyagishi A, Noguchi T, Ohashi N. Chem. Pharm. Bull. 1999; 47: 1538
• 40 Woo LW. L, Lightowler M, Purohit A, Reed MJ, Potter BV. L. J. Steroid Biochem. Mol. Biol. 1996; 57: 79
• 41 Anderson C, Freeman J, Lucas LH, Farley M, Dalhoumi H, Widlanski TS. Biochemistry 1997; 36: 2586
• 42 Lien J.-C, Jiang Y.-D, Chen C.-J, Kuo S.-C, Huang L.-J. J. Chin. Chem. Soc. (Taipei) 2008; 55: 1160
• 43 Ebisawa M, Ueno M, Oshima Y, Kondo Y. Tetrahedron Lett. 2007; 48: 8918