Cascade 4+1 Radical Annulations of 2,6-Disubstituted Phenyl Isonitriles with N-Propargyl-6-Iodopyridones: Scope, Mechanism and Regioselective Synthesis of 7,9-Disubstituted Camptothecin Analogs

Abstract

The reaction of o,o′-dialkyl-substituted aryl isonitriles with N-propargyl-6-iodopyridones provides 11H-indolizino[1,2-b]quinolin-9-ones with significant regioselectivity in favor of the more crowded product. The usefulness of the method is illustrated with a regioselective synthesis of (20S)-7-trimethylsilyl-9-isopropyl camptothecin.

Key words

cascade radical annulation - isonitrile - camptothecin - mappicine - quinoline

References

• 1a Lerchen H.-G. Drugs Fut.  2002,  29:  869 
• 1b Zunino F. Dallavalle S. Laccabue D. Beretta G. Merlini L. Pratesi G. Curr. Pharm. Design  2002,  8:  2505 
• 1c Kim D.-K. Lee N. Mini Rev. Med. Chem.  2002,  2:  611 
• 2a Pirillo A. Verotta L. Gariboldi P. Torregiani E. Bombardelli E. J. Chem. Soc., Perkin Trans. 1  1995,  583 
• 2b Pendrak I. Barney S. Wittrock R. Lambert DM. Kingsbury WD. J. Org. Chem.  1994,  59:  2623 
• 2c Pendrak I. Wittrock R. Kingsbury WD. J. Org. Chem.  1995,  60:  2912 
• 2d Boger DL. Hong JY. J. Am. Chem. Soc.  1998,  120:  1218 
• 3a Curran DP. Liu H. J. Am. Chem. Soc.  1991,  113:  2127 
• 3b Curran DP. Ko SB. Josien H. Angew. Chem., Int. Ed. Engl.  1995,  34:  2683 
• 3c Curran DP. Liu H. Josien H. Ko SB. Tetrahedron  1996,  52:  11385 
• 3d Josien H. Curran DP. Tetrahedron  1997,  53:  8881 
• 3e Josien H. Ko SB. Bom D. Curran DP. Chem.-Eur. J.  1998,  4:  67 
• 3f Zhang Q. Rivkin A. Curran DP. J. Am. Chem. Soc.  2002,  124:  5774 
• 4a Ryu I. Sonoda N. Curran DP. Chem. Rev.  1996,  96:  177 
• 4b Nanni D. In Radicals in Organic Synthesis   Vol. 2, 1st ed.:  Renaud P. Sibi MP. Wiley-VCH; Weinheim: 2001.  p.44-61  
• 5a Curran DP. Josien H. Bom D. Gabarda A. Du W. In The Camptothecins: Unfolding their Anticancer Potential   Vol. 922:  Liehr JG. Giovanella BC. Verschraegen CF. NY Acad. Sci.; NY: 2000.  p.112-21 
• 5b Josien H. Bom D. Curran DP. Zheng Y.-H. Chou T.-C. Bioorg. Med. Chem. Lett.  1997,  7:  3189 
• 5c Bom D. Du W. Garbarda A. Curran DP. Chavan AJ. Kruszewski S. Zimmer SG. Fraley KA. Bingcang AL. Wallace VP. Tromberg BJ. Burke TG. Clinical Cancer Research  1999,  5:  560 
• 5d Bom D. Curran DP. Kruszewski S. Zimmer SG. Thompson Strode J. Kohlhagen G. Du W. Chavan AJ. Fraley KA. Bingcang AL. Latus LJ. Pommier Y. Burke TG. J. Med. Chem.  2000,  43:  3970 
• 5e de Frutos O. Curran DP. J. Comb. Chem.  2000,  2:  639 
• 5f Luo ZY. Zhang QS. Oderaotoshi Y. Curran DP. Science  2001,  291:  1766 
• 5g Gabarda AE. Du W. Isarno T. Tangirala RS. Curran DP. Tetrahedron  2002,  58:  6329 
• 5h Gabarda AE. PhD Thesis   University of Pittsburgh; USA: 2002. 
• 7 A single example of a reaction with a disubstituted isonitrile has been described previously. See ref. and: Liu H. PhD Thesis   University of Pittsburgh; USA: 1991. 
• Fragmentation reactions of cyclohexadienyl-like radicals with rearomatization are well precedented. See, for example:
• 8a Binmore G. Walton JC. Cardellini L. J. Chem. Soc., Chem. Commun.  1995,  27 
• 8b Jackson L. Walton JC. Tetrahedron Lett.  1999,  40:  7019 
• 8c Jackson LV. Walton JC. Chem. Commun.  2000,  2327 

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Camptothecin numbering and ring designations are used for consistency throughout the manuscript.

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Supporting Information Available: A print or pdf file of the characterization data for the compounds in this paper can be obtained on request from DPC.