The Synthesis of Functionalised Bicyclo[3.3.1]nonanes Related to Huperzine A

Abstract

Radical cyclisation-based synthetic routes to the core structure of huperzine A, are described. Cyclisation of (2-pyridyl)methyl radicals derived from two model [(2-phenylseleno­methyl)-3-pyridyl]cyclohexenones, proceeds in 6-exo-trig mode to give bicyclo[3.3.1]nonanes. Cyclisation yields are related to the substitution pattern and relative stereochemistry about the enone ring. Cyclisation precursors were accessed by either conjugate addition of a (3-pyridyl)cuprate onto an enone or by Diels-Alder cycloaddition of a (3-pyridyl)-substituted alkene with Rawal’s diene.

Key words

huperzine A - radical cyclisation - cuprate - selenium - Diels-Alder

References

• 1 Liu J.-S. Zhou Y.-L. Yu C.-M. Zhou Y.-Z. Han Y.-Y. Wu F.-W. Qi B.-F. Can. J. Chem.  1986,  64:  837 
• 2 Ainge GD. Lorimer SD. J. Agric. Food Chem.  2002,  50:  491 
• 3a Wang H. Tang XC. Acta Pharmacol. Sin.  1998,  19:  27 
• 3b Tang XC. Han YF. CNS Drug Review  1999,  5:  281 
• 4a Ved HS. Koening ML. Dave JR. Doctor BP. Neuroreport  1997,  8:  963 
• 4b Xiao XQ. Wang R. Han Y. Tang XC. Neurosci. Lett.  2000,  286:  155 
• 4c Gordon RK. Nigam SV. Weitz JA. Dave JR. Doctor BP. Ved HS. J. Appl. Toxicol.  2001,  21 (Suppl. 1):  S47-S51  
• 4d Xiao XQ. Zhang HY. Tang XC. J. Neurosci. Res.  2002,  67:  30 
• 4e Zhang HY. Yan H. Tan XC. Cell Mol. Neurobiol.  2008,  28:  173 
• 5a Xu SS. Cai ZY. Qu ZW. Yang RM. Cai YL. Wang GQ. Su XQ. Zhong XS. Cheng RY. Xu WA. Li JX. Feng B. Acta Pharmacol. Sin.  1999,  20:  486 
• 5b Jiang H. Luo X. Bai D. Curr. Med. Chem.  2003,  10:  2231 
• 5c Zangara A. Curr. Top. Nutraceutical Res.  2003,  1:  193 
• 6a Lallement G. Demoncheaux JP. Foquin A. Baubichon D. Galonnier M. Clarencon D. Dorandeu F. Drug Chem. Toxicol.  2002,  25:  309 
• 6b Lallement G. Baille V. Baubichon D. Carpentier P. Collombet JM. Filliat P. Foquin A. Four E. Masquiliez C. Testylier G. Tonduli L. Dorandeu F. Neurotoxicology  2002,  23:  1 
• 8a Ward J. Caprio V. Tetrahedron Lett.  2006,  47:  553 
• 8b Ward J. Caprio V. Heterocycles  2009,  79:  791 
• 9 Busscher GF. Groothys S. De Gelder R. Rutjes FPJT. van Delft FL. J. Org. Chem.  2004,  69:  4447 
• 10 Caprio V. Mann J. J. Chem. Soc., Perkin Trans. 1  1998,  3151 
• 11 Agarwal KC. Knaus EE. J. Heterocycl. Chem.  1985,  22:  65 
• 12 Kao BC. Doshi H. Reyes-Rivera H. Titus DD. Yin M. Dalton DR. Heterocycl. Chem.  1991,  28:  1315 
• 13 Broering TJ. Morrow GW. Synth. Commun.  1999,  29:  1135 
• 14 Hiroya K. Zhang H. Ogasawara K. Synlett  1999,  529 
• 15a Takagi R. Miyanaga W. Tamura Y. Kojima S. Ohkata K. Heterocycles  2003,  60:  785 
• 15b Ohkata K. Tamura Y. Shetuni BB. Takagi R. Miyanaga W. Kojima S. Paquette LA. J. Am. Chem. Soc.  2004,  126:  16783 
• 16 Kelly SA. Foricher J. Mann J. Org. Biomol. Chem.  2003,  1:  2865 
• 17a Kozmin SA. Rawal VH. J. Org. Chem.  1997,  62:  5252 
• 17b Kozmin SA. Janey JM. Rawal VH. J. Org. Chem.  1999,  64:  3039 
• 17c Janey JM. Iwama T. Kozmin SA. Rawal VH. J. Org. Chem.  2000,  65:  9059 
• 17d Huang Y. Rawal VH. J. Am. Chem. Soc.  2002,  124:  9662 
• 17e Kozmin SA. He S. Rawal VH. Org. Synth.  2002,  78:  160 
• 18 Sheldrake GM. SHELXL-97   University of Göttingen; Germany: 1997. 

7

For a comprehensive list of previous syntheses of huperzine A and analogues, see ref. 8b and references cited therein

19

X-ray crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-734079. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB12 1EZM UK [fax: [phone]; e-mail: [e-mail]].