Synthetic Studies on a Model of Cylindrospermopsin

Abstract

A new strategy for the synthesis of cylindrospermopsin is described using an intramolecular Mannich reaction to form ring A. Guanylation of the piperidine nitrogen and reaction on an activated double bond generates ring B.

Key words

cylindrospermopsin - piperidines - intramolecular ­Mannich reaction

References and Notes

• 1 Ohtani I. Moore RE. Runnegar MTC. J. Am. Chem. Soc.  1992,  114:  7941 
• 2 Harada K. Ohtani I. Iwamoto K. Suzuki M. Watanabe MF. Watanabe M. Terao K. Toxicon  1994,  32:  73 
• 3 Banker R. Teltsch B. Sukenik A. Carmeli S. Hadas O. Porat R. J. Phycol.  1997,  33:  613 
• 4 Banker R. Teltsch B. Sukenik A. Carmeli S. J. Nat. Prod.  2000,  63:  387 
• 5a Norris RL. Eaglesham GK. Pierens G. Shaw GR. Smith MJ. Chiswell RK. Seawright AA. Moore MR. Environ. Toxicol.  1999,  14:  163 
• 5b Runnegar MT. Xie C. Snider BB. Wallace GA. Weinreb SM. Kuhlenkamp J. Toxicol. Sci.  2002,  67:  81 
• For the racemic total synthesis of cylindrospermopsin and its C-7 isomer, see:
• 6a Xie C. Runnegar MTC. Snider BB. J. Am. Chem. Soc.  2000,  122:  5017 
• 6b Heintzelman GR. Fang W.-K. Keen SP. Wallace GA. Weinreb SM. J. Am. Chem. Soc.  2002,  124:  3939 
• For the enantioselective total synthesis of cylindrospermopsin and its C-7 isomer, see:
• 7a White JD. Hansen JD. J. Am. Chem. Soc.  2002,  124:  4950 
• 7b Looper RE. Williams RM. Angew. Chem. Int. Ed.  2004,  43:  2930 
• 7c White JD. Hansen JD. J. Org. Chem.  2005,  70:  1963 
• 7d Looper RE. Runnegar MTC. Williams RM. Tetrahedron  2006,  62:  4549 
• 7e For a review on the synthesis and biological activities of cylindrospermopsin alkaloids, see: Murphy PJ. Thomas CW. Chem. Soc. Rev.  2001,  30:  303 
• 8a Ciblat S. Besse P. Papastergiou V. Veschambre H. Canet J.-L. Troin Y. Tetrahedron: Asymmetry  2000,  11:  2221 
• 8b Ciblat S. Calinaud P. Canet J.-L. Troin Y. J. Chem. Soc., Perkin Trans. 1  2000,  353 
• 8c Carbonnel S. Troin Y. Heterocycles  2002,  57:  1807 
• 8d Rougnon Glasson S. Tratrat C. Canet J.-L. Chalard P. Troin Y. Tetrahedron:Asymmetry  2004,  15:  1561 
• 10 Rougnon Glasson S. Canet J.-L. Troin Y. Tetrahedron Lett.  2000,  41:  9797 
• 11a Heck RF. Nolley JP. J. Org. Chem.  1972,  37:  2320 
• 11b For a recent review on Heck reactions, see: Link JT. Organic Reactions   Vol. 60:  Wiley; Hoboken: 2002.  Chap. 2.
• 12 White JD. Hansen JD. J. Org. Chem.  2005,  70:  1963 
• 13 Raucher S. Bray BL. Lawrence RF. J. Am. Chem. Soc.  1987,  109:  442 
• 14 McAlpine IJ. Armstrong RW. Tetrahedron Lett.  2000,  41:  1849 ; and references cited therein

9

SN₂ displacement of the bromide derivative by the guanydyl derivative in order to form cycle B of cylindrospermeopsin has been described, see reference 6a.