Model Studies for the Synthesis of Heliquinomycin: Preparation of New Spiroketals

Abstract

New model compounds were investigated within our efforts to synthesize the natural product heliquinomycin. We could provide good evidence that electronic effects prevent the spiroketal formation of compounds such as 5 incorporating an isocoumarin moiety. As a consequence, precursors 16 and 26 were prepared, which do not exert the strong electron-withdrawing effect of the methoxycarbonyl group present in 5. Dihydroisocumarin derivative 10 and phthalide 25 were coupled by Heck reactions with enone 4 to provide the required precursors 16 and 26. After reductive debenzylation the resulting intermediates were treated with anhydrous hydrochloric acid in alcohols to give spiroketals 18-20 and 28, 29 in reasonable yields. The spiroketalizations occur under thermodynamic control affording products with the hydroxyl group in a trans-relationship with respect to the pyran oxygen atom. Attempts to oxidatively convert dihydroisocumarin 19 into an isocoumarin derivative failed. In one attempt a ring contraction to new spiroketal 24 was observed.

Key words

acetals - spiro compounds - Heck reaction - natural products - heliquinomycin

References

• 1a Chino M. Nishikawa K. Umekita M. Hayashi C. Chigusa Y. J. Antibiot.  1996,  49:  752 
• 1b Chino M. Nishikawa K. Sawa R. Hamada M. Naganawa H. J. Antibiot.  1998,  51:  480 
• 2 Review: Brasholz M. Sörgel S. Azap C. Reissig H.-U. Eur. J. Org. Chem.  2007,  3801 
• 3a Niedenzu T. Röleke D. Bains G. Scherzinger E. Saenger W. J. Mol. Biol.  2001,  306:  479 
• 3b Xu H. Ziegelin G. Schröder W. Frank J. Ayora S. Alonso JC. Lanka E. Saenger W. Nucleic Acids Res.  2001,  29:  5058 
• 3c Xu H. Frank J. Trier U. Hammer S. Schröder W. Behlke J. Schäfer-Korting M. Holzwarth JF. Saenger W. Biochemistry  2001,  40:  7211 
• 3d Ziegelin G. Niedenzu T. Lurz R. Saenger W. Lanka E. Nucleic Acids Res.  2003,  31:  5917 
• 4a Capecchi T. de Koning CB. Michael JP. Tetrahedron Lett.  1998,  39:  5429 
• 4b Capecchi T. de Koning CB. Michael JP. J. Chem. Soc., Perkin Trans. 1  2000,  2681 
• 4c Thrash TP. Welton TD. Behar V. Tetrahedron Lett.  2000,  41:  29 
• 4d Waters SP. Kozlowski MC. Tetrahedron Lett.  2001,  42:  3567 
• 4e Xie X. Kozlowski MC. Org. Lett.  2001,  3:  2661 
• 4f Waters SP. Fennie MW. Kozlowski MC. Org. Lett.  2006,  8:  3243 
• 4g Lowell AN. Fennie MW. Kozlowski MC. J. Org. Chem.  2008,  73:  1911 
• 4h Tsang KY. Brimble MA. Bremner JB. Org. Lett.  2003,  5:  4425 
• 4i Brimble MA. Flowers CL. Trzoss M. Tsang KY. Tetrahedron  2006,  47:  3349 
• 4j Lindsey CC. Wu KL. Pettus TRR. Org. Lett.  2006,  8:  2365 
• 4k Marsini MA. Huang Y. Lindsey CC. Wu K.-L. Pettus TRR. Org. Lett.  2008,  10:  1477 
• 4l Zhou G. Zheng D. Da S. Xie Z. Li Y. Tetrahedron Lett.  2006,  47:  3349 
• 4m Zhou G. Zhu J. Xie Z. Li Y. Org. Lett.  2008,  10:  721 
• 5a Qin D. Ren RX. Siu T. Zheng C. Danishefsky SJ. Angew. Chem. Int. Ed.  2001,  40:  4709; Angew. Chem. 2001, 113, 4845 
• 5b Siu T. Qin D. Danishefsky SJ. Angew. Chem. Int. Ed.  2001,  40:  4713 ; Angew. Chem. 2001, 113, 4849
• 6 Akai S. Kakiguchi K. Nakamura Y. Kuriwaki I. Dohi T. Harada S. Kubo O. Morita N. Kita Y. Angew. Chem. Int. Ed.  2007,  46:  7458 ; Angew. Chem. 2007, 119, 7602
• 7a Sörgel S. Azap C. Reissig H.-U. Eur. J. Org. Chem.  2006,  4405 
• 7b Brasholz M. Reissig H.-U. Synlett  2004,  2736 
• 7c Brasholz M. Luan X. Reissig H.-U. Synthesis  2005,  3571 
• 7d Brasholz M. Reissig H.-U. Angew. Chem. Int. Ed.  2007,  46:  1634 ; Angew. Chem. 2007, 119, 1659
• 7e Azap C. Ph.D. Thesis   Freie Universität Berlin; Germany: 2004. 
• 7f Sörgel S. Azap C. Reissig H.-U. Org. Lett.  2006,  8:  4875 
• 7g Sörgel S. Ph.D. Thesis   Freie Universität Berlin; Germany: 2006. 
• 8a Jeffery T. Tetrahedron  1996,  52:  10113 
• 8b Jeffery T. J. Chem. Soc., Chem. Commun.  1984,  1287 
• 8c Jeffery T. Tetrahedron Lett.  1985,  26:  2667