APPLICATION OF NITRILE OXIDE CYCLOADDITION ?CLICK-CHEMISTRY? IN GLYCOCONJUGATE SYNTHESIS. SCOPE AND LIMITATIONS

RODRÍGUEZ OSCAR M.; BRAVO RODOLFO D.; COLINAS, PEDRO ALFONSO

Sorrento

Simposio; 16th European Carbohydrate Symposium; 2011

The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction of Cu(I) catalysis, leading to a major improvement in both rate and regioselectivity of the reaction. The great success of the Cu(I) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging.1 Despite the successes of these reactions a number of concerns persist. Apprehension exists over the handling of potentially toxic and explosive organic azides and whilst in situ dipole generation begins to address this problem, the requirement for a Cu(I) catalyst brings its own technical difficulties. In the search for new strategies for the covalent assembly of the different components of such multivalent structures, we2 and others3 have recently introduced the 1,3-dipolar cycloadditions of alkene and alkyne carbohydrate with nitrile oxides as an efficient, metal-free tool that allows the preparation of a variety of carbohydrate derivatives. The aim of the present work is to examine the scope and limitations of nitrile oxide cycloadditions to alkene and alkyne O- and C-glycosides. Nitrile oxides were obtained from aldoximes in an one-step operation using sodium hypochlorite (in the presence of triethylamine) in a biphasic system, or employing chloramine-T as halogenating reagent and base. This methodology allowed us to obtain the new glycoconjugates in 78-86 % yields and with excellent regioselectivity. As expected, alkene carbohydrates led mostly to very low diastereoselectivity. 4 The influence of oxime substituent on the cycloadditions will also be discussed.in vivo tagging.1 Despite the successes of these reactions a number of concerns persist. Apprehension exists over the handling of potentially toxic and explosive organic azides and whilst in situ dipole generation begins to address this problem, the requirement for a Cu(I) catalyst brings its own technical difficulties. In the search for new strategies for the covalent assembly of the different components of such multivalent structures, we2 and others3 have recently introduced the 1,3-dipolar cycloadditions of alkene and alkyne carbohydrate with nitrile oxides as an efficient, metal-free tool that allows the preparation of a variety of carbohydrate derivatives. The aim of the present work is to examine the scope and limitations of nitrile oxide cycloadditions to alkene and alkyne O- and C-glycosides. Nitrile oxides were obtained from aldoximes in an one-step operation using sodium hypochlorite (in the presence of triethylamine) in a biphasic system, or employing chloramine-T as halogenating reagent and base. This methodology allowed us to obtain the new glycoconjugates in 78-86 % yields and with excellent regioselectivity. As expected, alkene carbohydrates led mostly to very low diastereoselectivity. 4 The influence of oxime substituent on the cycloadditions will also be discussed. References 1. D. Simone, S. A. Nepogodieva, R. A. Field, Org. Biomol. Chem., 2007, 5, 1006?1017. 2. P. A Colinas, V. Jager, A. Lieberknecht, R. D. Bravo, Tetrahedron Lett., 2003, 44, 1071?1074. 3. F. Pérez-Balderas, F. Hernández-Mateo, F. Santoyo-González, Tetrahedron, 2005, 61, 9338?9348. 4. V. Jäger, P. A. Colinas, Nitrile Oxides en Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, Padwa A.; Pearson, W. H., eds.,Hoboken, New Yersey, USA. Wiley, 2003.Org. Biomol. Chem., 2007, 5, 1006?1017. 2. P. A Colinas, V. Jager, A. Lieberknecht, R. D. Bravo, Tetrahedron Lett., 2003, 44, 1071?1074. 3. F. Pérez-Balderas, F. Hernández-Mateo, F. Santoyo-González, Tetrahedron, 2005, 61, 9338?9348. 4. V. Jäger, P. A. Colinas, Nitrile Oxides en Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, Padwa A.; Pearson, W. H., eds.,Hoboken, New Yersey, USA. Wiley, 2003.Tetrahedron Lett., 2003, 44, 1071?1074. 3. F. Pérez-Balderas, F. Hernández-Mateo, F. Santoyo-González, Tetrahedron, 2005, 61, 9338?9348. 4. V. Jäger, P. A. Colinas, Nitrile Oxides en Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, Padwa A.; Pearson, W. H., eds.,Hoboken, New Yersey, USA. Wiley, 2003.Tetrahedron, 2005, 61, 9338?9348. 4. V. Jäger, P. A. Colinas, Nitrile Oxides en Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, Padwa A.; Pearson, W. H., eds.,Hoboken, New Yersey, USA. Wiley, 2003. 1. D. Simone, S. A. Nepogodieva, R. A. Field, Org. Biomol. Chem., 2007, 5, 1006?1017. 2. P. A Colinas, V. Jager, A. Lieberknecht, R. D. Bravo, Tetrahedron Lett., 2003, 44, 1071?1074. 3. F. Pérez-Balderas, F. Hernández-Mateo, F. Santoyo-González, Tetrahedron, 2005, 61, 9338?9348. 4. V. Jäger, P. A. Colinas, Nitrile Oxides en Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, Padwa A.; Pearson, W. H., eds.,Hoboken, New Yersey, USA. Wiley, 2003.Org. Biomol. Chem., 2007, 5, 1006?1017. 2. P. A Colinas, V. Jager, A. Lieberknecht, R. D. Bravo, Tetrahedron Lett., 2003, 44, 1071?1074. 3. F. Pérez-Balderas, F. Hernández-Mateo, F. Santoyo-González, Tetrahedron, 2005, 61, 9338?9348. 4. V. Jäger, P. A. Colinas, Nitrile Oxides en Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, Padwa A.; Pearson, W. H., eds.,Hoboken, New Yersey, USA. Wiley, 2003.Tetrahedron Lett., 2003, 44, 1071?1074. 3. F. Pérez-Balderas, F. Hernández-Mateo, F. Santoyo-González, Tetrahedron, 2005, 61, 9338?9348. 4. V. Jäger, P. A. Colinas, Nitrile Oxides en Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, Padwa A.; Pearson, W. H., eds.,Hoboken, New Yersey, USA. Wiley, 2003.Tetrahedron, 2005, 61, 9338?9348. 4. V. Jäger, P. A. Colinas, Nitrile Oxides en Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, Padwa A.; Pearson, W. H., eds.,Hoboken, New Yersey, USA. Wiley, 2003.