Studies of Pyridoneimine in Site-Selective Functionalization of Carbohydrates and in Multivalent Phenomenon

Abstract

Carbohydrates are functionally rich biomolecules with multiple hydroxy functionalities. As a result, the most often practiced chemical route is to install protecting groups that permit selective functionalization at the desired hydroxy functionality, including the anomeric lactol moiety in the chemical modifications of carbohydrates and in oligosaccharide synthesis. In this direction, an effort was undertaken for direct anomeric functionalization of unprotected carbohydrates in aq. solutions from unprotected mono- and oligosaccharides. A new base, namely pyridoneimine is developed for this purpose. Pyridoneimine is used as a suitable for deprotonation of the hemiacetal hydroxyl group selectively and subsequent reaction of the corresponding hemiacetal anion with allyl, benzyl, propargyl bromides and acid anhydrides afforded the corresponding anomeric mono-O-alkylated and acylated products. Several mono- and disaccharides are employed for anomeric alkylation and acylation reaction in aqueous solutions, fulfilling the solubilities of unprotected sugars in water, in a complete site-selective manner without the requirement of protecting groups. The method was further extended for the pyridoneimine-catalyzed oxa-Michael addition of protecting groups-free, native mono- and disaccharides with Michael acceptor namely, methylvinyl ketone in aq. solution. The anomeric oxa-Michael addition-derived -ketoglycosides are resourceful for further glycoconjugations with amino acids, through reductive amination. Furthermore, site-selective mono-O-acylations of partially protected glycopyranoside diol and triol derivatives are achieved using various acid anhydrides mediated by the multivalent DMAP catalyst. The trivalent-DMAP catalyst mediates the reaction with excellent site-selectivities in mono-O-acylation product formation in the studied glycopyranosides, in comparison to monovalent N,N-dimethylamino pyridine (DMAP) catalyst. Finally, an effort was undertaken to assess the multivalent effects on pyridoneimine resonance structures. For this purpose, poly(ether imine) (PETIM) dendrimers of 1 – 3 generations were utilized to covalently functionalize the pyridoneimine at the peripheries. Variable temperature 1H NMR, 15N NMR and solvatochromism studies are conducted across the dendritic generations to assess the resonance structures further. The data illustrates the benefit of clustering effects at the peripheries of dendrimers and the contributing resonance forms between non-aromatic pyridoneimine and zwitter ionic aromatic imidopyridinium species. Overall, the results presented in the thesis are (i) development of pyridoneimine as suitable base for site-selective deprotonation of anomeric lactol to facile formation of the corresponding anomer-functionalized derivatives in aq. solutions and further glycoconjugations; (ii) catalytic site-selective acylation of minimally protected glycopyranoside diol and triol derivative, employing a new trivalent-DMAP catalyst; (iii) dendritic clustering of pyridoneimines enables assessing the contributions of resonance structures between charge neutral, non-aromatic pyridoimine and zwitter ionic, aromatic imidopyridinium structures.