2,3-Dideoxy Sugars in Glycoconjugations and Cyclic Oligosaccharide Synthesis

Abstract

2,3- Dideoxy sugars are versatile synthons for organic synthesis. The applications are diverse in biological systems and organic synthesis. In the first part of the thesis, 2,3-unsaturated sugars are used for the glycoconjugation of amino acids, peptides and proteins. In the later part, 2,3-dideoxy sugar is used to synthesize carbohydrate macrocycle. Finally, sugar vinyl sulfoxide is used to synthesize substituted pyran via 2,6- anhydro sugar formation.

Chapter 1 of the thesis is divided into two parts. The first part describes the literature on unsaturated sugar, especially 2,3-unsaturated sugars, synthesis and their modifications. Attention is given to their addition reactions with nucleophiles and conjugation with biomolecules. A brief introduction to glycoconjugation is also reported in this part. Different glycoconjugation methods are discussed briefly, and the advantages are compared accordingly. The second part of this chapter elaborates on the synthesis of cyclic oligosaccharides. The approaches and the difficulties in the respective approaches are mentioned accordingly. Challenges with synthesising small cyclic oligosaccharides are cited according to the available literature. Current development in the field is also covered in the discussion.

Chapter 2 of the thesis deals with the glycoconjugation methods using sugar vinyl sulfoxide involving Michael addition reaction. Glycoconjugations of amino acids, peptides and protein, namely lysozyme are demonstrated in benign physiological conditions. The smaller glycoconjugated molecules are characterized with the help of NMR spectroscopy and mass spectrometry, while the larger glycoconjugated peptide and protein are characterized with the help of mass spectrometry. Biophysical studies of glycoconjugated lysozyme showed increased stability in the presence of trypsin while retaining its antimicrobial activity. Thus, a benign glycoconjugation method is developed.

Chapter 3 of the thesis unravels further potential of glycoconjugation using sugar vinyl sulfoxide. PETIM dendrimers of generation zero to three are glycoconjugated with sugar vinyl sulfoxide. The glycoconjugations of the lower generation dendrimers are confirmed using NMR spectroscopy and mass spectrometry; for higher generations, only NMR spectroscopy was employed for the characterization. The first-order reaction rate constant of the glycoconjugation reaction is also determined using NMR spectroscopy. Further biological evaluation of the native and glycoconjugated PETIM dendrimer reveals that PETIM dendrimers show selective antibacterial activity against M. smegmatis, and the native dendrimers show higher efficacy over the glycoconjugated dendrimer.

Chapter 4 of the thesis describes the synthesis of the cyclic disaccharide molecule composed of 2,3-dideoxy furanoside monomer units. The synthesis started from protected glucal molecules and followed a few simple reaction steps, including the Ferrier reaction, desulfurization reaction, and selective hydroxy group protection and finally, glycoconjugation reaction. While the formation of the disaccharide is confirmed using NMR spectroscopy and mass spectrometry, the conformation of the constituting monomeric unit of the cyclic disaccharide is ascertained through solid state structure determination using the single crystal X-ray diffraction method. The ring contraction of the pyranoside monomer to furanoside cyclic disaccharide is explained by two plausible mechanisms involved in the glycosylation step. Further encapsulation property of the cyclic disaccharide molecule was evaluated against the 1-aminoadamantane using the ITC method. This experiment allows looking into the thermodynamics of the encapsulation and the encapsulation mode of the molecule.

Chapter 5 of the thesis shows sugar vinyl sulfoxide's application and potential as a synthetic intermediate. Intra-molecular Michael addition reaction of the sugar vinyl sulfoxide in basic condition affords elusive 2,6-anhydro sugar molecules in a single step. Selective opening of the bicyclic ring of the anhydro sugar converts it to a substituted pyran. The applicability of this two-step, one-pot reaction is also tested on sugar vinyl sulfoxide derived from galactal.

The thesis describes the achievement of the diversification of 2,3-unsaturated sugar. A benign glycoconjugation method is developed and adequately characterized. The synthetic potential of 2,3-dideoxy sugar is demonstrated through the synthesis of cyclic disaccharide via a ring contraction of pyranoside to a furanoside. And finally, a two-step reaction protocol converts pyranoside sugar into a substituted pyran.