Development of the Regenerative Glycosylation Approach for Manual and Automated Oligosaccharide Synthesis

It has been recognized that carbohydrates are involved in all phases of life beginning with the embryonic development and cell growth. However, it is the involvement of carbohydrates in the progression of various deadly diseases that gave these natural compounds significant roles in diagnostics and as pharmaceuticals. Although carbohydrates are highly desirable to the biological and medical communities, these molecules are still very challenging targets for chemists. Functionalization, derivatization, controlling anomeric stereoselectivity, purification, and characterization are all existing experimental hurdles towards producing synthetic carbohydrates in large quantities and high purity. Advances in chemistry and biochemistry have certainly facilitated the synthesis and purification of carbohydrates. However, the development of practical and general methods for chemical glycosylation and expeditious oligosaccharide synthesis remain an important and challenging area of research. This topic has also become the basis for this doctoral dissertation wherein the focus was primarily placed on the development of new leaving groups for chemical glycosylation and designing novel methods and technologies for efficient oligosaccharide synthesis. One outcome of this study is the development of two new classes of building blocks for chemical glycosylation, O-benzoxazolyl (OBox) and 3,3-difluoro-3H-indol-2-yl (OFox) imidates. Based on our observation that the OFox leaving group has the same structure before its introduction and after its departure, 3,3-difluoroxindole (HOFox) aglycone, we developed a new regenerative concept for chemical glycosylation. This method allows for performing glycosylation reactions in a conceptually novel way using catalytic amounts of reagents and activators. Further application of the regenerative concept to the HPLC-assisted synthesis on polymer support, an automated technology being developed in our laboratory, was complementary for refining all chemical aspects of both methods.