Progress on synthesis of high mannose glycan mimetics using the Staudinger ligation
The purpose of this thesis is to synthesize high mannose glycan mimetics on the solid oligoproline scaffold using the Staudinger ligation for the development of antimicrobial agent. Mannose is believed to have a strong adhesive property on the cell surface, and microbes exploit this property to bind to host cells. Synthesis of high mannose glycan mimetics on the peptide scaffold is critical to present those highly functionalized mannoses, and proline was adapted in this research for having a rigid alpha-helical structure. In this research, we decided to focus on a Staudinger ligation approach to directly append the highly functionalized mannose with a carboxyl group and the oligoproline scaffold with an azido group. Despite the successful amidation linkage between a functionalized alpha-linked mannose residue and oligoproline scaffold, we faced a serious challenge purifying the product and yielding in a high quantity. Thus, we investigated the Staudinger ligation using model compounds, non-carbohydrate and carbohydrate based compounds, that contain the carboxyl linker. We successfully appended the model compounds with the oligoproline scaffold, and we observed that non-carbohydrate compounds generated significantly greater amount of target compounds than carbohydrate compounds. We also observed that appending two carboxylic linkers simultaneously at two different sites on the scaffold would yield significantly less amount of target compounds than that of one site. We successfully optimized the yield of the sugar compounds by repeating the Staudinger ligation for the second time. An attempt was made to append a functionalized mannose and oligoproline scaffold with an alternative synthetic route that involves both click reaction and Staudinger ligation. We successfully linked the functionalized mannose and the oligoproline scaffold with one binding site.