Sugar Silanes in Carbohydrate Synthesis: Applications Towards Site-Selective Glycosylation.

Abstract

Despite numerous elegant advances in the formation of O-glycosides, many opportunities for improvement still remain. The site-selective incorporation of glycosides into complex polyfunctional molecules, as well as the need to synthesize the aglycone in a separate operation from glycoside formation still needs to be addressed. In an effort to overcome the current limitations in glycosylation chemistry a carbohydrate-bearing silane reducing agent has been developed to be used in synergy with catalysis for the site-selective glycosylation of complex molecules. A variety of ketones were found to be directly converted into 1,2-cis glycosides by their reduction with sugar silanes, followed by glycosylation. This represents the first known example of the glycosylation of a ketone without directly going through a hydroxylic intermediate. Additionally the site-selective glycosylation of hydroxyketones was demonstrated with sugar silanes using both a nickel- and copper-IMes catalyst system. Sugar silanes were also utilized in the development of a mild, user-friendly method for the dehydrogenative silylation of alcohols. A bench stable, electrophilic triarylborane catalyst was used for the synthesis of silyl-linked compounds for the synthesis of 1,2-cis glycosides. This produces hydrogen gas as the only byproduct, and was demonstrated to site-selectively glycosylate secondary and tertiary alcohols in the presence of a ketone. Insight was gained into the site-selective glycosylation of diols by silylation with sugar silanes or a combination of a sacrificial silane and a sugar silane. xvi This led to a better understanding of the advantages, and limitations, of sugar silanes. Unreactive glycosyl acceptors, such as the 4-hydroxyl group of glucose, did not undergo glycosylation in an appreciable yield using silicon-tethered intramolecular aglycone delivery. Aglycone synthesis was merged with glycoside incorporation when sugar silanes were employed as reducing agents in the nickel-catalyzed reductive coupling of aldehydes and alkynes, producing carbohydrates tethered to di- and trisubstituted allylic alcohols. Challenges encountered in the glycosylation of tethered allylic alcohols, due to the generation of sensitive intermediates, resulted in production of the desired allylic alcohol glycosides in low to moderate yield. However, despite these limitations, this method highlights the utility of sugar silanes in the development of novel methods for the synthesis of glycosides.