Convergent N-linked glycopeptide synthesis and post-synthetically tunable glycosylations using sulfonamides

The development of new methods for the synthesis of oligosaccharides and oligosaccharide containing molecules is a major challenge for organic chemistry and biology. In this thesis, the unique reactivity of sulfonamides is investigated to determine their utility for the construction of saccharides and glycopeptides.; N-Linked glycoproteins are a vital component for many life processes, however the exact function for each glycosylation site is not known. Therefore the ability to chemically synthesize protein variants to probe these processes is needed. The convergent synthesis of N -linked glycopeptides through the reaction of a glycosyl amine with an acylsulfonamide-containing asparagine was investigated. Due to a combination of the poor nucleophilicity, steric congestion and hydrolytic instability of glycosylamines, the synthesis was not feasible. However, through the use of a variant of the newly described Staudinger Ligation, the construction of N-linked glycosyl-amino acids is possible in high yield.; The reactivity of acylsulfonamides can be tuned by selective alkylation with a variety of alkylating agents. It was hypothesized that the reactivity of glycosyl sulfonylcarbamate donors could be tuned. We tested this hypothesis and found that these serve as effective glycosylating agents. Unalkylated donors can form glycosyl bonds with a wide variety of alcohols in high yield and with excellent stereoselectivity. In addition, alkylated donors allow for the construction of glycosyl bonds to weak nucleophiles, such as phenols, in high yield and with high stereoselectivity. Conditions for selective promotion of glycosylation reactions of alkylated donors in the presence of unalkylated donors was observed. This orthogonality was pursued with the intention of developing a one-pot trisaccharide synthesis.; From a serendipitous result, a new method for the deprotection of para-methoxybenzyl (PMB) groups was developed. An attempted condensation of a PMB-protected glycosyl sulfonylcarbamate with a saccharide acceptor led to the unexpected formation of a PMB-functionalized sulfonamide. This side reaction was investigated and determined that the transfer of a PMB group to a sulfonamide under catalytic triflic acid conditions can be used to deprotect a wide variety of PMB ethers. In addition, a chromatography free method for the deprotection of PMB ethers can also be accomplished through the use of a resin-bound sulfonamide.