I. Stereoselective N-glycosylation by Staudinger ligation. II. Activation of the N-acylsulfonamide linker using lead-catalyzed allylation

N-Glycosylation is an important posttranslational modification of proteins. N-Glycoproteins and glycopeptides obtained from physiological sources are typically heterogeneous, thereby complicating the analysis of their biological roles. Chemical synthesis can provide access to homogeneous samples of these compounds. Current approaches for the synthesis of glycosyl amides have poor stereoselectivity and limited substrate compatibility.;We developed a version of the two-component Staudinger ligation reaction in which a phosphinothioester reacts with a glycosyl azide to form a beta-glycosyl amide bond stereoselectively. Three different phosphinothioesters with different electronic and steric properties were synthesized utilizing borane-protected phosphines. A general compatibility with various glycosyl azides with different reactivities was observed. More importantly, the desired beta-glycosyl amides were formed stereoselectively. The major byproduct of the Staudinger ligation reaction was isolated and characterized. A mechanism for its formation was proposed that should facilitate further reaction optimization.;In the second part of the thesis, the activation of the N-acylsulfonamide linker using Pd-catalyzed allylation is presented. The use of a solid-support synthesis has had a dramatic impact on organic synthesis. One of the key components of SPOS is the linker, which serves as the anchor between the product and the solid-support. The N-acylsulfonamide linker is a "safety-catch" linker that requires an activation via an alkylation before its cleavage. The original activation conditions either produced of the linker via methylation resulted in low reactivity. The linker is more reactive when activated via cyanomethylation. However, the cyanomethylation conditions are not compatible with base-sensitive substrates. We reported a neutral activation condition for the N-acylsulfonamide linker using a palladium-catalyzed allylation. The allylated N-acylsulfonamides generate desired peptides with good yields in high purities. We have also shown that this activation method can be used to effectively produce thioesters in good yields under mild conditions. The conditions for generating peptide thioesters are valuable---they should facilitate the synthesis of essential precursors for protein assembly. The neutral activation conditions developed should broaden the substrate compatibility of this versatile linker.