Abstract
Carbohydrates play fundamental roles in cell–cell recognition, immune signaling, and host–pathogen interactions, and the stereoselective chemical synthesis of oligosaccharides and glycoconjugates remains a central challenge in the field. A particularly important problem is the reliable, catalytic construction of glycosidic bonds with precise control of anomeric stereochemistry. This dissertation presents mechanistic studies and synthetic applications of iron-catalyzed stereoselective glycosylation methods.Chapter 1 describes a detailed mechanistic investigation and a synthetic application of the iron(III) porphyrin triflate-catalyzed 1,2-trans-selective glycosylation via stereospecific glycal epoxide ring-opening. Kinetic studies revealed a mechanistic divergence depending on the nature of the glycosyl acceptor: secondary acceptors react via a classical third-order SN2-type mechanism, while primary acceptors coordinate directly to the iron(III) porphyrin catalyst, rendering the reaction zero-order in acceptor concentration. Competition experiments confirmed that iron coordination, rather than a direct SN1 pathway, accounts for this distinctive behavior. This methodology was applied in a convergent, fully stereospecific synthesis of the proteoglycan tetrasaccharide linker, in which every glycosidic bond was assembled by this iron-catalyzed glycosylation method with high diastereoselectivity.
Chapter 2 reports the discovery and development of an iron(II)-catalyzed glycal 1,2-cis-aminoacyloxylation for the synthesis of 2-amino saccharides. This method employs a bifunctional acyloxy carbamate amination reagent to install both the C2-amino group and the anomeric ester in exclusively cis-selectivity, affording 1,2-cis-2-amino glycosyl esters as single diastereomers (dr > 20:1). The method tolerates a wide range of glycal donors bearing electron-rich and electron-withdrawing protecting groups, including disaccharide glycals, with excellent functional-group compatibility.
Chapter 3 describes the multigram-scale synthesis of Tn antigens (GalNAc-α-O-Ser/Thr) via an improved iron-catalyzed 1,2-cis-aminoglycosylation protocol, and the stereoselective assembly of seven mucin-type O-glycan core structures (cores 1–7). A new iron(III) porphyrin triflate-catalyzed 1,2-trans-aminoglycosylation via glycosyl imidates was developed to synthesize cores 3 and 4. By merging this method with the previously developed iron(II)-catalyzed 1,2-cis-aminoglycosylation and iron(III)-catalyzed glycal epoxide glycosylation, a unified, fully stereoselective strategy was established in which every glycosidic linkage across the seven core structures was constructed using one of the three iron-catalyzed methods.