Abstract
Chapter 1: This chapter describes an iron-catalyzed glycal aminoglycosylation that provides a general solution to the difficult formation of 1,2-cis-2-aminoglycosidic linkages. By shifting stereochemical control from substrate effects to catalyst control through cooperative atom transfer catalysis, an Fe–Pybox catalyst and tuned acyloxylamine-based amination reagents enable catalyst-directed delivery of alcohol acceptors to glycals with exclusive 1,2-cis- selectivity. The method exhibits broad scope across electronically diverse glycals and primary/secondary carbohydrate acceptors, as well as non-carbohydrate alcohols and diols, and it supports reiterative glycosylation via donor/acceptor electronic differentiation to enable modular oligosaccharide assembly. Mechanistic studies (radical trapping, counteranion and ligand-exchange effects, byproduct analysis, and initial-rate kinetics) support a pathway involving radical amination, oxidation to an oxocarbenium intermediate, and catalyst-controlled nucleophile transfer. Process-safety evaluation (DSC, ARC, impact testing) establishes a substantial safety margin for key reagents and validates the operational robustness of the catalytic system.Chapter 2: This chapter establishes practical and scalable deprotection and derivatization strategies for Tn antigens and mucin-type O-glycan core structures prepared via iron-catalyzed stereoselective glycosylation. Multigram Tn derivatives were efficiently converted to either fully deprotected glycans or N-Fmoc-protected building blocks through streamlined sequences while preserving glycosidic integrity and amino acid stereochemistry. For more complex core structures 1–3, tailored protocols enabled selective nitrogen protecting group manipulation and consolidated global deprotection steps. These studies provide robust post-glycosylation workflows that translate catalytic glycosylation products into solid-phase peptide synthesis (SPPS)-compatible mucin-type O-glycan building blocks.
Chapter 3: This chapter describes a chemoenzymatic strategy for assembling homogeneous heparan sulfate (HS) oligosaccharides by combining enzymatic transformations with two complementary iron-catalyzed glycosylations developed by our group. Glucuronal acceptors were prepared efficiently via lipase-enabled site-selective deacetylation/reacetylation, enabling multigram iron-catalyzed 1,2-cis glycal aminoglycosylation to deliver GlcN–(1→4)GlcA disaccharide modules with complete stereocontrol. Access to the GlcN–(1→4)IdoA motif was achieved through a practical epimerization route after direct glycosylation proved prone to intramolecular cyclization. These disaccharide modules were then coupled into tetrasaccharide, hexasaccharide, and octasaccharide HS backbones using a hemin-derived iron(III) porphyrin catalyst as single diastereomers. Late-stage deprotection and installation of an anthracene tag enabled streamlined purification and subsequent chemical N-sulfation followed by sulfotransferase-controlled, site-selective O-sulfation to furnish an anticoagulant HS hexasaccharide with anti–factor Xa potency comparable to fondaparinux and rapid clearance in mice. In addition, a fully protected HS octasaccharide was efficiently deprotected and derivatized to provide a homogeneous, unsulfated octasaccharide HS precursor, demonstrating the robustness of the platform for accessing higher-order, structurally defined HS fragments.