CARBENES AND NITRENES MEDIATED STEREOCONTROLLED GLYCOSYLATIONS

Abstract

Carbenes and nitrenes represent a unique class of highly reactive organicintermediates. These isoelectronic, neutral species have been known since the nineteenth century and have become powerful tools in modern synthetic chemistry. In recent decades, both intermediates have enabled a wide range of transformations, including C–H functionalization, single-atom C/N transfer, heteroatom insertion, rearrangements, and cycloaddition reactions. However, their application in carbohydrate chemistry remains largely unexplored. Glycosylation, the chemical process that links carbohydrate units to construct oligosaccharides and glycoconjugates, is essential for accessing biologically relevant molecules. Despite their significance, the stereoselective construction of glycosidic linkages remains challenging due to the structural complexity of carbohydrate building blocks. This work investigates the strategic use of carbene and nitrene intermediates to develop new catalytic glycosylation approaches for the precise synthesis of complex glycosylated molecules. In Chapter 2, two new classes of glycosyl donors were developed for stereocontrolled glycosylation: (1) enynal-based donors (first-generation) and (2) diazothioglycoside donors (second-generation). Both donors generate copper carbenes under catalytic conditions using earth-abundant copper catalysts. These donors are readily synthesized from commercially available starting materials and exhibit excellent bench stability. The developed systems enable efficient formation of both 1,2-cis and 1,2-trans glycosides with a broad range of glycosyl acceptors and allow iterative synthesis of trisaccharides. Mechanistic investigations highlight the critical role of the enynal linker and thioglycoside moiety in enabling effective donor activation. Together, these studies establish two complementary carbene-based glycosyl donor platforms operating under catalytic conditions. In pursuit of a more sustainable activation approach for stereocontrolled glycosylation, Chapter 3 introduces an MDMPA-based glycosyl donor that can be activated either by Fe(OTf)₃ catalysis or by photosensitizer-free visible-light irradiation. These donors are compatible with a wide range of protecting group patterns, including disarmed, armed, and superarmed systems. The use of earth-abundant iron catalysis and visible-light activation provides mild, sustainable, and scalable conditions for glycosylation. Mechanistic studies reveal that donor activation is independent of anomeric purity. The method demonstrates broad applicability across numerous glycosyl donors, including glucose, mannose, galactose, rhamnose, xylose, 2-deoxyaminoglucose, lactose, ribose, and arabinose, and diverse nucleophiles such as primary, secondary, and tertiary alcohols, phenols, carboxylic acids, glycosyl thiols, and amino acids. Importantly, the method enables the synthesis of complex hexasaccharides, glycosylated drug derivatives, and one-pot trisaccharide assemblies. Following the development of these donor systems, the work further explores mild activation approaches for readily accessible, widely used, bench-stable conventional thioglycosides in chapters 4 and 5. Iron-carbene-mediated activation was first employed to access challenging 1,2-cis furanosides. In this system, iron coordinates with a nucleophile chelated at the C2-O position, delivering the nucleophile selectively from the cis face. This strategy was effective for ribose and arabinose substrates and tolerated primary, secondary, and tertiary alcohol nucleophiles, enabling the synthesis of a challenging 1,2-cis ribotetrasaccharide. Building on this intermolecular iron-carbene strategy, photochemically generated sulfenylnitrenes were subsequently introduced as a mild activation platform for thioglycosides. Unlike traditional activation methods, which often lead to anomeric epimerization in furanosides, the sulfenylnitrene approach proceeds under neutral and mild conditions that prevent epimerization. In addition, a C5 steric and electronic control model was developed to achieve 1,2-cis selectivity. This concept proved general across sulfenylnitrene-mediated, iron-carbene-mediated, and related activation strategies. The approach enabled the synthesis of challenging α- deoxyribosides and 1,2-cis xylosides and demonstrated compatibility with diverse nucleophiles, including carboxylic acids, silylated olefins, amino acids, and complex bioactive molecules such as dehydrocholic acid and ciprofibrate. The methodology was further applied to the synthesis of a challenging 1,2-cis ribopentasaccharide. Notably, sulfenylnitrenes selectively react with glycosyl anomeric thioethers while remaining inert toward non-glycosylated thioethers. Overall, this dissertation establishes carbenes- and nitrenes-mediated activation as powerful platforms for glycosylation chemistry, providing sustainable catalytic strategies for the stereoselective synthesis of complex glycosides and glycoconjugates.