Addressing the Extremes of Reactivity in Small-Molecule-Catalyzed Stereoselective Glycosylation

Abstract

Glycosides play disparate yet essential roles in biology, and as such their study is of great importance to human health. To perform such studies, the stereocontrolled laboratory synthesis of glycosides remains a necessary endeavor. Despite this, the development of general methodology for stereoselective glycosylation is an unmet challenge in organic reaction development. This lack of generality can be attributed, among other reasons, to the incredible range of reactivities present across the various glycosyl donors of biological relevance, owing in turn to their diversity of structures. This is especially problematic for the stereoselective glycosylation of donors that sit at the extremes of reactivity, both high and low, where methodology for glycosylation with biomass sugars is typically not applicable. We aim to address these shortcomings through the development of general catalytic glycosylation protocols that are applicable across donor classes. In Chapter 1, we discuss the relationship between structure and reactivity in chemical glycosylation, highlighting key studies that probe this relationship. We will discuss the stereochemical implications of these structure-reactivity effects, with an emphasis on glycosylation with highly reactive 2-deoxyglycosyl donors and highly unreactive glucuronyl donors. We will then discuss current strategies for the stereoselective preparation of 2- deoxyglycosides and glucuronides, as well as the limitations of these strategies. Finally, we will summarize our research group’s development of bis-thiourea-catalyzed stereoselective glycosylation, including key findings, mechanistic studies, and limitations that studies documented in this dissertation aim to address. In Chapter 2, we document the development of bis-thiourea-catalyzed methods for βselective 2-deoxy- and 2,6-dideoxyglucosylations of natural products, carbohydrates, and amino acids. Disarming ester protecting groups were necessary to counter the high reactivity of 2- deoxyglycosyl electrophiles toward non-stereospecific SN1 pathways. Differing catalyst structures were found to be optimal for use of 2-deoxy- and 2,6-dideoxyglycosyl donors. Alcohol and phenol nucleophiles with both base- and acid-sensitive functionalities were compatible with the catalytic protocol, enabling access to a wide array of 2-deoxy-β-O-glucosides. In Chapter 3, we document the successful application of metal–salen catalysis towards β-glucuronidation of alcohols, phenols, and anilines via stereospecific opening of 1,2- anhydroglucuronate electrophiles. The optimized protocol is mild and pH-neutral, enabling β-glucuronidation of complex pharmaceuticals and natural products bearing acid-sensitive and Lewis-basic functionality. Kinetic studies are consistent with a transformation that is overall first order in catalyst, which contrasts previous metal–salen-catalyzed epoxide opening reactions where second-order rate dependence on catalyst is observed.