Chiral Phosphoric Acid Catalyzed Regioselective Functionalization of Carbohydrates

Abstract

Polyols, such as carbohydrates and other compounds containing multiple hydroxyl groups, represent an important class of molecules. The selective transformations of polyol-containing compounds are of great importance as relatively easily accessible polyol building blocks can be transformed into more synthetic useful compounds. Accomplishing selective transformations of polyols is challenging due to intrinsic complexity of these molecules and unpredictable inherent selectivity of primary and secondary alcohols in the structure. These challenges can be addressed by employing asymmetric catalysis. This dissertation describes the use of chiral phosphoric acids (CPAs) to address the challenges associated with polyol functionalization in carbohydrate system. The described in this dissertation methods, hence, streamline the selective modification of carbohydrates and the carbohydrate synthesis. In addition to the selective functionalization of carbohydrates, this thesis describes the development and use of asymmetric catalysis to address other existing synthetic challenges such as biomimetic Michael reactions. Chapter 1 describes the development of a new single-pot copper(II)-catalyzed decarboxylative Michael reaction between β-ketoacids and enones, followed by in situ aldol condensation. This reaction results in highly functionalized chiral and achiral cyclohexenones containing all carbon quaternary stereocenter. Chapter 2 provides an overview of regioselective functionalization of polyols by chiral Brønsted acids and other catalysts. The utility of these transformations as well as the discussion of the various catalyst-controlled regioselective reactions of polyols including acylation, silylation, acetalization and glycosylation reactions is provided. Chapter 3 describes CPA-catalyzed desymmetrizative glycosylation of a functionalized meso-diol derived from 2-deoxystreptamine. The chirality of CPA dictates the outcome of the glycosylation reactions, and the use of enantiomeric CPAs results in either C4-glycosylated or C6-glycosylated 2-deoxystreptamines. These glycosylated products can be converted to aminoglycosides, and the application of this strategy to the synthesis of protected iso-neamine and iso-kanamycin B with inverted connection at the C4 and C6 positions is described. Chapter 4 summarizes CPA-catalyzed regioselective and stereoselective glycosylation reactions in carbohydrate‐derived 2,3‐diols. These studies describe evaluation and optimization of CPA-catalyzed glycosylation reactions that helped to identify the most promising catalysts in terms of their ability to control regio- and stereoselectivity. In addition to the structure of the CPA-based catalysts, other factors that can affect stereoselectivity and regioselectivity of glycosylation were investigated. These studies included evaluating the effect of the stereochemistry of the anomeric position of the donor, type and chirality of the sugar donors as well as acidity in the reaction mixture. Chapter 5 illustrates the development of a regioselective single-pot functionalization of monosaccharides. A single-pot regioselective functionalization of the C2- and C3- hydroxyl groups in monosaccharides (e.g. D-glucose, D-galactose, and D-mannose) was accomplished using CPA-catalyzed regioselective acetalization as the initial step to differentiate the diol moieties in monosaccharides. From this, a single-pot regioselective protection and regioselective glycosylation of monosaccharide were developed with a wide range of protecting groups and sugars.