Mechanistic Studies on Phosphoric Acid Catalyzed Acetalizations and Development of Acetal-Containing Ligands for Transition Metal Catalysis

Abstract

The field of organic chemistry has evolved exponentially over the last decades. The development of catalysis has played an enormous role in this by allowing access to previously unthinkable targets, controlling the selectivity of challenging reactions, and improving on reaction greenness and efficiency. We often look up to Nature for inspiration on efficient and selective catalysis, but while Nature has found means to regio- and stereoselectively install acetals in complex molecules, finding nonbiological catalyst-controlled alternatives has been challenging. Given that acetals play a fundamental role in numerous natural and man-made products, such as key biological functions in glycosides, new stereoselective reactions to access these is highly desirable. Described herein is the development and mechanistic elucidation of phosphoric acid catalyzed regio- and stereoselective methods for the installation of spiroketals and glycosidic linkages. Inspired by our results on spiroketalizations strategies, we also designed and synthesized novel C2-symmetric spiroketal-containing ligands for asymmetric transition metal catalysis. Finally, based on mechanistic insights into the phosphoric acid-catalyzed glycosylation, we were able to develop a practical solid-phase glycosylation methodology using solid-supported sugar phosphonates. Chapter 1 is an introduction to transition state theory and an overview of experimental and computational ways to assess the reaction mechanism. Then, an introduction to organocatalysis is given. This chapter serves to lay a foundation for the mechanistic studies described in the context of organocatalysis for Chapters 3, 5, and 7. Chapter 2 details our efforts in the development of a practical interconversion of BINOL and H8-BINOL through a single-step Red/Ox manipulation. This chapter also gives an introduction to BIINOL-derived chiral phosphoric acids, which were crucial in the works described later in chapters. Chapter 3 describes our efforts towards the development of a powerful stereoselective spiroketalization method catalyzed by chiral phosphoric acids. This chapter also describes our work towards the mechanistic elucidation of this reaction using experimental techniques, state-of-the-art quantum chemical reaction path finding tools, and molecular dynamics simulations. Chapter 4 builds on our acquired knowledge of spiroketal reactivity in Chapter 3 to describe the development of novel acetal-containing C2-symmetric ligands for asymmetric transition metal catalysis. Our invention proved to be a very powerful tool in asymmetric catalysis, providing excellent enantiocontrol in a variety of unrelated transition metal-catalyzed reactions. Chapter 5 describes the application of chiral phosphoric acids to control the regio- and stereoselectivity of intermolecular glycosylations and acetalizations of polyols. The mechanism of these reactions was investigated in depth using spectroscopic and computational techniques. Chapter 6 encloses research on the development of a novel solid-phase glycosylation method that is based on the mechanistic conclusions drawn out in Chapter 5. The synthesis and characterization of a polystyrene-based resin functionalized with phosphonic acid moieties is described, as well as its application in the formation of solid-supported sugar phosphonates and their subsequent glycosylation with secondary alcohols. Chapter 7 discloses the application of phosphoric acids as catalysts for the regioselective opening of epoxides. Computational work on the mechanistic elucidation of this reaction is described.