Diastereoselective and Enantioselective Catalysis for Sustainable Synthesis of Carbohydrates and Heterocycles

Abstract

The development of new catalytic methods has undoubtedly played a crucial role in the recent rapid growth of chemical industries, especially in the pharmaceutical research and process development. Novel chiral catalytic methods have drastically improved the access to complex chiral organic molecules such as oxygen- and nitrogen-based heterocyclic compounds. These compounds have a long history of being essential building blocks for medicinal chemistry and numerous therapeutic agents contain chiral heterocyclic motifs including carbohydrates. This dissertation is focused on the development and mechanistic studies of regioselective modifications of trans-2,3-equatorial diols in carbohydrate molecules under immobilized CPA catalysis. Chiral Phosphoric Acids (CPAs) represent a particularly prospective subclass of chiral catalysts due to their versatility in catalyzing a broad spectrum of organic reactions. Combining stereoselective catalysis with immobilized CPAs and continuous flow methods we managed to improve the sustainability and achieve streamlined generation of chiral nitrogen-containing heterocycles with efficient catalyst recycling. Finally, based on theoretical mechanistic studies we explored the reactivity of fused previously pure studied aziridinoquinoxalines as useful precursors for the generation of aromatic aziridine ylides under photochemical energy transfer catalysis. Chapter 1 introduces various “green”-chemistry methods such as flow chemistry and photochemical catalysis used in this dissertation for developing sustainable catalytic protocols. In addition, this chapter describes the principles of CPA catalysis and recent progress toward the synthesis and application of immobilized CPA catalysts. Chapter 2 describes the application of (R)-BINOL- and (S)-SPINOL-based CPA catalysts incorporated into a polymer matrix for regioselective acetalization of monosaccharides with enol ethers. The QM/MM model based on the CHARMM force field and DFT method is developed for reaction potential energy surface exploration to investigate potential mechanisms of CPA-catalyzed regioselective acetalization. In combination with the experimental NMR studies two possible temperature-dependent mechanisms controlling regioselectivity of the acetalization were postulated. Chapter 3 details our efforts to improve the sustainability of the CPA-catalyzed transfer hydrogenation of aromatic heterocycles with Hantzsch esters. We designed the continuous flow system with immobilized CPA placed in the packed-bed reactor for performing enantioselective reduction of quinolines and 1,4-benzoxazines. The developed protocol allows large-scale and effective transfer hydrogenation with easily recyclable catalysts as well as improve enantioselectivity of the process. Chapter 4 provides an overview of the aziridinoquinoxalines properties and their application for ylide generation via the ring-opening reaction of the aziridine cycle. Theoretical investigations using DFT and TD-DFT methods assisted in the development of a photochemical energy transfer catalytic system to perform in-situ azomethine ylides synthesis. As a result, we demonstrated that cooperative Ir(III)/Cu(I) dual catalysis can be effectively used for generation and trapping generated ylides via asymmetric alkynylation reaction. Appendix A describes the initial development of enantioselective transfer hydrogenation with Hantzsch esters under CPA catalysis to achieve parallel kinetic resolution of aziridinoquinoxalines.