Development of Chiral Phosphoric Acids Catalyzed Site-selective Transformations and Synthesis and Applications of Immobilized CPAs towards Single-pot Functionalization of Monosaccharides

Abstract

Site-selective transformations are of great importance in natural products synthesis and modification of pharmaceutical compounds. Although traditionally site-selectivity has been accomplished by exploring the enharent substrate reactivity with achiral reagents or catalysts or by relying on enzymatic reactions, a variety of recent examples suggest that chiral catalysts may provide effective means for achieving alternative modes of selectivity. Chiral phosphoric acids (CPAs) represent a particularly promissing subclass of chiral catalysts, and these catalysts have demonstrated significant potential in controlling regioselectivity of various natural products. This dissertation focuses on exploring the potential of CPAs to accomplish regioselective intramolecular epoxide ring openings, single-pot functionalization of monosaccharides via CPA-catalyzed regioselective acetalization of trans-1,2-diols, and synthesis and applications of immobilized CPAs to achieve reusing and recycling of catalysts in the single-pot functionalization of monosaccharides. Chapter 1 provides an introduction to CPA catalysis and an overview of recent studies on chiral catalysts to achieve site-selective functionalization of polyol-based natural products. In addition, this chapter overviews the current state-of-the-art in using CPAs as the catalysts for the stereoselective and site-selective functionalization of natural products and other complex chiral molecules. Chapter 2 describes the development of CPA-controlled regiodivergent cycloisomerization of natural antibiotic mupirocin methyl ester. Mupirocin is an epoxide-containing natural polyol that is known to undergo unselective intramolecular epoxide cyclization leading to the mixture of regioisomeric products. We have developed a CPA-controlled methods for both endo- and exo-selective modes of cyclizations, forming either exo-product in 3:1 r.r. or endo-product in 18:1 r.r. Chapter 1 also describes the experimental and computational mechanistic studies focused on understanding the origins of regiocontrol. These studies suggest that both cyclizations happen through concerted and highly synchronous pathways strongly depending on the nature of the hydrogen bond network formed between the substrate and the catalyst. Chapter 3 describes the development of regioselective CPA-catalyzed acetal protection of saccharide-based diols and triols and its application to the one-pot regioselective synthesis of differentially protected monosaccharides. This chapter also illustrates synthesis, characterization and development of immobilized on polystyrene matrix (R)-Ad-TRIP CPA, which could be recycled by filtration. This immobilized catalyst features high catalytic activity (0.5-0.1 mol% on 1-5 g scale) and can be reused multiple times without erosion in yields or selectivities. These features allowed to achieve gram scale one pot syntheses of several different D-glucose derivatives with the same batch of the recycled polymeric catalyst. Chapter 4 provides the summary of the studies described in this dissertation. It also discusses the impact of this work and potential future studies using immobilized CPAs in continuous flow.