Nitrile-Directed C-H Functionalization and Lewis Acid-Catalyzed Oligosaccharide Synthesis

Abstract

The development of catalytic methods for critical bond-forming reactions has been vital in the progress of synthetic organic chemistry. Accessing straightforward, selective, and efficient methods for rapid assembly of biologically relevant motifs is important to the success of a variety of chemical industries. In particular, both divergent C–H functionalization, and glycosidic bond-formation, for glycoconjugate preparation, are underrepresented in the literature, despite being highly valued transformations. The work herein details progress made in the development of catalytic methods for the synthesis of unique molecular scaffolds. Chapter 1 provides background on historic and current state-of-the-art approaches to transition metal-catalyzed C–H functionalization, which leverages various directing groups to achieve selective reactivity. Of central focus is the nitrile, which can engage in dual coordination modes, to direct C–H activation both at remote and proximal aromatic sites. This offers a versatile and divergent handle to guide synthetic strategy. Despite this, limitations exist in current methods. The components of these reactions that help determine selectivity are also explored. Following this introduction, Chapter 2 describes work towards accessing methods for traceless nitrile-directed C–H activation. Using a previously reported cyanoborylation, in combination with newly developed, highly regioselective C–H functionalization, and a mild reductive decyanation, transition metal catalysis enables rapid functionalization of aromatic systems. Optimization, scope, and mechanistic hypotheses regarding the four transformations (acetoxylation, pivalation, methoxylation, and decyanation) are discussed in detail, along with a general demonstration of their orthogonality, when used in combination. The second half of this dissertation focuses on glycosylation methods, specifically borane-catalyzed transformations to enable the synthesis of polysaccharides and glyco-dendrimers. Chapter 3 begins with a general overview of the innate challenges present in carbohydrate synthesis, and the applications of these biopolymers. Established strategies for the synthesis of polysaccharides are outlined, as well as the current solutions to the stereo-, regio- and chemo-selectivity challenges which inevitably arise in glycosidic bond formation. The utility of glycosyl fluoride donors in conjunction with silyl-ether protected acceptors, and their role in recently developed tris(pentafluorophenyl) borane (B(C6F5)3 or BCF) catalysis are discussed in detail. Finally, the importance of dendrimers in molecular biology, and the drawbacks of current synthetic methods to access them are discussed. Following this brief introduction to carbohydrate chemistry, Chapter 4 demonstrates the progress made towards using BCF catalysis for one-pot polysaccharide synthesis. Strategy and experimental design are outlined, followed by initial insight into this challenging research area. The design and synthesis of a novel bifunctional silyl-ether protected glycosyl fluorides are discussed, and various systems to access mono-disperse oligosaccharides are explored. Approaches to mitigate unproductive deglycosylation pathways are also examined. Finally, the synthesis of fully glyco-based dendrimers, using BCF catalysis, is successfully demonstrated, and future work towards accessing complex glycoconjugates is outlined.