Synthesis of Sulfonyl Fluorides and the Total Synthesis of the Rhodocorane Natural Products

Abstract

The selective reactivity of different functional groups is at the forefront of modern synthetic chemistry. As predictable and controllable reactivity are the key to the synthesis of many bioactive and structurally challenging molecules, synthetic methodologies to install and understand these reactive moieties is always of interest to organic chemists. However, there is a fine line between too reactive and not reactive enough. Our studies on the development of new catalytic methods to synthesize sulfonyl fluorides via two separate photocatalytic methods and the synthesis of the rhodocorane family of bioactive natural products are described. In the first chapter, an overview of the development and the understanding of the reactivity of sulfonyl fluorides as a second generation "click" reaction is discussed. Various studies from the literature show that these moieties can undergo a selective activation and become reactive in both chemical and biological instances. The potential applications of these interesting functionalities are limitless, with the only hindrance being the lack of easily accessible syntheses. The understanding of that activation is discussed along with a variety of ways to synthesize both aliphatic and aryl sulfonyl fluorides. The second chapter describes our studies in the development of a photocatalytic method to convert anilines into sulfonyl fluorides through an activated and isolated substrate class of diazonium salts. Our approach allows for a mild and selective method to synthesize aryl sulfonyl fluorides from a widely available functional group while being tolerant of a range of other functionalities. We also present various experimental and theoretical studies to analyze the mechanistic pathways involved in the methodology. In the third chapter, we describe our effort to develop a separate organophotocatalytic methodology to synthesize aliphatic sulfonyl fluorides from potassium trifluoroborate salts. Our synthetic strategy leverages the activated boronate species to generate aliphatic radicals with the highly oxidizing organophotocatalyst, which undergoes a three-component coupling with a sulfur dioxide source and a fluorine source. The challenges associated with this methodology along with photophysical measurements and evidence for the mechanism are discussed. In the fourth chapter, we discuss our approach to the asymmetric synthesis of the rhodocorane family of bioactive natural products. These natural products possess a range of spirocyclic, fused rings, and highly oxygenated systems that allow for structurally diverse and complex molecules. We propose a common synthetic intermediate that can access a majority of this family through the addition of other commercially available molecules. The challenges and optimization of this synthesis and our approaches to solve these problems are discussed