Enantioselective Brønsted Acid Catalysis with Chiral Pentacarboxycyclopentadienes

This thesis details the design and development of pentacarboxycyclopentadienes (PCCPs) as a new platform for enantioselective Brønsted acid catalysis. Prior to this research, enantioselective Brønsted acid catalysis was limited to the BINOL (and variations thereof) framework. While this catalyst platform has paved the way for a myriad of novel asymmetric chemical transformations, the utility of this catalyst scaffold has suffered from its lengthy and expensive preparations. As an alternative, starting from readily available 1,2,3,4,5-pentacarbomethoxycyclopentadiene and various chiral alcohols and amines, the synthesis of a library of strongly acidic chiral catalysts is described. The utility of these novel acid catalysts is explored in various transformations. As a prelude to the heart of this work, Chapter 1 focuses on the advancements made in asymmetric Brønsted acid catalysis through BINOL-phosphate derived catalysts, focusing on the major accomplishments made by researchers since 2004. The provided review highlights the utility of these chiral acid catalysts but also reveals the need for a new scaffold that is more affordable and accessible. Chapter 2 discusses the background of PCCPs, including its initial discovery and subsequent applications. Our work in developing novel transesterified and amidated derivatives is discussed with accompanying crystal structures of achiral and chiral PCCPs. pKa measurements demonstrate the capacity of PCCPs to be used as strong Brønsted acid catalysts and are compared to literature values of known Brønsted acid catalysts. Chapter 3 focuses on the utility of PCCPs as enantioselective Brønsted acid catalysts in a variety of chemical transformations including the Mukaiyama-Mannich reaction, transfer hydrogenation, Pictet-Spengler reaction, diaryl alcohol substitution, Mukayaiama oxocarbenium aldol reaction, and [4+2]-cycloaddition. Catalyst loadings down to 0.01 mol% and reaction scale up to 25 grams in the Mukaiyama-Mannich reaction demonstrate the practical utility and robustness of PCCPs. Substrate scopes of these transformations show the breadth of accessible molecules that can be synthesized via PCCPs. Mechanistic rationales and transition state analyses are discussed in each of the transformations.