Enabling Predictive Catalyst and Reaction Design in Asymmetric Organocatalysis (Invited)

Over the past several decades, the burgeoning field of asymmetric organocatalysis has introduced novel solutions to a number of transformations that construct carbon-carbon and carbon-heteroatom bonds in organic synthesis directed toward medicinal chemistry and drug development. This work has produced a wealth of experimental observations – primarily concerning product selectivity – including the exciting concept of cascade reactions where consecutive reactions fix multiple stereocenters in one pot. The area is now poised to emerge from empirical discovery to prediction and design of reaction outcomes enabling practical application. This next stage requires an increased focus on the underlying reaction mechanisms that afford efficient and selective transformations. Understanding complexity in competitive reactivity patterns in these systems is key to the development of design tools for improving both reactivity and selectivity in known reactions as well as for enabling transformations that have eluded us to date.

Our goal is to enable predictive catalyst and reaction design by developing experimental kinetic and spectroscopic protocols to probe complex reaction pathways. Investigations to date have relied primarily on empirical optimization based on simple analysis of final reaction product outcomes, which may neglect the importance of reaction dynamics and the interplay between stability and reactivity of intermediates in competitive networks. The temporal monitoring of reaction and selectivity profiles combined with spectroscopic identification of dynamic intermediate species is an underutilized approach in organocatalysis. Its development will aid in the delineation, rationalization, and exploitation of unexpected modes of stereocontrol. In this work we explore the generality of a proposed Curtin-Hammett paradigm for different classes of organocatalysts, applying comprehensive kinetic and spectroscopic protocols to a series of key transformations in pyrrolidine-based organocatalytic systems involving enamine intermediates. The central theme is the incorporation of our pioneering approach to quantitative kinetic analysis into a range of mechanistic tools. Kinetic-assisted mechanistic analysis will be developed as an orthogonal tool for discovery and optimization by rational design based careful documentation of reactivity patterns. This approach will address unexplained features of existing reactions as well as enable design of new catalyst/substrate combinations for high efficiency and selectivity, including complex reaction networks with multiple sequential transformations that begin to resemble metabolic systems, whence the inspiration for organocatalysis originates.