UC Berkeley

Abstract

Pursuing Selectivity: Data-Science Driven Reaction Development and Catalysis

By

Caroline Rouget-Virbel Doctor of Philosophy in Chemistry University of California, Berkeley Professor F. Dean Toste, Chair

Throughout my doctoral studies, I have endeavored to address the questions and challenges stemming from structure-activity relationships in catalysis. Mechanistic understanding is of central importance in the reaction development and the design of novel catalyst classes to ensure control over reactivity and selectivity. Physical organic chemistry methods and statistical analysis, in particular, guide the rational and strategic construction of specific interactions between substrates and catalysts to achieve the desired transformations. The work presented in the following chapters encompasses collaborative efforts with the University of Utah, and Genentech, Inc., towards the efficient design of catalytic and synthetic platforms.

Chapter 1: The first chapter presented herein offers a brief overview of the historical development in organic synthesis and catalysis which have paved the way to the research work described thereafter. Some principles of selectivity in synthesis are explored, alongside with an introduction to physical organic tools such as linear-free energy relationships and statistical models. The principles delineated in this chapter are meant to provide a frame of reference for the discussion of rational catalyst design and reaction optimization outlined in the following chapters.

Chapter 2: The design of efficient catalysts for organic reactions often relies on understanding the subtle relationship between structure and reactivity. Historically, this process has laid the foundation for the development of catalysts heavily biased towards more rigid and sterically-incumbered structures. Indeed, venturing outside of these steric repulsion models often complicates the generation of accurate predictions for a potential catalyst class to offer selectivity, due to the poorly understood nature of flexibility and its role in effecting attractive non-covalent interactions between catalysts and substrates. Herein, we disclose a novel class of flexible chiral phosphoric acid scaffold incorporating a single point of chirality. Data science techniques were first used to select a diverse training set of catalysts. Using a univariate classification algorithm and multivariate linear regression, key catalyst features necessary for high levels of selectivity were deconvoluted for the transfer hydrogenation of 8-aminoquinolines. The resulting model was found to accurately predict the selectivity of out-of-set catalysts. This workflow enabled extrapolation to a new catalyst providing higher selectivity than both peptide-type and BINOL-type catalysts (up to 95:5 er). These techniques were then successfully applied towards two additional transformations to illustrate the power of combining rational design with data science (ab initio) in the development of new catalysts.

Chapter 3: Even though substituted pyrazoles have been shown to possess beneficial biological activity in a variety of medicinal chemistry fields, the challenges facing their efficient synthesis have hindered their widespread application in hit-to-lead pharmaceutical pipelines. The practical and regioselective introduction of substitution into pyrazole motifs remains elusive, especially with regards to nitrogen substitution with electronically or sterically neutral moieties. The work presented herein describes the optimization process for the regioselective cyclization of N-methyl pyrazoles. Hoping to move away from substrate-driven selectivity, the small size of the hydrazine partner, lack of significant electronic induction from either starting materials, as well as the high variability of selectivity on multiple reaction parameters presented a challenge for traditional optimization methods. We describe the iterative use of Bayesian statistics to obtain catalyst-free yet selective reaction conditions for the synthesis of 3-(4-fluorophenyl)-1-methyl-1H-pyrazole, as well as the progress made towards the selective synthesis of isomer 5-(4-fluorophenyl)-1-methyl-1H-pyrazole