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Title: A physical-organic approach to asymmetric catalysis : design and synthesis of chiral ligands using multivariate modelling
Author: Brethome, Alexandre
ISNI:       0000 0004 8507 2539
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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Discovery of new asymmetric metal-catalyzed transformations is closely related to the development of efficient and robust chiral ligands, such that ligand optimisation is a crucial step in reaction development but its success is highly uncertain. Mostly based on trial-and-error, such a daunting task can be intellectually frustrating and exhausting, wherein the use of any predictive tool is much appreciated. The limited mechanistic knowledge in asymmetric catalysis is unfortunately prohibitive to the use of many computational techniques. As a result, we turn our attention toward multivariate modelling, a data-driven statistical approach which is believed to be a promising platform to rationally drive the successful identification of a highly enantioselective ligand. In this work, we introduce the importance of ligands in asymmetric catalysis and detail the notion of ligand design, and more particularly, we fully report the multivariate modelling approach (Chapter 1). We then apply such a strategy on systems developed in our group where the ligand design previously failed using traditional approaches. For instance, Chapter 2 fully uses multivariate modelling to reoptimize a copper-catalysed asymmetric conjugate addition of alkylzirconium species that failed on sterically challenging linear substrates. While modelling this asymmetric transformation, we realized that conformational flexibility of ligands could produce large amplitudes of underestimated uncertainty in predictions. Thus, conformational effects on physical-organic descriptors are explored in Chapter 3 with the specific case of steric Sterimol parameters, from which new descriptors called wSterimol ("weighted Sterimol") were developed. Inspired by the success of our approach in Chapter 2, the ligand design workflow is applied to the development of a copper-catalysed asymmetric conjugate addition to exocyclic enones (Chapter 4). Finally, we examine the remaining challenges for the data-driven approach to become a go-to method and we envision the future of ligand design in asymmetric catalysis (Chapter 5).
Supervisor: Fletcher, Stephen ; Paton, Robert Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: ligand design ; multivariate modeling ; asymmetric catalysis