Chemoinformatic methods for the identification of more optimal copper-bis(oxazoline) catalysts and mechanistic investigations into the catalytic, enantioselective tin-amine protocol
Olen, Casey L.
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https://hdl.handle.net/2142/130077
Description
Title
Chemoinformatic methods for the identification of more optimal copper-bis(oxazoline) catalysts and mechanistic investigations into the catalytic, enantioselective tin-amine protocol
Author(s)
Olen, Casey L.
Issue Date
2025-06-30
Director of Research (if dissertation) or Advisor (if thesis)
Denmark, Scott E
Doctoral Committee Chair(s)
Denmark, Scott E
Committee Member(s)
Burke, Martin
Mirica, Liviu M
Zhao, Huimin
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
bis(oxazoline)
ligands
catalysis
copper
informatics
chemoinformatics
tin-amine protocol
morpholine
synthesis
piperazine
thiomorpholine
aldol reactions
Abstract
This thesis covers efforts into the synthesis of bis(oxazoline) ligands, the application of informatic methods for the in silico description of bis(oxazoline) ligands and subsequent quantitative structure-selectivity relationship modelling and proximity-informed ligand selection approaches, and elucidation of the mechanism of a copper-bis(oxazoline) catalyzed morpholine synthesis.
Chapter 1 describes efforts in developing a stereoselective synthetic protocol to produce bis(oxazoline) ligands compatible with diverse functional group substituents. A synthetic strategy based on organolithium additions to chiral sulfinimine auxiliaries was developed, and an investigation into examples that provide low diastereoselectivity is presented. Terphenyl- and anthracenyl-lithium nucleophiles were evaluated, and an interesting change in the sense of diasteroinduction in the case of anthracenyllithium addition was discovered.
In Chapter 2, a universal training set of 26 bis(oxazoline) ligands is identified by featurizing a large in silico library of ligands with conformer-averaged grid-based descriptors and selecting a diverse subset by clustering methods. Data acquisition in a vinylogous Mukaiyama aldol reaction provided data for additional catalyst selection approaches and an initial hit ligand. Supervised and unsupervised catalyst selection methods, including quantitative structure–selectivity relationship modeling, nearest neighbors analysis, and a focused analogue clustering strategy, were employed to identify an additional 12 new bis(oxazoline) ligands. The selected ligands outperformed the initial training set hit in four out of five product classes and in some cases demonstrated enantiocontrol exceeding 95% ee. The effectiveness of the unsupervised training set selection process is discussed, and the expediency of the nearest neighbor and focused analogue approaches are contrasted with the supervised quantitative structure–selectivity relationship modeling approach.
Chapter 3 details mechanistic investigations into the copper-bis(oxazoline) catalyzed tin-amine protocol for morpholine synthesis. Reaction profiling and initial rates analysis were used to define an empirical rates law. Additive effects were surveyed, and mechanistic discussions considering the effects of the additives and the empirical rate law are described. Future experiments for further mechanistic elucidation are described.
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