Chemoinformatic methods for the identification of more optimal copper-bis(oxazoline) catalysts and mechanistic investigations into the catalytic, enantioselective tin-amine protocol

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois Urbana-Champaign

Year dc:date

2025

Author dc:creator

• Olen, Casey L.

Contributors dc:contributor

• Denmark, Scott E.
• Denmark, Scott E
• Burke, Martin
• Mirica, Liviu M
• Zhao, Huimin

• Bis(oxazoline)
• Ligands
• Catalysis
• Copper
• Informatics
• Chemoinformatics
• Tin-amine Protocol
• Morpholine
• Synthesis
• Piperazine
• Thiomorpholine
• Aldol Reactions

Statement dc:rights

• Copyright 2025 Casey Olen

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/130077

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F130077