A Data-Driven Organocatalytic Platform for Site-Selective C(sp³)-H Hydroxylation: Kinetic Studies, Mechanistic Insights, and Late-Stage Oxidation 27 views

Late-stage C(sp³)–H functionalization has emerged as a pivotal strategy for rapidly diversifying complex molecules, yet predictable, chemoselective platforms remain scarce. Chapter 1 of my dissertation lays the conceptual foundation by tracing the evolution of oxaziridines from stoichiometric methods to versatile, catalytically generated oxidants that enable selective O- and N-atom transfer reactions in modern synthesis. Chapter 2 establishes an organocatalytic solution to this challenge. We develop a family of secondary-amine catalysts that condense with paraformaldehyde to form oxaziridinium electrophiles in situ, effecting remote C–H hydroxylation with urea hydrogen peroxide as the oxidant. Kinetic, mechanistic, and DFT studies confirm a first-order dependence on substrate, catalyst, and aldehyde, and identify hydrogen-atom abstraction by the oxaziridinium as the rate-determining step. These mechanistic insights highlight the essential roles of the co-catalyst diselenide and urea, laying the groundwork for subsequent secondary hydroxylation studies. Chapter 3 translates this methodology to the late-stage oxidation of the natural product (–)-ambroxide. Systematic screening of various cycloamine catalysts reveals that optimized methods deliver yields of up to 76%, >99% chemoselectivity, and C3:C2 site-selectivity as high as >99:1, constituting the first selective C3 methylene hydroxylation of (–)-ambroxide. Comparative solvent, oxidant-loading, and reaction rate studies rationalize the roles of hydrogen bonding and catalyst electronics, while broader substrate surveys highlight the method’s potential for directing methylene versus tertiary oxidation, with an unprecedented selectivity for C3 oxidation. Collectively, these findings provide a data-driven framework for organocatalytic C–H oxidation that combines predictable selectivity with green oxidants, and they set the stage for integrating computational models and binding-controlled catalysts to access previously inaccessible positions in complex scaffolds.

PHD (Doctor of Philosophy)

English

2025-08-05