Development of catalytic metal-mediated C--H hydroxylation methods with improved functional group compatibility
- James Booker Christianson Mack.
- [Stanford, California] : [Stanford University], 2018.
- Copyright notice
- Physical description
- 1 online resource.
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- Catalytic C--H hydroxylation methods constitute an enabling technology for the synthesis and structural diversification of organic molecules. Current methods are challenged by substrates that are densely functionalized and contain cross-reactive groups. In recent efforts to address such issues, we have developed two catalytic systems that advance the capability of chemists to functionalize highly complex molecules. Nitrogen-derived functional groups and N-heterocycles are ubiquitous in active pharmaceutical ingredients (APIs) and natural products, but are incompatible with most current chemical methods for oxidation. We describe the development of a new protocol for sp3-C--H hydroxylation. The reaction is performed in aqueous acid with catalytic cis-[Ru(dtbpy)2Cl2] (dtbpy = 4,4'-di-tert-butyl(2,2'-bipyridine)) and enables oxidation of structurally diverse amine- and heterocycle-containing molecules. Tertiary and benzylic C--H hydroxylation is strongly favored over N-oxidation in amine-derived and N-heterocyclic substrates. In efforts to further develop this technology, a multi-pronged mechanistic study was undertaken using techniques such as pressurized sample infusion high-resolution mass spectrometry (PSI-HRMS), 19F NMR spectroscopy, electrochemistry, and reaction kinetics analysis. This work has afforded insight into ligand structure-activity relationships and the identity of relevant active catalytic species. Turnover numbers (TONs) of a series of catalysts examined are strongly correlated to the rate and extent of ligand dissociation that occurs under the reaction conditions. Insights gained from these studies should give way to the design of next-generation catalysts for efficient C--H oxidation of complex molecules. In related studies, we describe the development of a Mn-catalyzed hydroxylation reaction that uses H2O2 or peracetic acid as the bulk oxidant. This method complements our Ru-based chemistry by enabling the functionalization of stronger, less reactive C--H bonds. The protocol features exceptionally low catalyst loadings, accommodates a variety of simple ligands (including 2,2'-bipyridine), and favors 2º alcohol products over the corresponding ketone derivatives. Preliminary studies aimed at understanding catalyst degradation/arrest mechanisms are also described.
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- Submitted to the Department of Chemistry.
- Thesis Ph.D. Stanford University 2018.
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