Remote C—H oxidations with manganese catalysts

The atomistic change from C(sp3)—H to C(sp3)—O can have a profound impact on the physical and biological properties of small molecules. Traditionally, synthetic organic chemists have relied on pre-existing functionality to transform molecules, using functional group manipulations to build up molecular complexity. In the past two decades an alternative approach has emerged wherein inert and ubiquitous C—H bonds can be directly functionalized via metal catalysis. The development of C—H functionalization reactions with controlled site-selectivity now allows for the diversification of complex structures at sites remote from existing functionality, without requiring individual de novo syntheses. However, this approach presents organic chemists with a new challenge: developing catalysts that are reactive enough to cleave strong, inert C—H bonds in a selective and predictable manner. Nature has evolved powerful enzymes containing earth abundant base metals, such as cytochrome P450 (CYP450) enzymes, that are capable of selectively cleaving and functionalizing C—H bonds, even in complex settings. However, scientists viewed the difference between aliphatic C—H bonds as negligible thus, mimicking nature’s transformation with high site- and chemoselectivity in a laboratory setting was seen as very “difficult”. The discovery of Fe(PDP) and Fe(CF3-PDP) catalysts in 2007 and 2013 respectively, showed for the first time that the site-selectivity for C—H oxidation reactions could be reliably predicted based on electronic, steric and stereoelectronic properties of C—H bonds. The development of these iron catalysts shifted how the chemistry community viewed the ability to functionalize individual C—H bonds in a controlled fashion. However, major limitations remained for the application of C(sp3)—H oxidation reactions to pharmaceuticals due to chemoselectivity issues when medicinally relevant aromatic and heterocyclic functionalities were present. This work describes the discovery and application of two manganese base metal catalysts for C(sp3)—H oxidation reactions that proceed with significantly improved chemoselectivity in compounds housing aromatic and nitrogen-containing heterocyclic (N-heterocyclic) functionality. The first chapter of this dissertation describes the development and application of Mn(PDP) catalyst for tertiary C—H hydroxylation reactions in the presence of aromatic functionality. By switching the metal center from iron to manganese, which reduces the redox potential of the active metal(oxo) intermediate, we discovered a catalyst with high selectivity for tertiary oxidation over aromatic oxidation. Optimization of the Mn(PDP) system led to the unexpected discovery that extremely low catalyst loadings (0.1 mol%) could be utilized, resulting in an amalgamation of high selectivity and synthetically useful levels of reactivity for a variety of aromatic containing molecules. However for complex substrates with pharmaceutically important basic nitrogen functionality, higher catalyst loadings were required. Late-stage oxidation was demonstrated on two drug derivatives and large scale oxidations were performed on bioactive molecules to rapidly furnish preparative amounts of oxidized drug derivatives with reduced catalyst loadings. The second chapter of this dissertation describes the application of Mn(CF3-PDP) catalyst for methylene oxidations in the presence of the broadest scope of N-heterocyclic functionality to date. Methylene oxidation is demonstrated in compounds bearing 25 distinct heterocycles (e.g. piperazine, morpholine, triazole, tetrazole) including 14 out of 27 of the most frequent N-heterocycles found in U.S. FDA approved drugs. Mn(CF3-PDP) oxidation of carbocyclic bioisostere drug candidates was demonstrated to match the major site of metabolism obtained with rat and human liver microsomes, highlighting the utility of this method in drug discovery for rapid structure-activity-relationship (SAR) and metabolite identification (MetID) studies. Mn(CF3-PDP) catalysis enables preparative, gram-scale synthesis of drug metabolites and their derivatives otherwise only accessible through lengthy de novo syntheses. This work opens the door for the use of a small molecule catalyst as a liver CYP450 enzyme mimic in pharmaceutical studies.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2023

Author dc:creator

• Chambers, Rachel Katherine

Contributors dc:contributor

• White, M Christina
• Hergenrother, Paul
• Sarlah, David
• Mirica, Liviu

• Catalysis
• C-h Oxidation

Statement dc:rights

• Copyright 2023 Rachel Chambers

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/120484

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F120484