Manganese-catalyzed C-H oxidation applied to the synthesis of complex molecules

Chemoselectivity remains a significant challenge in the field of undirected Csp3-H oxidation. The powerful oxidants required to functionalize these strong bonds often react with any oxidizable functional groups present in a substrate, furnishing undesired side products. Although there are many reports of applying C-H oxidation methodology to the total synthesis of natural products, the use of this chemistry has been largely limited in the context of complex and highly functionalized molecular scaffolds due to chemoselectivity issues. Significant progress has been made in this area to date with PDP catalysts, with recent advancements expanding functional group tolerance to allow methylene C-H oxidation in the presence of Lewis-basic nitrogen and electron-neutral aromatic functional groups. This dissertation focuses on efforts to expand pi-system tolerance in PDP-catalyzed Csp3-H oxidation and to leverage this enhanced chemoselectivity to oxidize complex substrates and intermediates in the context of natural product and metabolite synthesis. A novel system for oxidizing methylene C-H bonds in the presence of ,-unsaturated carbonyl functional groups was developed and optimized, with the highest degree of chemoselectivity accomplished by changing the reaction solvent from acetonitrile to 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and running the reaction in the absence of the carboxylic acid additive that is necessary for reactivity in previously reported systems. A Hammett analysis suggested that these changes resulted in a shift to a mechanism involving more positively-charged intermediates. Together with inductive deactivation of the pi-system resulting from solvent hydrogen-bonding to the carbonyl oxygen, the epoxidation pathway that previously outcompeted C-H oxidation in molecules containing ,-unsaturated carbonyls was successfully shut down. This method was applied to the total synthesis of platencin, a natural product with powerful antibacterial bioactivity. The expanded chemoselectivity enabled a key C-H oxidation step that established 2 of 3 stereogenic centers in the bridged tricyclic core of the natural product. This approach also furnished synthetically useful yields of two different oxidation products that were elaborated to novel platencin analogs, which were also found to exhibit antibiotic activity. Additionally, experimental validation of a neural network-based site prediction model was performed. Target substrates that were not included in the training set were selected, synthesized, and oxidized; then the major oxidation products were identified to assess the model’s predictive capabilities.

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

• Gomez, Alexander

Contributors dc:contributor

• White, Maria C
• Hergenrother, Paul J
• van der Donk, Wilfred A
• Chan, Jefferson

• C-H oxidation
• catalysis
• total synthesis

Statement dc:rights

• Copyright 2025 Alexander Gomez

Language dc:language

en

Handle dc:identifier

https://hdl.handle.net/2142/132724

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/132724