University of Illinois Urbana-Champaign

New horizons of aliphatic C—H amination and hydroxylation reactions with manganese catalysis

Zhao, Jinpeng

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ZHAO-DISSERTATION-2019.pdf

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https://hdl.handle.net/2142/105887

Description

Title
New horizons of aliphatic C—H amination and hydroxylation reactions with manganese catalysis
Author(s)
Zhao, Jinpeng
Issue Date
2019-07-02
Director of Research (if dissertation) or Advisor (if thesis)
White, Maria C
Doctoral Committee Chair(s)
White, Maria C
Committee Member(s)
  • Denmark, Scott E
  • Hergenrother, Paul J
  • Nuzzo, Ralph G
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Date of Ingest
2019-11-26T20:58:35Z
Keyword(s)
  • C—H functionalization
  • Manganese catalysts
  • synthetic methodology
Abstract
Functionalized aliphatic C(sp3)–H scaffolds are being increasingly incorporated into small molecule pharmaceutical molecules to gain access to novel chemical space and bioactivities. Given the ubiquitous of C—H bonds and their inertness toward a wide range of reaction conditions, late-stage aliphatic C—H functionalizations afford unique opportunities to quickly diversify complex bioactive molecules and access novel heterocyclic substitution patterns on the aliphatic core structures. Although methods with preparative yields and site-selectivities for aliphatic C—H functionalization are emerging, a significant challenge remained with an apparent inverse correlation between reactivity and chemoselectivity: catalysts that are highly reactive to strong aliphatic C—H bonds usually lacks chemoselectivity for -functionalities (aromatics and olefins). My doctoral research in the White group has focused on developing novel manganese catalysts for C—H amination and C—H hydroxylation reactions with unprecedented amalgamation of high reactivity with strong C—H bonds (2º and even 1º) while maintaining high chemoselectivity for aromatic -functionalities. These new catalysts afford opportunities to fully realize the potential of using late-stage aliphatic C—H functionalizations in drug discovery processes. The first chapter of this dissertation discussed the discovery of a novel manganese catalyst, Mn[tBuPc], for intramolecular C—H aminations. Mn[tBuPc] showcase as an outliner of the inverse correlation between reactivity and chemoselectivity traditionally shown in metallonitrene mediated intramolecular C—H aminations. Collectively in this project, we demonstrated Mn[tBuPc] is uniquely effective to aminate all types of C(sp3)–H bonds intramolecularly while maintaining chemoselectivity for the olefin -functionality. Particularly, I demonstrated Mn[tBuPc] capable to preparatively aminate a wide range of benzylic C—H bonds of aromatic and medicinally important heteroaromatic substrates. Impressively, even strongest 1º C—H bonds can be preparatively aminated with Mn[tBuPc] in simple and complex molecules settings with perfect site-selectivity. Mechanistic studies suggest the Mn[tBuPc] catalyst transfers the bounded nitrene to C—H bonds via a stepwise C—H abstraction/ fast rebound pathway with attenuated radical character on the metallonitrene compared to the iron catalyst. Late-stage C—H amination and sequential C—H hydroxylation/ C—H amination were demonstrated to quickly install heteroatomic functionalities (O and N) onto the aliphatic core of complex natural products. The second chapter of this dissertation described the discovery of a novel manganese catalyst Mn(CF3-PDP), that for the first time enabled highly reactive methylene C—H oxidation with high chemoselectivity tolerating a wide range of oxidatively labile aromatic functionalities via a synergetic effect between catalyst design and chloroacetic acid additive. A total of 50 aromatic substrates housing medicinally important halogen, oxygen, nitrogen, heteroaromatic and biaryl moieties were demonstrated with Mn(CF3-PDP) to afford preparative yields for 2º oxidation products. Late-stage oxidative derivatization on four aromatic pharmaceutical molecule scaffolds were shown with Mn(CF3-PDP), including a sequential 2º benzylic/remote 2º C—H hydroxylations on an ethinylestradiol derivative where other oxidant only oxidize the doubly activated tertiary benzylic site. Mn(CF3-PDP) was also demonstrated to potentially serve as a general approach to rapidly access and identify drug metabolites (piragliatin) from advanced synthetic intermediates. Additionally, the high chemoselectivity observed in 2º C—H oxidation with Mn(CF3-PDP) can be maintained in the 3º C—H oxidation of substrates housing a range of pharmaceutically important substitutions on aromatic rings with Mn(PDP) catalyst.
Graduation Semester
2019-08
Type of Resource
text
Permalink
http://hdl.handle.net/2142/105887
Copyright and License Information
Copyright 2019 Jinpeng Zhao

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