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Title:Selective C—H oxidations for complex molecule synthesis and diversification
Author(s):Gormisky, Paul
Director of Research:White, M. Christina
Doctoral Committee Chair(s):White, Christina M
Doctoral Committee Member(s):Denmark, Scott E.; van der Donk, Wilfred A.; Rauchfuss, Thomas B.
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Organic Chemistry
Organic Synthesis
C-H Oxidation
Catalyst Control
Synthetic Streamlining
Oxidative Heck Vinylation
Abstract:Synthetic chemists are continually challenged to develop more efficient and selective methods for the synthesis of both simple and complex molecules. Traditionally, starting materials for synthesis are derived from petroleum or other natural sources and have been pre-oxidized and pre-activated with reactive functional groups. These functional groups readily participate in a wide range of C—C and other bond forming processes, oxidations, and reductions, referred to as functional group manipulations. In contrast, the C—H bonds that make up the majority of organic frameworks are generally viewed as an inert scaffold upon which the chemistry of other functional groups takes place. Recently a novel strategy for synthesis has emerged that seeks to eliminate the requirement for pre-oxidation and carry out synthetic manipulations directly from a C—H bond, establishing it not simply as a bystander, but as a functional group in its own right. As a result, feedstock materials may be more rapidly transformed into final products. Nature has recognized the power of this approach and routinely oxidizes C—H bonds directly for the purpose of biosynthesis or metabolism. However, central to the application of C—H oxidation in the laboratory is the ability to not only break C—H bonds, but do so in a selective and predictable way. This work describes the development of novel C—H oxidation processes and strategies for their application to the synthesis and diversification of organic molecules. First, harnessing the abundance and simplicity of α-olefins as starting materials, a Pd(II)/bis-sulfoxide catalyst is utilized to carry out a selective intramolecular allylic C—H oxidation to generate a versatile synthetic intermediate (1,4-dioxanones). In contrast to many C—H oxidations, which transform a simple starting material into a single value added product, dioxanones can diverge to form motifs prevalent in natural products (i.e. differentially protected 1,2-diols, polyoxidized motifs and syn-pyrans). This work represents a novel application of C—H oxidation to achieve synthetic versatility. A highly selective intermolecular oxidative Heck vinylation is also described that forms di- and polyenes from simple α-olefins. Notably the Heck reaction requires only one pre-activated coupling partner. While traditional intermolecular Heck reactions are generally limited to resonance-activated olefins like styrenes, enol ethers and α,β-unsaturated carbonyls, Pd(II)/bis-sulfoxide catalysis enables a broad range of olefins to be vinylated in high yields and selectivities, expanding the applicability of this reaction in complex molecule synthesis. Finally, aliphatic C—H oxidation of unactivated bonds is perhaps the most challenging C—H transformation because of the ubiquity and strength of these bonds. Our group reported a non-heme iron catalyst [Fe(PDP)], which demonstrated that aliphatic C—H bonds could be selectively oxidized in both simple and complex molecules in preparative yields. Central to this reactivity was the sensitivity of Fe(PDP) to the electronic, steric and stereoelectronic properties of the substrate that differentiate C—H bonds from one another. This work describes the development of a novel C—H oxidation catalyst [Fe(CF3-PDP)] that is able to override these inherent substrate biases and access new sites of oxidation based on catalyst control. Furthermore, a predictive model was developed that quantitatively describes the site-selectivity of oxidation as a function of catalyst. The combination of catalyst-controlled reactivity and quantitative predictability should allow unprecedented application of aliphatic C—H oxidation to the synthesis, diversification, and study of metabolism of organic structures.
Issue Date:2014-05-30
URI:http://hdl.handle.net/2142/49588
Rights Information:Copyright 2014 Paul Gormisky
Date Available in IDEALS:2014-05-30
Date Deposited:2014-05


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