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Radical sp3 C-H Functionalization of Amines and Alcohols

Wappes, Ethan Albert
http://orcid.org/0000-0001-8615-8957
http://rave.ohiolink.edu/etdc/view?acc_num=osu1555519030868564

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Chemistry.
As our world continues to connect and develop, the need for new medicines and treatments for emerging diseases steadily grows. In recent years, global epidemics have posed serious health crises, while growing drug resistance (e.g. bacterial resistance to antibiotics) threatens pharmaceutical efficacy. To maintain global health, drug discovery must continue to innovate and solve these issues. A major bottleneck in drug discovery involves the process of testing thousands of molecules for biological activity against a target and then modifying them to tune their properties. The classical synthesis of these molecular libraries employs an iterative sequence of transformations from small building blocks for each drug candidate. Alternatively, this approach can be circumvented by converting carbon-hydrogen (C-H) bonds, the most common in organic molecules, into new species. This proposal aims to employ this process, known as C-H functionalization, to achieve direct derivatization of a drug candidate into a variety of new compounds thus improving the rate of pharmaceutical discovery. To achieve the desired C-H functionalization of medicines we must tackle the challenge of reactivity (since C-H bonds are inert) along with the issue of ubiquity. We aim to overcome bond strength by using highly reactive free-radical species which are known to cleave strong bonds. Additionally, we will circumvent the challenges associated with selecting specific C-H bonds in an organic framework by learning from biological systems like proteins which achieve selective C-H functionalization through coordination to common molecular features in a molecule. One such motif of interest is an alcohol which is prevalent in pharmaceuticals. To achieve selective derivatization of alcohol-containing drugs, we have the designed a radical chaperone strategy that can selectively bind to alcohols, affect radical C-H functionalization and finally be removed to generate a new derivative. Through the judicious design of our chaperone, we can access biologically relevant C-H functionalization reactions that have never been realized in alcohol-containing molecules. Specifically, we have achieved a radical-mediated -amination that is orthogonal to transition-metal strategies. This original discovery hinged upon the identification of a previously unidentified imidate chaperone that derives from the combination of an alcohol and nitrile. Imidate radicals have been understudied up until this point and have now been shown to achieve selective 1,5-hydrogen atom transfer. This first strategy employed a stoichiometric amount of oxidant which was deemed undesirable for more challenging synthetic applications. To address this, we developed and I2-catalyzed method that employs significantly less reagents and achieves improved selectively in oxidatively sensitive molecules. Following the development of this C-H amination, we expanded the utility of this imidate species to achieve the selective halogenation of alcohols. Five new C-H halogenations were developed by leveraging this imidate radical which provides a breadth of accessible compounds from a single starting alcohol. Mechanistic experiments provide insight into these unique transformations and the nature of the radical. Finally, this imidate species was employed as an intermediate towards the synthesis of valuable heterocycles. By combining alcohols and nitriles and performing a tandem C-H oxidation, we have streamlined the synthesis of oxazoles from feedstock chemicals. Empirical observations from this transformation have provided insight into the operative mechanism and have allowed the extension of this method to accessing imidazoles as well. These developed strategies will provide new opportunities for chemists to streamline the synthesis of drug candidates. Through the continued improvement of C-H functionalization, even the most inert and unactivated bonds in a molecule will become synthetic handles for derivatization.
David Nagib (Advisor)
T.V. Rajanbabu (Committee Member)
Dennis Bong (Committee Member)
242 p.
Chemistry; Organic Chemistry

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Citations

  • Wappes, E. A. (2019). Radical sp3 C-H Functionalization of Amines and Alcohols [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555519030868564

    APA Style (7th edition)

  • Wappes, Ethan. Radical sp3 C-H Functionalization of Amines and Alcohols. 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1555519030868564.

    MLA Style (8th edition)

  • Wappes, Ethan. "Radical sp3 C-H Functionalization of Amines and Alcohols." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555519030868564

    Chicago Manual of Style (17th edition)

osu1555519030868564
458
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