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Metal-Free Approaches to Sterically-Hindered Bonds

Dunham, Veronica Vin-yi
http://orcid.org/0000-0001-9389-598X
http://rave.ohiolink.edu/etdc/view?acc_num=osu1467360601

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Chemistry.
Developing methods to perform cross coupling reactions by means of catalysis is highly desirable in chemistry. Many industries in today’s society, such as the petroleum, agriculture, pharmaceutical, electronics, and polymer industry, use catalysis to some extent whether it is to make molecules that offer crop protection or toward the synthesis of the active ingredient of a medication. It is noteworthy that over 90% of chemicals are made through catalytic processes and that the catalyst market reached $17 billion in 2014, which demonstrates the demand for such methods. While transition metal catalysts have advantages such as low catalyst loading, broad reactivity, and that they have been well studied, some disadvantages are that they can be relatively expensive and sometimes air sensitive which can make them challenging to use. Organocatalysis, specifically non-covalent catalysis operating through hydrogen bond donating interactions, offers an environmentally-friendly alternative to transition metal catalysis. Our lab utilizes organocatalysis as a strategy to synthesize challenging, sterically-hindered bonds. Nitrimines have been identified as powerful coupling partners for the sustainable construction of new sterically congested carbon-carbon and carbon-heteroatom bonds. Using urea catalysis, a metal-free method to synthesize previously inaccessible enamines has been developed. Conventional routes to synthesize enamines as important building blocks toward target molecules generally require Lewis/Brønsted acids or expensive transition metals; however, these methods are often unsuccessful when sterically-hindered substrates are used. To address this synthetic challenge, it was hypothesized that hydrogen bonding interactions between a urea organocatalyst and nitrimine would generate a reactive species suited for the effective carbon-nitrogen coupling with amines to give the desired enamine products. This reaction provides high yields (up to 99%) of enamines using a variety of nitrimines and amines including piperidine, pyrrolidine, dibenzylamine, substituted indolines, and substituted N-methylanilines. Further investigations into the applicability of nitrimines for the synthesis of sterically-hindered bonds led to the discovery of formal carbon-carbon cross coupling reactions involving nitrimines and carbon nucleophiles such as indole, pyrrole, and hydroxycoumarin. Under optimized conditions, moderate to high yields of the desired di- or tri-substituted alkene product were obtained with electron-rich and electron-poor nitrimines. Furthermore, by strategic modification of the reaction conditions, control over the E/Z selectivity of the tri-substituted alkene products gave up to 19:1 ratio of Z:E isomers. This nitrimine-based formal carbon-carbon cross coupling methodology was then applied to the synthesis of a small target molecule, phenprocoumon, which was obtained in an overall 67% yield. The undeniable utility of urea catalysis operating through hydrogen bond donor (HBD) interactions has prompted the examination into enhanced HBD catalysts. Through the incorporation of a strategically placed Lewis acid on a urea scaffold, a new family of highly tunable HBD catalysts benefitting from enhanced activity was established. After determining the pKa of various urea catalysts using Bordwell’s method of overlapping indicators and comparing catalysts in two reaction systems, it was observed that the choice of Lewis acid and its associated ligands had an effect on urea reactivity, acidity, and polarization. In addition to Lewis acid assisted urea catalysts, silanediols have been discovered to participate as enhanced HBD catalysts. Taking advantage of the ability of our silanediol catalysts to participate in asymmetric anion-binding catalysis, a strategy toward an enantioselective synthesis of the sterically-encumbered molecule gonytolide A, an innate immune promoter, is underway.
Anita Mattson (Advisor)
Craig Forsyth (Committee Member)
Psaras McGrier (Committee Member)
196 p.
Chemistry
nitrimine; organocatalysis; urea catalysis; silanediol; chromanone; heterocycles; metal-free reactions

Recommended Citations

Citations

  • Dunham, V. V.-Y. (2016). Metal-Free Approaches to Sterically-Hindered Bonds [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1467360601

    APA Style (7th edition)

  • Dunham, Veronica. Metal-Free Approaches to Sterically-Hindered Bonds. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1467360601.

    MLA Style (8th edition)

  • Dunham, Veronica. "Metal-Free Approaches to Sterically-Hindered Bonds." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1467360601

    Chicago Manual of Style (17th edition)

osu1467360601
383
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This open access ETD is published by The Ohio State University and OhioLINK.