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Selective Ketyl Couplings via Atom Transfer Catalysis

Rafferty, Sean M
http://rave.ohiolink.edu/etdc/view?acc_num=osu1587494763808417

Abstract Details

2020, Doctor of Philosophy, Ohio State University, Chemistry.
Constructing unique synthetic cores via simple feedstock chemicals has the potential to provide pharmaceuticals, natural products, and materials efficiently from cheap, readily available precursors. Expanding the synthetic chemist’s toolkit via new methods offers access to valuable molecules in an efficient and cost-effective manner. However, synthesis of complex molecular scaffolds often utilize multi-step functional group transformations, unnecessary redox manipulations, or require protecting groups due to harsh conditions. Specifically, C-C bond formation can be challenging without depending on the aforementioned strategies. Recent developments in the realm of photoredox catalysis, however, allows formation of reactive radical intermediates selectively to achieve C-C bond coupling in a mild fashion. Ketyl radicals, derived from single-electron reduction of carbonyls, were of particular interest to access complex alcohols. While carbonyls typically couple with nucleophiles due to the electrophilic nature of the C=O, ketyl radicals are significantly nucleophilic and provide polarity reversed, or umpolung reactivity, and allow for new electrophile-electrophile couplings. To address this, we developed an activation strategy to convert aldehydes to -oxy iodides via acetyl iodide addition, which allowed for much milder access of ketyl radicals. This new mode of accessing ketyl radicals via -oxy iodides was showcased by a redox-neutral C-C coupling with alkynes providing synthetically valuable vinyl iodide products, which are useful C-C precursors. Along with mild generation of ketyl radicals with an earth abundant Mn catalyst, this strategy provides a new Atom Transfer Radical Addition (ATRA) mode of reactivity, that obviates the need of harsh reductants, and thus avoids reductive products. In depth mechanistic analysis was obtained to understand the nature of the radical intermediates and the observed vinyl iodide isomerization providing high Z-isomer selectivity. Next, a cross-selective aza-pinacol coupling was developed using this redox-neutral ketyl radical generation strategy. Typically, the aza-pinacol proceeds through a reductive coupling of aldehydes and imines, but consequently homo-coupled products are often formed alongside desired amino alcohol products – sometimes in greater quantities than the target molecule. This is a consequence of current reduction-based strategies that employ the use of strong reductants that are able to reduce both coupling partners. In contrast, we developed an atom transfer strategy wherein AcI activation provides selective ketyl radical formation from aldehydes in the presence of imines to achieve cross coupling as the only product. This selective cross-coupling has also been rendered catalytic using a mild reductant (Zn) to achieve catalyst turnover, which has been investigated. In summary, these ketyl radical-coupling strategies provide unique access to synthetically powerful vinyl iodide intermediates, as well as biologically relevant  amino alcohols via ketyl derived atom transfer catalysis conditions. Our ketyl radical methodology will provide a mild way to construct molecular complexity from diverse aldehyde precursors to access interesting C-C connections in a selective manner.
David Nagib (Advisor)
Thaliyil RajanBabu (Committee Member)
Jonathan Parquette (Committee Member)
184 p.
Chemistry
synthesis; methodology; ketyl; radicals; atom transfer; photoredox; polarity-reversal; amino alcohols; vinyl iodides; catalysis;

Recommended Citations

Citations

  • Rafferty, S. M. (2020). Selective Ketyl Couplings via Atom Transfer Catalysis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587494763808417

    APA Style (7th edition)

  • Rafferty, Sean. Selective Ketyl Couplings via Atom Transfer Catalysis. 2020. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1587494763808417.

    MLA Style (8th edition)

  • Rafferty, Sean. "Selective Ketyl Couplings via Atom Transfer Catalysis." Doctoral dissertation, Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587494763808417

    Chicago Manual of Style (17th edition)

osu1587494763808417
264
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