Dissertation
Use of trichloroacetimidate for iridium-catalyzed allylic fluorination
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2020
DOI: 10.17077/etd.005532
Abstract
The ability to use racemic allylic trichloroacetimidates as competent electrophiles in a chiral bicyclo[3.3.0]octadiene-ligated iridium-catalyzed asymmetric fluorination with Et3N•3HF is described. The methodology represents an effective route to prepare a wide variety of α-linear, α-branching, and β-heteroatom substituted allylic fluorides in good yields, excellent branched-to-linear ratios, and high levels of enantioselectivity. Additionally, the catalytic system is amendable to the fluorination of optically active allylic trichloroacetimidate substrates to afford the fluorinated products in good yields with exclusively branched selectivity. Excellent levels of catalyst-controlled diastereoselectivities using either (R,R) or (S,S)-bicyclo[3.3.0]octadiene ligand are observed. The synthetic utility of the fluorination process is illustrated in the asymmetric synthesis of 15-fluorinated prostaglandin and neuroprotective agent P7C3-A20. Asymmetric allylic fluorination has proven to be a robust and efficient methodology with potential applications for the development of pharmaceuticals and practical synthesis for 18F-radiolabeling. A combined computational (dispersion-corrected DFT) and experimental approach was taken to interrogate the mechanism of the diene-ligated, iridium-catalyzed regio- and enantioselective allylic fluorination. Mechanistic studies reveal the crucial role of the trichloroacetimidate as a potent leaving group and ligand to enable conversion of racemic allylic trichloroacetimidates to the corresponding enantioenriched allylic fluorides, via a dynamic kinetic asymmetric transformation (DYKAT), in the presence of the chiral bicyclo[3.3.0]octadiene-ligated iridium catalyst. This reaction was then translated to radiofluorination. The rapid and operationally simple radiosynthesis of branched allylic [18F]fluorides bearing a variety of functional groups, via iridium-catalyzed nucleophilic substitution reaction utilizing allylic trichloroacetimidates and [18F]KF·Kryptofix[2.2.2] complex in 5–15 min at room temperature, is reported. The versatility of the allyl functional group of the resulting radiofluorinated products offers the benefit of being subsequently available for further functionalization.
Details
- Title: Subtitle
- Use of trichloroacetimidate for iridium-catalyzed allylic fluorination
- Creators
- Alexandre Matthieu Sorlin
- Contributors
- Hien M Nguyen (Advisor)F Christopher Pigge (Committee Member)James B Gloer (Committee Member)David W Dick (Committee Member)Robert J Kerns (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Chemistry
- Date degree season
- Summer 2020
- DOI
- 10.17077/etd.005532
- Publisher
- University of Iowa
- Number of pages
- xxviii, 599 pages
- Copyright
- Copyright 2020 Alexandre Matthieu Sorlin
- Comment
- This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 352-363).
- Public Abstract (ETD)
Fluorine is an atom present in many drugs and can have multiple applications in material science, radiology and agriculture. It is important to find new ways of synthesizing carbon-fluorine bonds. This thesis describes a new method to incorporate fluorine into organic molecules with the aid of a transition metal catalyst: iridium. The starting material used for this methodology has a trichloroacetimidate leaving group. The mechanism of this reaction is also investigated and described here in detail, as are ways to isolate and analyze the intermediate of this reaction. Also, this reaction is attempted using radioactive fluorine [18F], which could show some application in radiochemistry.
- Academic Unit
- Chemistry
- Record Identifier
- 9983988297302771
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