Date of Award
Master of Science (MS)
Clark, Joseph R.
The development of novel deuterated and fluorinated bioisosteres has significantly impacted the pharmaceutical and agricultural industry and created a growing demand for new synthetic methodology. Both deuterated and fluorinated small molecules exist at the forefront of drug discovery due to their unique ability to attenuate the pharmacokinetic properties of new and currently existing drugs. Selective, high-throughput methods for deuteration and fluorination are scarce in the literature, especially methods that introduce D or F atoms asymmetrically. Benzylic CH bonds are oftentimes key sites for enzymatic manipulation in metabolic processes, alteration of CH bonds to CD or CF bonds at the benzylic site of organic molecules affects the metabolic process, making this a key site for bioisosterism. Using state-of-the-art methods to synthesize chiral by virtue of deuterium small molecules requires significant synthetic overhead with limited methods for chiral analysis due to the similar nature of H and D. Asymmetric fluorination has been restricted to ,-unsaturated carbonyl compounds that can transform into metal enolates, and only two literature examples of enantioselective fluorinations of aryl alkenes. Herein, enantioselective methods for both deuteration and fluorination are described.Regio- and enantioselective hydrodeuteration of the -bond of aryl alkenes was successfully achieved using a chiral CuH catalyst with a protic D-source. Molecular rotational resonance (MRR) spectroscopy was utilized as a novel analytical method for determining %ee, absolute stereochemistry, and identifying isotopomers and isotopologues. This substrate scope includes various aromatic and heteroaromatic alkenes with excellent yields and high enantioselectivities. By substituting the protic D-source for Selectfluor, an electrophilic fluorinating reagent, enantioselective fluorination was also achieved. Optimization of the catalytic conditions will reveal the feasibility of achieving high enantioselectivities and yields. In this work, my contributions to both the deuteration and fluorination projects is described.
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