Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Gary A. Molander

Abstract

The rapidly rising prevalence of fluorinated motifs in pharmaceutical compounds has spurred interest in the development of synthetic methods that allow the efficient incorporation of such fluorinated groups into complex molecules. Two fluorinated functional groups are of particular interest because of their properties as bioisoteres: the α–trifluoromethylalkene and the gem-difluoroalkene. As such, these two motifs are highly desirable; however, methods to access these functional groups remain limited by harsh reaction conditions and incompatibility with the late-stage functionalization of complex molecules.

Photoredox catalysis invites a paradigm shift in the understanding of our capabilities to access diverse gem-difluoroalkene-containing small molecules because of its characteristically mild reaction conditions. Net-neutral radical/polar crossover, a subclass of photoredox catalysis, offers a particularly compelling approach to these goals because of the inherently efficient nature of these reactions. Methods to access alkylated- and arylated gem-difluoroalkenes will be discussed herein. Ni/photoredox dual catalysis, which merges the capabilities of photoredox catalysis with Ni-mediated cross coupling, further expands accessible chemical space. A haloselective cross-coupling method enabled by this approach will also be discussed herein.

Access to diverse α–trifluoromethylalkenes has been achieved through the development of two orthogonal synthetic methods: 1) the invention of an unprecedented cross-coupling reagent and 2) the reimagination and diversification of the Peterson olefination. In the first method, one-step access to α–trifluoromethylalkenes is achieved through the cross-coupling of a 3,3,3-trifluoro-1-propenyl trifluoroborate. Alternatively, access to diversified α–trifluoromethylalkenes via the Peterson olefination approach capitalizes on silyl alcohol intermediates as ‘masked’ alkenes.

Continued interest in the synthesis of fluorinated small molecules has resulted in the pursuit of asymmetric hydrogenation of α–trifluoromethylalkenes to access chiral trifluoromethyl alkane products. This work has been enabled by the co-development of a new analytical technique, molecular rotational resonance spectroscopy, which enables the determination of enantioselectivity without the need for chromatography-derived analysis. In summary, six synthetic methods are described that allow access to highly desirable fluorinated small molecule building blocks. The development of these methods in addition to the technologies that enable that development will be discussed.

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