Asymmetric Conjugate Additions of Boronates to α,β-Unsaturated Trifluoromethyl Ketones and Strategies Towards Asymmetric Conjugate Additions of N-Boc-Pyrrole Boronic Acid
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Date
2016-08-24
Authors
Sands, Kai
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Publisher
University of Waterloo
Abstract
An important class of organic molecules are those that contain fluorine. Fluorinated molecules have found widespread use in medicinal chemistry, as well as in agrochemicals. This is due to the ability of fluorine to act as a bioisostere for hydrogen, while also imparting other, desirable properties to the molecules, such as increased lipophilicity, metabolic stability, and bioavailability. An important class of fluorinated molecules are trifluoromethyl ketones. Trifluoromethyl ketones have been used in a wide variety of applications, notably as potent enzyme inhibitors, as well as key intermediates in the synthesis of fluorinated heterocycles, medicinal compounds and natural product analogues.
Currently, there are very few methods reported for the conjugate addition to α,β-unsaturated trifluoromethyl ketones, and even fewer methods for the asymmetric conjugate addition. The majority of this thesis is focused on the development of the BINOL catalyzed asymmetric conjugate addition of organoboronates to α,β-unsaturated trifluoromethyl ketones yielding enantiomerically enriched trifluoromethyl ketones. Through this method, trifluoromethyl ketones bearing stereochemically defined β-substituents can be obtained in good yield and excellent enantioselectivity (up to 96% yield and >99.6:0.4 er). With so few protocols available for the conjugate addition to α,β-unsaturated trifluoromethyl ketones, this methodology may allow for the efficient synthesis of many novel enantiomerically enriched trifluoromethyl ketones.
The final chapter of this thesis presents preliminary studies and optimization on the asymmetric conjugate addition of N-Boc-pyrrole boronic acid to diaryl enones. Early results indicate that this may be an efficient methodology for the conjugate addition of pyrrole in a stereocontrolled manner.
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Keywords
Asymmetric conjugate addition, Trifluoromethyl ketones