UC Berkeley

Fluorine is a critically important element for the design of safe and effective drugs in the modern pharmaceutical industry. As the field of synthetic methodology for fluorination of organic compounds has flourished, biocatalysis has also been rapidly adopted as a means to achieve high reaction selectivity and process sustainability. However, the areas of biocatalysis and fluorine chemistry have rarely intersected directly, owing to the rarity of fluorine-processing enzymes in Nature. We envision that this methodology gap can be bridged by the action of carbon-carbon bond forming enzymes upon non-native fluorinated substrates, thus transforming simple organofluorine building blocks into more complex organofluorines. In this dissertation, we describe the application of enzymatic aldol addition to fluoro-aldol reactions that furnish value-added organofluorine products bearing fluorine stereocenters. Our development of a novel platform for biocatalytic organofluorine synthesis began with the discovery that Type II pyruvate aldolases of the HpcH family use fluoropyruvate as an alternative nucleophilic substrate. After studying the stereoselectivity, kinetics, and mechanism of the fluoropyruvate aldol reaction, the afforded products were converted to diversely functionalized organofluorines through downstream reactions. Next, the HpcH system was expanded beyond fluoropyruvate to generalized β-fluoro-α-ketoacids as nucleophiles. The investigation of these challenging substrates, aided by rational active site engineering, resulted in the first synthesis of tertiary fluorides via biocatalytic C-C bond formation. Usefulness of the HpcH platform was demonstrated with preparative syntheses of products relevant to drug fragments and bioactive natural products. Finally, we studied Type I aldolases with the unique ability to use simple aldehydes and ketones as nucleophiles. Their activity on fluorinated ketones may enable the efficient synthesis of fluorinated sugars, which are applicable to pharmaceuticals and chemical biology. Taken together, this dissertation delineates a selective and sustainable biocatalytic approach to access the unique properties conferred by fluorination, which may have broad implications for improved process design towards important organofluorines.