UC Berkeley

Macrolide natural products have been a rich source of medicinally relevant molecules. Macrolides are assembled by large protein complexes known as polyketide synthases (PKSs) via polymerization reactions of simple acetate and propionate derived building blocks. While these enzymes are capable of generating molecules of impressive structural diversity, the introduction of nonnative and potentially bioactive functional groups into the backbone of these molecules remains challenging and is mostly limited to synthetic methods. The incorporation of fluorine atoms or fluorinated moieties into both synthetic and semi-synthetic medicinally relevant molecules has been shown to improve their bioactivity, bioavailability, and stability. However, the very properties that make fluorine a valuable component of pharmaceuticals also makes it challenging to incorporate via synthetic methods. Seeking to capitalize on the modular nature of PKSs, previous work in our lab has shown that fluorinated polyketides can be synthesized by using fluorinated analogs of PKS building blocks. The work described in this dissertation follows a mechanistic approach to fluorinated extender unit incorporation into polyketides. By examining the nature of fluorinated extender unit incorporation into the 6-deoxyerythronolide B synthase modules, we were able to build a platform showing suitable promise for the site-specific incorporation of fluorine into the backbone of medicinally relevant natural products.