Methods are provided for the generation of parthenolide derivatives functionalized at carbon atoms C9 and C14. Natural cytochrome P450 enzymes, and engineered variants of these enzymes, are used to carry out the hydroxylation of these sites in parthenolide. These P450-catalyzed C&mdashH hydroxylation reactions are coupled to chemical interconversion of the enzymatically introduced hydroxyl group to install a broad range of functionalities at these otherwise unreactive sites of the molecule. The methods can also be used to produce bifunctionalized parthenolide derivatives, which in addition to modifications at the level of carbon atom C9 or C14, are also functionalized at the level of carbon atom C13.
