Synthesis of Oxygenated Sesquiterpenoids Enabled by Combining Metabolic Engineering and Visible‐Light Photocatalysis

The diversification of natural products to expand biologically relevant chemical space for drug discovery can be achieved by combining complementary bioprocessing and chemical transformations. Herein, genetically engineered Escherichia coli fermentation to produce amorphadiene and valencene was combined with metal-free photocatalysis transformations to further access nootkatone, cis-nootkatol and two hydration derivatives. In fermentation, using a closed, anaerobic condition avoided the use of organic overlay, increased the productivity, and simplified the work-up process. Metal-free photocatalysis hydration and allylic C-H oxidation were designed and implemented to make the whole process greener. It was shown that the anti-Markovnikov selectivity of photocatalyzed alkene hydration could be reversed by stereo-electronic and steric effects existing in complex natural products. The combination of bioprocessing and photocatalysis may provide an efficient and greener way to expand the chemical space for pharmaceutical, flavor and fragrance industry.