C–H fluorination plays a central role in pharmaceutical and agrochemical synthesis, as the introduction of fluorine often enhances a molecule's metabolic stability, potency, and bioavailability. Over 20% of approved drugs contain fluorinated functional groups, underscoring the demand for efficient and selective fluorination methods. However, traditional C–H fluorination techniques rely on harsh conditions or corrosive reagents that limit functional group tolerance, reduce selectivity, and pose significant safety and environmental risks. These challenges hinder scalability and prevent integration into biocompatible synthesis workflows or enzyme-driven reaction cascades.
This photoenzymatic platform enables regioselective benzylic C–H fluorination under mild, aqueous conditions using engineered protein scaffolds. The biocatalyst incorporates the unnatural amino acid p-benzoyl-L-phenylalanine and key active site mutations to achieve photoactivation under 365 nm light. The system catalyzes high-yield, benzylic monofluorination across a broad substrate range, including ethylbenzene derivatives, naphthalenes, and aryl ketones. The catalyst achieves total turnover numbers over 270 and product yields up to 44%. Importantly, it is compatible with other biocatalysts, enabling one-pot enzymatic cascades for the synthesis of fluorinated polyketides and chiral β-fluorinated alcohols. This method combines high selectivity and efficiency with sustainability, offering a transformative solution for the synthesis of fluorinated molecules.
Provisional US patent application was filed 11/26/2024