Journal Article

Engineering non-haem iron enzymes for enantioselective C(sp3)–F bond formation via radical fluorine transfer

Chen, Zhenhong, Zhao, Qun, Rui, Jinyan, Chen, Xiahe, Yu, Qinglan E., Soler, Jordi, Yang, Yunfang, Garcia-Borràs, Marc, Huang, Xiongyi, Ji, Nathan Tianlin

2024

Overview

In recent years there has been a surge in the development of methods for the synthesis of organofluorine compounds. However, enzymatic methods for C-F bond formation have been limited to nucleophilic fluoride substitution. Here, we report the incorporation of iron-catalysed radical fluorine transfer, a reaction mechanism that is not used in naturally occurring enzymes, into enzymatic catalysis for the development of biocatalytic enantioselective C( )-F bond formation. Using this strategy, we repurposed ( )-2-hydroxypropylphosphonate epoxidase from ( HppE) to catalyse an -fluoroamide directed C( )-H fluorination. Directed evolution has enabled HppE to be optimized, forming diverse chiral benzylic fluoride products with turnover numbers of up to 180 and with excellent enantiocontrol (up to 94% e.e.). Mechanistic investigations showed that the N-F bond activation is the rate-determining step, and the strong preference for fluorination in the presence of excess NaN can be attributed to the spatial proximity of the carbon-centered radical to the iron-bound fluoride.

• Publisher: Nature Publishing Group
• Subject: Bonding / Carbon / Catalysis / Crystal structure / Directed evolution / Drug development / Enantiomers / Enzymes / Fluorides / Fluorination / Fluorine / Haem / Iron / Optimization / Organofluorine compounds / Reaction mechanisms / Sodium azide / Sodium azides / Substitution reactions