Versatile Biocatalytic C(sp3)−H Oxyfunctionalization for the Site‐ Selective and Stereodivergent Synthesis of α‐ and β‐Hydroxy Acids

Abstract

AbstractC(sp3)−H oxyfunctionalization, the insertion of an O‐atom into C(sp3)−H bonds, streamlines the synthesis of complex molecules from easily accessible precursors and represents one of the most challenging tasks in organic chemistry with regard to site and stereoselectivity. Biocatalytic C(sp3)−H oxyfunctionalization has the potential to overcome limitations inherent to small‐molecule‐mediated approaches by delivering catalyst‐controlled selectivity. Through enzyme repurposing and activity profiling of natural variants, we have developed a subfamily of α‐ketoglutarate‐dependent iron dioxygenases that catalyze the site‐ and stereodivergent oxyfunctionalization of secondary and tertiary C(sp3)−H bonds, providing concise synthetic routes towards four types of 92 α‐ and β‐hydroxy acids with high efficiency and selectivity. This method provides a biocatalytic approach for the production of valuable but synthetically challenging chiral hydroxy acid building blocks.