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

C(sp(3))-H oxyfunctionalization, the insertion of an O-atom into C(sp(3))-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(sp(3))-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 & alpha;-ketoglutarate-dependent iron dioxygenases that catalyze the site- and stereodivergent oxyfunctionalization of secondary and tertiary C(sp(3))-H bonds, providing concise synthetic routes towards four types of 92 & alpha;- and & beta;-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.

Automated summary

C(sp(3))-H oxyfunctionalization, the insertion of an O-atom into C(sp(3))-H bonds, is a challenging task in organic chemistry for site and stereoselectivity. Biocatalytic C(sp(3))-H oxyfunctionalization overcomes the limitations of small-molecule-mediated approaches by delivering catalyst-controlled selectivity. We have developed a subfamily of α-ketoglutarate-dependent iron dioxygenases that catalyze the site- and stereodivergent oxyfunctionalization of secondary and tertiary C(sp(3))-H bonds, providing concise synthetic routes towards four types of 92 α- and β-hydroxy acids with high efficiency and selectivity. This method offers a biocatalytic approach for the production of valuable chiral hydroxy acid building blocks.