Biocatalytic Efficient and Enantiocomplementary Synthesis of 3‑Hydroxy-3-hydroxymethyloxindoles by Combining Halohydrin Dehalogenase and Epoxide Hydrolase

Enantiopure 3-hydroxyoxindoles are one class of basic
functional
molecules that hold particular interest in medicinal chemistry and
drug discovery due to their diverse pharmacological properties. While
many chemical methods have been developed for producing these molecules,
there remains a continuous demand for more efficient and greener approaches.
Herein, we present a novel dual-enzyme biocatalytic platform for the
enantiocomplementary synthesis of chiral 3-hydroxy-3-hydroxymethyloxindoles,
compounds that have not previously been synthesized stereoselectively.
This biocatalytic platform involves the halohydrin dehalogenase-catalyzed
kinetic resolution of racemic spiro-epoxyoxindoles with nitrite, paired
with the epoxide hydrolase-catalyzed enantiospecific hydrolysis of
the residual enantiopure spiro-epoxyoxindoles. Both enzymatic processes
demonstrate high catalytic selectivity and efficiency, enabling the
preparative synthesis of various (R)- and (S)-3-hydroxy-3-hydroxymethyloxindoles with high yields (up
to 50%) and optical purities (up to >99% ee).
In
addition, useful transformations of the chiral products were conducted
to further showcase the scalability and applicability of the biocatalytic
platform.