Artificial metalloenzymes based on copper heteroscorpionate complexes for C-H functionalization catalysis

This thesis capitalizes on the efforts of the Ward lab to develop artificial metalloenzymes based
on earth-abundant transition metals for C-H functionalization chemistry.
Herein, a novel approach for the design of heteroscorpionate complexes was developed using
pyrazole metathesis. This strategy enabled the access to an unprecedented
tris(pyrazolyl)borate ligand chiral at the boron and to biotinylated copper heteroscorpionate
complexes. Following supramolecular assembly with streptavidin, the resulting artificial
metalloenzymes were characterized by spectroscopic and computational methods. Chemical
optimization and single point mutation of these hybrid catalysts displayed high activity for
intramolecular C–H insertion reactions. A protein expression/purification platform in 96-well
plates was developed for the genetic optimization of the artificial metalloenzymes. Identification
of superior mutants enabled the regio- and enantioselective functionalization of unactivated C–
H bonds with high turnover numbers.
Additionally, an artificial metalloenzyme based on an iron(III) tetraamido macrocyclic ligand
(Fe(TAML) and the streptavidin technology was developed. Point mutations allowed to perform
enantioselective intermolecular hydroxylation of benzylic C–H bonds using hydrogen peroxide.
Kinetic studies revealed a kinetic resolution effect within the catalytic pocket. Finally, an
enzymatic cascade relying on glucose oxidase enabled to use molecular oxygen as terminal
oxidant.
Artificial metalloenzymes based on earth-abundant transition metals and C–H functionalization
catalysis currently stand at the forefront of chemical research. We believe that this work opens
promising avenues for the development of more efficient and sustainable chemical processes.