Artificial Copper Enzymes for Asymmetric Diels-Alder Reactions

The development of artificial copper enzymes from sterol carrier protein type 2 like domain (SCP‐2L) for the use in asymmetric catalysis was explored. For this purpose, proteins were modified with various nitrogen donor ligands. Maleimide‐containing ligands were found most suitable for selective cysteine bio‐conjugation. Fluorescence spectroscopy was used to confirm copper binding to an introduced phenanthroline ligand, which was introduced in two unique cysteine containing SCP‐2L mutants. Copper adducts of several modified SCP‐2L templates were applied in asymmetric Diels–Alder reactions. A clear influence of both the protein environment and the introduced ligand was found in the asymmetric Diels–Alder reaction between azachalcone and cyclopentadiene. A promising enantioselectivity of 25 % ee was obtained by using SCP‐2L V83C modified with phenanthroline–maleimide ligand. Good endo selectivity was observed for SCP‐2L modified with the dipicolylamine‐based nitrogen donor ligand. These artificial metalloenzymes provide a suitable starting point for the implementation of various available techniques to optimise the performance of this system. Finding the ligand: The covalent modification of sterol carrier protein type 2 like domain with nitrogen ligands affords artificial metalloenzymes for the copper‐catalyzed Diels–Alder reaction (see picture). A distinct influence of the location of the ligand within the host on the catalytic performance was observed. An ee of 25 % was found for one ligand–protein construct. The results provide a suitable framework for the development of more selective systems.