Efficient Synthesis for a Wide Variety of Patellamide Derivatives and Phosphatase Activity of Copper‐Patellamide Complexes

Copper complexes of patellamides have shown catalytic activity in a variety of reactions but their biological function remains unknown. There are significant differences between the natural macrocycles and synthetic analogues in the various catalytic activities. It therefore is essential to be able to perform in vivo and ex vivo reference measurements with the natural patellamide macrocycles, very similar derivatives and a large range of synthetic analogues. The preparative method described allows for a highly adaptable synthetic process producing building blocks for a large range of patellamide derivatives: apart from natural compounds, a new synthetic patellamide was prepared that does not have any substituents at any of the four heterocycles. Together with the variation of substituents at the aliphatic backbone, this allowed to elucidate the catalytic activity for phosphoester hydrolysis as a function of the structure and dynamics of the dicopper(II)‐patellamide complexes, both by experiment and DFT‐based mechanistic studies.