Co-ARMs · Development of new-to-nature reactions under the concept of synergistic catalysis through the design of novel cobalt-based artificial metalloenzymes.

Development of new-to-nature reactions under the concept of synergistic catalysis through the design of novel cobalt-based artificial metalloenzymes.

Enzyme catalysis has experienced a remarkable renaissance in research over the past decade. Its growing popularity is related to easy reaction set-up, environmentally friendly reaction conditions, such as aqueous media as solvent and non-cryogenic temperatures, and its renewable, biodegradable nature. However, its broader application in synthetic chemistry, especially at industrial level, has been constrained due to a series of limitations related to a relatively narrow reaction scope, substrate-dependence issues, and restricted product variability. Only recently, with the advancement of directed evolution and modern genetic engineering techniques, the discovery and development of biocatalysts for new-to-nature reactions started to flourish. With the aim to develop and expand new methods under the framework of sustainable chemistry, expanding the scope of homogeneous catalytic transformations into the realm of enzymes is imperative. The expansion of homogeneous catalytic reactions into the realm of enzymes is an absolute necessity to develop sustainable chemistry. A promising approach to this objective is the creation of artificial metalloenzymes (ARMs), engineered metalloproteins which cannot be found in nature and are capable to catalyze abiological chemical reactions. A transformation of high relevance to medicinal, agrochemical, and pharmaceutical chemistry is allylic and benzylic functionalization. These transformations can generate structural frameworks common to many biologically active molecules but currently lack natural enzymatic counterparts. The Co-ARMs (Cobalt-containing ARtificial Metalloenzymes) project aims to fill this gap by designing novel ARMs relying on the unique reactivity of cobalt in mediating these challenging transformations. To push the boundaries of ArM-catalyzed reactivity, we propose a synergistic catalysis strategy that combines two abiological catalytic elements within a single protein scaffold: (1) an unnatural amino acid (uAA) capable of performing nucleophilic activation (i.e., enamine formation); and (2) a synthetic cobalt complex designed to activate electrophilic allylic or benzylic substrates. This dual-site approach would allow the design of a powerful, versatile catalyst capable of unlocking new chemical transformations in a sustainable and selective manner.

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