A Dual‐Metal‐Catalyzed Sequential Cascade Reaction in an Engineered Protein Cage

Herein, we describe the creation of an artificial protein cage housing a dual‐metal‐tagged guest protein that catalyzes a linear, two‐step sequential cascade reaction. The guest protein consists of a fusion protein of HaloTag and monomeric rhizavidin. Inside the protein capsid, we established a ruthenium‐catalyzed allylcarbamate deprotection reaction followed by a gold‐catalyzed ring‐closing hydroamination reaction that led to indoles and phenanthridines with an overall yield of up to 66 % in aqueous solutions. Furthermore, we show that the encapsulation stabilizes the metal catalysts against deactivation by air, proteins and cell lysate. Inside an artificial protein cage, a dual‐metal‐tagged guest protein catalyzed a linear, two‐step sequential cascade reaction involving deprotection followed by hydroamination. This non‐orthogonal tandem catalysis in an encapsulin nanocompartment opens an exciting toolbox for the development of compartmentalized prodrug activation reactions in biological systems.