Shedding light on the deallenylation reaction promoted by Palladium-based catalyst

Our work addresses a key challenge in bioorthogonal chemistry: developing palladium catalysts capable of selectively activating prodrugs in aqueous biological environments. We investigate the Pd(II)-catalyzed cleavage of allenyl-protected prodrugs, a strategy for localized drug release that is limited by catalyst deactivation in water. Although previous computational studies proposed conflicting deactivation mechanisms, the molecular origins of this process remain unclear. To clarify this issue, we performed DFT calculations (PBE0/def2-TZVP//BP86(D3BJ)-def2-TZVP) on the deallenylation of the model prodrug Alle-5FU to release the anticancer agent 5-fluorouracil. Our results show a strong preference for water attack at the central allenyl carbon (C2), which exhibits the lowest activation barrier. Ongoing investigation of the subsequent C–O bond cleavage will identify the rate-determining step and provide mechanistic insights to guide the design of water-tolerant Pd catalysts for bioorthogonal applications.