Epoxide-Mediated Carbon Dioxide Coupling Yields the Five-Membered Cyclic Carbonate in Cytosporin Biosynthesis

Abstract Organic carbonates (OCs) have a wide range of applications across materials science, synthetic chemistry, and medicine. The development of efficient catalytic processes for converting carbon dioxide (CO2) into OCs represents a crucial objective in sustainable chemistry and energy research. Among available strategies, the coupling of CO2 with epoxides to form cyclic carbonates is one of the most technologically and economically promising routes for CO2 valorization. Although considerable progress has been made in designing high-performance catalysts for this transformation, several limitations remain, including dependence on organic solvents, transition metal-based catalytic systems, and energy-intensive conditions, typically involving elevated temperatures and high CO2 pressures. While an increasing number of naturally occurring OCs have been identified, the biosynthetic mechanisms underlying their formation, especially for fungal-derived five-membered cyclic carbonates, remain largely unknown. In this study, we identified and functionally characterized all enzymes involved in cytosporin biosynthesis and elucidated the complete biosynthetic pathway. We demonstrated that the five-membered cyclic carbonate moiety in cytosporin E arises through a nonenzymatic, epoxide-mediated CO2 coupling reaction under neutral aqueous conditions. This strategy for constructing a five-membered cyclic carbonate is unprecedented in natural product biosynthesis and may offer valuable insights for developing environmentally benign synthetic routes toward OCs.