A multi-enzyme cascade with internal cofactor cycling for the green conversion of inert n-alkanes to α,ω-dicarboxylic acids

Abstract

The selective conversion of chemically inert linear alkanes into α,ω-dicarboxylic acids remains a significant challenge in sustainable chemistry. α,ω-Dicarboxylic acids are key building blocks for high-performance polymers and pharmaceuticals, their industrial production relies on energy-intensive, poorly selective multi-step oxidation processes. These limitations stem from the intrinsic inertness of inactivated primary C-H bonds and the difficulty of achieving regioselective dual-terminal C-H bond oxyfunctionalization under mild conditions. Consequently, progress in the conversion of chemically inert linear alkanes into α,ω-dicarboxylic acids hinges on two central challenges: enabling highly regioselective terminal C-H oxidation and developing sustainable transformation pathways. To address these challenges, we developed a multi-enzyme cascade driven by internal cofactor cycling that enables one-pot deep oxidation of dodecane to dodecanedioic acid under mild conditions. In the first stage, a hydrogen-borrowing-based NADH regeneration strategy enables selective oxidative C-H functionalization, converting dodecane to dodecanoic acid. Coupling this step with a second hydrogen-borrowing cycle and in situ elimination of H2O2 further drives terminal oxidation, ultimately affording 1.49 mM dodecanedioic acid. In addition, nonane, decane, undecane, and tridecane were successfully converted into their corresponding α,ω-dicarboxylic acids. Overall, this study establishes a green biocatalytic paradigm for the deep transformation of inert alkanes using molecular oxygen as the sole oxidant, enabled by internal cofactor cycling and in situ reactive oxygen management. This strategy maximizes atom economy and provides an efficient and sustainable route for upgrading linear alkanes into value-added products.