Integrating Vitamin B ₁₂ with Immobilized Lipase for a Recyclable Chemoenzymatic Cascade

Chemoenzymatic cascades combine the strengths of chemical and biological catalysis, offering tremendous potential for applications in synthetic chemistry, but integrating natural metallocofactors with immobilized enzymes in aqueous media remains underdeveloped. Here, we report the example of a recyclable chemoenzymatic cascade through integrating a natural metal‐based catalyst (vitamin B 12 ) with an immobilized enzyme. By a two‐step‐sequence chemoenzymatic cascade, vitamin B 12 first catalyzes a deprotection of allyl ether to release 3‐phenyl‐1‐propanol, which is subsequently converted by immobilized Candida antarctica lipase B (CalB) into the target ester 3‐phenylpropyl butyrate. CalB is immobilized on tailored alkyl‐functionalized silica nanoparticles, creating a hydrophobic microenvironment that enhances enzyme immobilization and good chemoenzymatic cascade activity, outperforming the controls (free enzyme and Novozyme 435). Under optimized conditions, the designed cascade reaction achieves 62% conversion in 24 h, and interestingly, the system can be reused for at least five cycles while retaining over 90% of its initial activity. As a compelling demonstration of integrating a natural metal complex with immobilized enzymes in a cascade process, this article establishes a good example for chemoenzymatic synthesis, with broad potential for extension to other high‐value chemical transformations.