Merging Biocatalysis and Chemocatalysis in Flow: State-of-the-Art and Future Directions for Sustainable Synthesis.

The growing demand for complex molecules continues to drive innovation in organic synthesis, yet challenges in sustainability, selectivity, scalability, and harsh reaction conditions persist. Enzymes offer exquisite chemo-, regio-, and stereoselectivity under mild conditions, while chemocatalysis provides robust and versatile reactivity. However, integrating these approaches into streamlined processes remains difficult due to incompatible conditions and operational constraints. Continuous flow chemistry offers a promising solution by enabling the efficient combination of biocatalysis and chemocatalysis, while improving atom economy, reaction control, scalability, and energy efficiency. This review highlights key advances up to 2025 in merging enzymatic and chemical steps into streamlined continuous flow cascades. It analyzes examples involving various enzyme classes-hydrolases, oxidoreductases, lyases, transferases, and isomerases-used alongside chemical catalysts. Major challenges such as enzyme immobilization, catalyst leaching, and reactor clogging are discussed, along with innovative solutions. The review also discusses how advanced enzyme engineering and immobilization strategies enhance biocatalyst activity, stability, and compatibility with chemical steps. By outlining recent progress and future directions, this review emphasizes how the integration of biocatalysis, chemocatalysis, and flow chemistry can foster more sustainable and efficient synthetic methodologies, particularly relevant to the pharmaceutical and fine chemical industries.