Chemoenzymatic

Chemoenzymatic synthesis is an approach that combines chemical synthesis with enzymatic transformations to prepare complex molecules. In this strategy, chemical methods construct the molecular framework or introduce functional handles, while enzymes provide highly selective transformations that are difficult to achieve chemically, such as enantio- or diastereoselective oxidations, reductions, or stereoselective bond formations. Chemoenzymatic methods are widely used in natural product synthesis, pharmaceutical development, and carbohydrate or lipid chemistry.

There are two main modes: sequential and one-pot cascades. In sequential chemoenzymatic synthesis, a molecule is advanced by a chemical step to a substrate for an enzyme, followed by an enzymatic step, potentially repeated multiple times. In chemoenzymatic cascades, chemical and enzymatic steps are combined in a single pot, sometimes with cofactor recycling, to streamline the process. Enzymes employed include oxidoreductases, hydrolases, glycosyltransferases, and lyases, chosen for their ability to install or modify stereochemistry or introduce otherwise challenging functionalities.

Advantages of chemoenzymatic approaches include high regio- and stereoselectivity, milder reaction conditions, reduced protection–deprotection steps, and improved sustainability. They enable late-stage functionalization and access to chiral compounds that are difficult to obtain by chemistry alone.

Challenges include enzyme availability and stability, limited substrate scope, dependence on cofactors, and technical integration of enzymatic steps with chemical steps, especially at scale. Advances in enzyme engineering and process development continue to expand the utility of chemoenzymatic strategies.