Biocatalysis has revolutionized chemical synthesis, providing sustainable methods for preparing various organic molecules. In enzyme-mediated organic synthesis, most reactions involve molecules operating from their ground states. Over the past 25 years, there has been an increased interest in enzymatic processes that utilize electronically excited states accessed through photoexcitation. These photobiocatalytic processes involve a diverse array of reaction mechanisms that are complementary to one another. This comprehensive review will describe the state-of-the-art strategies in photobiocatalysis for organic synthesis until December 2022. Apart from reviewing the relevant literature, a central goal of this review is to delineate the mechanistic differences between the general strategies employed in the field. We will organize this review based on the relationship between the photochemical step and the enzymatic transformations. The review will include mechanistic studies, substrate scopes, and protein optimization strategies. By clearly defining mechanisticallydistinct strategies in photobiocatalytic chemistry, we hope to illuminate future synthetic opportunities in the area.

Biobased plasticizers, as substitutes for phthalates, have been synthesized from 5‐hydroxymethylfurfural (HMF) and carboxylic acids (or esters) through a chemoenzymatic cascade process that involves as its first step the reduction of 5‐hydroxymethylfurfural into 2,5‐bis(hydroxymethyl)furan (BHMF), followed by the esterification of BHMF with carboxylic acids (or esters) by using a supported lipase (Novozym 435). The reduction of HMF into BHMF is performed by using monodisperse metallic Co nanoparticles with a thin carbon shell (Co@C) with high activity and selectivity. After optimization of reaction conditions (temperature, hydrogen pressure, and solvent), it is possible to achieve 97 % conversion of HMF with 99 % selectivity to BHMF after 2 h reaction time. The reduction of HMF and esterification of BHMF using carboxylic acids or vinyl esters as acyl donors by lipase are optimized separately in batch and in fixed‐bed continuous reactors. The coupling of two flow reactors (for reduction and subsequent esterification) working under optimized reaction conditions affords the diesters of BHMF in roughly 90 % yield with no loss of activity during 60 h of operation.

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Tertiary nitroalkanes and the corresponding α-tertiary amines represent important motifs in bioactive molecules and natural products. The C-alkylation of secondary nitroalkanes with electrophiles is a straightforward strategy for constructing tertiary nitroalkanes; however, controlling the stereoselectivity of this type of reaction remains challenging. Here, we report a highly chemo- and stereoselective C-alkylation of nitroalkanes with alkyl halides catalyzed by an engineered flavin-dependent “ene”-reductase (ERED). Directed evolution of the old yellow enzyme from Geobacillus kaustophilus provided a triple mutant, GkOYE-G7, capable of synthesizing tertiary nitroalkanes in high yield and enantioselectivity. Mechanistic studies indicate that the excitation of an enzyme-templated charge-transfer complex formed between the substrates and cofactor is responsible for radical initiation. Moreover, a single-enzyme two-mechanism cascade reaction was developed to prepare tertiary nitroalkanes from simple nitroalkenes, highlighting the potential to use one enzyme for two mechanistically distinct reactions.

Citrus flavonoids, prunin and naringenin, are selectively produced from hydrolysis of naringin using the enzyme naringinase supported on graphene oxide.

Production of chiral alcohols from racemic mixtures with an integrated heterogeneous chemo-enzymatic two step relay catalyst in fixed bed continuous operation.

The crude naringinase from Penicillium decumbens and a purified naringinase with high α‐L‐rhamnosidase activity could be covalently immobilized on two‐dimensional zeolite ITQ‐2 after surface modification with glutaraldehyde. The influence of pH and temperature on the enzyme activity (in free and immobilized forms) as well as the thermal stability were determined using the specific substrate: p‐nitrophenyl‐alpha‐L‐rhamnopyranoside (Rha‐pNP). The crude and purified naringinase supported on ITQ‐2 were applied in the hydrolysis of naringin, giving the flavonoids naringenin and prunin respectively with a conversion >90 % and excellent selectivity. The supported enzymes showed long term stability, being possible to perform up to 25 consecutive cycles without loss of activity, showing its high potential to produce the valuable citrus flavonoids prunin and naringenin. We have also succeeded in the application of the immobilized crude naringinase on ITQ‐2 for debittering grapefruit juices in a continuous process that was maintained operating for 300 h, with excellent results.

Amino transaminases (ATAS) have been supported on a 2D ITQ-2 zeolite through electrostatic interactions, resulting in highly stable an active biocatalyst to obtain a variety of valuable chiral amines starting from prochiral ketones derived from biomass. We have extended the biocatalyst applications by designing a chemo-enzymatic process that allows to obtain as first step prochiral ketones from biomass derived compounds, through an aldol condensation-reduction step using a bifunctional metal/base catalyst. The prochiral ketone is subsequently converted in the chiral amine using the immobilized ATA. We show that it is feasible to couple both steps in a semi-continuous process to produce industrially relevant chiral amines with yields > 95% and ∼100% ee.