Enzymes and Photons: Incorporating Nature’s Tools for Sustainable Organic Synthesis

Recent advances in the fields of bio- and photocatalysis are reshaping how synthetic chemistry is conducted, steering it toward a more sustainable future. Leveraging natural enzymes in chemoenzymatic and photobiocatalytic strategies enables the discovery of new-to-nature reactivity, provided important incompatibility challenges can be addressed.

Text Janne Naapuri, photo iStock

Many traditional chemical methods rely on hazardous reagents, high energy input, and large amounts of harmful waste. In the modern research climate, driven by environmental concerns and industrial demands, synthetic chemists are searching for more sustainable alternatives. As so often before, nature again provides both inspiration and solutions to these problems.

Two such solutions are biocatalysis and photochemistry, both rooted in fundamental aspects of chemistry found in nature. In biocatalysis, inherently environmentally friendly enzymes carry out remarkably selective and efficient transformations, while photons in light-driven chemistry offer a traceless and mild source of energy.

The two fields have matured to the point of industrial relevance, yet I believe they still offer substantial untapped potential.

In my research, I look to expand the synthetic toolbox with greener enzymatic functions, mainly by bridging these two approaches through photobiocatalysis and by overcoming typical incompatibility challenges in chemoenzymatic synthesis.

Biocatalysis in Non-Conventional Media

Enzymes primarily prefer to operate in aqueous reaction environments and are easily deactivated under common synthetic conditions, such as organic solvents or elevated temperatures.

However, water is often a problematic solubilizer for organic structures. Addressing this mismatch is a central issue in synthetic biocatalysis.

Beyond commonly employed organic co‑solvents, promising non-conventional solvent systems have emerged recently, including emulsified media, highly tunable ionic liquids (ILs) and deep eutectic solvents (DESs).

“Ionic liquids and deep eutectic solvents based on biodegradable components such as choline are generally seen as green alternatives for organic solvents.”

During my PhD journey and postdoctoral work, I have studied heme- and vanadate-dependent peroxidases as catalysts in the synthesis of O-heterocyclic bioactive molecules and their precursors.

Here, additions of amphiphilic emulsifiers were found to greatly improve the performance of various transformations catalyzed by the peroxidases, either in purely aqueous or biphasic systems. The resulting micellar structures help solubilize hydrophobic substrates while simultaneously shielding enzymes from harmful conditions.

The choice of solvent also plays a key role in sustainability. Ionic liquids and deep eutectic solvents based on biodegradable components such as choline are generally seen as green alternatives for organic solvents due to benefits like low flammability and reduced toxicity.

In my research, choline-based ILs were tolerated as co-solvents by the oxidoreductase enzymes, and in some cases, choline even served a dual purpose, acting both as a solubilizer and as a source of hydrogen peroxide in combination with choline oxidase, generating the vital oxidant needed by heme-peroxidases directly within the reaction.

Chemoenzymatic One-Pot Processes

Another way to improve the overall sustainability of a synthesis is to combine several successive reactions in a single vessel as a one-pot process, reducing the number of separation and purification steps needed.

Enzymes are ideally suited for purely biocatalytic one-pot cascade designs, but their use in conjunction with a broader range of chemical reactivity is often challenging. For instance, pairing with metal catalysis can lead to deactivating interactions, unless contact between the two species is somehow limited.

In examples involving palladium, gold or silver, we addressed this issue by physically separating the proteins from the metal species either by compartmentalization using amphiphile-stabilized micellar media or by co-immobilization strategies.

Photobiocatalytic Synthesis

I recently joined Tampere University, where exploring light-driven technologies has been a central theme in chemistry research. The related infrastructure available there has encouraged me to direct my studies towards integrating visible-light applications with enzymatic synthesis.

“The most enticing prospects in the field lie in the direct activation of enzymes upon visible-light irradiation, prompting non-natural reactivity.”

The interplay of photons and enzymes is a fundamental process for life in the form of photosynthesis. Inspired by this, there has been a growing surge in one-pot synthesis methods that combine separate photo- and biocatalytic steps within a single process.

Such photobiocatalysis ranges from the use of metal complexes or organic dyes to produce reactants (e.g., hydrogen peroxide) for the biocatalysis on-site or to regenerate the enzyme cofactors, to linear cascades of complementary reactivity.

Moreover, the most enticing prospects in the field lie in the direct activation of enzymes upon visible-light irradiation, prompting non-natural reactivity through light-dependent enzyme promiscuity. This is made possible by certain enzyme cofactors, such as flavins or nicotinamides, being prone to excitation either directly or via formation of electron donor‑acceptor (EDA) complexes.

The approach combines the benefits of mild photochemical reactivity with the excellent selectivities induced by the enzyme active site geometry. In prominent examples, flavin-dependent ene-reductases have been employed for a variety of asymmetric C-C bond formations.