Biocatalytic Asymmetric Synthesis of Chiral Alcohols

Biocatalytic asymmetric synthesis of chiral alcohols harnesses the remarkable selectivity of enzymes to convert prochiral ketones into optically pure alcohols under mild conditions. Chiral alcohols serve as key building blocks in pharmaceuticals, agrochemicals and fine chemicals, and their production demands high enantiomeric excess, operational simplicity and sustainability. Oxidoreductases, especially short-chain dehydrogenases/reductases and aldo–keto reductases, catalyse stereoselective reductions using nicotinamide cofactors (NADH or NADPH). Advances in protein engineering, including structure-guided design and semi-rational mutagenesis, have yielded robust variants with tailored substrate scope and improved thermostability. In parallel, whole-cell biocatalytic platforms integrate cofactor recycling systems, often based on formate or glucose dehydrogenases, obviating the need for stoichiometric coenzyme addition. Gene mining and metagenomic screening continue to expand the repertoire of enzymes capable of reducing sterically hindered or electronically diverse ketones. Process engineering, from solvent optimisation to fed-batch substrate feeding, has further enhanced productivity and facilitated preparative-scale synthesis. Together, these developments underscore the global significance of biocatalytic routes as sustainable, cost-effective alternatives to conventional chemical methods and as enablers of greener manufacturing in the pharmaceutical and chemical industries.

Research from Nature Portfolio

Recent studies have elucidated the structural basis of anthrol reductase activity to achieve highly enantioselective reduction of bulky 1,3-cyclodiketones and α-haloacetophenones, revealing key active-site residues and enabling structure-guided engineering of variants that deliver enantiopure ketols and halohydrins. Another work employed semi-rational design of a thermostable aldo–keto reductase from Thermotoga maritima, using crystallographic and computational insights to generate mutants with enantiomeric excess exceeding 99% for both pro-R and pro-S conformations of ethyl-2-hydroxy-4-phenylbutyrate, demonstrating an effective strategy for tuning stereoselectivity in green catalysts.

Biocatalytic Asymmetric Synthesis of Chiral Alcohols publication trend

The graph below shows the total number of articles in biocatalytic asymmetric synthesis of chiral alcohols across all publications each year (not limited to Nature Index journals).

Technical terms

Enantioselectivity: The preference of an enzyme to catalyse formation of one mirror-image isomer over the other.

Prochiral ketone: A ketone substrate that can be converted into a chiral centre upon reduction.

Cofactor recycling: The in situ regeneration of redox cofactors such as NADH or NADPH to sustain enzymatic reactions.

Whole-cell biocatalysis: Use of intact microbial cells as catalysts, combining enzyme function and cofactor regeneration in one system.

Structure-guided engineering: The use of three-dimensional structural information to design enzyme variants with enhanced performance.

References

1. Structural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins. Nature Communications (2023).
2. Semi-rational engineering of a thermostable aldo–keto reductase from Thermotoga maritima for synthesis of enantiopure ethyl-2-hydroxy-4-phenylbutyrate (EHPB). Scientific Reports (2017).
3. Rules for biocatalyst and reaction engineering to implement effective, NAD(P)H-dependent, whole cell bioreductions. Biotechnology Advances (2015).
4. Gene mining-based identification of aldo–keto reductases for highly stereoselective reduction of bulky ketones. Bioresources and Bioprocessing (2018).
5. Carbonyl reductase identification and development of whole-cell biotransformation for highly efficient synthesis of (R)-[3,5-bis(trifluoromethyl)phenyl] ethanol. Microbial Cell Factories (2016).