Enantioselective Synthesis Of Chiral Alcohols Research Articles

Chiral Alcohols from Alkenes and Water: Directed Evolution of a Styrene Hydratase.

Enantioselective synthesis of chiral alcohols through asymmetric addition of water across an unactivated alkene is a highly sought-after transformation and a big challenge in catalysis. Herein we report the identification and directed evolution of a fatty acid hydratase from Marinitoga hydrogenitolerans for the highly enantioselective hydration of styrenes to yield chiral 1-arylethanols. While directed evolution for styrene hydration was performed in the presence of heptanoic acid to mimic fatty acid binding, the engineered enzyme displayed remarkable asymmetric styrene hydration activity in the absence of the small molecule activator. The evolved styrene hydratase provided access to chiral alcohols from simple alkenes and water with high enantioselectivity (>99 : 1 e.r.) and could be applied on a preparative scale.

Engineering ketoreductases for the enantioselective synthesis of chiral alcohols.

The use of engineered ketoreductases (KREDS), both as whole microbial cells and isolated enzymes, in the highly enantiospecific reduction of prochiral ketones is reviewed. The homochiral alcohol products are key intermediates in, for example, pharmaceuticals synthesis. The application of sophisticated protein engineering and enzyme immobilisation techniques to increase industrial viability are discussed.

The limits to biocatalysis: pushing the envelope.

In the period 1985 to 1995 applications of biocatalysis, driven by the need for more sustainable manufacture of chemicals and catalytic, (enantio)selective methods for the synthesis of pharmaceutical intermediates, largely involved the available hydrolases. This was followed, in the next two decades, by revolutionary developments in protein engineering and directed evolution for the optimisation of enzyme function and performance that totally changed the biocatalysis landscape. In the same period, metabolic engineering and synthetic biology revolutionised the use of whole cell biocatalysis in the synthesis of commodity chemicals by fermentation. In particular, developments in the enzymatic enantioselective synthesis of chiral alcohols and amines are highlighted. Progress in enzyme immobilisation facilitated applications under harsh industrial conditions, such as in organic solvents. The emergence of biocatalytic or chemoenzymatic cascade processes, often with co-immobilised enzymes, has enabled telescoping of multi-step processes. Discovering and inventing new biocatalytic processes, based on (meta)genomic sequencing, evolving enzyme promiscuity, chemomimetic biocatalysis, artificial metalloenzymes, and the introduction of non-canonical amino acids into proteins, are pushing back the limits of biocatalysis function. Finally, the integral role of biocatalysis in developing a biobased carbon-neutral economy is discussed.

A solar light-driven, eco-friendly protocol for highly enantioselective synthesis of chiral alcohols via photocatalytic/biocatalytic cascades

The judicious utilization of solar light for the asymmetric synthesis of optically active compounds by imitating natural photosynthesis introduces a new concept that harnesses this renewable energy in vitro for ultimate transformation into chiral chemical bonds. Herein, we present a comprehensive description of such a biomimetic endeavor towards the design and construction of an asymmetric artificial photosynthesis system that comprises an efficient method of nicotinamide cofactor (NADPH) regeneration under visible light employing a graphene-based light harvesting photocatalyst and its subsequent utilization in an enzyme-catalyzed asymmetric reduction of prochiral ketones to expediently furnish the corresponding chiral secondary alcohols. A detailed optimization study revealed a major dependency of the reaction outcome on the amount of cofactor, photocatalyst and enzyme used, as well as the mode of their addition. A series of structurally diverse ketones bearing an array of (hetero)aryl/alkyl substituents proved to be highly suitable to our photocatalytic–biocatalytic cascade approach, providing (R/S)-1-(hetero)aryl/alkylethanols in excellent enantioselectivities (ee ∼ 95–>99.9%) under mild and environmentally benign conditions. To the best of our knowledge, the synthesis of these enantiopure alcohols employing a visible-light-driven nicotinamide cofactor regeneration strategy has been reported for the first time. Such enantioenriched alcohols act as versatile chiral building blocks for the synthesis of compounds having industrial and pharmaceutical relevance. In addition, this solar-to-chiral chemicals prototype appears advantageous from ecological and economical perspectives. We describe mechanistic pathways to demonstrate how the present catalytic synthesis protocol functions through perfect orchestration between visible-light-driven photocatalysis and biocatalysis to be successively applied in inducing asymmetry in an achiral molecule for the ultimate goal of solar energy utilization in the synthesis of valuable chiral fine chemicals. This work highlights the potential advantages of a bioinspired system to the pertinence of solar energy in asymmetric transformations leading to enantioenriched alcohol precursors, and thus opens up a new field of research that might emerge as an important breakthrough with promising implications towards generating a sustainable and non-fossil/non-nuclear energy future.