Behind the Science: Enantioselective Preparation of δ-Valerolactones

Behind the Science: Enantioselective Preparation of δ-Valerolactones

Author: Kevin Jones

Dr. Kevin Jones, Associate Editor for ChemCatChem, talks to Professor Vicente Gotor-Fernández of the University of Oviedo, Spain, about his article on the enantioselective preparation of δ-valerolactones that was recently published in ChemCatChem.

Can you give a brief summary of the results described in your paper “Enantioselective Preparation of δ-Valerolactones with Horse Liver Alcohol Dehydrogenase”?

We reported an asymmetric synthesis of optically active lactones based on the desymmetrization of the corresponding prochiral 3-arylpentane-1,5-diols. To achieve this, alcohol dehydrogenases were selected as biocatalysts for screening. We found the best results with horse liver alcohol dehydrogenase (HLADH). In particular, 3-phenylpentane-1,5-diol was selected as the model substrate, and the recycling system, pH, and cosolvent influence were deeply studied and were found to favor the formation of the corresponding valerolactone towards the hemiacetal form.

Satisfyingly, we were able to extend this methodology to a representative set of prochiral diols bearing different pattern substitutions at C-3. By this, we achieved the formation of the corresponding optically active lactones in good to excellent conversions and enantiomeric excesses.

In addition, and to further rationalize the relation between the diol structure and the enantioselectivity, modeling studies were performed on selected substrates. We observed that the increase in the selectivity of this process might be facilitated by an intramolecular hydrogen-bond interaction.

How will you follow up on this discovery?

Lactones are relevant organic molecules mainly because of their role as intermediates in interesting final manufacturing products for the industrial sector. Our group is currently involved in the development of a number of synthetic approaches to obtain this family of products by using different classes of enzymes such as lipases, alcohol dehydrogenases, or laccases. In these approaches, the introduction of chirality is the key step and can be achieved by using a more selective enzyme, such as an engineered alcohol dehydrogenase, or by employing auxiliaries for lipases and laccases such as optically active carboxylic acid derivatives or chiral mediators, respectively.

Additionally, we are studying a new family of lactones including both prochiral and racemic diols as well as ketones depending on the enzyme considered. Reaction engineering studies are providing improvements in the isolation of the final products.

What benefits does biocatalysis have over traditional synthetic approaches?

Biocatalytic processes have demonstrated their potential in synthetic strategies, and nowadays they can be considered useful and complementary tools for both unexplored and already known transformations. In particular, the display of selectivity and the possibility to act under very mild reaction conditions with remarkable activities make enzymes attractive catalysts for synthetic chemists. Thus, protections and deprotection strategies can be overcome, leading to more efficient, sustainable, and shorter routes to the desired chemical targets.

Among biotransformations, asymmetric transformations are demanding tasks for the industrial sector, and many classes of enzymes have proved their potential not only in classical kinetic resolutions but also in dynamic kinetic resolutions, deracemizations, or desymmetrizations. In this context, the production of high value-added derivatives, pharmaceuticals, fragrances, and agrochemicals has been achieved with high levels of success.

What are the main challenges in developing biocatalytic methods?

First of all, scientists must make progress in the identification of novel enzymes. Enzyme engineering is much faster than it was ten years ago, but the screening and identification of potential candidates for a selected transformation is still time consuming. Computer design can also help to minimize the time it takes, although sometimes this method is not very accurate and a better understanding of the structure and mechanism of the enzymes may be required.

This issue is closely related to the use of unconventional media. In this sense, the use of organic cosolvents or unique media has been fully exploited with many classes of enzymes. These offer great advantages for the own biotransformation and the isolation of final products. In this context, neoteric solvents have attracted the attention of a vast number of researchers, but there is still some room to improve the results and engineer additional reaction media.

The idea of simplifying the systems by using combinations of various enzymes in one pot by means of preparing all-in-one catalysts or, alternatively, carrying out multicomponent reactions using multistep protocols is currently attracting the attention of many researchers.

The article they talked about:

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