A DFT study on chiral synthesis of R-phenylacetyl carbinol within the quantum chemical cluster approach

Significance Statement

α-hydroxyl ketones are important precursors in the pharmaceutical industry. α-hydroxyl ketones can be found in antitumor antibiotics and antidepressants. In addition, they are important as fine chemicals owing to their utility as building blocks for the synthesis of larger molecules. R-phenylacetylcarbinol is a precursor in the production of a number of drugs with β and α adrenergic attributes, for example, pseudoephedrine, norephedrine, and L-aphedrine.

However, the existing industrial production of R-phenylacetylcarbinol is majorly based on fermentation implementing yeast Saccharomyces cerevisiae. Unfortunately, these processes indicate low efficiency of substrate utilization, toxicity towards living organisms, and production of several by-products reference to the action of a number of intracellular enzymes. Therefore, a number of researchers, in the recent years, have focused on the development of processes based on purified enzymatic catalysts instead of the entire cell fermentation.

A number of experimental studies have been conducted for the analysis of R-phenylacetylcarbinol preparation catalyzed by enzymes owing to its importance as a pharmaceutical precursor and a building block for the synthesis of larger molecules. However, in view of the number of studies on this topic, the enzymatic reaction path resulting to R-phenylacetylcarbinol has not been considered from the first-principle methods. Therefore, some aspects remain unclear, for example, the molecular bases for the preference of the enzyme for the condensation with the natural substrates.

Omar Alvarado, Ignacio Lizana, and Eduardo Delgado at Universidad de Concepción in collaboration with Gonzalo Jaña at Universidad Andrés Bello and Iñaki Tuñon at Universidad de Valencia addressed the biosynthesis of R-phenylacetyl carbinol through the means of density functional theory computation within the quantum chemical cluster method. Their research work is published in Chemical Physics Letters.

In the proposed method, the authors took a limited number of atoms out of the enzyme to represent the active site and placed them in a dielectric cavity to give polarization effects. The researchers then quantum mechanically treated all the atoms in the model at highest possible level.

The study encompassed reactivity analysis in terms of Fukui functions, characterization of the transition states, potential energy surface scans, and computation of the activation free energies. Implicit solvation effects were incorporated as single point computations on the gas phase optimized structures. The outcomes of the study will be helpful in understanding the biosynthesis of R-phenylacetyl carbinol at molecular level.

The reaction that led to the formation of R-phenylacetyl carbinol proceeded through synchronous concerted mechanism. This means that the carboligation Cα-Cβ as well as the proton transfer from the hydroxyl group hydroxyl-ethylthiamin diphosphate to the carbonyl oxygen of benzaldehyde occurred simultaneously. The N1 atom of the aminopyrimidine moiety of hydroxyl-ethylthiamin diphosphate is deprotonated in the course of the reaction and the Glu139 residue was observed as glutamic acid.

The computed values of free energy of activation were 16.2 kcal/mol for the reaction in gas phase and 13.3kcal/mol in aqueous solution. The reaction results to be exergonic for both solution and gas phase, -5.6 and -4.0 kcal/mol, respectively. The outcomes of this study are important in gaining an in-depth understanding of the reaction mechanism in the enzyme.

About the author

Eduardo Delgado is full professor at the Department of Physical Chemistry, Faculty of Chemical Sciences, Universidad de Concepcion, Concepcion, Chile.  In 1990 he obtained the degree of Doctor in Sciences, major Chemistry, from the same university.

His current research interest is about the application of the computational chemistry methods (QSAR, QSPR, DFT and QM/MM calculations) on systems of biochemical interest in order to shed light at molecular level on the mechanism of action/inhibition of enzymes.


Omar Alvarado, Ignacio Lizana, Gonzalo Jaña, Iñaki Tuñon, Eduardo Delgado. A DFT study on the chiral synthesis of R-phenylacetyl carbinol within the quantum chemical cluster approach. Chemical Physics Letters, volume 677 (2017), pages 30–34.


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