Research paper A DFT study on the chiral synthesis of R-phenylacetyl carbinol within the quantum chemical cluster approach Omar Alvarado a , Ignacio Lizana a , Gonzalo Jaña b , Iñaki Tuñon c , Eduardo Delgado a,⇑ a Departamento de Físico-Química, Facultad de Ciencias Químicas, Universidad de Concepción, Concepción, Chile b Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, sede Concepción, Universidad Andrés Bello, Chile c Departamento de Química Física, Universidad de Valencia, 46100 Burjassot, Spain article info Article history: Received 3 February 2017 In final form 23 March 2017 Available online 28 March 2017 abstract The reaction pathway leading to R-phenylacetyl carbinol within the quantum chemical cluster approach is addressed by means of density functional theory (DFT) calculations. The study includes calculation of Fukui functions, activation free energies, and potential energy surface scans, both in gas and solution phase. The protonation states of the nitrogen atoms of the pyrimidine moiety are determined. The reac- tion appears to be slightly exergonic (DG 0 = 5.6 and 4.0 kcal/mol for gas and solution phase, respec- tively) following a concerted synchronous mechanism having activation free energy barriers of 16.2 and 13.3 kcal/mol, in gas phase and solution phase, respectively. Ó 2017 Published by Elsevier B.V. 1. Introduction a-hydroxy ketones are important precursors in the pharmaceu- tical industry. Thus, for example, a-hydroxy ketones are found in antidepressants and antitumor antibiotics. Moreover, they are of particular value as fine chemicals because of their utility as build- ing blocks for the production of larger molecules [1,2]. R-phenylacetylcarbinol, R-PAC, is an important precursor in the production of several drugs with a and b adrenergic properties, such as L-ephedrine, pseudoephedrine and norephedrine. Current industrial production of R-PAC is based mainly on fermentation using the yeast Saccharomyces cerevisiae. However, these processes show low efficiency of substrate utilization, substrate toxicity toward living cells, and production of significant amounts of by- products due to the action of multiple intracellular enzymes. In recent years substantial efforts have been made to develop pro- cesses based on purified enzymatic catalysts rather than whole- cell fermentation [3,4]. Acetohydroxy acid synthase (AHAS) belongs to a family of homologous thiamin diphosphate (ThDP) dependent enzymes, which catalyze processes in which the common first step is decar- boxylation of pyruvate [5–7]. The cofactor ThDP is composed of two aromatic rings, a 4-aminopyrimidine ring and a thiazolium ring, bridged by a methylene group. During the catalysis by ThDP-dependent enzymes the 4-amino-pyrimidine moiety can interconvert among four ionization/tautomeric states: the 4 0 - aminopyrimidine (AP), the N1 0 protonated 4 0 -aminopyrimidium ion (APH + ), the 1 0 ,4 0 -iminopyrimidine (IP). In addition to ThDP, AHAS requires a divalent metal ion (Mg 2+ ) and flavin adenine din- ucleotide (FAD) as additional cofactors. The biosynthesis of branched chain amino acid valine, leucine, and isoleucine in plants, bacteria and fungi, involves the participation of several enzymes being AHAS that one which catalyzes the first common step, fol- lowed by the participation of other enzymes finally leading to the formation of those essential amino acids. It has been reported [2–4] that in addition to catalyzing the physiological reactions leading to the formation of acetohydroxy butyrate and acetolactate, AHAS can catalyze, in the third step of its catalytic cycle, an alternative reaction in which the intermedi- ate hydroxyl-ethylthiamin diphosphate HEThDP  reacts with an aromatic aldehyde to form an aryl acetyl carbinol with high enan- tiomeric specificity. The reaction is triggered by the nucleophilic attack of HEThDP  on the carbonyl carbon of benzaldehyde, with the subsequent proton transfer from the hydroxyl group of HEThDP  to the carbonyl oxygen of benzaldehyde. However, the enzyme shows high preference for the physiological pyruvate and 2-ketobutyrate substrates compared to benzaldehyde. Differ- ent residues in the enzyme active site are involved in determining the preference for the natural substrates. Studies of mutagenesis on the rates and specificities of the physiological and unnatural reactions support a critical role of the residue Arg276 in the enzyme preference. Several experimental studies have been devoted to the study of R-PAC synthesis catalyzed by enzymes [8–11] due to its importance as pharmaceutical precursors and building blocks for the production of larger molecules. Despite http://dx.doi.org/10.1016/j.cplett.2017.03.066 0009-2614/Ó 2017 Published by Elsevier B.V. ⇑ Corresponding author. E-mail address: edelgado@udec.cl (E. Delgado). Chemical Physics Letters 677 (2017) 30–34 Contents lists available at ScienceDirect Chemical Physics Letters journal homepage: www.elsevier.com/locate/cplett