Quantum Mechanical Prediction of Dissociation Constants for Thiazol-2-imine Derivatives.

As weak acids or bases, in solution, drug molecules are in either their ionized or nonionized states. A high degree of ionization is essential for good water solubility of a drug molecule and is required for drug-receptor interactions, whereas the nonionized form improves a drug's lipophilicity, allowing the ligand to cross the cell membrane. The penetration of a drug ligand through cell membranes is mainly governed by the pKa of the drug molecule and the membrane environment. In this study, with the aim of predicting the acetonitrile pKa's (pKa(MeCN)) of eight drug-like thiazol-2-imine derivatives, we propose a very accurate and computationally affordable protocol by using several quantum mechanical approaches. Benchmark studies were conducted on a set of training molecules, which were selected from the literature with known pKa(water) and pKa(MeCN). Highly well-correlated pKa values were obtained when the calculations were performed with the isodesmic method at the M062X/6-31G** level of theory in conjunction with SMD solvation model for nitrogen-containing heterocycles. Finally, experimentally unknown pKa(MeCN) values of eight thiazol-2-imine structures, which were previously synthesized by some of us, are proposed.

Stable hemiaminals from axially chiral pyridine compounds.

In this study, we have synthesized a series of 3-(pyridin-2-yl)-2-(pyridin-2-ylimino)thiazolidin-4-ol derivatives regioselectively from 2-iminothiazolidin-4-ones using LiAlH4 at room temperature. Due to the presence of the restricted rotation around the N3-Caryl single bond, the formation of M/P isomers was observed. The OH group of the hemiaminal was found to orient itself on the same side with pyridyl nitrogen during this restricted rotation to form an intramolecular hydrogen bond, which was demonstrated by the computational DFT study. This orientation presumably inhibited the occurrence of dehydration and stabilized the molecule.

Solvent dependent hindered rotation versus epimerization in axially chiral thiohydantoin derivatives: an experimental and a computational study.

5-Benzyl-3-(o-aryl)-2-thiohydantoin and 5-isobutyl-3-(o-aryl)-2-thiohydantoin derivatives (o-aryl = o-tolyl and o-bromophenyl) have been synthesized by reacting o-aryl isothiocyanates with S-phenylalanine methyl ester hydrochloride or with S-leucine methyl ester hydrochloride in the presence of triethylamine (TEA). The synthesized compounds have a chirality center at C5 of the heterocyclic ring and a chirality axis, the N3-C(aryl) bond. The axially chiral compounds were shown to exist in unequal amounts of SM, SP, RM and RP stereoisomeric forms with a high prevalence of the P isomers over the M isomers. The isomeric assignments were done by comparing the 1H NMR spectra with the HPLC chromatograms. The stereoisomers were resolved micropreparatively by HPLC on chiral stationary phases and the interconversion of the single isomers has been investigated. The conversion type has been determined as epimerization or rotation by the HPLC analyses. It has been found that although the stereoisomers converted to each other only by rotation in toluene, in ethanol epimerization (racemization at C5 of the heteroring) was accompanied with rotation depending on the duration, temperature of the thermal interconversion experiment and the nature of the ortho substituent. The occurrence of epimerization was also proved through H/D exchange reactions via1H NMR experiments done in CD3OD. The rotation and epimerization mechanisms of synthesized compounds were further elucidated by Density Functional Theory (DFT) calculations at M062X/6-311 + G** level of theory and the results were shown to be in harmony with experimental findings.

Aldol Reactions of Conformationally Stable Axially Chiral Thiohydantoin Derivatives.

Two novel axially chiral ortho-trifluoromethylphenyl thiohydantoin derivatives have been prepared atroposelectively from the reaction of R and S alanine methyl ester HCl salts with ortho-trifluoromethylphenyl isothiocyanate in the presence of triethyl amine. It was found that after purification of the crude product by simple recrystallization, the R amino acid esters yielded thiohydantoins having solely M axial chirality whereas the S ones returned the P isomers only. This result prompted us to perform sterically controlled aldol reactions on M and P thiohydantoin atropisomers. It was found that during the aldol reaction of 3-o-trifluoromethyl-5-methylthiohydantoins, the o-trifluoromethyl group of the M isomers efficiently shielded the Si face of the intermediate and in this way, enabled the selective formation of only the R configured aldol products at C5 of the heterocyclic ring. The P thiohydantoins, on the other hand, yielded only the S C5 configured aldol products as a result of the Re face shielding of the ortho-trifluoromethyl group of intermediate enolates. A noteworthy face selectivity of the benzaldehyde molecule was not observed (anti/syn only 3/2) during the aldolization of trifluoromethylphenyl derivatives of thiohydantoins. Aldol reactions were also done using the previously synthesized axially chiral thiohydantoins with ortho-Cl, Br, and I phenyl substituents which had predominantly P conformations (P/M ratios > 95%), and the stereochemical outcomes were compared with those of the ortho-trifluoromethyl substituted ones. 80-90% face selectivity of the benzaldehyde molecule was observed for the axially chiral o-halophenyl substituted thiohydantoins. The syntheses done with axially chiral 3-ortho-trifluoromethylphenyl- and 3-ortho-iodophenyl-5-methyl thiohydantoins enabled stereoselective formation of quaternized chiral carbon centers at C5 of the thiohydantoin ring.

Using Atomic Charges to Describe the pKa of Carboxylic Acids.

In this study, we present an accurate protocol for the fast prediction of pKa's of carboxylic acids based on the linear relationship between computed atomic charges of the anionic form of the carboxylate fragment and their experimental pKa values. Five charge descriptors, three charge models, three solvent models, gas-phase calculations, several DFT methods (a combination of eight DFT functionals and fifteen basis sets), and four different semiempirical approaches were tested. Among those, the best combination to reproduce experimental pKa's is to compute the natural population analysis atomic charge using the solvation model based on density model at the M06L/6-311G(d,p) level of theory and selecting the maximum atomic charge on the carboxylic oxygen atoms (R2 = 0.955). The applicability of the suggested protocol and its stability along geometrical changes are verified by molecular dynamics simulations performed for a set of aspartate, glutamate, and alanine peptides. By reporting the calculated atomic charge of the carboxylate form into the linear relationship derived in this work, it should be possible to accurately estimate the amino acid's pKa's in a protein environment.

Axially chiral hemiaminals from nonracemic α-amino acid derivatives (thiohydantoins): Synthesis and isomer identification.

Stable, nonracemic axially chiral hemiaminals (O,N-hemiacetals) have been synthesized stereoselectively from lithium aluminum hydride (LiAlH4 ) reductions of nonracemic 5-methyl- and 5-isopropyl-3-(o-aryl)-2-thioydantoins in tetrahydrofuran (THF) at room temperature in 10 min. Predominantly S-configured hemiaminals at C-4 of the heterocyclic ring were produced from the S-configured thiohydantoins at C-5 (by 80% when the C5 substituent is methyl and by 97% when it is isopropyl). The configuration at C-5 was retained during the reduction reaction. The stereochemical outcome of the axially chiral hemiaminals resulted from their conformational preferences.

Synthesis of thiazol-2-imines from the reduction of single enantiomer 2-imino-thiazolidin-4-ones followed by a spontaneous water elimination.

Chiral hemiaminals (5-8RR and 5-8SS) have been synthesized from the corresponding 2-iminothiazolidine-4-ones (1-4RR and 1-4SS) by LiAlH4 reductions stereoselectively and were then converted to single enantiomer thiazol-2-imines (9-12RR and 9-12SS) by a water elimination reaction. The kinetics of the dehydration reactions which occurred spontaneously both in the solid state and in the solution have been followed by time dependent 1 H nuclear magnetic resonance spectroscopy. The corresponding first order rate constants and free energies of activation values for the conversions have been reported.

Elucidation of the atroposelectivity in the synthesis of axially chiral thiohydantoin derivatives.

Recently, Sarigul and Dogan have synthesized a number of enantiomerically enriched axially chiral atropoisomeric 2-thiohydantoins by the reaction of l-amino acid ester salts and o-aryl isothiocyanates in the presence of triethyl amine (TEA) in dichloromethane. The non-axially chiral derivative 5-methyl-3-phenyl-2-thiohydantoin gave a racemic product whereas the axially chiral 5-methyl-3-o-bromophenyl-2-thiohydantoin was less prone to racemize at C5 of the heterocyclic ring. In this study, we present a computational study (M06-2X/6-311+G(d,p) for C, H, O, N and S; M06-2X/6-311++G(3df,3pd) for Br) in order to propose plausible mechanisms for the racemization and cyclization steps for 2-thiohydantoin derivatives. The study includes rationalization based on steric as well as the electrostatic effects to elucidate the epimerization differences at C5.

Absolute configuration and biological profile of pyrazoline enantiomers as MAO inhibitory activity.

A new racemic pyrazoline derivative was synthesized and resolved to its enantiomers using analytic and semipreparative high-pressure liquid chromatography. The absolute configuration of both fractions was established using vibrational circular dichroism. The in vitro monoamine oxidase (MAO) inhibitory profiles were evaluated for the racemate and both enantiomers separately for the two isoforms of the enzyme. The racemic compound and both enantiomers were found to inhibit hMAO-A selectively and competitively. In particular, the R enantiomer was detected as an exceptionally potent and a selective MAO-A inhibitor (Ki  = 0.85 × 10-3  ± 0.05 × 10-3  µM and SI: 2.35 × 10-5 ), whereas S was determined as poorer compound than R in terms of Ki and SI (0.184 ± 0.007 and 0.001). The selectivity of the enantiomers was explained by molecular modeling docking studies based on the PDB enzymatic models of MAO isoforms.

Asymmetric synthesis, molecular modeling and biological evaluation of 5-methyl-3-aryloxazolidine-2,4-dione enantiomers as monoamine oxidase (MAO) inhibitors.

Single enantiomers of the new 5-methyl-3-aryloxazolidine-2,4-diones have been obtained either by an asymmetric synthesis using the chiral pool strategy or by a semipreparative resolution of the racemic compound by HPLC on an optically active stationary phase. The single enantiomers were assayed for their in vitro monoamine oxidase (hMAO) inhibitory activity and selectivity. The most potent inhibitor among the studied compounds has been found as (5R)-3-phenyl-5-methyl-2,4-oxazolidinedione (compound 1-R) which appeared to be a good antidepressant drug candidate since it inhibited hMAO-A selectively, competitively and reversibly with Ki values in the micromolar range (0.16 ±â€¯0.01 µM). To better understand the enzyme-inhibitor interaction and to explain the efficiency and selectivity of the compounds toward hMAOs, molecular modeling studies were carried out on new, high resolution hMAO-A and hMAO-B crystallographic structures. According to binding energies and inhibition constants obtained from molecular docking calculations, compound 1-R has been found as the most selective MAO-A inhibitor and its weak binding affinities to MAO-B (large Ki values) led to the enhancement in MAO-A selectivity. It bounded in close proximity to FAD in the active site of MAO-A and situated near the aromatic cage by means of π-alkyl interactions with Tyr407 and Phe352 whereas its position in MAO-B was 10 Šfar from FAD and it was situated outside the Ile199 gate of the active site. None of the studied compounds showed any cytototoxicity on HepG2 cells at 1 and 5 µM concentrations.

Aldol Reactions of Axially Chiral 5-Methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones.

Axially chiral 5-methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones have been subjected to aldol reactions with benzaldehyde to produce secondary carbinols which have been found to be separable by HPLC on a chiral stationary phase. Based on the reaction done on a single enantiomer resolved via a chromatographic separation from a racemic mixture of 5-methyl-2-(α-naphthyl)imino-3-(α-naphthyl)-thiazolidine-4-one by HPLC on a chiral stationary phase, the aldol reaction was shown to proceed via an enolate intermediate. The axially chiral enolate of the thiazolidine-4-one was found to shield one face of the heterocyclic ring rendering face selectivity with respect to the enolate. The selectivities observed at C-5 of the ring varied from none to 11.5:1 depending on the size of the ortho substituent. Although the aldol reaction proceeded with a lack of face selectivity with respect to benzaldehyde, recrystallization returned highly diastereomerically enriched products.

Atroposelective Synthesis of Axially Chiral Thiohydantoin Derivatives.

Nonracemic axially chiral thiohydantoins were synthesized atroposelectively by the reaction of o-aryl isothiocyanates with amino acid ester salts in the presence of triethylamine (TEA). The synthesis of the nonaxially chiral derivatives, however, gave thiohydantoins racemized at C-5 of the heterocyclic ring. The micropreparatively resolved enantiomers of the nonaxially chiral derivatives from the racemic products were found to be optically stable under neutral conditions. On formation of the 5-methyl-3-arylthiohydantoin ring, bulky o-aryl substituents at N3 were found to suppress the C-5 racemization and in this way enabled the transfer of chirality from the α-amino acid to the products. The corresponding 5-isopropylthiohydantoins turned out to be more prone to racemization at C-5 during the ring formation. The isomer compositions of the synthesized axially chiral thiohydantoins have been determined through HPLC analyses with chiral stationary phases. In most cases a high prevalence of the P isomers over the M isomers has been obtained. The barriers to rotation determined around the Nsp(2)-Caryl chiral axis were found to be dependent upon the size of the o-halo aryl substituents.

The origin of exo-stereoselectivity of norbornene in hetero Diels-Alder reactions.

In this study the exo selectivity in the hetero Diels-Alder reaction of atropisomeric 5-benzylidine-2-arylimino-3-aryl-thiazolidine-4-thiones with norbornene was investigated with computational tools. Taking into account the M/P chiral character of the o-methoxyphenyl substituted heterodienes in addition to the exo/endo selectivity, 8 different transition structures were located. Based on the direction of approach of the diene and the dienophile for each plausible path it is found that endo products are not preferred because of the large distortion of norbornene and the rather eclipsed conformations of these transition state structures. Computational results are consistent with the experimental exo/endo selectivity. The computational methodology (M06-2X/6-31+G(d)//B3LYP/6-31+G(d)) was justified by comparison of the experimental rotational barriers with the calculated ones for selected compounds.

Solvent-catalyzed ring-chain-ring tautomerization in axially chiral compounds.

The mechanism of ring-chain-ring tautomerization and the prominent effect of the solvent environment have been computationally investigated in an effort to explain the enantiomeric interconversion observed in 2-oxazolidinone derivatives, heterocyclic analogues of biphenyl atropisomers, which were isolated as single stable enantiomers and have the potential to be used as axially chiral catalysts. This study has shed light on the identity of the intermediate species involved in the ring-chain-ring tautomerization process as well as the catalytic effect of polar protic solvents. These mechanistic details will prove very useful in predicting and understanding ring-chain tautomeric equilibria in similar heterocyclic systems and will further enable experimentalists to devise appropriate experimental conditions in which axially chiral catalysts remain stable as single enantiomers.

Determination of barriers to rotation of axially chiral 5-methyl-2-(o-aryl)imino-3-(o-aryl)thiazolidine-4-ones.

Thermally interconvertible axially chiral 5-methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones have been synthesized diastereoselectively, and conformations of the major and minor enantiomeric pairs have been determined by (1)H nuclear magnetic resonance. Chromatographic resolutions of each compound have been performed by enantioselective high-performance liquid chromatography, and the barriers to rotation about the N(3)-C(aryl) bond have been determined by following the thermal interconversion process of the major to minor isomers until equilibrium. The rotational barriers range from 96.2 to 115.2 kJ/mol, depending on the size of ortho substituent on N(3)-aryl ring.

Stereochemical assignments of aldol products of 2-arylimino-3-aryl-thiazolidine-4-ones by 1H NMR.

The aldol reactions of 2-arylimino-3-aryl-thiazolidine-4-ones with benzaldehyde carried out at -78 °C were found to produce sec-carbinols. Intramolecular hydrogen bonding within the aldol products forming a six-membered ring enabled the assignment of stereochemistries of the major and minor diastereomers via analysis of the syn and anti (3)J(H,H) (1)H NMR coupling constants.

Axially chiral N-(o-aryl)-4-hydroxy-2-oxazolidinone derivatives from diastereoselective reduction of N-(o-aryl)-2,4-oxazolidinediones: thermally interconvertible atropisomers via ring-chain-ring tautomerization.

The reduction of the axially chiral N-(o-aryl)-5,5-dimethyl-2,4-oxazolidinediones by NaBH(4) yielded axially chiral N-(o-aryl)-4-hydroxy-5,5-dimethyl-2-oxazolidinone enantiomers having a chiral center at C-4, with 100% diastereoselectivity as has been shown by their (1)H and (13)C NMR spectra and by enantioselective HPLC analysis. The resolved enantiomeric isomers were found to interconvert thermally through an aldehyde intermediate formed upon ring cleavage via a latent ring-chain-ring tautomerization. It was found that the rate of enantiomerization depended on the size and the electronic effect of the ortho substituent present on the aryl ring bonded to the nitrogen of the heterocycle.

Atropisomeric 3-aryl-2-oxo-4-oxazolidinones and some thione analogues--enantiodifferentiation and ligand competition in applying the dirhodium method.

The atropisomeric 2-oxo-4-oxazolidinones 1Z bind weakly to the rhodium atoms in the complex Rh(II)2 [(R)-(+)-MTPA]4 (Rh*, MTPA-H = methoxytrifluoromethylphenylacetic acid identical with Mosher's acid), presumably via the C-2 carbonyl oxygen atom. There are some 1H and 13C NMR signals in these compounds which show small dispersion effects suitable for enantiodifferentiation. In contrast, the thiocarbonyl sulfur atoms in 2Z and 3Z bind strongly so that significant complexation shifts (Delta delta) and diastereomeric dispersion effects (Delta nu) can be observed, and chiral discrimination and the determination of enantiomeric ratios of these thiocarbonyl compounds is easy. So, it is shown that--as expected--C=S is a much better binding site when competing with C=O. In compounds of Series 2 a "syn-methyl effect" was discovered which describes the dependence of dispersion effects of syn-oriented methyl groups 6 on the nature of the substituents Z. A mechanism of combined steric and electronic interaction influencing the conformational equilibria inside the adducts is proposed. Determination of absolute configurations by correlation fails, at least on the basis of the data available.

Axially chiral 2-arylimino-3-aryl-thiazolidine-4-one derivatives: enantiomeric separation and determination of racemization barriers by chiral HPLC.

Axially chiral 2-arylimino-3-aryl-thiazolidine-4-ones have been synthesized as racemic mixtures, and each mixture with the exception of 2-(o-chlorophenyl)imino-3-(o-chlorophenyl)-thiazolidine-4-one has been converted to the corresponding 5-benzylidene-2-arylimino-3-aryl-thiazolidine-4-one racemates by reaction with benzaldehyde. The thermally interconvertible enantiomers of each compound have been obtained by enantioselective HPLC separation on columns Chiralpak AD-H and Chiralcel OD-H, and the barriers to racemization have been found to be 98.1-114.1 kJ/mol. The barriers determined were compared to those of structurally related compounds to provide evidence for the stereochemistry of the aryl imino bond.

Barriers to internal rotation around the C-N bond in 3-(o-aryl)-5-methyl-rhodanines using NMR spectroscopy and computational studies. Electron density topological analysis of the transition states.

We have investigated the pairs of rotational isomers for six 3-(o-aryl)-5-methyl-rhodanines (Z = H, F, Cl, Br, OH, and CH3) using NMR spectroscopy and density functional theory (DFT) calculations. Electron density topological and NBO analysis has demonstrated the importance of non-covalent interactions, characterised by (3, -1) bond critical points (BCPs), between the oxygen and sulfur atoms on the thiazolidine ring with the aryl substitutents in stabilizing the transition states. The energetic activation barriers to rotation have also been determined using computational results; rotational barriers for 3-(o-chlorophenyl)-5-methyl-rhodanine (3S) and 3-(o-tolyl)-5-methyl-rhodanine (6S) were determined experimentally based on NMR separation of the diastereoisomeric pairs, and the first-order rate constants used to derive the value of the rotational barrier from the Eyring equation.