Origins of the substituent effects in the aldol condensation of axially chiral thiohydantoins: a computational study.

Aldol reactions are one of the most fundamental organic reactions involving the formation of carbon-carbon bonds that are commonly used in the synthesis of complex molecules through the condensation of an enol or enolate with a carbonyl group. The aldol reaction of thiohydantoin derivatives with benzaldehyde starts with hydrogen removal from C5 by lithium diisopropylamide (LDA) to form the enolate. Benzaldehyde adds to the enolate either at the less or more hindered site.

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 p of the drug molecule and the membrane environment.

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 LiAlH at room temperature. Due to the presence of the restricted rotation around the N3-C 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.

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

5-Benzyl-3-(-aryl)-2-thiohydantoin and 5-isobutyl-3-(-aryl)-2-thiohydantoin derivatives (-aryl = -tolyl and -bromophenyl) have been synthesized by reacting -aryl isothiocyanates with -phenylalanine methyl ester hydrochloride or with -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 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 isomers over the isomers.

Aldol Reactions of Conformationally Stable Axially Chiral Thiohydantoin Derivatives.

Two novel axially chiral -trifluoromethylphenyl thiohydantoin derivatives have been prepared atroposelectively from the reaction of and alanine methyl ester HCl salts with -trifluoromethylphenyl isothiocyanate in the presence of triethyl amine. It was found that after purification of the crude product by simple recrystallization, the amino acid esters yielded thiohydantoins having solely axial chirality whereas the ones returned the isomers only. This result prompted us to perform sterically controlled aldol reactions on and thiohydantoin atropisomers.

Using Atomic Charges to Describe the p of Carboxylic Acids.

In this study, we present an accurate protocol for the fast prediction of p's of carboxylic acids based on the linear relationship between computed atomic charges of the anionic form of the carboxylate fragment and their experimental p 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 p'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 ( = 0.

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 (LiAlH ) 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.

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 LiAlH 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 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.

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.

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 K values in the micromolar range (0.

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.

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 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.

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.

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.

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.

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.

Conformational preferences in diastereomeric(5S)-methyl-3-(o-aryl)-2,4-oxazolidinediones.

The thermally interconvertible diastereomers of the (5S)-methyl-3-(o-aryl)-2,4-oxazolidinediones were synthesized and their conformers studied by (1)H NMR and HPLC. The barriers to rotation about the N-C(aryl) bond were found to be very much solvent dependent. For the o-fluoro oxazolidinedione, difference in barriers to rotation in deuterated methanol and deuterated chloroform amounted to 34 kJ/mol.