Absolute configuration of the four stereoisomers of valnoctamide (2-ethyl-3-methyl valeramide), a potentially new stereospecific antiepileptic and CNS drug

Valnoctamide (2-ethyl-3-methyl valeramide, Nirvanil^®, VCD), a mild tranquilizer endowed with anticonvulsant properties, exhibits diastereoselective and enantioselective pharmacokinetics in healthy subjects and epileptic patients. The purpose of this paper is to assign the absolute configuration of the four VCD stereoisomers and to describe the stereoselective synthesis used to prepare two-key VCD stereoisomers. We have synthesized two out of the four stereoisomers, with high diastereomeric excess, by two different synthetic methods. In both methods the (S) configuration at C-3 of VCD was fixed by synthesizing (S)-3-methyl valeric acid from l-isoleucine. In the first method the diastereomeric mixture (2RS,3S)-VCD was prepared. This mixture gave one of the diastereomers via repeated crystallizations, and its absolute configuration (2R,3S)-VCD, was established by X-ray crystallography using a single crystal. The absolute configuration of all four VCD stereoisomers, separated by chiral gas chromatography, was established on the basis of diastereomeric and enantiomeric correlations. In order to assess stereoselective pharmacodynamic properties of VCD, the single stereoisomers have to be synthesized. Stereoselective synthesis of (2R,3S)-VCD and (2S,3S)-VCD was accomplished by using chiral oxazolidinone auxiliaries. These diastereomers were obtained in 99.6% diastereomeric excess.     

Total synthesis and determination of the absolute stereochemistry of the squalene synthase inhibitors CJ-13,981 and CJ-13,982

The absolute and relative stereochemistries of the potent squalene synthase inhibitors CJ-13,981 and CJ-13,982 were determined to be 3S,4S by total synthesis of their antipodes using, as a key step, the diastereoselective alkylation of a chiral dioxolanone.     

Isoeichlerianic acid from Aglaia silvestris and revision of the stereochemistry of foveolin B

A new series of 20,24-epoxy (tetrahydrofuryl) type dammarane triterpenoids were established. So far two series were described, based on the stereochemistries of the tetrahydrofurane ring linked to the D ring of the triterpenoid skeleton. Eichlerianic acid was characterised by the absolute configuration (20S,24S) and shoreic acid by (20S,24R). Foveolins A and B were correlated with these compounds and published also as (20S,24S) and (20S,24R), respectively. ¹³C NMR analysis of a further stereoisomer of the acids isolated from Aglaia silvestris allowed the conclusion that the new isoeichlerianic acid, its methyl ester and the known foveolin B belonged to the new stereochemical series (20R,24S).     

Arylacetic acid derivatization of 2,3- and internal erythro-squalene diols. Separation and absolute configuration determination

We have studied a new approach for the resolution and absolute configuration determination of the enantiomers of squalene diols as intermediate precursors in the chemical synthesis of different squalene oxides (SOs); (3R)- and (3S)-2,3-SO, (6R,7R)- and (6S,7S)-6,7-SO, and (10R,11R)- and (10S,11S)-10,11-SO. Monoderivatization of the corresponding racemic squalene diol intermediates with pure stereoisomers of (S)-(+)-methoxyphenyl acetic acid ((S)-(+)-MPA), (S)-(+)-9-anthrylmethoxyacetic acid ((S)-(+)-9-AMA) and (S)-(+)-acetoxyphenylacetic acid ((S)-(+)-APA) afforded the diastereomeric esters which could be easily separated by column flash chromatography with silica gel. In addition, the absolute configuration for these diastereoisomers of the derivatized diols was advantageously inferred from ¹H NMR data according to the models depicted for these derivatizing chiral agents. In order to demonstrate the absolute configuration assignment of the different stereoisomers, (S)-(+)-AMA showed the larger Δδ by ¹H NMR, however, (S)-(+)-MPA esters were much more stable derivatives.     

Synthesis,Characterization and HPLC Analysis of the (1S,2S,5R)-Diastereomer and the Enantiomer of the Clinical Candidate AR-15512

AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1R,2S,5R), have been previously solved by cryo-electron microscopy. The route of synthesis of AR-15512 has also been reported, revealing that epimerization processes at the C-1 can occur at specific stages of the synthesis. In order to confirm that the desired configuration of AR-15512 does not change throughout the process and to discard the presence of the enantiomer in the final product due to possible contamination of the initial starting material, both the enantiomer of AR-15512 and the diastereomer at the C-1 were synthesized and fully characterized. In addition, the absolute configuration of the (1S,2S,5R)-diastereomer was determined by X-ray crystallographic analysis, and new HPLC methods were designed and developed for the identification of the two stereoisomers and their comparison with the clinical candidate AR-15512.     

Assignment of absolute configurations of permethrin and its synthon 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid by electronic circular dichroism,optical rotation,and X-ray crystallography

The availability of single stereoisomers of biologically/toxicologically relevant chiral compounds such as the pyrethroid-type insecticide permethrin (PM) and the reliable determination of their absolute configurations are of central importance for the detailed investigation and correct assignment of stereoselective effects. In this context, single stereoisomers of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (DCCA), a precursor, metabolite, and environmental degradation product of PM, were isolated from a mixture of all four stereoisomers in enantiomeric excesses of >99% via a two-step chromatographic process combining a diastereoselective reversed-phase separation in the first step with a direct enantiomer separation in the second step. Esterification of DCCA stereoisomers with 3-phenoxybenzyl alcohol yielded PM. Electronic circular dichroism (ECD) spectra of DCCA and PM stereoisomers were measured in non-polar (cyclohexane containing 5% v/v 1,2-dichloroethane) and non-protic polar (acetonitrile) solvents. Cotton effects suitable to distinguish the four stereoisomers of each DCCA and PM were obtained. Absolute configurations of DCCA were determined by confrontation of calculated (time-dependent density-functional theory using B3LYP hybrid functional) and experimental ECD and optical rotation (OR) data. Fully convergent results between ECD and X-ray diffractometry (analysis of DCCA isomers co-crystallized with O-9-(2,6-diisopropylphenylcarbamoyl)quinine), which was employed as a reference method, were obtained. The importance of considering dimer formation of DCCA in solution for the computational delineation of absolute configurations was demonstrated by (1R,3R)-cis-DCCA for which the ΔG Boltzmann averaged calculated monomeric form delivered the opposite sign of OR compared to the dimeric form and the value determined experimentally in dichloromethane. For (1S,3R)-trans-DCCA both monomer and dimer delivered the identical sign of OR and this was in agreement with the experimental measurement. In contrast to OR, the calculated ECD spectra of these two DCCA stereoisomers were less sensitive toward intermolecular association.     

Stereochemical revision of communiols D and H through synthesis

Based on the previously revised stereochemistries for communiols A-C, the ent-8-epi- and ent-6-epi-stereoisomers of the original structures proposed for communiols D and H, respectively, were synthesized as highly probable candidates for their genuine structures by using the Sharpless asymmetric dihydroxylation as the source of chirality. Complete accord in spectral properties between each synthetic candidate and the corresponding natural material as well as the fact that communiols A-D and H were all isolated from the same fungal source, led us to the conclusion that the stereochemistries of communiols D and H should also be revised to their (3S,5S,7R,8S,11R)- and (5S,7R,8S)-forms, respectively.     

Establishment of absolute stereostructure of falcarindiol, algicidal principle against Heterocapsa circularisquama from Notopterygii Rhizoma

Falcarindiol (1) was isolated as an algicidal principle against the harmful red tide dinoflagellate, Heterocapsa circularisquama, from Notopterygii Rhizoma through bioassay-guided separation. In order to determine the ambiguous absolute structure of this active principle, all three stereoisomers as well as falcarindiol (1) were synthesized. As a result of intensive analysis of their physicochemical properties, the configuration of 1 was revealed to be 3R,8S. On the other hand, (3S,8S)- and (3S,8R)-isomers were found to exhibit more potent algicidal activity than (3R,8S)-falcarindiol (1) isolated from Notopterygii Rhizoma. In addition, the diyne moiety of 1 was established as the crucial structural requirement for algicidal potency.     

Total synthesis of myxol and deoxymyxol stereoisomers and their application to determining the absolute configurations of the natural products

The total synthesis of myxol stereoisomers 1a,b and deoxymyxol (plectaniaxanthin) stereoisomers 2a,b was accomplished by Wittig reaction of (S)- and (R)-C₁₀-phosphonium salts 8a,b bearing a silyl-protected 1,2-dihydroxy-ψ end group with C₃₀-apocarotenals 6 and 7. The phosphonium salts 8a,b were derived from aldehydes 11a,b possessing a cyclopentylidene ketal moiety, prepared via Sharpless asymmetric epoxidation of allylic alcohol 12 followed by regioselective cleavage of the oxirane ring. We established an analytical HPLC method using a chiral column to separate stereoisomers 1a,b and 2a,b and thus determined the absolute configurations of the natural products. The HPLC analyses established that both myxol and deoxymyxol isolated from bacteria have the 2′S-configuration.     

Total synthesis and absolute stereochemistry of (9R,10S)-epoxyheptadecan-4,6-diyn-3-one, a diacylglycerol acyltransferase inhibitor from Panax ginseng

Asymmetric synthesis of four possible stereoisomers of (9,10)-epoxyheptadecan-4,6-diyn-3-one was accomplished, and the absolute configuration of the naturally occurring (9R,10S)-epoxyheptadecan-4,6-diyn-3-one (1) was elucidated.     

An efficient stereoselective synthesis of six stereoisomers of 3, 4-diaminocyclohexane carboxamide as key intermediates for the synthesis of factor Xa inhibitors

An efficient stereoselective route for the preparation of six stereoisomers of tert-butyl ((1R, 2S, 5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate 1 starting from simple 3-cyclohexene-1-carboxylic acid has been described. Stereochemistry of the title compounds was controlled at C2 center by Mitsunobu reaction and at C5 via a base-catalyzed epimerization. Only a limited usage of column chromatography has provided a direct and scalable route for the six stereoisomers.     

Total syntheses of four possible stereoisomers of resolvin E3

Resolvin E3, 17,18-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic acid, is a potent anti-inflammatory lipid mediator. To determine the stereochemistries of the C17- and C18-hydroxy groups of resolvin E3 and to supply a sufficient amount of material for future biological studies, we developed a highly convergent and practical route to its four possible stereoisomers. The key reactions employed here were the Horner–Wadsworth–Emmons coupling, the two copper(I)-mediated reactions between the alkynes and the propargyl tosylates, and the simultaneous reduction of the three triple bonds to the three Z-olefins.     

The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide

The key step in our synthetic strategy towards (S,S)-methylphenidate hydrochloride employs the ring-opening of an in situ formed aziridinium intermediate. Treatment of an α-hydroxy-β-amino ester with methanesulfonic anhydride promoted aziridinium formation and the subsequent addition of phenylmagnesium bromide resulted in stereospecific and regioselective ring-opening to give the corresponding α-phenyl-β-amino ester with overall retention of configuration. Subsequent functional group manipulation followed by N-deprotection and cyclisation generated the piperidine ring within the target compound, and transesterification gave (S,S)-methylphenidate hydrochloride, in only 8 steps from 1,5-pentanediol, in 15% overall yield. These results demonstrate the synthetic utility of enantiopure aziridinium intermediates as substrates for the generation of stereodefined C–C bonds, and crucially this methodology provides access to α-substituted-β-amino ester substrates that are not accessible via enolate alkylation chemistry. The strategy reported herein is potentially applicable to all possible stereoisomers of methylphenidate as well as differentially substituted analogues.     

Arabidopsides A and B, two new oxylipins from Arabidopsis thaliana

Two new oxylipins, arabidopsides A (1) and B (2), were isolated from the aerial parts of Arabidopsis thaliana, and their structures and absolute stereochemistries were elucidated by spectroscopic data and chemical means. Arabidopsides A (1) and B (2) were rare monogalactosyl diacylglycerides containing 12-oxophytodienoic acid and/or dinor-oxophytodienoic acid.     

Absolute stereochemistry and conformational analysis of achaetolide isolated from Ophiobolus sp.

Achaetolide, as reported by Bodo et al. in 1983, was isolated from a fermentation broth of Ophiobolus sp. We established the absolute stereochemistry of achaetolide to be 3S,6R,7S,9R by way of relative stereochemical assignment with ¹H NMR analyses employing the corresponding acetonide, determination of C3 and C9 stereochemistries by an extended Mosher method.     

The first total synthesis and structural determination of antibiotics K1115 B1s (alnumycins)

K1115 B₁, isolated from the broth of Streptomyces species, was found to be a mixture of stereoisomers. Authors synthesized all stereoisomers of K1115 B₁ by convergent synthesis coupling a rhamnose derivative, an isobenzofuranone, and a chiral tetraol. Comparison of ¹H NMR spectra and optical rotations made it clear that the absolute structures of K1115 B_1α (the major isomer) and K1115 B_1β (the minor isomer) were (1R, 17S)- and (1R, 17R)-configurations, respectively. The optical rotations of the stereoisomers revealed that alnumycin, reported as the identical structure with K1115 B₁, might be another mixture of stereoisomers.     

Pheromone synthesis. Part 245: Synthesis and chromatographic analysis of the four stereoisomers of 4,8-dimethyldecanal, the male aggregation pheromone of the red flour beetle, Tribolium castaneum

All four stereoisomers of 4,8-dimethyldecanal (1) were synthesized from the enantiomers of 2-methyl-1-butanol and citronellal. Enantioselective GC analysis enabled separation of (4R,8R)-1 and (4R,8S)-1 from a mixture of (4S,8R)-1 and (4S,8S)-1, when octakis-(2,3-di-O-methoxymethyl-6-O-tert-butyldimethylsilyl)-γ-cyclodextrin was employed as a chiral stationary phase. Complete separation of the four stereoisomers of 1 on reversed-phase HPLC at −54 °C was achieved after oxidation of 1 to the corresponding carboxylic acid 12 followed by its derivatization with (1R,2R)-2-(2,3-anthracenedicarboximido)cyclohexanol, and the natural 1 was found to be a mixture of all the four stereoisomers.     

A Cheminformatics Study Regarding the Human Health Risks Assessment of the Stereoisomers of Difenoconazole

Difenoconazole is a chemical entity containing two chiral centers and having four stereoisomers: (2R,4R)-, (2R,4S)-, (2S,4R)- and (2S,4S)-difenoconazole, the marketed product containing a mixture of these isomers. Residues of difenoconazole have been identified in many agricultural products and drinking water. A computational approach has been used to evaluate the toxicological effects of the difenoconazole stereoisomers on humans. It integrates predictions of absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles, prediction of metabolism sites, and assessment of the interactions of the difenoconazole stereoisomers with human cytochromes, nuclear receptors and plasma proteins by molecular docking. Several toxicological effects have been identified for all the difenoconazole stereoisomers: high plasma protein binding, inhibition of cytochromes, possible hepatotoxicity, neurotoxicity, mutagenicity, skin sensitization potential, moderate potential to produce endocrine disrupting effects. There were small differences in the predicted probabilities of producing various biological effects between the distinct stereoisomers of difenoconazole. Furthermore, there were significant differences between the interacting energies of the difenoconazole stereoisomers with plasma proteins and human cytochromes, the spectra of the hydrogen bonds and aromatic donor–acceptor interactions being quite distinct. Some distinguishing results have been obtained for the (2S,4S)-difenoconazole: it registered the highest value for clearance, exposed reasonable probabilities to produce cardiotoxicity and carcinogenicity and negatively affected numerous nuclear receptors.     

Stereocontrolled synthesis of all of the possible stereoisomers of 3,11-dimethylnonacosan-2-one and 29-hydroxy-3,11-dimethylnonacosan-2-one : The female sex pheromone of the german cockroach

All of the possible stereoisomers of 3, 11 - dimethylnonacosan - 2 - one 1 and 29 - hydroxy - 3, 11 -dimethylnonacosan - 2 - one 2 were synthesized from (R)-(+)- citronellic acid as the chiral source. The natural pheromones were shown to be (3S,11S)-1 and (3S, 11S)-2 by direct comparisons.     

Four stereoisomers of the novel μ‐opioid receptor agonist tapentadol hydrochloride

The crystal and molecular structures of four stereoisomers of tapentadol hydrochloride [systematic name: 3‐(3‐hydroxyphenyl)‐N,N,2‐trimethylpentan‐1‐aminium chloride], C₁₄H₂₄NO⁺·Cl⁻, a novel analgesic agent, have been determined by X‐ray crystal structure analysis. Resolution of the isomers was carried out by reverse‐phase and chiral high‐performance liquid chromatographic (HPLC) methods. Stereoisomers (I) and (II) crystallize in the monoclinic space group P2₁, each with two tapentadol cations and two chloride anions in the asymmetric unit, while stereoisomers (III) and (IV) crystallize in the orthorhombic space group P2₁2₁2₁, with one tapentadol cation and one chloride anion in the asymmetric unit. The absolute configurations of the four enantiomers were determined unambiguously by X‐ray crystallography. The crystal structures reveal the stereochemistries at the 3‐ethyl and 2‐methyl groups to be R,R, S,S, S,R and R,S in stereoisomers (I)–(IV), respectively. The ethyl and aminopropyl groups adopt different orientations with respect to the phenol ring for (I) and (IV). In all four structures, the chloride ions take part in N—H...Cl and O—H...Cl hydrogen bonds with the tapentadol molecules, resulting in one‐dimensional helical chains in the crystal packing in each case.