Determination Of Absolute Configuration Research Articles

Amino acids as chiral derivatizing agents for antiproliferative substituted N-benzyl isoindolinones.

The absolute configurations of the diastereomers of novel amino acid ester derivatives of 2,3-substituted isoindolinones, which are known as apoptosis activators due to their ability to inhibit the MDM2-p53 PPI, were assigned using NMR and computational methods. Procedures for diastereomer separation and determining the absolute configuration were developed to perform the study. The high significance of N-benzyl fragment for the determination of the diastereomer absolute configuration by NMR methods was established; it is determined by a number of factors inherent in this fragment and the structural features of the studied substrates. Analysis of the individual isomer activity showed that the target inhibitory effect of S- and R-isoindolinone L-valinates differs by less than 20%. It can be explained by the presence of a flexible linker between the isoindolinone core and amino acid fragment, which provides the optimal arrangement of the molecule in the hydrophobic cavity of MDM2 for both isomers.

Enantiomeric Mixtures in Natural Product Chemistry: Separation and Absolute Configuration Assignment.

Chiral natural product molecules are generally assumed to be biosynthesized in an enantiomerically pure or enriched fashion. Nevertheless, a significant amount of racemates or enantiomerically enriched mixtures has been reported from natural sources. This number is estimated to be even larger since the enantiomeric purity of secondary metabolites is rarely checked in the natural product isolation pipeline. This latter fact may have drastic effects on the evaluation of the biological activity of chiral natural products. A second bottleneck is the determination of their absolute configurations. Despite the widespread use of optical rotation and electronic circular dichroism, most of the stereochemical assignments are based on empirical correlations with similar compounds reported in the literature. As an alternative, the combination of vibrational circular dichroism and quantum chemical calculations has emerged as a powerful and reliable tool for both conformational and configurational analysis of natural products, even for those lacking UV-Vis chromophores. In this review, we aim to provide the reader with a critical overview of the occurrence of enantiomeric mixtures of secondary metabolites in nature as well the best practices for their detection, enantioselective separation using liquid chromatography, and determination of absolute configuration by means of vibrational circular dichroism and density functional theory calculations.

Self-Assembled Binuclear Cu(II)-Histidine Complex for Absolute Configuration and Enantiomeric Excess Determination of Naproxen by Tandem Mass Spectrometry.

Naproxen is one of the most consumed nonsteroidal anti-inflammatory drugs and marketed as S-naproxen since R-naproxen is hepatotoxic. In this study, chiral recognition of naproxen has been investigated by tandem mass spectrometry (MS/MS). Among all diastereomeric complexes formed between naproxen and the examined chiral selectors, including cyclodextrins (α/β/γ-CD), modified phenylalanines ( N-acetyl-phenylalanine, N-t-butoxycarbonyl-phenylalanine, N-9-fluorenylmethyloxycarbonyl-phenylalanine), amino acids (Trp, Phe, Tyr, His), glucose, tartaric acid, and vancomycin, a novel binuclear metal bound diastereomeric complexes [(M(II))2( S/ R-naproxen)(l-His)2-3H]+ (M = Cu, Ni, or Co with Cu being the best) could allow effective identification of the absolute configuration of naproxen and determination of its enantiomeric excess ( ee) through MS/MS analysis. The key candidate structure of [(Cu(II))2( S/ R-naproxen)(l-His)2-3H]+ has been revealed by means of collision-induced dissociation, ion mobility mass spectrometry and density functional theory calculations, indicating an interesting and unusual self-assembled compact geometry with the two Cu(II) ions bridged closely together (Cu-Cu distance is 3.04 Å) by the carboxylate groups of the two histidines. It was shown that the difference in dissociation efficiency between the two diastereomers was attributed to the interaction between the NH2 bond of the amino group of one histidine and the naphthyl ring of naproxen. The present report is the first to observe and characterize the complex of (Cu(II))2(His)2 with aromatic acid, which could contribute to the chiral recognition of other chiral aromatic acids, design of catalysts based on binuclear copper bound complex, as well as the better understanding of metal ion complexation by His or His-containing ligands.

Chiral imines prepared from 1-(2-aminoalkyl)aziridines as novel chiral shifts reagents for efficient recognition of acids

Optically pure, chiral imines synthesized from the corresponding aldehydes and 1-(2-aminoalkyl)aziridines in good chemical yields, have been assessed as an NMR chiral shift reagents for effective discrimination of the signals of some acids (mandelic acid and its derivatives and N-protected amino acid). The title compounds have proven to be very useful for the determination of enantiomeric purity and absolute configuration of the aforementioned acid derivatives.

Marine Natural Peptides: Determination of Absolute Configuration Using Liquid Chromatography Methods and Evaluation of Bioactivities.

Over the last decades, many naturally occurring peptides have attracted the attention of medicinal chemists due to their promising applicability as pharmaceuticals or as models for drugs used in therapeutics. Marine peptides are chiral molecules comprising different amino acid residues. Therefore, it is essential to establish the configuration of the stereogenic carbon of their amino acid constituents for a total characterization and further synthesis to obtain higher amount of the bioactive marine peptides or as a basis for structural modifications for more potent derivatives. Moreover, it is also a crucial issue taking into account the mechanisms of molecular recognition and the influence of molecular three-dimensionality in this process. In this review, a literature survey covering the report on the determination of absolute configuration of the amino acid residues of diverse marine peptides by chromatographic methodologies is presented. A brief summary of their biological activities was also included emphasizing to the most promising marine peptides. A case study describing an experience of our group was also included.

Absolute Configuration Determination by Quantum Mechanical Calculation of Chiroptical Spectra: Basics and Applications to Fungal Metabolites.

Quantum mechanical simulations of chiroptical properties, such as electronic circular dichroism (ECD), optical rotation (OR), and vibrational circular dichroism (VCD), have rapidly become very popular to assign the absolute configuration of novel natural products. We review the application of the ECD/OR/VCD computational methodology to chiral metabolites of fungal origin. First, we summarize the fundamentals of the three spectroscopies; then, we focus on the specific experimental and computational issues allied to the application of their calculations. We surveyed the entire literature describing the use of ECD/OR/VCD computations for fungal metabolites, and catalogued all papers according to the method employed and to the structural family of compounds. Then, we chose several examples to illustrate the use of the techniques and highlight the practical application of the computational approach. Our literature survey demonstrates that the simulation of ECD/OR/VCD spectra is nowadays widespread and accessible also to non-experts, although a good computational practice is necessary to avoid wrong assignments. ECD is still the most common technique used in the context of fungal metabolites. OR and VCD may be profitably employed when the compound of interest lacks chromophoric groups. Our examples illustrate that the combination of two or more chiroptical methods is strongly advisable in some cases, especially in the presence of high conformational flexibility, where a single technique does not lead to a safe conclusion. The ECD/OR/VCD computational approach is a reliable and versatile method to assign the absolute configuration of fungal metabolites and related natural products.

Activity, toxicity, molecular docking, and environmental effects of three imidazolinone herbicides enantiomers

All imidazolinone (IMI) herbicides are chiral consisting of two enantiomers; however, studies on the enantioselectivities of their interactions are limited. This study is a systematic assessment of the enantiomers and racemates of IMI herbicides, including semi-preparation and determination of absolute configurations, stereoselective bioactivity toward target organisms (Echinochloa crus-galli and Microcystis aeruginosa), and toxicity toward Michigan Cancer Foundation-7 (MCF-7) cells. R-imidazolinones were found to be more active than S-IMIs in the inhibition of target organisms, and neither enantiomer had estrogenic activity. Moreover, the relationship between the molecular structures and the efficiency of target growth inhibition by the IMI herbicides was investigated. Molecular modeling provided the rational structural basis for the enantioselectivity of the acetohydroxyacid synthase (AHAS) activity of the IMIs. These findings encourage the application of enantiopure R-IMI herbicides to capitalize on their advantages over the racemates.

Pair of Stereodynamic Chiral Benzylicaldehyde Probes for Determination of Absolute Configuration of Amino Acid Residues in Peptides by Mass Spectrometry

This paper describes a simple method to determine the absolute configuration of amino acids residues in peptides by mass spectrometry using a newly developed pair of mass-tagged chiral probes without the requirement of reference standards. A pair of benzylicaldehyde probes, 1-(S)-1H in S configuration and 2-(R)-2D in deuterium-labeled R configuration with the ratio of 1:1, were synthesized for in situ condensation with amino acid residues and transformed into a pair of stereodynamic imine products. The characteristic intensity difference observed in mass spectrometry can be used to determine the absolute configuration and to quantify the enantiomeric composition of chiral amino acid residues. Significant chiral recognition ability was achieved for 18 natural chiral amino acids and for one β-amino acid by comparing the ion intensity ratio of imine products I[1-(S)-1H-AA]- to I[2-(R)-2D-AA]-. For 16 kinds of amino acids, the L form of the amino acids was more reactive with 1-(S)-1H, while D configuration amino acids preferred to react with 2-(R)-2D. However, for three kinds of amino acid, the opposite result was obtained. The configurations of the residues in the peptides, Phe-Tyr-Ala, D-Phe-Tyr-Ala, Val-Pro-Phe-D-Leu-Met, Val-Pro-Phe-Leu-D-Met, as well as in a natural peptide with unknown chirality were determined by acid hydrolysis followed by the present method. In addition, molecular modeling results illustrate that the recognition process is mainly controlled by kinetic factors. Using the new probes coupled with a mass spectrometry approach avoids time-consuming workup and separation steps. We expect that the probes could be applied as tools to determine the absolute configuration of amino acid residues in proteins in future research.

Stereochemical analysis of β-keto sulfoxides by circular dichroism.

Three β-keto sulfoxides (1-3) were synthesized in enantiopure form and investigated by means of circular dichroism (CD) spectroscopy, both in electronic and vibrational range (ECD, VCD), in combination with quantum chemical calculations. For compound 2, the X-ray structure was available; thus, the ECD in the solid state was also considered to reveal the differences between the molecular species in both states. Despite the simplicity of all β-keto sulfoxides under investigation (29 atoms), reproducing even the major spectral VCD features failed for two compounds, making the use of VCD not ideal to assign their absolute configuration in a reliable way. We demonstrated, however, that the use of ECD spectroscopy, both in solution and solid state, can easily, unambiguously, and without any complication simulate all bands by applying the standard protocol for calculations. This study may stimulate the debate on the need of the use of two chiroptical methods simultaneously in the determination of absolute configurations.

Total Synthesis of (±)/(+)-Subincanadine E and Determination of Absolute Configuration.

A facile synthesis of (±)-subincanadine E was described from tryptamine-based maleimide. 1,2-Addition of Grignard reagent to maleimide, internal activation of formed lactamol for in situ 1,4-addition of Grignard reagent, and associated position-specific allylic rearrangement in diastereoselective Pictet-Spengler cyclization were the key steps. Enantioselective first total synthesis of naturally occurring cytotoxic (+)-subincanadine E was also accomplished from (S)-acetoxysuccinimide via an unusual syn-addition of cuprate to the α,β-unsaturated lactam. Sinister absolute configuration was assigned to (+)-subincanadine E on the basis of total synthesis. (S)-Acetoxy group in the succinimide precursor was initially employed to impart regio- and stereoselectivity and then as a suitable leaving group to generate the desired conjugated lactam.

Some experimental aspects of absolute configuration determination using single crystal X-ray diffraction

Students of single crystal X-ray diffraction are often give advice as to how best to collect their data when attempting absolute configuration determination. These ‘rules’ often have more grounding in gut-feeling than evidence. Thus, in an effort to provide advice and evidence that today’s crystallographers can pass onto to tomorrow’s young scientists, we present a systematic study of 1-deoxy-l-arabinitol, a straight chain sugar which crystalises well in the space group I41.

Determination of absolute configuration using X-ray diffraction

Methods for determination of absolute structure using X-ray crystallography are described, with an emphasis on applications for absolute configuration assignment of enantiopure light-atom organic compounds. The ability to distinguish between alternative absolute structures by X-ray crystallography is the result of a physical phenomenon called resonant scattering, which introduces small deviations from the inherent inversion symmetry of single-crystal X-ray diffraction patterns. The magnitude of the effect depends on the elements present in the crystal and the wavelength of the X-rays used to collect the diffraction data, but it is always very weak for crystals of compounds containing no element heavier than oxygen. The precision of absolute structure determination by conventional least squares refinement appears to be unduly pessimistic for light-atom materials. Recent developments based on Bijvoet differences, quotients and Bayesian statistics enable better and more realistic precision to be obtained. The new methods are sensitive to statistical outliers, and techniques for identifying these are summarised.

Heterocyclic pharmacochemistry of new rhinovirus antiviral agents: A combined computational and experimental study

Rhinovirus (RV), member of the Enterovirus genus, is known to be involved in more than half of the common colds. Through advances in molecular biology, rhinoviruses have also been associated with exacerbations of chronic pulmonary diseases (e.g. asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis). In the current investigation, we develop a novel series of 4,5-dimethoxybenzyl derivatives that potently inhibits rhinovirus replication. Compound (S)-7f blocks RV-B14 replication with an EC50 value of 0.25 μM and shows a low toxicity in HeLa cells (CC50 > 271 μM). Enantioseparation followed by an absolute configuration determination by a Mosher's method revealed the interest of enantiopure compounds. Molecular docking studies permitted the identification of key biological interactions within the drug-binding pocket and an in silico drug-like study revealed a good potential for the development of these derivatives.

Diagnostic Absolute Configuration Determination of Tetraphenylethene Core-Based Chiral Aggregation-Induced Emission Compounds: Particular Fingerprint Bands in Comprehensive Chiroptical Spectroscopy

Tetraphenylethylene (TPE) and its derivatives are the typical aggregation-induced emission (AIE) compounds with helical chirality, and they have enormous applications potential in chiral sensor, asymmetric catalyst, optoelectronic materials, and so on. The aggregation-induced helical chirality of TPE and its derivatives can only be observed in condensed phase such as crystalline or film state. The accurate determination of absolute configuration (AC) of TPE core compounds is complicated and difficult, especially when there is no heavy atoms exist in their structures. Herein, we demonstrate a powerful and convenient method to quickly determine the helical chirality of these stereochemically labile TPE core compounds through the combination of comprehensive solid-state chiroptical spectroscopy and theoretical calculation. Our study reveals that from lower to higher energy of the fingerprint region, the first electronic circular dichroism (ECD) band in the 300–450 nm or the first most intensive vibrational c...

Chiroptical properties of dithia[3.3]cyclophanes composed of anthracene and pyridine/pyridinium moieties: A combined experimental and theoretical study.

Circular dichroisms (CDs) of neutral and protonated [3.3]anthracenopyridinophane (1 and 1-H+ ) were investigated experimentally and theoretically. Introducing an anthracene moiety with extended conjugation affected the cyclophane structure with the bent angles being appreciably reduced from those of parent [3.3]pyridinophane. The Cotton effects (CEs) observed at the 1 Bb band for both 1 and 1-H+ were fairly strong and apparently bisignate, which, however, turned out not to be a simple exciton couplet but to be composed of multiple transitions. In contrast, the CEs were much weaker in the 1 La band region. The spectral changes upon protonation were less significant compared with the parent pyridinophane, being dominated by the local transitions of anthracene. Nevertheless, the CD spectra of 1 and 1-H+ were well reproduced by theoretical calculations to allow us an unambiguous absolute configuration determination of the first high-performance liquid chromatography (HPLC) elute (from Chiralcel IB column) as Sp . The transannular interactions between the anthracene and pyridine/pyridinium units were examined by UV-vis and fluorescence spectroscopy to reveal a charge-transfer (CT) band in the low-energy region, particularly for 1-H+ . Despite the comparable CT interactions, the CE at the CT band was much stronger for the anthracenopyridinophane than for the parent pyridinophane, affording an anisotropy (g) factor as large as 4 × 10-3 .

Racemic and enantiopure forms of 3-ethyl-3-phenylpyrrolidin-2-one adopt very different crystal structures.

3-Ethyl-3-phenylpyrrolidin-2-one (EPP) is an experimental anticonvulsant based on the newly proposed α-substituted amide group pharmacophore. These compounds show robust activity in animal models of drug-resistant epilepsy and are thus promising for clinical development. In order to understand pharmaceutically relevant properties of such compounds, we are conducting an extensive investigation of their structures in the solid state. In this article, we report chiral high-performance liquid chromatography (HPLC) separation, determination of absolute configuration of enantiomers, and crystal structures of EPP. Preparative resolution of EPP enantiomers by chiral HPLC was accomplished on the Chiralcel OJ stationary phase in the polar-organic mode. Using a combination of electronic CD spectroscopy and anomalous dispersion of X-rays we established that the first-eluted enantiomer corresponds to (+)-(R)-EPP, while the second-eluted enantiomer corresponds to (-)-(S)-EPP. We also demonstrated that, in the crystalline state, enantiopure and racemic forms of this anticonvulsant have considerable differences in their supramolecular organization and patterns of hydrogen bonding. These stereospecific structural differences can be related to the differences in melting points and, correspondingly, solubility and bioavailability.

Eutypellazines N−S, new thiodiketopiperazines from a deep sea sediment derived fungus Eutypella sp. with anti-VRE activities

Chemical investigation of a deep sea sediment derived fungus Eutypella sp. MCCC 3A00281 resulted in the isolation of six new thiodiketopiperazine alkaloids, namely eutypellazines N-S (1−6). Their structures were elucidated on the basis of the extensive NMR and mass spectroscopic analysis, including the ECD data for the determination of absolute configuration. The structures of eutypellazines N-P (1−3) were characteristic of unique spirocyclic skeletons, while eutypellazines N-O bearing a spirocyclic tetrahydrobenzothiophene motif were found from wide type fungus for the first time. The biogenetic generation of the spirocyclic skeletons was postulated. Compounds 3–5 exhibited inhibitory effects against vancomycin-resistant enterococci (VRE), suggesting that they may be the potential inhibitors toward drug resistant pathogenic bacteria after the structural modification.

Determination of absolute configuration of an isopimarane-type diterpenoid by experimental and theoretical electronic circular dichroism and vibrational circular dichroism

In this study, the stereochemistry of a new isopimarane-type diterpenoid isolated from the Callicarpa macrophylla Vahl, Callicapene M3, was studied by experimental electronic circular dichroism and vibrational circular dichroism with the aid of TDDFT theoretical calculations. The good consistence between the experimental and simulated circular dichroism has clearly confirmed the absolute configuration of the title compound as (4S, 5S, 9S, 10S, 13S, 14S)-14α-hydroxy-7,15-isopimaradien-18-oic acid.

Absolute configuration determination for light-atom structures using low-power microfocus X-ray source

Absolute configuration determination for light-atom structures using low-power microfocus X-ray source

Asymmetric Sequential Cu-Catalyzed 1,6/1,4-Conjugate Additions of Hard Nucleophiles to Cyclic Dienones: Determination of Absolute Configurations and Origins of Enantioselectivity.

The first stereocontrolled Cu-catalyzed sequential 1,6/1,4-asymmetric conjugate addition (ACA) of C-metalated hard nucleophiles to cyclic dienones is reported. The use of DiPPAM (diphenylphosphinoazomethinylate) followed by a phosphoramidite as the stereoinducing ligands facilitated both high ee values for the 1,6-ACA and high de values for the 1,4-ACA reaction components, which thus gave enantioenriched 1,3-dialkylated moieties. The absolute configurations were determined by using vibrational circular dichroism (VCD) and optical rotatory dispersion (ORD) spectroscopy, in combination with DFT calculations and X-ray analysis. Interestingly, DFT calculations for the mechanism of enantioselective 1,6-addition by using an unprecedented Cu-Zn bimetallic catalytic system confirmed this attribution. Lastly, exploring intramolecular cyclization avenues for enantioenriched 1,3-dialkylated products provided access to the challenging drimane skeleton.