Determination Of Absolute Configuration Research Articles

Absolute Configuration Determination of Two Diastereomeric Neovasifuranones A and B from Fusarium oxysporum R1 by a Combination of Mosher's Method and Chiroptical Approach.

Endophytic fungi are one of prolific sources of bioactive natural products with potential application in biomedicine and agriculture. In our continuous search for antimicrobial secondary metabolites from Fusarium oxysporum R1 associated with traditional Chinese medicinal plant Rumex madaio Makino using one strain many compounds (OSMAC) strategy, two diastereomeric polyketides neovasifuranones A (3) and B (4) were obtained from its solid rice medium together with N-(2-phenylethyl)acetamide (1), 1-(3-hydroxy-2-methoxyphenyl)-ethanone (2) and 1,2-seco-trypacidin (5). Their planar structures were unambiguously determined using 1D NMR and MS spectroscopy techniques as well as comparison with the literature data. By a combination of the modified Mosher’s reactions and chiroptical methods using time-dependent density functional theory-electronic circular dichroism (TDDFT-ECD) and optical rotatory dispersion (ORD), the absolute configurations of compounds 3 and 4 are firstly confirmed and, respectively, characterized as (4S,7S,8R), (4S,7S,8S). Bioassay results indicate that these metabolites 1–5 exhibit weak inhibitory effect on Helicobacter pylori 159 with MIC values of ≥16 μg/mL. An in-depth discussion for enhancement of fungal metabolite diversity is also proposed in this work.

Determining the Enantiomeric Excess and Absolute Configuration of In Situ Fluorine-Labeled Amines and Alcohols by 19F NMR Spectroscopy.

The determination of the enantiomeric excess and absolute configuration of chiral compounds is indispensable in synthetic, pharmaceutical, and biological chemistry. In this article, we describe an efficient 19F nuclear magnetic resonance (NMR)-based analytical protocol for determining the enantiomeric excess and absolute configuration of in situ fluorine-labeled amines and alcohols. 2-Fluorobenzoylation was used to convert analytes to fluorinated amides or esters. The resulting F-labeled analytes were mixed with a cationic cobalt(III) complex, [Co]BArF, resulting in clean baseline peak separations of analyte enantiomers in 19F{1H} NMR spectra. The measured ΔδRS signs were unambiguously used to correlate the absolute configurations of amines, amino alcohols, and alcohols. Moreover, the structure-dependent 19F{1H} NMR signals enabled absolute configuration determination by analyzing the relative chemical shifts of enantiopure analyte samples with [Co]BArF and ent-[Co]BArF.

Absolute configuration assignment of stigmasterol oxiranes.

Diastereoisomeric stigmasterol oxiranes 4, 5, 8, and 9 are known phytosterol oxidation products (POPs) that have been evaluated for their cytotoxicity, although the results are of limited significance since, in most cases, they were evaluated as mixtures. Consequently, to establish biological activity hierarchy of these oxides, it is critical to evaluate individual pure POPs. Therefore, we now describe the obtention of individual molecules and their absolute configuration (AC) determination. The two acetylated C-5-C-6 oxiranes 6 and 7; the two acetylated C-22-C-23 oxides 10 and 11, obtained by means of Δ5 double bond protection-deprotection; and the four C-5-C-6, C-22-C-23 diepoxystigmasteryl acetates 19-22 were now individually gained and their AC determined by vibrational circular dichroism. Vibrational modes associated with the C-5-C-6 and the C-22-C-23 bonds were identified in dioxiranes 19-22 and used to assign the AC of monoepoxides 6, 7, 10, and 11. The AC of biological active non-acetylated molecules follows immediately. Due to the scarce spectroscopic information available for these POPs, the 1 H and 13 C NMR chemical shifts of 3-22 were assigned using 1D- and 2D-NMR experiments.

Chiral resolution and absolute configuration determination of new metal-based photodynamic therapy antitumor agents

The advent of cisplatin as a cancer drug in the late 1960s generated considerable interest in the use of transition metal complexes as cancer therapy agents. Despite enhanced research in this area, there has yet to be any non-platinum-based transition metal complex cancer drugs approved by the Food and Drug Administration (FDA). Recently a Ru(II) metal-organic dyad (TLD1433) has provided promising results as a photodynamic therapy (PDT) agent for some types of cancer. This particularly effective PDT compound has an oligothiophene chain appended to an imidazophenanthroline ligand which chelates Ru(II). The entire complex is chiral and is synthesized as a racemate. Five such chiral Ru(II) and Os(II) PDT agents were synthesized and their enantiomers separated for the first time. The enantiomers of these compounds are not easily crystalized. However, preparative LC provided sufficient amounts of these novel PDT agents to determine their absolute configurations by vibrational circular dichroism (VCD). The synthesis, separation and absolute configuration determinations are described and discussed in detail.

Absolute Configuration of In Situ Crystallized (+)-γ-Decalactone

Knowledge about the absolute configuration of small bioactive organic molecules is essential in pharmaceutical research because enantiomers can exhibit considerably different effects on living organisms. X-ray crystallography enables chemists to determine the absolute configuration of an enantiopure compound due to anomalous dispersion. Here, we present the determination of the absolute configuration of the flavoring agent (+)-γ-decalactone, which is liquid under ambient conditions. Single crystals were grown from the liquid in a glass capillary by in situ cryo-crystallization. Diffraction data collection was performed using Cu-Kα radiation. The absolute configuration was confirmed. The molecule consists of a linear aliphatic non-polar backbone and a polar lactone head. In the solid state, layers of polar and non-polar sections of the molecule alternating along the c-axis of the unit cell are observed. In favorable cases, this method of absolute configuration determination of pure liquid (bioactive) agents or liquid products from asymmetric catalysis is a convenient alternative to conventional methods of absolute structure determination, such as optical rotatory dispersion, vibrational circular dichroism, ultraviolet-visible spectroscopy, use of chiral shift reagents in proton NMR and Coulomb explosion imaging.

Absolute Configuration Determination from Low ee Compounds by the Crystalline Sponge Method. Unusual Conglomerate Formation in a Pre-Determined Crystalline Lattice.

When chiral compounds with low enantiomeric excess (ee, R:S=m:n) were absorbed into the void of the crystalline sponge (CS), enantiomerically pure [(R)m (S)n ] chiral composites were formed, changing the centrosymmetric space group into non-centrosymmetric one. The absolute configuration of the analyte compounds was elucidated with a reasonable Flack (Parsons) parameter value. This phenomenon is characteristic to the "post-crystallization" in the pre-determined CS crystalline lattice, seldom found in common crystallization where the crystalline lattice is defined by an analyte itself. The results highlight the potential of the CS method for absolute configuration determination of low ee samples, an often encountered situation in asymmetric synthesis studies.

Absolute Configuration Determination from Low ee Compounds by the Crystalline Sponge Method. Unusual Conglomerate Formation in a Pre‐Determined Crystalline Lattice

AbstractWhen chiral compounds with low enantiomeric excess (ee, R:S=m:n) were absorbed into the void of the crystalline sponge (CS), enantiomerically pure [(R)m(S)n] chiral composites were formed, changing the centrosymmetric space group into non‐centrosymmetric one. The absolute configuration of the analyte compounds was elucidated with a reasonable Flack (Parsons) parameter value. This phenomenon is characteristic to the “post‐crystallization” in the pre‐determined CS crystalline lattice, seldom found in common crystallization where the crystalline lattice is defined by an analyte itself. The results highlight the potential of the CS method for absolute configuration determination of low ee samples, an often encountered situation in asymmetric synthesis studies.

Homochiral MOF as Chiroptical Sensor for Determination of Absolute Configuration and Enantiomeric Ratio of Chiral Tryptophan

AbstractThe development of a highly selective and sensitive optical method for quantitative enantioselective sensing of chiral amino acids in the presence of other amino acid interferences has remained a major challenge to date. Herein, a homochiral metal–organic framework (MOF), [Zn(L)(2,2′‐bipy)]·H2O (LNNU‐1) (H2L = HOOCC6H4CH2PO(OH)(OC2H5), 2,2′‐bipy = 2,2′‐bipyridine), is designed to interact with tryptophan via multiple noncovalent interactions. The interactions result in the emergence of a strong induced circular dichroism signal. This enables accurate determination of the absolute configuration and enantiomeric ratio of chiral tryptophan in water, mixed natural amino acids, and blood plasma components without any interference from other coexistent species. A simple device with advantageous characteristics of reusability and simple manipulation is designed for enantioselective sensing assay. The obtained results suggest that the rationally designed homochiral MOF is a promising candidate for enantioselective sensing of chiral species.

Structure elucidation and absolute configuration determination of C26, C27 and C30 tirucallane triterpenoids from the leaves of Picrasma quassioides (D. Don) Benn

Seven undescribed tirucallane-type triterpenoids, kumunorquassins A‒E and kumuquassins K and L, along with nine known analogues, have been isolated from the leaves of Picrasma quassioides (D. Don) Benn. Their structures and absolute configurations were elucidated based on comprehensive spectroscopic analyses, single-crystal X-ray diffraction analysis and electronic circular dichroism (ECD). The absolute configuration of cornusalterin J was unequivocally determined by X-ray diffraction based on its p-bromobenzoate derivative. A brief approach was presented in our study, which could rapidly and conveniently determine the relative and absolute configurations of OCH3-23 of kumuquassin L and cornusalterins J, H and G depending on the chemical shift differences (Δδ) of C-24 and C-25 and the chemical shifts of C-23, H-23 and H-24. In addition, the cytotoxicities of these compounds against two human tumour cell lines (HepG2 and Hep3B) were evaluated.

Exploring machine learning methods for absolute configuration determination with vibrational circular dichroism.

The added value of supervised Machine Learning (ML) methods to determine the Absolute Configuration (AC) of compounds from their Vibrational Circular Dichroism (VCD) spectra was explored. Among all ML methods considered, Random Forest (RF) and Feedforward Neural Network (FNN) yield the best performance for identification of the AC. At its best, FNN allows near-perfect AC determination, with accuracy of prediction up to 0.995, while RF combines good predictive accuracy (up to 0.940) with the ability to identify the spectral areas important for the identification of the AC. No loss in performance of either model is observed as long as the spectral sampling interval used does not exceed the spectral bandwidth. Increasing the sampling interval proves to be the best method to lower the dimensionality of the input data, thereby decreasing the computational cost associated with the training of the models.

Synthesis and application of methyl itaconate-anthracene adducts in configuration assignment of chiral secondary alcohols by 1H NMR.

Novel chiral derivatising agents (CDAs) such as methyl itaconate-anthracene adducts (MIAs) were reported for the absolute configuration determination of chiral secondary alcohols by the 1H NMR technique. These adducts were facilely prepared through well-known reactions, and furthermore, commercially available starting materials. According to these synthetic routes, the desired MIAs were afforded in 6 steps with 49% overall yield from dimethyl itaconate. Moreover, the represented MIAs provided significantly large differences of chemical shift values (ΔδSR). No racemisation from the tertiary characteristics of the adjacent alpha carbon was observed.

Labdane-Type Diterpenes from the Aerial Parts of Rydingia persica: Their Absolute Configurations and Protective Effects on LPS-Induced Inflammation in Keratinocytes.

Phytochemical investigations of an extract of the aerial parts of Rydingia persica led to the isolation of 14 labdane-type diterpenoids, of which compounds 1–5, 8, and 12–14 turned out to be new natural products, while the remaining compounds were isolated for the first time from the genus Rydingia. Their structures were elucidated using 1D- and 2D-NMR and mass spectrometry, and their absolute configurations were determined by quantum chemical calculation methods. Furthermore, DP4+ NMR chemical shift probability calculations were performed for compounds 12–14, in order to elucidate the orientation of the ambiguous chiral center at C-15, prior to absolute configuration determination. The methanol extract of the aerial parts of R. persica along with subfractions obtained and selected isolated compounds were evaluated for their effects on inflammation-related factors such as nitrotyrosine formation, IL-6 release, and TNF-α release, along with tight-junction proteins claudin-1 and occludin expression in LPS-stimulated HaCaT cells. Occludin and claudin-1 are tight-junction proteins, which play a pivotal role in wound repair mechanisms. Overall, the subfractions and compounds isolated showed moderate to high activity, indicating that labdane-type diterpenoids contribute to the anti-inflammatory and wound-healing activity of R. persica.

A sensitive micellar liquid chromatographic method for the rectification of enantiomers of esmolol, and determination of absolute configuration and elution order

A green chromatographic method is proposed for the enantioseparation of Esmolol (Amino alcohol) in which aqueous solution of the mixed surfactants is used as the alternative of organic solvents. In this work, the diastereomeric derivatives of racemic esmolol were prepared, under microwave heating conditions, using highly reactive activated chiral esters of the (S)-levofloxacin, (S)-ketoprofen, and (S)-ibuprofen. The prepared diastereomeric derivatives were separated using surfactant based mobile phase on RP-HPLC. The effect of the varying concentration of surfactant (Brij-35 and SDS) in the eluting phase was investigated for separation and elution of synthesized diastereomeric derivatives. The green assessment score was calculated (obtain score points were 82) for developed method. In addition, the density functional theory calculations were performed, using Gaussian 09 rev. A.02 and hybrid density functional B3LYP with 6-31 G* basis set program, in order to develop lowest energy optimized structures of diastereomeric derivatives. The optimized structures used to predict elution order of synthesized diastereomeric derivatives. Our method was characterized by the following validation parameter: LOD (0.289 ng mL−1), LOQ (0.867 ng mL−1), calibration range (0.006–6.0 mg mL−1), correlation coefficient (0.999) and recovery (99.97 and 99.85% for intra-day assay and 99.42 and 99.75% for inter-day assay).

Vibrational circular dichroism behavior of quinol cacalolides from Psacalium aff. sinuatum

In search to find levels of density functional theory (DFT) for the accurate prediction of vibrational circular dichroism (VCD) spectra of cacalolides, we undertook the evaluation of isomeric quinols. To gain compounds that provide experimental VCD spectra for comparative purposes to the calculated spectra, we prepared the hexanes extracts of the roots of Psacalium aff. sinuatum (Cerv.) H. Rob. & Brettell. They afforded the known furotetralin cacalol (1a), the isomeric quinols cacalone (2a) and epi‑cacalone (3a), and the furodehydrotetralin cacalohastine (4). In an earlier work we found that the absolute configuration (AC) determination of 1a by VCD required the study of its acetyl derivative 1b when comparing the experimental data with DFT spectra calculated at the commonly used B3LYP/DGDZVP level of theory. Herein the AC of acetylcacalone (2b) and of non-acetylated 3a were addressed using the same VCD methodology for which it is difficult to predict which DFT level of theory would provide satisfactory results for the uncommon quinol chromophores. It turned out that epi‑cacalone (3a) required the B3PW91/DGDZVP2 level of theory, while in the case of natural occurring 2a it was necessary, as in the case of 1a, to study the acetyl derivative 2b since in 2a the tertiary hydroxy group is prone to intermolecular associations in solution. In addition, the dihydronaphthofuran 4 required the PBEPBE/DGDZVP level of theory, mainly used for aromatic compounds, to be modeled satisfactorily.

Alkaloid constituents from the fruits of Flueggea virosa.

Three new indole alkaloids, flueindolines A-C (1-3), along with nine known alkaloids (4-12), were isolated from the fruits of Flueggea virosa (Roxb. ex Willd.) Voigt. Compounds 1 and 2 are two new fused tricyclic indole alkaloids possessing an unusual pyrido[1, 2-a]indole framework, and 3 presents a rare spiro (pyrrolizidinyl-oxindole) backbone. Their structures with absolute configurations were elucidated by means of comprehensive spectroscopic analysis, chemical calculation, as well as X-ray crystallography. Chiral resolution and absolute configuration determination of the known compounds 4, 10, and 11 were reported for the first time. The hypothetical biogenetical pathways of 1-3 were herein also proposed.

Application of a novel chromophoric reagent, 2,2′-binaphthyl-3,3′-dicarbonyl cyanide, to the absolute configuration determination of chiral secondary alcohols

2,2′-Binaphthyl-3,3′-dicarbonyl cyanide possessing two reaction sites was designed and synthesized as a new chromophoric reagent for exciton-coupled circular dichroism (ECCD), which is more effective in determination of the absolute stereochemistry of the target chiral alcohols than 2,2′-binaphthyl-3-methoxycarbonyl-3′-carbonyl cyanide, which contains only one reaction site. The CD spectra of the 2,2′-binaphthyl diesters derived from chiral secondary alcohols show bisignate curves centered at 240 nm, of which the Δε value was roughly twice as large as that of the binaphthyl methyl monoester.

Absolute Configuration of trans-Perhydroazulene.

We present the absolute configuration (AC) determination of an alkane, trans-perhydroazulene (1), that displays the naturally very common trans fused [5,7] ring system. We outline the first synthesis yielding enantiopure 1 and the application of optical rotatory dispersion (ORD) and vibrational circular dichroism (VCD) techniques. The spectroscopic results are in excellent agreement with the computed ORD at B3LYP/6-311++G(2d,2p) and the computed VCD spectrum at B3LYP/6-311++G(d,p), providing an assignment of the AC as (R,R)-(+)-1.

The enduring legacy of Koji Nakanishi's research on bioorganic chemistry and natural products. Part 1: Isolation, structure determination and mode of action.

In this brief review on Koji Nakanishi's remarkable career in natural products chemistry, we have highlighted a number of his accomplishments that illustrate the broad diversity of his interests. These include the isolation, structure determination, and biological mechanism of action of many natural products including the triterpenoid pristimerin; the diterpenoid ginkgolides; insect and crustacean molting hormones; phytoalexins; the toxic red tide principle brevetoxin; the vanadium tunicate pigments; philanthotoxin from killer wasps; antisickling agents; mitomycin DNA adducts; insect antifeedants; a mitotic hormone, the small molecule fish attractants from the sea anemone; new isolation and purification technologies; molecular chemistry of vision; age-related macular degeneration; and the development of the exciton circular dichroism (CD) chirality method for microscale determination of absolute configuration of natural products and chirality of other chiral molecules and supramolecular assembly.

Determination of absolute configuration of photo-degraded catechinopyranocyanidin A by modified Mosher's method.

Catechinopyranocyanidins A and B (cpcA and cpcB) are two purple pigments present in the seed-coat of red adzuki bean, Vigna angularis, of which cpcA is the major pigment, containing two chiral carbons in the catechin part. Their absolute configurations were determined by comparison of their experimental and quantum chemical calculated electronic circular dichroisms (ECDs). These purple pigments are labile on light irradiation and easily decompose to photo-degraded catechinopyranocyanidins A and B (pdcpcA and pdcpcB), while retaining the stereostructure of the catechin residue. We applied modified Mosher's method for determining the chirality of the secondary alcohol in pdcpcA. Hexamethylation of pdcpcA by diazomethane followed by esterification using (S)- and (R)-MTPACl gave (R)- and (S)-MTPA esters, respectively. By analysis of the NMR spectra of (R)- and (S)-MTPA esters of tetramethylated (+)-catechin, the chirality of pdcpcA was determined to be 2R, 3S, same as the absolute configuration of cpcA.

Frontispiece: Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)‐Tronocarpine Enabled by an Asymmetric Michael/Aldol Reaction

Natural Product Synthesis In their Communication on page 3834, F.-S. Han et al. report the asymmetric total synthesis and absolute configuration determination of (+)-tronocarpine. The [6.5.7.6.6] pentacyclic core was constructed by using a sequential cyclization strategy.