Absolute Configuration Of Secondary Alcohols Research Articles

Determination of the Absolute Configuration of Secondary Alcohols in a Compound Mixture via the Application of Competing Enantioselective Acylation Coupled with LC/MS Analysis.

The determination of natural product stereochemistry plays a significant role in drug discovery and development. Understanding the stereochemistry of natural products is essential for predicting and optimizing their interactions with biological targets, which, in turn, influences their therapeutic efficacy, safety, and overall impact on living organisms. Here, we present the first application of competitive enantioselective acylation (CEA) reactions in conjunction with LC/MS analysis for determining the absolute configuration of secondary alcohols in natural products which were purified as a mixture. This approach utilizes the enantiomeric pair of HBTM (homobenzotetramisole) catalysts, demonstrating sufficient kinetic resolution for the acylation of secondary alcohols. The rapid reaction kinetics were quantitatively estimated with LC/MS analysis as the characterization technique for the enantioselective transformations. Our study has expanded the application of the CEA reaction coupled with LC/MS analysis to mixtures. Utilizing LC/MS analysis, the CEA reaction offers a sensitive and simple method for stereochemistry determination. Additionally, the application of the CEA reaction is cost/time-effective since only small quantities of substrates and a short reaction time are required for characterizing the absolute configuration of secondary alcohols in natural products compared to other conventional methods.

Assignment of the absolute configuration of secondary alcohols by 13C NMR and its correlation with methyl-1-(chloromethyl)-oxopyrrolidine-2-carboxylate and quantum-mechanical GIAO calculations

The diastereoisomers from a chiral derivatizing agent with secondary alcohols allowed the assignment of the absolute configuration by 13C NMR spectroscopy.

Application of the 2-deoxyglucose scaffold as a new chiral probe for elucidation of the absolute configuration of secondary alcohols

Herein, we present the application of 2-deoxy-d-glucose derivatives as chiral probes for elucidation of the absolute configuration of chiral secondary alcohols. The probes are attached to the studied molecules via glycosylation reaction and the resulting products are examined by a set of standard 2D NMR experiments. The absolute configuration of an oxymethine carbon atom binding the probe is established on a basis of a set of diagnostic dipolar couplings (NOEs/ROEs). These correlations may be considered diagnostic due to a pronounced lack of conformational freedom of the formed glycosidic linkage. While the chance for an observation of the diagnostic signals is the highest when the resulting glycoside in an α-anomer. 2-deoxy-d-glucose was selected as a probe of choice since is it known to strongly prefer the formation of α-glycosides

Gancochlearols E − I, meroterpenoids from Ganoderma cochlear against COX-2 and triple negative breast cancer cells and the absolute configuration assignment of ganomycin K

Five new meroterpenoids, gancochlearols E − I (1, 3–6), and one compound ganomycin K (2) were isolated from the fruiting bodies of G. cochlear. Their structures were assigned by 1D and 2D NMR, MS, and CD analysis. Rh2(OCOCF3)4-induced ECD method was used to clarify the absolute configuration of secondary alcohol in 1 and 2. Biochemical evaluation showed that all the isolates significantly inhibit COX-2 enzyme in vitro with the IC50 values range from 1.03 μM to 2.71 μM. Further cellular assay revealed that (+)-3 and (−)-6 could suppress metastatic phenotype of triple-negative breast cancer (TNBC) cells via impeding the epithelial-mesenchymal transition (EMT).

Colletofurans A-E, 1-Octyl-1,3-dihydroisobenzofuran Derivatives from Colletotrichum boninense AM-12-2.

3-(3-Hydroxy-2-(hydroxymethyl)phenyl)propanoic acid, 2-hydroxymethyl-3-hydroxy-(E)-cinnamic acid, and colletofurans A-E were isolated from Colletotrichum boninense AM-12-2. Colletofurans A-E are the first natural compounds featuring a 1-octyl-1,3-dihydroisobenzofuran core. Their structures were initially established by 1D/2D-NMR and HRESITOFMS. Mosher's ester method was used to determine the absolute configurations of secondary alcohols in colletofurans A-C. The structures of colletofurans A and B-E were further confirmed by DFT GIAO calculations and the X-ray crystalline sponge method, respectively.

Fusaspirols A-D, novel oxaspirol derivatives isolated from Fusarium solani B-18

Four novel compounds with γ-methylidene-spirobutanolide core, fusaspirols A-D, were isolated from the brown rice culture of Fusarium solani B-18. Their structures were established by extensive spectroscopic analyses of 1D/2D-NMR, HRESITOFMS, and chemical derivatization. The absolute configurations of secondary alcohols in fusaspirols A and D were determined using modified Mosher's ester method. Fusaspirol A and 4,9-di-O-acetylfusaspirol A activated a signaling pathway in osteoclastic differentiation of murine macrophage derived RAW264.7 cells.

New isocoumarins, naphthoquinones, and a cleistanthane-type diterpene from Nectria pseudotrichia 120-1NP

Four new compounds, namely, nectriapyrones A (2) and B (3), nectriaquinone B (5), and zythiostromic acid C (8), were isolated from the brown rice culture of Nectria pseudotrichia 120-1NP together with four known compounds (1, 4, 6, and 7). To the best of our knowledge, this is the first report of 4 from a natural source. Their structures were determined on the basis of 1D/2D-NMR spectroscopy and HRESITOFMS data. In addition, the absolute configuration of secondary alcohols in 8 were determined using modified Mosher's ester method. All isolated compounds were evaluated for their antimicrobials activity, phytotoxicity, and cytotoxicity.

Monosaccharides as Potential Chiral Probes for the Determination of the Absolute Configuration of Secondary Alcohols.

Herein, a new method for the elucidation of the absolute configuration of chiral secondary alcohols is proposed. This method is an alternative for a widely used approach reported by Mosher and Dale and similar methods that are based on the 1H NMR shift (δ) changes of protons that are attached to the substituents of the oxymethine carbon atom. The presented method is not based on tracking the chemical shift changes and utilizes stereochemically defined monosaccharides as chiral probes. A secondary alcohol is glycosylated, and the resulting glycoside is subjected to NMR studies. The observation of dipolar couplings between the protons of the monosaccharide moiety and the protons of the secondary alcohol moiety via the NOESY/ROESY spectra enables the determination of the absolute configuration of the oxymethine carbon atom.

Nanomole-Scale Assignment and One-Use Kits for Determining the Absolute Configuration of Secondary Alcohols.

Two different protocols were developed and optimized to address the need for (1) high sensitivity or (2) convenient utilization in the determination of the absolute configuration of secondary alcohols. The first protocol uses the competing enantioselective conversion (CEC) method to determine configuration on nanomole scale. Reactions were conducted with 145 nmol of the substrate using a 50 μL microsyringe as the reaction vessel, and the absolute configuration was assigned via qualitative determination of the fast reaction by thin-layer chromatography. This protocol resulted in a 50-fold reduction in material required from previous CEC method studies. The approach was evaluated with benzylic and β-aryl systems. The second protocol was optimized to address the needs of practicing medicinal chemists. A one-use CEC kit was developed, where the fast reaction was identified by (1)H NMR spectroscopy and thin-layer chromatography. The CEC reaction conditions developed for the microsyringe protocol and the one-use kit both displayed data consistent with pseudo-first-order kinetics in substrate. Therefore, the lower limit of sensitivity for the substrate is limited only by the ability to effectively detect the reaction conversions between alcohol substrate and ester product.

ChemInform Abstract: FICA (I), a New Chiral Derivatizing Agent for Determining the Absolute Configuration of Secondary Alcohols by 19F and 1H NMR Spectroscopies.

ChemInform Abstract: FICA (I), a New Chiral Derivatizing Agent for Determining the Absolute Configuration of Secondary Alcohols by ¹⁹F and ¹H NMR Spectroscopies.

FICA, a new chiral derivatizing agent for determining the absolute configuration of secondary alcohols by 19F and 1H NMR spectroscopies

Optically active 1-fluoroindan-1-carboxylic acid (FICA) was designed and prepared as its methyl ester for determining the absolute configuration of chiral molecules by both 1H and 19F NMR spectroscopies. Enantiomerically pure isomers of FICA methyl esters (FICA Me esters) were obtained by chromatographic separation using HPLC with a Daicel Chiralcel OJ-H column. The absolute configuration of the (+)-FICA Me ester was deduced to be (S) by X-ray crystallographic analysis of the (+)-FICA amide of (R)-α-phenethylamine. Both enantiomers were derived to the diastereomeric esters of chiral secondary alcohols by an ester exchange reaction. In the 1H NMR spectra, the signs of ΔδH (δR−δS) were consistent on each side of the FICA molecular plane. Therefore, the concept of the modified Mosher’s method could be successfully applied to the FICA-based procedure. Moreover, the consistency in the signs of ΔδF (δR−δS) values suggests that the FICA method would be reliable in assigning the absolute configurations of secondary alcohols based on 19F NMR spectroscopy.

Determination of absolute configuration of secondary alcohols using thin-layer chromatography.

A new implementation of the competing enantioselective conversion (CEC) method was developed to qualitatively determine the absolute configuration of enantioenriched secondary alcohols using thin-layer chromatography. The entire process for the method requires approximately 60 min and utilizes micromole quantities of the secondary alcohol being tested. A number of synthetically relevant secondary alcohols are presented. Additionally, (1)H NMR spectroscopy was conducted on all samples to provide evidence of reaction conversion that supports the qualitative method presented herein.

Selective Excitation 1D-NMR Experiments for the Assignment of the Absolute Configuration of Secondary Alcohols

Routine selective excitation experiments, easy to set up on modern NMR spectrometers, allow for the determination of the absolute configuration of chiral secondary alcohols by double derivatization directly in the NMR tube. As a general method, TOCSY1D with selective excitation of the α proton in the MPA esters and with a short mixing time reveals only the nearby protons in the coupling network. Typically, the analysis takes less than 30 min. A longer mixing time, selective excitation of other signals, or NOESY1D experiments can be used for measuring ΔδRS of other protons.

N‐Arylcarbonylpseudoprolines as Tunable Chiral Derivatizing Agents for the Determination of the Absolute Configuration of Secondary Alcohols

AbstractNew chiral derivatizing agents, 3‐arylcarbonyl‐2,2‐dimethyloxazolidine‐4‐carboxylic acids (N‐arylcarbonylpseudoprolines), were prepared through a simple, short‐step synthesis. The absolute configuration of secondary alcohols can be assigned on the basis of the NMR spectroscopic chemical shift difference between diastereomeric pseudoproline esters. Preparation of more efficient agents was achieved simply by using aromatic groups with stronger anisotropic effect.

ChemInform Abstract: A New Method for the Establishment of Absolute Configurations of Secondary Alcohols by NMR Spectroscopy.

ChemInform Abstract: A New Method for the Establishment of Absolute Configurations of Secondary Alcohols by NMR Spectroscopy.

Paleic acid, a fatty acid from Paenibacillus sp.: taxonomy, fermentation, isolation, structure determination, and anti-Mannheimia and -Pasteurella activity

Paleic acid (1), an antibiotic, was obtained from a fermentation broth of Paenibacillus sp. BMK771-AF3. The compound is a fatty acid (9Z,16R)-16-hydroxy-9-octadecenoic acid ((R)-16-hydroxyoleic acid), whose isolation required protection of its polar functional groups. Mosher esters of paleic acid yielded information on the absolute configuration of secondary alcohol, and well-resolved (1)H NMR peaks around the double bond suggested that olefin adopted a Z geometry. Paleic acid showed potent antibacterial activity and narrow spectrum against Mannheimia haemolytica with MIC values ranging between 0.78 and 1.56 microg ml(-1).

Tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid: a chiral derivatizing agent for the determination of the absolute configuration of secondary alcohols

A new chiral derivatizing agent, tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid (THENA), with a represented syn-periplanar disposition of O–C α –C O as a part of the bicyclic system to lock the aromatic residue conformation and the availability of an internal reference proton for 1H NMR spectral alignment, is introduced. In the determination of the absolute configuration of chiral secondary alcohols, THENA offered good uniformity of Δ δ with high reliability, resulting in unambiguous assignment of the absolute configuration.

ChemInform Abstract: The 13C NMR Method for Determining the Absolute Configuration of the 1,2-Glycols Consisting of Secondary and Tertiary Hydroxyl Groups.

Abstract The fucofuranoside method, the 13 C NMR method for determining the absolute configuration of secondary alcohols, is applied to five known steroids having a 1,2-glycol group composed of secondary and tertiary hydroxyl groups. The 1,2-alignment of the polar fucofuranosyl and tertiary hydroxyl group was found to have little influence on the requisite conformation of the glycosidic linkage. It showed the normal pattern of the distribution of the Δ δ C (and Δ δ H ) values, as previously observed for simple monohydroxy derivatives, demonstrating the usefulness of the method for this type of compound.

Determination of absolute configuration of secondary alcohols using lipase‐catalyzed kinetic resolutions

Lipases show high enantioselectivity toward a wide range of secondary alcohols. An empirical rule based on the relative sizes of the substituents predicts which enantiomer reacts faster. X-ray structures of lipases provide a molecular basis for this empirical rule: their alcohol-binding pocket contains large hydrophobic pocket open to solvent and another smaller pocket. This predictable enantiopreference of lipases allows the determination of the absolute configuration of secondary alcohols using lipase-catalyzed kinetic resolution. Researchers have used this relative method to determine the configuration of approximately 50 secondary alcohols either as the only method or in combination with other methods.

Chiral Anisotropic Reagents for Determining the Absolute Configuration of Secondary Alcohols and Carboxylic Acids

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