Assignment Of Absolute Configuration Research Articles

Catalytic Enantioselective Alkylative Dearomatization−Annulation: Total Synthesis and Absolute Configuration Assignment of Hyperibone K

The asymmetric total synthesis of the polyprenylated acylphloroglucinol hyperibone K has been achieved using an enantioselective alkylative dearomatization-annulation process. NMR and computational studies were employed to probe the mode of action of a chiral phase-transfer (ion pair) catalyst.

ChemInform Abstract: Synthesis of the Bretonins, Polyolefinic Esterified Glyceryl Ethers of an Unidentified Sponge from the North-Brittany Sea: Absolute Configuration and Novel Structure Assignment.

The absolute configurations of acetylated bretonin A (= (+}-(R)-1-[(acetoxy)methyl]-2-{[(4E,6E,8E)-dodeca-4,6,8-trienyl]oxy}ethyl 4-acetoxybenzoate; (−)-1b) and isobretonin A (= (+)-(S)-3-{[(4E,6E,8E)-do-deca-4,6,8-trienyl]oxy}-2-hydroxypropyl 4-hydroxybenzoate; (+)-2), previously isolated from an undetermined sponge of the North Brittany sea, were established by comparison with synthetic (+)-lb and (+)-2, obtained from the condensation of commerical (−)-(R)-2,2-dimethyl-1,3-dioxolan-4-yl p-toluenesuifonate ((−)-(R)-15) with a mixture of (4E,6E,8E)- (14e) and (4E,6Z,8E)-dodeca-4,6,8-trien-1-ol (14z). This also allowed confirming the structure and configuration of bretonin B (= (S)-2-{[(4E,6Z,8E)-dodeca-4,6,8-trienyl]oxy}-1-(hydroxy-methyl)ethyl 4-hydroxybenzoate; 3) which was also isolated from the same sponge, albeit in a too small amount for a complete study. As concerns the glyceryl ethers precursors of the bretonins, co-occurrence of the usual (S)-con-figuration (from 1a) with the unusual (R)-configuration (from (+)-2)) poses intriguing biogenetic problems.

ChemInform Abstract: Synthesis, Resolution and Assignment of Absolute Configuration of 2-(. alpha.-Hydroxy)aryl Acrylate Esters.

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ChemInform Abstract: Synthesis, Separation and Absolute Configuration Assignment to Enantiomers of 1,3-Benzodithiole 1-Oxide and 2-Alkyl-1,3-benzodithiole 1-Oxides.

ChemInform Abstract: Synthesis, Separation and Absolute Configuration Assignment to Enantiomers of 1,3-Benzodithiole 1-Oxide and 2-Alkyl-1,3-benzodithiole 1-Oxides.

ChemInform Abstract: Synthesis of R- and S-3-Oxo-2-oxaspiro(4.4)-nonane-1-carboxylic Acid.

Abstract An efficient synthesis and temperature dependent resolution of R- and S-3-Oxo-2-oxaspiro[4.4]-nonane-1-carboxylic acid are described. The assignment of absolute configuration is based on single crystal X-ray analysis of an amide derivative.

Synthesis of All Enantiomerically Pure Diastereomers of Aprepitant

Syntheses of all eight enantiomerically pure diastereomers of aprepitant and assignment of absolute configuration at newly generated stereocenters by NMR and x-ray crystallographic analysis were achieved.

3+2]-Cycloaddition Reaction between Chiral Oxaziridines and Nitriles: Enantioselective Synthesis of 2,3-Dihydro-1,2,4-oxadiazoles

Enantiomerically pure 2,3-dihydro-1,2,4-oxadiazoles were synthesized by a cycloaddition reaction between chiral oxaziridines and nitriles. Assignment of absolute configurations was made by X-ray diffraction analysis, NOESY spectra, and theoretical calculations.

Absolute configuration determination of isoflavan-4-ol stereoisomers

Elucidation of the correct stereochemistry of the metabolite is essential for the mechanistic study of bioactive compounds. Isoflavan-4-ol has the same chiropical chromophore as THD, the biosynthetic precursor of the potent phytoestrogen S-equol. Interested in the correct absolute configuration of isoflavan-4-ol stereoisomers and to compare the available practical approaches for the absolute configuration determination, complete absolute configuration analysis of isoflavan-4-ol stereoisomers has been carried out with by means of ECD and VCD spectroscopy as well as modified Mosher method. Theoretical TD-DFT computations resulted in a poor simulation of the observed experimental ECD spectra, and thus inconclusive absolute configuration assignments of isoflavan-4-ol stereoisomers were obtained. However, DFT-assisted VCD spectroscopic analyses successfully determined correct absolute configurations, and further confirmed by modified Mosher method.

Absolute Configuration Assignment of Inherently Chiral Calix[4]arenes using DFT Calculations of Chiroptical Properties

The racemate of an inherently chiral meta-substituted calix[4]arene derivative 3 has been resolved via enantioselective HPLC. Measured optical rotation dispersion and electronic circular dichroism have been compared with DFT theoretical predictions. The comparison indicates that the absolute configuration of the dextrorotatory enantiomer (+)-3 is cS. The procedure has been successfully tested against a literature precedent confirming the validity of the method.

Resolution and absolute configuration assignment of a chiral hemicryptophane molecular cage

The racemic hemicryptophane molecular cage 2 was resolved by semipreparative HPLC on Whelk-O1 column. The absolute configuration of each isolated enantiomer was established from the analysis of their circular dichroism spectra and assigned as P-(+)-2 and M-(-)-2.

Absolute Configuration Assignment of Norcamphor-Derived Furyl Hydroperoxide Using Density Functional Theory Calculations of Optical Rotation and Vibrational Circular Dichroism

Density functional theory (DFT) calculations of sodium d line specific rotation and of vibrational circular dichroism (VCD) have been used to assign the absolute configuration of a recently prepared (1S,4R)-norcamphor-derived furyl hydroperoxide, (+)-3, introduced as a stereoselective oxidant. Both approaches give the same absolute configuration to the newly generated stereogenic carbon at position 2, i.e., (1S,2S,4R)-(+)-3, thus providing a confident assignment in a case made difficult by the large conformational flexibility and the small difference between the computed optical rotations of the two possible diastereoisomers. Although the computed IR absorption spectra of (1S,2S,4R)-3 and (1S,2R,4R)-3 are practically indistinguishable, a number of significant differences in the VCD spectra of these two nonmirror-image isomers can be observed, which allows the structural identification of the synthesized compound. This is clearly shown here for the first time.

Enantioselectivity of chiral zirconocenes as catalysts in alkene hydro-, carbo- and cycloalumination reactions

Abstract The enantioselectivity of chiral Zr catalysts L1L2ZrCl2 [L1 = L2 = 1-neomenthylindenyl (Ind∗), 1; L1 = Cp, L2 = Ind∗ 2; L1 = Cp, L2 = 1-neomenthylindenyl-4,5,6,7-tetrahydroindenyl (Cp∗) 3] in the hydro-, carbo- and cycloalumination of alkenes by organoaluminium compounds (OAC) (AlMe3, AlEt3, HAlBu 2 i ) has been studied. It was found that OAC exhibit the most effect on the reaction chemo- and enantioselectivity. The reaction chemo- and enantioselectivity depend on the catalyst structure and reaction conditions (solvent type, catalyst concentration, temperature) as well. It is shown that the lack of asymmetric induction in the reaction of α-methylstyrene hydroalumination by HAlBu 2 i , catalyzed with complexes 1 or 3, is the result of the formation of Zr hydride complexes of different structures as reaction intermediates. MTPA was used as a derivatization reagent for the enantiomeric excess estimation and absolute configuration assignment of β-chiral alcohols obtained after the oxidation and hydrolysis of the reaction products. The applicability of MTPA for the assignment of the absolute configuration of the stereogenic centre in β-ethyl substituted primary alcohols and β-alkyl-1,4-butanediols is shown.

Biphenyl dioxolanes as circular dichroism probes for the assignment of absolute configuration to aliphatic diols: Extending the scope to anti 1,n‐diols and cyclic syn 1,2‐diols

We describe herein the use of a flexible biphenyl moiety as efficient chirality probe in the assignment of the absolute configuration (AC) of aliphatic, non-chromophoric diols. The diols are transformed in the corresponding biphenyl dioxolanes in which the biphenyl system has either a P or M torsion depending on the chirality of the diol. As the correlation between biphenyl torsion and diol AC has been established and the sense of torsion is revealed by the sign of the biphenyl A band at 250 nm in the CD spectrum of the dioxolane, then the diols AC can be assigned simply looking at the CD spectra of these derivatives. This approach proved to be general, straightforward, and reliable for anti 1,2- 1,3-, and 1,4-diols bearing both one and two stereogenic centers and for cyclic syn 1,2-diols.

13C NMR as a general tool for the assignment of absolute configuration

(13)C NMR, alone or in combination with (1)H NMR, allows the assignment of the absolute configuration of chiral alcohols, amines, carboxylic acids, thiols, cyanohydrins, sec,sec-diols and sec,sec-aminoalcohols, derivatized with appropriate chiral auxiliaries. This extends the assignment possibilities of NMR to fully deuterated and to nonproton containing compounds.

Toward a generalization of the Clough‐Lutz‐Jirgensons effect: Chiral organic acids with alkyl, hydroxyl, and halogen substituents

The optical rotation of natural amino acids becomes more positive when the medium is changed from approximately neutral to strongly acidic (Clough-Lutz-Jirgensons (CLJ) effect). In this work, it is shown by time-dependent density functional computations that the effect can be generalized to other α-substituted chiral carboxylic acids. The physical origin of the generalized CLJ effect is similar to that in amino acids, linking the absolute configuration directly to the sign of CLJ. For conformationally flexible molecules with small magnitudes of the optical rotation, the presence of a CLJ effect might aid the assignment of absolute configurations based on comparing experimental data with computed chiroptical responses.

Polyketide-peroxides from a Species of Jamaican Plakortis (Porifera: Demospongiae)

A new cyclic peroxide plakortisinic acid (1), and a new ketone derivative (2), in addition to six known compounds, an α,β-unsaturated ester (3), plakortide N (4), plakortide F (5) and its free acid (6), plakortone D (7), and a furan-containing molecule (8), were isolated from a species of Plakortis from Jamaica. The structures were elucidated by interpretation of 1D and 2D NMR spectra, and mass spectrometry data and by comparison with data from the literature. Comparison between experimental and calculated optical rotations allowed the assignment of absolute configuration of 1 and 2. The isolated compounds have been evaluated for their antimicrobial, antimalarial, anticancer, anti-Mtb, and anti HIV-1 activity.

Absolute configuration assignment of (3‐phenyloxirane‐2,2‐diyl)bis(phenylmethanone) via density functional calculations of optical rotation and vibrational circular dichroism

Density Functional Theory (DFT) calculations of optical rotation (OR) and vibrational circular dichroism (VCD) have been used to assign the absolute configuration (AC) of a recently prepared (3-phenyloxirane-2,2-diyl)bis(phenylmethanone), 3, by asymmetric epoxidation of the corresponding 2-arylidene-1,3-diketone. The experimental OR at 589.3 nm and the VCD spectrum of the (+)- and (-)-enantiomer of 3 have been measured. The conformationally-averaged OR value and VCD spectrum of (R)-3 were calculated at B3LYP/6-311G(2d,2p) level of theory. Both approaches provide the same absolute configuration of the stereogenic carbon, i.e. the AC of (+)-3 is (R)-3, thus affording a confident assignment. Only two conformational isomers of 3 have been predicted to be populated at ambient temperature. Their presence is directly observed in the VCD spectrum.

Determination of the absolute configurations of bicyclo[3.1.0]hexane derivatives via electronic circular dichroism, optical rotation dispersion and vibrational circular dichroism spectroscopy and density functional theory calculations

The electronic circular dichroism (ECD), optical rotation dispersion (ORD), and vibrational circular dichroism (VCD) spectra of a pair of enantiomers, i.e. 3 and 4, of a bicyclo[3.1.0]hexane derivative have been measured in acetonitrile and acetonitrile-d(3), respectively. Extensive conformational searches at the B3LYP/6-311++G** level have been carried out for 3, which has four OH and one N(3) functional groups. For the bicyclo[3.1.0]hexane ring of 3, the boat-like conformers have been found to be much more stable than the chair-like conformers, while the number and the strength of the intramolecular hydrogen bonds have been identified as the dominant factors in the relative stability among the boat-like and among the chair-like conformers. DFT simulations of the ECD, ORD and VCD spectra have been performed for all low energy conformers at the B3LYP/6-311++G** and B3LYP/aug-cc-pVDZ level. Implicit continuum polarization model has been used to account for solvent effects in all these chiroptical measurements. Comparison of the DFT simulations with the experimental data shows that all three chiroptical properties yield the same absolute configuration assignment for . This work demonstrates that using multiple chiroptical spectroscopic methods in combination with DFT calculations allows one to determine absolute configurations with high confidence for chiral carbohydrates and their analogues, which possess a large number of rotatable bonds.

Synthesis and Assignment of Absolute Configuration of the Iridoid 9-Deoxygelsemide

The first enantioselective synthesis of 9-deoxygelsemide, belonging to a rare group of iridoids isolated from Gelsemium plants, is described. The key synthetic steps are a variant of the Woodward-Prevost reaction to install the characteristic cis-alpha-1,2-dioxygenated system at C-6 and C-7 with complete diastereoselectivity. Construction of the dihydropyran ring was achieved via formylation of lactone I, followed by dehydration of the corresponding lactol. The synthesis allowed assignment of absolute configuration to 9-deoxygelsemide and related iridoids.

Enantiomer separation and indirect chromatographic absolute configuration prediction of chiral pirinixic acid derivatives: Limitations of polysaccharide-type chiral stationary phases in comparison to chiral anion-exchangers

Chiral α-arylthiocarboxylic acids with different substitution patterns, representing new pirinixic acid derivatives with dual PPARα/γ agonistic activities, have been separated into enantiomers on tert-butylcarbamoylquinine and quinidine based chiral anion-exchangers and amylose tris(3,5-dimethylphenylcarbamate) coated silica on analytical and preparative scale. Absolute configurations of individual enantiomers were assigned chromatographically via elution orders on the chiral anion-exchangers and were confirmed by stereoselective syntheses via Ewans auxiliaries that have lead to enantiomeric products with known absolute configurations. The results of both methods were in full agreement. Moreover, the receptor stereoselectivity in PPARα transactivation activities was consistent within the test set of structurally related compounds. Limited correlation (between elution order and substitution) was observed within the set of α-arylthiocarboxylic acids on the amylose tris(3,5-dimethylphenylcarbamate) based chiral stationary phase (CSP), in particular the elution order changed with remote substitution. This clearly demonstrates the risks of chromatographic absolute configuration assignments by prediction from one structural analog to another one, especially with CSPs such as polysaccharide CSPs that are recognized for their broad applicability due to multiple binding and chiral recognition modes. It is therefore of utmost importance that such chromatographic absolute configuration predictions by extrapolation to structural analogs are combined with orthogonal methods for verification of the results.