Circular dichroism of 9,10-dihydrophenanthrene derivatives reveals both the absolute configuration and conformation: a novel approach to Mislow's helicity rule

The absolute configuration and the conformation of 9,10-trans-disubstituted 9,10-dihydrophenanthrenes, known chiral metabolites of phenanthrene-9,10-oxide, have been determined by circular dichroism. The absolute configuration assignment is based on the sign of the long-wavelength Cotton effect (A-band), which is conformation invariant and originates from benzylic chirality. This provides a new interpretation of the Mislow biphenyl-helicity rule for the case of the 9,10-dihydrophenanthrene chromophore. The sign of the B-band Cotton effect reflects the conformation of the biphenyl chromophore in 9,10-dihydrophenanthrenes. It is shown that the origin of chiroptical properties of 9,10-dihydrophenanthrenes is closely related to those of 5,6-trans-disubstituted 1,3-cyclohexadienes.     

Configurational assignment of vic-amino alcohols from their circular dichroism spectra with dirhodium tetraacetate as an auxiliary chromophore

The in situ formed complexes of dirhodium(II) tetraacetate with optically active derivatives of the 1,2-amino alcohols ephedrine and adrenaline show circular dichroism spectra suitable for determination of their absolute configuration. According to the M- or P-helicity of the N–C–C–O moiety the investigated compounds generate negative or positive Cotton effects at around 300 and 440 nm, respectively. The third prominent CE of an opposite sign to the first two occurs at ca. 380 nm. It is demonstrated that the in situ method allows fast and easy configurational assignment based on the helicity rule that connects the signs of the Cotton effects at around 300 and 440 nm with the sign of the N–C–C–O torsional angle.     

Absolute configuration of chiral [2.2]paracyclophanes with intramolecular charge-transfer interaction. Failure of the exciton chirality method and use of the sector rule applied to the cotton effect of the CT transition

Optically active 4,7-dicyano-12,15-dimethoxy[2.2]paracyclophanes have been separated by chiral HPLC and their absolute configurations determined by comparison of the experimental and the theoretical VCD spectra. X-ray crystallographic structures for both diastereomers are also reported. The electronic circular dichroism spectra of these enantiomeric pairs, as chiral intramolecular charge-transfer complexes, have been obtained for the first time. The exciton coupling method, usually used for determining the absolute configuration of chiral molecules, however, did not give a correct prediction for the present CT-paracyclophane system. Instead, empirical sector rules for the signs of the Cotton effects of the CT transition can be applied for the assignment of the absolute configuration.     

Chiral conformations induced by cyclodextrin

Studies of chiroptical properties need separation or at least enrichment of enantiomers. The separation is difficult with chiral conformers of molecules with very low barriers of internal rotation. However, in association with cyclodextrin, these labile molecules can exhibit a strong Cotton effect in solution: one chiral conformer is favoured by complexation. The cyclodextrins have the advantage to yield inclusion complex in solution as well as crystalline clathrates. Therefore, the absolute configuration of the guest can be obtained by determining the structure of the cyclodextrin. In this work, the first CD spectrum of 4-helicene is recorded and crystal structures of several clathrates of labile molecules are studied.     

Chiroptical Assignment of the Anomeric Configuration of 4-(α,β-D-lyxopyranosyl)- and 4-(α,β-D-lyxofuranosyl)-2-phenyl-2H-1,2,3-Triazole C-Nucleoside Anomeric Pairs: Extension of the CD Triazole Rule

The circular dichroism of the anomeric 4-(α,β-D-lyxopyranosyl)- and 4-(α,β-D-lyxofuranosyl)-2-phenyl-2H-1,2,3-triazole C-nucleoside analogs obtained by acid-catalyzed dehydrative cyclization of 4-(D-galacto-pentitol-1-yl)-2-phenyl-2H-1,2,3-triazole analog was studied. A correlation between the sign of the Cotton effect at the maximal UV absorption and the absolute configuration of the anomeric carbon atom was obtained and used for their anomeric configuration assignment. This correlation supports the CD triazole rule for anomeric assignment and is in accord with the assignment obtained by NMR spectral studies.     

Preparation of optically active allylic hydroperoxy alcohols and 1, 3-diols by enzyme-catalyzed kinetic resolution and photooxygenation of chiral homoallylic alcohols

All four possible enantiomers of the 3-hydroperoxy-4-penten-1-ols 2a, b and their corresponding 4-pentene-1,3-diols 4a,b have been prepared for the first time in high enantiomeric purity (up to 98% ee) and in preparative amounts according to two distinct ways: First the photooxygenation of the racemic homoallylic alcohols 1 gave the racemic hydroperoxy alcohols 2, which have subsequently been kinetically resolved by horseradish peroxidase (HRP); alternatively, first the lipase-catalyzed resolution afforded the optically active homoallylic alcohols 1 and subsequent photooxygenation led to the enantiomerically enriched hydroperoxy alcohols 2.     

The absolute configuration of simple aliphatic alcohols through a chemical/computational approach: triarylether derivatives of (+)-endo-2-norborneol as a case study

The reliable determination of the absolute configuration of (+)-endo-2-norborneol 1, chosen as a representative case of simple aliphatic UV–vis transparent alcohols, was obtained by transforming this compound in its 1-naphthyl-diphenylmethyl ether 5 whose ECD spectrum displays several, low-lying, intense Cotton effects, which can be satisfactorily simulated in position, sign, and intensity by TDDFT/B3LYP/6-31G¹ calculations. This result represents a possible, general, new approach to the absolute configuration of aliphatic alcohols.     

Developing a new class of axial chiral phosphorus ligands: preparation and characterization of enantiopure atropisomeric phosphinines

Both enantiomers of the first atropisomeric phosphinine (1) have been isolated by using analytical HPLC on a chiral stationary phase. The enrichment of one enantiomer and a subsequent investigation into its racemization kinetics revealed a barrier for internal rotation of DeltaG(298)(double dagger) = (109.5+/-0.5) kJ mol(-1), which is in excellent agreement with the theoretically predicted value of DeltaG(298)(double dagger) =116 kJ mol(-1). Further analysis with UV and circular dichroism spectroscopies and density functional theory calculations led to the determination and assignment of the absolute configurations of both enantiomers. These results are the basis for future investigations into this new class of axially chiral phosphinine-based ligands and their possible applications in asymmetric homogeneous catalysis.     

2,2,2-三氟-1-(9-蒽基)乙醇对映体在涂敷型手性固定相上的拆分

用高效液相色谱法在涂敷１５％（Ｗｔ）三苯基氨基甲酸纤维素醌手性柱上,考察了洗脱液正己烷／醇（Ｖ／Ｖ）中醇对分离－２,２,２－三氟－１（９－蒽基）乙醇对映体的影响,初步认为,在对映体分离过程中,洗脱液中醇与手性固定相的ＮＨ和Ｃ＝Ｏ形成氢键作用,此过程与对映体和手性固定相的ＮＨ和Ｃ＝Ｏ所形成氢键作用相竞争;洗脱液中醇的结构不同之所以影响对映体的分离效果,还与洗脱中醇改变固定相中手性空穴的立体环境有关,     

Cross interaction between auxiliaries: the chirality of amino alcohols by NMR

The absolute configuration of sec/prim- and prim/sec-1,2-amino alcohols is determined by comparison of the (1)H NMR chemical shifts of the auxiliary OMe or CalphaH groups at the corresponding bis-( R) and bis-( S)-MPA derivatives. This is the first NMR method that allows the assignment of absolute configuration without resorting to the shifts of hydrogens at the substrate and is based on the cross anisotropic interactions between auxiliaries.     

Enantiomeric separation of novel anticancer agent 5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-one

The enantiomers of 5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-one, a novel anticancer agent, were separated by derivatisation with caronaldehyde, separation of the resulting diastereoisomers of the corresponding esters by silica gel column chromatography and regeneration of alcohols (S)-5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-one and (R)-5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-one under aqueous conditions. The absolute configuration of the enantiomers was determined by 1H NMR studies of the corresponding Mosher esters. Alternatively, the enantiomers were separated by preparative HPLC to collect the (S)- and (R)-5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-ones with high purity which was comparable with that obtained by the chemical method. The details of these methods have been presented herein.     

Quinine-mediated parallel kinetic resolution of racemic cyclic anhydride: stereoselective synthesis,relative and absolute configuration of novel alicyclic β-amino acids

Four endo-isomers of (1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid (+)-1 (Icofungipen) have been prepared in enantiomerically pure form. Three endo-isomers were obtained by quinine-mediated kinetic resolution of a racemic anhydride, followed by Curtius rearrangement. The fourth isomer was obtained by an exo–endo isomerization of (+)-1. The assignment of the absolute configuration is based either on the Cotton effect in the CD spectra or in correlation to already known structures.     

Enantiomeric resolution of N,N'-dimethyldithiodianthranilide through diastereomeric silver(I) complex. Circular dichroism spectra, racemization barrier, and molecular self-assembly

Planar chiral N,N'-dimethyldithiodianthranilide (2b) was resolved to enantiomers through a diasteromeric complex with easily accessible silver(I) (1S)-camphorosulfonate (3). The (-)-2b enantiomer was assigned the R absolute configuration from the X-ray crystal structure of the silver complex. The compound is configurationally stable and its racemization occurs through boat-to-boat ring inversion (DeltaG(double dagger) = 36.5 +/- 0.2 kcal mol(-1) at 438 K). The analysis of the CD spectrum of the title compound showed that the n-pi* Cotton effect sign is determined by the helicity of the skewed thiobenzamide chromophore. The molecules of 2b are unable to achieve efficient crystal packing by themselves and easily form inclusion complexes with toluene or pentafluorophenol.     

Chiral resolution and bioactivity of enantiomeric furofuran lignans from Juglans mandshurica Maxim

Abstract

Enantiomers have generally been reported mostly for racemic mixtures with a 1:1 ratio, as in that case there were weak Cotton effects in the ECD spectrum and negligible optical rotations. A furofuran lignan (sesamin), with a remarkable rotation and significant Cotton effects, was isolated from Juglans mandshurica Maxim. Subsequently, sesamin was resolved by chiral HPLC to afford a pair of enantiomers, (+)-sesamin (a) and (?)-sesamin (b), in a ratio of approximately 1:3. Their absolute configurations were determined by computational analysis of their electronic circular dichroism (ECD) spectrum. In addition, the pair of enantiomers were evaluated for the inhibition of self-induced Aβ aggregation. Interestingly, (+)-sesamin (a) (67.7%) and (?)-sesamin (b) (80.6%) exhibited different degrees of anti-Aβ aggregation activity. The different inhibition profiles were further explained by molecular dynamics and docking simulation study.     

Enantiomer resolution of intrinsically chiral C21-alkylated N-confused porphyrin complexes

The resolution of stereoisomers of C21‐alkylated nickel(II) complexes of N‐confused porphyrin (NCP) was performed by means of chiral‐phase HPLC with an effectiveness of above 90 % molar ratio for each isomer. The reverse signs of the Cotton effects in the circular dichroism (CD) spectra of the separated fractions are indicative of the pair of enantiomers. The application of low‐temperature 2D NMR methods to the separated diastereomers of the system comprising a chiral 2‐(S)‐methylbutyl substituent, in connection with the CD spectra and relative HPLC migration rates, allowed the assignment of the absolute configuration of the chiral C21‐substituted complexes of NCP. The assignment was confirmed by time‐dependent DFT (TDDFT) calculations of CD spectra for the C21‐methylated nickel(II) complex. The system remains chiral after removal of the metal ion from the macrocyclic crevice, despite the fact that this demetalation is connected with a change of the C21 hybridization from pyramidal to trigonal. The retention of chirality was established by means of CD spectra and confirmed by TDDFT calculations for a C21‐methylated NCP free base. Stereoisomers were also separated for three covalently linked bis(NCP) systems with bridges involving one or two C21 carbon atoms. The occurrence of a pair of enantiomers was established for nonsymmetrical dimers comprising only one stereogenic center. In the case of the 21,21′‐(o‐xylene)‐linked dimer, three stereoisomers, that is, a pair of enantiomers and an optically inactive meso‐form, were separated and analyzed by CD and ¹H NMR spectroscopy. The stereoisomers of a diastereoselectively formed nonsymmetrical chloroplatinum(II)‐linked dimer, consisting of heterochiral C21‐alkylated NCP nickel(II) subunits, after separation displayed a strong optical activity, which can be ascribed to the rigid helical structure of the complex.     

Automatic assignment of absolute configuration from 1D NMR data

[reaction: see text] Opposite enantiomers exhibit different NMR properties in the presence of an external common chiral element, and a chiral molecule exhibits different NMR properties in the presence of external enantiomeric chiral elements. Automatic prediction of such differences, and comparison with experimental values, leads to the assignment of the absolute configuration. Here two cases are reported, one using a dataset of 80 chiral secondary alcohols esterified with (R)-MTPA and the corresponding (1)H NMR chemical shifts and the other with 94 (13)C NMR chemical shifts of chiral secondary alcohols in two enantiomeric chiral solvents. For the first application, counterpropagation neural networks were trained to predict the sign of the difference between chemical shifts of opposite stereoisomers. The neural networks were trained to process the chirality code of the alcohol as the input, and to give the NMR property as the output. In the second application, similar neural networks were employed, but the property to predict was the difference of chemical shifts in the two enantiomeric solvents. For independent test sets of 20 objects, 100% correct predictions were obtained in both applications concerning the sign of the chemical shifts differences. Additionally, with the second dataset, the difference of chemical shifts in the two enantiomeric solvents was quantitatively predicted, yielding r(2) 0.936 for the test set between the predicted and experimental values.     

Chromatographic resolution, solution and crystal phase conformations, and absolute configuration of tert-butyl(dimethylamino)phenylphosphine-borane complex

The enantiomers of tert-butyl(dimethylamino)phenylphosphine-borane complex 2 have been separated by HPLC using cellulose tris-p-methylbenzoate as chiral stationary phase. The borane protection could be removed without racemization and the P-configuration of the free aminophosphine 1 has shown to be stable in solution. Infrared (IR) and vibrational circular dichroism (VCD) spectra have been measured in CD2Cl2 solution for both enantiomers. B3LYP/6-31+G(d) DFT calculations allowed a prediction that complex (S)-2 exists as three conformers in equilibrium and computed population-weighted IR and VCD spectra. Predicted and experimental IR and VCD spectra compared very well and indicate that enantiomer (+)-2 has the S absolute configuration. This assignment has been confirmed by an X-ray diffraction study on a single crystal of (+)-2. The crystal structure of enantiomerically pure 2 appears to be very close to the most stable computed conformer which proved to be predominant in solution.     

Chromatographic Resolution,Circular Dichroism Spectra,Absolute Configurations,and Crystal Structures of Bridged Biphenyls,Containing Sulfide,Sulfoxide, and Sulfone Groups in the Bridge

Four chiral 1,1′‐biphenyls with one or two sulfur‐containing bridges in 2,2′‐ or 2,2′‐ and 6,6′‐positions, viz. 1,11‐dimethyl‐5,7‐dihydrodibenzo[c,e]thiepin ( 1 ), its S‐oxide ( 2 ) and S,S‐dioxide ( 3 ), and the doubly bridged 10,12‐dihydro‐4H,6H‐[2]benzothiepino[6,5,4‐def][2]benzothiepin ( 4 ) have been studied by chromatography, CD spectroscopy, X‐ray crystallography, and empirical force‐field and CNDO/S calculations. The structures obtained by force‐field calculations showed good agreement with the crystal structures determined for 2 and 3 . Compounds 2 , 3 , and 4 , but not 1 , could be resolved into enantiomers by chromatography on swollen microcrystalline triacetylcellulose. The barrier for biphenyl inversion in 2 was found to be higher than 167 kJ⋅mol⁻¹ by an attempted thermal racemization. The CD spectra of the enantiomers of 2 – 4 were recorded and resolved into individual bands, and the corresponding rotational strengths were calculated. The transitions showed considerable similarity to those of a 1,1′‐biphenyl with hydrocarbon bridge (cf. 5 ), albeit with bathochromic shifts, which permitted the assignment of the absolute configurations of the enantiomers of 2 – 4 . The assignments were supported by comparison of the experimental CD spectra with spectra calculated by the CNDO/S method. All first‐eluted enantiomers were found to have the (S)‐configuration.     

Lipase-catalyzed kinetic resolution of racemic 1-(10-alkyl-10H-phenothiazin-3-yl)ethanols and their butanoates

The synthesis of both enantiomers of 1-(10-alkyl-10H-phenothiazin-3-yl)ethanols and their butanoates by enantiomer-selective acylation of racemic alcohols with the lipase from Pseudomonas fluorescens (L-AK) or/and by methanolysis of the corresponding racemic esters with lipase B from Candida antarctica (CaL-B) is described. The absolute configuration of the enantiomerically pure enantiomers was determined by X-ray crystallography.     

Helicity induction in a bichromophore: a sensitive and practical chiroptical method for absolute configuration determination of aliphatic alcohols

[reaction: see text] A practical method for the determination of the absolute configuration of aliphatic secondary alcohols, based on the circular dichroism of the readily available N-(1,8-naphthaloyl)-2-aminobenzoyl (NAB) derivative, is presented. The origin of the induced Cotton effects is traced by ab initio calculations to the dominant helicity of the NAB pi-electron system.