A simple method for determining the absolute configuration of α-amino acids

Chiral α-amino acids react with 2-methoxy - 2,4 - diphenyl - 3 (2H) - furanone 1 to afford N-substituted 3,5 - diphenyl - 5 - hydroxy - 2 - pyrrolin - 4 - ones 2. The characteristic cotton effects given by these chromophoric derivatives provide a means for the determination of the absolute configuration of the parent amino acids. The longest wavelength(first) extremum in the chiroptical spectra (ORD and CD) of the l-amino acid derivatives is always positive, while it is negative for the d-amino acid derivatives.     

Circular Dichroism of Some 2-(Phenylmethyl)pyridine Derivatives

The absolute configuration of the 2-(phenylmethyl)pyridine derivatives 1 – 9 had been established by X-ray diffraction and chemical correlation. Their CD spectra have been studied in different solvents for the free and protonated forms. It has now been found that, from the sign of the strong CD couplet between 270 and 220 nm, which was observable for all these compounds besides 7 and 9 , their absolute configuration can be determined much quicker.     

Enantioselective synthesis of fluorene derivatives by chiral N-triflyl phosphoramide catalyzed double Friedel-Crafts alkylation reaction

A highly efficient tandem double Friedel-Crafts reaction between indoles and 2-formylbiphenyl derivatives by chiral N-triflyl phosphoramide was realized. Under mild conditions, various 9-(3-indolyl) fluorene derivatives have been obtained in good yield and up to 94% ee. Comparing to their corresponding chiral phosphoric acids, chiral N-triflyl phosphoramides catalyzed reactions led to products with opposite absolute configuration.     

A method for determining absolute configuratiom of β-amino acids by CD spectra of their DNP derivatives

Aromatic β-amino acids were converted to the Dnp derivatives, and aliphatic ones to Dnp-pMA derivatives. The sign of the Cotton effect near 400 nm reflected the configuration at the β-position without exception. Thus, the relation seems to afford a new reliable method for determining the absolute configuration of β-amino acids.     

The prediction of the absolute stereochemistry of primary and secondary 1,2-diols by 1H NMR spectroscopy: principles and applications

The absolute configuration of 1,2-diols formed by a primary and a secondary (chiral) hydroxyl group can be deduced by comparison of the 1H NMR spectra of the corresponding (R)- and bis-(S)-MPA esters (MPA = methoxyphenylacetic acid). This method involves the use of the chemical shifts of substituents L1/L2 attached to the secondary (chiral) carbon, and of the hydrogen atom linked to the chiral center (C alpha-H) as diagnostic signals. Theoretical (AM1, HF, and B3 LYP calculations) and experimental data (dynamic and low-temperature NMR spectroscopy, studies on deuterated derivatives, constant coupling analysis, circular dichroism (CD) spectra, and NMR studies with a number of diols of known absolute configuration) prove that the signs of the delta delta(RS) obtained for those signals correlate with the absolute configuration of the diol. A graphical model for the reliable assignment of the absolute configuration of a 1,2-diol by comparison of the NMR spectra of its bis-(R)- and bis-(S)-MPA esters is presented.     

Asymmetric intramolecular [2 + 2] photocycloadditions: alpha- and beta-hydroxy acids as chiral tether groups

Chiral alpha- and beta-hydroxy acids such as (S)-lactic acid, (S)-phenyllactic acid, (S)-mandelic acid, or (3R)-3-hydroxybutyric acid have been used as tether groups for intramolecular and diastereoselective [2 + 2] photocycloaddition of 3-oxocyclohexene carboxylic acid derivatives. Total regiocontrol toward the straight adduct and high diastereoselectivities (up to 94%) were observed in the case of butenyl lactate 11. After separation of the two diastereoisomers, cleavage of the chiral tether under basic conditions afforded cyclobutane lactones in good yield and enantiomeric pure form. An X-ray structure has been recorded that confirmed the relative and absolute configuration of the three contiguous stereogenic centers assigned according to CD spectra.     

Some new protocols for the assignment of absolute configuration by NMR spectroscopy using chiral solvating agents and CDAs

The utility of enantiopure BINOL (1,10-Bi-2-naphthol), in a ternary ion-pair complex, which is obtained using a carboxylic acid and an organic base, as a versatile chiral solvating agent (CSA) has been demonstrated for chiral analysis and the absolute configuration assignment of hydroxy acids. Another protocol where the utility of NOBIN as a CSA has been developed for discrimination and absolute configuration assignment of acids, hydroxy acids and their derivatives with a distinct strategy where a third ingredient, p-toluenesulfonic acid (p-TsOH) serves as a linker. In addition some three component chiral derivatization protocols have been introduced, such as the use of 2-formylphenylboronic acid and enantiopure mandelic acid or a primary amine for the determination of the configuration of primary amines and hydroxy acids, respectively. A simple, rapid and highly efficient three component chiral derivatizing protocol has also been discussed which was developed for assigning the absolute configuration of chiral α-hydroxy acids and their derivatives, which involves the coupling of 2-formylphenylboronic acid with (R)-[1,1-binaphthalene]-2,2-diamine, and (S)-[1,1-binaphthalene]-2,2-diamine separately. In a few examples, the DFT based theoretical calculations have been carried out to determine the geometry optimized structures of the complexes.     

Enantioselective alkylidenecyclopropanation of norbornenes with terminal alkynes catalyzed by palladium–phosphinous acid complexes

Pd(II)-coordinated phosphinous acids catalyzed the formal enantioselective [2+1] cycloaddition of norbornene derivatives with terminal alkynes. The absolute configuration of (+)-3aa was assigned using VCD.     

Chiroptical properties of 2-substituted piperidines : A simple helicity rule

The CD spectra of fifteen 2-substituted piperidines 2 and their N-methylated derivatives 1 have been determined. The sign of the Cotton effect observed for the n→σ^* transition of nitrogen is shown to be correlated, for a given absolute configuration, with the axial or equatorial orientation of the nitrogen lone pair, and to be determined by the screw sense of the helicity between the nitrogen lone pair and the 2-substituent R in 1 and 2: for compounds of the absolute D configuration, a positive helicity gives a positive CD and vice versa.     

Circular Dichroism of Transition Metal Complexes and Sugar Derivatives Having a Free 1,3-Diol System or “Isolated” Hydroxyl Group

Abstract

Heptofuranose derivatives 1–6 having free 1, 3-diol systems form in situ complexes with Mo₂(OAc)₄ whose CD spectra permit the assignment of absolute configuration at C-5 using a sector rule proposed by G. Snatzke.^2–6 The interpretation of CD spectra of analogous complexes formed from derivatives 7–12 was more complicated and did not lead to direct configuralional conclusions. CD spectra of complexes formed from Rh₂(CF₃COO)₄ and sugar derivatives 13–21, containing an “isolated” hydroxyl group, permit the assignment of absolute configuration. Conclusions were corroborated by the investigation of CD spectra of rhodium complexes with compounds 22–27.     

Synthesis and absolute configuration of substituted morpholines

We studied methods of stereospecific synthesis that enabled us to obtain variously substituted morpholinic compounds and to determine their absolute configuration. From a study of the chiroptical properties of synthetic N-[2-pyridyl-N-oxide] derivatives of optically active morpholines, it was possible to correlate the sign of the Cotton effect with the absolute configuration. This correlation agrees with that previously established for derivatives of the piperidine type. By evaluating the various contributions to the Cotton effect of substituents in positions 2 and 3, we established the absolute configuration of bicyclic compounds condensed in the two positions mentioned above.     

Abnormal elution behavior of ornitine derivatized with 1-fluoro-2,4-dinitrophenyl-5-leucinamide in advanced Marfey's method

During the course of establishing the advanced Marfey's method that has been developed to non-empirically determine the absolute configuration of constituent amino acids in a peptide using LC-MS, we encountered the "ornitine mystery" in the di-DLA (2,4-dinitrophenyl-5-leucinamide) derivative such that the elution order of ornitine (Orn) was opposite (D-->L) in spite of their relatively long retention time. In order to resolve this problem, the elution behavior of several mixed DLA and DPEA (2,4-dinitrophenyl-5-phenylethylamine) derivatives with different absolute configurations was carefully observed during HPLC. The length of the methylene chain in basic amino acids was obviously critical for this behavior, because Dab (2,4-diamino-n-butyric acid) and lysine (Lys) did not exhibit this abnormality. The presence of the carboxyamide moiety at the omega position was also essential for this phenomenon, because it was never observed in the DPEA derivatives at the omega position. Furthermore, it was found that the following combination of absolute configurations of Orn and DLA at the omega position only induced this abnormality: D-Orn and L-DLA, and L-Orn and D-DLA. This suggested that the structural interaction such as hydrogen bonding between the carboxyamide of DLA at the omega position and carboxylic acid at the alpha position in these derivatives reduced their retention power on the reversed-phase column.     

Chirality and numbering of substituted tropane alkaloids

The strict application of IUPAC rules for the numbering of tropane alkaloids is not always applied by authors and there is hence a lot of confusion in the literature. In most cases, the notation of 3, 6/7-disubstituted derivatives has been chosen arbitrarily, based on NMR and MS data, without taking into account the absolute configuration of these two carbons. This paper discusses the problem and the relevance of CD and NMR to determine molecular configurations. We report on the use of (1)H-NMR anisochrony (Δδ) induced by the Mosher's chiral auxiliary reagents (R)-(-)- and (S)-(+)-α-methoxy-α-trifluoromethyl-phenylacetyl chlorides (MTPA-Cl), to determine the absolute configuration of (3R,6R)-3α-hydroxy-6β-senecioyloxytropane, a disubstituted tropane alkaloid isolated from the aerial parts of Schizanthus grahamii (Solanaceae). These analytical tools should help future works in correctly assigning the configuration of additional 3, 6/7 disubstituted tropane derivatives.     

Absolute Konfiguration der Equisetumalkaloide (+)-Palustrin,Palustridin ((+)-Monohydrochlorid) sowie der (−)-Dihydropalustraminsäure und weiterer Derivate. 16. Mitteilung über Schachtelhalmalkaloide

Determination of the absolute configuration of alkaloids from Equisetum sp.,e.g. (+)-palustrin, palustridin ((+)-hydrochloride), and (?)-dihydropalustramic acid and derivatives The absolute configuration of the title alkaloids has been determined using chiroptical methods (ORD., superposition of CD. values of appropriate models and a modified Horeau method). (+)-Palustrin is (13R, 17 S, 1′S)-17-(1-hydroxypropyl)-1,5,10-triazabicyclo [11.4.0]heptadec-15-en-11-on.     

Elution behavior of diaminopimelic acid and related diamino acids using the advanced Marfey's method

The advanced Marfey's method consists of a chromatography technique for the separation of amino acids into each enantiomer by derivatization with 1-fluoro-2,4-dinitrophenyl-5-L-leucinamide (L-FDLA), and a detection method using liquid chromatography/mass spectrometry (LC/MS) which can determine the non-empirically the absolute configuration of various amino acids including the non-protein ones. However, this method has not been applied to the determination of the absolute configuration of an amino acid with a "meso" configuration such as diaminopimelic acid (A2pm). In the present study, this method was successfully applied to determine the absolute configurations of diaminosuccinic acid (DAS), A2pm, cystine (Cys), selenocystine (SeCys) and homocystine (HomoCys) using a racemization procedure and the DL-FDLA method, and the resulting elution behavior was summarized as follows: (1) the LL- and meso-isomers were eluted prior to the DD-isomer except for one case; (2) the LL- and meso-isomers are closely eluted and the elution was occasionally reversed; (3) the retention time for both the L- and D-derivatives of the meso-isomer was not changed; (4) the complementary use of the two solvent systems using CH3CN and MeOH was effective to obtain a chromatogram with a high resolution; (5) the abnormality, such as the elution order and peak shape, was observed in the elution behavior of DAS.     

Absolute configuration assignment of ortho,meta, or para isomers by mass spectrometry

A general method based solely on mass spectrometric techniques for the absolute configuration assignment of ortho, meta, or para isomers of acyl nitrobenzenes and derivatives is described. Instead of comparing the mass spectra of the three intact molecules of each positional isomer and investigating each one of the many sets of positional isomers, the method generalizes the effort by performing structural analysis on configurationally diagnostic fragment ions that are common for a given class of compounds. These ions must therefore retain the positional information of the parent molecules and be unequivocally distinguished. Nitrobenzoyl cations are common and stable fragment ions of most acyl nitrobenzenes and derivatives retaining the respective ortho, meta, or para configuration of the precursor molecules. The different NO₂ and CO⁺ ring alignments profoundly influence their collision-induced dissociation and bimolecular reactivity, and the isomeric 2-, 3-, and 4-nitrobenzoyl cations are found to be unequivocally distinguished using both approaches. Absolute ortho, meta, or para positional assignment by tandem MS of every isomeric molecule of the acyl nitrobenzene class and derivatives forming detectable amounts of any of those diagnostic nitrobenzoyl cations is, therefore, possible. The ability to perform absolute (non-comparative) configuration assignment using such diagnostic ions is exemplified for a single test molecule of (2R)-(−)-2-methylglycidyl 4-nitrobenzoate. The general application of this absolute MS-only method for other classes of positional isomers is discussed.     

Transmetallation reactions of planar chiral cyclopalladated ferrocenylimines with metallic mercury

A series of optically active 2-chloromercurio-1-[1-(arylimino)ethyl] ferrocenes was synthesized by transmetallation of optically active cyclopalladated ferrocene derivatives with metallic mercury. The structure and absolute configuration of complexes Rp-4b were determined by X-ray diffraction, on the basis of which and the CD spectra the absolute configuration of other optically active compounds was ascertained.     

Determination of the Absolute Configuration of Rohitukine

The absolute configuration of rohitukine, isolated from the stem-bark of Dysoxylum binectariferum, was determined to be 5,7-dihydroxy-2-methyl-8-[4-(3S, 4R-3-hydroxy-1-methyl)-piperidinyl]-4H-l-benzopyran-4-one by X-ray crystallographic analysis on the crystal of,4-bromobenzoyl derivatives of rohitukine. At the same time, the modified Mosher method was proved to be unsuitable for determining the absolute configuration of C-3‘ position in rohitukine.     

The 1H NMR method for the determination of the absolute configuration of 1,2,3-prim,sec,sec-triols

The absolute configuration of 1,2,3-prim,sec,sec-triols can be assigned by comparison of the 1H NMR spectra of the tris-(R)- and the tris-(S)-MPA ester derivatives. An experimental demonstration of this correlation with 24 triols of known absolute configuration and a protocol using two parameters-Deltadelta(RS)(H3) and the difference between Deltadelta RS (H2) and Deltadelta RS (H3) = absolute value (Delta(Deltadelta RS))-for its application to the determination of the absolute configuration of other triols are presented.     

A general and nonempirical approach to the determination of the absolute configuration of 1-aryl-1,2-diols

We describe herein a simple, general, and reliable nonempirical approach, based on the exciton coupling method, to assign the absolute configuration of the benzylic stereogenic center of 1-aryl-1,2-diols. According to this method, it is only necessary to prepare the 4-biphenylboronic esters of the diols and to record their CD spectra in the 230-300 nm range, i.e., in the range corresponding to the long-axis (1)L(a) transition of the biphenyl chromophore. From the sign of the CD couplet or Cotton effect at 260 nm it is possible to know the chirality defined by the aryl and biphenyl chromophore transitions and then to determine the absolute configuration of the benzylic carbon. By this approach, simple rules have been formulated which allow us to establish the absolute configuration of many classes of 1-aryl-1,2-diols.