Resolution of racemic carbonucleosides and assignment of the absolute configuration by NMR

Resolution of racemic cis-6-chloro-9-[2-(hydroxymethyl)cyclopentyl]-9H-purine 1 was performed using HPLC with a semipreparative column of β-cyclodextrin using 85:15 water/acetonitrile as eluent. The absolute configurations of the enantiomers were determined by NMR studies of their (R)- and (S)-methoxyphenylacetates.     

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.     

Chiral thiols: the assignment of their absolute configuration by 1H NMR

A general NMR spectroscopy protocol for determination of absolute configuration of thiols, that includes the introduction of new aryl-tert-butoxyacetic acids as chiral derivatizing agents (CDAs), is described.     

The assignment of the absolute configuration of 1,2-diols by low-temperature NMR of a single MPA derivative

[reaction: see text] The absolute configuration of 1,2-primary/secondary diols can be easily assigned by low-temperature NMR of a bis-MPA ester derivative. The assignment requires the analysis of just the methylene protons, is not limited by the absence of signals from the R group of the diol, and requires a very small and recoverable sample.     

Total structural assignment and absolute configuration of terreinol by 13C and 1H NMR

The carbon-carbon connectivity of terreinol, a new metabolite isolated from Aspergillus terreus, and its previous (13)C assignments were confirmed by a two-dimensional INADEQUATE experiment using a few milligrams of the compound with natural (13)C abundance. The carbon-carbon correlations were determined by computational analysis (with >99% probability) of this experiment. Additionally, the absolute configuration of terreinol was achieved indirectly via its corresponding secondary alcohol by the modified Mosher method allied to conformational analysis. The shielding effect of the phenyl group of methoxytrifluoromethylphenylacetic acid (MTPA) on the substituents of the carbonylic centre gave a fully regular Deltadelta(SR) sign distribution, allowing reliable assignment of the R configuration for terreinol.     

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.     

Determination of absolute configuration by 31P NMR

The determination of absolute configuration is crucial for all chiral molecules; therefore many techniques have been developed to serve this purpose. It is especially important for the invention of new medicines, as in some cases only one enantiomer has a positive medical effect, while the other is inactive or even harmful. Herein we present the usefulness of the ³¹P NMR technique in the determination of the absolute configuration of chiral molecules, as an alternative to other methods. The models presented herein, often developed on the basis of ¹H NMR, describe conformations and configurations and following shielding effects in chiral molecules, that can be applied to determine the stereochemistry of a molecule by ³¹P NMR spectroscopy. Numerous examples of the use of some of the described models are presented as well.     

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.     

A practical guide for the assignment of the absolute configuration of alcohols,amines and carboxylic acids by NMR

A practical guide for the assignment of the absolute configuration of alcohols, amines and carboxylic acids by NMR is presented. The guide includes information required for the judicious selection of the most suitable auxiliary reagent (MPA, MTPA, BPG, 9-AMA and 9-AHA), derivatization procedures and NMR conditions (solvent and temperature) for each substrate, as well as a critical account on the reliability, scope and limitations of these applications.     

Chiral information transfer by solid-solid interaction: application for absolute configuration assignment

Host-guest complexes of calix[4]resorcarene with chiral molecules were efficiently formed by solid-solid grinding and exhibited CD Cotton effects reflecting the absolute configuration of the guest.     

Assignment of absolute configuration of holadyson by computed NMR chemical shifts

The unassigned configurations of holadyson in the C8, C9, C13, C14, and C17 were assigned as S, S, R, S, and S, respectively. In this assignment, the extensive density functional theory calculations followed by chemical shift predictions were employed. Predicted chemical shifts were correlated to experimental ones to find the correct configuration, shown here.     

Resin-bound chiral derivatizing agents for assignment of configuration by NMR spectroscopy

A general methodology for assigning the configuration of chiral mono- and polyfunctional compounds by NMR is presented. The approach is based on the use of polystyrene-bound chiral derivatizing agents (CDA-resins) specifically designed to achieve the high-yield formation of the covalent linkages (amide or ester bonds) between the substrate and the chiral auxiliary within the NMR tube, without the need for other manipulations, on a microscale level and in a short time. The deuterated NMR solvents (CDCl3, CD3CN, CS2/CD2Cl2) are also the reaction solvents and separations, purifications or workups of any kind are not necessary prior to recording the spectra. The CDA-resins prepared included MPA, 9-AMA, BPG, MTPA, and 2-NTBA as auxiliary agents incorporated either as single enantiomers or as mixed combinations of the (R)- and the (S)-enantiomers at unequal and known ratios. The high versatility of these systems was successfully demonstrated in a variety of ways based on double and single derivatization, low temperature experiments, or the formation of metal complexes. The approach allowed the absolute configurations of chiral primary amines, primary and secondary alcohols, cyanohydrins, thiols, diols, triols, and amino alcohols to be determined. Extensive high-resolution magic angle spinning (HR-MAS) NMR experiments allowed the characterization of the new CDA-resins and enabled the study of their stability and regioselectivity.     

Three challenges toward the assignment of absolute configuration of gymnocin-B

The absolute configuration of gymnocin-B has been determined to be (S)-10 and (S)-37. Three challenges toward the configurational assignment of this largest of the polyether marine toxin include (i) introduction of p-(meso-triphenylporphyrin)-cinnamate group (TPPcinnamate) on sterically hindered 10-, 37-hydroxyls under mild conditions, (ii) conformational analysis in the presence of TPPcinnamates at C-10 and C-37 positions on the flexible seven-membered rings embodied in a large polyether ladder-like scaffold structure, and (iii) determination of the chirality at C-10 and C-37 on the basis of porphyrin/porphyrin circular dichroism exciton-coupled interaction over a large distance. The experimentally obtained positive exciton couplet by CD and FDCD of the bis-TPPcin derivative of gymnocin-B is in good agreement with that of theoretically calculated CD of the MMFF optimized structures, by employing DeVoe's coupled oscillator approach, thus establishing the full absolute configuration of gymnocin-B.     

Synthesis of eupomatilone-6 and assignment of its absolute configuration

[Reaction: see text]. The Zn-mediated Barbier reaction of the biarylaldehyde 8 with crotyl bromide followed by hydroboration and oxidation provided the gamma-butyrolactones 4 and 5. The stereoselective installation of methyl group at C-3 by using LiHMDS and MeI completed the synthesis of racemic eupomatilone-6 (2) and its diastereomer 3. The spectroscopic data of 2 was in full agreement with reported spectra of natural product, thus confirming the revised relative configuration of eupomatilone-6. Similarly, an optically active (3R,4R,5S)-isomer of eupomatilone-6 (23) was prepared in which the aldol reaction with thiazolidinethione as a chiral auxiliary was employed as a key step. On the basis of the spectroscopic data and optical rotation values of 23, the absolute configuration of eupomatilone-6 was proposed.     

Application of chiral bidentate NMR solvents for assignment of the absolute configuration of alcohols: scope and limitation

The ¹³C NMR behaviors of several cyclic and biaryl secondary alcohols as well as acyclic tertiary alcohols have been studied in the chiral bidentate NMR solvent BMBA-p-Me (1). An empirical rule has been advanced to correlate the absolute configuration of each type of alcohols with the ¹³C chemical shift behaviors in (R,R)- and (S,S)-BMBA-p-Me.     

The use of MPA amide for the assignment of absolute configuration of a sterically hindered cyclic secondary amine by 'mix and shake' NMR method

We present here a new method using methoxyphenylacetic acid (MPA) as the chiral derivatizing agent (CDA) for the assignment of absolute configuration of cyclic secondary amines. The MPA amides were prepared using the purification-free 'mix and shake' method. A detailed conformational analysis for the two diastereomeric amides was conducted by 2D NMR experiments and molecular mechanics calculations. We have established that, in the most stable conformation of each syn rotamer of MPA amides, the H-alpha in the MPA moiety is oriented toward the bulky substituent group at the asymmetric carbon in the chiral amine, presumably to avoid steric and/or electrostatic interactions. The observed NMR data were correlated with the conformational model to allow unambiguous assignment of absolute configuration of secondary amines. The results demonstrate that the MPA can be used as a useful CDA in the case of sterically crowded cyclic secondary amines from which the MTPA amides are usually difficult to make.     

Assignment of the absolute configuration of hydroxy- and aminophosphonates by NMR spectroscopy

Phosphonate analogues of amino- and hydroxy acids have received considerable attention in bioorganic and medicinal chemistry due to their unique activities as peptidomimetics, being known as inhibitors of such enzymes as human renin, HIV protease and polymerase, leucine aminopeptidase and serine proteases. They have also been exploited as haptens for catalytic antibody research, herbicides, antibiotics, antiviral and anticancer agents and neuromodulators. Therefore, the demand for the asymmetric synthesis of hydroxy- and aminophosphonates should be accompanied by reliable methods for their absolute configuration assignment. NMR spectroscopy is one of the most commonly used techniques for the assignment of absolute configuration of different classes of compounds. This report describes the principles and practical aspects of applying chiral discriminating agents for the assignment of absolute configuration of 1- and 2-hydroxyphosphonates and 1- and 2-aminophosphonates by NMR spectroscopy. The report is organized in sections discussing the types of the chiral discriminating agents (including the models used for configuration assignment, if this was proposed) and the scope of their applications (with the list of all the examples of hydroxy- and aminophosphonates examined by this method). The application of the chiral derivatizing agents (CDA) and chiral solvating agents (CSA) used for these purposes, such as α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA), α-methoxyphenylacetic acid (MPA), amino acids, diazaphospholidine, camphanic acid, naproxen, quinine and t-butylphenylphosphinothioic acid is discussed. Easy access to the selected values of the NMR chemical shifts observed for the diastereomeric species of the tested hydroxy- and aminophosphonates examined, will enable the reader to compare trends observed in spectra and subsequent absolute configuration assignment. In addition, any available complementary data confirming the configuration established by NMR (X-ray, chemical correlations, optical rotation) is also provided.     

Chiral silylation reagents for the determination of absolute configuration by NMR spectroscopy

We have investigated the use of chiral silylating reagents as analytical probes for determining the absolute stereochemistry of natural products by NMR spectroscopy. These reagents are prepared in high chemical yield in one step and can be used to derivatize chiral allylic alcohols which are incompatible with ester-based methodologies. Microscale ( approximately 400 nmol) derivatization conditions have been defined. The resulting siloxane diastereomers are readily distinguished by their (1)H NMR spectra.     

Ferrocene derivatives of liquid chiral molecules allow assignment of absolute configuration by X-ray crystallography

The present study investigates a synthetically simple ferrocene derivatization of natural products and active pharmaceutical ingredients. Seven new crystal structures are analyzed together with 16 structures of ferrocene derivatives reported previously. In all cases, the unambiguous determination of the absolute structure was established from anomalous dispersion using the methods of Flack and Parsons. A comparison with other derivatization approaches shows the advantage of the described ferrocene derivatization for establishing the absolute configuration of novel compounds.