NMR determination of the absolute configuration of a macrophomate synthase inhibitor by using an axial chiral reagent

Macrophomate synthase catalyzes an extraordinary four-step transformation from oxalacetate and 2-pyrone to macrophomic acid by an intermolecular Diels-Alder reaction. The absolute configuration of the most potent macrophomate synthase inhibitor; (-)-2-carboxylmethyl-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic acid, was determined to be (1S, 2R, 4R) by using an axial chiral reagent.     

Chiral reagents for the determination of enantiomeric excess and absolute configuration using NMR spectroscopy

Recent advances in the development of chiral derivatizing and solvating agents that facilitate the determination of enantiomeric excess and absolute configuration are reviewed. These include metal-containing species, host-guest systems, donor-acceptor compounds, and liquid crystal discriminating agents. In the aggregate, these reagents can be used to analyze a wide range of compound classes.     

Assignment of absolute configuration using chiral reagents and NMR spectroscopy

An overview of chiral reagents that are used to assign the absolute configuration of particular classes of compounds using NMR spectroscopy is presented. The use of chiral derivatizing agents, chiral solvating agents, metal complexes, and liquid crystals is described. Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

NMR assignment of the absolute configuration of C-25 in furostanol steroidal saponins

The chemical shifts of the geminal proton resonances of H(2)-26 (δa and δb) are a widely used predictor of C-25 stereochemistry in furostanol steroidal saponins, being in general more resolved in 25S than 25R compounds. Unexpectedly, we found that application of this empirical rule in different solvents led to conflicting assignments of stereochemistry. An experimental survey revealed that, while the chemical shifts of H(2)-26 exhibit a dependence on C-25 configuration, it is less pronounced in methanol-d4 than pyridine-d5 solvent, and thus the general rule derived for pyridine-d5 fails when NMR spectra are acquired in methanol-d4. We propose a modified empirical method for the direct assignment of C-25 stereochemistry in furostanol saponins in methanol-d4 (Δ(ab)=0.45-0.48 ppm for 25S; Δ(ab)=0.33-0.35 ppm for 25R), and provide several detailed examples. In addition, the absolute configuration of compound 8, a steroidal saponin isolated in previous work from Ruscus colchicus, is corrected from 25R to 25S stereochemistry.     

Resolution of 1- and 2-naphthylmethoxyacetic acids,NMR reagents for absolute configuration determination,by use of L-phenylalaninol

Racemic 1- and 2-naphthylmethoxyacetic acids (1NMA and 2NMA), the chiral anisotropic reagents used for absolute configuration determination of chiral secondary alcohols and primary amines, were conveniently resolved to enantiomers (>99% ee) by condensation with L-phenylalaninol (2-amino-3-phenylpropanol), chromatographic separation of the diastereomers, and hydrolysis. This method enables large-scale preparation of enantiomeric 1NMA and 2NMA.     

CD exciton chirality method for determination of the absolute configuration of beta-hydroxy-alpha-amino acid derivatives

The absolute configuration of beta-hydroxy-alpha-amino acids was studied by CD exciton chirality method using 7-diethylaminocoumarin-3-carboxylate as a red-shifted chromophore. The CD spectra of bischromophoric derivatives of (S)-serine and (2S,3R)-threonine methyl esters (2 and 7) were compared with those of acyclic vic-aminoalcohols and diols (3--6 and 8--9). This study indicates that the polar carboxylate group of beta-hydroxy-alpha-amino acids makes them a unique subclass of vic-aminoalcohols. By combining the data of CD and NMR coupling constants, we are able to correlate their preferred conformer B and positive CD to the corresponding absolute configuration.     

Chiral doping of nematic phases and its application to the determination of absolute configuration

Doping nematic liquid crystals with nonracemic chiral compounds induces a twisted nematic (cholesteric) phase. The ability of solutes to twist the nematic phase may be related to the overall shape of the chiral dopant and consequently to its absolute configuration. The cholesteric induction is therefore a powerful tool complementary to chiroptical techniques to obtain stereochemical information on chiral molecules.     

Determination of the absolute configuration of Anisotome irregular diterpenes: application of CD and NMR methods

Several Anisotome diterpene derivatives were synthesized in an attempt to obtain a crystalline compound for X-ray analysis. Although we were unable to obtain a suitable crystal, the absolute configuration of the irregular diterpene skeleton was determined using two other techniques: a circular dichroism (CD) protocol based on a tetraarylporphyrin molecular tweezer that allowed prediction of the absolute stereochemistry on a microscale level, and a method employing differences in NMR shifts from derivatization of the naturally occurring acid 1 with enantiomers of a phenylglycine methyl ester (PGME) chiral anisotropic reagent. The excellent agreement between the CD and NMR methods led to the assignment of a 2S-absolute configuration for anisotomenoic acid 1.     

Assignment of absolute configuration to an improved enantioselective naproxen selector

Assignment of absolute configuration to a recently developed chiral selector useful in the separation of the underivatized enantiomers of naproxen and other nonsteroidal anti-inflammatory drugs (NSAIDs) is described. Circular dichroism, ¹H NMR, and X-ray diffraction have been used to confirm the original assignment which was based solely upon elution orders from HPLC chiral stationary phases. All of these techniques agree in the assignment of the (S,S) absolute configuration to the enantiomer of the chiral selector which associates preferentially with (S)-naproxen. © 1994 Wiley-Liss, Inc.     

Assignment of absolute configuration of 3-hydroxy beta-lactams by the NMR "mix and shake" method

The absolute configurations of several 3-hydroxy beta-lactams were assigned by the NMR "mix and shake" methodology developed by Riguera and co-workers. The results from the NMR study correlated perfectly with the absolute configurations obtained from X-ray crystallographic structure analyses and chiral-phase HPLC data.     

The absolute configuration of benproperinium dihydrogen phosphate, an antitussive drug

The (+)- and (-)-enantiomers of benproperinium dihydrogen phosphate, an antitussive drug, have been assigned the R- and S-configurations, respectively, by syntheses of both enantiomers using (S)-2-hydroxypropanoic acid (L-lactic acid) as chiral synthon. The key intermediate, (S)-1-methyl-2-[2-(phenylmethyl)phenoxy]ethyl p-toluenesulfonate, was subjected to an SN2-type reaction with piperidine furnishing (+)-(R)-benproperinium dihydrogen phosphate. (-)-(S)-Benproperinium dihydrogen phosphate was obtained by submitting the same tosylate to two consecutive SN2-type reactions with Br- and piperidine, respectively, acting as nucleophiles.     

Mosher ester analysis for the determination of absolute configuration of stereogenic (chiral) carbinol carbons

This protocol details the most commonly used nuclear magnetic resonance (NMR)-based method for deducing the configuration of otherwise unknown stereogenic, secondary carbinol (alcohol) centers (R1R2CHOH (or the analogous amines where OH is replaced by NH2)). This 'Mosher ester analysis' relies on the fact that the protons in diastereomeric alpha-methoxy-alpha-trifluoromethylphenylacetic acid (MTPA) esters (i.e., those derived from conjugation of the carbinol under interrogation with MTPA) display different arrays of chemical shifts (deltas) in their 1H NMR spectra. The protocol consists of the following: (i) preparation of each of the diastereomeric S- and R-MTPA esters and (ii) comparative (Delta delta(SR)) analysis of the 1H NMR spectral data of these two esters. By analyzing the sign of the difference in chemical shifts for a number of analogous pairs of protons (the set of Delta delta(SR) values) in the diastereomeric esters (or amides), the absolute configuration of the original carbinol (or amino) stereocenter can be reliably deduced. A typical Mosher ester analysis requires approximately 4-6 h of active effort over a 1- to 2-d period.     

Comformation and absolute configuration of -methyllanthionine

If the bicyclic peptide ring proposed by Gross $\text{et}$$\text{al}$. (1,2) does in fact exist in nisin and related antibiotics, then the unusual β-methyllanthionine component must be significantly distorted from its conformation in the free state, as determined by x-ray structure analysis. The torsion angles about the SC_β bonds are 50–100° from the torsion angles in models of the sulfur-bridged peptide ring proposed for nisin. The chirality of the methylated β-carbon atom is (S). The conformation of the amino acid differs from that of $\text{meso}$-lanthionine only by a 180° rotation of a carboxyl group about the $\text{C}{}_{\mathrm{\alpha }}{}^{\mathrm{D}}\text{C}{}_{\mathrm{\beta }}\text{(CH}{}_3\text{)}$ bond.     

Structure and absolute configuration of the sesquiterpenoid emmotins

The trunk wood of Emmotum nitens (Icacinaceae) contains the aromatic sesquiterpenes (2R,3S)-2-hydroxy-3-(2′-hydroxyisopropyl)-5,8-dimethyl-1-oxo-1,2,3,4-tetrahydronaphthalene (emotin-F), 2-hydroxy-3-(2′-hydroxyisopropyl)-5,8-dimethylnaphthalene (emmotin-G) and 3-(2′-hydroxyisopropyl)-5,8-dimethyl-1,2-naphtho-quinone (emmotin-H). The identity of the carbon skeletons of these emmotins was proved by conversion of all three into an identical quinoxaline derivative. The nature of this skeleton and the absolute configuration of emmotin-F, as well as of the previously described emmotins A and B, was established by conversion of emmotin-F into (+)-occidol.     

The absolute configuration of the acetylenic compound falcarindiol

The absolute configuration of the acetylenic compound falcarindiol is established as (3R,8S) and falcarindiol is thus (+)-(3R,8S)-(Z)-heptadeca-1,9-dien-4,6-diyn-3,8-diol. (R)-Heptadecan-8-ol and (S)-heptadecan-8- ol are synthesized and (3R,8S)-heptadecan-3,8-diol is characterized.