Philippe Lesot

Enantiomeric excess measurements in weakly oriented chiral liquid crystal solvents through 2D 1H selective refocusing experiments

Abstract In this article, a simple and robust method is proposed for simplifying the analysis of proton spectra of molecules dissolved in weakly oriented chiral media. The NMR approach investigated is based on the use of proton selective refocusing 2D experiments (SERF) to measure proton–proton dipolar couplings from unresolved lines. This technique is applied to the case of enantiomers dissolved in chiral polypeptide liquid crystals. It is shown that an accurate determination of enantiomeric excess is possible within a short experimental time.

Enantiomeric visualization using proton-decoupled natural abundance deuterium NMR in poly(γ-benzyl-l-glutamate) liquid crystalline solutions

Abstract We report the first visualization of chiral molecules oriented in a polypeptide liquid crystalline system (PBLG) using proton-decoupled natural abundance deuterium NMR. The chiral discrimination is observed through measurements of the quadrupolar splitting differences and we demonstrate that the sensitivity of natural abundance deuterium NMR is sufficient to measure the differential ordering effects (DOEs) without the need for isotopic enrichment. The feasibility and the potential of this novel method were investigated using a 5.87 T spectrometer (proton frequency 250 MHz). Several examples of chiral discrimination are presented and particular emphasis is given to demonstrate the potential of this approach.

Theoretical and experimental aspects of enantiomeric differentiation using natural abundance multinuclear nmr spectroscopy in chiral polypeptide liquid crystals

Liquid crystalline organic solutions of poly-γ-benzyl-L-glutamate generate a sufficient differential ordering effect to visualize enantiomers using multinuclear high-resolution NMR spectroscopy at natural isotopic abundance levels. Chiral discrimination can be observed through a difference in the order-sensitive NMR observables, namely: proton–proton, carbon–proton and carbon–carbon residual internuclear dipolar couplings, carbon chemical shift anisotropies, and deuterium quadrupolar splittings. In most cases, the enantiodifferentiation is large enough to allow determation of the enantiomeric excesses satisfactorily. All theoretical considerations and significant experimental parameters that affect the efficiency of this methodology are presented and discussed. The various possible anisotropic NMR techniques provide a very reliable and powerful alternative to the current analytical techniques which operate in the isotropic phase.

First Evidence of a Photoinduced Spin Change in an FeIII Complex Using Visible Light at Room Temperature

An iron(III) complex [Fe(salten)(Mepepy)]BPh4 containing only one photoisomerizable ligand (Mepepy) has been synthesized, it exhibits a thermally-induced spin crossover in the solid state and in solution {H2salten = 4-azaheptamethylene-1,7-bis(salicylideneiminate); Mepepy = 1-(pyridin-4-yl)-2-(N-methylpyrrol-2-yl)ethene}. The photoisomerizations of both the free and coordinated Mepepy ligand have been observed at room temperature with visible-light irradiation and monitored by UV/Vis and 1H NMR spectrometries. trans-to-cis isomerization of only one photosensitive ligand in the iron(III) complex is sufficient to detect a partial spin change of the iron(III) ion. This photoinduced spin change is seen for the first time from a high-spin state to a low-spin state.

The relationship between molecular symmetry and second-rank orientational order parameters for molecules in chiral liquid crystalline solvents

From group theoretical arguments, we demonstrate that the effective molecular symmetry is reduced in a chiral liquid crystalline phase. This reduction changes the location of the principal axes of the orientational order matrices for four molecular point groups, namely Cs, C2v, S4, and D2d. These symmetries correspond to compounds which have prochiral faces, groups, or directions. The change in effective molecular symmetry can be detected by NMR spectroscopy, and this is illustrated by the example of acenaphthene dissolved in a chiral nematic solvent.

Fast and high-resolution stereochemical analysis by nonuniform sampling and covariance processing of anisotropic natural abundance 2D 2H NMR datasets.

Natural abundance deuterium (NAD) 2D NMR spectroscopy using chiral or achiral liquid crystals is an efficient analytical tool for the stereochemical analysis of enantio- or diastereomers by the virtue of proton-to-deuterium substitution. In particular, it allows the measurement of enantiopurity of organic synthetic molecules or the determination of the natural isotopic (1)H/(2)H fractionation in biological molecules, such as fatty acid methyl esters (FAME). So far, the NAD 2D spectra of solutes were acquired by using uniform sampling (US) and processed by conventional 2D Fourier transform (FT), which could result in long measurement times for medium-sized analytes or low solute concentrations. Herein, we demonstrate that this conventional approach can be advantageously replaced by nonuniform sampling (NUS) processed by covariance (Cov) transform. This original spectral reconstruction provides a significant enhancement of spectral resolution, as well as a reduction of measurement times. The application of Cov to NUS data has required the introduction of a regularization procedure in the time domain for the indirect dimension. The analytical potential of combining Cov and NUS is demonstrated by measuring the enantiomeric excess of a scalemic mixture of 2-ethyloxirane and by determining the diastereomeric excess of methyl vernoleate, a natural FAME. These two organic compounds were aligned in a polypeptide (poly(γ-benzyl-L-glutamate)) mesophase. In the case of NAD 2D NMR spectroscopy, we show that Cov and NUS methods allow a decrease in measurement time by a factor of two compared with Cov applied to US data and a factor of four compared with FT applied to US data.

Is Enantiomer Assignment Possible by NMR Spectroscopy Using Residual Dipolar Couplings from Chiral Nonracemic Alignment Media?—A Critical Assessment

The discovery of Jean-Baptiste Biot in 1815 that optical activity is not a property bound to a certain aggregation state of matter but a property of the constituting molecules themselves, has had an enormous influence on the structural models that chemists developed at the end of the 19th century, long before the description of the chemical bond was based on quantum mechanics. Pasteur achieved the first separation of enantiomers in 1847, namely by crystallization of a racemic tartrate mixture that separated the two enantiomers into enantiomorphic crystals, solutions of which rotated the plane of linearly polarized light in opposite directions. Not until 1951, when Bijvoet used anomalous X-ray diffraction, it was possible to assign the absolute configuration to a specific enantiomer. However, anomalous X-ray diffraction has not put the problem of assigning absolute configurations to rest, because many chemical compounds cannot be crystallized. Moreover, anomalous X-ray diffraction of molecules that consist exclusively of lightweight atoms commonly lacks the needed accuracy to allow unambiguous assignment of absolute configurations. An alternative method for resolving enantiomers is to convert them to diastereoisomers, either by chemical derivatization with chiral nonracemic moieties or by intermolecular coordination with chiral nonracemic reagents. In this way it is possible to determine absolute configuration from NMR observables, most commonly chemical shifts. The use of chiroptical spectroscopies such as optical rotatory dispersion, and electronic or vibrational circular dichroism is well established, sometimes in combination with ab initio calculations. Further methods are conceivable but impractical momentarily. Yet, there is currently not a simple and universally applicable approach to determine the absolute configuration of molecules with few stereogenic centers. Two recent papers published in 2007 and 2011 have therefore created a lot of excitement in the chemistry and NMR spectroscopy communities. Their titles are: “Stereochemical Identification of (R)and (S)-Ibuprofen Using Residual Dipolar Couplings, NMR, and Modeling”, henceforth called “article 1”, and more recently: “Spin-Selective Correlation Experiment for Measurement of Long-Range J Couplings and for Assignment of (R/S) Enantiomers from the Residual Dipolar Couplings and DFT”, henceforth called “article 2”. Both articles describe the assignment of the absolute configuration of the chiral molecules, ibuprofen 1 (article 1) and 4-methyl-1,3-dioxolan-2-one 2 (article 2), using NMR spectroscopy in chiral nonracemic alignment media (Figure 1). Under chiral nonracemic conditions, the authors measured residual dipolar couplings (RDCs), a NMR parameter only visible in oriented samples, such as in liquid crystals, but not in isotropic solvents. The interaction of the enantiomers with the chiral nonracemic alignment medium gives rise to diastereomorphic associates for which reason the authors indeed found different sets of anisotropic parameters for each enantiomer, in total

Deuterium NMR stereochemical analysis of threo–erythro isomers bearing remote stereogenic centres in racemic and non-racemic liquid crystalline solvents

Abstract We report the proton-decoupled deuterium NMR study of labelled diastereomers with remote stereogenic carbons dissolved in various mixtures of poly-γ-benzyl- l -glutamate (PBLG) and poly-γ-benzyl- d -glutamate (PBDG) liquid crystalline solutions. The evolution of quadrupolar splitting as well as the diastereomeric and the enantiomeric discrimination versus the proportion of PBLG and PBDG in the liquid crystalline phase is studied. It is shown that racemic liquid crystalline solutions of PBLG and PBDG may be used to measure diastereomeric excess ( de ). Thereafter the spectrum in PBLG solution allows for measuring the enantiomeric excess ( ee ) of each diastereomer. These first results suggest substantial prospects in the field of the analysis of diastereomers with remote stereogenic carbons.

Investigation of Fatty Acid Elongation and Desaturation Steps in Fusarium lateritium by Quantitative Two-dimensional Deuterium NMR Spectroscopy in Chiral Oriented Media

The origin of hydrogen atoms during fatty acid biosynthesis in Fusarium lateritium has been quantified by isotope tracking close to natural abundance. Methyl linoleate was isolated from F. lateritium grown in natural abundance medium or in medium slightly enriched with labeled water, glucose, or acetate, and the 2H incorporation was determined by quantitative 2H-{1H} NMR in isotropic and chiral oriented solvents. Thus, the individual (2H/1H)i ratio at each pro-R and pro-S hydrogen position of the CH2 groups along the chain can be analyzed. These values allow the isotope redistribution coefficients (aij) that characterize the specific source of each hydrogen atom to be related to the nonexchangeable hydrogen atoms in glucose and to the medium water. In turn, these can be related to the stereoselectivity that operates during the introduction or removal of hydrogens along the fatty acid chain. First, at even CH2 the pro-S hydrogen comes only from water by protonation, whereas the pro-R hydrogen is introduced partly via acetate but principally from water. Second, the nonexchangeable hydrogens of glucose (positions H-6,6 and H-1) are shown to be introduced to the odd CH2 via the NAD(P)H pool used by both reductases involved in the elongation steps of the fatty acid chain. Third, it is proved that hydrogens removed at sites 9,10 and 12,13 during desaturation by Δ9- and Δ12-desaturases are pro-R, and that during these desaturation steps α-secondary kinetic isotope effects occur at the 9 and 12 positions and not at the 10 and 13 positions.

Synthesis of 2-Trifluoromethyl-1,3-oxazolidines as Hydrolytically Stable Pseudoprolines

Trifluoromethyl group containing oxazolidines (Fox) are conveniently synthesized by condensation of serine esters with trifluoroacetaldehyde hemiacetal or trifluoroacetone. These oxazolidines can undergo N-acylation and amidification reactions and are completely configurationally and hydrolytically stable. Therefore, they can be considered as highly valuable proline surrogates (Tfm-pseudoprolines).