Uwe M. Reinscheid

Challenge of large-scale motion for residual dipolar coupling based analysis of configuration: the case of fibrosterol sulfate A.

Fibrosterol sulfate A is a polysulfated bis-steroid with an atypical side chain. Due to the flexibility of the linker, large-scale motions that change dramatically the shape of the entire molecule are expected. Such motions pose major challenges to the structure elucidation and the correct determination of configuration. In this study, we will describe the determination of the relative configuration of fibrosterol sulfate A through a residual dipolar coupling based multiple alignment tensor analysis complemented by molecular dynamics. For completeness, we applied also the single tensor approach which is unreliable due to the large-scale motions and compare the results.

Determining the absolute configuration of (+)-mefloquine HCl, the side-effect-reducing enantiomer of the antimalaria drug Lariam.

Even though the important antimalaria drug rac-erythro-mefloquine HCl has been on the market as Lariam for decades, the absolute configurations of its enantiomers have not been determined conclusively. This is needed, since the (-) enantiomer is believed to cause adverse side effects in malaria treatment resulting from binding to the adenosine receptor in the human brain. Since there are conflicting assignments based on enantioselective synthesis and anomalous X-ray diffraction, we determined the absolute configuration using a combination of NMR, optical rotatory dispersion (ORD), and circular dichroism (CD) spectroscopy together with density functional theory calculations. First, structural models of erythro-mefloquine HCl compatible with NMR-derived (3)J(HH) scalar couplings, (15)N chemical shifts, rotational Overhauser effects, and residual dipolar couplings were constructed. Second, we calculated ORD and CD spectra of the structural models and compared the calculated data with the experimental values. The experimental results for (-)-erythro-mefloquine HCl matched our calculated chiroptical data for the 11R,12S model. Accordingly, we conclude that the assignment of 11R,12S to (-)-erythro-mefloquine HCl is correct.

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

Effect of the Solvent on the Conformation of a Depsipeptide: NMR-Derived Solution Structure of Hormaomycin in DMSO from Residual Dipolar Couplings in a Novel DMSO-Compatible Alignment Medium.

The macrocyclic compound hormaomycin has been investigated by NMR spectroscopy and by restrained molecular‐dynamics simulations. Measurement of residual dipolar couplings induced by dissolving the depsipeptide in a polyacrylamide gel compatible with DMSO and their incorporation into the structure calculation of the title compound improved the precision of the family of structures. In DMSO the macrocyclic ring shows two β‐turns, whose positions in the sequence differ from those found in the CDCl3 solution structure and in the crystal structure obtained from hexylene glycol/H2O (50:50). The bulky side chain consisting of a 3‐(2‐nitrocyclopropyl)alanine and a chlorinated N‐hydroxypyrrole moiety is flexible in DMSO.

The Absolute Configuration of (+)‐ and (−)‐erythro‐Mefloquine

The controversy over the absolute configuration of (+)-erythro-mefloquine, the less psychosis-causing enantiomer of the anti-malarial drug Lariam, has been resolved by Mosher ester crystallization. The configuration determined previously by physical methods is correct, whereas the configuration determined by three enantioselective syntheses is wrong.

Bijvoet in solution reveals unexpected stereoselectivity in a Michael addition.

The absolute configuration of small crystallizable molecules can be determined with anomalous X-ray diffraction as shown by Bijvoet in 1951. For the majority of compounds that can neither be crystallized nor easily be converted into crystallizable derivatives, stereocontrolled organic synthesis is still required to establish their absolute configuration. In this contribution, a new fundamental methodology for resolving the absolute configuration will be presented that does not require crystallization. With residual dipolar coupling enhanced NMR spectroscopy, ensembles of a limited number of structures are created reflecting the correct conformations and relative configuration. Subsequently, from these ensembles, optical rotation dispersion (ORD) spectra are predicted by DFT calculations and compared to experimental results. The combination of these two steps reveals the absolute configuration of a flexible molecule in solution, which is a big challenge to chiroptical methods and DFT in the absence of NMR spectroscopy. Here the absolute stereochemistry of the product of a new Michael addition, synthesized via a niobium(V) chiral enolate, will be elucidated by using the new methodology.

Chiral discrimination of amines by anisotropic NMR parameters using chiral polyacrylamide-based gels.

A new chiral alignment medium for dimethyl sulfoxide, methanol, and water as solvents was developed. Because both enantiomers of the gel are available, it is possible to enantiodiscriminate natural products such as strychnine HCl that naturally occurs as single enantiomer. With the two methods of achieving anisotropy, namely stretching and confinement, the degree of alignment can be adjusted, and the director changed from horizontal to vertical. This increases the applicability. Three compounds were enantiodiscriminated on the basis of residual dipolar coupling data: mefloquine HCl, strychnine HCl, and menthylamine HCl. Copyright

Trapped in Misbelief for Almost 40 Years: Selective Synthesis of the Four Stereoisomers of Mefloquine

Here we report the synthesis of all four stereoisomers of mefloquine. Mefloquine (Lariam) is an important anti-malaria drug that is applied as a racemate of the erythro form. However, the (-)-isomer induces psychosis, while the (+)-enantiomer does not have this undesired side effect. There are six syntheses of which five lead to the wrong enantiomer without the authors of these syntheses noting that they had synthesized the wrong compound. At the same time physical chemistry investigations had assigned the absolute configuration correctly and the last enantioselective synthesis that took these results into account delivered the correct absolute configuration. Since various synthetic approaches failed to provide the correct stereoisomers in previous syntheses, we submit here a synthetic approach with a domino Sonogashira-6π-electrocyclisation as key step that confirmed synthetically the correct absolute configuration of all four isomers.

Predicting the structure of cyclic lipopeptides by bioinformatics: Structure revision of arthrofactin.

Arthrofactin, a bioactive cyclic lipopeptide from Pseudomonas sp. MIS38, was reinvestigated for its structural and stereochemical features due to discrepancies between the genetics-based sequence prediction and the currently suggested structure. The structure of arthrofactin and its derivatives was reassigned on the basis of chiral HPLC analysis and extensive NMR and MS experiments. Furthermore, derivatives of arthrofactin were discovered.

Elucidation of the enantiodiscrimination properties of a nonracemic chiral alignment medium through gel-based capillary electrochromatography: Separation of the mefloquine stereoisomers.

Abstract Enantiodiscrimination and enantioseparation are two highly important processes in chemistry, often performed by using NMR spectroscopy and chromatography. For a better understanding of the mechanistic details, the same system should be studied by both methods. In addition, isotropic and anisotropic NMR parameters should be obtained, the latter using alignment media so that residual dipolar couplings and chemical‐shift anisotropies can be measured. Consequently, a chiral alignment medium was used for the first time in chiral gel‐based capillary electrochromatography with the four stereoisomers of the antimalaria drug mefloquine as test compounds. Chromatographic data verify that enantiodiscrimination obtained with this alignment gel is caused by differences in the equilibrium constants related to associate formation. Hence, the chromatographic separation provides physicochemical data that form a basis for the understanding and optimization of alignment processes, and vice versa.