Stereochemistry Determination by Powder X‐Ray Diffraction Analysis and NMR Spectroscopy Residual Dipolar Couplings

Abstract

Traditional techniques for stereochemistry analysis have limitations; for example solution NMR spectroscopy has spatial limitation for the transference of stereochemical information, and suitable single crystals for X-ray analysis may not be available. Residual dipolar coupling (RDC) and powder X-ray diffraction (PXRD) are both techniques whose use is not yet widespread. We report a double-blind solution of the structure of jaborosalactol 24 (1), a new withanolide isolated from Jaborosa parviflora (Phil.) A. T. Hunziker et Barboza, by RDCs and PXRD, since conventional NMR spectroscopy experiments such as nuclear Overhauser effect (NOE) and 3 J analysis did not provide a unique solution.NOE, [1] frequently combined with 3 J coupling constants analysis, [2] is one of the most powerful tools for structural and conformational analysis by solution NMR spectroscopy. Unfortunately, the determination of relative stereochemistry between remotely located stereocenters becomes problematic arising from the limitations imposed by the 1/r 6 dependence of NOE (where r = internuclear distance). However, when molecules are forced to adopt a minor degree of alignment in solution and no longer tumble isotropically, a measurable fraction of the dipolar coupling (0.01-0.1 %) can be observed in the NMR spectrum. These so called residual dipolar couplings [3][4][5][6][7] (RDCs) contain important structural information of non-local character, since their values depend not only on the internuclear distances but also on the angles between the internuclear vectors and the external magnetic field. Hence, they provide information about the relative orientation between the internuclear vectors (e.g., H-H, H-C, H-N, C-C, etc.), regardless of the distance between them. Since the pioneering work by Courtieu and co-workers on the determination of relative configuration by RDCs using poly-gbenzyl-l-glutamate (PBLG)/CDCl 3 , [8,9] more alignment media compatible with organic solvents are now available. [10][11][12][13][14][15][16][17][18][19][20][21][22] In natural products in particular, the power of RDCs for the resolution of configurational problems has been tested against known molecules such as menthol, [23] cyclosporin, [15] ludartin, [22] strychnine, [21,24] sphaeropsidin A, [11] sagittamide A, [25] archazolid A, [26] sodium cholate, [27] and even used, in the case of the novel glycoside sucro-neo-lambertellin [28] for the determination of the unknown configuration in several stereocenters. Another case is the configuration of a synthetic a-methylene-g-butyrolactone that could not be resolved by conventional means. [29] At present, PXRD analysis can be used to determine the crystal structures of small organic molecules. [30] One fruitful technique is realspace simulated annealing, in which trial structures are generated and optimized using a set of structural parameters that define the location, orientation, and conformation of the molecules in the solid, consistent with bond lengths and angles from the known (or hypothesized) molecular stru...

Residual Dipolar Couplings (RDCs) Analysis of Small Molecules Made Easy: Fast and Tuneable Alignment by Reversible Compression/Relaxation of Reusable PMMA Gels

“…We have introduced the use of poly(methyl methacrylate) (PMMA) gels to measure RDCs, mainly for applications to small molecules soluble in CDCl 3 and CD 2 Cl 2 31. 32 PMMA gels have shown very good aligning properties when swollen in these solvents and they present little polymer background signal in the HSQC experiments used for the RDCs measurement.…”

Configurational analysis by residual dipolar couplings: A critical assessment of diastereomeric differentiabilities

“…Modern computer‐assisted structure elucidation (CASE) algorithms use combinations of experimental and predicted chemical shifts, scalar J couplings, nuclear Overhauser effect (NOE) derived intramolecular distances, etc for the constitutional and configurational assignments of analytes. Increasingly, anisotropic NMR parameters such as residual dipolar couplings (RDCs), residual quadrupolar couplings (RQCs), and residual chemical shift anisotropies (RCSAs), which now can be measured routinely in anisotropic weakly aligning environments, add particularly valuable information to the problem of configurational assignment. In combination with NOEs, these quantities provide nonlocal, long‐range correlations for the relative orientation of bond vectors, which are inaccessible otherwise.…”

Constitutional, Configurational, and Conformational Analysis of Small Organic Molecules on the Basis of NMR Residual Dipolar Couplings

“…Various research groups have taken advantage of the availability of this wide variety of alignment media compatible with organic solvents and used RDCs for the configurational and conformational analysis of several small molecules 12. Owing to challenging structural problems, the use of NOEs and 3 J coupling constants for the structural analysis of some of these molecules failed to provide a unique solution 12b,g,j. The methodology has proven very effective for rigid and semirigid small molecules.…”