NMR for Stereochemical Elucidation

Abstract

Nuclear magnetic resonance (NMR) spectroscopy plays a fundamental role in the stereochemical elucidation of chiral organic molecules. Together with X-ray crystallography, they belong to the mostly used methods for establishing the relative configuration. Conventional NMR methods rely on the usage of chemical shifts, nuclear Overhauser effects (NOEs), and homonuclear and heteronuclear scalar couplings ( J -couplings). In this chapter, basic theory of each NMR parameter is discussed, while several examples are demonstrated showing the power of isotropic NMR restraints in the determination of relative configuration. The application of anisotropic NMR data, such as residual dipolar couplings (RDCs) and residual chemical shift anisotropies (RCSAs), has emerged as a powerful technique in the past 20 years for establishing constitution, relative configuration, and conformation of flexible and complex molecules. In strong contrast to NOE and scalar coupling, RDC and RCSA are long-range structural parameters. In this chapter, a number of successful examples illustrating the application of anisotropic NMR data in the determination of relative configuration will be given, where in some cases their absolute configuration could be established by a combination of anisotropic NMR and chiroptical spectroscopy. We also review recent advances in the development of new alignment media that is essential for anisotropic NMR measurements. Novel computational approaches for analyzing the anisotropic NMR parameters are briefly discussed, as these methods significantly accelerated the procedure for establishing the complete three-dimensional structures of organic molecules. In the last part, we review recent progress and application of computational NMR methods based on density functional theory (DFT) such as DP4/DP4+ and CASE-3D, which become more and more popular in determining the relative configuration of chiral organic molecules. For establishing the absolute configuration, we discuss both methods relying on chiral derivatizing agents and chiral solvents. We put a special focus on Mosher ester method based on chiral derivatization, as this method is among the most popular one. The principal and application of Mosher ester method is illustrated with published example.