Absolute Configuration from Chiroptical Spectroscopy

The determination of absolute configuration (AC) has been a long-standing problem in several small molecule-based research areas, such as natural product chemistry, organic synthesis, and drug discovery. There are several methods capable of determining the AC of chiral molecules, such as the X-ray crystallography, NMR methods, and stereoselective organic synthesis. However, each of these techniques needs some specific requirements that may limit their application. As an alternative, chiroptical spectroscopic methods, such as optical rotation (OR), optical rotatory dispersion (ORD), electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and vibrational Raman optical activity (VROA), have emerged as powerful tools for the determination of the AC of chiral molecules. They are non-destructive spectroscopic methods that investigate different aspects of optical activity. Therefore, in this chapter, we intent to provide the reader with an overview of the main chiroptical methods available for stereochemical assignments of organic compounds as well as the best practices for their application in different classes of molecules. It will cover the current state-of-the-art of chiroptical spectroscopy in combination with quantum chemistry calculations for determining both the AC and conformations of chiral molecules. Finally, recent selected examples of the application of chiroptical methods, either alone or in combination, for the analysis of pharmaceuticals, as well as synthetic and natural product compounds are provided.