Determination of Absolute Configuration Using Chiroptical Methods

Abstract

Among different methods capable of determining the absolute configuration (AC) of chiral organic compounds, including pharmaceutical drugs and natural products, the use of chiroptical spectroscopic methods has recently faced a renaissance. These methods involve optical rotation (OR), optical rotatory dispersion (ORD), electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and Raman optical activity (ROA). The widespread use of such spectroscopic tools derives mainly from the availability of commercial instrumentation and the recent advances in quantum chemical calculations to predict theoretical spectra. This chapter is aimed at covering the current state‐of‐the‐art of chiroptical spectroscopy in combination with quantum chemical calculations to determine the AC of chiral molecules. While providing some background and examples on OR and ORD, as well as in more recent techniques, such as ROA, this chapter will be focused on the use of both electronic and vibrational forms of circular dichroism to solve stereochemical problems. A practical stepwise approach will be adopted to guide the reader through the advantages and limitations of each technique pointing out how to measure and calculate chiroptical properties. Finally, recent examples of the application of the above‐mentioned chiroptical methods, either alone or in combination, for the analysis of pharmaceutical drugs and natural products will be provided.