Determination of the absolute configuration of natural product molecules using vibrational circular dichroism

Abstract

The determination of absolute configuration (AC) has been a long-standing problem in natural product chemistry. Although there are several methods capable of determining the AC of chiral molecules, some specific requirements may limit their application, such as the presence of high-quality single crystals for X-ray analysis, UV-vis chromophores for electronic circular dichroism (ECD), chiral auxiliaries for NMR methods, and derivatizations for stereoselective organic synthesis. As an alternative, vibrational circular dichroism (VCD) has become a powerful tool for the determination of the AC and conformations of chiral compounds in the solution state after nearly 40 years of evolution. VCD results from the difference in the infrared (IR) absorbance of a chiral molecule for left versus right circularly polarized radiation. VCD is thus the extension of ECD into infrared and near-infrared regions of the spectrum where vibrational transitions occur within the ground electronic state of the molecule. By comparing the sign and intensity of the measured VCD spectrum with the corresponding ab initio density functional theory (DFT)-calculated VCD spectrum of a chosen configuration, one can unambiguously assign the AC of a chiral molecule. This chapter is aimed at covering the current state of the art of VCD spectroscopy in combination with quantum chemical calculations to determining the AC of bioactive natural product molecules, pointing out how to measure and calculate quality VCD spectra. Following up an extensive review [Nat. Prod. Commun. 3 (2008) 451-466] on the determination of AC of natural products using VCD, in this chapter we will also provide an up-to-date compilation on the latest (2008-2012) examples of application of VCD to solve stereochemical problems of structurally diverse natural products. Copyright © 2014 Elsevier B.V. All rights reserved.