Determination of Absolute Configuration of Chiral Molecules Using Vibrational Optical Activity: A Review

Abstract

Determination of the absolute handedness, known as absolute configuration (AC), of chiral molecules is an important step in any field related to chirality, especially in the pharmaceutical industry. Vibrational optical activity (VOA) has become a powerful tool for the determination of the AC of chiral molecules in the solution state after nearly forty years of evolution. VOA offers a novel alternative, or supplement, to X-ray crystallography, permitting AC determinations on neat liquid, oil, and solution samples without the need to grow single crystals of the pure chiral sample molecules as required for X-ray analysis. By comparing the sign and intensity of the measured VOA spectrum with the corresponding ab initio density functional theory (DFT) calculated VOA spectrum of a chosen configuration, one can unambiguously assign the AC of a chiral molecule. Comparing measured VOA spectra with calculated VOA spectra of all the conformers can also provide solution-state conformational populations. VOA consists of infrared vibrational circular dichroism (VCD) and vibrational Raman optical activity (ROA). Currently, VCD is used routinely by researchers in a variety of backgrounds, including molecular chirality, asymmetric synthesis, chiral catalysis, drug screening, pharmacology, and natural products. Although the application of ROA in AC determination lags behind that of VCD, with the recent implementation of ROA subroutines in commercial quantum chemistry software, ROA will in the future complement VCD for AC determination. In this review, the basic principles of the application of VCD to the determination of absolute configuration in chiral molecules are described. The steps required for VCD spectral measurement and calculation are outlined, followed by brief descriptions of recently published papers reporting the determination of AC in small organic, pharmaceutical, and natural product molecules.

Studying the stereostructures of biomolecules and their analogs by vibrational circular dichroism

“…The left-handedness of PLLA in solution has also been suggested by other researchers. 39 (3) The VCD spectra of the PLLA solutions of CDCl 3 and DMSO-d 6 were nearly superimposable, suggesting the solvent has little influence on its secondary structure. (4) The VCD signals in the C = O stretching region for the PLLA-amylose complex were also virtually superimposable with the other two spectra.…”

“…On the other hand, the applicability of solution-state nuclear magnetic resonance spectroscopy is primarily limited to molecules in which hydrogen atoms are suitably located. To understand the details of biological systems, we have been applying vibrational circular dichroism (VCD) spectroscopy [1][2][3] to analyze the three-dimensional structures of various biomolecules. For virtually all chiral organic molecules, VCD spectroscopy is capable of detecting signals whose shape reflects their stereostructure.…”

VCD to determine absolute configuration of natural product molecules: secolignans from Peperomia blanda

“…5 By comparing the signs and intensities of the measured VCD spectrum with the corresponding ground electronic state ab initio density functional theory (DFT) calculated VCD spectrum of a chosen configuration, one can unambiguously assign the AC of a chiral molecule. 11 The applicability of VCD associated with DFT calculations to AC determination of chiral natural product molecules has been previously demonstrated, 2,10,[12][13][14][15] including some examples from our research group. [16][17][18] Recently, ECD spectroscopy and time-dependent density functional theory (TDDFT) calculations were used to determine the AC of a novel secolignan (1) with rare cis configuration at the γ-butyrolactone ring, isolated from Peperomia blanda, 19 however, other two similar compounds with one additional chiral center each could not be investigated due to limitations inherent to the ECD.…”

Implementing and Operating Computer Graphics in the Contemporary Chemistry Education

“…The prime and important thing in chemistry, especially in organic chemistry and biochemistry, is the ability to represent 3D molecules in space 6 . Unfortunately, many students are incapable to visualize in space and have difficulties in resolving the structure of the substance 1 .…”