Absolute Configurations of Synthetic Molecular Scaffolds from Vibrational CD Spectroscopy

Abstract

Vibrational circular dichroism (VCD) spectroscopy is one of the most powerful techniques for the determination of absolute configurations (AC), as it does not require any specific UV/vis chromophores, no chemical derivatization, and no growth of suitable crystals. In the past decade, it has become increasingly recognized by chemists from various fields of synthetic chemistry such as total synthesis and drug discovery as well as from developers of asymmetric catalysts. This perspective article gives an overview about the most important experimental aspects of a VCD-based AC determination and explains the theoretical analysis. The comparison of experimental and computational spectra that leads to the final conclusion about the AC of the target molecules is described. In addition, the review summarizes unique VCD studies carried out in the period 2008−2018 that focus on the determination of unknown ACs of new compounds, which were obtained in its enantiopure form either through direct asymmetric synthesis or chiral chromatography.

Towards theoretical spectroscopy with error bars: systematic quantification of the structural sensitivity of calculated spectra

“…1 In many cases, structural information can only be extracted from experimental spectra by combining them with computations. 2 Examples include the elucidation of the gas-phase structure of polypeptides with vibrational spectroscopy, [3][4][5][6][7] the assignment of the absolute conguration of chiral molecules with chiroptical spectroscopic techniques, [8][9][10][11] and the identication of active species and catalytic intermediates with X-ray spectroscopy. [12][13][14][15] While in some cases, high-resolution spectroscopic experiments can resolve the individual spectroscopic transition, this is usually not the case for most common applications that aim at obtaining structural information from spectroscopic experiments, such as those mentioned above.…”

Stereochemistry of the Reaction Intermediates of Prolinol Ether Catalyzed Reactions Characterized by Vibrational Circular Dichroism Spectroscopy

“…Moreover, as vibrational spectroscopic technique, VCD spectroscopy has shown a remarkable sensitivity for solute–solvent and solute–solute interactions . All these applications rely on the direct comparison of experimental and computed spectra and a good match directly confirms the predicted conformational preferences . In several studies, we could already show that VCD spectroscopy can significantly contribute to a better understanding of stereochemical information transfer in asymmetric catalysis.…”

Vibrational optical activity: From discovery and development to future challenges

“…These papers, with software available from Gaussian 95, established a baseline for the accurate calculation of VCD spectra in which MFP theory is used for the atomic axial tensors together with direct derivatives and gauge‐invariant atomic orbitals (GIAOs) at the 6‐31G(d) level and the hybrid functionals B3LYP or B3PW91. Since this landmark advance, a number of reviews have been written that featured the use of VCD for the determination of AC in molecules of sufficient size as to be appropriate for chiral organic drug molecules under development . Today, virtually all major pharmaceutical companies and many smaller ones are using VCD as a preferred method for the determination of AC …”