Determination of Absolute Stereochemistry of Flexible Molecules Using a Vibrational Circular Dichroism Spectra Alignment Algorithm

Abstract

Experimental determination of the absolute stereochemistry of chiral molecules has been a fundamental challenge in natural sciences for decades. Vibrational circular dichroism (VCD) spectroscopy represents an attractive alternative to traditional methods like X-ray crystallography due to the use of molecules in solution. The interpretation of measured VCD spectra and thus the assignment of the absolute configuration relies on quantum-mechanical calculations. While such calculations are straightforward for rigid molecules with a single conformation, the need to estimate the correct conformational ensemble and energy landscape to obtain the appropriate theoretical spectra poses significant challenges for flexible molecules. In this work, we present the development of a VCD spectra alignment (VSA) algorithm to compare theoretical and experimental VCD spectra. The algorithm determines which enantiomer is more likely to reproduce the experimental spectrum and thus allows the correct assignment of the absolute stereochemistry. The VSA algorithm is successfully applied to determine the absolute chirality of highly flexible molecules, including commercial drug substances. Furthermore, we show that the computational cost can be reduced by performing the full frequency calculation only for a reduced set of conformers. The presented approach has the potential to allow the determination of the absolute configuration of chiral molecules in a robust and efficient manner.

Vibrational and Electronic Circular Dichroism Study of Chiral Seleno Compounds Prepared from a Naphthol Based Diselenide

“…In this respect the availability of reliable chiroptical methods for the absolute configuration (AC) assignment is a must. Here we use vibrational circular dichroism (VCD) [16–25] together with ab‐initio ‐DFT calculations [26–29] . The cited literature and other relevant recent papers for assigning AC by chiroptical methods [30–33] reveal the usefulness of VCD in the study of chiral molecules belonging to the classes of natural products, peptides/proteins, metal complexes, molecules with hydrogen bonds.…”

“…Here we use vibrational circular dichroism (VCD) [16][17][18][19][20][21][22][23][24][25] together with ab-initio-DFT calculations. [26][27][28][29] The cited literature and other relevant recent papers for assigning AC by chiroptical methods [30][31][32][33] reveal the usefulness of VCD in the study of chiral molecules belonging to the classes of natural products, peptides/proteins, metal complexes, molecules with hydrogen bonds. However, to the best of our knowledge, little has been done to date both experimentally and computationally on chiral seleno-containing compounds.…”

β-Sheet Richness of the Circulating Tumor-Derived Extracellular Vesicles for Noninvasive Pancreatic Cancer Screening

“…Superior to the tertiary and quaternary structure of the proteins, which require elaborate measurement apparatus, the methods to evaluate the secondary structure are comparatively more accessible for clinical translation. Various direct and indirect approaches such as CD or nuclear magnetic resonance (NMR) are commonly used to explore the secondary structure. , However, the size, cost, and delicate nature of these systems limit their utility in field hospitals, clinical laboratories, and other settings where these factors become obstructive to translation. We studied the BR of EV proteins in relation to the malignancy because it can be captured noninvasively and quantified by fluorescence labeling, which is more feasible to be applied in clinical settings.…”

Tackling Stereochemistry in Drug Molecules with Vibrational Optical Activity

“…A scaling factor (0.95–1.05) on the calculated frequencies will often be applied to account for systematic errors in the vibrational frequencies caused by the harmonic approximation and the use of a limited basis set. The similarity between experimental and calculated spectra can be determined by either visual inspection or various quantitative methods that make use of similarity measures [ 36 , 37 , 38 , 39 ]. When none of the predicted spectra match the experimental spectrum to a satisfying degree, after ruling out errors in the structure elucidation one should either increase the basis set size (if of limited size) or consider the environment of the molecule.…”