New computational approaches for establishing the absolute configuration of chiral molecules based on anisotropic NMR spectroscopy

• Applicants: Privatdozent Dr.-Ing. Stefan Immel; Professorin Dr. Han Sun
• Subject Area: Analytical Chemistry ; Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553513584

Determining the absolute configuration has long been considered the most challenging task in the structure determination process of chiral organic molecules. For pharmaceutical compounds, this information is nonetheless crucial for assessing their therapeutic activity. Recent advancements in developing new chiral aligning media with strong enantiodiscriminating effects offer new hope for assigning the absolute configuration of organic molecules using NMR alone, without requiring derivatization. In these chiral alignment media, enantiomers exhibit distinct orientational preferences, providing two unique sets of anisotropic NMR data, such as residual dipolar couplings (RDC). However, a critical challenge remains: how to use the distinct anisotropic NMR parameters obtained for both enantiomers to determine the absolute configuration. In this project, we aim to tackle this challenge and develop a robust computational approach for predicting solute orientational orders, ultimately enabling the determination of the absolute configuration of complex and flexible chiral systems. Our approach integrates atomistic molecular dynamics (MD) simulations with floating chirality-restrained distance geometry and distance bounds driven dynamics (fc-rDG/DDD) calculations. Atomistic MD simulations of chiral analytes in chiral aligning media with explicit solvents will be employed to predict the differences in orientational orders of enantiomers. Relative configuration and precise conformational ensembles will be determined by fc-rDG/DDD calculations, using isotropic and anisotropic NMR data to cross-validate and limit the conformational space of the flexible systems sampled by the MD simulations. We anticipate that this combined approach will enable the simultaneous and reliable determination of both the conformation and the absolute configuration of chiral molecules. Our ultimate goal is to provide the NMR, organic, and natural product chemistry communities with a robust computational approach based on a combination of isotropic and anisotropic NMR spectroscopy, allowing the reliable and routine assignment of the absolute configuration of novel and challenging chiral molecules.

• DFG Programme: Research Grants
• International Connection: Canada, China
• Cooperation Partners: Professor Dr. Bin-Gui Wang; Professor Andrei K. Yudin, Ph.D.