Public Summary

Like human hands, chiral molecules exist in a right-hand and a left-hand form. The process of discriminating between the left- and right- hand forms of a chiral molecule is called absolute configuration (AC) determination. This process is a key step for determining the usage of a given molecule in chemical, biological and health sciences. For example, many of the pharmaceutical drugs consist of chiral molecules and most often only one of the chiral forms of the drug has the desired pharmacological activity, the other form can be less potent or even poisonous. For this reason it is extremely important to make accurate AC assignments.

Chiroptical spectroscopy assigns the AC of a compound by studying how it interacts with left and right circularly polarised light. The AC assignment is done based on a direct comparison between the experimental and simulated spectra of the studied molecule. While this approach was applied rather successfully in the last two decades, it possesses an inherent weakness. Specifically, the simulated spectra are computed as a Boltzmann average of the spectra computed for the individual conformers of the studied molecule using Density Functional Theory (DFT). Therefore, this average depends sensitively on the Boltzmann weights predicted with DFT, which are known to exhibit very large uncertainties. (Unlike the Boltzmann factors, the structures and the spectra predicted with DFT are quite accurate.)

The main goal of the present research project was to develop and perfect a new chiroptical spectroscopy protocol for assigning the AC of chiral compounds. By employing a combination of genetic and hierarchical clustering artificial intelligence algorithms, we have successfully circumvented the shortcomings of the DFT Boltzmann factors. This has enabled us to make highly reliable AC assignments. Unlike the standard protocol which relies blindly on the inaccurate DFT Boltzmann factors and often neglects important conformations, the approach developed in this research project performs a thorough analysis of the spectra of all considered conformers. This allows it to solve difficult cases and also to identify on-the-fly the situations when a particular chiroptical technique is intrinsically not able to provide a reliable AC prediction. This newly developed protocol, was validated using an in-house developed database of chiroptical spectra, i.e. vibrational circular dichroism (VCD) spectra. This database can be access online and is available freely to the entire chiroptical spectroscopy community (and anyone else). The kick-start of a VCD spectra database represented the second main objective of this research project. Since seven different international groups have already contributed spectra to the vcd-machine database, it is clear that the objective of kick-starting a database for the entire community has been accomplished.

These developments were received well by the international chiroptical community. In 2022 and 2023 I delivered oral presentation at the most important conferences in the field of molecular chirality: Circular Dichroism 2022 (CD2022 New York, USA), Vibrational Optical Activity 2022 (VOA7 Edmonton, Canada, where I was an invited speaker), Chirality 2023 Rome, Italy and Circular Dichroism 2023 (CD2023 Hiroshima, Japan). Additionally, five scientific articles have been published so far based on the results obtained during this research project. Particularly noteworthy is the publication documenting and validating the newly developed chiroptical protocol, which was published on the cover of the Angewandte Chemie International Edition — the flagship journal of the German Chemical Society (with an impact factor of 16.8). There are two additional articles that I have coauthored, which should also be highlighted. The first one is the result of the collaboration I had with Dr. Prashant Kumar and Prof. Dr. Nicholas Kotov, both from University of Michigan, USA. This article was published on the cover of the Nature journal, the most important scientific journal in the world (with an impact factor of 69.5). The second article is the result of a collaboration with Prof. Dr. Ben Feringa, winner of the 2016 Nobel Prize in Chemistry. This article was submitted on November 14 to the prestigious Science journal. Finally, it should be noted that we are presently collaborating with seven international groups that are keen on utilising and evaluating our newly developed chiroptical protocol. As a result, more articles are expected to be publishes in 2024.