A Holistic Approach to Determining Stereochemistry of Potential Pharmaceuticals by Circular Dichroism with β-Lactams as Test Cases.

Marcin Górecki,Jadwiga Frelek

doi:10.3390/ijms23010273

Abstract

This paper’s main objective is to show that many different factors must be considered when solving stereochemical problems to avoid misleading conclusions and obtain conclusive results from the analysis of spectroscopic properties. Particularly in determining the absolute configuration, the use of chiroptical methods is crucial, especially when other techniques, including X-ray crystallography, fail, are not applicable, or give inconclusive results. Based on various β-lactam derivatives as models, we show how to reliably determine their absolute configuration (AC) and preferred conformation from circular dichroism (CD) spectra. Comprehensive CD analysis, employing both approaches, i.e., traditional with their sector and helicity rules, and state-of-the-art supported by quantum chemistry (QC) calculations along with solvation models for both electronic (ECD) and vibrational (VCD) circular dichroism ranges, allows confident defining stereochemistry of the β-lactams studied. Based on an in-depth analysis of the results, we have shown that choosing a proper chiroptical method/s strictly depends on the specific case and certain structural features.

Highlights

Unambiguous assignment of the absolute configuration (AC) of compounds isolated from natural sources or synthesized in laboratories continually remains essential in chemistry, biochemistry, structural biology, and medicinal chemistry
Conformational analysis is the fundamental step, as it allows for identifying a set of possible conformers on the potential energy surface (PES) of a molecule, i.e., determining the most stable conformations and their energy
In this study, we conducted a systematic circular dichroic study of structurally different β-lactams to demonstrate the importance of chiroptical methods in practical stereochemical analysis and their effectiveness in determining the absolute configuration

Summary

Introduction

Unambiguous assignment of the absolute configuration (AC) of compounds isolated from natural sources or synthesized in laboratories continually remains essential in chemistry, biochemistry, structural biology, and medicinal chemistry. In recent times CD, in its electronic and vibrational ranges (ECD and VCD, respectively), is becoming an increasingly important and productive research tool because it effectively determines the absolute configuration, conformation, and optical purity of chiral molecules This is evidenced by, for example, the constantly growing number of literature reports on its practical and successful use, such as these few newest links indicated here [9,10,11,12,13,14,15,16,17]. We will denote the strengths and weaknesses of each of the approaches presented and indicate the challenges and prospects for further development of chiroptical methods

General Information on Calculation Methods

Solving Stereochemical Problems Step by Step

Materials and Methods

Computational Section

Conclusions