Stereochemical analysis of β‐keto sulfoxides by circular dichroism

Abstract

Three β-keto sulfoxides (1-3) were synthesized in enantiopure form and investigated by means of circular dichroism (CD) spectroscopy, both in electronic and vibrational range (ECD, VCD), in combination with quantum chemical calculations. For compound 2, the X-ray structure was available; thus, the ECD in the solid state was also considered to reveal the differences between the molecular species in both states. Despite the simplicity of all β-keto sulfoxides under investigation (29 atoms), reproducing even the major spectral VCD features failed for two compounds, making the use of VCD not ideal to assign their absolute configuration in a reliable way. We demonstrated, however, that the use of ECD spectroscopy, both in solution and solid state, can easily, unambiguously, and without any complication simulate all bands by applying the standard protocol for calculations. This study may stimulate the debate on the need of the use of two chiroptical methods simultaneously in the determination of absolute configurations.

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

“…To ensure that the obtained results are comparable, we also simulated the electronic and vibrational CD spectra at different levels of approximation; however, for the discussion here, we selected only the ones that demonstrate the best fit with the experimental spectra, i.e., obtained at the ωB97X-D/6–311+G(d,p) level of theory with the PCM solvent model. Additional motivation for using this approximation level was prior identification of its effectiveness and accuracy in reproducing chiroptical spectral features of various organic molecules of synthetic and natural origin [ 26 , 39 , 40 , 41 , 42 , 43 , 44 ]. In our previous work on β-lactams, we also showed that using the PCM solvent model significantly impacted the assignments’ credibility [ 22 , 31 , 33 , 45 , 46 , 47 ].…”

“…Usually, VCD provides in-depth knowledge of molecular interactions due to its higher sensitivity to local molecules’ changes [ 50 ]. Other oxacepham 5 -like cases in which stereochemical analysis using VCD fails in contrast to the ECD method are also known in the literature [ 26 ]. Nevertheless, the positive sign of the decisive ECD band in both experimental and Boltzmann-averaged ECD spectra of oxacepham 5 and the very satisfactory agreement between both curves in the long-wavelength range corroborates the correctness of the ECD-based assignment for the C6 carbon atom.…”

“…Consequently, two theoretically assisted chiroptical techniques are highly recommended for routine use as, in some cases, this is the only way to identify the spatial structure correctly [ 15 , 21 , 22 , 23 , 24 , 25 ]. However, relatively often, one can come across cases when the combined use of ECD and VCD is impossible or ineffective [ 26 ]. Such circumstances are mainly driven by limitations of the given method and the structural complexity of samples tested and/or their interactions with the solvent.…”

A Critical Appraisal of Dimolybdenum Tetraacetate Application in Stereochemical Studies of vic-Diols by Circular Dichroism

“…14 Sometimes problems also arise with the reproducibility of VCD experimental spectra and simulated by DFT calculations. 17,20 The main reasons for this may be the sensitivity of the chiroptical response to any structural changes, even leading occasionally to qualitative deviations from the experiment, 20,21 or high sensitivity to environmental changes such as solvent effect and selfaggregation. 22,23 In the case of, for example, tolterodine, a potent muscarinic receptor antagonist, the lack of conformity between theory and experiment is explained by possible solute aggregation in the chosen solvent and concentration required for VCD measurement.…”

“…Examples of such compounds are principally natural products, because often their available amounts, as isolated from natural sources, are insufficient to perform reliable VCD measurements . Sometimes problems also arise with the reproducibility of VCD experimental spectra and simulated by DFT calculations. , The main reasons for this may be the sensitivity of the chiroptical response to any structural changes, even leading occasionally to qualitative deviations from the experiment, , or high sensitivity to environmental changes such as solvent effect and self-aggregation. , In the case of, for example, tolterodine, a potent muscarinic receptor antagonist, the lack of conformity between theory and experiment is explained by possible solute aggregation in the chosen solvent and concentration required for VCD measurement . On the other hand, in the case of natural products without a suitable chromophoric system in the skeleton, its absence makes them silent in ECD, thus preventing the use of this chiroptical method.…”