Absolute configurations of chiral molecules with multiple stereogenic centers without prior knowledge of the relative configurations: A case study of inuloxin C

Abstract

Electronic circular dichroism (ECD) and discrete wavelength resolved specific optical rotations, referred to as optical rotatory dispersion (ORD), have been remeasured for inuloxin C and analysed with corresponding quantum chemical (QC) predicted data for all diastereomers of inuloxin C. The QC‐predicted sign of ORD and of a major ECD band are found to match the experimental observations for more than one diastereomer. However, these ECD and ORD analyses combined with electronic dissymmetry factor analyses narrowed the choices of absolute configuration (AC) of inuloxin C to (5R,7S,8R,10R) and (5S,7S,8S,10S). Supplementing these analyses with corresponding analyses for acetylated inuloxin C resulted in a unique choice for the AC of inuloxin C as (5S,7S,8S,10S). This result is independent of NMR analysis. Furthermore, this AC is in full agreement with previously determined relative configuration by NMR and the AC derived therefrom using ECD and ORD. Therefore, the present study identifies a pathway for determining the ACs of chiral molecules with multiple stereogenic centers when relative configurations are not known, or when it is desired to deduce ACs independent of the known relative configurations.

Further secondary metabolites produced by the fungus Pyricularia grisea isolated from buffelgrass (Cenchrus ciliaris)

“…A computational conformational analysis of 1 and 2 was then carried out taking into account the (3R*,4S*)-1 and (3S*,4S*)-2 relative configurations established by NMR (vide supra). In this case, being the relative configuration known, it is possible to avoid to carry out computation on all diastereomers 37 considering only a single pair of enantiomers for the analysis.…”

Dissymmetry Factor Spectral Analysis Can Provide Useful Diastereomer Discrimination: Chiral Molecular Structure of an Analogue of (−)-Crispine A

“…41,42 To ascertain if the chiroptical spectroscopic methods by themselves can provide enough diastereomer discrimination and determine the AC without depending on prior knowledge of relative configuration information, or of ACs at some of the stereogenic centers, one has to undertake QC predictions of chiroptical spectra for all possible diastereomers and evaluate if the correct diastereomer can be ascertained. 43−46 For this purpose, we have undertaken conformational analysis and QC predictions for all possible diastereomers. Due to the presence of three chiral centers, eight diastereomers are possible for 5 .…”

“…Thus, the criterion of matching the predicted ORD with the experimental ORD alone cannot be used as the sole criterion for assigning the unknown ACs of chiral molecules. 46…”

“…To recognize new opportunities, and any limitations, chiroptical spectroscopic predictions should be undertaken for all possible diastereomers (regardless of the availability of prior knowledge on relative configurations), as recommended previously. 43−46…”

Chiroptical Sensing: A Conceptual Introduction

“…The stable MM-identified geometries within~10-20 kcal/mol energy window [56], depending on the intrinsic degrees of freedom, are subsequently fully optimized under appropriate quantum mechanical levels of theory. For larger molecular systems, it is not uncommon to first apply semi-empirical AM1 or PM3 methods, followed by full geometry optimization at a higher ab initio level of theory.…”