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Determination of the absolute configuration of chiral molecules is a prerequisite for obtaining a fundamental understanding in any chirality‐related field. The interaction with polarised light has proven to be a powerful means to determine this absolute configuration, but its application rests on the comparison between experimental and computed spectra for which the inherent uncertainty in conformational Boltzmann factors has proven to be extremely hard to tackle. Here we present a novel approach that overcomes this issue by combining a genetic algorithm that identifies the relevant conformers by accounting for the uncertainties in DFT relative energies, and a hierarchical clustering algorithm that analyses the trends in the spectra of the considered conformers and identifies on‐the‐fly when a given chiroptical technique is not able to make reliable predictions. The effectiveness of this approach is demonstrated by considering the challenging cases of papuamine and haliclonadiamine, two bis‐indane natural products with eight chiral centres and considerable conformational heterogeneity that could not be assigned unambiguously with current approaches. [ABSTRACT FROM AUTHOR]

Density Functional Calculations, Absolute configuration, Chiroptical spectroscopies, Genetic algorithm, Hierarchical clustering Keywords: Density Functional Calculations; Absolute configuration; Chiroptical spectroscopies; Genetic algorithm; Hierarchical clustering EN Density Functional Calculations Absolute configuration Chiroptical spectroscopies Genetic algorithm Hierarchical clustering 1 1 1 09/19/23 20230918 NES 230918 B The assignment of the absolute configuration b of chiral compounds critically depends on the comparison with predictions of chiroptical spectra with intrinsically inaccurate quantum chemical calculations. Cover Picture: An Artificial Intelligence Approach for Tackling Conformational Energy Uncertainties in Chiroptical Spectroscopies (Angew. [Extracted from the article]