Solvation effects on the chiroptical properties of austdiol investigated by TD-DFT calculations and ab initio MD simulations

Time-dependent density functional theory (TD-DFT) has become the standard method for chiroptical properties calculations on small-to-medium sized molecules, due to the reasonable balance between chemical accuracy and computational efficiency [1]. However, the intrinsic shortcomings of TD-DFT methods and the high demands in terms of computational resources are still limiting a broader applicability to pharmaceutically relevant systems [2]. The description of solvation is arguably one of the most challenging tasks in computational chiroptical spectroscopy [3]; solvation may exert its influence on chiroptical properties at several levels, such as electric perturbations to the electronic transitions and conformational perturbations due to weak intermolecular interactions. TD-DFT calculations are then very likely to fail in predicting the correct properties if solvation is not accurately described. The fungal metabolite austdiol is the building block of a series of newly discovered natural products from Mycoleptodiscus indicus, named mycoleptones A–C; the stereochemistry of mycoleptone A was fully characterised by a combination of ECD and NMR spectroscopies, TD-DFT calculations and X-ray crystallography [4]. Austdiol, however, shows the importance of a proper description of solvation effects for a correct stereochemical characterisation: when solvation is only described with a continuum solvation model, the wrong absolute configuration (AC) is predicted from the calculated [α]D values. When solvation is treated explicitly through ab initio molecular dynamics (AIMD) simulations of the solvation dynamics of austdiol in methanol, the description of the chiral environment around the carbonyl chromophores is dramatically improved, and TD-DFT calculations are able to reproduce the experimental chiroptical properties with high accuracy. The improvement is mainly due to a small conformational change involving the hydroxyl group in α-position to the ketone moiety of austdiol, confirming the extreme sensitivity of chiroptical properties to small perturbations to the molecular geometry. The constant improvement of theoretical models and methods, both in terms of reliability and computational requirements, is a very promising path towards chemical accuracy, which will also benefit stereochemical and pharmaceutical analysis in the investigation of non-trivial effects on chiroptical properties in solvated systems and in the characterisation of the relationship between the AC and the biological activity of complex chiral drugs. [1] Autschbach, J. Computing Chiroptical Properties with First-Principles Theoretical Methods: Background and illustrative examples. Chirality 2009, 21, E116-E152. [2] Goerigk, L.; Kruse, H.; Grimme, S. Theoretical Electronic Circular Dichroism Spectroscopy of Large Organic and Supramolecular Systems. In Comprehensive chiroptical spectroscopy, vol. 1; Berova, N., Polavarapu, P. L., Nakanishi, K., Woody, R. W., Eds.; Hoboken: Wiley & Sons, 2012; pp 643-673. [3] Mennucci, B.; Cappelli, C.; Cammi, R.; Tomasi, J. Modeling Solvent Effects on Chiroptical Properties. Chirality 2011, 23, 717-729. [4] Andrioli, W.J.; Conti, R.; Araújo, M.J.; et al.. Mycoleptones A–C and Polyketides from the Endophyte Mycoleptodiscus indicus. J. Nat. Prod. 2014, 77, 70-78.