Good Computational Practice in the Assignment of Absolute Configurations by TDDFT Calculations of ECD Spectra

Abstract

Quantum-mechanical calculations of chiroptical properties have rapidly become the most popular method for assigning absolute configurations (AC) of organic compounds, including natural products. Black-box time-dependent Density Functional Theory (TDDFT) calculations of electronic circular dichroism (ECD) spectra are nowadays readily accessible to nonexperts. However, an uncritical attitude may easily deliver a wrong answer. We present to the Chirality Forum a discussion on what can be called good computational practice in running TDDFT ECD calculations, highlighting the most crucial points with several examples from the recent literature. Chirality 28:466-474, 2016. © 2016 Wiley Periodicals, Inc.

Varioloid A, a new indolyl-6,10b-dihydro-5aH-[1]benzofuro[2,3-b]indole derivative from the marine alga-derived endophytic fungus Paecilomyces variotii EN-291

“…These conformers were reoptimized at two different DFT levels, namely B3LYP/6-31G(d) in vacuo and B97D/TZVP [16–17] with a Polarizable Continuum Model (PCM) for MeCN [18]. The B3LYP optimization yielded 10 low-energy conformers above 2% Boltzmann population, while the number of low-energy conformers was 14 at the applied B97D level (Fig.…”

Hydroquinone derivatives from the marine-derived fungus Gliomastix sp.

“…1) To determine the absolute conguration of 1, the solution TDDFT-ECD method was applied on the arbitrarily chosen (5S,6R,8S,7 0 R)-1 enantiomer. 18,19 The 14 MMFF conformers obtained in the conformational search of the NMR calculations were reoptimized at the B3LYP/6-31G(d), B97D/TZVP 20,21 PCM/ MeCN and CAM-B3LYP/TZVP 22,23 PCM/MeCN levels and ECD computations were performed for the low-energy conformers with various functionals (B3LYP, BH&HLYP, CAM-B3LYP, PBE0) combined with the TZVP basis set. Computed ECD spectra obtained at all of the applied combination of levels gave moderate to good mirror-image agreement with the experimental spectrum, allowing determination of the absolute conguration of 1 as (5R,6S,8R,7 0 S) (Fig.…”

Reassignments and Corroborations of Oxo‐Bridged Natural Products Directed by OSE and DU8+ NMR Computation

“…[1] However,m isinterpretations of spectroscopic and/or physical data have often been known to result in structural misassignments.S uch occurrences are particularly prevalent in the natural product (NP) arena, where complex atom connectivities and stereochemical complexity abound. [3] There are now numerous in silico methods to help with structure elucidation by predicting spectra (e.g., NMR, [4] ECD [5] )from chemical structure input or conversely by predicting chemical structure from spectroscopic data (e.g.,A CDLabs [6] ). [3] There are now numerous in silico methods to help with structure elucidation by predicting spectra (e.g., NMR, [4] ECD [5] )from chemical structure input or conversely by predicting chemical structure from spectroscopic data (e.g.,A CDLabs [6] ).…”

“…[14] To adapt this protocol to oxo-bridged bicyclica lkenes (i.e., structures with an oxygen atom directly connected to the double bond within the bicyclicf ramework), fifteen bicyclic oxo-bridged alkenes were chosen as shown in Figure 2. Five structures (5,8,10,13,17)a re analogues of molecules contained in the original hydrocarbon calibration set. Themolecules span abroad range of OSEs (i.e., from À3.9 to 24.7 kcal mol À1 ).…”