Vibrational Circular Dichroism Similarity-Guided Absolute Configuration Determination of 11-Acyloxytremetones

Abstract

Although tremetone [5-acetyl-2-(1-methylvinyl)-2,3-dihydrobenzofuran] has only one stereogenic center, the absolute configuration (AC) determination of its naturally occurring 11-acyloxy derivatives 1 and 2 by vibrational circular dichroism (VCD) turned out to be difficult. Similarity-based comparison of the experimental VCD spectrum of 11-coumaryloxytremetone (1), isolated from Parastrephia quadrangularis, with spectra calculated using popular density functional theory (DFT) levels of theory, provided poor enantiomeric similarity indices ( ESI), even when the p-coumaroyl ester group of 1 was replaced by the acetyl group in 2. In search for a better understanding of these results, IR-guided individual scaling factors (ISFs), recently introduced as part of the Vibrational Spectra Similarity and Analysis Tool (VISSAT) software, were used to correct DFT frequencies, while a VCD-guided conformational analysis was developed to explore conformational preferences. These studies showed that for both molecules 72% of the individual conformations gave ESI values in favor of the ( R) enantiomer. Likewise, when conformer abundances were optimized to produce the best possible similarity for each enantiomer, the obtained ESI values were always larger for the ( R) isomer than for the ( S) isomer. These results point toward the ( R) AC in both compounds and highlight the incorrect conformer abundance prediction by DFT calculations as the potential source of the initial difficulties. In addition, the AC of 1 was independently verified using the Flack and Hooft parameters gained after a single-crystal x-ray diffraction (XRD) study.