Methodology for the Absolute Configuration Determination of Epoxythymols Using the Constituents of Ageratina glabrata

Abstract

A methodology to determine the enantiomeric excess and the absolute configuration (AC) of natural epoxythymols was developed and tested using five constituents of Ageratina glabrata. The methodology is based on enantiomeric purity determination employing 1,1'-bi-2-naphthol (BINOL) as a chiral solvating agent combined with vibrational circular dichroism (VCD) measurements and calculations. The conformational searching included an extensive Monte Carlo protocol that considered the rotational barriers to cover the whole conformational spaces. (+)-(8S)-10-Benzoyloxy-6-hydroxy-8,9-epoxythymol isobutyrate (1), (+)-(8S)-10-acetoxy-6-methoxy-8,9-epoxythymol isobutyrate (4), and (+)-(8S)-10-benzoyloxy-6-methoxy-8,9-epoxythymol isobutyrate (5) were isolated as enantiomerically pure constituents, while 10-isobutyryloxy-8,9-epoxythymol isobutyrate (2) was obtained as a 75:25 (8S)/(8R) scalemic mixture. In the case of 10-benzoyloxy-8,9-epoxythymol isobutyrate (3), the BINOL methodology revealed a 56:44 scalemic mixture and the VCD measurement was beyond the limit of sensitivity since the enantiomeric excess is only 12%. The racemization process of epoxythymol derivatives was studied using compound 1 and allowed the clarification of some stereochemical aspects of epoxythymol derivatives since their ACs have been scarcely analyzed and a particular behavior in their specific rotations was detected. In more than 30 oxygenated thymol derivatives, including some epoxythymols, the reported specific rotation values fluctuate from -1.6 to +1.4 passing through zero, suggesting the presence of scalemic and close to racemic mixtures, since enantiomerically pure natural constituents showed positive or negative specific rotations greater than 10 units.

Vibrational Circular Dichroism Absolute Configuration of Natural Products From 2015 to 2019

“…Monoterpenoids 19 and 20 ( Figure 4), and dextrorotatory oxocycloneroledol (29) (Figure 7), a main constituent of the leaf oil (49.4 to 55.6%) of Bubonium graveolens, was separated on a chiral HPLC column. The VCD spectrum provided its AC as (+)-(2R,6R)−29 after solvation model density (in CCl 4 ) B3LYP/6-31G(d,p) DFT calculations.…”

Antioxidant and Leishmanicidal Evaluation of Pulicaria Inuloides Root Extracts: A Bioguided Fractionation

“…The active F1B fraction (36 mg) was purified on a preparative silica gel thin layer chromatography (PTLC), using mixtures of hexanes-ethyl acetate (50:50) to obtain sub-fractions F1B1-F1B3. Sub-fraction F1B3 yielded compound 1, as a pale yellow amorphous solid (10 mg), which was identified as 10-isobutyryloxy-8,9-epoxy-thymol isobutyrate by comparison of its spectroscopic and spectrometric data with those previously reported [23,24].…”

“…Therefore, spectrometric and spectroscopic studies, including 1D-and 2D-NMR spectra (Supplementary Materials, Figures S2-S6), led to the characterization of F1B3 as 10-isobutyryloxy-8,9-epoxy-thymol isobutyrate (1) [23] as an enantiomeric mixture with around a 75:25 scalemic proportion as determined by the integration of the signals in its 1 HNMR spectrum. Previously, the absolute configuration and scalemic proportion determination of epoxy-thymol derivatives using (S)-BINOL as a chiral solvating agent combined with vibrational circular dichroism (VCD) studies has been reported [24]. By applying this methodology the authors determined the enantiomeric ratio of this expoxy-thymol derivative as (8S:8R)-(75:25 er) with specific rotation value [α] 436 +18.9.…”

Conformational, configurational, and supramolecular studies of podocephalol acetate from Lasianthaea aurea

“…Despite these reports, conformational analyses have not been described for ar-himachalanes, but they are available for himachalenes. 22,[25][26][27][28][29] Consequently, a deeper understanding of the preferred conformation of 2 was gained through DFT computational calculations, a methodology successfully employed in conformational and configurational studies of natural terpenes 30 and terpene derivatives. 31 Thus, a model of 2 was built using the Spartan'04 software, and a conformational distribution analysis by the Monte Carlo protocol was undertaken.…”

“…The optimal anharmonicity factor (anH) was 1.011, which is in concordance with values for correcting IR, Raman, and VCD calculations of organic compounds [36][37][38] due to underestimated vibration frequencies (around 20 cm −1 ) 39 inherent to the PBEPBE functional. 40,41 This functional has been used successfully when calculating some molecules possessing an aromatic ring, like epoxythymols 30,42 and an aporphine alkaloid, 43 for which the anharmonicity factor was always above the unit, specifically in the 1.002-1.020 range. Anharmonicity factors above the unit are not exclusive for the PBEPBE functional, as a 1.007 value became evident when myrtenal was calculated at the B3PW91/DGTZVP level of theory.…”