Difficulties to Determine the Absolute Configuration of Guaiaretic Acid

Natural Product Communications

2021

Self Cite

Although demonstrated in 1975, vibrational circular dichroism (VCD) finally started to popularize during this century as a reliable tool to determine the absolute configuration (AC) of organic molecules. This research field continues to be a very dynamic one, in particular for the study of natural products which are a unlimited source of chiral molecules. It therefore turns of interest to summarize the accomplishments published in recent years and to comment on some eventual difficulties that emerged in rare cases to complete the AC determination task. Therefore the aim of this review is to update VCD results for the AC assignment of natural products published from 2015 to 2019, a period in which VCD was reported in some 126 publications involving almost 300 molecules. They are organized according the type of studied metabolite allowing an easily search. The molecules correspond to 28 monoterpenes concerning 17 papers, to 42 sesquiterpenes in 14 papers, to 51 diterpenes in 19 publications, to 5 other terpenoids in three papers, to 48 aromatic molecules in 15 reports, to 20 polyketides in 10 publications, to 27 miscellaneous formulas also in 10 papers, and to 76 nitrogen containing compounds, which include alkaloids and their synthetic analogs, in 38 articles. The landscape of reviewed molecules is quite wide as it goes from simple monoterpenes, like borneol or camphor, to very relevant biological molecules like the alkaloid cocaine or tadalafil samples to distinguish genuine and counterfeit Cialis®. In addition, 5 natural products and a simple derivative published outside the reviewed period, were used to illustrate some aspects of density functional theory calculations.

Section: Resultsmentioning

confidence: 99%

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

Río

Natural Product Communications

2021

Self Cite

“…In certain sense, this is indicative of the ISF that would be required for a perfect fit. This methodology was used for guaiaretic acid diacetate 19 after the failure of classic approaches.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…It is just of further relevance to mention that they are in line with other natural products cases like perezone 17,18 and guaiaretic acid diacetate. 19…”

Section: Resultsmentioning

confidence: 99%

“…16 These low energy modes, that can be characterized as internal rotations of functional groups, rather than as molecular vibrations, could be the main source of the difficulties found herein and in other cases. [17][18][19] Alternatively, applying the same principle used by VISSAT to obtain a set of ISF values that maximizes IR similarity, it is also possible to search for the optimal linear combination that maximizes similarity between observed and calculated VCD spectra. Since enantiomers produce antipode VCD spectra, the searches need to be performed independently for each enantiomer, producing separated similarity values for the (R) and the (S) enantiomer.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

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

Muñoz

Simirgiotis

Natural Product Communications

2022

Self Cite

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.

Vibrational circular dichroism enantiomeric similarity index improvement for absolute configuration discrimination using individual infrared scaling factors

Muñoz

2022

Chirality

The use of IR individual scaling factors (ISF) for the correction of DFT‐calculated frequencies, and its effect on IR and VCD similarity functions, has been evaluated using (+)‐(R)‐3‐methylcyclopentanone as a probe molecule. Contrary to using a single scaling factor to improve spectra matching, this approach sequentially searches for the optimal scaling factor for each calculated transition using a computational search algorithm to maximize the overlap of the calculated and observed IR spectra expressed as the IR similarity (SIR) function. The obtained ISFs are then applied to the calculated frequencies, which are used to produce a scaled VCD spectrum for comparison with the observed trace, thereby yielding enantiomeric similarity index (ESI) values as a similarity measure. This procedure provides a significant improvement of the SIR and ESI values when compared with the use of a single scale factor, showing 15.1% and 34.1% in average increments, respectively, and values as high as 0.98 and 0.94, respectively. When a set of manually found ISFs is used, most differences in SIR and ESI performance disappear, and nearly perfect spectra matches are found throughout the levels of theory tested. This suggests that the observed differences in computed IR/VCD spectra with commonly used levels of theory are related to differences in frequency rather than to intensity accuracy. Finally, the use of ISFs is expected to enhance the ability to aide stereochemical assignments, particularly in cases where sufficiently accurate frequencies are difficult to obtain due to the system size or complexity.