Chirality determination in crystals

Valentín-Pérez, Ángela; Hillard, Elizabeth A.; Giorgi, Michel

doi:10.1002/chir.23377

Cited by 19 publications

(20 citation statements)

References 125 publications

(214 reference statements)

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“…As a consequence, a complete stereochemical elucidation, including the assignment of the absolute configuration (AC), is a necessary requirement in natural products isolation and drug discovery. By far, the most accurate method for assigning ACs is x‐ray diffraction 3–5 . This method is however restricted to crystalline materials of compounds containing “heavy” elements, that is, exhibiting strong enough anomalous dispersion.…”

Section: Introductionmentioning

confidence: 99%

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ECD exciton chirality method today: a modern tool for determining absolute configurations

Pescitelli

2021

Chirality

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The application of the exciton chirality method (ECM) to interpret electronic circular dichroism (ECD) spectra is a well-established and still popular approach to assign the absolute configuration (AC) of natural products, chiral organic compounds, and organometallic species. The method applies to compounds containing at least two chromophores with electric dipole allowed transitions (e.g., π-π* transitions). The exciton chirality rule correlates the sign of an exciton couplet (two ECD bands with opposite sign and similar intensity) with the overall molecular stereochemistry, including the AC. A correct application of the ECM requires three main prerequisites: (a) the knowledge of the molecular conformation, (b) the knowledge of the directions of the electric transition moments (TDMs), and (c) the assumption that the exciton coupling mechanism must be the major source of the observed ECD signals. All these prerequisites can be easily verified by means of quantum-mechanical (QM) calculations. In the present review, we shortly introduce the general principles that underpin the use of the ECM for configurational assignments and survey its applications, both classic ones and some reported in the recent literature. Based on these examples, we will stress the advantages of the ECM but also the key requisites for its correct application. Additionally, we will discuss the dependence of the couplet sign on geometrical parameters (angles α,β,γ between TDMs), which can be helpful for discerning the sign of exciton chirality in ambiguous situations. Finally, we will present a molecular orbital (MO) description of the exciton coupling phenomenon.

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Section: Introductionmentioning

confidence: 99%

“…By far, the most accurate method for assigning ACs is x-ray diffraction. [3][4][5] This method is however restricted to crystalline materials of compounds containing "heavy" elements, that is, exhibiting strong enough anomalous dispersion.…”

Section: Introductionmentioning

confidence: 99%

ECD exciton chirality method today: a modern tool for determining absolute configurations

Pescitelli

2021

Chirality

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“…Although a chiral structure can occur in any of the 65 Sohncke space groups, the ACPA enantiomers crystallize within the 22 chiral space groups forming enantiomorphous pairs, P 4 1 2 1 2 and P 4 3 2 1 2, characterized by screw axes of opposite handedness. Notably, the occurrence of tetragonal space groups among chiral substances is scarce, mainly dominated by P 2 1 (monoclinic) and P 2 1 2 1 2 1 (orthorhombic) Sohncke groups, neither being inherently chiral space groups. , The positive effect of one or more binary screw axes to accommodate pure enantiomers has been related to an optimal close-packing favored by electrostatic interactions. In fact, the binary axis along with glide planes also occurs in the most frequently encountered groups for racemic crystals, mostly belonging to the P 2 1 / c systems…”

Section: Resultsmentioning

confidence: 99%

Revisiting HomochiralversusHeterochiral Interactions through a Long Detective Story of a Useful Azobis-Nitrile and Puzzling Racemate

García de la Concepción,

Flores-Jiménez,

Cuccia

et al. 2023

Crystal Growth & Design

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This paper documents and reinvestigates the solid-state and crystal structures of 4,4′-azobis-4-cyanopentanoic acid (ACPA), a water-soluble azobis-nitrile of immense utility as a radical initiator in living polymerizations and a labile mechanophore that can be embedded within long polymer chains to undergo selective scission under mechanical activation. Surprisingly, for such applications, both the commercially available reagent and their derivatives are used as “single initiators” when this azonitrile is actually a mixture of stereoisomers. Although the racemate and meso compounds were identified more than half a century ago and their enantiomers were separated by classical resolution, there have been confusing narratives dealing with their characterization, the existence of a conglomeratic phase, and fractional crystallization. Our results report on the X-ray crystal structures of all stereoisomers for the first time, along with further details on enantiodiscrimination and the always intriguing arguments accounting for the stability of homochiral versus heterochiral crystal aggregates. To this end, metadynamic (MTD) simulations on stereoisomer molecular aggregates were performed to capture the incipient nucleation events at the picosecond time scale. This analysis sheds light on the driving homochiral aggregation of ACPA enantiomers.

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“…X-ray single-crystal diffraction (XRSCD) is regarded as the most reliable strategy for absolute configuration determination. Differences in the X-ray anomalous scattering effect of each atom are used to determine the absolute configuration of molecules and can provide the precise spatial position of all of the atoms in a compound in the solid state, including how the atoms are connected, the molecular conformation, and accurate bond length and bond angle data [ 10 ]. The strength of the anomalous scattering effect is proportional to the electron cloud density of the atom, which is manifested as the stronger anomalous scattering effect of the atom with a larger atomic number [ 11 , 12 ].…”

Section: X-ray Single-crystal Diffraction (Xrscd)mentioning

confidence: 99%

Approaches to Configuration Determinations of Flexible Marine Natural Products: Advances and Prospects

et al. 2022

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Flexible marine natural products (MNPs), such as eribulin and bryostatin, play an important role in the development of modern marine drugs. However, due to the multiple chiral centers and geometrical uncertainty of flexible systems, configuration determinations of flexible MNPs face great challenges, which, in turn, have led to obstacles in druggability research. To resolve this issue, the comprehensive use of multiple methods is necessary. Additionally, configuration assignment methods, such as X-ray single-crystal diffraction (crystalline derivatives, crystallization chaperones, and crystalline sponges), NMR-based methods (JBCA and Mosher’s method), circular dichroism-based methods (ECCD and ICD), quantum computational chemistry-based methods (NMR calculations, ECD calculations, and VCD calculations), and chemical transformation-based methods should be summarized. This paper reviews the basic principles, characteristics, and applicability of the methods mentioned above as well as application examples to broaden the research and applications of these methods and to provide a reference for the configuration determinations of flexible MNPs.

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Chirality determination in crystals

Cited by 19 publications

References 125 publications

ECD exciton chirality method today: a modern tool for determining absolute configurations

ECD exciton chirality method today: a modern tool for determining absolute configurations

Revisiting HomochiralversusHeterochiral Interactions through a Long Detective Story of a Useful Azobis-Nitrile and Puzzling Racemate

Approaches to Configuration Determinations of Flexible Marine Natural Products: Advances and Prospects

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