Absolute Configuration Determination of Chiral API Molecules by MicroED Analysis of Cocrystal Powders Formed Based on Cocrystal Propensity Prediction Calculations**

Shah, Harsh; Yuan, Jiuchuang; Xie, Tian; Yang, Zhuocen; Chang, Chao; Greenwell, Chandler; Zeng, Qun; Sun, Geng; Read, Brandon; Wilson, Timothy; Valle, Henry U.; Kuang, Shan-Ming; Wang, Jian; Sekharan, Sivakumar; Bruhn, Jessica F.

doi:10.1002/chem.202203970

Cited by 2 publications

(2 citation statements)

References 42 publications

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“…Given that this method depends on the particular circumstance of specimens, the cocrystals of chiral molecules can be designed through virtual cocrystal screening. 71 72 PEDT data were automatically collected at multiple positions of the pharmaceutical crystal, which reduced the influence of electron-beam damage. The target structure was ab initio solved and kinematically refined.…”

Section: Convergent-beam Electron Diffraction (Cbed) and Precession E...mentioning

confidence: 99%

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Chirality Determination of Nanocrystals by Electron Crystallography

Wang,

Chu

et al. 2024

J. Phys. Chem. Lett.

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Chirality is a common phenomenon in nature and plays an important role in the properties of matter. The rational synthesis of chiral compounds and exploration of their applications in various fields require an unambiguous determination of their handedness. However, in many cases, determinations of the chiral crystal structure and chiral morphology have been a challenging task due to the lack of proper characterization methods, especially for nanosized crystals. Therefore, it is crucial to develop novel and efficient characterization methods. Owing to the strong interactions between matter and electrons, electron crystallography has become a powerful tool for structural analysis of nanomaterials. In recent years, methods based on electron crystallography, such as high-resolution electron microscopy imaging and electron diffraction, have been developed to unravel the chirality of nanomaterials. This brings new opportunities to the design, synthesis, and applications of versatile chiral nanomaterials. In this perspective, we summarize the recent methodology developments and ongoing research of electron crystallography for chiral structure and morphology determination of nanocrystals, including inorganic and organic materials, as well as highlight the potential and further improvement of these methods in the future.C hirality is a geometric property of a rigid object being nonsuperposable on its mirror image. 1 In nature, chirality is ubiquitous at multiple levels, from subatomic particles, organic molecules such as amino acids, macromolecules including proteins and DNA, macroscopic entities like sea shells, to even spiral galaxies. 2 Chirality has attracted great interest from multidisciplinary fields, including chemistry, biology, pharmacy, and materials science. 3 The Nobel Prize in Chemistry has recognized outstanding research in chiral synthesis and asymmetric catalysis twice in the past two decades. 4,5 In the pharmaceutical industry, more than half of clinical drugs belong to chiral molecules. 6 Moreover, chiral materials exhibit a wide range of exploitable properties, including optical behavior, enantioselectivity, ferroelectricity, electrochemical properties, and biological activity. 7−10 These cumulative factors highlight the significance of studying chirality in various scientific fields.With the rapid development of synthesis and applications of chiral compounds, one important and challenging task becomes prominent: how to effectively characterize the handedness of chiral materials. One of the difficulties is that two enantiomers usually exhibit similar physical and chemical properties, which makes it not easy to distinguish them using common characterization methods. Chirality of nanocrystals can be divided into two categories: chiral morphology and chiral crystal structure (Figure 1). Chiral morphology is a macroscopic property of a material. For example, some chiral materials show a special morphology (such as a helical shape). However, when we talk about chiral crystal structure, it means that the spa...

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Section: Convergent-beam Electron Diffraction (Cbed) and Precession E...mentioning

confidence: 99%

“… However, conducting this approach is heavily reliant on the formation of chiral cocrystals. Given that this method depends on the particular circumstance of specimens, the cocrystals of chiral molecules can be designed through virtual cocrystal screening …”

Section: Electron Diffraction: Chiral Structure Determination In Reci...mentioning

confidence: 99%

Chirality Determination of Nanocrystals by Electron Crystallography

Wang,

Chu

et al. 2024

J. Phys. Chem. Lett.

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Structural Elucidation and Absolute Stereochemistry for Pharma Compounds Using MicroED

de Moraes,

Burch,

Delgadillo

et al. 2024

Org. Lett.

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Microcrystal electron diffraction (microED) is an emerging technique for rapid crystallographic analysis of small molecule micro- and nanocrystals. In this report, we evaluate the applicability of microED to pharmaceutical compounds through the analysis of 30 samples obtained from the process and medicinal chemistry groups at Amgen Inc. Using only 40 h of microscope time, 15 of 30 crystal structures were elucidated. From these crystal structures, all chiral compounds had the correct absolute stereochemistry assigned by dynamical refinement of continuous rotation electron diffraction data, confirming dynamical refinement as a promising tool for the absolute stereochemistry determination of pharmaceutically relevant compounds.

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Absolute Configuration Determination of Chiral API Molecules by MicroED Analysis of Cocrystal Powders Formed Based on Cocrystal Propensity Prediction Calculations**

Cited by 2 publications

References 42 publications

Chirality Determination of Nanocrystals by Electron Crystallography

Chirality Determination of Nanocrystals by Electron Crystallography

Structural Elucidation and Absolute Stereochemistry for Pharma Compounds Using MicroED

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