Determination of Relative Configuration from Residual Chemical Shift Anisotropy

Nath, Nilamoni; Schmidt, Manuel; Gil, Roberto R.; Williamson, R. Thomas; Martin, Gary E.; Navarro‐Vázquez, Armando; Griesinger, Christian; Liu, Yizhou

doi:10.1021/jacs.6b04082

Cited by 89 publications

(155 citation statements)

References 52 publications

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“…The scaling parameter for this procedure can be optimized along with the alignment tensor during the SVD fitting procedure, simplifying and unbiasing the use of the protocol while still retaining the capability to discriminate relative configuration. As became obvious with the example of 10‐epi‐8‐deoxycumambrin B, the assumption for the isotropic correction introduced in Nath and coworker's study is shown to be wrong due to anisotropic distribution of CSA tensors in the molecule. This prevented the determination of the correct configuration.…”

Section: Discussionmentioning

confidence: 96%

“…In a recent collaborative work, some of us, with other collaborators, presented two robust approaches to measure RCSAs based on the use of polymethylmethacrylate (PMMA) gels . The first one was based on a device developed by Liu and Prestegard that uses a tube with two parts of different diameter that is open at both ends.…”

Section: Introductionmentioning

confidence: 99%

“…By measuring the chemical shift difference

normalΔ δ_{\min}^{i} - normalΔ δ_{iso}^{i}

between these signals, the effect of the gel on the isotropic chemical shift of each signal i can be estimated. When going from the minimum to the maximum compression state, the ratio between the concentration of the polymer gel and the solvent increases, and therefore, the isotropic component of the signals changes its chemical shift . Then, it was assumed that the isotropic contribution to the

normalΔ δ_{\max}^{i} - normalΔ δ_{\min}^{i}

shift difference is proportional, first, to the degree of compression and, second, to the observed chemical shift changes between outside and inside the polymer gel when in its relaxed state.…”

Section: Introductionmentioning

confidence: 99%

“…The proportionality constant c is determined on the basis that, for a sufficiently large number of sp 3 carbon signals, their associated CSA tensor principal frames equally span all the three‐dimensional space, and thus, their mean RCSA should be zero. Under this condition, the constant c can be computed, from Equation , as an average of the observed shifts over all the sp 3 carbons according to Nath and coworkers

c = \frac{{\overset{normalΔ δ_{\max}^{i} - normalΔ δ_{\min}^{i}}{true}}^{{sp}^{3}}}{{\overset{normalΔ δ_{\min}^{i} - normalΔ δ_{iso}^{i}}{true}}^{{sp}^{3}}} .

…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Measurement of residual chemical shift anisotropies in compressed polymethylmethacrylate gels. Automatic compensation of gel isotropic shift contribution

Hallwass

Teles

Hellemann

et al. 2018

Magnetic Reson in Chemistry

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Mechanical compression of polymer gels provides a simple way for the measurement of residual chemical shift anisotropies, which then can be employed, on its own, or in combination with residual dipolar couplings, for structural elucidation purposes. Residual chemical shift anisotropies measured using compression devices needed a posteriori correction to account for the increase of the polymer to solvent ratio inside the swollen gel. This correction has been cast before in terms of a single-free parameter which, as shown here, can be simultaneously optimized along with the components of the alignment tensor while still retaining discriminating power of the different relative configurations as illustrated in the stereochemical analysis of α-santonin and 10-epi-8-deoxycumambrin B.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

“…By measuring the chemical shift difference

normalΔ δ_{\min}^{i} - normalΔ δ_{iso}^{i}

normalΔ δ_{\max}^{i} - normalΔ δ_{\min}^{i}

shift difference is proportional, first, to the degree of compression and, second, to the observed chemical shift changes between outside and inside the polymer gel when in its relaxed state.…”

Section: Introductionmentioning

confidence: 99%

c = \frac{{\overset{normalΔ δ_{\max}^{i} - normalΔ δ_{\min}^{i}}{true}}^{{sp}^{3}}}{{\overset{normalΔ δ_{\min}^{i} - normalΔ δ_{iso}^{i}}{true}}^{{sp}^{3}}} .

…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Measurement of residual chemical shift anisotropies in compressed polymethylmethacrylate gels. Automatic compensation of gel isotropic shift contribution

Hallwass

Teles

Hellemann

et al. 2018

Magnetic Reson in Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, the possibility to perform NMR experiments in anisotropic media allows the exploration of interesting interactions, such as residual dipolar couplings (RDCs) and residual chemical shift anisotropy (RCSAs), which can be highly valuable for structural determination purposes. 5 The use of computerassisted structural elucidation (CASE) programs has been significantly helpful to handle information provided by different NMR experiments and transform it into a plausible 2D, or even 3D, structure. 6 All in all, NMR spectroscopy has advanced to such a stage that nowadays we can routinely run NMR experiments that would have been unthinkable some years ago.…”

Section: Introductionmentioning

confidence: 99%

Computer-Guided Total Synthesis of Natural Products. Recent Examples and Future Perspectives

Della‐Felice¹,

Pilli²,

Sarotti³

2018

J. Braz. Chem. Soc.

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Quantum chemical calculations of nuclear magnetic resonance (NMR) shifts and coupling constants have been extensively employed in recent years mainly to facilitate structural elucidation of organic molecules. When the results of such calculations are used to determine the most likely structure of a natural product in advance, guiding the subsequent synthetic work, the term "computer-guided synthesis" could be coined. This review article describes the most relevant examples from recent literature, highlighting the scope and limitations of this merged computational/experimental approach as well.

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Advances in NMR‐Based Characterization of Drug Substances, Impurities, Degradants, and Drug Metabolites

Saurí

Reibarkh

Williamson

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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In the approximately 70 years since the first reports of experiments that led to what is now known as nuclear magnetic resonance or NMR spectroscopy, the technique has become the cornerstone of molecular structure characterization. From the isolation of strychnine to the confirmation of its complex structure in a total synthesis reported by Woodward consumed a century and a half. In contrast, using a modern 600 MHz NMR instrument equipped with a 1.7 mm MicroCryoProbe™, that task can now be accomplished in 24 hours, including the acquisition of 15 N chemical shift information on a few milligrams of sample. Such is the magnitude of the advances that have been made in the discipline. This article is not intended to make NMR spectroscopists out of a practicing medicinal chemistry; rather, the article is intended to acquaint the reader with recent advances in NMR techniques that are making it possible to successfully and unequivocally characterize ever increasingly more complex structures being synthesized in the laboratory as potential drug candidates or isolated from nature. Our goal was to augment the NMR knowledge of the medicinal chemist, better equipping him or her to more effectively interact with the NMR spectroscopy staff at the chemist's facility. The article begins with a discussion of new experimental methods that allow the acquisition of broadband decoupled 1 H NMR spectra that resemble an 1 H‐decoupled 13 C spectrum, with every proton resonance reduced to a singlet. Pure‐shift heteronuclear shift correlation methods are described next, followed by new long‐range heteronuclear chemical shift correlation experiments and then hyphenated techniques to identify components of complex, overlapped proton homonuclear spin systems. Techniques are also described for the unequivocal identification of vicinal neighbor carbon resonances that can be invaluable when dealing with complex impurities or degradation products. Covariance NMR data processing methods that allow 2D NMR experiments to be treated as large numerical matrices that can be manipulated using matrix algebraic operations are briefly discussed. Finally, anisotropic NMR methods are considered, which afford investigators the means of orthogonally verifying chemical structure constitution and configuration without investigator bias that often can lead to erroneously assigned structures. The latter eventuality, of course, can slow development timelines or could potentially have devastating patent protection consequences and regulatory implications.

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Determination of Relative Configuration from Residual Chemical Shift Anisotropy

Cited by 89 publications

References 52 publications

Measurement of residual chemical shift anisotropies in compressed polymethylmethacrylate gels. Automatic compensation of gel isotropic shift contribution

Measurement of residual chemical shift anisotropies in compressed polymethylmethacrylate gels. Automatic compensation of gel isotropic shift contribution

Computer-Guided Total Synthesis of Natural Products. Recent Examples and Future Perspectives

Advances in NMR‐Based Characterization of Drug Substances, Impurities, Degradants, and Drug Metabolites

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