Homodecoupled 1,1‐ and 1,n‐ADEQUATE: Pivotal NMR Experiments for the Structure Revision of Cryptospirolepine

Saurí, Josep; Bermel, Wolfgang; Buevich, Alexei V.; Sherer, Edward C.; Joyce, Leo A.; Sharaf, Maged H. M.; Schiff, Paul L.; Parella, Teodor; Williamson, R. Thomas; Martin, Gary E.

doi:10.1002/anie.201502540

Cited by 52 publications

(93 citation statements)

References 27 publications

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“…1,1-ADEQUATE spectrum of 1 prompted the acquisition of a 40-Hz optimized 1,1-HD-ADEQUATE spectrum. [18] The corresponding trace at the F 1 chemical shift of C11 from the 1,1-HD-ADEQUATE spectrum is shown in Fig. 2C.…”

Section: Synthetically Elaborated Spiroketal Rearrangement Productmentioning

confidence: 99%

“…The weak nature of some of the methylene correlations in the conventional 40 Hz Figure 1. Amplitude transfer functions calculated for the 1,1-HD-ADEQUATE experiment [18] optimized across the range from 20 to 60 Hz. Blue = 20 Hz; cyan = 30 Hz; red = 40 Hz; grey = 50 Hz; and black = 60 Hz.…”

Section: Synthetically Elaborated Spiroketal Rearrangement Productmentioning

confidence: 99%

“…[18] The original structure assignment for this alkaloid was, in part, based on a complete absence of any correlations to the carbonyl resonance in the structure regardless of the optimization of HMBC spectra when the structure was reported in 1993. [22] To probe the structure, a 2-Hz optimized LR-HSQMBC [23] experiment was first acquired, which gave a weak hint of a correlation from a vinyl singlet to the carbonyl.…”

Section: Cryptospirolepinementioning

confidence: 99%

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Observation of potentially troublesome²J_CCcorrelations in 1,1-ADEQUATE spectra

et al. 2016

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Despite the tremendous usage of HMBC to establish long-range (1) H-(13) C and (1) H-(15) N heteronuclear correlations, an inherent drawback of the experiment is the indeterminate nature of the (n) JXH correlations afforded by the experiment. A priori there is no reliable way of determining whether a given (n) JCH correlation is, for example, via two-, three-, or sometimes even four-bonds. This limitation of the HMBC experiment spurred the development of the ADEQUATE family of NMR experiments that rely on, in the case of 1,1-ADEQUATE, an out-and-back transfer of magnetization via the (1) JCC homonuclear coupling constant, which is significantly larger than (n) JCC (where n = 2-4) couplings in most cases. Hence, the 1,1-ADEQUATE experiment has generally been assumed to unequivocally provide the equivalent of (2) JCH correlations. The recent development of the 1,1- and 1,n-HD-ADEQUATE experiments that can provide homodecoupling for certain (1) JCC and (n) JCC correlations has increased the sensitivity of the ADEQUATE experiments significantly and can allow acquisition of these data in a fraction of the time required for the original iterations of this pulse sequence. With these gains in sensitivity, however, there occasionally come unanticipated consequences. We have observed that the collapse of proton multiplets, in addition to providing better s/n for the desired (1) JCC correlations can facilitate the observation of typically weaker (2) JCC correlations across intervening carbonyl resonances in 1,1-HD-ADEQUATE spectra. Several examples are shown, with the results supported by the measurement of the (2) JCC coupling constants in question using J-modulated-HD-ADEQUATE and DFT calculations. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Synthetically Elaborated Spiroketal Rearrangement Productmentioning

confidence: 99%

Section: Synthetically Elaborated Spiroketal Rearrangement Productmentioning

confidence: 99%

Section: Cryptospirolepinementioning

confidence: 99%

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Observation of potentially troublesome²J_CCcorrelations in 1,1-ADEQUATE spectra

et al. 2016

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“…Detailed NMR comparison with the C-1/C-16 region of the natural product indicated some deviations at C-15, C-16 and C-30, expected for the truncated macrocycle, but the remaining 1 H and 13 C resonances fell within ± 0.03 and ± 1.0 ppm, respectively, of the corresponding values of leiodermatolide. In addition, good correlation was also observed for the 3 J HH coupling constants of the macrolide, as well as key NOE enhancements, providing a strong argument in favor of the proposed stereostructure for this region of the natural product.…”

Section: Leiodermatolidementioning

confidence: 73%

“…Nowadays, structural elucidation of natural products relies heavily on nuclear magnetic resonance (NMR) spectroscopy, and impressive advances have been made in this field. 2 For instance, apart from the now classical through-bond correlation spectroscopy (COSY), total correlation spectroscopy (TOCSY), heteronuclear singlequantum correlation spectroscopy (HSQC), heteronuclear multiple-bond correlation spectroscopy (HMBC) and through-space nuclear Overhauser effect spectroscopy (NOESY), rotating frame nuclear Overhauser effect spectroscopy (ROESY) correlations, other exciting methods are gaining popularity, including 1,1 and 1,n-ADEQUATE 3 and Pure-Shift 4 methodologies. 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.…”

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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Homodecoupled 1,1‐ and 1,n‐ADEQUATE: Pivotal NMR Experiments for the Structure Revision of Cryptospirolepine

Cited by 52 publications

References 27 publications

Observation of potentially troublesome²J_CCcorrelations in 1,1-ADEQUATE spectra

Observation of potentially troublesome²J_CCcorrelations in 1,1-ADEQUATE spectra

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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Homodecoupled 1,1‐ and 1,n‐ADEQUATE: Pivotal NMR Experiments for the Structure Revision of Cryptospirolepine

Cited by 52 publications

References 27 publications

Observation of potentially troublesome2JCCcorrelations in 1,1-ADEQUATE spectra

Observation of potentially troublesome2JCCcorrelations in 1,1-ADEQUATE spectra

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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Observation of potentially troublesome²J_CCcorrelations in 1,1-ADEQUATE spectra

Observation of potentially troublesome²J_CCcorrelations in 1,1-ADEQUATE spectra