A Novel Method for the Determination of Stereochemistry in Six-Membered Chairlike Rings Using Residual Dipolar Couplings

Yan, Jiangli; Kline, Allen D.; Mo, Huaping; Shapiro, Michael J.; Zartler, Edward R.

doi:10.1021/jo020670i

Cited by 82 publications

(95 citation statements)

References 51 publications

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“…Most 1 J CH coupling constants with the corresponding dipolar couplings (D CH ) could be measured from these spectra (see Table 1). For exact measurement we used the procedure described by Yan et al [28] Altogether 35 D CH couplings in the range of À22.3 to 27.9 Hz could be obtained. RDCs were then fitted to the existing crystal and the NOEderived NMR structures by using the program PALES.…”

Section: Rdc Measurementmentioning

confidence: 99%

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Structure Refinement of Cyclosporin A in Chloroform by Using RDCs Measured in a Stretched PDMS‐Gel

et al. 2005

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New developments concerning alignment media for apolar solvents like chloroform make it possible to measure anisotropic parameters such as residual dipolar couplings (RDCs) at relatively low concentrations and natural isotopic abundance. As RDCs provide structural restraints with respect to an external coordinate system, long-range structural arrangements of the time-averaged structure can be determined with high precision. The method is demonstrated on the well-studied cyclo-undecapeptide Cyclosporin A (CsA), for which crystal and conventionally derived NMR structures are available. Neither crystal nor NMR structure are consistent with heteronuclear D(CH) RDCs measured in a stretched poly(dimethylsiloxane) gel, and refinement by using the anisotropic parameter results in a highly defined structure with a slightly changed backbone conformation. The applied methods and interpretation of the structural model are discussed.

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Section: Rdc Measurementmentioning

confidence: 99%

“…RDCs were extracted from the spectra by using the procedure described in detail in ref. [28]. Altogether 35 reliable D CH residual dipolar couplings with an estimated error of 1 Hz could be measured for nonoverlapped signals.…”

mentioning

confidence: 94%

Structure Refinement of Cyclosporin A in Chloroform by Using RDCs Measured in a Stretched PDMS‐Gel

et al. 2005

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“…These data therefore add little value to the structural determination, especially if sufficient precise RDCs are in hand. The 1 D CH coupling appears to be the most useful RDC and is easily measured by one-and two-demensional HMQC or HSQC experiments in both the direct 33,35 and indirect 58,59 dimensions, using either intensity-based 60 or frequency-based 61 methods. Because of linewidth difficulties, accurate measurement of the RDC in the indirect dimension requires complex analysis 59,62 -64 involving complex fitting schemes.…”

Section: Measurement Of Rdcs At Natural Abundancementioning

confidence: 99%

“…The asymmetric lineshape of isolated 13 C satellites in the direct dimension 66 introduces a deviation of ¾1 Hz into J and J C D measurements. 35 This deviation can be minimized by phasing each of the 13 C satellites 13 C natural abundance carbohydrates by using BIRD pulses and long intervals of the modulation period. 67 This method is easily extended to other small molecules, with a precision of a few hundredths of a hertz.…”

Section: Measurement Of Rdcs At Natural Abundancementioning

confidence: 99%

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Application of residual dipolar couplings in organic compounds

Yan¹,

Zartler²

2004

Magnetic Reson in Chemistry

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INTRODUCTIONThe classic NMR strategy for determining the structure or stereochemistry of small molecules is by using a combination of nuclear overhauser effect (NOE) and scalar J couplings. dependence, where r is the internuclear distance and can be used to connect protons up to 5Å apart. 2 1 H-1 H NOEs have the most utility in small-molecule studies. H-X NOEs usually require isotopic labeling, which can be difficult synthetically for small molecules.1 H-1 H scalar couplings are easy to measure and have high information content; 3 J HH leads to the relative orientations of the atoms by sequential connectivity and estimation of dihedral angles through the well-known Karplus equation.3 Long-range heteronuclear J couplings ( >2 J XH ) are also useful for structural determinations but the data are more difficult to obtain. Typically, these involve 13 C or 15 N as the X-nucleus and if the sample is not isotopically enriched the experiment, such as heteronuclear multiple bond coherence spectroscopy (HMBC), 4,5 can be very time consuming. If the molecule of interest has an overall dearth of protons, has NOEs that cannot be assigned unambiguously or has breaks in the NOE or scalar connectivities, the typical NOE/J analysis fails. Additionally, in order to obtain the relative orientation of remote centers, multiple NOE or J-coupling connections have to be performed in series to transverse the entire molecule. The further away the stereocenters are from each other, the greater the number of necessary connections and measurements needed to confirm unambiguously the connectivity. If one of the connections fails, the pathway fails. Thus, a method that does not rely upon these connectivities would be extremely useful for stereochemistry

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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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A Novel Method for the Determination of Stereochemistry in Six-Membered Chairlike Rings Using Residual Dipolar Couplings

Cited by 82 publications

References 51 publications

Structure Refinement of Cyclosporin A in Chloroform by Using RDCs Measured in a Stretched PDMS‐Gel

Structure Refinement of Cyclosporin A in Chloroform by Using RDCs Measured in a Stretched PDMS‐Gel

Application of residual dipolar couplings in organic compounds

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

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