Heteronuclear Shift Correlation Methods Research Articles

NMR Structure Elucidation of Small Organic Molecules and Natural Products: Choosing ADEQUATE vs HMBC

Long-range heteronuclear shift correlation methods have served as the cornerstone of modern structure elucidation protocols for several decades. The (1)H-(13)C HMBC experiment provides a versatile and relatively sensitive means of establishing predominantly (3)J(CH) connectivity with the occasional (2)J(CH) or (4)J(CH) correlation being observed. The two-bond and four-bond outliers must be identified specifically to avoid spectral and/or structural misassignment. Despite the versatility and extensive applications of the HMBC experiment, it can still fail to elucidate structures of molecules that are highly proton-deficient, e.g., those that fall under the so-called "Crews rule". In such cases, recourse to the ADEQUATE experiments should be considered. Thus, a study was undertaken to facilitate better investigator understanding of situations where it might be beneficial to apply 1,1- or 1,n-ADEQUATE to proton-rich or proton-deficient molecules. Equipped with a better understanding of when a given experiment might be more likely to provide the necessary correlation data, investigators can make better decisions on when it might be advisible to employ one experiment over the other. Strychnine (1) and cervinomycin A2 (2) were employed as model compounds to represent proton-rich and proton-deficient classes of molecules, respectively. DFT methods were employed to calculate the relevant (n)J(CH) heteronuclear proton-carbon and (n)J(CC) homonuclear carbon-carbon coupling constants for this study.

13C‐15N Connectivity networks via unsymmetrical indirect covariance processing of 1H‐13C HSQC and 1H‐15N IMPEACH spectra

Abstractmagnified imageLong‐range 1H‐15N heteronuclear shift correlation methods at natural abundance to facilitate the elucidation of small molecule structures have assumed a role of growing importance over the past decade. Recently, there has also been a high level of interest in the exploration of indirect covariance NMR methods. From two coherence transfer experiments, A→B and A→C, it is possible to indirectly determine B⟷C. We have shown that unsymmetrical indirect covariance methods can be employed to indirectly determine several types of hyphenated 2D NMR data from higher sensitivity experiments. Examples include the calculation of hyphenated 2D NMR spectra such as 2D GHSQC‐COSY and GHSQC‐NOESY from the discrete component 2D NMR experiments. We now wish to report the further extension of unsymmetrical indirect covariance NMR methods for the combination of 1H‐13C GHSQC and 1H‐15N longrange (GHMBC, IMPEACH‐MBC, CIGAR‐HMBC, etc.) heteronuclear chemical shift correlation spectra to establish 13C‐15N correlation pathways.

Long‐Range 1H—15N Heteronuclear Shift Correlation

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Utilizing unsymmetrical indirect covariance processing to define 15N13C connectivity networks

There has been considerable interest over the past decade in the utilization of direct and long-range 1H- 15N heteronuclear shift correlation methods at natural abundance to facilitate the elucidation of small molecule structures. Recently, there has also been a high level of interest in the exploration of indirect covariance NMR methods. Our initial explorations in this area led to the development of unsymmetrical indirect covariance methods, which allow the calculation of hyphenated 2D NMR spectra such as 2D GHSQC-COSY and GHSQC-NOESY from the discrete component 2D NMR experiments. We now wish to report the utilization of unsymmetrical indirect covariance NMR methods for the combination of 1H- 13C GHSQC and 1H- 15N long-range (GHMBC, IMPEACH-MBC, CIGAR-HMBC, etc.) heteronuclear chemical shift correlation spectra to determine 15N- 13C correlation pathways.

Comparison of 1.7 mm submicro and 3 mm micro gradient NMR probes for the acquisition of 1H13C and 1H15N heteronuclear shift correlation data

A variety of specialized probes are now available for the NMR characterization of small samples. The performance characteristics for 3 mm gradient micro inverse and 1.7 mm submicro inverse-detection gradient (SMIDG) NMR probes for the characterization of small samples using gradient inverse heteronuclear shift correlation methods are compared. Results of three 48 min 1H13C GHSQC experiments performed using a 0.5 µmol sample of the drug ibuprofen dissolved in either 30 or 150 µl are compared. A similar set of 12 min 1H13C GHSQC experiments were performed using 1 µmol samples of strychnine. The results of both sets of GHSQC experiments demonstrate an ∼2.3 fold improvement in the signal-to-noise ratio attainable using the 1.7 mm submicro vs a 3 mm micro NMR probe with a given molar quantity of sample when data are accumulated for the same length of time. Data acquired using a 1.7 mm sample in the 3 mm probe gave intermediate results that represent a significant advantage relative to data for a 3 mm sample in the 3 mm micro NMR probe. These results parallel those reported in 1992 for a comparison of the then new 3 mm NMR probe vs a conventional 5 mm NMR probe. Finally, results are also compared for the acquisition of a series of 18 hr 1H15N GHMBC spectra on a 3 µmol (1 mg) sample of strychnine at natural abundance. The 3 µmol sample of strychnine represents about the practical limit of the 3 mm micro NMR probe for 1H15N at natural abundance overnight. The results obtained with the 1.7 mm submicro probe were ∼2.3 fold better than with the 3 mm micro probe. Furthermore, the signal intensity of the weaker responses in the spectra was significantly better, relative to the noise floor of the spectrum, than were the corresponding responses in the 3 mm micro probe data. Copyright © 1999 John Wiley & Sons, Ltd.

Comparison of 1.7 mm submicro and 3 mm micro gradient NMR probes for the acquisition of1H13C and1H15N heteronuclear shift correlation data

A variety of specialized probes are now available for the NMR characterization of small samples. The performance characteristics for 3 mm gradient micro inverse and 1.7 mm submicro inverse-detection gradient (SMIDG) NMR probes for the characterization of small samples using gradient inverse heteronuclear shift correlation methods are compared. Results of three 48 min 1H13C GHSQC experiments performed using a 0.5 µmol sample of the drug ibuprofen dissolved in either 30 or 150 µl are compared. A similar set of 12 min 1H13C GHSQC experiments were performed using 1 µmol samples of strychnine. The results of both sets of GHSQC experiments demonstrate an ∼2.3 fold improvement in the signal-to-noise ratio attainable using the 1.7 mm submicro vs a 3 mm micro NMR probe with a given molar quantity of sample when data are accumulated for the same length of time. Data acquired using a 1.7 mm sample in the 3 mm probe gave intermediate results that represent a significant advantage relative to data for a 3 mm sample in the 3 mm micro NMR probe. These results parallel those reported in 1992 for a comparison of the then new 3 mm NMR probe vs a conventional 5 mm NMR probe. Finally, results are also compared for the acquisition of a series of 18 hr 1H15N GHMBC spectra on a 3 µmol (1 mg) sample of strychnine at natural abundance. The 3 µmol sample of strychnine represents about the practical limit of the 3 mm micro NMR probe for 1H15N at natural abundance overnight. The results obtained with the 1.7 mm submicro probe were ∼2.3 fold better than with the 3 mm micro probe. Furthermore, the signal intensity of the weaker responses in the spectra was significantly better, relative to the noise floor of the spectrum, than were the corresponding responses in the 3 mm micro probe data. Copyright © 1999 John Wiley & Sons, Ltd.

Complete proton and carbon-13 NMR assignment of the alkaloid gephyrotoxin through the use of homonuclear Hartmann-Hahn and two-dimensional spectroscopy

Three different types of modem NMR techniques have been used to obtain a complete proton and carbon- 13 assignment of the alkaloid gephyrotoxin. In addition to the two-dimensional phase-sensitive homo- and heteronuclear shift correlation methods, use of the recently proposed one-dimensional homonuclear Hartmann-Hahn difference experiment was crucial for obtaining the required long-range connectivity. Guidelines are presented for optimal use of these techniques. Experiments were performed at 500-MHz 'H frequency, using 8 mg of sample. The introduction of two-dimensional (2D) NMR techniques has greatly simplified the NMR analysis of many natural products, permitting the study of problems hitherto considered intractable. As an example, we present here a study of the alkaloid gephy- rotoxin (GyTx), extracted from the skin of the frog Dendrobates histrionicus. Routine application of standard 2D NMR techniques is not sufficient in this case because of the complexity of the 'H