Structural elucidation of small molecules

Conformational analysis and stereochemical determination of natural products and bioactive peptides using anisotropic NMR spectroscopy

Our group has long-standing expertise in studying the structure and stereochemistry of challenging natural products and other organic molecules. We have combined anisotropic NMR spectroscopy with atomistic MD simulations to determine the relative configuration of flexible natural products [13]. We have applied similar approach to a wide variety of natural products whose stereochemistry was difficult to establish using conventional methods. Furthermore, we introduced a simple yet highly effective solution for extracting residual chemical shift anisotropy (RCSA) of analytes in a liquid crystalline phase formed by AAKLVFF oligopeptides (Figure 3) [14]. This anisotropic NMR parameter contains valuable structural information for nonprotonated carbons, which have been scarcely employed so far due to the practical difficulty in measuring them precisely. Our method does not require any special instruments, devices, or corrections during post-acquisition data analysis, making it easily applicable in any chemistry laboratory. We have demonstrated the effectiveness of this method on a variety of novel natural products [15-17]. These projects were previously supported by a DFG-CAPES research funding and will continue with follow-up funding from the DFG starting in 2025.

Workflow to measure residual chemical shift anisotropy.

Figure 3. Workflow to measure residual chemical shift anisotropy using a liquid crystalline phase [14].

References

[13] Sun, H.; Reinscheid, U. M.; Whitson, E. L.; d’Auvergne, E. J.; Ireland, C. M.; Navarro-Vázquez, A.; Griesinger, C. Challenge of Large-Scale Motion for Residual Dipolar Coupling Based Analysis of Configuration: The Case of Fibrosterol Sulfate A, J. Am. Chem. Soc. 2011, 133(37), 14629-14636. doi:10.1021/ja205295q

[14] Li, X.-L.; Chi, L.-P.; Navarro-Vázquez, A.; Hwang, S.; Schmieder, P.; Li, X.-M.; Li, X.; Yang, S.-Q.; Lei, X.*; Wang, B.-G.*; Sun, H.* Stereochemical elucidation of natural products from residual chemical shift anisotropies in a liquid crystalline phase, J. Am. Chem. Soc. 2020, 142(5), 2301-2309. doi:10.1021/jacs.9b10961

[15] Li, X.-L.; Ru, T.; Navarro-Vázquez, A.; Lindemann, P.; Nazaré, M.; Li, X.-W.; Guo, Y.-W.*; Sun, H.* Weizhouochrones: Gorgonian-derived symmetric dimers and their structure elucidation using anisotropic NMR combined with DP4+ probability and CASE-3D, J. Nat. Prod. 2022, 85(7), 1730-1737. doi:10.1021/acs.jnatprod.2c00257

[16] Doro-Goldsmith, E.; Song, Q.; Li, X.-L.; Li, X.-M.; Hu, X.-Y.; Li, H.-L.; Liu, H.-R.; Wang, B.-G.*; Sun, H.*, Absolute Configuration of 12S-Deoxynortryptoquivaline from Ascidian-Derived Fungus Aspergillus clavatus Determined by Anisotropic NMR and Chiroptical Spectroscopy. J. Nat. Prod. 2024, 87(2), 381-387, doi: 10.1021/acs.jnatprod.3c01157

[17] Ketzel, A. F.; Li, X.; Kaupp, M.; Sun, H.*; Schattenberg, C. J.*, Benchmark of Density Functional Theory in the Prediction of 13C Chemical Shielding Anisotropies for Anisotropic Nuclear Magnetic Resonance-Based Structural Elucidation. J. Chem. Theory Comput., 2025, 21(2): 871-885. doi: 10.1021/acs.jctc.4c01407