NMR characterization of complex natural products: Assigning novel, proton-deficient alkaloid scaffolds

NMR provides powerful structural elucidation tools that are particularly well suited for natural products studies. Comprehensive spectroscopic characterization of a native metabolite is often sufficient to fully assign a new structure. However assignment of novel molecular architectures that incorporate numerous heteroatoms and proton-deficient fused ring systems can be challenging. Two new families of marine alkaloids were recently discovered that each had quite novel structural features. One series of alkaloids had two pyrimidine rings and an imidazole ring fused to generate an unprecedented tetracyclic core with embedded guanidine and amidine functionalities [1]. The other class of metabolites incorporated multiple halogen substituents and six fused heterocyclic rings to generate a new structural motif. Structure characterization of these proton-deficient alkaloid scaffolds was quite challenging using only HMBC heteronuclear correlation data, which generally provides only two- and three-bond correlations with good sensitivity. However, application of some new NMR pulse sequences (LR-HSQMBC, HD-ADEQUATE) [2,3] and strategies ultimately allowed the complete structural elucidation of these new marine alkaloids. Continued development, refinement, and application of enhanced NMR capabilities is crucial for the successful assignment of novel structural scaffolds and functional group arrays that are often found in natural products.

Acknowledgements: We thank Gary Martin, R. Thomas Williamson, and Josep Saurí (Merck & Co. Inc.) for assistance with NMR experiments and Arvin Moser and Scott McDonald (ACD/Labs) for assistance with CASE analyses.

References:

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