Survey of marine natural product structure revisions: A synergy of spectroscopy and chemical synthesis

Abstract

The structural assignment of new natural product molecules supports research in a multitude of disciplines that may lead to new therapeutic agents and or new understanding of disease biology. However, reports of numerous structural revisions, even of recently elucidated natural products, inspired the present survey of techniques used in structural misassignments and subsequent revisions in the context of constitutional or configurational errors. Given the comparatively recent development of marine natural products chemistry, coincident with the modern spectroscopy, it is of interest to consider the relative roles of spectroscopy and chemical synthesis in the structure elucidation and revision of those marine natural products which were initially misassigned. Thus, a tabulated review of all marine natural product structural revisions from 2005 to 2010 is organized according to structural motif revised. Misassignments of constitution are more frequent than perhaps anticipated by reliance on HMBC and other advanced NMR experiments, especially considering the full complement of all natural products. However, these techniques also feature prominently in structural revisions, specifically of marine natural products. Nevertheless, as is the case for revision of relative and absolute configuration, total synthesis is a proven partner for marine, as well as terrestrial, natural products structure elucidation. It also becomes apparent that considerable ‘detective work’ remains in structure elucidation, in spite of the spectacular advances in spectroscopic techniques.

Caryolene-forming carbocation rearrangements

“…Structure validation: We first computed 1 H and 13 C chemical shifts for 1 to assure ourselves that the assigned structure was reasonable [9–10]. Our calculated chemical shifts and the reported data matched well (Fig.…”

Determination of Relative Configuration from Residual Chemical Shift Anisotropy

“…Eq (1) where Aαβ (equals to 2 3  , representing the Saupe order matrix) are the molecular alignment tensor matrix elements. We notated the chemical shift tensor elements as CSAαβ instead of  to avoid confusion since  symbol is reserved for the chemical shifts observed in the spectra.…”

Nuclear Magnetic Resonance of Small Molecules in Natural Products

“…Even small differences in NMR shift values from expected chemical shifts (e.g., as reported in reliable literature) or additional COSY/NOE/HMBC correlation signals which can not be explained within the geometrical limitations of the molecular skeleton might be a clear hint that this structure proposal is not valid. This has been proven more than once as review literature dramatically tells (Nicolaou andSnyder, 2005, Suyama, Gerwick, andMcPhail, 2011). However, once a correct solution is found, the reward is usually high -uncharted biosynthetical terrain is entered, ecosystematic or biogenetic pathways and correlations might be traced, or a bioactive compound of unknown structure matures to a molecular graph stimulating both organic chemists and pharmacologists to further research.…”

“…In natural product structure analysis efforts, with more complex molecular scaffolds to cover, incorrect identification of an analyte is the constant companion of confirmative natural product synthesis frequently unveiling such errors (Nicolaou and Snyder, 2005;Suyama, Gerwick, and McPhail, 2011). Consequently, a state-of-the-art natural product laboratory devoted to analytical chemistry research approaches involving purified small organic molecules from natural sources, as novel secondary metabolites in uncharted species or hit candidates in bioactivity screens, should be definitively in the position to unequivocally characterize these analytes on their own (Berger and Sicker, 2009).…”