Chem. SCI.: new and old spectral techniques work together to decipher complex natural products

Scientists have identified the structures of two marine natural products that were previously thought to be too complex to characterize Using well-known spectroscopy tools and new experiments to explore bonding orientations, the team was able to characterize the structure Natural products are rich sources of pharmacological compounds The problem: they are often difficult to purify and identify Gary Martin of Merck Research Laboratory and Kirk Gustafson of National Cancer Institute have been researching and identifying natural products for many years It has been reported that there are wrong structural identification results of complex natural products in the published literature At present, more than 1200 papers need to revise the structure of natural products identified Helping researchers reduce structural errors in their reports will free them more time to pursue and identify new natural product molecules, they said As early as 2000, Gustafson was working on a marine invertebrate called bryozoan His team isolated a series of cytotoxic compounds from the creature They also extracted two non cytotoxic components, known as caulamidine A and caulamidine B They used the available tools to characterize the spectrum of caulamidine a, and then they came up with a structure, but because there was no definitive evidence and sufficient confidence to publish it The samples were then decomposed, so the project stagnated at this point They tried to collect samples of compounds for 15 years, but failed Now, a research team led by Gustafson and Martin, with improved instruments and experimental capabilities as means, is able to characterize fresh samples and identify the structures of caulamidine A and caulamidine B Caulamidine A and B structures (source: chem SCI.) caulamidines are alkaloids composed of unusual six ring scaffolds and several chiral centers Heterocyclic core is unique, there is no precedent in the chemical literature, and no one knows how to synthesize compounds, whether in biosynthesis or chemical synthesis Robert Capon, a natural products expert from the University of Queensland in Australia, commented that the structure of these compounds has been cracked, which is a great achievement It also shows that we may need to redefine the achievable and unrealized boundaries in spectral analysis and structural interpretation The advanced NMR technology is the key to help unlock the structure of natural products Most synthetic chemists know that the standard NMR map provides some connection information, which the research team uses to guide computer-assisted structural analysis (case) This requires information from NMR experiments and analysis of data to suggest possible molecular structures Initially, the software ran for 250 hours without a definite answer The breakthrough came when the team used some newer MRI techniques, one of which was recently developed by Williamson, Martin and other colleagues at Merck's research lab It observed a long-range proton carbon interaction, spanning four to six bonds However, the general NMR spectrum is only limited to two or three bonds With these new data, case analyzed in less than one second and proposed two possible caulamidine a structures The final step is to independently verify whether the proposed structure is correct For this reason, Martin and Gustafson studied two anisotropic NMR parameters When the molecules are not allowed to roll randomly in the solution, the anisotropic NMR phenomenon can be observed For example, by using stretched polymer gels to arrange them in NMR magnetic field, anisotropic NMR data can provide information about the relative orientation of different structural units, such as carbon hydrogen bonds, without controlling the distance between these units Therefore, they are complementary to the more commonly used NMR spectra that provide direct structural information Comparison of RDC and RCSA data (source: chem SCI.) residual dipolar coupling (RDC) is an anisotropic NMR parameter used by chemists for decades, but it is only recently that residual chemical shift anisotropy (RCSA) has become a feasible measurement method By using both RDC and RCSA data and comparing them with theoretical calculations, the team determined a single correct structure of caulamidine a They also found a second compound, caulamidine B, very similar to caulamidine a, but with different halogen atoms Although they are not cytotoxic, they have some antimalarial properties According to the RDC data of caulamidine a (source: chem SCI.) RCSA data of caulamidine a (source: chem SCI.) Martin and Gustafson, this study represents the first application of RDC and rcsas to provide a new way to study the structure of natural products They say RCSA data is relatively easy to obtain, even for non-technical experts, so researchers don't need to be afraid to try this method Although it is no problem to continue to rely on and use the method for many years, the old technology can not completely solve the complex structure identification It is possible that the anisotropic nuclear magnetic resonance (NMR) spectrum will make a great change in the identification of organic chemical structure Paper link: http://pubs.rsc.org/en/content/articlelanding/2018/sc/c7sc01996c ා divabstract