Summary NMR
Our main objective in this line of research is the development of NMR methodologies that efficiently establish the relative configuration of NPs that exhibit conformational complexity. An example of this is organic compounds that possess stereogenic centers in acyclic carbon chains or those with great conformational freedom. The main NMR strategies these studies are focusing on are:
JBCA Methodology. Coupling constant-based configuration analysis (JBCA), also known as the Murata methodology, employs proton-proton and carbon-proton NMR coupling constants at two and three bonds. JBCA is a standardized tool that allows the determination of the relative configuration of asymmetric centers in acyclic systems or those with great conformational freedom. These analyses are complemented by computational calculations using density functional theory (DFT). We have been able to determine the relative configuration of several NPs that we isolated and that could not be resolved using classical methods: dysithiazolamide from a sponge of the genus Dysidea; gunungamide A from a sponge of the genus Discodermia; and enigmazole C, a macrocyclic lactone from a new species of the sponge Homophymia. The coupling constants were obtained using two-dimensional NMR methods, and the experimental values were also compared with those obtained theoretically using computational calculations at the level of density functional theory (DFT).
We have developed a new strategy based on comparing the values of these J at room temperature with those obtained at low temperatures. This allows us to deduce which conformer each NP tends toward and to apply the Murata methodology in cases where a complex conformational equilibrium exists.
Anisotropic Nuclear Magnetic Resonance. The application of anisotropic NMR in resolving the relative configuration of a natural product is based on the fact that, through the induction of an aligning medium, anisotropic components of NMR parameters, such as residual dipolar couplings (RDCs) and residual quadrupolar couplings (RQCs), can be observed and measured. This contrasts with what occurs in isotropic media, where the anisotropic components of NMR parameters average to zero, making measurement impossible. All these anisotropic components provide valuable information about the orientation of the vectors between the nuclear spins present in a natural product and the anisotropic contribution of the local environment to their chemical shifts.
Analysis of residual dipolar couplings (RDCs) provides information about the angles between internuclear vectors, providing a concise and comprehensive description of the orientational properties of structural fragments. On the other hand, residual chemical shift anisotropy (RCSA) provides evidence on the relative orientation of chemical shift tensors and can therefore account for information about protonated and unprotonated carbons in any organic structure.
Compared to RDCs, 13C-RCSA has the additional advantage of providing relative orientation information on quaternary carbons, which is otherwise only available through less sensitive long-range RDC measurements. This advantage can be exploited to determine the orientation of quaternary carbons in proton-deficient molecules, where NOE, coupling (J), and RDC (1DCH) data to a bond may be insufficient. Interestingly, 1H-RCSA has not been developed to date.
Proton residual chemical shift anisotropy (1H-RCSA). This methodology is based on the RCSA measurement of a chiral organic compound using the more abundant 1H nucleus instead of 13C. Through a collaboration with Dr. Christian Griesinger, we participated in the development of the methodology for measuring 1H RCSA with the determination of the relative configuration of briarane, briarane B-3, isolated from the gorgonian Briareum asbestinum, using deuterated gels as the aligning medium and only 35 micrograms of sample.
Additionally, the application of two anisotropic measurements, carbon residual chemical shift anisotropy (13C-RCSA) and 1H-13C residual dipolar couplings (1DCH-RDC) to a bond, were used to confirm the relative configuration of a meroterpene with a tetraprenyltoluquinol chroman nucleus isolated from the seaweed Sargassum muticum.