Structural Studies on Flexible Small Molecules Based on NMR in Oriented Media. Methodology and Application to Natural Products

Abstract

This thesis describes the development and application of structural elucidation methodologies based on NMR in aligned media. Nuclear magnetic resonance is arguably the most important technique for the structural analysis of organic molecules in solution. In the last decade, Residual Dipolar Coupling (RDC) analysis emerged as a powerful tool for the determination of the three-dimensional structure of organic molecules in solution, complementing and even outperforming the approach based on the classical NMR observables such as NOE or 3J couplings. While application of RDCs to the structural analysis of proteins developed rapidly, their use with “small” molecules (typically organic compounds and natural products with MW < 1000 Da) is still scarce. From the spectroscopic point of view, two features of small molecules pose the main obstacles to the application of RDC to their analysis: the scarcity of observable couplings and the complexity stemming from conformational flexibility in solution. Besides, sample preparation with the optimal degree of alignment is still an issue for most classes of compounds. In this thesis, all these topics are addressed and new experimental and computational advancements are presented. i) Sample preparation. Weak alignment in water and aligning properties of polyacrylamide gels. ii) New observables. Long-range proton–carbon RDCs. iii) Analysis of flexible organic molecules.