Elucidation of the Conformational Rate Processes of the Macrocyclic Lactone (–)‐Nonenolide Through Variable Temperature NMR, Quantum Mechanics, and Molecular Dynamics

Variable‐temperature NMR spectra of the ten‐membered lactone (–)‐nonenolide reveal that the molecule undergoes a hindered conformational interconversion process, which appears to be characteristic of this class of natural products. Using a combination of quantum mechanics (QM) calculations and molecular dynamics (MD) simulations, we show that the hindered rate process involves a ‘jump‐rope rotation’ that reorients the endocyclic alkene moiety with respect to the rest of the ring. Quantum mechanical calculations provide reasonably accurate predictions of the interconverting species’ chemical shifts, but several discrepancies exist, which we trace to inadequacies in the description of conformer energies in solution. Closer agreement is obtained from an MD‐based analysis of the conformer populations in explicit solvent. This study illustrates some important ways in which solvent effects can influence the accuracy of theoretical chemical shift predictions.