Advanced Structural Determination of Diterpene Esters Using Molecular Modeling and NMR Spectroscopy

Three new jatrophane esters (<b>1</b>–<b>3</b>) were isolated from <i>Euphorbia amygdaloides</i> ssp. <i>semiperfoliata</i>, including an unprecedented macrocyclic jatrophane ester bearing a hemiketal substructure, named jatrohemiketal (<b>3</b>). The chemical structures of compounds <b>1</b>–<b>3</b> and their relative configurations were determined by spectroscopic analysis. The absolute configuration of compound <b>3</b> was determined unambiguously through an original strategy combining NMR spectroscopy and molecular modeling. Conformational search calculations were performed for the four possible diastereomers <b>3a</b>–<b>3d</b> differing in their C-6 and C-9 stereocenters, and the lowest energy conformer was used as input structure for geometry optimization. The prediction of NMR parameters (¹H and ¹³C chemical shifts and ¹H–¹H coupling constants) by density functional theory (DFT) calculations allowed identifying the most plausible diastereomer. Finally, the stereostructure of <b>3</b> was solved by comparison of the structural features obtained by molecular modeling for <b>3a</b>–<b>3d</b> with NMR-derived data (the values of dihedral angles deduced from the vicinal proton–proton coupling constants (³<i>J</i>_HH) and interproton distances determined by ROESY). The methodology described herein provides an efficient way to solve or confirm structural elucidation of new macrocyclic diterpene esters, in particular when no crystal structure is available