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

Abstract

Three new jatrophane esters (1-3) were isolated from Euphorbia amygdaloides ssp. semiperfoliata, including an unprecedented macrocyclic jatrophane ester bearing a hemiketal substructure, named jatrohemiketal (3). The chemical structures of compounds 1-3 and their relative configurations were determined by spectroscopic analysis. The absolute configuration of compound 3 was determined unambiguously through an original strategy combining NMR spectroscopy and molecular modeling. Conformational search calculations were performed for the four possible diastereomers 3a-3d 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 ((1)H and (13)C chemical shifts and (1)H-(1)H coupling constants) by density functional theory (DFT) calculations allowed identifying the most plausible diastereomer. Finally, the stereostructure of 3 was solved by comparison of the structural features obtained by molecular modeling for 3a-3d with NMR-derived data (the values of dihedral angles deduced from the vicinal proton-proton coupling constants ((3)JHH) 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.

Iodinated Meroditerpenes from a Red Alga Callophycus sp.

“…22 It was further validated by comparison of dihedral angles and interproton distances obtained by molecular modeling with the corresponding values derived by vicinal 1 H– 1 H coupling constants and ROESY. In another example, the absolute stereochemistry of abibalsamin C ( 10 ) was determined by semiquantitative ROESY distance calculation and DFT modeling.…”

So Uncommon and so Singular, but Underexplored: An Updated Overview on Ethnobotanical Uses, Biological Properties and Phytoconstituents of Sardinian Endemic Plants

“…cupanii and H. italicum subsp. thyrenicum [57,81,82,[197][198][199][200], as shown in Figure 4. The identification and isolation of original metabolites is worth noting, since they could provide new scaffolds for drug design.…”

Diterpenoids of terrestrial origin

“…Molecular modeling and advanced NMR methods have been used in locating esters in the jatrophanes of Euphorbia amydaloides. 180 192 Daphne genkwa (Thymelaeaceae), 193 Gnidia polycephela (Thymelaeaceae), 194 and Stellera chamaejasme (Thymelaeaceae) 195 whilst some more tigliane (phorbol) esters with cytotoxic and anti-viral activity were obtained from Croton tiglium (Euphorbiaceae), 196,197 Daphne aurantica, 198 and Stillingia lineata (Euphorbiaceae). 199 The anti-viral activity of these compounds (e.g.…”