Can Stereoclusters Separated by Two Methylene Groups Be Related by DFT Studies? The Case of the Cytotoxic Meroditerpenes Halioxepines

Abstract

QM/NMR-DFT (quantum mechanics combined with nuclear magnetic resonance parameters calculated by density functional theory approximations) studies allowed us to link two stereoclusters separated by two methylene groups present in the new meroditerpenes halioxepine B (2) and halioxepine C (3) and the known halioxepine (1), isolated from two Indonesian sponges of the genus Haliclona (Reniera). DP4 and DP4+ probabilities were used to discriminate the two diastereotopic arrangements of the two stereoclusters, whose unconnected relative configurations were determined by ROESY and J-based configurational analysis. To confirm the DFT studies, the full relative configuration of 1 was deduced using a mixture of benzene-d and pyridine-d as the NMR solvent. ROESY measurements connected the two stereoclusters and demonstrated that DFT calculations accurately predict the configuration when two methylenes separate the two stereoclusters. The different arrangements of the distant stereoclusters C-1/C-2/C-7 and C-10/C-15 for compounds 2 and 3 were deduced by DFT calculations and explained the opposite optical rotations observed for the two compounds. Halioxepines B (2) and C (3) display moderate cytotoxicity against different human cancer cell lines.

NMR and Computational Studies as Analytical and High-Resolution Structural Tool for Complex Hydroperoxides and Diastereomeric Endo-Hydroperoxides of Fatty Acids in Solution-Exemplified by Methyl Linolenate

“…The development of quantum chemical methods for calculating NMR chemical shifts has led to a significant number of studies that combine experimental chemical shifts with computations [ 39 , 40 , 41 , 42 ]. Nevertheless, a few examples of organic molecules whose structures have been determined by both computations of NMR chemical shifts in solution and X-ray structures have been published [ 43 , 44 , 45 , 46 , 47 , 48 , 49 ].…”

DFT Calculations of 1H- and 13C-NMR Chemical Shifts of Geometric Isomers of Conjugated Linoleic Acid (18:2 ω-7) and Model Compounds in Solution

“…A significant number of studies have been published that combine experimental NMR chemical shifts with computations [ 24 , 25 , 26 , 27 , 28 ] and investigating high resolution structures in solution [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. When we consider the importance of calculations of NMR parameters in structural chemistry, it is surprising that no applications in lipid research have so far been reported.…”

Solvent-Dependent Structures of Natural Products Based on the Combined Use of DFT Calculations and 1H-NMR Chemical Shifts

“…The development of quantum chemical methods for calculating NMR parameters, with emphasis on chemical shifts, as well as advances in computational techniques and computer power, have led to an increasing number of studies that combine calculation with experiment [16,17,18,19,20]. Several examples of using computed NMR chemical shifts to confirm proposed structures or to aid the reassignment of structures can be found in the literature [20,21,22,23,24,25]. To date, however, only a handful examples of organic molecules whose structures have been determined by both computation of NMR chemical shifts in solution and X-ray were reported [26,27,28,29,30,31].…”