Cyclohelminthol CPs: Scope and Limitations of Density Functional Theory-Based Structural Elucidation of Natural Products.

The effectiveness and limitations of density functional theory (DFT) calculations in the structural determination of complexed and conformationally flexible natural products were demonstrated using the cyclohelminthols CP-1 (1) CP-2 (2), CP-3 (3), and CP-4 (4) newly isolated from Helminthosporium velutinum yone96. Prior to DFT calculations, the structures were tentatively assigned using conventional spectroscopic analyses. The structures were verified with reference to DFT-derived 13C and 1H NMR chemical shifts, 3JHH and nJCH values, and electronic circular dichroism (ECD) spectra. The 13C chemical shift calculations were very effective for verifying the ring-structure moieties but less effective for verifying the geometry of the side chain in which the juncture asymmetric carbon (C-16) was apart from the ring-structure moiety. However, 1H chemical shift calculations compensated for the imperfection of the latter. ECD spectral calculations were used to determine the absolute configurations. Calculations for virtual simple model molecules enabled us to evaluate the reliability of the ECD spectral calculation and derive the chiral torsion responsible for the characteristic Cotton effects.