Absolute configuration and conformational analysis of brevipolides, bioactive 5,6-dihydro-α-pyrones from Hyptis...

The (6'S)-configuration of brevipolides A-J (1-10), isolated from Hyptis brevipes, was established by X-ray diffraction analysis of 9 in conjunction with Mosher's ester analysis of the tetrahydro derivative 11 obtained from both geometric isomers 8 and 9 as well as by chemical correlations. The structure of the new brevipolide J (10) was characterized through NMR and MS data as having the same 6-heptyl-5,6-dihydro-2H-pyran-2-one framework possessing the cyclopropane moiety of all brevipolides but substituted by an isoferuloyl group instead of the p-methoxycinnamoyl moiety found in 8 and 9. Conformational analysis of these cytotoxic 6-heptyl-5,6-dihydro-α-pyrones was carried out on compound 9 by application of a protocol based on comparison between experimental and DFT-calculated vicinal (1)H-(1)H NMR coupling constants. Molecular modeling was used to correlate minimum energy conformers and observed electronic circular dichroism transitions for the isomeric series of brevipolides. Compounds 7-10 exhibited moderate activity (ED(50) 0.3-8.0 μg/mL) against a variety of tumor cell lines.