Application of molecular mechanics in the total stereochemical elucidation of spicigerolide, a cytotoxic 6-tetraacetyloxyheptenyl-5,6-dihydro-α-pyrone from Hyptis spicigera

Abstract

Bioactivity-directed fractionation of the crude extract prepared from the medicinal Mexican plant Hyptis spicigera (Lamiaceae) tested on KB cells led to the isolation of spicigerolide (1). The structure for this novel cytotoxic compound was elucidated as 6R-[3S,4S,5S,6S-tetraacetyloxy-1Z-heptenyl]-5,6-dihydro-2H-pyran-2-one. The relative stereochemistry of this flexible molecule was determined by a combination of molecular mechanics calculations and 1H–1H coupling constant data, while the absolute configuration was established according to CD measurements. The MM/3JH–H calculations, as applied to 1, was validated with model linear compounds prepared from l-rhamnose: 2,3,4,5-tetra-O-acetyl-6-deoxy-l-mannose (5) and tetra-O-acetyl-1,6-dideoxy-l-mannitol (8). Both compounds possess the same stereochemistry predicted to be present in the acyclic moiety of spicigerolide (1) but lacking the stereochemical influence of the chiral pyrone.