Enantiospecific semisynthesis of (+)-almuheptolide-A, a novel natural heptolide inhibitor of the mammalian mitochondrial respiratory chain

The development of novel styryl lactone derivatives as bioactive compounds and the semisynthesis of both 4,5-dialkoxylated eight-membered-ring lactone s with a heptolide skeleton (almuheptolide-A (1) type) and 7-alkoxylated de lta-lactones with a saturated furanopyrone skeleton (etharvensin (8) type) have been successfully achieved from the chiral unsaturated alpha-pyrone al tholactone (7). This new method is a direct and one-step enantiospecific al koxylation of altholactone (7) in concentrated acid medium, followed by for mation of the eight-membered-ring zeta-lactone. The reaction mechanism oper ating in the synthesis of the heptolide skeleton is postulated to be a dire ct Michael-type addition. Concerted opening of both the alpha-pyrone and te trahydrofuran rings and subsequent intramolecular rearrangement with the ri ng closure lead to almuheptolide-A (1). This compound (1) and its diacetate d derivative (1a) showed potent and selective inhibitory activity toward ma mmalian mitochondrial respiratory chain complex I. This mechanism of action , reported here for the first time, provides a possible explanation for the cytotoxic and antitumor activities previously described for related natura l compounds.