Synthesis of four chiral isomers of β-lactone DU-6622 and inhibition of HMG-CoA synthase by the specific (2R,3R)-isomer

Four chiral forms of the β-lactone DU-6622 (3-hydroxy-2-(hydroxymethyl)-5-[7-(methoxycarbonyl)naphthalen-1-yl]pen tanoic acid 1,3-lactone) were prepared to investigate their inhibitory activity against 3-hydroxy-3-methylglutarly-CoA (HMC-CoA) synthase. The (2R,3R)-β-lactone isomer (+)8a, having the same stereochemistry as that of the fungal β-lactone 1233A, showed the most potent HMG-CoA synthase inhibitory activity (IC₅₀: 0.098 μM). The other three β-lactone isomers, (2S,3R)((-)-8b), (2S,3S)-((-)-8a), and (2R,3S)-isomers ((+)-8b), were weaker inhibitors with larger IC₅₀ values of 9.4, 31, and 360 μM, respectively. Thus, it was concluded that the (2R,3R) stereochemistry of the β-lactone ring is responsible for HMG-CoA synthase inhibition.