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

Four chiral forms of the beta-lactone DU-6622 (3-hydroxy-2-(hydroxymethyl)-5-[7-(methoxycarbonyl)-naphthalen-1-yl]pentanoic acid 1,3-lactone) were prepared to investigate their inhibitory activity against 3-hydroxy-3-methylglutarly-CoA (HMG-CoA) synthase. The (2R,3R)-beta-lactone isomer (+)-8a, having the same stereochemistry as that of the fungal beta-lactone 1233A, showed the most potent HMG-CoA synthase inhibitory activity(IC50: 0.098 mu M). The other three beta-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 mu M, respectively. Thus, it was concluded that the (2R,3R) stereochemistry of the beta-lactone ring is responsible for HMG-CoA synthase inhibition.