SYNTHESIS OF 4 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 )-5-[7-(methoxycarbonyl) -naphthalen-1-yl]pentanoic acid 1,3-lactone) were prepared to investig ate 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 larg er IC50 values of 9.4, 31, and 360 mu M, respectively. Thus, it was co ncluded that the (2R,3R) stereochemistry of the beta-lactone ring is r esponsible for HMG-CoA synthase inhibition.