SYNTHESIS AND INHIBITORY-ACTION ON HMG-COA SYNTHASE OF RACEMIC AND OPTICALLY-ACTIVE OXETAN-2-ONES (BETA-LACTONES)

A homologous series of both C3-unsubstituted and C3-methyl substituted oxetan-2-ones (beta-lactones) was investigated as potential inhibitor s of yeast 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase. S everal reported methods for racemic beta-lactone synthesis were studie d for preparation of the target series. In addition, a novel aluminum- based Lewis acid obtained by combination of Et2AlCl with (IR,2R)-2-[(d iphenyl)hydroxymethyl] cyclohexan-1-ol was studied for the asymmetric [2+2] cycloaddition of aldehydes and trimethylsilylketene. This Lewis acid exhibited good reactivity but variable enantioselectivity (22-85% ee). In in vitro assays using both native and recombinant HMG-CoA syn thase from Saccharomyces cerevisiae, oxetan-2-ones mono-substituted at C4 with linear alkyl chains gave IC(50)s that decreased monotonically with chain length up to 10 carbons and then rose rapidly for longer c hains. The irans isomers of 3-methyl-4-alkyl-oxetan-2-ones showed a si milar trend but had 1.3- to 5.6-fold lower IC(50)s. The results imply a substantial hydrophobic pocket in this enzyme that interacts with bo th C-3 and C-4 substituents of oxetan-2-one inhibitors. (C) 1998 Elsev ier Science Ltd. All rights reserved.