Irreducible Analogues of Mevaldic Acid Coenzyme A Hemithioacetal as Potential Inhibitors of HMG-CoA Reductase. Synthesis of a Carbon-Sulfur Interchanged Analogue of Mevaldic Acid Pantetheine Hemithioacetal

Article abstract of DOI:10.1021/jo00212a002

Synthesis of (3,5)-threo- and (3,5)-erythro-6-<<<<3-(2,4-dihydroxy-3,3-dimethylbutanoyl)amino>propanamido>methyl>thio>-3,5-dihydroxy-3-methylhexanoic acid, threo- and erythro-7d, as well as the corresponding δ-lactones, cis- and trans-13a, is described.The key step in the syntheses is the selective amidomethylation of the sulfhydryl in cis- or trans-4-hydroxy-6-(mercaptomethyl)-4-methyl-3,4,5,6-tetrahydro-2H-pyran-2-one, cis- or trans-13d, with N-(hydroxymethyl)pantothenamide, 23.The target compounds are the first in a class being explored as potential inhibitors of HMG-CoA reductase, the key regulated enzyme in cholesterol biosynthesis.They are structurally identical with mevaldic acid pantetheine hemithioacetal, 2b (a known substrate for the enzyme and an analogue of the enzyme-bound intermediate 2a), but they are unable to be reduced by the enzyme because the labile C-S bond in 2b has been replaced with a stable C-C bond in 7d by interchanging a carbon and a sulfur atom.