Irreducible Analogues of Mevaldic Acid Coenzyme A Hemithioacetal as Potential Inhibitors of HMG-CoA Reductase. 2. Synthesis of a secondary Alcohol Analogue of Mevaldic Acid Pantetheine Hemithioacetal and an Amide Analogue of 3-Hydroxy-3-methylglutaryl-S-pantetheine

Article abstract of DOI:10.1021/jo00361a003

Syntheses of erythro-3b, threo-3b, and 4, which are irreducible analogues of mevaldic acid coenzyme A hemithioacetal, 1, and mevaldic acid pantetheine hemithioacetal, 2, are described.Synthesis of 4 required conversion of the acetal ester 8 to 7 with ethylenediamine followed by coupling of 7 with pantothenic acid, 6, to give 9.The acetal in 9 was hydrolyzed to provide 10, oxidation of which completed the synthesis.Preparation of the two diastereomers of 3b began with ozonization of 11 to give aldehyde ester 12 which was in turn converted to the triol 14 by treatmentwith the Grignard reagent 13.Hydrolysis of 14 followed by lactonization provided 16.The primary alcohol in 16 was converted, via the tosylate 17 and the azide 18, to the amine 19.Coupling 19 with 6 provided the cis and trans lactones 21 which could be separated by HPLC and hydrolyzed to threo- and erythro-3b, respectively.The products, which were initially designed as inhibitors, are being examined as probes of the enzyme HMG-CoA reductase for which 1 is postulated to be a strongly enzyme-bound intermediate.