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SYNTHESIS OF A CON FORMATIONALLY RESTRAINED 4-ARYLTHIOPHENE-3-HEPTENOIC ACID AND ITS EVALUATION AS AN HMG COENZYME A REDUCTASE INHIBITOR

A 4-phenylthiophene tethered to the 5-position of the heterocycle was synthesized from 1benzosuberone. The key steps in the synthesis were the tandem thiolacetate hydrolysis Michael addition intramolecular Wittig reaction (5 -> 2) and the chelation-controlled reduction of the hydroxy ß-ketoester (12 —> 13). The product 14 exhibited nearly identical in vivo potency to the non-tethered analogs. Introduction Coronary heart disease remains one of the leading causes of death in western civilization. Elevated levels of serum cholesterol, and in particular, low density lipoprotein (LDL) cholesterol are strongly correlated with risk of morbidity and mortality due to this disease (1-3). The primary defense against elevated LDL cholesterol levels is dietary intervention. However, for patients nonresponsive to this intervention pharmacological treatment is indicated. The goal of developing safe and effective therapeutic agents to lower LDL-cholesterol has focused primarily on inhibitors of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase, the key enzyme which catalyzes the conversion of HMG-CoA to mevalonic acid in the cholesterol biosynthetic pathway. A variety of HMG-CoA reductase inhibitors with a common eryiAro-ß^dihydroxyheptenoic acid motif have been reported (4). We recently described the design and biological evaluation of a series of highly functionalized thiophene-based 3,5-dihydroxyheptenoic acid derivatives (D as inhibitors of HMG-CoA reductase (5). Within this series of compounds we found that the in vitro activity was generally higher when the substituent R2 at C-4 of the thiophene ring was a phenyl group (either substituted or unsubstituted). The biological activity was less sensitive to the nature of the substituent Ri at C-5. Groups such as phenyl, alkenyl, or small alkyl moieties like methyl or isopropyl were tolerated. With this data in hand we wished to investigate the effect of tethering the phenyl group at C-4 to the C-5 position of the thiophene ring which would effectively rigidify the conformation of the phenyl with respect to the plane of the thiophene heterocycle (2). We initially considered a one, two, or three-carbon chain as likely candidates, however, we ruled out the one-carbon (CH2) analog which would possess a highly oxidizable methylene unit between two aromatic groups. The next higher homolog, the two-carbon (CH2CH2) analog was also ruled out for synthetic reasons. The conditions used for the aromatization of the thiophene ring (Scheme 1,