CHEMICAL SYNTHESIS OF 3-ETHYLCOMPACTIN, AN INHIBITOR OF 3-HYDROXY-3-METHYLGLUTARYLCOENZYME-A REDUCTASE

A method is described for stereocontrolled synthesis of (+)-3-ethylcompactin (1c), a compound that inhibits rat liver HMG CoA reductase with a similar potency to mevinolin. The synthetic approach is a general one and involves linking a pent-4-enal (3) with a substituted cyclohexenone (2). Evans asymmetric alkylation was used (Scheme 2) to prepare the oxazolidinone (6). Ozonolysis, acetalization, and reduction (LiAIH4) then gave the alcohol (9), and this was transformed by Swern oxidation, Wittig methylenation, and acid hydrolysis into (R)-3-ethylpent-4-enal (12). Aldol condensation (Scheme 3) of the cyclohexenone (2) with the aldehyde (12), followed by triethylsilylation, and ozonolysis gave the enone aldehyde (15). A modified McMurry reaction, requiring an excess of a reagent prepared from C8K and TiCI3 (2:1 molar ratio) in 1,2-dimethoxyethane, then produced the hexahydronaphthyl ether (16), which was converted into (+)-3-ethylcompactin by appropriate modification of the oxygen functionality.