Chemical synthesis of 3-ethylcompactin, an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A reductase

Abstract

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 (LiAlH₄) 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 TiCl₃(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.