Total synthesis of both (+)-compactin and (+)-mevinolin. A general strategy based on the use of a special titanium reagent for dicarbonyl coupling

Article abstract of DOI:10.1021/ja00164a024

A strategy is described for stereocontrolled synthesis of hypocholesterolemic compounds, (+)-compactin and (+)-mevinolin, by an approach (Scheme II) based on 6, 7, 4-pentenal (9a), and (R)-3-methyl-4-pentenal (9b). The Evans asymmetric Diels-Alder technique was used (Scheme III) to prepare 13, which was converted into the cis ester 17. Chain extension, iodolactonization, and elimination of HI then gave optically pure 6. The homochiral epoxide 24, made (Scheme IV) from (S)-malic acid, was converted into 25 and then, by iodocarbonation, hydrolysis, and ketalization, into the iodo ketal 7. Evans asymmetric alkylation was used (Scheme V) to prepare 9b. Ozonolysis, ketalization, and reduction (LiAlH₄) of 28 gave 31, which was transformed by Swern oxidation, Wittig methylenation, and acid hydrolysis into 9b. An optically pure intermediate (8), common to both syntheses, was assembled (Scheme VI) by alkylation of 6 with 7, reduction to a mixture of lactols, allylic oxidation, and decarbonylation. Aldol condensation (Scheme VII) of 8 with 4-pentenal, triethylsilylation, and ozonolysis gave the enone aldehydes 39, epimeric at C-1. A modified McMurry reaction requiring an excess of a reagent prepared from C₈K and TiCl₃ (2:1 molar ratio) in DME, produced the ethers 40, which were converted into (+)-compactin by appropriate modification of the oxygen functionality. The strategy is general and was applied with minor modifications (Scheme VIII) to the synthesis of (+)-mevinolin.