ENANTIOSELECTIVE TOTAL SYNTHESIS OF (-6-EPI-MEVINOLIN AND ITS ANALOGS- EFFICIENT CONSTRUCTION OF THE HEXAHYDRONAPHTHALENE MOIETY BY HIGH PRESSURE-PROMOTED INTRAMOLECULAR DIELS-ALDER REACTION OF HYLSILYL)OXY]-6-METHYL-2,8,10-DODECATRIEN-4-ONE())

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, (+)-6-epi-mevinolin (2a) and (+)-6-epi-4a,5-dihydromevinolin (2b), wer e prepared by combining two nonracemic units, phosphonate 3 and decali n 4, which were prepared from enantiopure 3-substituted pentanedioic a cid monoesters 5a and 5b, respectively. Each acid was synthesized from cyclic anhydrides 7a and 7b by diastereoselective ring opening by mea ns of (S)-benzyl mandelate as a common chiral auxiliary. The construct ion of decalin moiety 4 was accomplished by asymmetric intramolecular Diels-Alder (IMDA) reaction of nonracemic trienone 6 bearing a methyl group as a chiral controller. The IMDA diastereoselectivity of trienon e 6 is discussed in terms of the configuration of(E)- and (Z)-dienophi les which are activated by an endogenous carbonyl group. The IMDA reac tion of(R)-(Z)-6 under high pressure is highly selective and gives cis -decalins exclusively with preferential formation of 4 over 16. The in hibitory activity of (+)-6-epi-mevinolin (2a) and several analogs agai nst HMG-CoA reductase was compared with mevinolin (1b). (+)-6-epi-Mevi nolin (2a) was shown to be half as potent as mevinolin (1b) while (+)- 6-epi-4a,5-dihydromevinolin (2b) was as potent as mevinolin.