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 (R,2Z,8E,10E)-1-[(tert-Butyldimethylsilyl)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 ), were prepared by combining two nonracemic units, phosphonate 3 and decalin 4, which were prepared from enantiopure 3-substituted pentanedioic acid monoesters 5a and 5b, respectively. Each acid was synthesized from cyclic anhydrides 7a and 7b by diastereoselective ring opening by means of ( S )-benzyl mandelate as a common chiral auxiliary. The construction 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 trienone 6 is discussed in terms of the configuration of ( E )- and ( Z )-dienophiles which are activated by an endogenous carbonyl group. The IMDA reaction of ( R )-( Z )- 6 under high pressure is highly selective and gives cis -decalins exclusively with preferential formation of 4 over 16 . The inhibitory activity of (+)-6- epi -mevinolin ( 2a ) and several analogs against HMG-CoA reductase was compared with mevinolin ( 1b ). (+)-6- epi -Mevinolin ( 2a) was shown to be half as potent as mevinolin ( 1b ) while (+)-6- epi -4a,5-dihydromevinolin ( 2b) was as potent as mevinolin.