SYNTHESES OF HMG-COA REDUCTASE INHIBITORS

The rate-limiting enzyme in the cholesterol biosynthesis has been shown to be 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), which converts HMG-CoA to mevalonic acid. Inhibition of the enzyme is proved to be an effective method for therapeutic intervention in hypercholesterolemia. For example, treatment of atherosclerosis has been convincingly established by recent clinical success of lovastatin, pravastatin, simvastatin or its relative. Accordingly, efforts have been made to discover more potent and better tolerating synthetic analogs, having trans-4-hydroxytetrahydro-2-pyrone ring or its seco acid form 3,5-dihydroxy-pentanoic acid moiety in common. Although earlier syntheses suffered from low overall yields along with many steps and low selectivity, efficient and highly stereoselective syntheses have been developed last few years. Herein is reviewed recent progress in synthetic efforts of HMG-CoA reductase inhibitor with the emphasis on (1) connection of an aryl unit with the mevalonic acid moiety through multistep synthesis, Wittig-Horner-Emmons reaction, elmination reaction, or cross-coupling reaction and (2) synthesis of optically active lactone moiety by optical resolution, asymmetric reaction, or use of a chiral synthon.