Highly stereoselective hydrogenations—As key‐steps in the total synthesis of statins

Abstract

Statins are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase) and became the standard of care for treatment of hypercholesterolemia because of their efficacy, safety, and long-term benefits. They are administered as diastereo- and enantiomerically pure compounds. We summarize here two new approaches for the total synthesis of the most important representatives, atorvastatin, and rosuvastatin, based on highly stereoselective hydrogenations as key-steps.

Ru-Catalyzed Asymmetric Hydrogenation of 3-Oxoglutaric Acid Derivatives via Solvent-Assisted Pinpoint Recognition of Carbonyls in Close Chemical Propinquity

“…These hydrogenation products may provide important intermediates for statins . For extension, several geminal substituents were introduced onto the methylenes in hoping that they may influence the competing coordinations between the two pairs of the β-dicarbonyl system to the catalyst center.…”

A Practical Synthesis of Rosuvastatin and Other Statin Intermediates

“…Using a side chain with a pre‐existing chiral centre in correspondence to the protected hydroxyl function presents the advantage that the selective reduction of the carbonyl group of intermediates 11 and 14 to the corresponding syn di‐hydroxyl products can be easily achieved after removal of TBDMS group, as previously reported for rosuvastatin ( 7 )7b,7f and pitavastatin ( 6 ) 7d,14. Finally, the free acid form of statins can be easily obtained through the basic cleavage of the methyl ester group.…”