A new approach to the total synthesis of rosuvastatin

A new multi-step synthesis of the lipid-lowering agent rosuvastatin, involving two homogeneously catalyzed reaction steps, is described. The key building block, N-[4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-methylmeth- anesulfonamide (2), was prepared by Pd-catalyzed formylation with CO/H-2 (1:1, 50 bar, phosphane ligand/substrate ratio of 1:10). Several alternative pathways for the preparation of 2 were also tested, but were found to be inferior. Rosuvastatin precursor I was assembled by Wittig coupling of aldehyde 2 and ylide (R)-3, derived from a Ru-catalyzed asymmetric hydrogenation. The second stereogenic center was finally created by stereoselective reduction with Et2BOMe and NaBH4 to afford rosuvastatin ethyl ester. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008).