No abstract

An efficient and concise asymmetric synthesis of pitavastatin calcium (1) starting from commercially available (S)-epichlorohydrin is described. A convergent C1 + C6 route allowed for the assembly of the pitavastatin C7 side chain via a Wittig reaction between phosphonium salt 2 and the enantiomerically pure C6-formyl side chain 3. The 1,3-syn-diol acetal motif in 3 was established with excellent stereo control by a diastereoselective bismuth-promoted two-component hemiacetal/oxa-Michael addition reaction of (S)-α,β-unsaturated ketone 4 with acetaldehyde.

A novel, stereoselective approach towards rosuvastatin calcium from the known (S)-homoallylic alcohol has been developed. The synthesis is highlighted by a regio- and stereocontrolled ICl-induced intramolecular cyclization of chiral homoallylic carbonate to deliver the C6-formyl statin side chain with a syn-1,3-diol moiety. An improved synthesis of the rosuvastatin pyrimidine core moiety is also included. Moreover, this methodology is useful in the asymmetric synthesis of structural variants of statins such as pitavastatin calcium and atorvastatin calcium and their related analogs.