Lactone Pathway to Statins Utilizing the Wittig Reaction. The Synthesis of Rosuvastatin

Abstract

The first entry to statins via lactonized side chain is reported, exemplified by the synthesis of rosuvastatin. The key step is Wittig coupling of (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxotetrahydro-2H-pyran-2-carbaldehyde and phosphonium salt of an appropriately functionalized pyrimidine heterocycle. One-pot deprotection and hydrolysis of the resulting 4-O-TBS rosuvastatin lactone provided rosuvastatin in high yield.

A Highly Productive, Whole-Cell DERA Chemoenzymatic Process for Production of Key Lactonized Side-Chain Intermediates in Statin Synthesis

“…Measurement of the reaction intermediate ( 8 ) and side-product ( 3a ) accumulation allowed optimization of the feeding strategy, which proved to be a yield-determining parameter. Further conversion to advanced downstream statin intermediates confirms the efficient total synthesis of super-statins based on enzymatic technology and employing our previously described methodology [15]–[16], [78]–[81], [83].…”

“…The compounds were isolated and characterized with 1 H-NMR, 13 C-NMR and HRMS (Information S2). The confirmation of the structure of 3f and 3g, previously shown to be excellent starting material for super-statin synthesis [15]–[16], [78]–[81], [83], broadens the scope of molecules which can be obtained by DERA-catalyzed reactions, and this is the first time these molecules have been synthesized enzymatically. The successful production of the dimethoxy-substituted lactol 3f for which unsuccessful synthesis attempts (using DERA) have been reported [57], was especially surprising.…”

“…These studies have demonstrated that statins are readily accessible through a variety of different approaches utilizing various types of side-chain precursors. Indeed, statins have been built from open side-chain derivatives, lactol type precursors [14] and very recently from a lactonized side-chain derivative [15], [16]. Due to the increased commercial demand for statins and the need for a simple preparation on industrial scale, impetus for even more efficient, environmentally friendly and easily scalable preparation of the side-chain derivatives appeared.…”

“…Furthermore, the obtained hydroxymethylene-lactone (6) was for the first time successfully transformed to its formylated analogue (7) suitable for coupling with the heterocyclic counterpart [81]. Moreover, we have demonstrated for the first time that statins can be directly assembled from the lactonized side-chain precursor (7) [15], [16].…”

An efficient approach to the key intermediate of rosuvastatin

“…Statins [1,2] such as atorvastatin [3,4] and rosuvastatin ( Figure 1) [5,6] are very effective inhibitors [7] of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) and are the most powerful lipid-lowering agents in use for people with or at risk of cardiovascular disease [8]. Rosuvastatin [9] has been called a super statin because it appears to reduce low-density lipoprotein (LDL) cholesterol to a greater degree than competitors in its class without additional adverse effects.…”