Chemo‐Enzymatic Approach to Statin Side‐Chain Building Blocks

Abstract

A versatile statin side-chain building block is obtained by an enzymatic desymmetrisation of the symmetrical glutaric acid diethyl ester. The monoacid is produced in almost quantitative yield in the desired high optical purity. The monoacid is easily converted to the corresponding acid chloride, which is a key compound to be elaborated to some statin side-chain derivatives. The optically active C-5 chain is subsequently elongated by two carbon atoms and syn-reduced to the final diol fragment.

Stereoselective synthesis of 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors

“…In 2003, Öhrlein and coworkers (Switzerland) published a asymmetric approach toward atorvastatin precursor 139 via a chiral C 7 -azido ester that utilized enzymatic desymmetrization of the symmetric diester 114 with requisite stereochemistry (Scheme 25). 65 This reaction was used to form chiral monoacid 135 in 94% yield and 98.1% ee using α-chymotrypsin as a biocatalyst, which was converted to chiral hydroxy-β-ketoester 136 by treatment with oxalyl chloride and side extension followed by hydrolysis of the methoxyacetyl group with pig-liver esterase. Chiral C 7 -azido ester 138 was formed in 94% yield and 98% ee from 136 through a series of classical reactions.…”

Biocatalyzed Synthesis of Statins: A Sustainable Strategy for the Preparation of Valuable Drugs

“…Aldehyde 34 can be easily obtained [186], while the preparation of enantiopure ylide 35 is much more complicated. Thus, several examples can be found in the literature starting from racemic diethyl 3-hydroxyglutarate, which had to be previously transformed in an activated derivative to react with the corresponding methyltriphenylphosphonium ylide to finally yield 35; although this route has been described using an enzymatic desymmetrization step [187,188], different side reactions were observed to decrease either the final yield or the enantiomeric excess. Recently, a bi-enzymatic process has been described for obtaining enantiopure monoester (R)-40 (Figure 9), combining a stereoselective hydrolysis of prochiral 38 to obtain (R)-39 with high yield and enantiopurity, and a subsequent removal of the acetyl group with cephalosporin acetyl esterase [189].…”

Cloning, expression, and characterization of a novel diketoreductase from <italic>Acinetobacter baylyi</italic>

“…1), are the top-selling cholesterol-lowering drugs in the world. However, because of the current complex and expensive route for synthesizing the chiral side chains, biocatalytic production of chiral side chain of statins has become a highly competitive area in which a number of approaches and routes have been reported [32][33][34]. Due to the exactly same stereochemistry of 2 compared with the chiral side chain of statins, the unique characteristics of DKR, in terms of the catalytic activity and the excellent stereoselectivity, make this enzyme as an attractive biocatalyst for the development of a practical, efficient, and economic process for the synthesis of statin drugs.…”