Biocatalysis statin side chains

Bergeron S, Chaplin D, Edwards JH, Ellis BS, Hill CL, Holt-Tiffin K, Knight JR, Mahoney T, Osborne AP, Ruecroft G (2006) Nitrilase-catalyzed desym-metrization of 3-hydroxyglutaronitrile preparation of a statin side-chain intermediate. Org Proc Res Dev 10 661-665 Burns M, Weaver J, Wong J (2005) Stereoselective enzymic bioconversion of aliphatic dinitriles into cyano carboxylic acids. WO 2005100580 DeSantis G, Zhu Z, Greenberg W, Wong K, Chaplin J, Hanson SR, Farwell B, Nicholson LW, Rand CL, Weiner DP, Robertson D, Burk MJ (2002) An enzyme library approach to biocatalysis development of nitrilases for enantioselective production of carboxylic acid derivatives. J Am Chem Soc 124 9024-9025... 

Several approaches to statin side-chain intermediates have so far been discussed. Whereas these chemoenzymatic approaches provide clear benefits over the chemical processes, they do not harness the tme potential of biocatalysis as the biotransformations have simply been inserted into the existing chemical route. Wong and co-workers have developed a more biosynthetic-hke approach by using a mutant 2-deoxyiibose-5-phosphate aldolase (DERA)... 

Biocatalysis plays a central role in the manufacturing of statin side chains (Figure 6.2). A first set of approaches exploits enzymatic desymmetrization reactions, for example, of the methoxyacetyl ester of glutaric acid diethyl ester with commercially available a-chymotrypsin as explored by Ciba SC with a yield of 94% and enantiomeric excess of up to 98% [1]. In the optimized procedure, the substrate was available in a concentration of 1 M at an enzyme/substrate ratio of 7% (wt/wt), and the reaction took approximately a day. The subsequent steps to the final acetonide also involved a pig-liver esterase (PLE) catalyzed selective hydrolysis of the methoxyacetyl group (Figure 6.2a). 

Developments of enzymatic routes for the side chain of various drugs in the statin family, such as Lipitor from Pfizer and Crestor from Astra Zeneca, are very elegant applications of biocatalysis. Early on, several chemoenzymatic routes were developed to synthesize the side chain for statins, and these were based on replacing a chemical catalysis step with a biocatalytic step for the desired FGIs [18]. The substitution of stereoselective chemical reduction of keto ester to diol imder cryogenic... 

---