Desymmetrizations 3-hydroxyglutaronitrile

The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

An alternative approach, explored by Dowpharma, involved the desymmetrization of prochiral dinitrile (meso)-3-hydroxyglutaronitrile (3-HGN) with a nitrUase provided by Diversa (Figure 6.2b). The resulting (R)-3-hydroxy-4-cyanobutyrate can in several steps be converted into ethyl 6-cyano-3R,5R-dihydroxyhexanoate, an advanced intermediate to atorvastatin. 3-HGN could be easily prepared from... 

FIGURE 17.17 Enzymatic desymmetrization of 3-hydroxyglutaronitrile, key synthon for the production of Lipitor. 

Bergeron, S., Chaphn, D.A., Edwards, J.H., etal. 2006. Nitrilase-catalysed desymmetrization of 3-hydroxyglutaronitrile Preparation of a statin side-chain intermediate. Organic Process Reseach and Development, 10 661-5. 

Scheme 4.18 Desymmetrization of hydroxyglutaronitrile using a nitrilase enzyme...

Desymmetrization of S-hydroxyglutaronitrile 17 toward (l9-4-cyano-3-hydroxybutyric acid 18, a key intermediate in the synthesis of Atorvastalin 19, L-Camitine 20 and (/ )-4-amino-3-hydroxybutyric acid (GABOB, 21) [29,30. ... 

A nitrilase enzyme (BD9570,0.1 unit/mg, Diversa) was used to desymmetrize prochiral substrate 14 to afford (R)-15. In this process, an aqueous solution of 100 mM NaH PO at pH 7.5 (510 mL) was added to lyophilized nitrilase enzyme powder (15.15 g). The mixture was stirred at 27°C (to rehydrate the lyophilized enzyme powder) for 40 min. 3-Hydroxyglutaronitrile (252.5 g) was then charged over 10 min. The mixture was stirred at 27°C for 16 h and then cooled to 2°C prior to acidification to give pH 2. Celite was charged (25 g) and the slurry filtered. The filtrate was extracted with methyl ethyl ketone. The combined methyl ethyl ketone extracts were evaporated in vacuo (15 mbar, 40°C) to yield the product 15 as a brown liquid (240.8 g, 81% yield ee 98.8%). 

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