| UPDATE | 02.02 |
| USES |
Co started a program to discover enzymes in this class 2 years ago, when only 14 such enzymes were known. Since then, Co has discovered of about 200 novel & unique nitrilases. And of these 175 are in bottles, available for screening. That rate of discovery would have been impossible with traditional screening of whole organisms. “EVEN IF NATURE does not get you to a enzyme with the exact properties you require, you can EVOLVE what you’ve discovered to your desired end point”. Evolution can yield a range of enzymes to handle a range of substrates & optimize a enzyme to the required process parameters. It may even enable access to both product enantiomers instead of just one. “Having enzymes available & evolution capabilities facilitates development considerably” To date, Co has nitrilases useful for enantioselective one-carbon homologa tion of aldehydes, prepn. of (R)-MANDELIC ACID deriv. at ee of up to 99% & prepn of (S)-PHENYLLACTIC ACID at 99% ee. Prepn of ETHYL (R)-3-HYDROXY-4-CYANOBUTYRATE. This beta-hydroxy ester is a intermediate in the synthesis of ATORVASTATIN All the enzymes previously discovered provide the S enantiomer. “We have 4 enzymes that give the R enantiomer & we’re getting 95-99% ee” A published route to the atorvastatin intermediate requires 6 steps, starting from 2,3-dihydroxychloropropane. Using NITRILASES & starting with EPICHLOROHYDRIN, Co proposes a different route that takes only THREE steps. First epichlorohydrin is chemically converted to 3-hydroxy-glutaronitri le. Next the symmetric prochiral prodt is desymmetrized by the action of a NITRILASE to a (R)-beta-hydroxy acid. And finally, chemical esterification yields the required R intermediate. Thus far, Co has performed the nitrilase step on the half-gram scale. “We’re scaling to 10 g right now” |
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