Chirotech Technology Ltd.

BACKGROUND: Pharmaceutical companies continue to evaluate β‐amino acids and β‐lactams in a range of drug candidates. The development of a highly efficient and selective bioresolution of cyclic β‐lactam substrates could yield enantiopure lactams and β‐amino acids with medicinal potential. The aim of this work was to discover and develop a biocatalyst capable of selectively hydrolysing β‐lactam substrates.RESULTS: Screening of our in‐house culture collection led to the discovery of a microorganism, Rhodococcus globerulus (NCIMB 41042) with β‐lactamase activity. Whole‐cell bioresolutions of the β‐lactams 1–4 were successfully carried out and in all cases enantiomeric excesses of the residual lactam and amino acid product were found to be greater than 98%. For one example, the bioresolution was optimised to operate at 60 g L−1 substrate concentration with a 20% wt/wt cell paste loading.CONCLUSION: A microorganism, Rhodococcus globerulus (NCIMB 41042), capable of selectively hydrolysing a range of cyclic β‐lactams, has been discovered. A scalable whole‐cell bioresolution process has been developed, leading to the synthesis of multigram quantities of enantiomerically pure β‐lactams and β‐amino acids. Copyright © 2007 Society of Chemical Industry

Stoichiometric sodium borohydride is frequently used in the chemoselective reduction of ketones to racemic secondary alcs.Catalytic homogeneous hydrogenation using (diphosphine)RuCl₂(diamine) complexes provides a practical and economic alternative.A range of substrates were investigated and the optimum precatalyst identified in each case.Norcamphor was reduced with high diastereoselectivity using (Ph₃P)₂RuCl₂(en); (E)-4-phenylbut-3-en-2-one was reduced with good chemoselectivity, and acetophenone was hydrogenated very efficiently using the same precatalyst.Isophorone and 3-dimethylaminopropiophenone were effectively hydrogenated using (dppf)RuCl₂(en).

An efficient, scaleable synthesis of Et (R)-4-cyano-3-hydroxybutyrate, a potential intermediate in the synthesis of Atorvastatin (Lipitor), has been developed.The three-stage process starts with reaction of low-cost epichlorohydrin with cyanide to give 3-hydroxyglutaronitrile (3-HGN).The second stage utilizes a nitrilase-catalyzed desymmetrisation of 3-HGN.The nitrilase reaction has been optimized to work at 3 M (330 g/L) substrate concentration, pH 7.5, 27 °C.Under these conditions, with an enzyme loading of 6 wt %, 100% conversion and 99% ee product is obtained in 16 h.This material is then esterified to give the target compound, Et (R)-4-cyano-3-hydroxybutyrate.The cost-effectiveness of the process is determined by three factors: use of a low-cost starting material, the introduction of the chiral center by desymmetrisation as opposed to kinetic resolution, and the use of Pfe̅nex Expression Technol. to allow a lower-cost supply of biocatalyst.