Biocatalytic synthesis of some chiral drug intermediates by oxidoreductases

Chiral intermediates were prepared by biocatalytic processes with oxidoreductases for the chemical synthesis of some pharmaceutical drug candidates. These include: (i) the microbial reduction of 1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-butanone (1) to R-(+)-1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-butanol (2) [R-(+)-BMY 14802], an antipsychotic agent; (ii) the reduction of N-4-(1-oxo-2-chloroacetyl ethyl) phenyl methane sulfonamide (3) to the corresponding chiral alcohol (4), an intermediate for D-(+)-N-4-(1-hydroxy-2-[(-methylethyl)amino]ethyl)phenyl methanesulfonamide [D-(+) sotalol], a beta-blocker with class III antiarrhythmic properties; (i) biotransformation of N epsilon-carbobenzoxy (CBZ)-L-lysine (7) to N epsilon-CBZ-L-oxylysine (5), an intermediate needed for synthesis of (S)-1-[6-amino-2-{[hydroxy(4-phenyl butyl)phosphinyl]oxy}1-oxohexyl]-L-proline (ceronapril), a new angiotensin converting enzyme inhibitor (6) and (iv) enzymatic synthesis of L-beta-hydroxyvaline (9) from alpha-keto-beta-hydroxyisovalerate (16). L-beta-Hydroxyvaline (9) is a key chiral intermediate needed for the synthesis of S-(Z)-{[1-(2-amino-4-thiazolyl)-2-{[2,2-dimethyl-4-oxo-1-(sulfooxy)-3-azetidinyl]amino}-2-oxoethylidene]amino}oxyacetic acid (tigemonam) (10), an orally active monobactam.