TY  - GEN
T1  - Process development with bifunctional chiral epoxides to acess single enantiomers of pharmaceutical intermediates
A1  - Ikunaka, Masaya
LA  - English
PB  - Malaysian Palm oil Board
YR  - 2015
UL  - http://discoverylib.upm.edu.my/discovery/Record/oai:http:--agris.upm.edu.my:0-8328
AB  - Two selected case studies on process development will be discussed: one is on the enantiocontrolled synthesis of (S)-3-hydroxytetradecanoic acid (2), an intermediate of ONO-4007 (3) possessing anti tumor activity, which employs terminally differentiated double homologation on (S)-epichlorohydrin (ECH) (1b). The other is on the enantioselective access to N-4-cyano-3-trifluoromethylphenyl (S)-2,3-dihydroxy2-methylpropanamide (5a), an intermediate of (R)-bicultamde (5b) exhibiting potent anti androgen activity, which starts with enantioconvergent preparation of (R)-3-benzyloxy-2-methylpropane-1, 2-diol (4) from O-benzyl (±)-2-methylglycidol (1c) by the enantiocomplementary hydrolysis using Bacillus subtills epoxide hydrolase (BSEH) and H2S04 in sequence. In each case study, emphasis will be placed on how to select viable synthetic routes on the basis of availability of single enantiomers of chiral starting materials and preparative methods thereof. In the chemoenzymatic synthesis of (S)-5a, BSEH indispensable for building its quaternary stereogenie center is developed from scratch, which culminates in successful over expression of its gene from B. subtilis JCM 10629 under the influence of an amylase promoter and terminator of B. amyloliquefaciens NBRC 15535 in an engineered strain of B. subtilis MT-2 defiCient in neutral protease.
KW  - Hydrolysis
KW  - Bacillus subtilis
KW  - Epoxides
KW  - Hydrolases
KW  - Proteases
ER  -