Process Development with Bifunctional Chiral Epoxides to Access Single Enantiomers of Pharmaceutical Intermediates

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-tumour activity, which employs double homologation of (S)-epichlorohydrin (ECH) (1b) with its termini being differentiated. The other is on the enantioselective access to N-4-cyano-3-trifluoromethylphenyl-(S)-2,3-dihydroxy-2methylpropanamide (5a), an intermediate of (R)-bicultamide (5b) exhibiting potent anti-androgen activity, which starts with enantioconvergent preparation of (R)-3-benzyloxy-2-methylpropane-1,2-diol (4) from Obenzyl (±)-2-methylglycidol (1c) by the enantiocomplementary hydrolysis using Bacillus subtilis epoxide hydrolase (BSEH) and H2SO4 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 stereogenic centre is developed from scratch, which culminates in successful overexpression 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. The discussion should help to develop process chemistry in producing value-added fine chemicals from glycerol, one of its natural sources being palm oil. PROCESS DEVELOPMENT WITH BIFUNCTIONAL CHIRAL EPOXIDES TO ACCESS SINGLE ENANTIOMERS OF PHARMACEUTICAL INTERMEDIATES MASAYA IKUNAKA* and TAKESHI SUGAI** Journal of Oil Palm Research (Special Issue October 2008) p. 143-158