Process development with Bifunctional chiral epoxides to access single enantiomrs 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) processing anti-Tnmour activity, which employs double homologation of (S)-epichlorohydrin (ECH) (1b) with its ter mini being differentiated The other is on the enantioselective access to N-4-cyano-3-Trifluoromethyiphenyl-(S)-2,3-dihydroxy-2-methylpropananmide (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 O-benzyl (±)-2- methylglycidol (1c) by the enantiocomplementary hydroxysis 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 anantiomers of chiral starting materials and preparative methods thereof. In the chemoenzymatic synthesis of (S)-5a, BSEH indispensable for building its quatermary stereogenic center is developed from scratch, which culminates in successful overexpression of its gene from B. subtilis JCM 10629 under the infuence of an amylase promother 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 plam oil.