Process development with bifunctional chiral epoxides to acess single enantiomers of pharmaceutical intermediates

Ikunaka Masaya, . and Sugai Takeshi, . (2007) Process development with bifunctional chiral epoxides to acess single enantiomers of pharmaceutical intermediates. [Proceedings Paper]

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.

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Abstract

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.

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Item Type:	Proceedings Paper
Additional Information:	Available at Perpustakaan Sultan Abdul Samad Universiti Putra Malaysia 43400 UPM Serdang Selangor Malaysia. TP684 P3I61 2007 Call Number
AGROVOC Term:	Hydrolysis
AGROVOC Term:	Bacillus subtilis
AGROVOC Term:	Epoxides
AGROVOC Term:	Hydrolases
AGROVOC Term:	Proteases
Geographical Term:	MALAYSIA
Depositing User:	Ms. Suzila Mohamad Kasim
Last Modified:	24 Apr 2025 05:14
URI:	http://webagris.upm.edu.my/id/eprint/11769

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