Back to Search
Start Over
Enzymatic synthesis of chiral intermediates for Omapatrilat, an antihypertensive drug
- Source :
- Biomolecular Engineering. 17:167-182
- Publication Year :
- 2001
- Publisher :
- Elsevier BV, 2001.
-
Abstract
- Biocatalytic processes were used to prepare chiral intermediates required for the synthesis of Omapatrilat 1 by three different routes. The synthesis and enzymatic conversion of 2-keto-6-hydroxyhexanoic acid 3 to L-6-hydroxynorleucine 2 was demonstrated by reductive amination using beef liver glutamate dehydrogenase. To avoid the lengthy chemical synthesis of the ketoacid 3, a second route was developed to prepare the ketoacid by treatment of racemic 6-hydroxy norleucine [readily available from hydrolysis of 5-(4-hydroxybutyl) hydantoin 4] with D-amino acid oxidase from porcine kidney or Trigonopsis variabilis followed by reductive amination to convert the mixture completely to L-6-hydroxynorleucine in 98% yield and 99% enantiomeric excess (e.e.). The enzymatic synthesis of (S)-2-amino-5-(1,3-dioxolan-2-yl)-pentanoic acid (allysine ethylene acetal, 5) was demonstrated using phenylalanine dehydrogenase (PDH) from T. intermedius. Phenylalanine dehydrogenase was cloned and overexpressed in Escherichia coli and Pichia pastoris. Using PDH from E. coli or P. pastoris, the enzymatic process was scale-up to prepare kg quantity of allysine ethylene acetal 5. The reaction yields of >94% and e.e. of >98% were obtained for allysine ethylene acetal 5. An enzymatic process was developed for the synthesis of [4S-(4a,7a,10ab)]1-octahydro-5-oxo-4 [[(phenylmethoxy)carbonyl]amino]-7H-pyrido-[2,1-b] [1,3]thiazepine-7-carboxylic acid [BMS-199541-01]. The enzymatic oxidation of the epsilon-amino group of lysine in the dipeptide dimer N(2)-[N[[(phenyl-methoxy)carbonyl] L-homocysteinyl] L-lysine)-1,1-disulphide [BMS-201391-01] to produce BMS-199541-01 using a novel L-lysine epsilon-aminotransferase (LAT) from Sphingomonas paucimobilis SC 16113 was demonstrated. This enzyme was overexpressed in E. coli and a process was developed using the recombinant enzyme.
- Subjects :
- D-Amino-Acid Oxidase
Pyridines
Thiazepines
Stereochemistry
L-Lysine 6-Transaminase
Norleucine
Lysine
Hydantoin
Bioengineering
Reductive amination
Chemical synthesis
Pichia
chemistry.chemical_compound
Bioreactors
Glutamate Dehydrogenase
Escherichia coli
Organic chemistry
Enantiomeric excess
Molecular Biology
Antihypertensive Agents
Transaminases
Dipeptide
Stereoisomerism
Recombinant Proteins
Enzymes
Phenylalanine dehydrogenase
chemistry
Fermentation
Amino Acid Oxidoreductases
Biotechnology
Subjects
Details
- ISSN :
- 13890344
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Biomolecular Engineering
- Accession number :
- edsair.doi.dedup.....0388319578c35b4b4efc40e17e93ae93