Back to Search
Start Over
Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture.
- Source :
-
Science (New York, N.Y.) [Science] 2010 Jul 16; Vol. 329 (5989), pp. 305-9. Date of Electronic Publication: 2010 Jun 17. - Publication Year :
- 2010
-
Abstract
- Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.
- Subjects :
- Biocatalysis
Catalytic Domain
Hypoglycemic Agents metabolism
Ketones metabolism
Models, Molecular
Molecular Structure
Mutagenesis
Protein Conformation
Pyrazines metabolism
Sitagliptin Phosphate
Solubility
Stereoisomerism
Substrate Specificity
Transaminases genetics
Transaminases metabolism
Triazoles metabolism
Amines chemical synthesis
Directed Molecular Evolution
Hypoglycemic Agents chemical synthesis
Ketones chemistry
Protein Engineering
Pyrazines chemical synthesis
Transaminases chemistry
Triazoles chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9203
- Volume :
- 329
- Issue :
- 5989
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 20558668
- Full Text :
- https://doi.org/10.1126/science.1188934