16397-19-6Relevant articles and documents
Data mining of amine dehydrogenases for the synthesis of enantiopure amino alcohols
Guo, Jinggong,Li, Jun-Kuan,Ma, Jun-An,Miao, Yuchen,Qu, Ge,Sun, Zhoutong,Wang, Hongyue
, p. 5945 - 5952 (2020/10/08)
Chiral amino alcohols are essential building blocks for the pharmaceutical industry, and are widely present in natural and synthetic bioactive compounds. Amine dehydrogenases (AmDHs) can asymmetrically reduce prochiral ketones with low-cost ammonia to chiral amines and water as by-products, using NAD(P)H as a cofactor under mild conditions, but hydroxy ketones with formation of chiral hydroxy amines have rarely been investigated. In this study, six new bacterial AmDHs derived from amino acid dehydrogenases (AADHs) were identified by data mining, and five out of the six enzymes were able to efficiently reduce 1-hydroxybutan-2-one (1a) to (S)-2-aminobutan-1-ol ((S)-2a) with 19-99% conversions and 99% ee. The five AmDHs were purified and biochemically characterized for reductive amination activity towards substrate 1a with the optimal pH at 8.5 or 9.0 and the optimal temperature at 45 °C, 50 °C or 55 °C, and provided reductive amination of a broad range of prochiral α-hydroxy ketones, and even of a model β-hydroxy ketone leading to β-hydroxy amine with 99% ee. Our study expands the toolbox of AmDHs in the synthesis of chiral amino alcohols.
Enantioselective Synthesis of Chiral Vicinal Amino Alcohols Using Amine Dehydrogenases
Chen, Fei-Fei,Cosgrove, Sebastian C.,Birmingham, William R.,Mangas-Sanchez, Juan,Citoler, Joan,Thompson, Matthew P.,Zheng, Gao-Wei,Xu, Jian-He,Turner, Nicholas J.
, p. 11813 - 11818 (2019/12/02)
Chiral vicinal amino alcohols are an important motif found in many biologically active molecules. In this study, biocatalytic reductive amination of α-hydroxy ketones with ammonia was investigated using engineered amine dehydrogenases (AmDHs) derived from the leucine amino acid dehydrogenase (AADH) from Lysinibacillus fusiformis. The AmDHs thus identified enabled the synthesis of (S)-configured vicinal amino alcohols from the corresponding α-hydroxy ketones in up to 99% conversions and >99% ee. One of the AmDH variants was used to prepare a key intermediate for the antituberculosis pharmaceutical ethambutol.
Discovery of narlaprevir (SCH 900518): A potent, second generation HCV NS3 serine protease inhibitor
Arasappan, Ashok,Bennett, Frank,Bogen, Stephane L.,Venkatraman, Srikanth,Blackman, Melissa,Chen, Kevin X.,Hendrata, Siska,Huang, Yuhua,Huelgas, Regina M.,Nair, Latha,Padilla, Angela I.,Pan, Weidong,Pike, Russell,Pinto, Patrick,Ruan, Sumei,Sannigrahi, Mousumi,Velazquez, Francisco,Vibulbhan, Bancha,Wu, Wanli,Yang, Weiying,Saksena, Anil K.,Girijavallabhan, Viyyoor,Shih, Neng-Yang,Kong, Jianshe,Meng, Tao,Jin, Yan,Wong, Jesse,McNamkra, Paul,Prongay, Andrew,Madison, Vincent,Piwinski, John J.,Cheng, Kuo-Chi,Morrison, Richard,Malcolm, Bruce,Tong, Xiao,Ralston, Robert,Njoroge, F. George
scheme or table, p. 64 - 69 (2010/12/29)
Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (～10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.
