5992-23-4Relevant academic research and scientific papers
Application of Transaminases in a Disperse System for the Bioamination of Hydrophobic Substrates
Berglund, Per,Fiorati, Andrea,Humble, Maria S.,Tessaro, Davide
, (2020/02/04)
The challenging bioamination of hydrophobic substrates has been attained through the employment of a disperse system consisting of a combination of a low polarity solvent (e. g. isooctane or methyl-tert-butylether), a non-ionic surfactant and a minimal amount of water. In these conditions, amine transaminases (ATA) were shown to efficiently carry out the reductive amination of variously substituted cyclohexanones, providing good conversions often coupled with a superior stereoselectivity if compared with the corresponding chemical reductive amination. An array of synthetically useful 4-substituted aminocyclohexanes was consequentially synthesized through biocatalysis, analyzed and stereochemically characterized. (Figure presented.).
Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases
Cosgrove, Sebastian C.,Grogan, Gideon,Mangas-Sanchez, Juan,Marshall, James R.,Palmer, Ryan B.,Ramsden, Jeremy I.,Sharma, Mahima,Thorpe, Thomas W.,Turner, Nicholas J.
, p. 5052 - 5057 (2020/06/09)
Chiral primary amines are important intermediates in the synthesis of pharmaceutical compounds. Fungal reductive aminases (RedAms) are NADPH-dependent dehydrogenases that catalyse reductive amination of a range of ketones with short-chain primary amines supplied in an equimolar ratio to give corresponding secondary amines. Herein we describe structural and biochemical characterisation as well as synthetic applications of two RedAms fromNeosartoryaspp. (NfRedAm andNfisRedAm) that display a distinctive activity amongst fungal RedAms, namely a superior ability to use ammonia as the amine partner. Using these enzymes, we demonstrate the synthesis of a broad range of primary amines, with conversions up to >97% and excellent enantiomeric excess. Temperature dependent studies showed that these homologues also possess greater thermal stability compared to other enzymes within this family. Their synthetic applicability is further demonstrated by the production of several primary and secondary amines with turnover numbers (TN) up to 14 000 as well as continous flow reactions, obtaining chiral amines such as (R)-2-aminohexane in space time yields up to 8.1 g L?1h?1. The remarkable features ofNfRedAmand NfisRedAm highlight their potential for wider synthetic application as well as expanding the biocatalytic toolbox available for chiral amine synthesis.
Reductive amination of ketonic compounds catalyzed by Cp*Ir(III) complexes bearing a picolinamidato ligand
Tanaka, Kouichi,Miki, Takashi,Murata, Kunihiko,Yamaguchi, Ayumi,Kayaki, Yoshihito,Kuwata, Shigeki,Ikariya, Takao,Watanabe, Masahito
, p. 10962 - 10977 (2019/09/03)
Cp*Ir complexes bearing a 2-picolinamide moiety serve as effective catalysts for the direct reductive amination of ketonic compounds to give primary amines under transfer hydrogenation conditions using ammonium formate as both the nitrogen and hydrogen source. The clean and operationally simple transformation proceeds with a substrate to catalyst molar ratio (S/C) of up to 20,000 at relatively low temperature and exhibits excellent chemoselectivity toward primary amines.
Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors
Hu, Carol H.,Wang, Tammy C.,Qiao, Jennifer X.,Haque, Lauren,Chen, Alice Y.A.,Taylor, David S.,Ying, Xiaohong,Onorato, Joelle M.,Galella, Michael,Shen, Hong,Huang, Christine S.,Toussaint, Nathalie,Li, Yi-Xin,Abell, Lynn,Adam, Leonard P.,Gordon, David,Wexler, Ruth R.,Finlay, Heather J.
, p. 3721 - 3725 (2018/10/24)
Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.
Synthesis, GluN2B affinity and selectivity of benzo[7]annulen-7-amines
Gawaskar, Sandeep,Schepmann, Dirk,Bonifazi, Alessandro,Wünsch, Bernhard
, p. 6638 - 6646 (2015/02/19)
Due to their beneficial side effect profile, NMDA receptor antagonists interacting selectively with the allosteric ifenprodil binding site of the GluN2B subunit are of major interest for the treatment of neurological and neurodegenerative disorders. A series of benzo[7]annulen-7-amines 6 was designed by conformational restriction of ifenprodil (1). At first the benzo[7]annulen-7-one 11 was prepared in a three-step synthesis comprising of a double Knoevenagel condensation of phthalaldehyde (7) with dimethyl 3-oxoglutarate (8), hydrogenation of 9 and saponification/decarboxylation of 10. Reductive amination of the ketone 11 with primary amines and NaBH(OAc)3 led to the secondary amines 6a-d, cis-6h and trans-6i. The tertiary amines 6e-g were obtained by SN2-substitution of the nosylate 13. Although H-bond forming substituents in 2- and 5-position are missing, the amines 6 exhibit high affinity towards GluN2B containing NMDA receptors. A distance of four to five bond lengths between the basic amino moiety and the phenyl ring in the side chain appears to be optimal for high GluN2B affinity. The phenylcyclohexylamine cis-6h and the 4-benzylpiperidine 6g show the highest GluN2B affinities (Ki = 2.3 nM and 2.9 nM, respectively). With respect to selectivity against the PCP binding site, σ1 and σ2 receptors the phenylpiperazine 6f is the most promising GluN2B antagonist.
Discovery of novel orally active ureido NPY Y5 receptor antagonists
Li, Guoqing,Stamford, Andrew W.,Huang, Ying,Cheng, Kuo-Chi,Cook, John,Farley, Constance,Gao, Jun,Ghibaudi, Lorraine,Greenlee, William J.,Guzzi, Mario,van Heek, Margaret,Hwa, Joyce J.,Kelly, Joe,Mullins, Deborra,Parker, Eric M.,Wainhaus, Sam,Zhang, Xiaoping
, p. 1146 - 1150 (2008/09/18)
We have derived a novel series of neuropeptide Y (NPY) Y5 receptor antagonists from the biphenylurea 3. Cyclohexylurea 21c, a member of the series, is a potent NPY Y5 receptor antagonist that exhibits excellent pharmacokinetic parameters in rats and dogs. On chronic oral administration to diet-induced obese rats, 21c displayed an anti-obesity profile, causing a modest reduction in food intake, a significant decrease in body weight gain, a decrease in adipose mass, and an increase in lean tissue mass.
