- New enzymatic methods for the synthesis of primary α-aminonitriles and unnatural α-amino acids by oxidative cyanation of primary amines with d-amino acid oxidase from porcine kidney
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Oxidation of amino groups in amines or amino acids activates the sp3 Cα-H bond to form imines, making the alpha carbon atom a preferable target for nucleophilic reagents such as cyanide. Therefore, we focused on the oxidase reaction for the production of primary α-aminonitriles via imines. d-Amino acid oxidase from porcine kidney (pkDAO) and l-amino acid oxidase from Crotalus atrox catalyzed the synthesis of 2-amino-2-cyano-3-phenylpropanoic acid from phenylalanine and potassium cyanide (KCN). Mutant pkDAO (Y228L/R283G) catalyzed the synthesis of racemic-2-methyl-2-phenylglycinonitrile from (R)-α-methylbenzylamine and KCN. Based on these results, we developed a new cascade reaction for the synthesis of unnatural α-amino acids from primary amines using mutant pkDAO and nitrilase AY487533. This is the first report of the enzymatic synthesis of primary α-aminonitriles and unnatural α-amino acids. These methods will contribute widely to the synthesis of primary α-aminonitriles and unnatural α-amino acids in aqueous systems.
- Kawahara, Nobuhiro,Yasukawa, Kazuyuki,Asano, Yasuhisa
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supporting information
p. 418 - 424
(2017/08/14)
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- Versatile synthesis of free and N-benzyloxycarbonyl-protected 2,2-disubstituted taurines
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An effective and versatile method was developed to synthesize N-benzyloxycarbonyl-protected and free 2,2-disubstituted taurines. Several novel 2,2-disubstituted taurines, including aliphatic/aromatic and cyclic/acyclic derivatives, were obtained, which demonstrates the generality of this method. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Wang, Boyuan,Zhang, Wei,Zhang, Leilei,Du, Da-Ming,Liu, Gang,Xu, Jiaxi
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p. 350 - 355
(2008/09/18)
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- Structure-Activity Study of Tripeptide Thrombin Inhibitors Using α-Alkyl Amino Acids and Other Conformationally Constrained Amino Acid Substitutions
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In our continuing effort to design novel thrombin inhibitors, a series of conformationally constrained amino acids (e.g. α-alkyl, N-alkyl cyclic, etc.) were utilized in a systematic structure-activity study of the P3, P2, and P1 positions of tripeptide arginal thrombin inhibitors.Early examples of this effort include: D-MePhe-Pro-Arg-H (15), Boc-D-Phg-Pro-Arg-H (18), D-1-Tiq-Pro-Arg-H (23, D-1-Tiq = D-1,2,3,4-tetrahydroisoquinolin-1-ylcarbonyl), and Boc-D-Phe-Pro-Arg-H (25).10a,20 The current work clarifies the contribution of each residue of the tripeptide arginals toward the potent and selective inhibition of thrombin relative to that of t-PA and plasmin.The α-methylarginal modification in the P1 residue resulted in analogs 30 (D-MePhe at P3) and 32 (D-1-Tiq at P3) which had lower potency toward thrombin while exhibiting improved selectivity.Analogs modified at the P2 site were found to be very sensitive to the conformational changes induced by variations in side chain ring size with the flexible pipecolinic acid 31 being 2 orders of magnitude less potent at thrombin inhibition than the conformationally constrained azetidine analog 20.Examination of the P3 binding region indicated that α-alkylphenylglycine residues resulted in a tendency to exhibit substantional improvements in selectivity over the nonalkylated residues.Combinations of optimal P3 and P2 changes led to compounds TFA-D-Phg(αEt)-Azt-Arg-H (16), TFA-D-Phg(αMe)-Azt-Arg-H (17), Ac-D-Phg(αMe)-Azt-Arg-H (21), TFA-D-Phg(αMe)-Pro-Arg-H (27), 30, and 32, which are clearly more selective for thrombin versus plasmin than the nonconformationally constrained compounds.
- Shuman, Robert T.,Rothenberger, Robert B.,Campbell, Charles S.,Smith, Gerald F.,Gifford-Moore, Donetta S.,et al.
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p. 4446 - 4453
(2007/10/03)
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