6945-32-0Relevant academic research and scientific papers
Asymmetric α-arylation of amino acids
Leonard, Daniel J.,Ward, John W.,Clayden, Jonathan
, p. 105 - 109 (2018/10/15)
Quaternary amino acids, in which the α-carbon that bears the amino and carboxyl groups also carries two carbon substituents, have an important role as modifiers of peptide conformation and bioactivity and as precursors of medicinally important compounds1,2. In contrast to enantioselective alkylation at this α-carbon, for which there are several methods3–8, general enantioselective introduction of an aryl substituent at the α-carbon is synthetically challenging9. Nonetheless, the resultant α-aryl amino acids and their derivatives are valuable precursors to bioactive molecules10,11. Here we describe the synthesis of quaternary α-aryl amino acids from enantiopure amino acid precursors by α-arylation without loss of stereochemical integrity. Our approach relies on the temporary formation of a second stereogenic centre in an N′-arylurea adduct12 of an imidazolidinone derivative6 of the precursor amino acid, and uses readily available enantiopure amino acids both as a precursor and as a source of asymmetry. It avoids the use of valuable transition metals, and enables arylation with electron-rich, electron-poor and heterocyclic substituents. Either enantiomer of the product can be formed from a single amino acid precursor. The method is practical and scalable, and provides the opportunity to produce α-arylated quaternary amino acids in multi-gram quantities.
Asymmetric α-arylation of amino acids
Leonard, Daniel J.,Ward, John W.,Clayden, Jonathan
, p. 105 - 109 (2019/10/21)
Quaternary amino acids, in which the α-carbon that bears the amino and carboxyl groups also carries two carbon substituents, have an important role as modifiers of peptide conformation and bioactivity and as precursors of medicinally important compounds1,2. In contrast to enantioselective alkylation at this α-carbon, for which there are several methods3–8, general enantioselective introduction of an aryl substituent at the α-carbon is synthetically challenging9. Nonetheless, the resultant α-aryl amino acids and their derivatives are valuable precursors to bioactive molecules10,11. Here we describe the synthesis of quaternary α-aryl amino acids from enantiopure amino acid precursors by α-arylation without loss of stereochemical integrity. Our approach relies on the temporary formation of a second stereogenic centre in an N′-arylurea adduct12 of an imidazolidinone derivative6 of the precursor amino acid, and uses readily available enantiopure amino acids both as a precursor and as a source of asymmetry. It avoids the use of valuable transition metals, and enables arylation with electron-rich, electron-poor and heterocyclic substituents. Either enantiomer of the product can be formed from a single amino acid precursor. The method is practical and scalable, and provides the opportunity to produce α-arylated quaternary amino acids in multi-gram quantities.
UNNATURAL AMINO ACIDS
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Paragraph 00190; 00296, (2018/07/05)
The present invention relates to a process for the preparation compounds of Formula (I): Formula (I) wherein X, Z, Q, Ar, R1, R2, R3 and R4 are each as defined herein. The present invention also relates to processes for the preparation of the compounds of quaternary amino acids and hydantions, to compound of Formula(I), to intermediate compounds of Formula (II), to quaternary amino acid compounds of Formula (III) and to hydantoin compounds of Formula (IV).
α-Methyl phenylglycines by asymmetric α-arylation of alanine and their effect on the conformational preference of helical Aib foldamers
Costil, Romain,Fernández-Nieto, Fernando,Atkinson, Rachel C.,Clayden, Jonathan
supporting information, p. 2757 - 2761 (2018/04/27)
α-Arylated alanine derivatives were made enantioselectively by migratory rearrangement of a urea derivative using (R,R)-pseudoephedrine as a chiral auxiliary. Incorporation of a single residue of the product α-methyl phenylglycine into an otherwise achiral oligomer of aminoisobutyric acid oligomer induced a preferred screw sense, detectable by a NMR reporter located at the remote terminus of the oligomer. The magnitude of the screw sense induction was greater when the chiral residue was located at the N-terminus of the foldamer, and in some cases the sense of induction was opposite to that of related α-methylated amino acids with α-substituents other than aryl.
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
Kawahara, Nobuhiro,Yasukawa, Kazuyuki,Asano, Yasuhisa
supporting information, p. 418 - 424 (2017/08/14)
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.
Pseudoephedrine-Directed Asymmetric α-Arylation of α-Amino Acid Derivatives
Atkinson, Rachel C.,Fernández-Nieto, Fernando,Mas Rosell?, Josep,Clayden, Jonathan
supporting information, p. 8961 - 8965 (2015/08/03)
Available α-amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N′-aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N′-aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy-metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character.
Enantioselective Synthesis of α-Quaternary Amino Acids by Alkylation of Deprotonated α-Aminonitriles
Netz, Isabelle,Kucukdisli, Murat,Opatz, Till
, p. 6864 - 6869 (2015/10/06)
A series of α-quaternary arylglycines were prepared in high optical purity (up to 98% ee) by α-alkylation of deprotonated α-aminonitriles derived by the Strecker reaction from (4S,5S)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane. The procedure includes only chromatographic purification of the final products and is devoid of chromatography or crystallization operations on intermediates to raise the optical purity.
Nitrilases, nucleic acids encoding them and methods for making and using them
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Page/Page column 52, (2016/01/09)
The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition methods of designing new nitrilases and method of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
Palladium Catalyzed C-Arylation of Amino Acid Derived Hydantoins
Fernández-Nieto, Fernando,Mas Roselló, Josep,Lenoir, Simone,Hardy, Simon,Clayden, Jonathan
, p. 3838 - 3841 (2015/08/18)
Palladium(II) trifluoroacetate (5 mol %) catalyzes the C-arylation of N,N-disubstituted hydantoins by aryl iodides in good yield. The reaction proceeds through base-promoted enolization of the amino acid derived hydantoins, and the resulting 5,5-disubstituted hydantoins may be deprotected at one or both N atoms to yield biologically active structures or alternatively hydrolyzed to the parent α-aryl α-amino acids. The reaction is successful with a variety of parent amino acids and a range of electron-rich and electron-poor aryl iodides.
