- Asymmetric synthesis of (S)-α-methyl α-amino acids by alkylation of chiral 3,6-dihydro-2h-1,4-oxazin-2-ones using unactivated alkyl halides and organic bases
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3,6-Dihydro-2H-1,4-oxazin-2-ones 1 have been diastereoselectively (>96% de) alkylated using unactivated alkyl halides and organic bases such as 2- tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature in the presence of LiI. Hydrolysis of the resulting alkylated systems afforded enantiomerically enriched (S)-α-methyl α-amino acids. When 1,3- diiodopropane was used, spontaneous N-alkylation also took place giving bicyclic oxazinone 6 which was hydrolyzed to (S)-α-methylproline.
- Chinchilla, Rafael,Galindo, Nuria,Najera, Carmen
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Read Online
- Synthetic method of (2S)-2-N-fluorene methoxycarbonyl amino-2,4-dimethyl valerate
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The invention relates to a synthetic method of (2S)-2-N-fluorene methoxycarbonyl amino-2,4-dimethyl valerate. According to the synthetic method, the technical problems that potassium cyanide is highlytoxic, and the enzymatic resolution yield is low in an
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Paragraph 0010; 0011; 0012
(2019/03/08)
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- METHOD FOR PRODUCING AMINO ACID AND AMINO ACID SYNTHESIS KIT
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PROBLEM TO BE SOLVED: To provide a method for producing an amino acid and an amino acid synthesis kit, which enable synthesis of a desired amino acid in high stereoselectivity efficiently and in a very short time, irrespective whether a radioactive isotope is contained or not. SOLUTION: A method for producing an amino acid and an amino acid synthesis kit are disclosed. The method for producing an amino acid of the present invention comprises a step of alkylating a substrate compound with an alkylating agent in the presence of an optically active phase transfer catalyst as well as a medium and an inorganic base. An amount of use of the optically active phase transfer catalyst is 1 equivalent or more and 1000 equivalents or less relative to the alkylating agent. According to the present invention, a desired amino acid and a derivative thereof can be produced in high stereoselectivity efficiently and in a very short time. Therefore, the present production method is useful, for example, for research and development, and production of a radioactively labelled amino acid and a derivative thereof, which can be used as a tracer for neurodegenerative diseases such as Parkinson disease and Alzheimer disease, heart diseases, and cancerous diseases. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0130-0133
(2017/04/03)
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- SN2 displacement at the quaternary carbon center: A novel entry to the synthesis of α,α-disubstituted α-amino acids This Letter is dedicated to the late Professor Harry Wasserman, a great chemist as well as a splendid artist
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A novel method for the SN2 reaction on quaternary carbon atoms using bis(p-nitrophenyl)phosphorazidate has been developed. Chiral tertiary alcohols were directly converted into the corresponding chiral tertiary azides with complete inversion of configuration. Several α,α-disubstituted α-amino esters or amino acids were prepared through the conversion of azides to the corresponding amines by catalytic hydrogenation.
- Ishihara, Kotaro,Hamamoto, Hiromi,Matsugi, Masato,Shioiri, Takayuki
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p. 3169 - 3171
(2015/05/27)
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- Asymmetric synthesis of α-methyl-α-amino acids via diastereoselective alkylation of (1s)-(+)-3-carene derived tricyclic iminolactone
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A novel carene-based alanine-equivalent tricyclic iminolactone 16 has been synthesized via stereoselective dihydroxylation of the double bond, IBX oxidation of the secondary alcohol, esterification of the tertiary alcohol, deprotection of the resulting ester, and subsequent cyclization from commercially available (1S)-(+)-3-carene in 79% overall yield. The iminolactone 16 demonstrated high reactivity toward alkylation with a wide range of electrophiles at room temperature under phasetransfer catalysis conditions. The alkylated products were produced with excellent diastereoselectivities (>98% de) in good isolated yields (86-94%). High yields (83-91%) of optically pure (S)-R-methyl-R-substituted-R-amino acids were obtained by basic hydrolysis of the dialkylated iminolactones with the recovery of the chiral auxiliary 15 (78-87%).
- Lu, Ta-Jung,Lin, Cheng-Kun
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experimental part
p. 1621 - 1633
(2011/06/17)
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- Chiral 3,6-dihydro-2H-1,4-oxazin-2-ones as alanine equivalents for the asymmetric synthesis of α-methyl α-amino acids (AMAAs) under mild reaction conditions
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3,6-Dihydro-2H-1,4-oxazin-2-ones 1 act as very reactive chiral cyclic alanine equivalents and can be diastereoselectively alkylated or allylated using mild reaction conditions: potassium carbonate under phase-transfer catalysis (PTC) conditions when using activated alkyl halides, organic bases such as tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2- diazaphosphorine (BEMP) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) when using unactivated alkyl halides, and neutral Pd(0)-catalysis when allylic carbonates are used. In most cases, the diastereoselectivity under all these different reaction conditions is excellent although the reactions are always carried out at room temperature. Hydrolysis of the obtained alkylated or allylated oxazinones allows the preparation of enantiomerically enriched (S)- α-methyl α-amino acids (S)-AMAAs. The PTC and organic base methodologies have also been applied to the synthesis of (R)-α-methyl α-amino acids starting from (R)-alanine. When dihalides are used as electrophiles under PTC or BEMP conditions, a spontaneous N-alkylation also takes place giving bicyclic oxazinones, which can be hydrolyzed to enantiomerically pure cyclic (S)-AMAAs.
- Chinchilla, Rafael,Galindo, Nuria,Nájera, Carmen
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p. 704 - 717
(2007/10/03)
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- Enantiomerically Enriched α-Methyl Amino Acids. Use of an Acyclic, Chiral Alanine-Derived Dianion with a High Diastereofacial Bias
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Hindered esters derived from N-benzoylalanine and the following chiral alcohols have been synthesized: (1) (-)-isopinocampheol, (2) (-)-trans-2-phenylcyclohexanol, and (3) (-)-8-phenylmenthol.Sequential treatment of these esters with LDA (1.2 equiv) and n-butyllithium (2.4 equiv) at -78 deg C in THF generates the corresponding chiral dianions.Alkylation of each of these with benzyl bromide reveals that only the (-)-8-phenylmenthyl auxiliary confers a high diastereofacial bias upon its derivative dianion.In fact, that dianion (6) consistently displays diastereomeric ratios in the range of 89:11 to 94:6 for alkylations with a spectrum of nine alkyl halides.If one recrystallization step is included, a single diastereomeric product may be obtained, as is demonstrated for the benzylation of 6.Of particular note, the alkylation with 3,4-bis((tert-butyldimethylsilyl)oxy)benzyl bromide (18) (94:6 diastereomeric ratio, 72percent yield) constitutes a formal synthesis of the clinically important antihypertensive (S)-α-methyl-DOPA (Aldomet), in enantiomerically enriched form.In all cases studied, yields are markedly improved, yet diastereoselectivities unchanged, by the addition of 10percent HMPA to the reaction milieu.The (-)-8-phenylmenthol chiral auxiliary is conveniently recovered via ester cleavage with KO2/18-crown-6, following alkylation.Complete deprotection affords enantiomerically enriched (S)-α-methyl amino acids, in all cases examined, indicating that dianion 6 displays a substantial bias in favor of si face alkylation.This sense of diastereoselection is consistent with a chain-extended, internal chelate model for the reactive conformation of the dianion.
- Berkowitz, David B.,Smith, Marianne K.
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p. 1233 - 1238
(2007/10/02)
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- Synthesis of Optically Pure α-Alkylated α-Amino Acids and a Single-Step Method for Enatiomeric Excess Determination
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A method for the enzymatic resolution of the amides of some racemic α-alkylated amino acids is described as well as a method involving derivatization with (S)-2-chloropropionyl chloride followed by 1H NMR analysis to establish the enantiomeric excesses of the free amino acids.
- Kruizinga, Wim H.,Bolster, John,Kellogg, Richard M.,Kamphuis, Johan,Boesten, Wilhelmus H. J.,et al.
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p. 1826 - 1827
(2007/10/02)
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