- Enantioselective synthesis of (S)-α-methylphenylalanine using (S)-BINOLAMs as new phase-transfer catalysts
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A series of (S)-bis(aminomethyl)binaphthols [(S)-BINOLAMs] 4 have been prepared and used as catalysts in the enantioselective C-alkylation reaction of the aldimine Schiff bases of alanine esters 5 under solid-liquid phase-transfer catalysis (PTC) conditio
- Casas, Jesus,Najera, Carmen,Sansano, Jose M.,Gonzalez, Jose,Saa, Jose M.,Vega, Manuel
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Read Online
- Enantiospecific conversion of (S)-alanine to (R)-α-methyl phenylalanine
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Based on the strategy of self-reproduction of chirality, a practical enantiospecific conversion of (S)-alanine to (R)-α-methyl phenylalanine via the N-pivaloyl 1,3-oxazolidin-5-one derived from ferrocene carboxaldehyde and sodium alaninate is described.
- Alonso,Davies
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Read Online
- Preparation of Optically Pure α-Methyl-α-amino Acids via Alkylation of the Nickel(II) Schiff Base of (R,S)-Alanine with (S)-2-N-(N'-Benzylprolyl)aminobenzaldehyde
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Chiral nickel(II) complexes of Ala with (S)-2-N-(N'-benzylprolyl)aminobenzaldehyde were alkylated with alkyl halides and the diastereoisomeric complexes formed were separated on SiO2; their decomposition led to the isolation of enantiomerically pure (R)- and (S)-α-alkyl-α-amino acids with recovery of the initial (S)-bba.
- Belokon', Yuri N.,Chernoglazova, Nina I.,Kochetkov, Constantin A.,Garbalinskaya, Natalia S.,Belikov, Vasili M.
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Read Online
- Application of Threonine Aldolases for the Asymmetric Synthesis of α-Quaternary α-Amino Acids
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We report the synthesis of diverse β-hydroxy-α,α-dialkyl-α-amino acids with perfect stereoselectivity for the α-quaternary center through the action of l- and d-specific threonine aldolases. A wide variety of aliphatic and aromatic aldehydes were accepted by the enzymes and conversions up to >80 % were obtained. In the case of d-selective threonine aldolase from Pseudomonas sp., generally higher diastereoselectivities were observed. The applicability of the protocol was demonstrated by performing enzymatic reactions on preparative scale. Using the d-threonine aldolase from Pseudomonas sp., (2R,3S)-2-amino-3-(2-fluorophenyl)-3-hydroxy-2-methylpropanoic acid was generated in preparative amounts in one step with a diastereomeric ratio >100 favoring the syn-product. A Birch-type reduction enabled the reductive removal of the β-hydroxy group from (2S)-2-amino-3-hydroxy-2-methyl-3-phenylpropanoic acid to generate enantiopure l-α-methyl-phenylalanine via a two-step chemo-enzymatic transformation.
- Blesl, Julia,Trobe, Melanie,Anderl, Felix,Breinbauer, Rolf,Strohmeier, Gernot A.,Fesko, Kateryna
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p. 3453 - 3458
(2018/07/30)
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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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- Chiral ligand-exchange resolution of underivatized amino acids on a dynamically modified stationary phase for RP-HPTLC
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The synthesis of Spi(τ-dec), derived from the selective alkylation of L-spinacine (4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid) at the τ-nitrogen of its heteroaromatic ring, with a linear hydrocarbon chain of 10 carbon atoms, is described here for the first time. Spi(τ-dec) was successfully employed in the past to prepare home-made chiral columns for chiral ligand-exchange high-performance liquid chromatography. In the present article a new method is described, using Spi(τ-dec) as a chiral selector in high-performance thin-layer chromatography (HPTLC): commercial hydrophobic plates were first coated with Spi(τ-dec) and then treated with copper sulfate. The performance of this new chiral stationary phase was tested against racemic mixtures of aromatic amino acids, after appropriate optimization of both the conditions of preparation of the plates and the mobile phase composition. The enantioselectivity values obtained for the studied compounds were higher than those reported in the literature for similar systems. The method employed here for the preparation of chiral HPTLC plates proved practical, efficient, and inexpensive. Chirality 26:313-318, 2014. 2014 Wiley Periodicals, Inc.
- Remelli, Maurizio,Faccini, Stefania,Conato, Chiara
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p. 313 - 318
(2014/06/09)
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- Rapid asymmetric synthesis of amino acids via NiII complexes based on new fluorine containing chiral auxiliaries
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New fluorine-containing chiral auxiliaries (S)-N-(2-benzoylphenyl)-1-(2- fluorobenzyl)-, (S)-N-(2-benzoylphenyl)-1-(3-fluorobenzyl)-, and (S)-N-(2-benzoylphenyl)-1-(4-fluorobenzyl)-pyrrolidine-2-carboxamide and their NiII complexes of Schiff bases with glycine and alanine have been synthesized. The greater efficiency of the complexes in terms of faster reaction rates and stereoselectivities in the asymmetric synthesis of (S)-α-amino acids has also been demonstrated.
- Saghyan, Ashot S.,Dadayan, Ani S.,Dadayan, Slavik A.,Mkrtchyan, Anna F.,Geolchanyan, Arpine V.,Manasyan, Luiza L.,Ajvazyan, Hrant R.,Khrustalev, Victor N.,Hambardzumyan, Hasmik H.,Maleev, Victor I.
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experimental part
p. 2956 - 2965
(2011/03/19)
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- Mitsunobu approach to the synthesis of optically active α,α-disubstituted amino acids
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Chiral tertiary α-hydroxy esters of known stereochemical configuration were transformed to α-azido esters by Mitsunobu reaction with HN3. Optimization of this reaction was shown to proceed at room temperature with high chemical yield using 1,1-(azodicarbonyl)dipiperidine (ADDP) and trimethylphosphine (PMe3). Complete inversion of configuration was observed at the α-carbon. Several α,α- disubstituted amino acids were synthesized in high overall chemical yield and optical purity.
- Green, Jonathan E.,Bender, David M.,Jackson, Stona,O'donnell, Martin J.,Mccarthy, James R.
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supporting information; experimental part
p. 807 - 810
(2009/08/08)
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- NOVEL IMIDAZOLIDINONE DERIVATIVE, METHOD OF PRODUCING THE SAME AND METHOD OF PRODUCING OPTICALLY ACTIVE AMINO ACID
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The objective of the present invention is to provide an optically active imidazolidinone derivative widely usable for synthesizing an optically active amino acid, a method of easily producing the derivative, and a method of easily producing an optically active amino acid by using the derivative. The objective can be achieved by producing an optically active amino acid using a novel optically active imidazolidinone derivative represented by a general formula (3) and the like. According to the method of the present invention, an optically active imidazolidinone derivative can be obtained by preferential crystallization from a mixture of isomers of the imidazolidinone derivative. Therefore, an optically active amino acid can be easily and stereoselectively produced without cumbersome procedures required for the conventional methods, such as resolution of diastereomers, synthesis from an optically active amino acid and resolution of isomers by silica gel column cromatography.
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Page/Page column 35-36
(2009/05/29)
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- Asymmetric synthesis of α,α-disubstituted α-amino acids by diastereoselective alkylation of camphor-based tricyclic iminolactone
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A novel and convenient route for the preparation of chiral tricyclic iminolactones 9 and 10 from camphorquinone has been developed. Alkylation of iminolactones 9 and 10 provided iminolactones 16 and 17 in high yields which were, in turn, alkylated again t
- Xu, Peng-Fei,Li, Shuo,Lu, Ta-Jung,Wu, Chen-Chang,Fan, Botao,Golfis, Georgia
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p. 4364 - 4373
(2007/10/03)
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- OPTICALLY ACTIVE QUATERNARY AMMONIUM SALT HAVING AXIAL ASYMMETRY AND PROCESS FOR PRODUCING ALPHA-AMINO ACID AND DERIVATIVE THEREOF WITH THE SAME
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The present invention provides a compound of the following formula (I) below. This compound (I) can be produced by reacting a 2,2'-dimethylene bromide-1,1'-binaphthyl derivative, which can be produced by a relatively small number of processes, with an eas
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Page/Page column 103
(2008/06/13)
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- Enantioselective synthesis of diversely substituted quaternary 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones
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Benzodiazepines are privileged scaffolds in medicinal chemistry, but enantiopure examples containing quaternary stereogenic centers are extremely rare. We demonstrate that installation of the di-(p-anisyl)methyl (DAM) group at N1 of 1,4-benzodiazepin-2-on
- Carlier, Paul R.,Zhao, Hongwu,MacQuarrie-Hunter, Stephanie L.,DeGuzman, Joseph C.,Hsu, Danny C.
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p. 15215 - 15220
(2007/10/03)
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- Allyl cyanate-to-isocyanate rearrangement for the synthesis of quaternary stereocenter with nitrogen substituent
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The stereochemistry and efficiency of an allyl cyanate-to-isocyanate rearrangement for the construction of quaternary stereocenter with nitrogen substituent was investigated by the synthesis of (R)-α- methylphenylalanine. The rearrangement was found to be
- Ichikawa, Yoshiyasu,Yamauchi, Eiji,Isobe, Minoru
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p. 939 - 943
(2008/02/03)
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- Potassium trimethylsilanolate induced cleavage of 1,3-oxazolidin-2- and 5-ones, and application to the synthesis of (R)-salmeterol.
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A convenient and efficient method for the cleavage of 1,3-oxazolidin-5-ones and 1,3-oxazolidin-2-ones utilising potassium trimethylsilanolate in tetrahydrofuran is described. The benzyloxycarbonyl-protecting group is readily removed under the reaction conditions, whereas the N-benzoyl group is stable. A synthesis of (R)-salmeterol exploiting the 2-oxazolidinone ring as a protecting group for the ethanolamine moiety is also described.
- Coe, Diane M,Perciaccante, Rossana,Procopiou, Panayiotis A
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p. 1106 - 1111
(2007/10/03)
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- Enantioselective synthesis of "quaternary" 1,4-benzodiazepin-2-one scaffolds via memory of chirality
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Glycine-derived 1,4-benzodiazepine-2-ones such as diazepam are chiral by virtue of the boat-shaped conformation of the diazepine ring and exist as a racemic mixture of conformational enantiomers. However, the presence of a chiral center at C-3 of the benz
- Carlier, Paul R.,Zhao, Hongwu,DeGuzman, Joe,Lam, Polo C.-H.
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p. 11482 - 11483
(2007/10/03)
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- Practical synthesis of optically active α,α-disubstituted malonamic acids through asymmetric hydrolysis of malonamide derivatives with Rhodococcus sp. CGMCC 0497
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A variety of α,α-disubstituted malonamides undergo enantioselective hydrolysis with Rhodococcus sp. CGMCC 0497 to give challenging enantiopure α,α-disubstituted malonamic acids with up to >99% enantiomeric excesses and 98% chemical yields. The enantiosele
- Wu, Zhong-Liu,Li, Zu-Yi
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p. 2479 - 2482
(2007/10/03)
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- Highly enantioselective synthesis of α,α-disubstituted malonamic acids through asymmetric hydrolysis of dinitriles with Rhodococcus sp. CGMCC 0497
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Highly enantioselective hydrolysis of α,α-disubstituted malononitriles by the strain Rhodococcus sp. CGMCC 0497 expressing both nitrile hydratase and amidase activity to give (R)-α,α-disubstituted malonamic acids which could be converted to valuable (R)-
- Wu, Zhong-Liu,Li, Zu-Yi
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p. 386 - 387
(2007/10/03)
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- Application of metal reagent to the asymmetric synthesis of α-αamino acids
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Using "mix-ligands" type chiral synthons containing metal ions, a,a-amino acids were obtained in "one-pot" reactions in moderate to high yields and ee% values.
- Hu, Ai-Guo,Zhang, Ling-Yun,Wang, Shan-Wei,Wang, Ji-Tao
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p. 2143 - 2147
(2007/10/03)
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- Optical resolution by preferential crystallization of (RS)-2-benzoylamino-2-benzyl-3-hydroxypropanoic acid and its use in synthesizing optically active 2-amino-2-methyl-3-phenylpropanoic acid.
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To synthesize optically active 2-amino-2-methyl-3-phenylpropanoic acid (1), (RS)-2-benzoylamino-2-benzyl-3-hydroxypropanoic acid [(RS)-2] was first optically resolved using cinchonidine as a resolving agent to yield optically pure (S)- and (R)-2 in yields of about 70%, based on half of the starting amount of (RS)-2. Next, the racemic structure of (RS)-2 was examined based on melting point, solubility, IR spectrum, and binary and ternary phase diagrams, with the aim of optical resolution by preferential crystallization of (RS)-2. Results indicated that the (RS)-2 exists as a conglomerate at room temperature, although it forms a racemic compound at the melting point. The optical resolution by preferential crystallization yielded (S)- and (R)-2 with optical purities of about 90%, which were fully purified by recrystallization. After O-tosylation of (S)- and (R)-2, reduction by zinc powder and sodium iodide gave (R)- and (S)-1, respectively.
- Shiraiwa, Tadashi,Suzuki, Masahiro,Sakai, Yoshio,Nagasawa, Hisashi,Takatani, Kazuhiro,Noshi, Daisuke,Yamanashi, Kenji
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p. 1362 - 1366
(2007/10/03)
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- Halo-substituted (S)-N-(2-benzoylphenyl)-1-benzylpyrolidine-2-carboxamides as new chiral auxiliaries for the asymmetric synthesis of (S)-α-amino acids
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The synthesis of new chiral auxiliaries (S)-N-(2-benzoylphenyl)-1-(3,4-dichlorobenzyl)-pyrrolidine-2-carboxamide (1a), (S)-N-(2-benzoylphenyl)-1-(pentafluorobenzyl)pyrrolidine-2-carboxamide (1b), and (S)-N-(2-benzoylphenyl)-1-(4-isopropoxytetrafluorobenzyl) pyrrolidine-2-carboxamide (1c) and their application in the asymmetric synthesis of amino acids using NiII complexes of their Schiff's bases with alanine and glycine are described. Compound la is particularly appropriate for highly stereoselective synthesis of α-methyl-α -amino acids with high enatiomeric purity (ee >95%).
- Belokon,Maleev,Petrosyan,Savel'eva,Ikonnikov,Peregudov,Khrustalev,Saghiyan
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p. 1593 - 1599
(2007/10/03)
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- Chiral salen-metal complexes as novel catalysts for the asymmetric synthesis of α-amino acids under phase transfer catalysis conditions
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Chiral salen-metal complexes have been tested as catalysts for the C-alkylation of Schiff's bases of alanine and glycine esters with alkyl bromides under phase-transfer conditions (solid sodium hydroxide, toluene, ambient temperature, 1-10 mol% of the catalyst). The best catalyst, which was derived from a Cu(II) complex of (1R, 2R or 1S,2S)-[N,N′-bis(2′-hydroxybenzylidene)]-1,2-diaminocyclohexane, gave α-amino and α-methyl-α-amino acids with enantiomeric excesses of 70-96%.
- Belokon, Yuri N,North, Michael,Churkina, Tatiana D,Ikonnikov, Nikolai S,Maleev, Victor I
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p. 2491 - 2498
(2007/10/03)
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- Asymmetric PTC C-Alkylation Catalyzed by Chiral Derivatives of Tartaric Acid and Aminophenols. Synthesis of (R)- and (S)-α-Methyl Amino Acids
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A new type of efficient chiral catalyst has been elaborated for asymmetric C-alkylation of CH acids under PTC conditions. Sodium alkoxides formed from chiral derivatives of tartaric acid and aminophenols (TADDOL's 2a-e and NOBIN's 3a-h) can be used as chiral catalysts in the enantioselective alkylation, as exemplified by the reaction of Schiffs bases la-e derived from alanine esters and benzaldehydes with active alkyl halides. Acid-catalyzed hydrolysis of the products formed in the reaction afforded (R)-α-methylphenylalanine, (R)-α-naphthylmethylalanine, and (R)-α-allylalanine in 61-93% yields and with ee 69-93%. The procedure could be successfully scaled up to 6 g of substrate 1b. When (S,S)-TADDOL or (R)-NOBIN are used, the (S)-amino acids are formed. A mechanism rationalizing the observed features of the reaction has been suggested.
- Belokon, Yuri N.,Kochetkov, Konstantin A.,Churkina, Tatiana D.,Ikonnikov, Nikolai S.,Chesnokov, Alexey A.,Larionov, Oleg V.,Singh, Ishwar,Parmar, Virinder S.,Vyskocil, Stepan,Kagan, Henri B.
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p. 7041 - 7048
(2007/10/03)
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- Hippuryl-α-methylphenylalanine and hippuryl-α-methylphenyllactic acid as substrates for carboxypeptidase A. Syntheses, kinetic evaluation and mechanistic implication
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(R)- and (S)-Hippuryl-α-methylphenylalanine [(R)- and (S)-Hipp-α- MePhe] and (S)-hippuryl-α-methylphenyllactic acid [(S)-Hipp-α-MeOPhe] were synthesized and evaluated as substrates for carboxypeptidase A (CPA) in an effort to shed further light on the catalytic mechanism of the enzyme. The rate of CPA-catalyzed hydrolysis of (S)-Hipp-α-MePhe was reduced by 105-fold compared with that of (S)-Hipp-Phe, but the hydrolysis rate of (S)-Hipp-OPhe was lowered by only 6.8-fold by the introduction of a methyl group at the α- position. (R)-Hipp-α-MePhe failed to be hydrolyzed initially, then started to undergo hydrolysis in about 2 h at a much reduced rate. The results of present study may be envisioned on the basis of the proposition that while peptide substrate is hydrolyzed via a tetrahedral transition state formed by the attack of the zinc-bound water molecule at the peptide carbonyl carbon, ester hydrolysis takes the path that involves an anhydride intermediate generated by the attack of the carboxylate of Glu-270 at the ester carbonyl carbon. (C) 2000 Elsevier Science Ltd.
- Lee, Mijoon,Kim, Dong H.
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p. 815 - 823
(2007/10/03)
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- Asymmetric alkylation catalyzed by chiral alkali metal alkoxides of TADDOL. Synthesis of α-methyl amino acids
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It is shown that sodium alkoxides formed from (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-bis(diphenylmethanol) ((R,R)-TADDOL) and some of its derivatives can be used as chiral catalysts for enantioselective alkylation of Schiff's bases derived from alanine with reactive alkyl halides. Acid hydrolysis of the reaction products affords (R)-α-methytphenyl-alanine, (R)-α-allylalanine, and (R)-α-methylnaphthylalanine in 61-93% yields and with ee 69-94%. When (S,S)-TADDOL is used, the (3)-amino acid is formed. A mechanism explaining the observed features of the reaction is proposed.
- Belokon',Kochetkov,Churkina,Ikonnikov,Chesnokov,Larionov,Kagan
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p. 917 - 923
(2007/10/03)
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- Asymmetric memory at labile, stereogenic boron: Enolate alkylation of oxazaborolidinones
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Oxazaborolidinones 3, 25, 32, 42, 49, and 53 can be obtained as single diastereomers by crystallization-induced asymmetric transformation (AT). Asymmetric memory is maintained in the derived enolates because the stereogenic boron resists equilibration wit
- Vedejs,Fields,Hayashi,Hitchcock,Powell,Schrimpf
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p. 2460 - 2470
(2007/10/03)
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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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- Stereoselective syntheses
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The present invention relates to the synthesis of chiral amino acids and to novel ferrocene-substituted oxazolidinone derivatives useful in such syntheses.
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- Stereoselective synthesis of uncommon α,α'-dialkyl-α- aminoacids. Part 1
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The alkylation of the diastereomeric mixture of chiral morpholinone derivatives 4 and 5 occurs with good yield and trans induction. Cleavage of the alkylated products 6a,b,c,e gives enantiomerically pure uncommon (and sterically constrained) α,α'-dialkyl-α-aminoacids. The absolute configuration of the new stereocentres of 4, 5, 6 and 7 has been assigned on the basis of the 1H-NMR spectra and NOE measurements.
- Carloni, Armando,Porzi, Gianni,Sandri, Sergio
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p. 2987 - 2998
(2007/10/03)
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- An asymmetric synthesis of optically pure α,α-disubstituted amino aldehydes, α,α-disubstituted amino acids, and sterically demanding dipeptides
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Optically pure α-methyl-α-alkyl amino aldehydes were efficiently synthesized from the cyclohexylimine of propanal bearing an α-4(R),5(S)- diphenyl-2-oxazolidinone by asymmetric alkylation of the imine anion. α- Methylphenylalanine and α-methylleucine were
- Wenglowsky, Steve
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p. 12468 - 12473
(2007/10/03)
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- Enantiospecific alkylations of alanine
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Reaction of ferrocenecarbaldehyde 3 with sodium (S)-alaninate followed by pivaloyl chloride generates (2S,4S)-2-ferrocenyl-3-pivaloyl-4-methyl-1,3-oxazolidin-5-one 5 (>98% de). Compound 5 undergoes stereospecific 4-alkylation with complete retention of configuration on treatment sequentially with lithium diisopropylamide and an appropriate alkyl bromide {benzyl bromide, allyl bromide, crotyl [(E)-2-enyl] bromide, α-bromo-o-xylene, cinnamyl bromide, 2-(bromomethyl)naphthalene, 1-(tert-butoxycarbonyl)-3-(bromomethyl)indole and bromoacetonitrile} to generate the corresponding (2S,4R)-2-ferrocenyl-3-pivaloyl-4-alkyl-4-methyl-1,3-oxazolidin-5-ones 7a-h. Hydrolysis of (2S,4R)-7a-h on Amberlyst-15 generates the free (R)-α-methyl-α-amino acids (R)-8a-h.
- Alonso, Francisco,Davies, Stephen G.,Elend, Almut S.,Haggitt, Jane L.
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p. 257 - 264
(2007/10/03)
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- Catalytic enantioselective addition of hydrogen cyanide to benzaldehyde and p-methoxybenzaldehyde using cyclo-His-(αMe)Phe as catalyst
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Two cyclo-dipeptides based on His and the unnatural (αMe)Phe have been examined as catalysts in the enantioselective addition of hydrogen cyanide to benzaldehyde and p-methoxy-benzaldehyde. The synthesis, catalytic activity and NMR study towards the mechanism of this reaction are presented.
- Hulst, Ron,Broxterman, Quirinus B.,Kamphuis, Johan,Formaggio, Fernando,Crisma, Marco,Toniolo, Claudio,Kellogg, Richard M.
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p. 1987 - 1999
(2007/10/03)
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- 2-Methyl N-(p-toluenesulfinyl)aziridine-2-carboxylic acid: Asymmetric synthesis of α-methylphenylalanine and α-methyl-β-phenylserine
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2-Substituted aziridine 2a, prepared from sulfinimine 1 via a Darzens-type condensation, undergoes a highly regio- and stereocontrolled ring-opening to give α-methylphenylalanine and α-methyl-β-phenylserine in high enantiomeric purity.
- Davis, Franklin A.,Liu, Hu,Reddy, G. Venkat
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p. 5473 - 5476
(2007/10/03)
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- α-Hydroxymethylphenylglycine and α-hydroxymethylphenylalanine: Synthesis, resolution, and absolute configuration
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Racemic α-hydroxymethylphenylglycine and α-hydroxymethylphenylalanine have been synthesized by selective hydroxymethylation of oxazolones derived from phenylglycine and phenylalanine, and resolved into enantiomers by fractional crystallization of their di
- Olma
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p. 1442 - 1447
(2007/10/03)
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- L-phenylalanine cyclohexylamide: A simple and convenient auxiliary for the synthesis of optically pure α,α-disubstituted (R)- and (S)-amino acids
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This work describes L-phenylalanine cyclohexylamide (5c) as a simple, cheap, and powerful chiral auxiliary for the synthesis of a series of optically pure α,α-disubstituted (R)- and (S)-amino acids of type 1, such as (R)- and (S)-2-methyl-phenylalanine (1a), (R)- and (S)-2-methyl-2-phenylglycine (1b), and (R)- and (S)-2-methylvaline (1c). These amino acids were efficiently transformed into the suitably protected and activated amino-acid building blocks (R)- and (S)-12b and (R)- and (S)-12c which are ready for incorporation into peptides by solution or solid-phase techniques. Based on the crystal structures of 6b, 6c, and 7a belonging to the diastereoisomeric peptides series 6 and 7, the absolute configurations of each member of the series were determined. β-Turn geometries of type II' and I were observed for 6b and 7a, respectively, whereas 6c crystallized in an extended conformation. The impacts of side-chain variation on conformation and crystal packing of these triamides are discussed.
- Obrecht,Bohdal,Broger,Bur,Lehmann,Ruffieux,Schonholzer,Spiegler,Muller
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p. 563 - 580
(2007/10/02)
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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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- Enantioselective Synthesis of α-Branched α-Amino Acids with Bulky Substituents
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Enantiopure 5,5-disubstituted t-butyl 2-t-butyl-3-methyl-4-oxoimidazolidine-1-carboxylates readily available by diastereoselective double alkylation of the parent compound (Boc-BMI) can be converted to α-branched α-amino acids with two bulky substituents (PhCH2/Et, PhCH2/i-Pr, PhCH2/CH2C6H11) in four simple steps: hydrolysis to the amino acid amides, N-benzoylation, cleavage of the amino acid amide group, and debenzoylation (Scheme 3, products 6-10, overall yields >50percent).This procedure constitutes an extension of the scope of amino acid synthesis from (R)- and (S)-Boc-BMI. - Key Words: Amino acids, α-branched/ Highly hindered amides/ Hydrolysis of amino acid amides/ Anchimeric effect/ Phenylalanine, 2-ethyl, 2-i-propyl- and 2-cyclohexylmethyl-
- Studer, Armido,Seebach, Dieter
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p. 217 - 222
(2007/10/02)
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- New approaches to the asymmetric synthesis of α-methylphenylalanine
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A strategy of highly selective alkylation of chiral 2-cyanoesters followed by the corresponding degradation process allows a divergent asymmetric synthesis of (R) and (S)-α-methylphenylalanine.
- Cativiela,Diaz-de-Villegas,Galvez
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p. 261 - 268
(2007/10/02)
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- Kinetic Resolution of Unnatural and Rarely Occuring Amino Acids: Enantioselective Hydrolysis of N-Acyl Amino Acids Catalyzed by Acylase I
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Acylase I (aminoacylase; N-acylamino-acid amidohydrolase, EC 3.5.1.14, from porcine kidney and the fungus Aspergillus) is broadly applicable enzymatic catalyst for the kinetic resolution of unnatural and rarely occuring α-amino acids.Its enantioselectivity for the hydrolysis of N-acyl L-α-amino acids is nearly absolute, yet it accepts substrates having a wide range of structure and functionality.This paper reports the initial rates of enzyme-catalyzed hydrolysis of over 50 N-acyl amino acids and analogues, the stabilities of the enzymes in aqueous and aqueous/organic solutions, and the effects of different acyl groups and metal ions on the rates of enzymatic hydrolysis.Eleven α-amino and α-methyl α-amino acids were resolved on a 2-29-g scale.Crude L- and D-amino acid products had generally >90percent ee.The utility of resolved amino acids as chiral synthons was illustrated by the preparation of (R)- and (S)-1-butene oxide and the diastereoselective (cis:trans, 7-8:1) iodolactonization of three 2-amino-4-alkenoic acid derivatives.
- Chenault, H. Keith,Dahmer, Juergen,Whitesides, George M.
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p. 6354 - 6364
(2007/10/02)
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- ASYMMETRIC SYNTHESIS OF α-ALKYLATED α-AMINO ACIDS VIA SCHMIDT REARRANGEMENT OF α,α-BISALKYLATED β-KETO ESTERS
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α-Alkylated α-amino acids are obtained in high yield and optical purity through Schmidt rearrangement of optically active α,α-bisalkylated β-keto esters.
- Georg, Gunda I.,Guan, Xiangming,Kant, Joydeep
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p. 403 - 406
(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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- NEW APPROACHES TO THE ASYMMETRIC SYNTHESIS OF NON-PROTEINOGENIC α-AMINO ACIDS AND DIPEPTIDES THROUGH CHIRAL β-LACTAM INTERMEDIATES
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Novel and effective routes to optically pute aromatic α-amino acids, α-methyl-α-amino acids and their derivatives including dipeptides are developed via homochiral β-lactams which are obtained through asymmetric cycloadditions of ketenes to imines.
- Ojima, Iwao,Chen, Hauh-Jyun C.,Qiu, Xiaogang
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p. 5307 - 5318
(2007/10/02)
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- GENERAL METHOD FOR THE ASYMMETRIC SYNTHESIS OF α-AMINO ACIDS VIA ALKYLATION OF THE CHIRAL NICKEL(II) SCHIFF BASE COMPLEXES OF GLYCINE AND ALANINE
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Nickel(II) complexes of Schiff bases derived from (S)-o-benzaldehyde and alanine (3), or (S)-O-benzophenone and alanine (4), or glycine (5) have been used for the asymmetric synthesis of α-amino acids under a variety of conditions.The method of choice consists of the reaction of the corresponding complex with the appropriate alkyl halide in DMF at 25 deg C using solid NaOH as a catalyst.Low diastereoselective excess (d.e.) is observed for the alkylation of complex (3) with benzyl bromide and allyl bromide.Large selectivity (80 percent) is observed for the alkylation of complex (4).Optically pure(R)- and (S)-O-benzyl-α-methyl-α-amino acids were obtained (70-90 percent) after the alkylated diastereoisomeric complexes had been seperated on SiO2 and hydrolysed with aqueous HCl.The initial chiral reagents were recovered (80-92 percent).The alkylation of complex (5) gave (S)-alanine, (S)-valine, (S)-phenylalanine, (S)-tryptophan, (S)-isoleucine, (S)-2-aminohexanoic acid, and 3,4-dimethoxyphenylalanine with optical yields of 70-92 percent.The optically pure α-amino acids were obtained after the separation of the alkylated diastereoisomeric complexes on SiO2.The stereochemical mechanism of the alkylation reaction is discussed.
- Belokon, Yuri N.,Bakhmutov, Vladimir I.,Chernoglazova, Nina I.,Kochetkov, Konstantin A.,Vitt, Sergei V.,et al.
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p. 305 - 312
(2007/10/02)
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- Process for preparation of alpha-alkyl amino acids
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A process for preparing α-alkyl amino acids by enantioretentive α-alkylation of α-amino acids is described. The products are bioactive compounds including some useful as therapeutic agents.
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- N,O-Acetals from Pivalaldehyde and Amino Acids for the α-Alkylation with Self-Reproduction of the Center of Chirality. Enolates of 3-Benzoyl-2-(tert-butyl)-1,3-oxazolidin-5-ones
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The sodium salt of (S)-alanine, (S)-phenylalanine, (S)-valine, and (S)-methionine are condensed with pivalaldehyde to imines 5.Cyclization by treatment with benzoyl chloride in cold CH2Cl2 gives mainly (4:1 to > 99:1) the (2S,4S)-4-alkyl-3-benzoyl-2-(tert-butyl)-1,3-oxazolidin-5-ones (6; cis-configuration) in high yields (85-95 percent).The oxazolidinones 6 and 7 are deprotonated with lithium diethylamide (LDEA) in tetrahydrofuran (THF) and alkylated (MeI, benzyl bromide) or hydroxyalkylated (benzaldehyde) to 4,4-disubstituted oxazolidinones 9 and 10, respectively, with high diastereoselectivity (9:1 to 50:1; relative topicity ul).Hydrolysis of three of the oxazolidinones to amino acids of known configuration and optical purity indicates that little if any racemization occurs in the process.
- Seebach, Dieter,Fadel, Antoine
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p. 1243 - 1250
(2007/10/02)
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- ENANTIORETENTIVE ALKYLATION OF ACYCLIC AMINO ACIDS
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A stereospecific method is described for the alkylation of acyclic amino acids (alanine and phenylalanine) which proceeds with retention of configuration.The method involves a) conversion of the amino acid to the predominantly cis 2-aryl-3-carbobenzyloxy oxazolidinones (2 and 8), b) alkylation of the potassium enolate with CH3I or PhCH2Br, c) base hydrolysis and hydrogenolysis to afford the alkylated amino acid.
- Karady, Sandor,Amato, Joseph S.,Weinstock, Leonard M.
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p. 4337 - 4340
(2007/10/02)
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- RESOLUTION OF α-METHYL AMINO ESTERS BY CHYMOTRYPSIN
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The resolution of DL-α-MeTrp-OMe HCl, DL-α-MePhe-OMe HCl and DL-α-Me-pF-Phe-OMe HCl have been achieved using α-chymotrypsin at pH 5.0.
- Anantharamaiah, G. M.,Roeske, Roger W.
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p. 3335 - 3336
(2007/10/02)
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- Asymmetric Syntheses via Heterocyclic Intermediates, V. - Asymmetric Synthesis of α-Methyl Amino Acids by Alkylation of the Lithiated Lactim Ether of cyclo-(L-Ala-L-Ala)
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The (3S,6S)-2,5-dimethoxy-3,6-dimethyl-3,6-dihydropyrazine (7) is obtained from cyclo-(L-Ala-L-Ala) 5 (93-95percent optically pure) and trimethyloxonium tetrafluoroborate.With butyllithium the lithio derivative 8 is formed which reacts with alkyl halides in good chemical yields and with more than 90percent diastereoselectivity, whereby R-configuration is induced at C-3.A model concept is discussed, which explains the remarkably high asymmetric induction. - Hydrolysis (0.25 N HCl, room temp.) gives L-alanine methyl ester (4) and the (R)-α-methyl amino acid methyl esters 13.The two amino acid esters are separable by distillation or chromatography.
- Schoellkopf, Ulrich,Hartwig, Wolfgang,Groth, Ulrich,Westphalen, Karl-Otto
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p. 696 - 708
(2007/10/02)
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