- Memory of chirality of tertiary aromatic amides: A simple and efficient method for the enantioselective synthesis of quaternary α-amino acids
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A new methodology for the asymmetric synthesis of quaternary R-substituted amino acids using memory of chirality has been developed. The strategy utilizes the dynamic axial chirality of tertiary aromatic amides to memorize the initial chirality of an α-amino acid during an enolization step. Starting from five different L-amino acids, the corresponding oxazolidin-5-ones containing a tertiary aromatic amide group have been synthesized in one step and then alkylated with various electrophiles, with good yields and enantioselectivities (up to 96% and up to >99% after recrystallization). One-step deprotection affords enantioenriched or enantiopure quaternary α-amino acids. We describe here the optimization process, the results obtained in each series and a plausible explanation, based on NMR studies, DFT calculations and crystallographic structures. The methodology presented herein constitutes an efficient synthesis of enantiopure quaternary R-amino acids (three steps only) starting from tertiary L-amino acids, without any external source of chirality.
- Branca, Mathieu,Pena, Sebastien,Guillot, Regis,Gori, Didier,Alezra, Valerie,Kouklovsky, Cyrille
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scheme or table
p. 10711 - 10718
(2009/12/04)
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- Tertiary aromatic amide for memory of chirality: Access to enantioenriched α-substituted valine
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A new methodology for the asymmetric synthesis of quaternary α-substituted amino acids using memory of chirality has been developed. This strategy employs dynamic axial chirality of tertiary aromatic amides to memorize the initial chirality of an α-amino acid during the enolization step. Starting from l-valine, an oxazolidin-5-one containing a tertiary aromatic amide was synthesized in one step and then alkylated with various electrophiles with good yield and enantioselectivity (up to 96%). Quaternary products can be obtained enantiomerically pure by recrystallization. One-step deprotection affords enantioenriched (S)-α-methyl valine (ee = 94%) or enantiopure (S)-α-isopropyl aspartic acid (ee >99%) in only three steps starting from L-valine. Copyright
- Branca, Mathieu,Gori, Didier,Guillot, Regis,Alezra, Valerie,Kouklovsky, Cyrille
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p. 5864 - 5865
(2008/09/20)
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- Enantioselective synthesis and enantiomeric amplification of amino acids under prebiotic conditions
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(Chemical Equation Presented) A plausible origin of biomolecular homochirality is advanced, where α-methyl amino acids found on meteorites transfer their chirality in the synthesis of normal amino acids. This asymmetry can be amplified to nearly homochiral levels, thus providing the necessary prerequisite for life to start on this planet and elsewhere in the universe.
- Levine, Mindy,Kenesky, Craig Scott,Mazori, Daniel,Breslow, Ronald
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supporting information; experimental part
p. 2433 - 2436
(2009/05/27)
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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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- Chiral 2-cyano esters as synthetic intermediates in the synthesis of R and S-α-methylvaline
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A divergent stereoselective synthesis of R and S α-methylvaline from (2RS) (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl 2-cyano-3-methylbutanoate has been developed.
- Cativiela,Diez-De-Villegas,Galvez,Lapena
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p. 5921 - 5928
(2007/10/02)
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- Synthesis of dipeptides containing α-substituted amino acids; their use as chiral ligands in Lewis-acid-catalyzed reactions
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L-α-Methylphenylalanine, obtained by enzymatic resolution of the corresponding racemic amide with amidase from Ochrobactrum anthropi NCIMB 40321, was used in the synthesis of dipeptides containing α-substituted amino acids.The 2-hydroxynaphthalene-1-carboxaldehyde Schiff bases of the dipeptides (1 and 2) were tested as Ti(IV) and Al(III) complexes in asymmetric Lewis-acid-catalyzed reactions.Only the Al(III) complex of 2 showed moderate enantioselectivity in the cyanation reaction of benzaldehyde with TMS-CN.
- Kaptein, Bernard,Monaco, Vania,Broxterman, Quirinus B.,Schoemaker, Hans E.,Kamphuis, Johan
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p. 231 - 238
(2007/10/02)
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- Enzymatic resolution of α,α-disubstituted α-amino acid esters and amides
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The scope and limitations of the enzymatic resolution of α,α-disubstituted α-amino acid amides by an amino acid amidase from Mycobacterium neoaurum and of the corresponding ethyl esters with Pig liver esterase (PLE) have been studied. Moderate enantiomeric excesses were obtained with PLE, with only a narrow substrate specificity. Mycobacterium neoaurum on the contrary yields a broad range of S-α,α-disubstituted α-amino acids 1 and the corresponding R-amides 2.
- Kaptein,Boesten,Broxterman,Peters,Schoemaker,Kamphuis
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p. 1113 - 1116
(2007/10/02)
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- A NOVEL APPLICATION OF THE CHIRAL REAGENT (S)-2-N-(N'-BENZYLPROLYL)-AMINOBENZALDEHYDE: SYNTHESIS OF OPTICALLY PURE α-METHYLVALINE AND α-METHYLGLUTAMIC ACID
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The synthesis of α-methyl substituted amino acids using Ni(II) complexes of the Schiff base obtained from alanine and (S)-2-N-(N'-benzylpropyl)aminobenzaldehyde is described.This complex was alkylated with isopropyl bromide, gramine iodomethylate, and methyl acrylate (in a Michael reaction).From the resulting mixtures of products, diastereomerically pure complexes were obtained by crystallization or silica gel chromatography.Both (S)- and (R)-enantiomers of the optically active amino acids α-Me-Val and α-MeGlu were obtained after decomposing the diastereomerically pure complexes.
- Belokon, Yu. N.,Motsishkite, S. M.,Tararov, V. I.,Maleev, V. I.
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p. 1355 - 1360
(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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- 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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- α-Alkylation of Amino Acids without Racemization. Preparation of Either (S)- or (R)-α-Methyldopa from (S)-Alanine
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Enantiomerically pure cis- and trans-5-alkyl-1-benzoyl-2-(tert-butyl)-3-methylimidazolidin-4-ones (1, 2, 11, 15, 16) and trans-2-(tert-butyl)-3-methyl-5-phenylimidazolidin-4-one (20), readily available from (S)-alanine, (S)-valine, (S)-methionine, and (R)-phenylglycine are deprotonated to chiral enolates (cf. 3, 4, 12, 21).Diastereoselective alkylation of these enolates to 5,5-dialkyl- or 5-alkyl-5-arylimidazolidinones (5, 6, 9, 10, 13a-d, 17, 18, 22) and hydrolysis give α-alkyl-α-amino acids such as (R)- and (S)-α-methyldopa (7 and 8a, resp.), (S)-α-methylvaline (14), and (R)-α-methyl-methionine (19).The configuration of the products is proved by chemical correlation and by NOE 1H-NMR measurements (see 23, 24).In the overall process, a simple, enantiomerically pure α-amino acid can be α-alkylated with retention or with inversion of configuration through pivalaldehyde acetal derivatives.Since no chiral auxiliary is required, the process is coined 'self-reproduction of a center of chirality'.The method is compared with other α-alkylations of amino acids occuring without racemization.The importance of enantiomerically pure, α-branched α-amino acids as synthetic intermediates and for the preparation of biologically active compounds is discussed.
- Seebach, Dieter,Aebi, Johannes D.,Naef, Reto,Weber, Theodor
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p. 144 - 154
(2007/10/02)
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