- Identification and application of threonine aldolase for synthesis of valuable α-amino, β-hydroxy-building blocks
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Chiral β-hydroxy α-amino acid structural motifs are interesting and common synthons present in multiple APIs and drug candidates. To access these chiral building blocks either multistep chemical syntheses are required or the application of threonine aldolases, which catalyze aldol reactions between an aldehyde and glycine. Bioinformatics tools have been utilized to identify the gene encoding threonine aldolase from Vanrija humicola and subsequent preparation of its recombinant version from E. coli fermentation. We planned to implement this enzyme as a key step to access the synthesis of our target API. Beyond this specific application, the aldolase was purified, characterized and the substrate scope of this enzyme further investigated. A number of enzymatic reactions were scaled-up and the products recovered to assess the diastereoselectivity and scalability of this asymmetric synthetic approach towards β-hydroxy α-amino acid chiral building blocks.
- Ligibel, Mathieu,Moore, Charles,Bruccoleri, Robert,Snajdrova, Radka
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- Exploring the scope of an α/β-aminomutase for the amination of cinnamate epoxides to arylserines and arylisoserines
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Biocatalytic process-development continues to advance toward discovering alternative transformation reactions to synthesize fine chemicals. Here, a 5-methylidene-3,5-dihydro-4H-imidazol-4-one (MIO)-dependent phenylalanine aminomutase from Taxus canadensis (TcPAM) was repurposed to irreversibly biocatalyze an intermolecular amine transfer reaction that converted ring-substituted trans-cinnamate epoxide racemates to their corresponding arylserines. From among 12 substrates, the aminomutase ring-opened 3′-Cl-cinnamate epoxide to 3′-Cl-phenylserine 140 times faster than it opened the 4′-Cl-isomer, which was turned over slowest among all epoxides tested. GC/MS analysis of chiral auxiliary derivatives of the biocatalyzed phenylserine analogues showed that the TcPAM-transamination reaction opened the epoxides enantio- A nd diastereoselectively. Each product mixture contained (2S)+(2R)-anti (erythro) and (2S)+(2R)-syn (threo) pairs with the anti-isomers predominating (-90:10 dr). Integrating the vicinal proton signals in the 1H NMR spectrum of the enzyme-catalyzed phenylserines and calculating the chemical shift difference (?"?) between the anti and syn proton signals confirmed the diastereomeric ratios and relative stereochemistries. Application of a (2S)-threonine aldolase from E. coli further established the absolute stereochemistry of the chiral derivatives of the diastereomeric enzymatically derived products. The 2R:2S ratio for the biocatalyzed anti-isomers was highest (88:12) for 3′-NO2-phenylserine and lowest (66:34) for 4′-F-phenylserine. This showed that the stereospecificity of TcPAM is in part directed by the substituent-type on the cinnamate epoxide analogue. The catalyst also converted each cinnamate epoxide analogue to its corresponding isoserine, highlighting a biocatalytic route to arylisoserines, which play a key role in building the pharmacophore seen in anticancer and protease inhibitor drugs.
- Shee, Prakash K.,Ratnayake, Nishanka Dilini,Walter, Tyler,Goethe, Olivia,Onyeozili, Edith Ndubuaku,Walker, Kevin D.
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p. 7418 - 7430
(2019/08/20)
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- Cyclizing pentapeptides: Mechanism and application of dehydrophenylalanine as a traceless turn-inducer
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Dehydrophenylalanine is used as a traceless turn-inducer in the total synthesis of dichotomin E. Macrocyclization of the monomer is achieved in high yields and selectivity over cyclodimerization under conditions 100 times more concentrated than previously achieved. The enamide facilitates ring closing, and Rh-catalyzed hydrogenation of the unsaturated cyclic peptide results in selective formation of the natural product or its epimer, depending on our choice of phosphine ligand. NMR analysis and molecular modeling revealed that the linear peptide adopts a left-handed α-turn that preorganizes the N- and C-termini toward macrocyclization.
- Le, Diane N.,Riedel, Jan,Kozlyuk, Natalia,Martin, Rachel W.,Dong, Vy M.
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supporting information
p. 114 - 117
(2017/11/27)
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- A PRODUCING METHOD OF D-FORM OR L-FORM AMINO ACID DERIVATIVES HAVING A THIOL GROUP
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This invention provides a producing method of an optical active D-form and/or L-form amino acid having a thiol group on its side chain by a simple method with good yield. This invention provides a producing method of an amino acid derivative having a thiol group on its side chain, and an intermediate thereof, wherein the producing method is characterized by producing an intermediate composition comprising a D-form and L-form of amino acid derivate having a thiol group at β -position, reacting D- or L-amino acid selective hydrolytic enzyme, and isolating the hydrolyzed D- or L-amino acid derivative.
- -
-
Paragraph 0174; 0175
(2016/10/31)
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- Diastereo- And enantioselective synthesis of β-Hydroxy-α-amino acids: Application to the synthesis of a key intermediate for lactacystin
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The development of a highly efficient and stereoselective methodology for the preparation of β-hydroxy-α- amino acids is described. Nucleophilic addition of enolates of tricyclic iminolactones 1a and 1b to aldehydes in the presence of 6 equiv of lithium chloride in THF at -78 °C leads to aldol adducts in good yield (63-86%) and high diastereoselectivity (up to >25:1 dr). Subsequently, hydrolysis of the aldol adducts under acidic conditions leads to the corresponding β-hydroxy-a-amino acids in good yields (up to 83%) and excellent enantiomeric excesses (99% ee) with good recovery yields of the chiral auxiliaries 6 and 7. This methodology was applied to the facile synthesis of the key intermediate for lactacystin along with several isomers.
- Li, Qiong,Yang, Shao-Bo,Zhang, Zhihui,Li, Lei,Xu, Peng-Fei
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supporting information; experimental part
p. 1627 - 1631
(2009/09/24)
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- Gymnangiamide, a Cytotoxic Pentapeptide from the Marine Hydroid Gymnangium regae
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A cytotoxic aqueous extract from the marine hydroid Gymnangium regae provided a novel linear pentapeptide, designated gymnangiamide (1). The planar structure of 1 was elucidated by interpretation of spectral data as well as chemical degradation and derivatization studies. In addition to the amino acids isoleucine and phenylserine, this peptide contained N-desmethyldolaisoleuine, O-desmethyldolaproine, and α-guanidino serine, three residues that have not previously been reported in a natural product. The absolute configurations of the constituent amino/guanidino acids were determined by chemical degradation and derivatization, followed by HPLC and LC-MS comparison with authentic standards. Gymnangiamide (1) was moderately cytotoxic against a number of human tumor cell lines in vitro.
- Milanowski, Dennis J.,Gustafson, Kirk R.,Rashid, Mohammad A.,Pannell, Lewis K.,McMahon, James B.,Boyd, Michael R.
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p. 3036 - 3042
(2007/10/03)
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- Preparation of optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (threo-beta-phenylserine) via optical resolution.
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To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1), (2RS,3SR)-2-benzoylamino-3-hydroxy-3-phenylpropanoic acid [(2RS,3SR)-2] was first optically resolved using (1S,2S)- and (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol as the resolving agents to afford (2R,3S)- and (2S,3R)-2 in yields of 73% and 66%, based on half of the starting amount of (2RS,3SR)-2. Next, the racemic structures of ammonium and some organic ammonium salts of (2RS,3SR)-2 were examined based on melting point, solubility, and infrared spectrum, with the aim of optical resolution by preferential crystallization. The benzylammonium salt of (2RS,3SR)-2 was suggested to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. The optical resolution by preferential crystallization of the racemic salt afforded the (2R,3S)- and (2S,3R)-salts with optical purities of 90-97%. The (2R,3S)- and (2S,3R)-2 obtained from the purified salts were hydrolyzed by reflux in hydrochloric acid to give (2R,3S)- and (2S,3R)-1.
- Shiraiwa, Tadashi,Saijoh, Reiichi,Suzuki, Masahiro,Yoshida, Kyosuke,Nishimura, Satoshi,Nagasawa, Hisashi
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p. 1363 - 1367
(2007/10/03)
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- Synthesis of all stereoisomers and some congeners of isocytoxazone
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cis-Isocytoxazone 2a and trans-isocytoxazone 2b, structural isomers of the antiasthmatic agent cytoxazone (-)-1, and their 5-substituted congeners 23-28 have been prepared. Aldol reaction of para-substituted benzaldehydes with 7-chloro-1-methyl-5-phenyl-1,4-benzodiazepin-2-one, followed by separation of diastereomeric racemates afforded 3-10. Acid-catalyzed 1,4-benzodiazepine ring opening, and transformation of the methyl esters of β-aryl-β-hydroxy-α-amino acids (11-16) via 4-methoxycarbonyl derivatives of 1,3-oxazolidin-2-one (17-22) and their reduction afforded the target oxazolidin-2-one derivatives 23-28. Racemic isocytoxazones 2a and 2b were prepared by an independent route starting from 4-methoxystyrene epoxide. Pure enantiomers of these diastereomeric racemates were separated by HPLC chromatography on chiral stationary phases. Their CD spectra, along with those of previously prepared enantiomers of cis-cytoxazone 1a and trans-cytoxazone 1b are discussed.
- Hamer?ak, Zdenko,?epac, Dragan,?iher, Dinko,?unji?, Vitomir
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p. 375 - 382
(2007/10/03)
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- syn/anti Diastereoselectivity in the aldol reaction of aldehydes with the C(3) carbanion of 1,3-dihydro-2H-1,4-benzodiazepin-2-one
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The aldol reaction of the C(3) carbanion of 7-chloro-1,3-dihydro-1- methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (2) with a series of aromatic and aliphatic aldehydes at -78°afforded threo/erythro diastereoisomers 3-16 of 7-chloro-1,3-dihydro-3-(hydroxymethyl)-1-methyl-5-phenyl-2H-1,4- benzodiazepinones, substituted at the C(3) side chain, in a ratio from 55:45 to 94:6 (Scheme 1). Lewis acids exhibited limited effect on the syn/anti diastereoselectivity of this reaction, and kinetic control of the reaction was confirmed. 1H-NMR Data suggested the assignment of the threo relative configuration to the first-eluted diastereoisomers 3, 5 7, and 9 on reversed- phase HPLC, and the erythro configuration to the second-eluted counterparts 4, 6, 8, and 10, respectively. The structures and relative configurations threo and erythro of the diastereoisomers 5 and 6, respectively, were established by single-crystal X-ray analysis, confirming the assignment based on the 1H-NMR data. A tentative mechanistic explanation of the diastereoselectivity invokes the enolate anion of 1,3-dihydro-2H-1,4- benzodiazepin-2-one as the reactive species (Scheme 2). Acid-catalyzed hydrolytic ring opening of 3 afforded threo-β-hydroxy-phenylalanine 17, whereas from 4, the N-(benzyloxy)carbonyl derivative 18 of erythro-β- hydroxy-phenylalanine was obtained (Scheme 3); in both cases, neither elimination of H2O from the C(3)-CHOH moiety nor epimerization at C(3) were observed. This result opens a new pathway to various configurationally uniform α-amino-β-hydroxy carboxylic acids and their congeners of biological importance.
- Markovic, Dean,Hamersak, Zdenko,Visnjevac, Aleksandar,Kojic-Prodic, Biserka,Sunjic, Vitomir
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p. 603 - 615
(2007/10/03)
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- Novel synthesis of 4-carboxymethyl 5-alkyl/aryl oxazolidin-2-ones by rearrangement of 2-carboxymethyl 3-alkyl/aryl N-tert-butoxycarbonyl aziridines
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(matrix presented) A two-step approach for the diastereoselective synthesis of 4-carboxymethyl 5-alkyl/aryl oxazolidin-2-ones is described, which proceeds via the intermediate formation of 2-carboxymethyl 3-alkyl/aryl N-tert-butoxycarbonyl (N-Boc) aziridines. By reaction of N-Boc β-amino methyl esters with LiHMDS and iodine, trans 2,3-disubstituted N-Boc aziridines are obtained with high stereoselectivities and yields. The final rearrangement to oxazolidin-2-ones is achieved by treatment with a catalytic amount of a Lewis acid and proceeds with high yield and complete regio- and stereoselectivity.
- Tomasini, Claudia,Vecchione, Andrea
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p. 2153 - 2156
(2008/02/09)
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- Preparation and use in amino acid synthesis of a new chiral glycine derivative - (R)- and (S)-tert-Butyl 2-tert-Butyl-4-methoxy-2,5-dihydroimidazole-1-carboxylate (BDI)
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The title compound BDI is prepared on multigram scale, either by resolution of the precursor 2-tert-butylimidazolidin-4-one (from glycine amide and pivalaldehyde) through diastereomeric salts (Scheme 2) or by preparative chromatographic enantiomer separation on a chiral column. Lithiated BDI derivatives are highly nucleophilic species, combining the structural elements of a Li enaminate, of an enolether and of an N-Boc-enaminate (E, G). They react with complete diastereoselectivity (NMR analysis) from the face trans to the tert-butyl group. The electrophiles employed are primary and secondary alkyl, allyl, benzyl, and propargyl halides (Schemes 3 and 5), enoates (in Michael additions, Scheme 7), as well as aliphatic and aromatic aldehydes (in aldol additions, Scheme 8). When a third, exocyclic, stereocenter is formed in these reactions, there is a high degree of enantiomer differentiation (with tac. sec. halides, products 10-12) and of enantiotopic face differentiation (with enoates and aldehydes, products 40-50). The reactions are so clean that highly efficient in-situ double alkylations are feasible, in which the sequence of addition of the two different electrophiles determines the configuration at the newly formed stereogenic center (Scheme 5). In contrast to derivatives of previously reported chiral glycine reagents, the products from BDI are converted to methyl esters of amino acids under mild conditions and without concomitant formation (... and the need for recovery or removal) of a chiral auxiliary; the method is compatible with acid-sensitive side chains in the α-amino acids and α-branched α-amino acids to be synthesized (Schemes 4 and 6). The addition of Li-BDI to aldehydes furnishes, after hydrolysis, α-amino-β-hydroxy acids of erythro configuration (allo-threonine analogs, Scheme 8); a model for the stereochemical course of this reaction (rel. topicity unlike) is proposed, and compared with the corresponding conversions of analogous oxazolidinone and imidazolidinone Li enolates which occur with rel. topicity like.
- Seebach, Dieter,Hoffmann, Matthias
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p. 1337 - 1351
(2007/10/03)
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- Preparation of (2R,3S)-β-hydroxy-α-amino acids by use of novel Streptomyces aldolase as a resolving agent for racemic material
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A unique aldolase, which was isolated from Streptomyces amakusaensis, is used to catalyse a reverse aldol reaction on representative racemic β-hydroxy-α-amino acids (3-6) to give samples of the (2R,3S)-(D-threo)-enantiomers with excellent enantiomeric purity.
- Herbert, Richard B.,Wilkinson, Barrie,Ellames, George J.
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p. 114 - 117
(2007/10/02)
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- Stereoselective Synthesis of β-Phenylserine from Glycine and Benzaldehyde as Mediated by Catalytic Bilayer Membranes, Artificial Vitamin B6-dependent Enzymes
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The aldolation of glycine with benzaldehyde to yield β-phenylserine was catalyzed by supramolecular assemblies formed with a synthetic peptide lipid, a hydrophobic vitamin B6 derivative, and zinc(II) ions in aqueous media under mild conditions.A diastereomeric ratio of the reaction products was much dependent on a size and a phase property of the vesicular catalyst.
- Kikuchi, Jun-ichi,Takashima, Toru,Nakao, Hidetoshi,Hie, Ken-ichi,Etoh, Hiroshi,et al.
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p. 553 - 556
(2007/10/02)
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- ON THE SYNTHESIS OF β-PHENYLALANINE
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A practical, economical and efficient two-step synthesis of β-phenylalanine and its methyl ester is reported: ?-phenylserine, 1, is chlorinated to β-chloro-β-phenylalanine, 2; the latter is hydrogenated in the presence of 10percent Pd/C catalyst to give the desired amino acid. β-Phenylalanine is separated (yield based upon β-phenylserine) as the free amino acid 3 (65.3percent yield) or as the hydrochloride 4 (79.8percent yield) or esterified to the methyl ester hydrochloride 5 (78.7percent yield).
- Portelli, Mario
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p. 215 - 216
(2007/10/02)
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- DIBENZYLAMINOACETATES AS USEFUL SYNTHETIC EQUIVALENTS OF GLYCINE IN THEi SYNTHESIS OF α-AMINO-β-HYDROXYACIDS
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The stereochemical course of three new simple methodologies for the preparation of α-amino-β-hydroxyacids starting from dibenzylaminoacetates as synthetic equivalents of glycine is described.While the aldol-type condensation via lithium enolates gave results highly dependent on the aldehyde employed, producing in some cases diastereoselectivities up to 5:1 for the anti isomers, the acid-catalysed aldol condensation of silyl ketene acetals yielded predominantly syn adducts with selectivities from 5:1 to 32:1.Finally the acylation-reduction procedure gave the best results in terms of yields and stereoselectivities, affording syn isomers with excellent induction ( 13:1).
- Guanti, Giuseppe,Banfi, Luca,Narisano, Enrica,Scolastico, Carlo
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p. 3671 - 3684
(2007/10/02)
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- SOLID-LIQUID PHASE TRANSFER CATALYTIC SYNTHESIS OF α-AMINO ACID VIA ALKYLATION AND NUCLEOPHILIC ADDITION OF BENZALDEHYDE IMINES
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A short, mild and efficient synthetic route of α-amino acid via alkylation, Michael addition and carbonyl addition as well as cycloaddition of aldimines derived from glycine and alanine esters with benzaldehyde under solid-liquid phase transfer catalytic condition has been studied.The key to solid-liquid phase transfer catalyzed reactions is the selection of a base for the various reactants.The yield is dependent on the base used.The results obtained using KOH, K2CO3 and Na2CO3 are discussed.The kinetics of solid-liquid PTC benzylation has been investigated and we propose a possible mechanism of solid-liquid PTC as an interface auto-catalytic procedure.The details of some syntheses of α-amino acids are presented.
- Yaozhong, Jiang,Changyou, Zhou,Shengde, Wu,Daimo, Chen,Youan, Ma,Guilan, Liu
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p. 5343 - 5354
(2007/10/02)
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- SYNTHESIS OF α-AMINO-β-HYDROXY ACIDS USING KETENE BIS(TRIMETHYLSILYL) ACETAL OR ITS N-METHYL-N-TRIMETHYLSILYL ANALOG
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Condensation of the title compounds with aldehydes and ketones in the presence of trimethylsilyl triflate provided the correspondig α-amino-β-hydroxy acids in fair to good yields as a mixture of diastereomers.
- Hvidt, Torsten,Martin, Oliver R.,Szarek, Walter A.
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p. 3807 - 3810
(2007/10/02)
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- DIASTEREOSELECTIVE SYNTHESIS OF α-AMINO-β-HYDROXYACIDS
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threo-α-Dibenzylamino-β-hydroxyesters (2) have been synthesised with high diastereoselectivity through the reduction of α-dibenzylamino-β-oxoesters (4) and then transformed into threo-α-amino-β-hydroxyacids.
- Guanti, Giuseppe,Banfi, Luca,Narisano, Enrica,Scolastico, Carlo
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p. 4693 - 4696
(2007/10/02)
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