- Direct Synthesis of Free α-Amino Acids by Telescoping Three-Step Process from 1,2-Diols
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A practical telescoping three-step process for the syntheses of α-amino acids from the corresponding 1,2-diols has been developed. This process enables the direct synthesis of free α-amino acids without any protection/deprotection step. This method was also effective for the preparation of a 15N-labeled α-amino acid. 1,2-Diols bearing α,β-unsaturated ester moieties afforded bicyclic α-amino acids through intramolecular [3 + 2] cycloadditions. A preliminary study suggests that the resultant α-amino acids are resolvable by aminoacylases with almost complete selectivity.
- Inada, Haruki,Shibuya, Masatoshi,Yamamoto, Yoshihiko
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supporting information
p. 709 - 713
(2019/01/25)
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- Enantioselective biomimetic transamination of α-keto acids catalyzed by H4-naphthalene-derived axially chiral biaryl pyridoxamines
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Asymmetric biomimetic transamination is a highly attractive method for synthesis of chemically and biologically important chiral amino acids and chiral amines. Development of chiral pyridoxamines/pyridoxals is the key for the reaction. New axially chiral biaryl pyridoxamines based on H4-naphathene skeleton have been developed. The pyridoxamines display good enantioselectivity and high catalytic activity in asymmetric biomimetic transamination of α-keto acids, affording various optically active unnatural amino acids in 61–98% yields with up to 91% ee's.
- Hou, Chengkang,Zhao, Guoqing,Xu, Dongfang,Zhao, Baoguo
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supporting information
p. 1028 - 1033
(2018/02/15)
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- Novel chiral open-chain pyridoxamine catalyst and synthesis method and application thereof
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The invention relates to a novel chiral open-chain pyridoxamine catalyst and a synthesis method and application thereof. The structural general formula of the pyridoxamine catalyst is shown in the specification, wherein R1, R2, R3 and R4 are one of hydrogen, C1-24 alkyl, C1-24 alkyl containing substituent groups, substances shown in the specification and halogen, the substituent groups on C1-24 alkyl are a substance shown in the specification or a substance shown in the specification or a substance shown in the specification or O-Rw or S-Rw' or halogen, and Rx, Rx', Ry, Ry', Ry'', Rz, Rz', Rw and Rw' are one of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, (1-phenyl)ethyl, 1-naphthyl, 2-naphthyl and halogen. Compared with the prior art, the pyridoxamine catalyst can achieve rapid and efficient synthesis of chiral amino acid, the preparation raw materials are easy to obtain, reaction conditions are mild, cost is low, and when the novel chiral open-chain pyridoxamine catalyst is used for a transamination reaction, the conditions are mild, and the reaction is stable.
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Paragraph 0175; 0176; 0177; 0178; 0213; 0214; 0215; 0216
(2017/01/19)
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- SYNTHESIS METHOD FOR L-CYCLIC ALKYL AMINO ACID AND PHARMACEUTICAL COMPOSITION HAVING THEREOF
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A synthesis method for L-cyclic alkyl amino acid and a pharmaceutical composition having the said amino acid are provide in the present disclosure provides. The synthesis method comprises: step A.) preparing a cyclic alkyl keto acid or a cyclic alkyl keto acid salt having Structural Formula (I) or Structural Formula (II), and step B.) mixing the cyclic alkyl keto acid or the cyclic alkyl keto acid salt with ammonium formate, a leucine dehydrogenase, a formate dehydrogenase and a coenzyme NAD+, and carrying out a reductive amination reaction to generate the L-cyclic alkyl amino acid, wherein the Structural Formula (I) is where n1≧1, m1≧0 and the M1 is H or a monovalent cation; the Structural Formula (II) is where n2≧0, m2≧0, the M2 is H or a monovalent cation, an amino acid sequence of the leucine dehydrogenase is SEQ ID No.1.
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Paragraph 0086; 0097
(2016/11/17)
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- A new type of chiral-pyridoxamines for catalytic asymmetric transamination of α-keto acids
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A new type of chiral pyridoxamines bearing an adjacent chiral stereocenter has been developed via multi-step synthesis. The pyridoxamines displayed catalytic activity in asymmetric transamination of α-keto acids to give a variety of optically active amino acids in 27–78% yields with 34–62% ee's under very mild conditions. This work provides a synthetic strategy to construct new chiral pyridoxamines using bromopyridine 7 as a key synthon and also represents an early example of the applications of chiral pyridoxamines in asymmetric catalysis.
- Chen, Jianfeng,Zhao, Junyu,Gong, Xing,Xu, Dongfang,Zhao, Baoguo
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supporting information
p. 4612 - 4615
(2016/09/23)
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- Chiral Pyridoxal-Catalyzed Asymmetric Biomimetic Transamination of α-Keto Acids
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A series of chiral pyridoxals 8 and 9 have been developed from commercially available pyridoxine and (S)-α,α-diarylprolinols. The pyridoxals exhibited good catalytic activity in an asymmetric transamination of α-keto acids with 2,2-diphenylglycine (7f) as the amine source to give various α-amino acids in 29-85% yields with 53-80% ee's. The current asymmetric transamination has successfully mimicked a complete biological transamination process characterized by two half-transaminations, a small chiral pyridoxal molecule acting as the catalyst, and enantioselective control.
- Shi, Limin,Tao, Chuangan,Yang, Qin,Liu, Yong Ethan,Chen, Jing,Chen, Jianfeng,Tian, Jiaxin,Liu, Feng,Li, Bo,Du, Yongling,Zhao, Baoguo
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supporting information
p. 5784 - 5787
(2015/12/11)
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- FPR1 ANTAGONIST DERIVATIVES AND USE THEREOF
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A dipeptide derivative as formyl peptide receptor 1 (FPR1) antagonist is provided. The dipeptide derivative is represented by formula (I), wherein: the chiral centers in formula (I) are S and R configurations respectively; each of RK and RT is selected from a group consisting of a hydrogen, a hydroxyl group, a C1-C4 alkyl-substituted hydroxyl group, a C1-C4 alkoxyl group, a carboxylic acid group, a C1-C4 alkyl nitrile-substituted, C1-C4 alkyl-substituted or C1-C4 alkoxyl-substituted amido group, a C1-C4 alkyl-substituted ester group and a benzoyl group having a C1-C4 alkyl-substituted benzene ring; and each of RM and RS is selected from a group consisting of a hydrogen, a hydroxyl group, a phenyl group, a pyridinyl group, a carboxylic acid group, a C1-C4 alkoxyl substituted ester group, and a benzoyl group having a hydroxyl-substituted, a halogen-substituted, a C1-C4 alkoxyl-substituted or a C1-C4 alkyl-substituted benzene ring.
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Page/Page column
(2015/04/15)
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- FPR1 ANTAGONIST DERIVATIVES AND USE THEREOF
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A dipeptide derivative as formyl peptide receptor 1 (FPR1) antagonist is provided. The dipeptide derivative is represented by formula (I), wherein: the chiral centers in formula (I) are S and R configurations respectively; each of RK and RT is selected from a group consisting of a hydrogen, a hydroxyl group, a C1-C4 alkyl-substituted hydroxyl group, a C1-C4 alkoxyl group, a carboxylic acid group, a C1-C4 alkyl nitrile-substituted, C1-C4 alkyl-substituted or C1-C4 alkoxyl-substituted amido group, a C1-C4 alkyl-substituted ester group and a benzoyl group having a C1-C4 alkyl-substituted benzene ring; and each of RM and RS is selected from a group consisting of a hydrogen, a hydroxyl group, a phenyl group, a pyridinyl group, a carboxylic acid group, a C1-C4 alkoxyl substituted ester group, and a benzoyl group having a hydroxyl-substituted, a halogen-substituted, a C1-C4 alkoxyl-substituted or a C1-C4 alkyl-substituted benzene ring.
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Paragraph 0119-0124
(2015/11/16)
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- Design and synthesis of tryptophan containing dipeptide derivatives as formyl peptide receptor 1 antagonist
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Our previous studies identified an Fmoc-(S,R)-tryptophan-containing dipeptide derivative, 1, which selectively inhibited neutrophil elastase release induced by formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP) in human neutrophils. In an attempt to improve pharmacological activity, a series of tryptophan-containing dipeptides were synthesized and their pharmacological activities were investigated in human neutrophils. Of these, five compounds 3, 6, 19a, 24a, and 24b exhibited potent and dual inhibitory effects on FMLP-induced superoxide anion (O2-) generation and neutrophil elastase release in neutrophils with IC50 values of 0.23/0.60, 1.88/2.47, 1.87/3.60, 0.12/0.37, and 1.32/1.03 μM, respectively. Further studies indicated that inhibition of superoxide production in human neutrophils by these dipeptides was associated with the selective inhibition of formyl peptide receptor 1 (FPR1). Furthermore, the results of structure-activity relationship studies concluded that the fragment N-benzoyl-Trp-Phe-OMe (3) was most suitable as a core structure for interaction with FPR1, and may be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases. As some of the synthesized compounds exhibited separable conformational isomers, and showed diverse bioactivities, the conformation analysis of these compounds is also discussed herein. The Royal Society of Chemistry 2013.
- Hwang, Tsong-Long,Hung, Chih-Hao,Hsu, Ching-Yun,Huang, Yin-Ting,Tsai, Yu-Chi,Hsieh, Pei-Wen
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p. 3742 - 3755
(2013/06/27)
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- Efficient and Practical Arene Hydrogenation by Heterogeneous Catalysts under Mild Conditions
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An efficient and practical arene hydrogenation procedure based on the use of heterogeneous platinum group catalysts has been developed. Rh/C is the most effective catalyst for the hydrogenation of the aromatic ring, which can be conducted in iPrOH under neutral conditions and at ordinary to medium H 2 pressures (10 atm). A variety of arenes such as alkylbenzenes, benzoic acids, pyridines, furans, are hydrogenated to the corresponding cyclohexyl and heterocyclic compounds in good to excellet yields. The use of Ru/C, less expensive than Rh/C, affords an effective and practical method for the hydrogenation of arenes including phenols. Both catalysts can be reused several times after simple filtration without any significant loss of catalytic activity.
- Maegawa, Tomohiro,Akashi, Akira,Yaguchi, Kiichiro,Iwasaki, Yohei,Shigetsura, Masahiro,Monguchi, Yasunari,Sajiki, Hironao
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experimental part
p. 6953 - 6963
(2010/02/28)
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- Self-association-free dimeric cinchona alkaloid organocatalysts: Unprecedented catalytic activity, enantioselectivity and catalyst recyclability in dynamic kinetic resolution of racemic azlactones
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Self-association-free, bifunctional, squaramide-based dimeric cinchona alkaloid organocatalysts show unprecedented catalytic activity, enantioselectivity and catalyst recyclability in the dynamic kinetic resolution (DKR) reaction of a broad range of racemic azlactones. The Royal Society of Chemistry 2009.
- Woong Lee, Ji,Hi Ryu, Tae,Suk Oh, Joong,Yong Bae, Han,Bin Jang, Hyeong,Eui Song, Choong
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supporting information; experimental part
p. 7224 - 7226
(2010/03/25)
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- A mild and facile method for complete hydrogenation of aromatic nuclei in water
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A mild and complete hydrogenation of aromatic rings catalyzed by heterogeneous 10% Rh/C proceeds at 80 °C in water under 5 atm of H 2 pressure. This method is applicable to the hydrogenation of various carbon and heteroaromatic compounds such as alkylbenzenes, biphenyls, pyridines and furans. Georg Thieme Verlag Stuttgart.
- Maegawa, Tomohiro,Akashi, Akira,Sajiki, Hironao
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p. 1440 - 1442
(2007/10/03)
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- Creation of a broad-range and highly stereoselective D-amino acid dehydrogenase for the one-step synthesis of D-amino acids
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Using both rational and random mutagenesis, we have created the first known broad substrate range, nicotinamide cofactor dependent, and highly stereoselective D-amino acid dehydrogenase. This new enzyme is capable of producing D-amino acids via the reductive amination of the corresponding 2-keto acid with ammonia. This biocatalyst was the result of three rounds of mutagenesis and screening performed on the enzyme meso-diaminopimelate D-dehydrogenase. The first round targeted the active site of the wild-type enzyme and produced mutants that were no longer strictly dependent on the native substrate. The second and third rounds produced mutants that had an increased substrate range including straight-and branched-aliphatic amino acids and aromatic amino acids. The very high selectivity toward the D-enantiomer (95 to >99% ee) was shown to be preserved even after the addition of the five mutations found in the three rounds of mutagenesis and screening. This new enzyme could complement and improve upon current methods for D-amino acid synthesis.
- Vedha-Peters, Kavitha,Gunawardana, Manjula,Rozzell, J. David,Novick, Scott J.
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p. 10923 - 10929
(2007/10/03)
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- Enantioselective synthesis of non-natural amino acids using phenylalanine dehydrogenases modified by site-directed mutagenesis
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The substrate scope of three mutants of phenylalanine dehydrogenase as biocatalysts for the transformation of a series of 2-oxo acids, structurally related to phenylpyruvic acid, to the analogous -amino acids, non-natural analogues of phenylalanine, has been investigated. The mutant enzymes are more tolerant than the wild type enzyme of the non-natural substrates, especially those with substituents at the 4-position on the phenyl ring. Excellent enantiocontrol resulted in all cases.
- Busca, Patricia,Paradisi, Francesca,Moynihan, Eamonn,Maguire, Anita R.,Engel, Paul C.
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p. 2684 - 2691
(2007/10/03)
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- A convergent solution-phase synthesis of the macrocycle Ac-Phe-[Orn-Pro-D-Cha-Trp-Arg], a potent new antiinflammatory drug
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Relatively few cyclic peptides have reached the pharmaceutical marketplace during the past decade, most produced through fermentation rather than made synthetically. Generally, this class of compounds is synthesized for research purposes on milligram scales by solid-phase methods, but if the potential of macrocyclic peptidomimetics is to be realized, low-cost larger scale solution-phase syntheses need to be devised and optimized to provide sufficient quantities for preclinical, clinical, and commercial uses. Here, we describe a cheap, medium-scale, solution-phase synthesis of the first reported highly potent, selective, and orally active antagonist of the human C5a receptor. This compound, Ac-Phe[Orn-Pro-D-Cha-Trp-Arg], known as 3D53, is a macrocyclic peptidomimetic of the human plasma protein C5a and displays excellent antiinflammatory activity in numerous animal models of human disease. In a convergent approach, two tripeptide fragments Ac-Phe-Orn-(Boc)-Pro-OH and H-D-Cha-Trp(For)-Arg-OEt were first prepared by high-yielding solution-phase couplings using a mixed anhydride method before coupling them to give a linear hexapeptide which, after deprotection, was obtained in 38% overall yield from the commercially available amino acids. Cyclization in solution using BOP reagent gave the antagonist in 33% yield (13% overall) after HPLC purification. Significant features of the synthesis were that the Arg side chain was left unprotected throughout, the component Boc-D-Cha-OH was obtained very efficiently via hydrogenation of D-Phe with PtO2 in TFA/water, the tripeptides were coupled at the Pro-Cha junction to minimize racemization via the oxazolone pathway, and the entire synthesis was carried out without purification of any intermediates. The target cyclic product was purified (> 97%) by reversed-phase HPLC. This convergent synthesis with minimal use of protecting groups allowed batches of 50-100 g to be prepared efficiently in high yield using standard laboratory equipment. This type of procedure should be useful for making even larger quantities of this and other macrocyclic peptidomimetic drugs.
- Reid, Robert C.,Abbenante, Giovanni,Taylor, Stephen M.,Fairlie, David P.
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p. 4464 - 4471
(2007/10/03)
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- Process research of (R)-cyclohexyl lactic acid and related building blocks: A comparative study
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(S)-Cyclohexyl lactic acid is a component of the selective E-selectin inhibitor 2 ((S)-cHexLact-2-0-(3-Galβ(1→3)ddGlc-(4→1)αFuc). We describe the evaluation of various synthetic routes to this building block: (A) diazotation of phenylalanine followed by phenyl ring hydrogenation; (B) phenyl ring hydrogenation of phenyl alanine followed by diazotation; (C) acidic hydrolysis of the cyanohydrin derived from phenylacetaldehyde, enantiomeric resolution of the resulting, racemic phenyl lactic acid via diasteromeric salt formation and phenyl ring hydrogenation; (D) enantioselective dihydroxylation of a cinnamate ester, followed by hydrogenation of the benzylic hydroxy group and the aromatic nucleus; (E) enantioselective biocatalytic reduction of phenylpyruvic acid, followed by phenyl ring hydrogenation. The development of (2R)-2-0-(4-nitrophenyl)sulfonyl-cyclohexyl lactic acid p-bromobenzylester 21 as a buidling block with improved crystallinity and stability is also described.
- Storz, Thomas,Dittmar, Peter,Fauquex, Pierre Francois,Marschal, Philippe,Lottenbach, Willy Urs,Steiner, Heinz
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p. 559 - 570
(2013/09/05)
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- New synthetic routes to α-amino acids and γ-oxygenated α-amino acids. Reductive denitration and oxidative transformations of γ-nitro-α-amino acids
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Transformation of γ-nitro-α-amino acid derivatives into α-amino acids by reductive denitration, into the γ-oxo-α-amino acids by ozonolysis of the corresponding amino acid ester nitronate derivatives, and into γ-hydroxy-α-amino acid derivatives by subsequent reduction of the oxo functionality, can be achieved in good yields. As the γ-nitro-α-amino acid derivatives are prepared from N,O-protected dehydroalanines derivable from the corresponding alanine, serine and cysteine derivatives by specific routes, the overall procedures provide a means for selective conversion of these simple α-amino acids into more complex ones.
- Crossley, Maxwell J.,Fung, Yik M.,Kyriakopoulos, Efstathia,Potter, Jeffrey J.
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p. 1123 - 1130
(2007/10/03)
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- Arylsulfonamide derivative and pharmaceutical compositions and use thereof
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An arylsulfonamide derivative of the formula (I): STR1 wherein R1 is unsubstituted phenyl or naphthyl, or phenyl substituted by 1 to 3 same or different substituents selected from the group consisting of halogen, alkyl, nitro and alkoxy, R2 is straight, branched, or branched cyclic alkyl with 1 to 15 carbon atoms, phenyl, phenyloxyl, phenyloxy substituted by one or more halogen atoms, cycloalkyl with 5 to 7 carbon atoms, indolyl, alkylthiol with 1 to 4 carbon atoms, hydroxyl, protected hydroxyl, imidazolyl, pyridyloxyl, or --OSO2 R4, R4 is straight or branched alkyl with 1 to 15 carbon atoms, or unsubstituted phenyl or thienyl, or phenyl or thienyl substituted by 1 to 3 same or different substituents of halogen, alkyl, nitro and alkoxy, R3 is hydrogen or straight or branched alkyl with 1 to 20 carbon atoms, n is an integer of 0 to 10, p is an integer of 0 to 10, X is a group of the formula m and q are independently an integer of 0 to 8, and A is a direct bond or phenylene, or a salt thereof; a process for manufacture thereof and a pharmaceutical composition containing same. The above compound exhibits thromboxane A2 antagonism.
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- Asymmetric synthesis of α-amino acids by copper-catalyzed conjugate addition of Grignard reagents to optically active carbamatoacrylates
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Optically active ene carbamates were α-lithiated by lithium tetramethylpiperidide in the presence of trialkylstannyl chlorides to produce α-stannylated compounds. These underwent facile palladium-catalyzed couplings with acid chlorides to produce α-keto ene carbamates in good yield. Treatment of the α-stannyl ene carbamates with butyllithium followed by quenching with carbon dioxide and esterification gave optically active carbamatoacrylates. Copper-catalyzed addition of tert-butyl-, 1-naphthyl-, 2-propenyl-, p-methoxyphenyl-, (trimethylsilyl)methyl-, cyclohexyl-, 1-adamantyl-, and isopropyl Grignard reagents followed by quenching at -10 to 25°C and removal of the protecting groups gave the corresponding α-amino acids in 70-90% yield and 73-97% ee. Quenching the reaction at low temperature resulted in little if any asymmetric induction.
- Lander, Peter A.,Hegedus, Louis S.
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p. 8126 - 8132
(2007/10/02)
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- Site-specific incorporation of non-natural residues into peptides: Effect of residue structure on suppression and translation efficiencies
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A systematic survey of the structural requirements for biosynthetic incorporation of non-natural residues into a polypeptide is presented. Relative translation efficiencies for a series of 12 semi-synthetic acylated suppressor tRNAs ranged from 0 to 91% depending on the structure of the residue incorporated.
- Bain,Wacker, Dean A.,Kuo, Eric E.,Chamberlin, A. Richard
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p. 2389 - 2400
(2007/10/02)
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- Process for preparing ACHPA
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Process comprising coupling of an acylimidazole-activated derivative of a reduced and protected phenylalanine with the magnesium salt of malonic acid monoethyl ester to produce the beta-ketoester, which is subsequently reduced with NaCNBH3 /THF in glacial acetic acid to afford a separable mixture of 3-S and 3-R 3-hydroxy-(4S)-4-(N-α-BOC)amino-5-cyclohexylpentanoic acid, such that large-scale, high yield production of optically-active ACHPA is significantly improved.
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