- Asymmetric Synthesis of Functionalized Phenylalanine Derivatives via Rh-Catalyzed Conjugate Addition and Enantioselective Protonation Cascade
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The asymmetric conjugate addition of arylboronic acids to N-phthalimidodehydroalanine 1i catalyzed by Rh(I)/L1a enables the facile preparation of chiral functionalized phenylalanines. The reaction proceeds by a conjugate addition and enantioselective protonation cascade, affording a rhodium enolate that undergoes re-face protonation. The reaction tolerates various arylboronic acids and can be used in the gram-scale synthesis of (S)-phenylalanine hydrochloride, demonstrating the reaction scope and the synthetic feasibility of the process.
- Jian, Jia-Hong,Zeng, Hao-Wei,Kuo, Ting-Shen,Wu, Ping-Yu,Wu, Hsyueh-Liang
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supporting information
p. 9468 - 9472
(2019/11/28)
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- LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs
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The transporter protein Large-neutral Amino Acid Transporter 1 (LAT-1, SLC7A5) is responsible for transporting amino acids such as tyrosine and phenylalanine as well as thyroid hormones, and it has been exploited as a drug delivery mechanism. Recently its role in cancer has become increasingly appreciated, as it has been found to be up-regulated in many different tumor types, and its expression levels have been correlated with prognosis. Substitution at the meta position of aromatic amino acids has been reported to increase affinity for LAT-1; however, the SAR for this position has not previously been explored. Guided by newly refined computational models of the binding site, we hypothesized that groups capable of filling a hydrophobic pocket would increase binding to LAT-1, resulting in improved substrates relative to parent amino acid. Tyrosine and phenylalanine analogs substituted at the meta position with halogens, alkyl and aryl groups were synthesized and tested in cis-inhibition and trans-stimulation cell assays to determine activity. Contrary to our initial hypothesis we found that lipophilicity was correlated with diminished substrate activity and increased inhibition of the transporter. The synthesis and SAR of meta-substituted phenylalanine and tyrosine analogs is described.
- Augustyn, Evan,Finke, Karissa,Zur, Arik A.,Hansen, Logan,Heeren, Nathan,Chien, Huan-Chieh,Lin, Lawrence,Giacomini, Kathleen M.,Colas, Claire,Schlessinger, Avner,Thomas, Allen A.
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supporting information
p. 2616 - 2621
(2016/05/09)
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- LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates
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Large neutral amino acid transporter 1 (LAT1) is a solute carrier protein located primarily in the blood–brain barrier (BBB) that offers the potential to deliver drugs to the brain. It is also up-regulated in cancer cells, as part of a tumor's increased metabolic demands. Previously, amino acid prodrugs have been shown to be transported by LAT1. Carboxylic acid bioisosteres may afford prodrugs with an altered physicochemical and pharmacokinetic profile than those derived from natural amino acids, allowing for higher brain or tumor levels of drug and/or lower toxicity. The effect of replacing phenylalanine's carboxylic acid with a tetrazole, acylsulfonamide and hydroxamic acid (HA) bioisostere was examined. Compounds were tested for their ability to be LAT1 substrates using both cis-inhibition and trans-stimulation cell assays. As HA-Phe demonstrated weak substrate activity, its structure–activity relationship (SAR) was further explored by synthesis and testing of HA derivatives of other LAT1 amino acid substrates (i.e., Tyr, Leu, Ile, and Met). The potential for a false positive in the trans-stimulation assay caused by parent amino acid was evaluated by conducting compound stability experiments for both HA-Leu and the corresponding methyl ester derivative. We concluded that HA's are transported by LAT1. In addition, our results lend support to a recent account that amino acid esters are LAT1 substrates, and that hydrogen bonding may be as important as charge for interaction with the transporter binding site.
- Zur, Arik A.,Chien, Huan-Chieh,Augustyn, Evan,Flint, Andrew,Heeren, Nathan,Finke, Karissa,Hernandez, Christopher,Hansen, Logan,Miller, Sydney,Lin, Lawrence,Giacomini, Kathleen M.,Colas, Claire,Schlessinger, Avner,Thomas, Allen A.
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supporting information
p. 5000 - 5006
(2016/10/05)
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- Recyclable Ligands for the Non-Enzymatic Dynamic Kinetic Resolution of Challenging α-Amino Acids
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Structurally simple and inexpensive chiral tridentate ligands were employed for substantially advancing the purely chemical dynamic kinetic resolution (DKR) of unprotected racemic tailor-made α-amino acids (TM-α-AAs), enabling the first DKR of TM-α-AAs bearing tertiary alkyl chains as well as multiple unprotected functional groups. Owing to the operationally convenient conditions, virtually complete stereoselectivity, and full recyclability of the source of chirality, this method should find wide applications for the preparation of TM-α-AAs, especially on large scale. The non-enzymatic dynamic kinetic resolution of racemic α-amino acids bearing tertiary alkyl chains and multiple unprotected functional groups is based on the enantioselective formation of nickel(II) complexes and their hydrolysis under convenient conditions. The specially designed chiral ligands are inexpensive and can be quantitatively recycled.
- Nian, Yong,Wang, Jiang,Zhou, Shengbin,Wang, Shuni,Moriwaki, Hiroki,Kawashima, Aki,Soloshonok, Vadim A.,Liu, Hong
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supporting information
p. 12918 - 12922
(2015/11/02)
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- Organocatalytic asymmetric biomimetic transamination of α-keto acetals to chiral α-amino acetals
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This paper describes a chiral base-catalyzed asymmetric biomimetic transamination of α-keto acetals. A wide variety of α-amino acetals containing various functional groups can be synthesized in 50-85% yield and 82-86% ee.
- Pan, Hongjie,Xie, Ying,Liu, Mao,Shi, Yian
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p. 2389 - 2392
(2014/01/06)
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- Isolation and structural determination of the antifouling diketopiperazines from marine-derived Streptomyces praecox 291-11
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Marine derived actinomycetes constituting 185 strains were screened for their antifouling activity against the marine seaweed, Ulva pertusa, and fouling diatom, Navicula annexa. Strain 291-11 isolated from the seaweed, Undaria pinnatifida, rhizosphere showed the highest antifouling activity and was identified as Streptomyces praecox based on a 16S rDNA sequence analysis. Strain 291-11 was therefore named S. praecox 291-11. The antifouling compounds from S. praecox 291-11 were isolated, and their structures were analyzed. The chemical constituents representing the antifouling activity were identified as (6S,3S)-6-benzyl-3-methyl-2,5-diketopiperazine (bmDKP) and (6S,3S)-6-isobutyl-3- methyl-2,5-diketopiperazine (imDKP) by interpreting the nuclear magnetic resonance and high-resolution mass spectroscopy data. Approximately 4.8mg of bmDKP and 3.1 mg of imDKP were isolated from 1.2 g of the S. praecox 291-11 crude extract. Eight different compositions of culture media were investigated for culture, the TBFeC medium being best for bmDKP and TCGC being the optimum for imDKP production. Two compounds respectively showed a 17.7 and 21 therapeutic ratio (LC50/EC50) to inhibit zoospores, and two compounds respectively showed a 263 and 120.2 therapeutic ratio to inhibit diatoms.
- Cho, Ji Young,Kang, Ji Young,Hong, Yong Ki,Baek, Hyo Hyun,Shin, Hyoun Woong,Kim, Myoung Sug
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experimental part
p. 1116 - 1121
(2012/10/07)
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- Cyclopeptides and polyketides from coral-associated fungus, Aspergillus versicolor LCJ-5-4
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Three new cyclopentapeptides, versicoloritides A-C (1-3), a new orcinol tetramer, tetraorcinol A (4), and two new lactones, versicolactones A and B (5 and 6) together with three known metabolites, diorcinol, glyantrypine, and cordyol C were isolated from the fermentation broth of the coral-associated fungus Aspergillus versicolor LCJ-5-4. Their structures were elucidated by spectroscopic and chemical methods. The new compounds 1-4 were evaluated for their radical-scavenging activity and antimicrobial activity against Staphylococcus aureus, Escherichia coli, Enterobacter aerogenes, Bacillus subtilis, Pseudomonas aeruginosa, and Candida albicans and cytotoxicity against P388 and Hela cell lines. Compound 4 showed weak radical-scavenging activity against the DPPH radical with an IC50 value of 67 μM.
- Zhuang, Yibin,Teng, Xiancun,Wang, Yi,Liu, Peipei,Wang, Hui,Li, Jing,Li, Guoqiang,Zhu, Weiming
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experimental part
p. 7085 - 7089
(2011/10/09)
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- Hydration of amino acids from ultrasonic measurements
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In this paper the results of compressibility of aqueous solutions of amino acids in water and in aqueous HCl and NaOH solutions at 25 °C are presented. The effect of the charged protonated amino groups and deprotonated carboxylic groups on the hydration number was tested. The idea of additivity of the hydration number with the constituents of the solute molecule was successfully applied and discussed.
- Burakowski, Andrzej,Gliński, Jacek
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experimental part
p. 12157 - 12161
(2011/01/11)
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- Novel cyclopeptide and unique flavone from Desmos rostrata. Total synthesis of desmorostratone
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Two new compounds, a cyclic peptide desmocyclopeptide (1) and a special flavone desmorostratone (2) were isolated from the stem bark of Desmos rostrata, along with two known compounds, desmosdumotins B (3) and C (4). Their structures were established on the basis of the spectral data, including mass spectrometry and 2D NMR. The total synthesis of desmorostratone (2) was performed in order to confirm its structure as well as that of desmosdumotin C (4), which was a tautomeric mixture in the solution. Finally, cytotoxity of these compounds were evaluated. Desmosdumotin C (4) displayed a moderate inhibition activity against KB cell line with an IC50 of 19.2 μM, whereas the other products showed a weak inhibition against the same cell line target.
- Nguyen, Ngoc Tuan,Pham, Van Cuong,Litaudon, Marc,Guéritte, Fran?oise,Bodo, Bernard,Nguyen, Van Tuyen,Nguyen, Van Hung
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experimental part
p. 7171 - 7176
(2009/12/24)
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- A new method for the preparation of functionalized unnatural α-H-α-amino acid derivatives
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A new method for the preparation of α-H-α-amino acids is reported based on the α-alkylation of iminoacetic acid esters or amides. These imines are readily available by the reaction of glyoxylic acid esters with branched primary amines. The subsequent reaction with methanolic ammonia gave the corresponding iminoacetic acid amides. α-Alkylation of these imines with various electrophiles under basic conditions, followed by an acidic hydrolysis, gave α-amino acids, esters, or amides in up to 93% yield. α-Alkylation under chiral PTC conditions resulted in mono-alkylated amino acids with 90% ee.
- Hyett, David J.,Didonè, Mara,Milcent, Thierry J.A.,Broxterman, Quirinus B.,Kaptein, Bernard
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p. 7771 - 7774
(2007/10/03)
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- A novel strategy for oligopeptide synthesis using a polymer-supported ammonium fluoride
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A novel method for the preparation of oligopeptides with a PS-ammonium fluoride in the solution phase is reported. The synthesis of lipid II pentapeptide is efficiently synthesized via a PS-ammonium fluoride without chromatographic purifications. The method reported here is very convenient to synthesize a relatively large amount of oligopeptides with abundantly available Fmoc-protected amino acids in a time efficient manner.
- Kurosu, Michio,Crick, Dean C.
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p. 5325 - 5328
(2007/10/03)
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- Highly functionalised organolithium and organoboron reagents for the preparation of enantiomerically pure α-amino acids
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Homochiral, highly functionalised organolithium reagents derived from l-serine have been generated and reacted with electrophiles. The novel enantiomerically pure adducts thus obtained were then converted, through β-amino alcohols, into novel non-proteinogenic α-amino acids. The methodology also made available a novel boronic acid which was then employed as a Suzuki cross-coupling partner, elaborating a new pathway to phenylalanine analogues.
- Barfoot, Christopher W.,Harvey, Joanne E.,Kenworthy, Martin N.,Kilburn, John Paul,Ahmed, Mahmood,Taylor, Richard J.K.
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p. 3403 - 3417
(2007/10/03)
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- Method for the synthesis of compounds of formula 1 and derivatives thereof
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Mono-substituted and di-substituted alpha-amino acids and derivatives thereof, substituted at the alpha positon with one (mono-) or two (di-) substituents (R2 and/or R3) as shown in Formula 1: N(R4R5)C(R2R3)CO(OR1).
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- Synthesis of non-proteinogenic phenylalanine analogues by Suzuki cross-coupling of a serine-derived alkyl boronic acid
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Protected serine-derived boronic acids have been prepared as β-anionic alanine equivalents, and undergo efficient Suzuki cross-coupling with a variety of aryl halides to give, after elaboration, non-proteinogenic phenylalanine analogues.
- Harvey, Joanne E.,Kenworthy, Martin N.,Taylor, Richard J. K.
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p. 2467 - 2471
(2007/10/03)
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- Conjugate additions of organocuprates to a 3-methylene-6-isopropyldiketopiperazine acceptor for the asymmetric synthesis of homochiral α-amino acids
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Addition of a range of organocuprates to (S)-N,N′-bis(p-methoxybenzyl)-3-methylene-6-isopropylpiperazine-2, 5-dione 8 affords cis-3-isopropyl-6-alkyldiketopiperazines in excellent yield and >95% de. Subsequent deprotection and hydrolysis of these cis-3-isopropyl-6-alkyldiketopiperazines affords homochiral (S)-α-amino acids in excellent yield.
- Bull,Davies,Garner,O'Shea
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p. 3281 - 3287
(2007/10/03)
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- (R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in the enantioselective preparation of α-amino acids
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rac-α-Amino acids (rac-1a-d) were formally deracemized by a four-step reaction sequence: (a) protection of the amino function as the phthalimido derivative; (b) acyl chloride formation; (c) diastereoselective reaction with the chiral auxiliaries (R)- or (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2- pyrrolidinone, (R)- or (S)-3; and (d) acid hydrolysis to deprotect both the ester and phthalimido functions. Diastereoselectivities of the intermediate esters 4 were good (82-96% d.e.), except for the case of 4b (41% d.e.), the precursor of valine. The main diastereoisomer of esters 4 was (αR,3S)- or (αS,3R)-, except for 4d: in this case, working at -78°C, the (αR,3R)- diastereoisomer was the main product, which epimerizes easily at the α- position when at room temperature. Acid hydrolysis of esters 4 directly gave the deprotected α-amino acids, with little or no epimerization at the α- position of the α-amino acid and complete recovery of the chiral auxiliary. Only (αR,3R)-4d on acid hydrolysis partially epimerized at the α-position. Moreover, some α-amino acids and their N,N-dibenzyl derivatives were obtained by dynamic kinetic resolution of diastereoisomeric mixtures of α- bromo esters 5 derived from the chiral auxiliaries (R)- or (S)-3 during reaction with dibenzylamine.
- Camps, Pelayo,Perez, Francesc,Soldevilla, Nuria,Borrego, Miguel A.
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p. 493 - 509
(2007/10/03)
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- Empirical rules for the enantiopreference of lipase from Aspergillus niger toward secondary alcohols and carboxylic acids, especially α-amino acids
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Lipase from Aspergillus niger (ANL, Amano lipase AP) catalyzes enantioselective hydrolysis and acylation reactions. To aid in the design of new applications of this lipase, we propose two empirical rules that predict which enantiomer reacts faster. For secondary alcohols, a rule proposed previously for other lipases also works for ANL, but with lower reliability (77%, 37 of 48 examples). For carboxylic acids, we examined both crude and partially-purified ANL because commercial ANL contains contaminating hydrolases. Partial purification removed a contaminating amidase and increased the enantioselectivity of ANL toward many α-amino acids, including cyclic amino acids. Unlike other lipases, ANL readily accepts positively-charged substrates and shows the highest enantioselectivity towards α-amino acids. Although a rule based on the sizes of the substituents could not predict the fast-reacting enantiomer, a rule limited to α-amino acids did predict the fast-reacting enantiomer. We estimate that the charged α-amino group contributes a factor of 40-100 (ΔΔ≠ = 2.2-2.7 kcal/mol) to the enantioselectivity of ANL towards carboxylic acids.
- Janes, Lana E.,Kazlauskas, Romas J.
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p. 3719 - 3733
(2007/10/03)
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- Beam-induced dehalogenation in LSIMS: Effect of halogen type and matrix chemistry
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The LSIMS beam-induced dehalogenation of several 4-halo-phenylalanine methyl esters (I, Br, Cl, F) was investigated and compared to that of atrazine using 12 different matrix compounds including diethyl phthalate for which the empirical electron affinity was known. The extent of dehalogenation, induced by a one-electron reduction process, is in agreement with the leaving group ability of the corresponding halogens (I > Br > Cl > F) and the dehalogenation inhibiting efficiency of the matrices. The latter is rationalized in terms of electron scavenging capacity and matrix structural features relating to that capacity. The extent of dehalogenation observed for 4-I-phenylalanine methyl ester is similar to that of atrazine, a chlorinated compound, which indicates that the halogen effect is not overwhelming in determining the extent of dehalogenation. The bracketing of matrix reduction potential was attempted based on the propensity of the matrices to induce M+. formation from analytes of known oxidation potentials. The ability of matrices to induce M+. formation parallels their dehalogenation and reduction inhibiting efficiencies. The last observation underlines the importance of matrix redox properties in effecting or inhibiting beam-induced processes, be they reductive or oxidative.
- Theberge,Bertrand
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p. 163 - 171
(2007/10/02)
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- Asymmetric synthesis of L-diphenylalanine and L-9-fluorenylglycine via room temperature alkylations of a sultam-derived glycine imine
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L-diphenylalanine and L-9-fluorenylglycine were prepared from a sultam-derived glycine imine 3 via room temperature-asymmetric-alkylation/hydrolysis/mild-sultam-clivage. The L-configuration was ascertained using an X-ray analysis of the alkylation product 4b.
- Josien,Martin Chassaing
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p. 6547 - 6550
(2007/10/02)
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- Novel amino acid derivatives possessing renin-inhibitory activities
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An amino acid derivative of the general formula: wherein, R1? is a lower alkyl group and R11 is (wherein R111 is a lower alkyl group and n is an integer of 1 to 5) or a lower alkyl group which may be substituted by hydroxy group or methoxyethoxymethoxy group, or R1? and R11 are combinedly together with the adjacent nitrogen atom; R12 is a hydrogen atom, CnH2n+ 1-O-CO-(n is as defined above) or R13 is a lower alkyl group which may be substituted by substituent(s) selected from HOOC-(H?C)n-O-, R12-NH-(n and R12 are as defined above) and pyridyl group; X is-CH?-,-O-or-NH-and Y is-O-or-NH-; wherein (wherein Z is-O-,-S-,-S(O)-,-S(O)?-,-CH?-,-CH(OH)-,---,-NH-or and a and b are independently an integer of 1 to 4 and the total of a and b is not more than 5) ; R2 is an aralkyl group which may be substituted by lower alkyl group(s); R3 is a hydrogen atom or a lower alkyl group; R? is a lower alkyl group; and A is hydroxy group and B is a hydrogen atom, or A and B are carbonyl group combinedly together with the adjacent carbon atom, a pharmaceutically acceptable acid addition salt or an ester thereof is described. The compounds of the invention possess inhibitory activities against renin and are useful as an antihypertensive agent.
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- Regioselective Azide Opening of 2,3-Epoxy Alcohols by : Synthesis of α-Amino Acids
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Treatment of 2,3-epoxy alcohols with affords the corresponding 3-azido 1,2-diols, which are readily transformed in two steps to the α-amino acids.
- Caron, Maurice,Carlier, Paul R.,Sharpless, K. Barry
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p. 5185 - 5187
(2007/10/02)
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- Diastereomer salts of phenylalanine and N-acyl derivatives thereof and process for the separation of optically active phenylalanine and N-acyl derivatives thereof
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The present invention relates to the separation of optically active phenylalanine and N-acyl derivatives thereof and novel diastereomer salts of the said compounds. According to the invention a racemic compound of the formula STR1 is reacted with an optically active resolving agent of the formula STR2 in a polar solvent and/or a mixture of solvents comprising at least one apolar solvent and optionally an achiral acid or base, thereafter (a) when using the D-isomer of the resolving agent of the formula II, the crystalline diastereomer salt formed with the L-isomer of the compound of the formula I is separated, or (b) when using the L-isomer of the resolving agent of the formula II, the crystalline diastereomer salt formed with the D-isomer of the compound of the formula I is separated, and the enantiomers of the compound of the formula I from the diastereomer salt or the mother liquor are liberated by the aid of an achiral acid or base and the optically active product is separated in crystalline form.
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