- Enantiopure 5-CF3-Proline: Synthesis, Incorporation in Peptides, and Tuning of the Peptide Bond Geometry
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The straightforward synthesis of enantiopure 5-(R)-and 5-(S)-trifluoromethylproline is reported. The key steps are a Ruppert-Prakash reagent addition on l-pyroglutamic esters followed by an elimination reaction and a selective reduction. The solution-phase and solid-phase incorporation of this unprotected enantiopure fluorinated amino acid in a short peptide chain was demonstrated. Compared to proline, the CF3 group provides a decrease of the trans to cis amide bond isomerization energy and an increase of the cis conformer population.
- Sanchez, Clément A.,Gadais, Charlène,Chaume, Grégory,Girard, Sylvaine,Chelain, Evelyne,Brigaud, Thierry
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supporting information
p. 382 - 387
(2021/01/13)
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- A high-quality N - tert-butoxycarbonyl - L - pyroglutamic acid benzyl ester industrial production method
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The invention relates to a bio-chemical technology field, in particular to a high-quality N - tert-butoxycarbonyl - L - pyroglutamic acid benzyl ester industrial production method, the raw material capture and L - pyroglutamic acid in the presence of a catalyst, with the chlorinated animal pen or bromination animal pen reaction to obtain the intermediate L - pyroglutamic acid benzyl ester; intermediate L - pyroglutamic acid benzyl ester organic phase under the catalyst condition, with the Boc anhydride reaction, to obtain the target crude N - tert-butoxycarbonyl - L - pyroglutamic acid benzyl ester; crude N - tert-butoxycarbonyl - L - pyroglutamic acid benzyl ester, in mixed crystals in the recrystallization solvent, for obtaining high-purity N - tert-butoxycarbonyl - L - pyroglutamic acid benzyl ester. Compared with the prior process, the present invention provides N - tert butoxycarbonyl - L - pyroglutamic acid benzyl ester industrial production method has the advantages of: can be efficient, stable production of the high-quality powder N - tert butoxycarbonyl - L - pyroglutamic acid benzyl ester, the purity is greater than 99.5%, a single impurities less than 0.1%.
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Paragraph 0027-0029; 0037-0039
(2019/05/16)
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- Synthesis of the Siderophore Coelichelin and Its Utility as a Probe in the Study of Bacterial Metal Sensing and Response
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A convergent total synthesis of the siderophore coelichelin is described. The synthetic route also provided access to acetyl coelichelin and other congeners of the parent siderophore. The synthetic products were evaluated for their ability to bind ferric iron and promote growth of a siderophore-deficient strain of the Gram-negative bacterium Pseudomonas aeruginosa under iron restriction conditions. The results of these studies indicate coelichelin and several derivatives serve as ferric iron delivery vehicles for P. aeruginosa.
- Williams, Jade C.,Sheldon, Jessica R.,Imlay, Hunter D.,Dutter, Brendan F.,Draelos, Matthew M.,Skaar, Eric P.,Sulikowski, Gary A.
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supporting information
p. 679 - 682
(2019/02/07)
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- Production technology of L-pyroglutamic acid benzyl ester
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The invention belongs to the technical field of medicine chemical engineering, and particularly relates to a production technology of L-pyroglutamic acid benzyl ester. The technology comprises the following steps that an organic solvent, L-pyroglutamic acid and an acid binding agent are mixed and stirred to be uniform, the temperature of reaction liquid is controlled below 20 DEG C, benzyl chloride is dropwise added, after benzyl chloride is completely added, the temperature rises to 50-80 DEG C, a reaction is conducted for 6-20 h, raw materials are detected to react completely through TLC, aftertreatment is conducted after cooling is conducted, an organic layer is dried and filtered, concentration is conducted, and L-pyroglutamic acid benzyl ester is obtained. According to the production technology of L-pyroglutamic acid benzyl ester, 1,2-dichloroethane serves as a solvent for the reaction, after the reaction is conducted, water is added for liquid separation, the obtained organic solvent 1,2-dichloroethane solution is dried and can be distilled for recycling, environmental friendliness is achieved, and the production cost is greatly reduced. By means of the selected reaction condition, the reaction time is obviously shortened, and human and material resources are saved.
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Paragraph 0024
(2016/11/02)
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- A new class of non-C2-symmetric ligands for oxidative and redox-neutral palladium-catalyzed asymmetric allylic alkylations of 1,3-diketones
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We report the discovery, synthesis, and application of a new class of non-C2-symmetric phosphoramidite ligands derived from pyroglutamic acid for use in both oxidative and redox-neutral palladium-catalyzed asymmetric allylic alkylations of 1,3-diketones. The resulting chiral products are typically obtained in high yield with good to excellent levels of enantioselectivity.
- Trost, Barry M.,Donckele, Etienne J.,Thaisrivongs, David A.,Osipov, Maksim,Masters, James T.
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supporting information
p. 2776 - 2784
(2015/03/04)
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- THIOPHOSPHATE NUCLEOSIDES FOR THE TREATMENT OF HCV
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Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, the compounds are according to Formula 2001: where PD, Base, RA and RB are as provided herein. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.
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Paragraph 0402; 0403
(2014/09/16)
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- Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors
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We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53.
- Miyazaki, Masaki,Naito, Hiroyuki,Sugimoto, Yuuichi,Yoshida, Keisuke,Kawato, Haruko,Okayama, Tooru,Shimizu, Hironari,Miyazaki, Masaya,Kitagawa, Mayumi,Seki, Takahiko,Fukutake, Setsuko,Shiose, Yoshinobu,Aonuma, Masashi,Soga, Tsunehiko
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p. 4319 - 4331
(2013/07/27)
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- Catalytic, enantioselective N-acylation of lactams and thiolactams using amidine-based catalysts
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In contrast to alcohols and amines, racemic lactams and thiolactams cannot be resolved directly via enzymatic acylation or classical resolution. Asymmetric N-acylation promoted by amidine-based catalysts, particularly Cl-PIQ 2 and BTM 3, provides a convenient method for the kinetic resolution of these valuable compounds and often achieves excellent levels of enantioselectivity in this process. Density functional theory calculations indicate that the reaction occurs via N-acylation of the lactim tautomer and that cation-π interactions play a key role in the chiral recognition of lactam substrates.
- Yang, Xing,Bumbu, Valentina D.,Liu, Peng,Li, Ximin,Jiang, Hui,Uffman, Eric W.,Guo, Lei,Zhang, Wei,Jiang, Xuntian,Houk,Birman, Vladimir B.
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supporting information
p. 17605 - 17612
(2013/01/15)
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- Substituted 4-carboxymethylpyroglutamic acid diamides as potent and selective inhibitors of fibroblast activation protein
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Fibroblast activation protein (FAP) belongs to the prolyl peptidase family. FAP inhibition is expected to become a new antitumor target. Most known FAP inhibitors often resemble the dipeptide cleavage products, with a boroproline at the P1 site; however, these inhibitors also inhibit DPP-IV, DPP-II, DPP8, and DPP9. Potent and selective FAP inhibitor is needed in evaluating that FAP as a therapeutic target. Therefore, it is important to develop selective FAP inhibitors for the use of target validation. To achieve this, optimization of the nonselective DPP-IV inhibitor 8 led to the discovery of a new class of substituted 4-carboxymethylpyroglutamic acid diamides as FAP inhibitors. SAR studies resulted in a number of FAP inhibitors having IC50 of 50 > 100 μM). Compounds 18a, 18b, and 19 are the only known potent and selective FAP inhibitors, which prompts us to further study the physiological role of FAP.
- Tsai, Ting-Yueh,Yeh, Teng-Kuang,Chen, Xin,Hsu, Tsu,Jao, Yu-Chen,Huang, Chih-Hsiang,Song, Jen-Shin,Huang, Yu-Chen,Chien, Chia-Hui,Chiu, Jing-Huai,Yen, Shih-Chieh,Tang, Hung-Kuan,Chao, Yu-Sheng,Jiaang, Weir-Torn
-
scheme or table
p. 6572 - 6583
(2010/11/17)
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- Synthetic approaches to peptides containing the l-Gln-l-Val-D(S)-Dmt motif
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The pseudoprolines S-Dmo (5,5-dimethyl-4-oxaproline) and R-Dmt (5,5-dimethyl-4-thiaproline) have been used to study the effects of forcing a fully cis conformation in peptides. Synthesis of peptides containing these (which have the same configuration as l-Pro) is straightforward. However, synthesis of peptides containing S-Dmt is difficult, owing to the rapid cyclisation of l-Aaa-S-Dmt amides and esters to form the corresponding diketopiperazines (DKP); thus the intermediacy of l-Aaa-S-Dmt amides and esters must be avoided in the synthetic sequence. Peptides containing the l-Gln-l-Val-D(S)-Dmt motif are particularly difficult, owing to the insolubility of coupling partners containing Gln. Introduction of Gln as N-Boc-pyroglutamate overcame the latter difficulty and the dipeptide active ester BocPygValOC6F5 coupled in good yield with S-DmtOH. BocPygVal-S- DmtNH(CH2)2C6H4NO2 was converted quantitatively to BocGlnVal-S-DmtNH(CH2)2C6H4NO2 with ammonia, demonstrating the utility of this approach. Two peptide derivatives (CbzSerLysLeuGlnVal-S-DmtNH(CH2)2C6H4NO2 and CbzSerSerLysLeuGlnVal-S- DmtNH(CH2)2C6H4NO2) were assembled, using these new methods of coupling a dipeptide acid active ester with S-DmtOH and introduction of Gln as Pyg, followed by conventional peptide couplings. The presence of the Val caused these peptides to be cleaved very slowly by prostate-specific antigen (PSA) at Leu ↓ Gln, rather than the expected Gln ↓ Val.
- Suaifan, Ghadeer A.R.Y.,Arafat, Tawfiq,Threadgill, Michael D.
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p. 3474 - 3488
(2008/02/05)
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- ALTERNATIVE SYNTHESIS OF RENIN INHIBITORS AND INTERMEDIATES THEREOF
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The present invention relates to synthetic routes to prepare a compound of the formula (A); wherein R1 is halogen, C1-6 halogenalkyl, C1-6 alkoxy-C1-6 alcoxy or C1-6alkoxy-C1-6alkyl; R2 is halogen, C1-4alkyl or C1-4alkoxy; R3 and R4 are independently branched C3-6alkyl; and R5 is cycloalkyl, C1-6alkyl, C1-6hydroxyalkyl, Cl-6alkoxy-C 1-6alkyl, C1-6alkanoyloxy-C1-6alkyl, C1-6aminoalkyl, C1-6alkylamino-C 1-6alkyl, Cl-6dialkylamino-C1-6alkyl, C1-6alkanoylamino- C1-6alkyl, HO(O)C-Cl-6alkyl, C1-6alkyl-O-(O)C-C1-6alkyl, H2N-C(O)-Cl-6alkyl, C1-6alkyl-HN-C(O)-C1-6alkyl or (C1-6alkyl)2N-C(O)-C1-6alkyl; or a pharmaceutically acceptable salt thereof as well as key intermediates obtained when following these routes as well as their preparation.
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Page/Page column 40
(2010/10/20)
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- A concise asymmetric route to the bridged bicyclic tropane alkaloid ferruginine using enyne ring-closing metathesis
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Enyne metathesis has been used to prepare bridged azabicycles and applied in a short asymmetric synthesis of the tropane ferruginine. A Grubbs first generation catalyst proved to be superior to the second generation catalyst in the enyne metathesis reaction.
- Aggarwal, Varinder K.,Astle, Christopher J.,Rogers-Evans, Mark
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p. 1469 - 1471
(2007/10/03)
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- Hetero-Diels-Alder and pyroglutamate approaches to (2S,4R)-2-methylamino-5- hydroxy-4-methylpentanoic acid
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The stereoselective syntheses of fully protected (2S,4R)-2-methylamino-5- hydroxy-4-methylpentanoic acid, a non-coded amino acid of cyclomarin A, and its diastereomer are reported. A pyroglutamate template was employed in the key diastereoselective alkylation used for introducing the 4-methyl stereochemistry. In addition, the first diastereoselective intramolecular hetero-Diels-Alder of a 2-cyano-1-azadiene with an electron deficient dienophile is described. Graphical Abstract
- Tarver Jr., James E.,Terranova, Kristen M.,Joullié, Madeleine M.
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p. 10277 - 10284
(2007/10/03)
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- Pseudopeptide foldamers: the homo-oligomers of pyroglutamic acid.
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As a part of a program evaluating substituted gamma-lactams as conformationally constrained building blocks of pseudopeptide foldamers, we synthesized the homo-oligomers of L-pyroglutamic acid up to the tetramer level by solution methods. The preferred conformation of this pseudopeptide series in structure-supporting solvents was assessed by FT-IR absorption, 1H NMR and CD techniques. In addition, the crystal structure of the N alpha-protected dimer was established by X-ray diffraction. A high-level DFT computational modeling was performed based on the crystallographic parameters. In this analysis, we demonstrated that an alpha C-H...O=C intramolecular hydrogen bond is responsible for the stabilization of the s-trans L-pGlu-L-pGlu conformation by 1.4 kcal mol-1. This effect can be easily detected by 1H NMR spectroscopy, owing to the anomalous chemical shifts of the alpha CH protons present in all of the oligomers. In summary, we have developed a new polyimide-based, foldameric structure that, if appropriately functionalized, has promise as a rigid scaffold for novel functions and applications.
- Bernardi, Fernando,Garavelli, Marco,Scatizzi, Marco,Tomasini, Claudia,Trigari, Valerio,Crisma, Marco,Formaggio, Fernando,Peggion, Cristina,Toniolo, Claudio
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p. 2516 - 2525
(2007/10/03)
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- Synthesis of benzyl (6S)-1,3-dichloro-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6- carboxylic ester, a new conformationally constrained peptidomimetic derivative
-
We describe the synthesis of benzyl (6S)-1,3-dichloro-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6- carboxylic ester, a new conformationally constrained peptidomimetic derivative. This compound is prepared in seven steps from (S)-pyroglutamic acid as starting material.
- Gloanec, Philippe,Hervé, Yolande,Brémand, Nathalie,Lecouvé, Jean-Pierre,Bréard, Fabienne,De Nanteuil, Guillaume
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p. 3499 - 3501
(2007/10/03)
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- Rigid Dipeptide Surrogates: Syntheses of Enantiopure Quinolizidinone and Pyrroloazepinone Amino Acids from a Common Diaminodicarboxylate Precursor
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A versatile and practical approach for synthesizing azabicyclo[X.Y.0]alkane amino acids of different ring sizes from a common diaminodicarboxylate precursor has been developed as a means for mimicking different peptide conformations. (2S,9S)-1-tert-Butyl 10-benzyl 5-oxo-2-[-N-(PhF)amino] 9-[N-(BOC)amino]dec-4-enedioate (18) was first prepared in 83% yield by the Horner-Wadsworth-Emmons olefination of N-(PhF)aspartate β-aldehyde 8 with pyroglutamate-derived β-keto phosphonate 12 (PhF = 9-phenylfluoren-9-yl). The practicality of this approach for making azabicyclo-[X.Y.0]alkane amino acids was then illustrated by the first synthesis of enantiopure quinolizidin-2-one amino acid 6 in seven steps and 40% overall yield from L-pyroglutamic acid. Hydrogenation of δ-keto α,ω-diaminosebacate 18, followed by lactam cyclization and protection, gave quinolizidin-2-one amino acid 6 as a single diastereomer. The versatility of this approach was next demonstrated by the synthesis of both ring-fusion isomers of pyrroloazepin-2-one amino acid 6 in 11 steps and 13% overall yield from pyroglutamic acid. Hydride reduction of 18, followed by methanesulfonate displacement, gave 5-alkylproline 22. Protective group manipulations, lactam cyclization, and removal of the ester group afforded readily separable pyrroloazepinone amino acids (7S)- and (7R)-7 in a 1:2 diastereomeric ratio. By introducing two new azabicycloalkane amino acids using our olefination approach, we have expanded the diversity of these important heterocycles for studying the conformational requirements for peptide biological activity.
- Gosselin, Francis,Lubell, William D.
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p. 2163 - 2171
(2007/10/03)
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- New amino acids derived from L-pyroglutamic acid: Synthesis of trans-4- benzyl-cis-5-phenyl-L-proline, L-α-(2-benzyl-3-phenylpropyl)-glycine and L- α-(3-phenylpropyl)-glycine
-
A convenient synthesis of three new amino acids, L-α-(3-phenylpropyl)- glycine, L-α-(2-benzyl-3-phenylpropyl)-glycine and its conformationally constrained analog, trans-4-benzyl-cis-5-phenyl-L-proline is reported. All compounds were prepared in good diastereomeric or enantiomeric purity from L- pyroglutamic acid. Trans-4-benzyl-cis-5-phenyl-L-proline was prepared by benzylation of Boc-L-Pyr-OBn, ring opening with phenyllithium and subsequent cyclisation. Hydrogenolysis under mild conditions then furnished L-α-(2- benzyl-3-phenylpropyl)-glycine. In a similar way, L-α(3-phenylpropyl)- glycine was prepared from cis-5-phenyl-L-proline by catalytic hydrogenolysis.
- Van Betsbrugge, Jo,Van Den Nest, Wim,Verheyden, Patricia,Tourwe, Dirk
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p. 1753 - 1762
(2007/10/03)
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- Stereoselective synthesis of cis-5-alkyl-(S)-prolines from (S)-pyroglutamic acid via 5-alkyl-5-hydroxy-(S)-prolines
-
Introduction of alkyl groups with trialkylaluminums in the 5-position of the pyroglutamic ring system without ring opening and subsequent hydrogenation over Pt/C lead to exclusively cis-5-alkyl-(S)-prolines without epimerization of the chiral centre.
- Li, Hao,Sakamoto, Takeshi,Kikugawa, Yasuo
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p. 6677 - 6680
(2007/10/03)
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- Stereospecific synthesis of (2S,4R)-[5,5,5-2H3]leucine
-
The first stereospecific chemical synthesis of a sample of the amino acid (2S)-leucine labelled in one of the diastereotopic methyl groups has been achieved using (2S)-pyroglutamic acid as a chiral template. This has been used to develop a method for assigning resonances to the diastereotopic methyl groups of the leucine residues in the 1H NMR spectra of proteins.
- August, Ryan A.,Khan, Jeffrey A.,Moody, Claire M.,Young, Douglas W.
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p. 507 - 514
(2007/10/03)
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- Adamantanamine derivatives, processes for their preparation and drugs in which they are present
-
The present invention relates to new adamantanamine derivatives. These derivatives correspond to the general formula I: STR1 in which: R represents hydrogen or a substituted or unsubstituted, linear or branched alkyl radical containing from 1 to 7 carbon
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-
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- Amino Acids, 9 - Reactions of 5-Oxoproline Derivatives with Phosphorus Pentachloride - Synthesis of Chloro-pyrrole-2-carboxylic Acid Derivatives
-
N-Benzyl-4,5-dichloro-1H-pyrrole-2-carboxylic esters 6 are formed from N-benzyl-5-oxoproline esters 5 and PCl5 via differently chlorinated intermediates.The N-benzhydryl- L-3 and N-acyl-5-oxoproline esters L-4, on the other hand, suffer cleavage of the N-substituent in the course of this reaction sequence to give L-4,4,5-trichloro-3,4-dihydro-2H-pyrrole-2-carboxylic esters 18, which are dehydrohalogenated in the presence of base, yielding 4,5-dichloro-1H-pyrrole-2-carboxylic esters 20.These reactions provide the best access to 4,5-dichloro-1H-pyrrole-2-carboxylic acid derivatives which, in turn, can serve as precursors in the synthesis of pyoluteorin type compounds.
- Effenberger, Franz,Mueller, Wolfgang,Isak, Heinz
-
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- Synthesis and Pharmacology of the Potent Angiotensin-Converting Enzyme Inhibitor N--(S)-alanyl-(S)-pyroglutamic Acid
-
Structure 3a, a potent angiotensin-converting enzyme inhibitor, was prepared in five steps from L-(+)-α-amino-4-phenylbutyric acid by construction of the activated side-chain ester 16, displacement with L-pyroglutamate ester anion, and deblocking.Diastereomer separation was accomplished by chromatography at the diester stage, 17.Pharmacological assays established that 3a parallels enalapril in its ability to inhibit converting enzyme and lower blood pressure.
- Johnson, Alexander L.,Price, William A.,Wong, Pancras C.,Vavala, Robert F.,Stump, John M.
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p. 1596 - 1602
(2007/10/02)
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