- Synthesis and in vitro activity towards Mycobacterium tuberculosis of L-serinyl ester and amino derivatives of pyrazinoic acid
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Reactions between either L-serine methyl ester hydrochloride (1), or the cbz derivative, methyl (S)-(+)-2-(benzyloxycarbonylamino)-3-hydroxypropanoate (2), and pyrazinoyl chloride (3), have been studied. Methyl (S)-(+)-2- benzyloxycarbonylamino-3-[(pyrazinecarbonyl)oxy]propionate (4), methyl (S)-(+)-3-hydroxy-2-[(pyrazine-2-carbonyl) aminolpropionoate (7), methyl 2-[(pyrazinecarbonyl)amino]acrylate (8) were obtained. Additional products, methyl (S)-(+)-2-benzyloxycarbonylamino-3-formyloxypropionoate (5) and methyl (R)-(+)-2-benzyloxycarbonylamino-3-chloropropionoate (6), were isolated from reaction of 2 with 3, in the presence of DMF remaining from the preparation of 3, from pyrazinecarboxylic acid. The coupling of pyrazinecarboxylic acid with 1, in the presence of DCC was prevented by the formation of the unreactive adduct between DCC and pyrazinoic acid. The compounds were tested against M. tuberculosis: compounds (8) and (6) exhibited a MIC (μg/ml) value of 50 and 100, respectively, compared to the MIC value of 100 for the first line TB drug, pyrazinamide. The confirmation of the structure of (8) was obtained via X-ray crystallography.
- Pinheiro, Alessandra C.,Kaiser, Carlos R.,Lourenco, Maria C.S.,De Souza, Marcus V. N.,Wardell, Solange M.S.V.,Wardell, James L.
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Read Online
- Glycosylated tris-bipyridine ferrous complexes as molecular mimics of densely packed glycoclusters on cell surfaces: spatial carbohydrate packing of glycoclusters changes on additions of salts
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Tris-bipyridine ferrous complexes having β-lactosides, β-maltosides or α-mannosides with serinol spacers were prepared as molecular mimics of densely packed carbohydrate clusters on cell surfaces. Conformational analysis on these glycosylated complexes we
- Chigira, Naoto,Maeda, Nao,Tachikawa, Kanako,Sekiguchi, Maki,Amano, Yoshitsugu,Inokuchi, Mayu,Li, Qintong,Hasegawa, Teruaki
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Read Online
- On the mechanism of oxazoline-directed metalations: Evidence for nitrogen-directed reactions
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We recently described a method for the synthesis of ferrocene complexes possessing planar chirality which relies on the asymmetric deprotonation of chiral ferrocenyloxazolines. The unexpected stereochemical outcome of these reactions led us to examine whether the metalation is directed by the oxygen or the nitrogen of the oxazoline. In this paper, we describe the synthesis of a constrained ferrocenyloxazoline (compound 13) in which oxygen- and nitrogen-directed metalations provide different stereochemical outcomes. Our results show that nitrogen is responsible for the directive effects of the oxazoline when alkyllithium reagents are used to deprotonate the ferrocene. The implications of this result on the origin of asymmetric induction in the metalation of the unconstrained ferrocenyloxazolines 19 and 20 are discussed.
- Sammakia, Tarek,Latham, Hallie A.
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Read Online
- Green Esterification of Carboxylic Acids Promoted by tert-Butyl Nitrite
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In this work, the green esterification of carboxylic acids promoted by tert-butyl nitrite has been well developed. This transformation is compatible with a broad range of substrates and exhibits excellent functional group tolerance. Various drugs and substituted amino acids are applicable to this reaction under near neutral conditions, with good to excellent yields.
- Cheng, Xionglve,Jiang, Gangzhong,Li, Xingxing,Tao, Suyan,Wan, Xiaobing,Zhao, Yanwei,Zheng, Yonggao
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supporting information
p. 2713 - 2718
(2021/06/25)
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- Me3SI-promoted chemoselective deacetylation: a general and mild protocol
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A Me3SI-mediated simple and efficient protocol for the chemoselective deprotection of acetyl groups has been developedviaemploying KMnO4as an additive. This chemoselective deacetylation is amenable to a wide range of substrates, tolerating diverse and sensitive functional groups in carbohydrates, amino acids, natural products, heterocycles, and general scaffolds. The protocol is attractive because it uses an environmentally benign reagent system to perform quantitative and clean transformations under ambient conditions.
- Gurawa, Aakanksha,Kashyap, Sudhir,Kumar, Manoj
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p. 19310 - 19315
(2021/06/03)
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- An efficient, stereocontrolled and versatile synthetic route to bicyclic partially saturated privileged scaffolds
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Herein, we describe the development of a simple, high yielding and stereocontrolled strategy for the synthesis of a series of triazolopiperazines and other biologically relevant fused scaffolds from optically active amino acids. This route was applied to the synthesis of 22 scaffolds containing new, previously inaccessible vectors and used to access a novel analogue of ganaplacide.
- Bond, Andrew D.,Hanby, Abigail R.,King, Thomas A.,Moss, Thomas A.,Sore, Hannah F.,Spring, David R.,Stewart, Hannah L.
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supporting information
p. 6818 - 6821
(2020/07/04)
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- TOLL-LIKE RECEPTOR LIGANDS
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Toll-like receptor (TLR) ligands having an allose-based core are stable in aqueous formulation and are useful in treating, preventing, or reducing susceptibility to diseases or conditions mediated by TLRs, such as cancer, infectious disease, allergy, autoimmune disease, sepsis, and ischemia reperfusion.
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Paragraph 00316
(2019/08/29)
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- Total Synthesis of Ecumicin
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The first total synthesis of the potent anti-mycobacterial cyclic depsipeptide natural product ecumicin is described. Synthesis was achieved via a solid-phase strategy, incorporating the synthetic non-proteinogenic amino acids N-methyl-4-methoxy-l-tryptophan and threo-β-hydroxy-l-phenylalanine into the growing linear peptide chain. The synthesis employed key on-resin esterification and dimethylation steps as well as a final macrolactamization between the unusual N-methyl-4-methoxy-l-tryptophan unit and a bulky N-methyl-l-valine residue. The synthetic natural product possessed potent antimycobacterial activity against the virulent H37Rv strain of Mycobacterium tuberculosis (MIC90 = 312 nM).
- Hawkins, Paige M. E.,Giltrap, Andrew M.,Nagalingam, Gayathri,Britton, Warwick J.,Payne, Richard J.
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supporting information
p. 1019 - 1022
(2018/02/23)
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- Simple and Practical Real-Time Analysis of Solid-Phase Reactions by Thin-Layer Chromatography
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Solid-phase synthesis is a practical approach for simplifying the time-consuming and routine purification steps in the preparation of numerous naturally occurring molecules; however, studying such reactions is difficult due to the lack of a convenient monitoring method. By using thin-layer chromatography in conjunction with a photolabile linker on a resin, we developed a convenient and simple method for monitoring solid-phase reactions in real time by thin-layer chromatography. This method provides a user-friendly protocol for examining reaction conditions for solid-state syntheses.
- Wu, Chia-Hui,Chen, Chun C.,Lin, Su-Ching,Wang, Cheng-Chung
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supporting information
p. 1430 - 1436
(2018/05/15)
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- Solution-phase automated synthesis of an α-amino aldehyde as a versatile intermediate
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A solution-phase automated synthesis of the versatile synthetic intermediate, Garner's aldehyde, was demonstrated. tert-Butoxycarbonyl (Boc) protection, acetal formation, and reduction of the ester to the corresponding aldehyde were performed utilizing our originally developed automated synthesizer, ChemKonzert. The developed procedure was also useful for the synthesis of Garner's aldehyde analogues possessing fluorenylmethyloxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz) protection.
- Masui, Hisashi,Yosugi, Sae,Fuse, Shinichiro,Takahashi, Takashi
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supporting information
p. 106 - 110
(2017/02/15)
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- Vinyl Ether/Tetrazine Pair for the Traceless Release of Alcohols in Cells
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The cleavage of a protecting group from a protein or drug under bioorthogonal conditions enables accurate spatiotemporal control over protein or drug activity. Disclosed herein is that vinyl ethers serve as protecting groups for alcohol-containing molecules and as reagents for bioorthogonal bond-cleavage reactions. A vinyl ether moiety was installed in a range of molecules, including amino acids, a monosaccharide, a fluorophore, and an analogue of the cytotoxic drug duocarmycin. Tetrazine-mediated decaging proceeded under biocompatible conditions with good yields and reasonable kinetics. Importantly, the nontoxic, vinyl ether duocarmycin double prodrug was successfully decaged in live cells to reinstate cytotoxicity. This bioorthogonal reaction presents broad applicability and may be suitable for in vivo applications.
- Jiménez-Moreno, Ester,Guo, Zijian,Oliveira, Bruno L.,Albuquerque, Inês S.,Kitowski, Annabel,Guerreiro, Ana,Boutureira, Omar,Rodrigues, Tiago,Jiménez-Osés, Gonzalo,Bernardes, Gon?alo J. L.
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supporting information
p. 243 - 247
(2016/12/30)
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- Formamides as Lewis Base Catalysts in SNReactions—Efficient Transformation of Alcohols into Chlorides, Amines, and Ethers
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A simple formamide catalyst facilitates the efficient transformation of alcohols into alkyl chlorides with benzoyl chloride as the sole reagent. These nucleophilic substitutions proceed through iminium-activated alcohols as intermediates. The novel method, which can be even performed under solvent-free conditions, is distinguished by an excellent functional group tolerance, scalability (>100 g) and waste-balance (E-factor down to 2). Chiral substrates are converted with excellent levels of stereochemical inversion (99 %→≥95 % ee). In a practical one-pot procedure, the primary formed chlorides can be further transformed into amines, azides, ethers, sulfides, and nitriles. The value of the method was demonstrated in straightforward syntheses of the drugs rac-Clopidogrel and S-Fendiline.
- Huy, Peter H.,Motsch, Sebastian,Kappler, Sarah M.
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p. 10145 - 10149
(2016/08/16)
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- Synthesis and evaluation of phenylalanine-derived trifluoromethyl ketones for peptide-based oxidation catalysis
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We report the synthesis of phenylalanine-derived trifluoromethyl ketones for the in situ generation of dioxiranes for the purpose of oxidation catalysis. The key features of this synthesis include the use of a masked ketone strategy and a Negishi cross-coupling to access the parent amino acid. The derivatives can be readily incorporated into a peptide for use in oxidation chemistry and exhibit good stability and reactivity.
- Featherston, Aaron L.,Miller, Scott J.
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supporting information
p. 4871 - 4874
(2016/10/04)
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- Synergism between genome sequencing, tandem mass spectrometry and bio-inspired synthesis reveals insights into nocardioazine B biogenesis
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Marine actinomycete-derived natural products continue to inspire chemical and biological investigations. Nocardioazines A and B (3 and 4), from Nocardiopsis sp. CMB-M0232, are structurally unique alkaloids featuring a 2,5-diketopiperazine (DKP) core functionalized with indole C3-prenyl as well as indole C3- and N-methyl groups. The logic of their assembly remains cryptic. Bioinformatics analyses of the Nocardiopsis sp. CMB-M0232 draft genome afforded the noz cluster, split across two regions of the genome, and encoding putative open reading frames with roles in nocardioazine biosynthesis, including cyclodipeptide synthase (CDPS), prenyltransferase, methyltransferase, and cytochrome P450 homologs. Heterologous expression of a twelve gene contig from the noz cluster in Streptomyces coelicolor resulted in accumulation of cyclo-l-Trp-l-Trp DKP (5). This experimentally connected the noz cluster to indole alkaloid natural product biosynthesis. Results from bioinformatics analyses of the noz pathway along with challenges in actinomycete genetics prompted us to use asymmetric synthesis and mass spectrometry to determine biosynthetic intermediates in the noz pathway. The structures of hypothesized biosynthetic intermediates 5 and 12-17 were firmly established through chemical synthesis. LC-MS and MS-MS comparison of these synthetic compounds with metabolites present in chemical extracts from Nocardiopsis sp. CMB-M0232 revealed which of these hypothesized intermediates were relevant in the nocardioazine biosynthetic pathway. This established the early and mid-stages of the biosynthetic pathway, demonstrating that Nocardiopsis performs indole C3-methylation prior to indole C3-normal prenylation and indole N1′-methylation in nocardioazine B assembly. These results highlight the utility of merging bioinformatics analyses, asymmetric synthetic approaches, and mass spectrometric metabolite profiling in probing natural product biosynthesis.
- Alqahtani, Norah,Porwal, Suheel K.,James, Elle D.,Bis, Dana M.,Karty, Jonathan A.,Lane, Amy L.,Viswanathan, Rajesh
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supporting information
p. 7177 - 7192
(2015/07/01)
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- Synthesis of 2-oxazolines by in situ desilylation and cyclodehydration of β-hydroxyamides
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A powerful method for the synthesis of 2-oxazolines from silyl-protected β-hydroxyamides is reported. Using diethylaminosulfur trifluoride (DAST) or its tetrafluoroborate salt (XtalFluor-E), silyl-protected β-amidoalcohols can be in situ deprotected and d
- Brandst?tter, Marco,Roth, Fabian,Luedtke, Nathan W.
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- SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having enhanced potency in the modulation of NMD A receptor activity. Such compounds are contemplated for use in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Paragraph 00208
(2014/08/19)
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- Highly efficient and selective phosphorylation of amino acid derivatives and polyols catalysed by 2-aryl-4-(dimethylamino)pyridine-N-oxides-towards kinase-like reactivity
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The chemoselective phosphorylation of hydroxyl containing amino acid derivatives and polyols by phosphoryl chlorides catalyzed by 2-aryl-4-(dimethylamino)pyridine-N-oxides is described.
- Murray, James I.,Woscholski, Rudiger,Spivey, Alan C.
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supporting information
p. 13608 - 13611
(2015/01/09)
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- Asymmetric α-allylation of α-branched aldehydes with allyl alcohols by synergistic catalysis using an achiral palladium complex and a chiral primary amino acid
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Highly enantioselective direct α-allylation of α-branched aldehydes with simple allyl alcohols was achieved by the combined use of an achiral transition-metal catalysis with a palladium complex and a chiral organocatalysis with a readily obtainable primary α-amino acid. Various α-allylated aldehydes possessing a stereocontrolled quaternary carbon stereogenic center were synthesized in high yields with high enantioselectivity. Georg Thieme Verlag Stuttgart New York.
- Yoshida, Masanori,Masaki, Erika,Terumine, Tatsuaki,Hara, Shoji
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p. 1367 - 1373
(2014/06/09)
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- SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having enhanced potency in the modulation of NMD A receptor activity. Such compounds are contemplated for use in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Paragraph 00152
(2014/08/19)
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- Direct asymmetric α-allylation of α-branched aldehydes by two catalytic systems with an achiral Pd complex and a chiral primary α-amino acid
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Direct α-allylation of α-branched aldehydes was successfully carried out with a readily available allyl ester by combined use of two catalytic systems: Tsuji-Trost allylation reaction with an achiral palladium complex and enamine catalysis with a chiral primary α-amino acid. A quaternary carbon stereogenic center was constructed stereoselectively to give various 2,2-disubstituted pent-4-enals in good yields with high enantioselectivity.
- Yoshida, Masanori,Terumine, Tatsuaki,Masaki, Erika,Hara, Shoji
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p. 10853 - 10859
(2013/11/19)
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- A new synthesis of chiral oxazolidinones from the amino acid L-serine
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Cyclization of the (4S)-PhCH2OCONHCH(CH2OH)CONHN=CH- aryl, obtained in 4 steps from L-serine, on treatment with MeI and potassium carbonate, generates the chiral oxazolidinones, (4S)-N'-[(E)-(phenyl) methylidene]-Nmethyl- 2-oxo-1,3-o
- Nogueira, Thais C. M.,Pinheiro, Alessandra C.,Kaiser, Carlos R.,Wardell, James L.,Wardell, Solange M. S. V.,De Souza, Marcus V. N.
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p. 626 - 631
(2013/12/04)
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- Sulfonylcarbamate as a versatile and unique hydroxy-protecting group: A protecting group stable under severe conditions and labile under mild conditions
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The sulfonylcarbamate group is a unique hydroxyl protecting group. In contrast to typical acyl protecting groups, the sulfonylcarbamate group is stable under harsh basic conditions, while showing labile behavior under mild basic conditions. Its compatibility with other hydroxyl protecting groups and application to carbohydrate chemistry is demonstrated.
- Manabe, Shino,Yamaguchi, Masanori,Ito, Yukishige
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supporting information
p. 8332 - 8334
(2013/09/23)
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- Synthesis and antitumoral evaluation of benzyl (1S)-2-[2-(monosubstituted- benzylidene)hydrazino]-1-(hydroxymethyl)-2-oxoethylcarbamate
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A series of 14 N-acyl-hydrazones L-serine derivatives have been synthesized and evaluated for their in vitro antitumoral activities against four neoplastic cancer cells: HL-60 (leukemia), MDA-MB-435 (melanoma), HCT-8 (colon) and SF-295 (nervous system). F
- Montenegro, Raquel Carvalho,Lotufo, Leticia Veras Costa,De Moraes, Manoel Odorico,Pessoa, Claudia Do O.,Rodrigues, Felipe Augusto Rocha,Pinheiro, Alessandra Campbell,Nogueira, Thais Cristina Mendonca,De Souza, Marcus Vinicius Nora
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experimental part
p. 257 - 262
(2012/06/18)
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- Selection of an enantioselective process for the preparation of a CGRP receptor inhibitor
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(R)-N-(3-(7-Methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl) piperazine-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl) piperidine-1-carboxamide (1) is a potent calcitonin gene-related peptide (CGRP) receptor antagonist. We have developed a convergent, stereoselective, and economical synthesis of the hydrochloride salt of 1 and demonstrated the synthesis on a multikilogram scale. Two different routes to the chiral indazolyl amino ester subunit were developed utilizing either a Rh-catalyzed asymmetric hydrogenation or a biocatalytic process to install the single chiral center. The advantages and disadvantages of each of these process routes are discussed, as are challenges addressed in the assembly of the final drug substance.
- Cann, Reginald O.,Chen, Chung-Pin H.,Gao, Qi,Hanson, Ronald L.,Hsieh, Daniel,Li, Jun,Lin, Dong,Parsons, Rodney L.,Pendri, Yadagiri,Nielsen, R. Brent,Nugent, William A.,Parker, William L.,Quinlan, Sandra,Reising, Nathan P.,Remy, Brenda,Sausker, Justin,Wang, Xuebao
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p. 1953 - 1966
(2013/03/14)
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- Direct asymmetric aldol reaction of acetone with α-ketoesters catalyzed by primary-tertiary diamine organocatalysts
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Novel primary-tertiary diamine organocatalysts derived from l-serine were utilized to promote enantioselective aldol reaction of acetone with α-ketoesters. The desired products were obtained in high yields and with good to excellent enantioselectivities (up to 95% ee).
- Jiang, Zhaoqin,Lu, Yixin
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supporting information; experimental part
p. 1884 - 1886
(2010/09/07)
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- A tetranuclear-zinc-cluster-catalyzed practical and versatile deprotection of acetates and benzoates
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A new catalytic deacylation of acetates and benzoates through transesterification with methanol was developed (see scheme). Reactions with various acidand nucleophile-sensitive functional groups proceeded efficiently in the presence of a catalytic amount of the tetranuclear zinc cluster. The present catalysis is applicable to less-reactive tertiary acetates, the deacylation of which is difficult to achieve by transesterification with other catalysts.
- Iwasaki, Takanori,Agura, Kazushi,Maegawa, Yusuke,Hayashi, Yukiko,Ohshima, Takashi,Mashima, Kazushi
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supporting information; experimental part
p. 11567 - 11571
(2010/11/24)
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- Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative
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In response to various exogenous stimuli, mast cells (MCs) release a wide variety of inflammatory mediators stored in their cytoplasmic granules and this release initiates subsequent allergic reactions. Lysophosphatidylserine (lysoPS) has been known as an exogenous inducer to potentiate histamine release from MCs, though even at submicromolar concentrations. In this study, through SAR studies on lysoPS against MC degranulation, we identified lysoPT, a threonine-containing lysophospholipid and its 2-deoxy derivative as novel strong agonists. LysoPT and its 2-deoxy derivative induced histamine release from MCs both in vitro and in vivo at a concentration less than one-tenth that of lysoPS. Notably, lysoPT did not activate a recently proposed lysoPS receptor on MCs, GPR34, demonstrating the presence of another undefined receptor reactive to both lysoPS and lysoPT that is involved in MC degranulation. Thus, the present strong agonists, lysoPT and its 2-deoxy derivative, will be useful tools to understand the mechanisms of lysoPS-induced activation of degranulation of MCs. 2009 American Chemical Society.
- Iwashita, Masazumi,Makide, Kumiko,Nonomura, Taro,Misumi, Yoshimasa,Otani, Yuko,Ishida, Mayuko,Taguchi, Ryo,Tsujimoto, Masafumi,Aoki, Junken,Arai, Hiroyuki,Ohwada, Tomohiko
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experimental part
p. 5837 - 5863
(2010/03/24)
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- AMIDO ANTI-VIRAL COMPOUNDS
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Disclosed are compounds, stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs thereof of having Formula (I), their preparation, use, and compositions thereof for treating an infection mediated at least in part by a virus in the Flaviviridae family of viruses, wherein A, R3, X, V, W, T, Z, R, Y1, and p are as defined herein.
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Page/Page column 102; 114
(2008/12/05)
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- Iminosugar glycoconjugates
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The iminosugar conjugates according to the invention are N-alkylated 1,5-dideoxy-1,5-iminohexitol or 1,5-dideoxy-1,5-iminopentitol derivatives. The iminosugar component can be, for example, D-gluco-, L-ido-, D-galacto-, D-manno-, 2-acetamido-2-deoxy-D-gluco- or xylo-configuration. The N-substituent is a protected L-α-aminoacid derivative, showing L-lysine-like structural features. The linkage between the carbohydrate and the peptide component is not via the usual glycosidic position, but shows structural features of a very stable tertiary amine. Thus the linkage is very stable. These new compounds are synthesised by using catalytic intramolecular reductive amination of dicarbonyl sugars with partially protected amino acids. The process of intramolecular reductive amination itself is carried out using Pearlman's catalyst (Pd(OH)2/C) and H2 at ambient pressure and room temperature. The resulting accessible class of iminosugar conjugate compounds is represented by the general structure shown in Figure 4(c). The alkyl chain length parameter n can be freely chosen from n=0 upwards. Preferably n is between 0 and 10, and more preferably n is 2, 3, or 4. Residue R1 can be chosen from H, OH, or NHAc, with Ac being Acetyl. R2 can be H, OH, or NHAc. R3, R4, R5, R6 can be H or OH. R7 and R8 can be H, CH2OH CH3, COQH, or COOR with R being Alkyl or Aryl. R9 and R10 can be chosen from H, NH2, NHR, with R being a protective group, an amino acid, a peptide, or a protein. R11 can be OH, O-Alkyl, O-Aryl, NH2, N-Alkyl, N-Aryl, amino acid or peptide, connected via an amide bond.
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Page/Page column 7
(2008/06/13)
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- Design and synthesis of 6-amino-1,4-oxazepane-3,5-dione derivatives as novel broad spectrum anticonvulsants
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Based on the structural estimations of the typical anticonvulsant drugs, a series of 6-amino-1,4-oxazepane-3,5-dione derivatives, novel structures of 7-membered heterocyclic imides, which were hybridized with pharmacophores such as cyclic imide and N-CO-C
- Sharma, Gitalee,Park, Jin Yup,Park, Min Soo
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body text
p. 3188 - 3191
(2009/04/11)
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- The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K
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Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.
- Gauthier, Jacques Yves,Chauret, Nathalie,Cromlish, Wanda,Desmarais, Sylvie,Duong, Le T.,Falgueyret, Jean-Pierre,Kimmel, Donald B.,Lamontagne, Sonia,Leger, Serge,LeRiche, Tammy,Li, Chun Sing,Masse, Frederic,McKay, Daniel J.,Nicoll-Griffith, Deborah A.,Oballa, Renata M.,Palmer, James T.,Percival, M. David,Riendeau, Denis,Robichaud, Joel,Rodan, Gideon A.,Rodan, Sevgi B.,Seto, Carmai,Therien, Michel,Truong, Vouy-Linh,Venuti, Michael C.,Wesolowski, Gregg,Young, Robert N.,Zamboni, Robert,Black, W. Cameron
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p. 923 - 928
(2008/12/22)
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- Synthesis of a homologous series of side-chain-extended orthogonally protected aminooxy-containing amino acids
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Practical methodology is reported for the synthesis of a homologous series of side-chain-extended amino acids containing aminooxy functionality bearing orthogonal protection suitable for Fmoc peptide synthesis. These reagents may be useful for the preparation of libraries containing fragments joined by peptide linkers. Georg Thieme Verlag Stuttgart.
- Liu, Fa,Thomas, Joshua,Burke Jr., Terrence R.
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body text
p. 2432 - 2438
(2009/04/11)
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- New boron(III)-catalyzed amide and ester condensation reactions
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In 1996, we reported that benzeneboronic acids bearing electron-withdrawing groups at the meta- or para-position are highly effective catalysts for the amide condensation reaction in less-polar solvents. In this paper, we report that N-alkyl-4-boronopyridinium halides are more effective catalysts than the previous ones in more polar solvents. N-Alkyl-4-boronopyridinium halides are effective not only for amide condensation between equimolar mixtures of carboxylic acids and amines but also for the esterification of α-hydroxycarboxylic acids in alcohol solvents. Furthermore, perchlorocatecholborane is more effective than areneboronic acids for the amide condensation of sterically demanding carboxylic acids. In addition, Lewis acid-assisted Br?nsted acid (LBA), which is prepared from a 1:2 M mixture of boric acid and tetrachlorocatechol, is effective for the Ritter reaction from alcohols and nitriles to amides.
- Maki, Toshikatsu,Ishihara, Kazuaki,Yamamoto, Hisashi
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p. 8645 - 8657
(2008/02/08)
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- N-alkyl-4-boronopyridinium halides versus boric acid as catalysts for the esterification of α-hydroxycarboxylic acids
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(Chemical Equation Presented) Boric acid is a highly effective catalyst for the dehydrative esterification reaction between equimolar mixtures of α-hydroxycarboxylic acids and alcohols. In contrast, N-methyl-4- boronopyridinium iodide (2a) is a more effective catalyst than boric acid for the similar esterification in excess alcohol. A heterogeneous catalyst, such as N-polystyrene-bound 4-boronopyridinium chloride, is also an effective catalyst and can be recovered by filtration.
- Maki, Toshikatsu,Ishihara, Kazuaki,Yamamoto, Hisashi
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p. 5047 - 5050
(2007/10/03)
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- "Polar patch" proteases as glycopeptiligases
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The strategy of combined site directed mutagenesis and chemical modification with polar prosthetic groups was used to broaden substrate specificity of proteases resulting in the first successful formation of glycopeptides through the use of glucoamino acid acyl donors in yields of up to 90%.
- Doores, Katie J.,Davis, Benjamin G.
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p. 168 - 170
(2007/10/03)
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- First Practical Protection of α-Amino Acids as N, N-Benzyloxycarbamoyl Derivatives
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The consecutive treatment of N-Cbz amino protected compounds with LiHMDS and CbzCl provides a practical method for the preparation of N,N-benzyloxycarbamoyl (N,N-di-Cbz) derivatives in good yield. When α-amino acids are used the protection occurs without racemization. The method is compatible with a wide range of other functional and protecting groups. The procedure is also valid for the synthesis of mixed N,N-carbamoyl derivatives.
- Hernandez, J. Nicolas,Martin, Victor S.
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p. 3590 - 3592
(2007/10/03)
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- Utility of tetrathiomolybdate and tetraselenotungstate: Efficient synthesis of cystine, selenocystine, and their higher homologues
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Efficient synthesis of cystine, selenocystine, and their higher homologues like homo and bishomo amino acid derivatives from natural amino acid derivatives using tetrathiomolybdate and tetraselenotungstate reagents under mild and neutral conditions is reported. The generality of the reaction has been studied by capping various groups to amino and carboxyl components of canonical amino acids.
- Bhat, Ramakrishna G.,Porhiel, Emmanuel,Saravanan, Vadivelu,Chandrasekaran, Srinivasan
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p. 5251 - 5253
(2007/10/03)
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- Homochiral 4-azalysine building blocks: Syntheses and applications in solid-phase chemistry
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Anomalous amino acids not only play central roles as mimics of natural amino acids but also offer opportunities as unique building blocks for combinatorial chemistry. This paper describes the chiral syntheses and solid-phase applications of a versatile atypical amino acid, 4-azalysine (2,6-diamino-4-azahexanoic acid) 1. The syntheses of differentially protected 4-azalysine derivatives 28a-e have been developed by two efficient and inexpensive routes that start either from Garner's aldehyde 16 or the chiron (S)-Nα-Cbz-2,3-diaminopropionic acid 23. Both approaches employ the convergent modular concept and exploit reductive amination of aldehydes with amines as the key step for the fusion of the two segments. In the first route, the overall process inverts the chirality of the starting material, L-serine, and thus provides an excellent route to the unnatural D-isomers. The alternative route starting from L-asparagine provides a shorter and high-yielding route to orthogonally protected 4-azalysine derivatives. The corresponding N2-Fmoc-4-azalysines 31a-e, readily derived from the key intermediate 27, are compatible with the Fmoc-based solid-phase peptide synthesis (SPPS) and solid-phase organic chemistry (SPOC) protocols. Furthermore, the utility and versatility of another key structure, tris-Boc-4-azalysine 2 in the engineering of novel high-loading dendrimeric polystyrene resins 33 and 36, have been demonstrated. Following derivatization with the Rink amide linker 34, the stability and robustness of these resin-bound dendrimers 35 and 37 in the synthesis of small molecules using a range of reaction conditions (e.g., Mitsunobu and Suzuki reactions) have been effectively illustrated.
- Chhabra, Siri Ram,Mahajan, Anju,Chan, Weng C.
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p. 4017 - 4029
(2007/10/03)
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- Synthesis of new 3- and 4-substituted analogues of acyl homoserine lactone quorum sensing autoinducers
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The quorum sensing mechanism in Gram-negative bacteria uses small intercellular signal molecules, N-acyl-homoserine lactones (AHLs), to control transcription of specific genes in relation to population density. In this communication, we describe the parallel synthesis of new AHL analogues, in which substituents have been introduced into the 3- and 4-positions of the lactone ring. These analogues have been screened for their ability to activate and inhibit a Vibrio fischeri LuxI/LuxR-derived quorum sensing reporter system.
- Olsen,Severinsen,Rasmussen,Hentzer,Givskov,Nielsen
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p. 325 - 328
(2007/10/03)
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- Useful synthesis of the main dehydrohexapeptide segment of a macrocyclic antibiotic, berninamycin B
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The useful synthesis of tetradehydrohexapeptide segment 2, which is the main skeleton of a macrocyclic antibiotic, berninamycin B, was first achieved. The skeleton 2 is constructed, in turn, of 2-[(Z)-1-amino-1-propenyl]-5-methyl-oxazole-4-carboxylic acid, α-dehydroalanine (ΔAla), L-Val, 2-[1-amino-1-ethenyl]-5-methyloxazole-4-carboxylic acid residues, besides L-Thr and ΔAla at the N- and C-termini, respectively.
- Yamada, Takahiro,Okumura, Kazuo,Yonezawa, Yasuchika,Shin, Chung-Gi
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p. 102 - 103
(2007/10/03)
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- A practical route to regiospecifically substituted (R)- and (S)-oxazolylphenols
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New, diversely substituted phenolic oxazolines 14a-d and 15a-d were prepared by two complementary routes A and B, starting from salicylic derivatives 4-7 and various enantiomerically pure 1,2-amino alcohols 13a-d. In route A, the 1,2amino alcohols 13a-d were directly condensed with the salicylic acids 5 and 7, using the Appel reaction, whereas in route B the amino alcohols 13b-d were treated with the 2-hydroxybenzonitriles 4 and 6, under Witte-Seeliger conditions. The latter route was advantageous for L-valinol 13b and L-tert-leucinol 13c, while route A was the method of choice for the new, sterically demanding amino alcohol 13a, prepared from D- and L-serine. The nitro group in the salicylic derivatives 5 and 6 was introduced by means of a regiospecific ipso substitution of a tert-butyl group by nitric acid. The structure of the nitro product 5 was unambiguously assigned by NOE spectroscopy on the basis of the recently developed DPFGSE-ROE pulse sequence.
- Scheurer, Andreas,Mosset, Paul,Bauer, Walter,Saalfrank, Rolf W.
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p. 3067 - 3074
(2007/10/03)
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- Broadening of the substrate tolerance of α-chymotrypsin by using the carbamoylmethyl ester as an acyl donor in kinetically controlled peptide synthesis
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In the kinetically controlled approach of peptide synthesis mediated by α-chymotrypsin, the broadening of the protease's substrate tolerance is achieved by switching the acyl donor from the conventional methyl ester to the carbamoylmethyl ester. Thus, as a typical example, the extremely low coupling efficiency obtained by employing the methyl ester of an inherently poor amino acid substrate, Ala, is significantly improved by the use of this particular ester. Its ameliorating effect is observed also in the couplings of other amino acid residues such as Gly and Ser as carboxy components.
- Miyazawa, Toshifumi,Tanaka, Kayoko,Ensatsu, Eiichi,Yanagihara, Ryoji,Yamada, Takashi
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- Process for a phenylthiobutyl-isoquinoline and intermediates therefor
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The present invention relates to a new method for making compounds of formula and intermediates for making compounds of formual II. The compounds of this invention are useful intermediates for the manufacture of pharmacologically active compounds suitable
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- High yielding synthesis of dehydroamino acid and dehydropeptide derivatives
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By using a 4-dimethylaminopyridine (DMAP) catalysed reaction of β-hydroxyamino acid derivatives with tert-butyl pyrocarbonate [(Boc)2O], dehydroamino acid derivatives are obtained in high yields. The same methodology applied to dipeptides with
- Ferreira, Paula M.T.,Maia, Hernani L.S.,Monteiro, Luis S.,Sacramento, Joana
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p. 3697 - 3703
(2007/10/03)
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- IOOC route to substituted chiral pyrrolidines. Potential glycosidase inhibitors
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Branched-chain five-membered ring aza-sugar analogues, synthesized from amino acids by an intramolecular oxime-olefin cycloaddition reaction, the IOOC route, were found to be selective glycosidase inhibitors. The derivative 2,4(S)-di(hydroxymethyl)-3(S)-aminopyrrolidine, obtained from D-serine, was about 1 order of potency more active than its enantiomer obtained from L- serine.
- Falb, Eliezer,Bechor, Yosi,Nudelman, Abraham,Hassner, Alfred,Albeck, Amnon,Gottlieb, Hugo E.
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p. 498 - 506
(2007/10/03)
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- One pot conversion of alcohols to disulfides mediated by benzyltriethylammonium tetrathiomolybdate
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A one pot conversion of alcohols to disulfides in good yields via the activation of a hydroxyl group with DCC or P(NMe2)3 / CCl4 followed by treatment with benzyltriethylammonium tetrathiomolybdate is reported.
- Sinha, Surajit,Ilankumaran,Chandrasekaran
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p. 14769 - 14776
(2007/10/03)
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- Effective and mild method for preparation of optically active α-amino aldehydes via TEMPO oxidation
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The TEMPO oxidation method is successfully applied to preparation of variously protected, optically active α-amino aldehydes without racemization and in very good yield.
- Jurczak, Janusz,Gryko, Dorota,Kobrzycka, Elzbieta,Gruza, Henryk,Prokopowicz, Piotr
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p. 6051 - 6064
(2007/10/03)
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- Efficient synthesis of (R)-6-benzyloxycarbonylamino-1-methyl-4-(3- methylbenzyl)hexahydro-1,4-diazepine. I
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An efficient and practical method for large scale synthesis of (R)-6- benzyloxycarbonylamino-1-methyl-4-(3-methylbenzyl)hexahydro-1,4-diazepine (R- 3), which is a key intermediate in the synthesis of DAT-582, a potent and selective serotonin-3 receptor antagonist, is described. The precursor of R- 3, the (S)-2,3-diaminopropylaminoacetate S-5, was obtained from the chiral triaminopropane derivative R-19. Nucleophilic reaction of the chiral mesylate R-11 with 3-methylbenzylamine gave the racemic 2,3-diaminopropylaminoacetate (±)-5 via the achiral azetidinium cation 12, while the reaction of the N- protected mesylate R-14 produced the desired triamine S-15 but in poor yield. However, reaction of the N-protected mesylate S-18 with a large excess of methylamine proceeded smoothly to afford R-19 in good yield. S-5 was converted into R-3 with >99% enantiomeric excess using an intramolecular reductive cyclization method.
- Harada, Hiroshi,Morie, Toshiya,Kato, Shiro
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p. 1160 - 1164
(2007/10/03)
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- Method for preparation of optically active diarylalanines
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A method for preparing a diarylalanine compound is provided. The method includes reacting a diarylaminopropanediol with a reducing agent to form a diarylaminopropanol compound and/or contacting a serine ester derivative with an aryl metal reagent to form diarylaminopropanediol. A diarylmethyloxazolidinone compound is also provided.
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- MERCAPTOACETYLAMIDE BICYCLIC LACTAM DERIVATIVES USEFUL AS INHIBITORS OF ENKEPHALINASE AND ACE
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The present invention relates to certain novel mercaptoacetylamide bicyclic lactam derivatives useful as inhibitors of enkephalinase and of ACE.These mercaptoacetylamide bicyclic lactam derivatives can be described by the following formula: STR1 whe
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- BENZOTHIAZEPINE AND BENZOXAZEPINE DERIVATIVES AS CHOLECYSTOKININ RECEPTOR ANTAGONISTS
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The present invention relates to novel substituted benzothiazepines and benzoxazepines of the formula STR1 wherein R 1, R 2, R. sup. 7, R 8, R 9 and X are as defined below, and to novel intermediates used in the synthesis of such compounds. Such compounds are useful in the treatment and prevention of gastrointestinal disorders, pain and anxiety disorders.
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