- Nickel-Catalyzed Cross-Coupling of Amino-Acid-Derived Alkylzinc Reagents with Alkyl Bromides/Chlorides: Access to Diverse Unnatural Amino Acids
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Unnatural α-amino acids are important synthetic targets in the field of peptide science. Herein we report an efficient, versatile, and straightforward strategy for the synthesis of homophenylalanine derivatives via the nickel-catalyzed Csp3–Csp3 cross-coupling of (fluoro)benzyl bromides/chlorides with natural α-amino-acid-derived alkylzinc reagents. The current protocol features the advantages of a low-cost nickel catalyst system, synthetic convenience, and the tolerance of rich functionality and stereochemistry.
- Gou, Fei-Hu,Ma, Ming-Jian,Wang, An-Jun,Zhao, Liang,Wang, Haoyang,Tong, Jie,Wang, Ze,Wang, Zhen,He, Chun-Yang
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supporting information
p. 240 - 244
(2022/01/12)
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- Efficient Hydro- and Organogelation by Minimalistic Diketopiperazines Containing a Highly Insoluble Aggregation-Induced, Blue-Shifted Emission Luminophore**
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We report the synthesis, gelation abilities and aggregation-induced, blue-shifted emission (AIBSE) properties of two minimalistic diketopiperazine-based gelators. Despite containing a highly insoluble luminophore that makes up more than half of their respective molecular masses, efficient hydrogelation by multiple stimuli for one and efficient organogelation for the other compound are reported. Insights into the aggregation and gelation properties were gained through examination of the photophysical and material properties of selected gels, which are representative of the different modes of gelation. The synthesis of the gelators is highly modular and based on readily available amino acid building blocks, allowing the efficient and rapid diversification of these core structures and fine-tuning of gel properties.
- Molkenthin, Martin,Nachtsheim, Boris J.,Nau, Werner M.
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p. 16488 - 16497
(2021/10/25)
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- ELONGATION FACTOR 1-ALPHA INHIBITORS AND USES THEREOF
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Disclosed herein, inter alia, are compounds for inhibiting Elongation Factor 1-alpha and uses thereof.
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Paragraph 0551-0554; 0598-0603
(2021/08/13)
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- MODULATORS OF THE INTEGRATED STRESS RESPONSE PATHWAY
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The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, wherein R1 to R3, A1 and A2 have the meaning as indicated in the description and claims. The invention further relates to pharmaceutical compositions comprising said compounds, their use as medicament and in a method for treating and preventing one or more diseases or disorders associated with integrated stress response.
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Page/Page column 36; 37; 38
(2020/11/04)
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- Alkyl Carbagermatranes Enable Practical Palladium-Catalyzed sp2-sp3 Cross-Coupling
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Pd-catalyzed cross-coupling reactions have achieved tremendous accomplishments in the past decades. However, C(sp3)-hybridized nucleophiles generally remain as challenging coupling partners due to their sluggish transmetalation compared to the C(sp2)-hybridized counterparts. While a single-electron-transfer-based strategy using C(sp3)-hybridized nucleophiles had made significant progress recently, fewer breakthroughs have been made concerning the traditional two-electron mechanism involving C(sp3)-hybridized nucleophiles. In this report, we present a series of unique alkyl carbagermatranes that were proven to be highly reactive in cross-coupling reactions with our newly developed electron-deficient phosphine ligands. Generally, secondary alkyl carbagermatranes show slightly lower, yet comparable activity to its Sn analogue. Meanwhile, primary alkyl carbagermatranes exhibit high activity, and they were also proved stable enough to be compatible with various reactions. Chiral secondary benzyl carbagermatrane gave the coupling product under base/additive-free conditions with its configuration fully inversed, suggesting that transmetalation was carried out in an "SE2(open) Inv" pathway, which is consistent with Hiyama's previous observation. Notably, the cross-coupling of primary alkyl carbagermatranes could be performed under base/additive-free conditions with excellent functional group tolerance and therefore may have potentially important applications such as stapled peptide synthesis.
- Xu, Meng-Yu,Jiang, Wei-Tao,Li, Ying,Xu, Qing-Hao,Zhou, Qiao-Lan,Yang, Shuo,Xiao, Bin
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supporting information
p. 7582 - 7588
(2019/05/16)
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- Synthesis of C3-symmetric star-shaped molecules containing α-amino acids and dipeptides via Negishi coupling as a key step
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We demonstrate a new synthetic strategy toward star-shaped C3-symmetric molecules containing α-amino acid (AAA) derivatives and dipeptides. In this regard, trimerization and Negishi cross-coupling reactions are used as the key steps starting fr
- Kotha, Sambasivarao,Todeti, Saidulu
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p. 371 - 377
(2019/02/20)
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- Synthesis of selenocysteine-containing dipeptides modeling the active site of thioredoxin reductase
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Four cyclic dipeptides modeling the active site of thioredoxin reductase (TrxR), UU, CU, UC, and CC, where U and C represent selenocystine and cystine, respectively, were synthesized and their glutathione peroxidase (GPx)-like catalytic activity was evaluated by the reaction of hydrogen peroxide (H2O2) with glutathione (GSH) in the presence of glutathione reductase (GR). Among these, only UC exhibited the significant antioxidant capacity, suggesting that an atomic environment around the Se–S bond is relevant to the reactivity toward a thiol substrate.
- Shimodaira, Shingo,Iwaoka, Michio
-
supporting information
p. 750 - 752
(2019/04/26)
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- SYNTHESIS OF 4-CHLOROKYNURENINES AND INTERMEDIATES
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The invention relates to an overall enantio-specific synthesis of 4-chlorokynurenine compounds, in particular L-4-chlorokynurenine, with improved yields. Large-scale syntheses are disclosed. The invention also relates to novel intermediates in the synthes
- -
-
Paragraph 70-91
(2019/08/29)
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- Painting argyrins blue: Negishi cross-coupling for synthesis of deep-blue tryptophan analogue β-(1-azulenyl)-L alanine and its incorporation into argyrin C
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The argyrins are a family of non-ribosomal peptides that exhibits different biological activities through only small structural changes. Ideally, a biologically active molecule can be tracked and observed in a variety of biological and clinical settings in a non-invasive manner. As a step towards this goal, we report here a chemical synthesis of unnatural deep blue amino acid β-(1-azulenyl)-L alanine with different fluorescence and photophysical properties, which allows a spectral separation from the native tryptophan signal. This might be especially useful for cell localization studies and visualizing the targeted proteins. In particular, the synthesis of β-(1-azulenyl)-L alanine was achieved through a Negishi coupling which proved to be a powerful tool for the synthesis of unnatural tryptophan analogs. Upon β-(1-azulenyl)-L alanine incorporation into argyrin C, deep blue octapeptide variant was spectrally and structurally characterized.
- Stempel, Erik,Kaml, Robert Franz-Xaver,Budisa, Nediljko,Kalesse, Markus
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p. 5259 - 5269
(2018/05/16)
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- Application of bis-2-(trimethylsilyl)ethyl diselenide to the synthesis of selenium-containing amino acid derivatives
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Selenium-containing amino acids play a pivotal role as biomaterials for the synthesis of Se-dependent enzymes and repair proteins. Especially, selenocysteine and selenoglutathione are prominently involved in fundamental biological processes. In this study
- Yonezawa, Tsubasa,Yamaguchi, Masahito,Ninomiya, Masayuki,Koketsu, Mamoru
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p. 6085 - 6091
(2017/09/23)
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- Improved synthetic routes to the selenocysteine derivatives useful for Boc-based peptide synthesis with benzylic protection on the selenium atom
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Selenocysteine (Sec) derivatives, i.e., Boc-Sec(MBn)-OH (1) and Boc-Sec(MPM)-OH (2), which are useful for chemical synthesis of selenopeptides, were obtained from L-serine in five steps with total yields of 73% and 74%, respectively. The enantiomeric excesses were confirmed to be >99% e.e. by optical resolution using a chiral column on HPLC. On the other hand, for the case of a Fmoc-protected Sec derivative, i.e., Fmoc-Sec(MPM)-OH, similar reactions resulted in low yields and partial racemization taking place. [PRESENTED EQUATION]
- Shimodaira, Shingo,Iwaoka, Michio
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p. 260 - 271
(2017/03/09)
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- Z-SELECTIVE OLEFIN METATHESIS OF PEPTIDES
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The invention relates generally to the synthesis of modified amino acids and modified peptides in the presence of cyclometalated catalysts. The invention has utility in the fields of catalysis, organic synthesis, polymer chemistry, and industrial and fine
- -
-
Paragraph 0383; 0384; 0385
(2016/08/03)
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- Rapid Synthesis of Boc-2′,6′-dimethyl- l -tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics
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The unnatural amino acid 2′,6′-dimethyl-l-tyrosine has found widespread use in the development of synthetic opioid ligands. Opioids featuring this residue at the N-terminus often display superior potency at one or more of the opioid receptor types, but the availability of the compound is hampered by its cost and difficult synthesis. We report here a short, three-step synthesis of Boc-2′,6′-dimethyl-l-tyrosine (3a) utilizing a microwave-assisted Negishi coupling for the key carbon-carbon bond forming step, and employ this chemistry for the expedient synthesis of other unnatural tyrosine derivatives. Three of these derivatives (3c, 3d, 3f) have not previously been examined as Tyr1 replacements in opioid ligands. We describe the incorporation of these tyrosine derivatives in a series of opioid peptidomimetics employing our previously reported tetrahydroquinoline (THQ) scaffold, and the binding and relative efficacy of each of the analogues at the three opioid receptor subtypes: mu (MOR), delta (DOR), and kappa (KOR).
- Bender, Aaron M.,Griggs, Nicholas W.,Gao, Chao,Trask, Tyler J.,Traynor, John R.,Mosberg, Henry I.
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supporting information
p. 1199 - 1203
(2015/12/23)
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- SULFONAMIDE DERIVATIVE AND MEDICINAL USE THEREOF
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Provided are sulfonamide derivatives of a specific chemical structure in which a sulfonamide group having, as a substituent, a phenyl group or a heterocyclic group having a hetero atom(s) as a constituent element(s) is present at its terminal, and pharmaceutically acceptable salts thereof. These compounds are novel compounds having excellent α4 integrin-inhibitory action.
- -
-
Paragraph 0584-0585
(2015/02/25)
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- Synthesis of chiral Nβ-protected amino diselenides from the corresponding amino alkyl iodides using NaBH2Se3 as a selenating reagent and their conversion to seleninic acids
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A convenient approach has been presented for the synthesis of Nβ-protected amino diselenides from the corresponding amino alkyl iodides using in situ generated NaBH2Se3 as an efficient selenating reagent. All the diselenid
- Panguluri, Nageswara Rao,Panduranga, Veladi,Prabhu, Girish,Vishwanatha,Sureshbabu, Vommina V.
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p. 51807 - 51811
(2015/06/25)
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- DIPEPTIDE AND TRIPEPTIDE EPOXY KETONE PROTEASE INHIBITORS
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Provided herein are dipeptide and tripeptide epoxy ketone protease inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula (X): and pharmaceutically acceptable salts and compositions including the same. The compounds and compositions provided herein may be used, for example, in the treatment of proliferative diseases including cancer and autoimmune diseases.
- -
-
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- Z-selective olefin metathesis on peptides: Investigation of side-chain influence, preorganization, and guidelines in substrate selection
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Olefin metathesis has emerged as a promising strategy for modulating the stability and activity of biologically relevant compounds; however, the ability to control olefin geometry in the product remains a challenge. Recent advances in the design of cyclom
- Mangold, Shane L.,Oleary, Daniel J.,Grubbs, Robert H.
-
supporting information
p. 12469 - 12478
(2014/11/07)
-
- Use of a tandem Prins/Friedel-Crafts reaction in the construction of the indeno-tetrahydropyridine core of the haouamine alkaloids: Formal synthesis of (-)-haouamine A
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A tandem Prins/Friedel-Crafts reaction useful for the construction of the indeno-tetrahydropyridine core of the haouamine alkaloids and a formal synthesis of (-)-haouamine A are described.
- Fenster, Erik,Fehl, Charlie,Aube, Jeffrey
-
supporting information; experimental part
p. 2614 - 2617
(2011/07/08)
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- HALOALKYL CONTAINING COMPOUNDS AS CYSTEINE PROTEASE INHIBITORS
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The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.
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Page/Page column 53
(2010/06/15)
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- Prolonged stability by cyclization: Macrocyclic phosphino dipeptide isostere inhibitors of β-secretase (BACE1)
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Cyclization of recently reported linear phosphino dipeptide isostere inhibitors of BACE1 via side chain olefin metathesis yielded macrocyclic BACE1 inhibitors. The most potent compound II-P1 (IC50 of 47 nM) and the corresponding linear analog I were tested for serum stability. The approach led to three times prolonged half life serum stability of 44 min for the macrocyclic inhibitor II-P1 compared to the linear compound I.
- Huber, Timo,Manzenrieder, Florian,Kuttruff, Christian A.,Dorner-Ciossek, Cornelia,Kessler, Horst
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body text
p. 4427 - 4431
(2010/04/05)
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- Thiomaleic anhydride: A convenient building block for the synthesis of α-substituted γ- and δ-lactones through free-radical addition, nucleophilic ring opening, and subsequent thiocarboxylate manipulation
-
(Chemical Equation Presented) Iodoalkyl tert-butyl carbonates and carbamates undergo clean free-radical addition to thiomaleic anhydride to give substituted thiosuccinic anhydrides in high yield on treatment with tris-(trimethylsilyl)silane and a radical initiator. After removal of the tert-butyloxycarbonyl group, cyclization then affords lactones or lactams substituted in the α-position by a thiocarboxylic acid residue. This group is converted to amides through reaction with electron-deficient sulfonamides or to aldehydes and/or ketones by the reaction of derived thioesters with either thiophenol, an electron-deficient allyl phenyl sulfide, or phenylboronic acid.
- Crich, David,Rahaman, Md. Yeajur
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supporting information; experimental part
p. 6792 - 6796
(2009/12/31)
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- Readily available amino acid building blocks for the synthesis of phosphole-containing peptides
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Nucleophilic substitution of a phospholide anion onto protected 3-iodoalanine leads to the formation of an amino acid with an appended phosphole in excellent yield. Manipulation of the protecting groups, leads to building blocks suitable for the synthesis of phosphole-containing polypeptides.
- van Zutphen, Steven,Margarit, Vicente J.,Mora, Guilhem,Le Floch, Pascal
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p. 2857 - 2859
(2007/10/03)
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- BICYCLIC COMPOUNDS USEFUL AS CATHEPSIN S INBHIBITORS
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Compounds of formula (I), wherein R1, R2, R3, Ra and E are are defined within, and pharmaceutically acceptable salts, solvates, hydrates and N-oxides thereof having utility in the treatment of disorders mediated by cathepsin S.
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Page/Page column 34
(2010/11/29)
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- Macrocyclic peptidomimetic inhibitors of β-secretase (BACE): First X-ray structure of a macrocyclic peptidomimetic-BACE complex
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The synthesis of novel macrocyclic peptidomimetic inhibitors of the enzyme BACE1 is described. These macrocycles are derived from a hydroxyethylene core structure. Compound 7 was co-crystallized with BACE1 and the X-ray structure of the complex elucidated at 1.6 A resolution. This molecule inhibits the production of the Aβ peptide in HEK293 cells overexpressing APP751sw.
- Rojo, Isabel,Martin, Jose Alfredo,Broughton, Howard,Timm, David,Erickson, Jon,Yang, Hsiu-Chiung,McCarthy, James R.
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p. 191 - 195
(2007/10/03)
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- Chemoselectivity of the Ruthenium-Catalyzed Hydrative Diyne Cyclization: Total Synthesis of (+)-Cylindricine C, D, and E
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(Matrix presented) The chemoselectivity of the ruthenium-catalyzed hydrative diyne cylization is explored In an expeditious synthesis of the tricyclic alkaloids cylindricine C, D, and E.
- Trost, Barry M.,Rudd, Michael T.
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p. 4599 - 4602
(2007/10/03)
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- Lanthanide triple helical complexes with a chiral ligand derived from 2,6-pyridinedicarboxylic acid
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The ligand 3-[2,6-bis(diethylcarbamoyl)pyridine-4-yl]-N-(tert-butoxycarbonyl)alanine methyl ester (L4) bearing a chiral group in the 4-position of the pyridine ring has been synthesised and its interaction with trivalent lanthanide ions studied. L4 yields stable [Ln(L4)3]3+ complexes in acetonitrile, with logβ3 in the range 19-20. The specific rotary dispersion of the complexes is about ten times as large as that of the ligand alone, consistent with triple helical structures in solution. NMR data show the presence of only one time-averaged species in acetonitrile solution with a trigonal symmetry, that is, the helical P ? M interconversion is fast on the NMR time scale. Circularly polarised luminescence on the Eu and Tb triple helical complexes displays weak effects, pointing to only a small diastereomeric excess in solution. High resolution luminescence spectra of the Eu complex in the solid state reveal a local symmetry derived from a trigonal arrangement around the metal ion and the long 5D0 lifetime (1.58 ms) is indicative of the absence of water molecules bound in the inner co-ordination sphere. Energy transfer processes in the luminescent Eu and Tb triple helical complexes are discussed.
- Muller,Schmidt,Jiricek,Hopfgartner,Riehl,Buenzli,Piguetf
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p. 2655 - 2662
(2007/10/03)
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- Synthesis of Se- and Te-Containing Amino Acids: Useful Probes for Structural Studies of Proteins.
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The synthesis of (1)-Se-cystine, (1)-[77Se]-cystine and (1)-Te-cystine in 4 steps from commercially available 2(S)-[(tert-butoxycarbonyl)amino]-3-hydroxy-propionate has been accomplished. [4-13C]Te-Met has been synthesized in a one pot reaction.
- Silks, L. A. "Pete"
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p. 611 - 616
(2007/10/03)
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- Synthesis of L-selenocystine, L-[77Se]selenocystine and L-tellurocystine
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Synthetic routes for the synthesis of stable isotope labelled amino acids which contain either a selenium or a tellurium atom have been explored. L-Selenocystine, L-[77Se]selenocystine and L-tellurocystine have been constructed in four steps from commercially available methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionate. The sequence of reactions has been successfully scaled up giving significant quantities of the chalcogen based amino acids in fair to good overall yield. Copyright 1997 by the Royal Society of Chemistry.
- Stocking, Emily M.,Schwarz, Jessie N.,Senn, Hans,Salzmann, Michael,Silks, Louis A.
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p. 2443 - 2447
(2007/10/03)
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- Synthesis of all Three Regioisomers of Pyridylalanine
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Pyridylalanines 4-6, differing from one another by the position of attachment on the heterocyclic ring were synthesized in moderate yield starting from serine and 2-, 3- and 4-bromopyridine respectively.
- Walker, Michael A.,Kaplita, Khane Pham,Chen, Ti,King, H. Dalton
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p. 169 - 170
(2007/10/03)
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- Enantioselective synthesis of N-Boc and N-Fmoc protected diethyl 4-phosphono(difluoromethyl)-L-phenylalanine; agents suitable for the solid-phase synthesis of peptides containing nonhydrolyzable analogues of O-phosphotyrosine
-
Enantioselective convergent syntheses of N-Boc and N-Fmoc protected diethyl 4-phosphono(difluoromethyl)-L-phenylalanine are reported.
- Smyth,Burke Jr.
-
p. 551 - 554
(2007/10/02)
-
- LES ORGANOCUPRATES DANS UNE NOUVELLE SYNTHESE D'AMINOACIDES ENANTIOMERIQUEMENT PURS
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A new general method of synthesis of optically pure α- amino esters was elaborated during studies on the reaction of organocuprates with tosyl and halogeno derivatives of L-serine and L-homoserine.
- Bajgrowicz, J. A.,Hallaoui, A. El,Jacquier, R.,Pigiere, Ch.,Viallefont, Ph.
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p. 1833 - 1845
(2007/10/02)
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- LITHIUM DIORGANOCUPRATE REACTIONS WITH L-SERINE DERIVATIVES
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The lithium diorganocuprate reactions with L-serine derivatives are studied.Retention of configuration, or at least a high enantiomeric excess (> 80percent) of the formed α-amino esters is observed in all cases.Attempts are made to restrict side-reactions.
- Bajgrowicz, J. A.,Hallaoui, A. El,Jacquier, R.,Pigiere, Ch.,Viallefont, Ph.
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p. 2759 - 2762
(2007/10/02)
-