- Dehydration of Chiral α-Amides to Chiral α-Nitriles Under the Appel Reaction Conditions
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An efficient synthesis of Nα-protected amino nitriles from Nα-protected amino acid amides employing Ph3P, I2 and NMM was described. Various amino acid amides, protected by Fmoc, Z and Boc were conveniently conve
- Shekharappa,Roopesh Kumar,Srinivasulu,Sureshbabu, Vommina V.
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p. 497 - 502
(2020/07/30)
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- Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry
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Optimization of small-molecule probes or drugs is a synthetically lengthy, challenging, and resource-intensive process. Lack of automation and reliance on skilled medicinal chemists is cumbersome in both academic and industrial settings. Here, we demonstr
- Cappiello, John R.,Chen, Emily,Dillon, Nicholas,Hull, Mitchell V.,Kitamura, Seiya,Kitamura, Shinichi,Kotaniguchi, Miyako,Nizet, Victor,Sharpless, K. Barry,Solania, Angelo,Woehl, Jordan L.,Wolan, Dennis W.,Zheng, Qinheng
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supporting information
p. 10899 - 10904
(2020/07/13)
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- α-Amino Diphenyl Phosphonates as Novel Inhibitors of Escherichia coli ClpP Protease
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Increased Gram-negative bacteria resistance to antibiotics is becoming a global problem, and new classes of antibiotics with novel mechanisms of action are required. The caseinolytic protease subunit P (ClpP) is a serine protease conserved among bacteria that is considered as an interesting drug target. ClpP function is involved in protein turnover and homeostasis, stress response, and virulence among other processes. The focus of this study was to identify new inhibitors of Escherichia coli ClpP and to understand their mode of action. A focused library of serine protease inhibitors based on diaryl phosphonate warheads was tested for ClpP inhibition, and a chemical exploration around the hit compounds was conducted. Altogether, 14 new potent inhibitors of E. coli ClpP were identified. Compounds 85 and 92 emerged as most interesting compounds from this study due to their potency and, respectively, to its moderate but consistent antibacterial properties as well as the favorable cytotoxicity profile.
- Moreno-Cinos, Carlos,Sassetti, Elisa,Salado, Irene G.,Witt, Gesa,Benramdane, Siham,Reinhardt, Laura,Cruz, Cristina D.,Joossens, Jurgen,Van Der Veken, Pieter,Br?tz-Oesterhelt, Heike,Tammela, P?ivi,Winterhalter, Mathias,Gribbon, Philip,Windshügel, Bj?rn,Augustyns, Koen
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p. 774 - 797
(2019/01/30)
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- LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates
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Large neutral amino acid transporter 1 (LAT1) is a solute carrier protein located primarily in the blood–brain barrier (BBB) that offers the potential to deliver drugs to the brain. It is also up-regulated in cancer cells, as part of a tumor's increased metabolic demands. Previously, amino acid prodrugs have been shown to be transported by LAT1. Carboxylic acid bioisosteres may afford prodrugs with an altered physicochemical and pharmacokinetic profile than those derived from natural amino acids, allowing for higher brain or tumor levels of drug and/or lower toxicity. The effect of replacing phenylalanine's carboxylic acid with a tetrazole, acylsulfonamide and hydroxamic acid (HA) bioisostere was examined. Compounds were tested for their ability to be LAT1 substrates using both cis-inhibition and trans-stimulation cell assays. As HA-Phe demonstrated weak substrate activity, its structure–activity relationship (SAR) was further explored by synthesis and testing of HA derivatives of other LAT1 amino acid substrates (i.e., Tyr, Leu, Ile, and Met). The potential for a false positive in the trans-stimulation assay caused by parent amino acid was evaluated by conducting compound stability experiments for both HA-Leu and the corresponding methyl ester derivative. We concluded that HA's are transported by LAT1. In addition, our results lend support to a recent account that amino acid esters are LAT1 substrates, and that hydrogen bonding may be as important as charge for interaction with the transporter binding site.
- Zur, Arik A.,Chien, Huan-Chieh,Augustyn, Evan,Flint, Andrew,Heeren, Nathan,Finke, Karissa,Hernandez, Christopher,Hansen, Logan,Miller, Sydney,Lin, Lawrence,Giacomini, Kathleen M.,Colas, Claire,Schlessinger, Avner,Thomas, Allen A.
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p. 5000 - 5006
(2016/10/05)
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- Carbohydrates as efficient catalysts for the hydration of α-amino nitriles
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Directed hydration of α-amino nitriles was achieved under mild conditions using simple carbohydrates as catalysts exploiting temporary intramolecularity. A broadly applicable procedure using both formaldehyde and NaOH as catalysts efficiently hydrated a variety of primary and secondary susbtrates, and allowed the hydration of enantiopure substrates to proceed without racemization. This work also provides a rare comparison of the catalytic activity of carbohydrates, and shows that the simple aldehydes at the basis of chemical evolution are efficient organocatalysts mimicking the function of hydratase enzymes. Optimal catalytic efficiency was observed with destabilized aldehydes, and with difficult substrates only simple carbohydrates such as formaldehyde and glycolaldehyde proved reliable.
- Chitale, Sampada,Derasp, Joshua S.,Hussain, Bashir,Tanveer, Kashif,Beauchemin, André M.
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supporting information
p. 13147 - 13150
(2016/11/09)
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- Synthesis of Nitriles from Aldoximes and Primary Amides Using XtalFluor-E
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The dehydration reaction of aldoximes and amides for the synthesis of nitriles using [Et2NSF2]BF4 (XtalFluor-E) is described. Overall, the reaction proceeds rapidly (normally 1 h) at room temperature in an environmentally benign solvent (EtOAc) with only a slight excess of the dehydrating agent (1.1 equiv). A broad scope of nitriles can be prepared, including chiral nonracemic ones. In addition, in a number of cases, further purification of the nitrile after the workup was not required.
- Keita, Massaba,Vandamme, Mathilde,Paquin, Jean-Fran?ois
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p. 3758 - 3766
(2015/11/28)
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- Glycosylation mediated - BAIL in aqueous solution
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The use of Br?nsted acid ionic liquid (BAIL) as a catalyst for the activation of unreactive and unprotected glycosyl donors has been demonstrated for the first time in aqueous solution.
- Delacroix, Sébastien,Bonnet, Jean-Pierre,Courty, Matthieu,Postel, Denis,Van Nhien, Albert Nguyen
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- AmIno Acid Homologation by the Blaise Reaction: A new entry into nitrogen heterocycles
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(Chemical Equation Presented) A general strategy for the amino acid homologation via Blaise reaction and subsequent reduction is presented. This strategy involves the preparation of protected α-amino nitriles from the corresponding amino acids, followed by the zinc-mediated condensation of tert-butyl bromoacetate, to give the imidazolidones after iminozincate cyclization. Reduction gave the saturated imidazolidinones with cis or trans stereochemistry, depending on the reduction conditions. This strategy was applied to nonfunctionalized amino acids and to functionalized amino acids such as serine and aspartic acid. Additionally, acidic hydrolysis of cis or trans imidazolidinones to the corresponding chiral 4-aminopyrrolidones is described.
- Cam, Thuy Hoang,Bouillere, Francelin,Johannesen, Sine,Zulauf, Anais,Panel, Cecilia,Pouilhes, Annie,Gori, Didier,Alezra, Valerie,Kouklovsky, Cyrille
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experimental part
p. 4177 - 4187
(2009/09/08)
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- N-urethane-protected amino alkyl isothiocyanates: Synthesis, isolation, characterization, and application to the synthesis of thioureidopeptides
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(Chemical Equation Presented) Synthetically useful N-Fmoc amino-alkyl isothiocyanates have been described, starting from protected amino acids. These compounds have been synthesized in excellent yields by thiocarbonylation of the monoprotected 1,2-diamines with CS2/TEA/p-TsCl, isolated as stable solids, and completely characterized. The procedure has been extended to the synthesis of amino alkyl isothiocyanates from Boc- and Z-protected amino acids as well. The utility of these isothiocyanates for peptidomimetics synthesis has been demonstrated by employing them in the preparation of a series of dithioureidopeptide esters. Boc-Gly-OH and Boc-Phe-OH derived isothiocyanates 9a and 9c have been obtained as single crystals and their structures solved through X-ray diffraction. They belong to the orthorhombic crystal system, and have a single molecule in the asymmetric unit (Z′ = 1). 9a crystallizes in the centrosymmetric space group Pbca, while 9c crystallizes in the noncentrosymmetric space group P212121.
- Sureshbabu, Vommina V.,Naik, Shankar A.,Hemantha,Narendra,Das, Ushati,Guru Row, Tayur N.
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supporting information; experimental part
p. 5260 - 5266
(2009/12/06)
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- A new chiral synthesis of a bicyclic enedione containing a seven-membered ring mediated by a combination of chiral amine and Bronsted acid
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Several chiral amines bearing a heterocyclic moiety such as pyrrolidine, piperazine or tetrazole were prepared from l-phenylalanine. The enantioselectivity of the intramolecular asymmetric aldol reaction mediated by a combination of the synthetic chiral a
- Nagamine, Takashi,Inomata, Kohei,Endo, Yasuyuki
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experimental part
p. 1191 - 1204
(2009/06/28)
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- Microwave-assisted one-pot tandem reactions for direct conversion of primary alcohols and aldehydes to triazines and tetrazoles in aqueous media
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(Chemical Equation Presented) A series of primary alcohols and aldehydes were treated with iodine in ammonia water under microwave irradiation to give the intermediate nitriles, which without isolation underwent [2 + 3] cycloadditions with dicyandiamide and sodium azide to afford high yields of the corresponding triazines and tetrazoles, including the α-amino- and dipeptidyl tetrazoles in high optical purity.
- Shie, Jiun-Jie,Fang, Jim-Min
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p. 3141 - 3144
(2008/02/13)
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- MONOMETHYLVALINE COMPOUNDS HAVING PHENYLALANINE CARBOXY MODIFICATIONS AT THE C-TERMINUS
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Auristatin peptide analogs of MeVal-Val-Dil-Dap-Phe (MMAF) having a carboxylic acid equivalent at the C-terminal phenylalanine were prepared and attached to ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.
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Page/Page column 147
(2008/06/13)
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- A Stereoselective entry into functionalized 1,2-diamines by zinc-mediated homologation of α-aminoacids
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A general, stereoselective synthsis of 4,5-disubstituted imidazolidines-2-ones from α-aminoacids has been developed: the key steps are a Biaise reaction of bromoacetate on α-aminonitriles and further reduction. Although reduction with sodium cyanoborohydride afforded a mixture of cis and trans isomers 6a-e with moderate to good stereoselectivity, reduction with sodium in liquid ammonia gave the trans isomers 8a-e with complete stereoselectivity. Acidic hydrolysis of the urea gave 4-amino-pyrrolidinones, which can be precursors to β,γ-diaminoacids or 3-aminopyrrolidines.
- Hoang, Cam Thuy,Alezra, Valerie,Guillot, Regis,Kouklovsky, Cyrille
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p. 2521 - 2524
(2008/02/05)
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- A simple preparation of N-protected chiral α-aminonitriles from N-protected α-amino acid amides
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N-protected α-amino-acid amides are dehydrated to N-protected α-aminonitriles in good yields and with excellent purities by reaction of the corresponding primary amides with cyanuric chloride in DMF.
- Maetz, Philippe,Rodriguez, Marc
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p. 4221 - 4222
(2007/10/03)
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- Thioesters of Amino Acid Derivatives as Thioacylating Agents in Thiopeptide Synthesis
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Thioesters, mainly of N-substituted glycine, have been synthesized and examined for their ability to thioacylate amino acids, peptides, and esters and amides of amino acids and peptides.Methyl, ethyl, and benzyl thioesters have been obtained in high yield by thiohydrolysis of the corresponding imino esters.All were found to be excellent thioacylating agents for amino acids, though under the conditions used, they reacted much less readily with amino acid esters and amides including peptides, except where the reacting nucleophile was the amino group of Gly or the imino group of Pro.Attempts to improve the leaving properties of the alkoxy group (OR') in O-alkyl thioesters (RCSOR') by introduction of a 2-nitro substituent result in poorer yields of the thioester, probably because of competing elimination between the iminium group and OR' on treatment of the imino ester with H2S, although the nitro substituted thioesters are slightly more reactive than simple alkyl derivatives.The reaction of N-benzyloxycarbonylaminoacetonitrile with phenol gives a 30percent yield of a product which failed to yield any thioester on reaction with H2S.
- Elmore, Donald T.,Guthrie, David J. S.,Kay, Gillian,Williams, Carrell H.
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p. 1051 - 1056
(2007/10/02)
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