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Synthesis of the peptide bond in aqueous solution using 2a proceeded successfully withstandard lipophilic Z and Boc protecting group without precipitation of activatedintermediates, although in case of more hydrophobic Boc-Phe-Leu-OMe better yields wereobtained in the presence of co-solvent such as DMF, THF or acetonitrile (compare Table 1,entry 4 and 5).Table 1. Synthesis of peptides using 2a in aqueous solutionEntryCarboxyliccomponentAmino componentSolventYield[%]1 Z-Ala-OH H 2 N-Ala-OMe water 832 Z-Ala-OH H 2 N-Phe-OMe water 943 Boc-Gly-OH H 2 N-Ala-OMe water 954 Boc-Phe-OH H 2 N-Leu-OMe water 635 Boc-Phe-OH H 2 N-Leu-OMe DMF/water 956 Boc-Gly-OH H 2 N-Phe-Leu-OMe DMF/water 877 Boc-Gly-OH H 2 N-Gly-Phe-Leu-OMe DMF/water 988 N-Boc-Tyr(Boc)-OH H 2 N-Gly-Gly-Phe-Leu-OMe DMF/water 75The presence of sulphonic group in 3a and in appropriate side-products facilitated isolationof final product [3]. In most cases protected peptides precipitated almost quantitatively inthe pure form the aqueous solution, but excess of acylating reagent and any impuritiesremained in solution. This advantageous procedure was found useful in the synthesisdipeptides and Leu-enkephalin in 75-98% yield.AcknowledgmentsFinancial support of this studies by grant 9/PMPP/U/29-09.08/E-370/2009 donated by Ministry andSciences and Higher Education (MNiSzW) is gratefully acknowledged.References1. Hojo, K., Maeda, M., Tanakamaru, N., Mochida, K., Kawasaki, K. Protein Peptide Lett. 13, 189-192 (2006) and references cited therein.2. Jung, R., Steinle, D., Anliker, R. Food Chem. Toxicol. 30, 635-660 (1992).3. Kaminski, Z.J., Zajac, K.J. Acta Pharm. Poloniae, in press.127
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Synthesis of Novel Non-Proteinogenic Amino Acids:N-Ethyldehydroamino AcidsLuís S. Monteiro, Joanna Kołomańska, and Ana C. SuarezChemistry Centre, University of Minho, Gualtar, 4710-057, Braga, PortugalIntroductionNon-proteinogenic amino acids are an important class of organic compounds that can haveintrinsic biological activity or can be found in peptides with antiviral, antitumor, antiinflammatoryor immunosuppressive activities. Among non-proteinogenic amino acids areN-alkylamino acids and -dehydroamino acids which can be found in many biologicallyimportant peptides [1].N-Alkylation of the peptide bond causes changes in the volume and conformation ofpeptides leading to reduced flexibility, increase of permeability for the membrane(increased lipophilicity) and prevention of cleavage by proteolytic enzymes [2]. SeveralN-alkylated peptides show antibiotic, anticancer or antiviral activity. For exampleN-methyl-leucine is found in cyclosporines [3]. Many methods of synthesis ofN-alkylamino acids have been developed, most of them are N-methylations [2]. However,only a few methods for the synthesis of N-ethylated amino acids and their derivatives areavailable in the literature [4]. Recently, Liguori et al. proposed the use of a strong electronwithdrawingamine protecting group, 4-nitrobenzenesulfonyl (Nosyl), to enhance the lowacidity of the α-amide hydrogen in order to accomplish alkylation using triethyloxoniumtetrafluoroborate (Et 3 OBF 4 ) as an alkylating agent [5].Dehydroamino acids can be found in several yeasts and bacteria, in which theycontribute with a catalytic role in the active sites of some enzymes, as well as in a variety ofpeptide antibiotics of bacterial origin that include the lantibiotics (nisin, epidermin, subtilin,gallidermin) [6]. In our laboratories we developed an efficient method for the synthesis ofN,N-diacyl- -dehydroamino acid derivatives from -hydroxyamino acid derivatives byusing 2 eq. of tert-butylpyrocarbonate (Boc 2 O) and 4-dimethylaminopyridine (DMAP) ascatalyst in dry acetonitrile [7]. In order to allow the synthesis of N-acyl- -dehydroaminoacid derivatives, a modification of this method was subsequently reported [8].Herein, we report the use of a combination of the alkylation procedure reported byLiguori et al. [5] and the dehydration methodology developed by Ferreira et al. [7,8] toobtain new non-proteinogenic amino acids, namely, N-ethyl- -dehydroamino acids.Results and DiscussionThe methodology proposed by Liguori for N-ethylation of N-Nosyl protected amino acidderivatives requires the use of side chain protection in the case of side chain functionalizedamino acids [5]. To avoid the need for side chain protecting and subsequent deprotecting,our initial approach for the synthesis of N-ethyl- -dehydroamino acid derivatives was atwo step procedure in which the first step was dehydration followed by alkylation (RouteA, Scheme 1). Thus, dehydration of the methyl esters of 4-nitrobenzenesulfonyl-hydroxyamino acids (compounds 1a-c, Scheme 1) was initially attempted by reactionwith 1 eq. of Boc 2 O using DMAP as catalyst, followed by treatment with N,N,N’,N’-tetramethylguanidine (TMG) [8]. However, due to the high electron-withdrawing effect ofthe 4-nitrobenzenesulfonyl group, this method led to complex mixtures resulting fromO 2NOSOHN CO 2CH 3ROHBoc 2ODMAPO 2NOSOBocN CO 2CH 3RRoute AOO 2NSTfa 4% HN CO2CH 3CH 2Cl 2O1a-c 2b, 2c 3b, 3cROO 2NSEt 3OBF 4 N CO2CH 3DIPEAOR4a-cR = H, a; CH 3, b; C 6H 5, c.DIPEAEt 3OBF 4Route BO1) Boc 2O/DMAP2) TMGO 2NSN CO 2CH 3Scheme 1Scheme 1.OROH5a-c128
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Peptides 2010Tales of PeptidesProce
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Peptides 2010Tales of PeptidesProce
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IntroductionWe had the distinct hon
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Scientific programIn planning the 3
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31 st EUROPEAN PEPTIDE SYMPOSIUMSep
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published by John Wiley & Sons as a
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The Josef Rudinger AwardThis award
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Young Investigators' SymposiumThe y
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xxiv
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Design of Peptidyl-Inhibitors for G
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Synthetic Antifreeze Glycopeptide A
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Synthesis and Oxidative Folding of
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Convergent Syntheses of Huprp106-12
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Bactericidal Activity of Small Beta
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Bradykinin Analogues Acylated on Th
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Antimicrobial Activity of Small 3-(
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Interaction of Curcumin with A-Synu
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Fluorescent and Luminescent Fusion
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Cellular Expression of the Human An
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2D IR Spectroscopy of Oligopeptides
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large, non-redundant subset of prot
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The aberrantly glucosylated peptide
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Table 1. Proline cis/trans ratios o
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Table 1. Yields, UV-vis absorption
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Table 1. Purity of the targeted tri
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processes are blocked. Interestingl
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(tb4 n ,1 m )MTII(tb1 n ,4 m )MTIIF
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Fig. 2. a) Part of the 400 MHz HR-M
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Once printed, the amino acid partic
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A) PSA, few seconds73B) PSA, 45 min
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short β strands. In contrast, nume
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neg. control Cs9-Rhd MM-218Fig. 2.
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Table 1. The general structure of t
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% ID in the liver 1 h p.i.100908070
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Peptidyl phosphoranes were first re
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obtained from the same sardines and
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MccJ25 variants were produced by si
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Fig. 2. Proposed signaling mechanis
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Table 1. mCD4-HS12 antiviral activi
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Subject index(S)-2-(1-adamantyl)gly
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chip 18chiral triazine condensing r
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heat stress 348helical conformation
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O-acyl isopeptide method 112obesity
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SH2-ligands 210short collagen-relat
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Author indexAboye, Teshome Leta 142
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Chi, Hongfang 480Chiche, Laurent 6C
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Geronikaki, Athina 444Gessmann, Ren
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Kostova, Kalina 528Kotzia, Georgia
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Nagata, Koji 162Nagayev, Igor Yu. 5
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Salvarese, Nicola 518Sammet, Benedi
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Vauquelin, Georges 138Veiga, Ana Sa
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