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AcknowledgmentsThis work was partially supported by CICYT (CTQ2009-07758 and CTQ2008-02856/BQU), theGeneralitat de Catalunya (2009SGR 1024, 2009SGR-1472) and the IRB. We thank the BarcelonaScience Park (Mass Spectrometry Core Facility, Nuclear Magnetic Resonance Laboratory) and theUniversitat de Barcelona (Xavier Alcobé, Mercè Font, Unitat de Difracció de Raigs X ServeisCientificotècnics) for the facilities.References1. Comprehensive reviews of applications in organic synthesis: (a) Coppola, G. M., Schuster, H.F.Chiral α-Hydroxy Acids in Enantioselective Synthesis, Wiley-VCH, Weinheim, 1997; (b)Gawronski, J., Gawronska, K. Tartaric and Malic Acids in Synthesis: A Source Book of BuildingBlocks, Ligands, Auxiliaries, and Resolving Agents, John Wiley, New York, 1999.2. (a) Nagashima, N., Ohno, M. Chem. Lett. 141-144 (1987); (b) Nagashima, N., Ohno, M. Chem.Pharm. Bull. 39, 1972-1982 (1991).3. Spengler, J., Fernandez-Llamazares, A.I., Ruiz-Rodriguez, J., Burger, K., Albericio, F. J. Org.Chem. 75, 5746-5749 (2010).131
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010DTT Reacts with TFA to Form a Novel Bicyclic DithioorthoesterJan Pawlas 1 , Stefan Hansen 1 , Anne H. Sørensen 1 , Gunnar Stærkær 1 ,Anette Møller 1 , Neil Thompson 1 , Thomas Pagano 2 , Fangming Kong 2 ,Steve Koza 2 , Mark Pozzo 3 , Jari Finneman 3 , and Patricia Droege 31 PolyPeptide Laboratories A/S, Herredsvejen 2, 3400, Hillerød, Denmark; 2 Pfizer GlobalBiologics, One Burtt Rd., Andover, MA, 01810, U.S.A.; 3 Pfizer Global Biologics, 700Chesterfield Parkway West, St Louis, MO, 63017, U.S.A.IntroductionDithiothreitol (DTT, Cleland’s reagent [1]) is a cheap, non-odorous reducing agent [2],which is produced by a safe and environmentally friendly process [3]. In fact, DTT wasrecently used as a scavenger during large scale preparation of the HIV fusion inhibitorFuzeon [4]. We now report that DTT reacts with trifluoroacetic acid (TFA) to form abicyclic dithioorthoester which can be difficult to detect by HPLC.Results and DiscussionDuring a large scale production of a 37-mer peptide, we found that solutions of the peptidecontained small amounts of an impurity, which were not easily detected by HPLC. At lowpeptide concentrations during purification, this impurity was virtually undetectable byHPLC. However, this material could be detected by 1 H NMR in highly concentratedsamples of the peptide obtained after lyophilisation. Furthermore, we found that performingHPLC analyses with theUV detector set at 210nm, this compound couldbe detected much easierthan for example at 220nm (see Figure 1). We setout to identify this compoundand after someexperimentation we wereable to isolate a smallquantity of this materialFig. 1. Overlay of chromatograms of a 37-mer peptide (ca20 g/l) containing 1.from its mixture with thepeptide. The bicyclicdithioorthoester 1 is fullyconsistent with the NMRand MS data for the isolated material, and we propose that this compound is formed via thedithianylium salt 2 (Figure 2). In fact, it is known that dithiols react with trifluoroaceticanhydride in the presence of strong acids to give dithianylium salts, which can be convertedto -trifluoromethyl substituted dithioorthoesters upon treatment with alcoholates [5].The peptide in which we detected dithioorthoester 1 was prepared by a standard FmocSPPS-cleavage-RP HPLC-lyophilisation process. Thus, the peptide resin was exposed to aDTT containing TFA cocktail and it is therefore conceivable that 1 was formed during thecleavage step of the process. In order to establish the precise conditions required for theformation of 1, we allowed DTT to react with TFA in the presence of various additivescommon in cleavage cocktails. In all these experiments, DTT was fully consumed uponstanding in TFA, and regardless of the presence of other reactants, 1 was formed as a majorcomponent of the reaction mixture. In fact, simply mixing DTT with TFA in the presence oftriisopropylsilane (TIS) afforded 1 essentially quantitatively [6]. Finally, it is worth noting thatDTT was completely stable when TFA (pK a 0.30) was replaced by acetic acid (pK a 4.76).Fig. 2. Proposed mechanism of formation of 1 via dithianylium salt 2.132
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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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Proceedings of the 31 st European P
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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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