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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010The Oxime-Based Family of Coupling ReagentsRamon Subirós-Funosas 1,2 , Ayman El-Faham 1,3 , andFernando Albericio 1,2,41 Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10,Barcelona, 08028, Spain; 2 CIBER-BBN, Networking Centre on Bioengineering,Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, Barcelona,08028, Spain; 3 Department of Chemistry, Faculty of Science, Alexandria University,Ibrahimia, 21321, Egypt; 4 Department of Organic Chemistry, University of Barcelona,Martí i Franquès 1-11, Barcelona, 08028, SpainIntroductionHOBt and other parent benzotriazoles show explosive properties, a feature that isincreasingly limiting their commercial availability. Consequently, alternative scaffolds arerequired for safe and efficient amide bond formation. A few decades ago, several stable andacidic ketoximes were proposed as additives, although with little success because of thelack of relevant data [1,2]. Recently, exhaustive studies on ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma, 1), and the derived uronium salt, bearing a dimethylmorpholinocarbocation skeleton (COMU, 2), have proved that oximes are indeed a reliable choice ascoupling reagents (Figure 1) [3,4]. Thus, here we further studied the potential of oximebasedcompounds by testing new reactive phosphonium and uronium salts, along withnovel Fmoc- and Alloc-oxime carbonates.Results and DiscussionTwo tris(pyrrolidino)phosphonium salts of Oxyma were easily obtained in 75-80% yield ina one-pot fashion by reaction of its potassium salt with a bromotris(pyrrolidino)phosphonium salt, obtaining either the hexafluorophosphate (PyOxP, 3) ortetrafluoroborate (PyOxB, 4) versions (Figure 2, left)[5]. The higher stability of PyOxP (commerciallyknown as PyOxyme) than PyOxB confers the reagentgreater suitability in the assembly of peptide fragmentsor cyclizations. PyOxyme also combined impressivesolubility with high stability, compared with knownbenzotriazole-based PyAOP, PyBOP and PyClock. Inaddition, PyOxyme induced outstanding control ofoptical purity and shows high efficiency in theFig. 1. Structure of Oxyma andCOMU.assembly of sterically demanding linear sequences.Last but not least, PyOxyme afforded the highestpercentage of target peptide during cyclization studies,exceeding the performance of PyAOP (Table 1).Fig. 2. Structure of oxime-based coupling and alkyloxycarbonyl-introducing reagents.176