DOI: 10.1002/chem.200900615 COMU: A Safer and More Effective Replacement for Benzotriazole-Based Uronium Coupling Reagents** Ayman El-Faham,* [a, b, c] Ramon Subirós Funosas, [a, d] Rafel Prohens, [e] and Fernando Albericio* [a, d, f] Introduction Peptide synthesis is based on an appropriate combination of protecting groups and a suitable choice of coupling method. [1] Nowadays, almost all peptide bonds are formed in the presence of 1-hydroxybenzotriazole (HOBt, 1, Figure 1, left) [2] or its derivatives (HOAt, 2 ; 6-Cl-HOBt, 3). [3, 4] HOBt derivatives are therefore either used in combi- nation with a carbodiimide or another coupling agent or are built into a stand-alone reagent such as an immonium [HATU (4), HBTU (5), HCTU, (6), Figure 1, right] or phos- phonium (PyAOP, PyBOP, PyClock) salt. [5, 6] An onium salt consists of two parts: a leaving group (YL) and the iminium moiety (Figure 1, center). Recently we showed that the incorporation of a hydrogen bond acceptor in the iminium part resulted in performances superior to those described previously. [7] As reported in our previous work, the presence of an oxygen in the iminium Abstract: We describe a new family of uronium-type coupling reagents that differ in their iminium moieties and leaving groups. The presence of the morpholino group in conjunction with an oxime derivative—especially ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma)—had a marked influence on the solubilities, stabilities, and reactivi- ties of the reagents. Finally, the new uronium salt derived from Oxyma (COMU) performed extremely well in the presence of only 1 equiv of base, thereby confirming the effect of the hy- drogen bond acceptor in the reaction. COMU also showed a less hazardous safety profile than the benzotriazole- based HDMA and HDMB, which ex- hibited unpredictable autocatalytic de- compositions. Furthermore, the Oxyma moiety contained in COMU suggests a lower risk of explosion than in the case of the benzotriazole derivatives. Keywords: coupling reagents · Oxyma · peptides · solid-phase synthesis · uronium salts [a] Prof. A. El-Faham, R.S. Funosas, Prof. F. Albericio Institute for Research in Biomedicine, Barcelona Science Park Baldiri Reixac 10, 08028 Barcelona (Spain) Fax: (+ 34) 93-403-71-26 E-mail : aymanel_faham@hotmail.com albericio@irbbarcelona.org [b] Prof. A. El-Faham Department of Chemistry, College of Science King Saud University, P.O. Box 2455 Riyadh 11451 (Saudi Arabia) [c] Prof. A. El-Faham Department of Chemistry, Faculty of Science Alexandria University, Ibrahimia 21321, Alexandria (Egypt) [d] R. S. Funosas, Prof. F. Albericio CIBER-BBN, Networking Centre on Bioengineering Biomaterials and Nanomedicine, Barcelona Science Park Baldiri Reixac 10, 08028 Barcelona (Spain) [e] R. Prohens Plataforma de Polimorfisme i Calorimetria Serveis Cientificotcnics, University of Barcelona Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona (Spain) [f] Prof. F. Albericio Department of Organic Chemistry, University of Barcelona Martí i FranquØs 1–11, 08028 Barcelona (Spain) [**] All abbreviations used in the text are given in reference [1]. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200900615. Figure 1. General structures of HOBt derivatives (left), immonium/uroni- um salts (center), and the most commonly used immonium salts (right). Chem. Eur. J. 2009, 00,0–0  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! ÞÞ &1& FULL PAPER