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Table 1.Cyclization of H-Ala-Ala-MeAla-Ala-Ala-OHCoupling Reagent Cyclic penta (%) Linear penta (%) Linear dimer (%)PyAOP 54 10 36PyBOP 43 28 29PyClock 61 15 24PyOxyme 70 10 20PyOxB 47 15 38Other oxime scaffolds have been evaluated, like that derived from Meldrum’s acid(HONM, 5, Figure 2 center). This additive can be readily prepared in nearly 70% yield bynitrosation followed by acidification [6]. The corresponding uronium salts, bearing variouscarbocation skeletons, are obtained directly in 3 steps from dimethylcarbamoyl chlorideand a secondary amine, in high yield and purities. Unfortunately, the high reactivity ofHONM (5) causes the appearance of side reactions, thereby compromising its applicationas peptide additive. However, the parent uronium salts have proved to be useful reagentsfor the acylation of poor nucleophiles, such as anilines, probably as a result of the presenceof a neighboring group effect. In agreement with previous studies, the dimethylmorpholinoderivativeHMMU (6, Figure 2 center) performed better than the tetramethyl anddimethylpyrrolidino counterparts and thus represent a reliable alternative for peptide bondformation by ensuring low racemizations and high coupling extentions.With the aim of improving traditional strategies for the introduction of Fmoc andAlloc urethane-type protecting groups, we have synthesized several oxime carbonates fromthe corresponding chloroformates in >80% yield and high purities [7]. These carbonates,formed by the inclusion of oximes with electron-withdrawing substituents, such as dicyano,diethylcarboxylate or cyano ethyl carboxylate (Oxyma), were tested in the N- protectionof H-Gly-OH, the most prone amino acid to dipeptide formation, conducted in the presenceof sodium carbonate at pH=8 in a few hours. The N-Hydroxypicolinimidoyl cyanidederivatives (7 and 8, Figure 2 right) were found to efficiently protect the N-terminus(>99.5% purity) and simultaneously prevent the increase of side-products, such asdipeptides (0.01% for Fmoc-Gly-OH, 0.02% for Alloc-Gly-OH), as confirmed bycoinjection with pure samples.AcknowledgmentsThis work was partially supported by Centro de Investigación Científica y Tecnológica (CICYT)(CTQ2009-07758), the Generalitat de Catalunya (2009SGR 1024), Luxembourg Bio Technologies,Ltd. (Rehovot), the Institute for Research in Biomedicine and the Barcelona Science Park. RS-F thanksthe Ministerio de Educación y Ciencia for a FPU PhD fellowship. Suzhou Highfine Biotech Co., Ltd.is thanked for a sample of the Fmoc-oxime.References1. Itoh, M. Bull. Chem. Soc. Japan 46, 2219-2221 (1973).2. Izdebski, J. Pol. J. Chem. 53, 1049-1057 (1979).3. Subirós-Funosas, R., Prohens, R., Barbas, R., El-Faham, A., Albericio, F. Chem. Eur. J. 15, 9394-9403 (2009).4. El-Faham, A., Subiros-Funosas, R., Prohens, R., Albericio, F. Chem. Eur. J. 15, 9404-9416 (2009).5. Subiros-Funosas, R., El-Faham, A., Albericio, F. Org. Biomol. Chem. 8, 3665-3673 (2010).6. El-Faham, A., Subiros-Funosas, R., Albericio, F. Eur. J. Org. Chem. 3641-3649 (2010).7. Khattab, S.N., Subiros-Funosas, R., El-Faham, A., Albericio, F. Eur. J. Org. Chem. 3275-3280(2010).177