Straightforward synthesis of cyclic and bicyclic peptides Xavier Elduque, Enrique Pedroso and Anna Grandas* Departament de Química Orgànica and IBUB, Facultat de Química, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain anna.grandas@ub.edu Received Date (will be automatically inserted after manuscript is accepted) ABSTRACT Cyclic peptide architectures can be easily synthesized from cysteine-containing peptides with appending maleimides, free or protected, through an intramolecular Michael-type reaction. After peptide assembly, the peptide can cyclize either during the trifluoroacetic acid treatment, if the maleimide is not protected, or upon deprotection of the maleimide. The combination of free and protected maleimide moieties and two orthogonally protected cysteines gives access to structurally different bicyclic peptides with isolated or fused cycles. Cyclization has been long recognized to provide peptides with increased stability to enzymatic degradation and better cell permeability (see 1 for recent reviews). Cyclization imposes structural constraints and allows for structural preorganization of functional groups, but the degree of flexibility still permitted is expected to enhance and facilitate interaction with the receptor target. In addition to their potential role as enzyme inhibitors, cyclic peptides are considered useful tools to interrogate complex structures, and show promise to interfere with protein-protein interactions. 1 Cyclic peptides can also mimic protein loops. In this respect, appending conformationally constrained peptides from a scaffold can simulate the distribution of protein loops in space, 2 and this is of interest for immunological studies. In a different context, a Zinc-finger-type phosphorylated peptide with a cycle formed by metal chelation was able to distinguish between DNAs incorporating one of the two cytosines 1 (1) (a) Marsault, E.; Peterson, M. L. J. Med. Chem. 2011, 54, 1961- 2004. (b) Madsen, C. M.; Clausen, M. H. Eur. J. Org. Chem. 2011, 3107-3115. (c) White, C. J.; Yudin, A. K. Nat. Chem. 2011, 3, 509-524. 2 (2) (a) Timmerman, P.; Beld, J.; Puijk, W. C.; Meloren, R. H. ChemBioChem 2005, 6, 821-824. (b) Heinis, C.; Rutherford, T.; Freund, S.; Winter, G. Nat. Chem. Biol. 2009, 5, 502-507. (c) Ghosh, P. S.; Hamilton, A. D. J. Am. Chem. Soc. 2012, 134, 13208-13211. involved in epigenetic regulation, namely 5- hydroxymethylcytosine and 5-methylcytosine. 3 Peptide macrocycles can be obtained by bridging the two ends of the peptide chain (head-to-tail), internal positions, or both. Chemical synthesis has provided the most frequently occurring natural bridges (disulfides, macrolactames, macrolactones), 1,4 as well as rings with biaryls and diaryl ethers. 5 Moreover, ring-closing metathesis, the Cu(I)-catalyzed azide-alkyne cycloaddition, 1,4 the reaction between a nucleophile and an activated pyridine-N-oxide 6 and sulfur-mediated reactions 7 have also afforded peptide cycles. When the latter involve a thiol and an alkene, thioether formation may take place either through radical 8 or Michael-type 3 (3) Nomura, A.; Sugizaki, K.; Yanagisawa, H.; Okamoto, A. Chem. Commun. 2011, 47, 8277-8279. 4 (4) (a) Jiang, S.; Li, Z.; Ding, K.; Roller, P. P. Curr. Org. Chem. 2008, 12, 1502-1542. (b) Driggers, E. M.; Hale, S. P.; Lee, J.; Terret, N. K. Nat. Rev. Drug Discov. 2008, 7, 608-624. 5 (5) (a) Pitsinos, E. N.; Vidali, V. P.; Coladouros, E. A. Eur. J. Org. Chem. 2011, 1207-1222. (b) Meyer, F.-M.; Collins, J. C.; Borin, B.; Bradow, J.; Liras, S.; Limberakis, C.; Mathiowtz, A. M.; Philippe, L.; Price, D.; Song, K.; James, K. J. Org. Chem. 2012, 77, 3099-3114. 6 (6) Londregan, A. T.; Farley, K. A.; Limberakis, C.; Mullins, P. B.; Piotrowski, D. W. Org. Lett. 2012, 14, 2890-2893. 7 (7) Hoyle, C. E.; Lowe, A. B.; Bowman, C. N. Chem. Soc. Rev. 2010, 39, 1355-1387. 8 (8) Aimetti, A. A.; Shoemaker, R. K.; Lin, C.-C.; Anseth, K. S. Chem. Commun. 2010, 46, 4061-4063. N N PEPTIDE O O O O O H H S-Prot S-Prot' PEPTIDE PEPTIDE