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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, 2010En Route to Bicyclic Biaryl PeptidesSoledad Royo and Ernest GiraltInstitute for Research in Biomedicine, IRB Barcelona, Barcelona Science Park,Baldiri Reixac 10, Barcelona, 08028, SpainIntroductionNatural cyclic peptides containing an aryl-aryl bond are abundant, diverse and constitute aheterogeneous group, including compounds which show antimicrobial or cytotoxicactivities [1]. A common feature of all of them is the rigidity imposed by the presence ofthe biaryl bridge. The biaryl system also provides a site for aromatic-aromatic or -cationinteractions with the residues present on protein surfaces. This last structural feature has sofar not been exploited in the design of peptide ligands for protein surface recognition. Withthis in mind, the scope of our project is to prepare cyclic peptide ligands which are furtherconstrained by means of a biaryl bond. We envision this type of biaryl-containing bicyclicpeptides as constrained scaffolds, which can be customized according to the correspondingtarget. The peptide ring is obtained by head-to-tail cyclization, while the synthesis of thebiaryl bond is achieved through the Suzuki-Miyaura reaction [2]. A few examples haverecently shown the applicability of this reaction to peptide modification [3-7]. We havefocused our initial efforts on setting-up reaction conditions for the individual steps leadingto the bicyclic systems. A model pentapeptide sequence containing two aromatic aminoacids (Phe) and three aliphatic residues (Ala, D Pro) has been chosen for this purpose.Results and DiscussionThe precursor linear peptides have been assembled on resin using Fmoc/ t Bu chemistry. TheFmoc-protected borylated amino acid 1 was synthesized in solution, starting from thecommercially available Boc-(4I)Phe-OH in four steps with good yields (Scheme 1). Giventhe instability of the Fmoc group under the basic conditions in which borylation proceeds,the reaction was carried out on the Boc-protected precursor and the protecting group wasreplaced subsequently.Alternatively, on-resin borylation was achieved following a recently describedmethodology [7]. Due to the experimental conditions of this reaction, certain restrictionsapply to the choice of both the resin and the protecting groups which can be used, inparticular that of the -amino functionality. As already mentioned, the Fmoc group is ruledout due to its instability under basic conditions. The Boc group, though compatible with thereaction conditions, cannot be used in combination with acid-labile resins, which we wishto use for our peptide synthesis, due to simultaneous cleavage from the resin during Bocremoval. The p-nitrobenzyloxycarbonyl group (pNZ) was finally selected as the mostsuitable for on-resin borylation and subsequent peptide elongation. This protecting group isremoved in nearly neutral conditions by treatment with a 6M SnCl 2 , 1.6 mM HCl/dioxanesolution in DMF [8], which makes it compatible with some acid-labile resins, such asWang resin. Due to the tendency towards DKP formation shown by this sequence,tripeptide pNZ-Ala-(4I)Phe- D Pro-Wang 2 was assembled through incorporation of thesecond residue also bearing the pNZ protecting group. Its deprotection under slightly acidicBocHNCOOHBocHNCOOBnBocHNCOOBnB 2Pin 2, KOAcPd(dppf)Cl 2, DMF85ºC, 48h72%i) Cs 2CO 3, MeOH/H 2Oii) BnBr, DMF 60ºC 6h90%IFmocHN COOHIH 2 Pd/C EtOH o.n.FmocHNCOOBnOBOi) TFA / DCMii) FmocOSuNa 2CO 3dioxane/H 2O87%quantitative1OBOOBOScheme 1. Solution-phase synthesis of Fmoc-protected borylated amino acid 1.116