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conditions and the subsequent coupling of the third amino acid with in situ neutralization(using PyBOP and DIEA) prevented this side reaction. Borylation of iodo peptide 2proceeded satisfactorily under the described conditions [7]. Acidic cleavage of a sample ofresin yielded boronopeptide 3 (Scheme 2).Peptide elongation through stepwise couplingafforded Boc-Ala-(4I)Phe-Ala-(4Bpin)Phe- D Pro-Wang(4). Additionally, Boc-Ala-(4Bpin)Phe-Ala-(4I)Phe-D Pro-Wang (5) was synthesized by incorporation of thepreformed borylated amino acid 1. Both pentapeptidesshould yield the same biaryl bicyclic peptide whensubjected to intramolecular head-to-tail cyclization andSuzuki-Miyaura reaction (Scheme 2). Resins 4 and 5were initially treated with K 3 PO 4 and Pd(PPh 3 ) 4 inDMF at 60 ºC during 48h, leading to the linear biarylFig. 1. Biaryl bicyclic peptide 6.pentapeptide. Due to its low solubility in DMF, K 3 PO 4was replaced by Cs 2 CO 3 . The reaction could be scaledup successfully (until at least 400 mg resin). The linear biaryl pentapeptide was isolatedafter acidic cleavage and purification by RP-HPLC. Finally, head-to-tail cyclization wasachieved by reaction with DPPA and NaHCO 3 in DMF for 24 h. A last purification step byRP-HPLC gave the desired biaryl bicyclic peptide 6 (Figure 1).pNZHNONHONIOi) B 2Pin 2 (4 eq), KOAc (6 eq),Pd(dppf)Cl 2 (0.18 eq), dppf (0.09 eq)DMSO, 24h @ 80ºii) sample cleavage: TFA/H 2O, 9:1pNZHNONHONOHB OHOOH2 3Boc-Ala-(4I)Phe-Ala-(4Bpin)Phe- D Pro4orBoc-Ala-(4Bpin)Phe-Ala-(4I)Phe- D Pro5i) Cs 2CO 3 (3 eq, 2M aq. solution)Pd(PPh 3) 4 (0.1 eq) in DMF @ 60ºC 48hii) TFA/TIS/H 2O, 95:2.5:2.5iii) DPPA (2 eq), NaHCO3 (8 eq) in DMF(c = 0.005M) rt 24hc-(-Ala-(4&)Phe-Ala-(4&)Phe- D Pro-)6Scheme 2. On-resin borylation of 2 (above); on-resin Suzuki-Miyaura and head-to-tailcyclization in solution leading to bicyclic peptide 6 (below).AcknowledgmentsThis research is financially supported by the Spanish Ministry of Science and Innovation(Bio2008-00799) and by the European Commission through a Marie Curie European reintegrationgrant (ERG-2009-248668) to S. R.References1. Feliú, L., Planas, M. Int. J. Pept. Res. Ther. 11, 53-97 (2005).2. Miyaura, N., Suzuki, A.J. Chem. Rev. 95, 2457-2483 (1995).3. Haug, B.E., Stensen, W., Svendsen, J.S. Bioorg. Med. Chem. Lett. 17, 2361-2364 (2007).4. Vilaró, M., Arsequell, G., Valencia, G., Ballesteros, A., Barluenga, J. Org. Lett. 10, 3243-3245(2008).5. Cerezo, V., Amblard, M., Martinez, J., Verdie, P., Planas, M., Feliú, L. Tetrahedron Lett. 64, 10538-10545 (2008).6. Doan, N.D., Bourgault, S., Letourneau, M., Fournier, A. J. Comb. Chem. 10, 44-51 (2008).7. Afonso, A., Rosés, C., Planas, M., Feliú, L. Eur. J. Org. Chem. 2010, 1461-1468 (2010).8. Isidro-Llobet, A., Guasch-Camell, J., Álvarez, M., Albericio, F. Eur. J. Org. Chem. 2005, 3031-3039 (2005).117