A Synthesis of RGD Model Cyclic Peptide by Palladium-Catalyzed Carbonylative MacrolactamizationDoi, T.; Kamioka, S.; Shimazu, S.; Takahashi, T. Org. Lett. 2008, 10, ASAPAndrey SolovyevFebruary 11, 2008OHNNH2IPd(P(t-Bu)3)2CO (10 atm)4 Å MS, THF50oC, 12 hPeptidomimetics• Target protein-protein interactions: - Mimic a counterpart in protein-protein interactions;- Disrupt protein-protein interactions;• Both types of action are therapeutically interesting.Difference from “classical” peptides:• Contain unnatural amino acids (for example, D-amino acids, β-amino acids);• Conformationally constrained (cyclic);• Stable to proteolysis;•Penetrate through the cell membrane.•Penetrate through the cell membrane.OONOMeONHNHONHOLeualacin Analog.Possesses vasodilatory and antiplatelet activities.Hu, M.-K. et al. Bioorg. & Med. Chem. Lett. 1999, 22, 563-568.RGD Cyclic Peptidomimetics• RGD (Arg-Gly-Asp) sequence presents in many proteins of extracellular matrix.• This sequence is responsible for the binding with integrins – receptor proteins on the cell surface.• Specificity of binding and biological response depends on the RGD response depends on the RGD conformation.• RGD peptidomimetics can block integrins, prevent them from interactions with other cells and matrix, and thus inhibit tumor metastasis, angiogenesis, thrombosis, and inflammatory disorders.Shimaoka, M. and Springer, T. A. Nature Rev. Drug Discovery 2003, 2, 703-716.Synthesis of cyclic peptidomimeticsArg Gly AspHNHNOBrSCO2PolymerArg Gly AspNHHNOCO2HS1) HF2) NH4OH, pH = 7-8PMB• SN2 alkylation with S-nucleophilesBarker, P. L. et al. J. Med. Chem. 1992, 35, 2040-2048.•(3+2)-Cycloaddition•(3+2)-CycloadditionBurgess, K. et al. J. Org. Chem. 2005, 70, 9595-9598.N3COHNCOHNCOHNR1R2COHNCOHNCOHNR1R2CuI, DIPEATHF, rt (8-14%)NNNSynthesis of cyclic peptidomimeticsHNNHBocHNOOOBnHNNHBocHNOOOBn(Cy3P)2Cl2Ru=CHPhCH2Cl2(88%)• Alkene metathesisRipka, A. S. et al. Bioorg. & Med. Chem. Lett. 1998, 357-360.Iqbal, J. et al. Tetr. Lett. 2005, 46, 5207-5210.• Radical CyclizationBrHN OR2HNOR1HNOHN OR2HNOR1HNOBu3SnH, AIBNPhH, reflux (47-59%)Synthesis of cyclic peptidomimeticsLiskamp, R. M. J. et al. J. Org. Chem. 2006, 71, 1817-1824.• Sonogashira Coupling and MacrolactamizationNHNHBocONHCbztBuO OONHHNIONHNHOOONHBocOONHR10% Pd(PPh3)4,10% CuI(14%)1) TFA/CH2Cl22) HATU/HOAt,DIPEADMF (54%)Et2NH, THFIqbal, J. et al. Tetr. Lett. 2006, 47, 3569-3571.HNNHOR1O R2HN(CH2)nOR3O NHHNNHOR1O R2HN(CH2)nOR3O NHPd(OAc)2(o-tolyl)3PAcOH-MeCN, 110oC(33-54%)• Ene-yne CycloisomerizationPalladium-Catalyzed Carbonylative MacrolactamizationDoi, T.; Kamioka, S.; Shimazu, S.; Takahashi, T. Org. Lett. 2008, 10, ASAPOHNNH2IPd(P(t-Bu)3)2CO (10 atm)4 Å MS, THF50oC, 12 hSynthesis of the PrecursorIHNRFmocHN CO2HCO2t-Bu, PyBropDIEA, CH2Cl2, DMF, rt, 3 h1)2) Et2NH, CH3CN, rt, 2 hHClINROH2NCO2t-BuR = H (86%); R = Bn (81%)FmocHN CO2H, PyBropDIEA, CH2Cl2, DMF, rt, 5 h1)2) Et2NH, CH3CN, rt, 2 hR = H (81%); R = Bn (88%)NRNHCO2t-BuOFmocHN CO2H(H2C)3NBoc, PyBropDIEA,CH2Cl2,DMF,rt,5h1)NHBocHNNRONHCO2t-BuONHOBocPyBrOPPBrN3PF6IOHNH2DIEA,CH2Cl2,DMF,rt,5h2) Et2NH, CH3CN, rt, 2 hR = H (82%); R = Bn (83%)INH2(CH2)3(CH2)3FmocHNPyBrop, DIEA, CH2Cl2, DMF, rt, 5 h1)2) Et2NH, CH3CN, rt, 2 hR = H (87%); R = Bn (71%)CO2HBocNBocHNNHINRONHCO2t-BuONHONH(CH2)3BocNBocHNNH(CH2)3NH2OCarbonylative MacrolactamizationINRONHCO2t-BuONHONH(CH2)3BocNBocHNNH(CH2)3NH2OPd(P(t-Bu)3)2(10 mol %),CO (10 atm)4 Å MS, THF50oC, 12 hCOt-BuCOt-BuNRONHCO2t-BuONHONH(CH2)3BocNBocHNNH(CH2)3NHOONRONHCO2t-BuONHONH(CH2)3BocNBocHNNH(CH2)4NHO+OO(79%)(9%)I IIR=HR=Bn (83%) (0%)R=HR=BnAmide αααα−−−−KetoamideOptimization of Conditionsentry Pd catalyst additivesCO (atm)solventtemp (ºC)yield (%) of I (II)1 Pd(P(t-Bu)3)2NEt3-DMAP 10 DMF 50 412 [PdCl2P(OH)(t-Bu)2]2NEt3-DMAP 10 DMF 50 123 Pd(PPh3)4NEt3-DMAP 10 DMF 50 94 Pd(P(t-Bu)3)24 Å MS10 DMF 50 64 (7)5Pd(P(t-Bu)3)24Å MS5DMF5043 (trace)5Pd(P(t-Bu)3)24Å MS5DMF5043 (trace)6 Pd(P(t-Bu)3)24 Å MS20 DMF 50 61 (9)7 Pd(P(t-Bu)3)24 Å MS30 DMF 50 63 (7)8 Pd(P(t-Bu)3)24 Å MS10 THF 50 79 (9)9 Pd(P(t-Bu)3)24 Å MS10 dioxane 50 trace10 Pd(P(t-Bu)3)24 Å MS10 DMPU 50 4111 Pd(P(t-Bu)3)24 Å MS10 THF 40 4912 Pd(P(t-Bu)3)24 Å MS10 THF 65 21Catalytic CyclePdL2ArIArPdIL2COArPd(CONHR)L2ArCONHR?BHIBH IArCOPd(CONHR)L2ArCOCONHRPdAr ILL[ArPd(CO)L2]I?ArCOPdIL2RNH2+ B:RNH2PdL2IRH2NArOB:ArCONHRBH IPdL2COPdArCO ILLCO?[ArCOPd(CO)L2]IPdILLOOArRNH2+ B:?Yamamoto, Y. et al. Pure & Appl. Chem. 1991, 63, 687-696.Summary• Palladium-catalyzed carbonylative macrolactamization was employed for the synthesis of RGD cyclic peptidomimetics.• The reaction conditions were
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