A Novel Strategy of Ugi-4CR/Huisgen 1,3-Dipolar Synthesis of 1H-1,2,3-Triazole-Modified Peptidoimetics

Document Type : Research Article


Faculty of Chemistry, Shahid Beheshti University, P.O Box 19396-4716, Tehran, I.R. IRAN


In this protocol, we report a novel approach for the synthesis of a new class of heterocyclic 1H-1,2,3-triazole-modified peptidomimetic compounds. The process consists of an Ugi four-component condensation reaction of amines, an isocyanide, an aldehyde and acids followed by a Huisgen 1,3-dipolar cycloaddition reaction with an azide group in the presence of a catalytic amount of CuSO4.5H2O/sodium ascorbate. The copper-catalyzed Huisgen cycloaddition reactions provide such a general synthetic method, with the resulting 1,2,3-triazoles being good peptide bond mimics. This protocol was highly efficient for structurally diverse heterocyclic molecules containing an active aldehyde group and will find applications in combinatorial chemistry, diversity-oriented synthesis, and drug discovery.


Main Subjects

[1] (a) Banfi L., Riva R., The Passerini Reaction, Org. React., 65: 1-140 (2005).
[2] (a) Zhu J., Recent Developments in the Isonitrile-Based Multicomponent Synthesis of Heterocycles, Eur. J. Org. Chem., 7: 1133–1144 (2003);
      (b) Salvador C. E. M., Pieber B., Neu P. M., Torvisco A., Andrade C. K. Z., Kappe C. O., A Sequential
Ugi Multicomponent/Cu-Catalyzed Azide-Alkyne Cycloaddition Approach for the Continuous Flow Generation of Cyclic Peptoids
, J. Org. Chem., 80(9): 4590–4602 (2015).
[3] Ugi I., Werner B., Domling A., The Chemistry of Isocyanides, Their MultiComponent Reactions and Their Libraries, Molecules, 8: 53-66 (2003).
[4] Hulme C., Gore V., Multi-Component Reactions: Emerging Chemistry in Drug Discovery from Xylocain to Crixivan, Curr. Med. Chem., 10: 51-80 (2003).
[5] Nixey T., Kelly M., Hulme C., The One-Pot Solution Phase Preparation of Fused Tetrazole-Ketopiperazines, Tetrahedron Lett., 41: 8729-8733 (2000).
[6] Nixey T., Kelly M., Semin D., Hulme C., Short Solution Phase Preparation of Fused Azepine-tetrazoles via a UDC (Ugi/de-Boc/Cyclize) Strategy, Tetrahedron Lett., 43: 3681-3684 (2002).
[7] Gunawan S., Ayaz M., De Moliner F., Frett B., Kaiser C., Patrick N., Xu Z., Hulme C., Synthesis of Tetrazolo-Fused Benzodiazepines and Benzodiazepinones by a Two-Step Protocol Using an Ugi-Azide Reaction for Initial Diversity Generation, Tetrahedron, 68: 5606-5611 (2012).
[8] Gunawan S., Nichol G., Hulme C., Concise Route to A Series of Novel 3-(Tetrazol-5-yl)quinoxalin-2(1H)-ones, Tetrahedron Lett., 53: 1664-1667 (2012).
[9] Niu T.-f., Gu L., Yi W.-b., Cai C., Copper-Free Route to Triazole-Modified Peptidomimetic by the Combination of Two Multicomponent Reactions in One Pot, ACS Comb. Sci., 14: 309–315 (2012).
[10] Horne W.S., Yadav M.K., Stout C.D., Ghadiri M.R., Heterocyclic Peptide Backbone Modifications in an Alpha-Helical Coiled Coil, J. Am. Chem. Soc., 126: 15366-15367 (2004).
[11] Bock V.D., Hiemstra H., Maarseveen J.H., Cu1-Catalyzed Alkyne-Azide “Click” Cycloadditions from a Mechanistic and Synthetic Perspective, Eur. J. Org. Chem., 1: 51-68 (2005).
[12] Angell Y.L., Burgess K., Peptidomimetics via Copper-Catalyzed Azide-Alkyne Cycloadditions, Chem. Soc. Rev., 36: 1674-1689 (2007).
[13] Pedersen D.S., Abell A., 1,2,3-Triazoles in Peptidomimetic Chemistry, Eur. J. Org. Chem., 13: 2399-2411 (2011).
[14] Brik A., Muldoon J., Lin Y.C., Elder J.H., Goodsell D.S., Olson A.J., Fokin V.V., Sharpless K.B., Wong C.H., Rapid Diversity-Oriented Synthesis in Microtiter Plates for in Situ Screening of HIV Protease Inhibitors, Chem. Bio. Chem.,4: 1246-1248 (2003).
[15] Soltis M.J., Yeh H.J., Cole K.A., Whittaker N., Wersto R.P., Kohn E.C., Identification and Characterization of Human Metabolites of CAI [5-Amino-1-1(4'-chlorobenzoyl-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide, Drug. Metab. Dispos.,24: 799-806 (1996).
[16] Alvarez R., Velazquez S., San-Felix A., Aquaro S., De Clercq E., Perno C.F.N., Karlsson A., Balzarini J., Camarasa M.J., 1,2,3-Triazole-[2,5-Bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole 2'',2''-dioxide) (TSAO) Analogs: Synthesis and Anti-HIV-1 Activity,
J. Med. Chem., 37: 4185-4194 (1994).
[17] Beraa S., Zhanel G.G., Schweizera F., Evaluation of Amphiphilic Aminoglycoside-Peptide Triazole ConjuGates as Antibacterial Agents, Bio. Med. Chem. Lett., 20: 3031-3035 (2010).
[18] Bock V.D., Speijer D., Hiemstra H., Maarseveen J.H., 1,2,3-Triazoles as Peptide Bond Isosteres: Synthesis and Biological Evaluation of Cyclotetrapeptide Mimics, Org. Biomol. Chem.,5: 971-975 (2007).
[19] Nenajdenko V.G., Gulevich A.V., Sokolova N.V., Mironov A.V., Balenkova E.S., Chiral Isocyanoazides: Efficient Bifunctional Reagents for BioconjugationEur. J. Org. Chem., 8: 1445–1449 (2010).
[20] Sokolova N.V., Latyshev G.V., Lukashev N.V., Nenajdenko V.G., Design and Synthesis of Bile Acid-Peptide Conjugates Linked via Triazole Moiety, Org. Biomol. Chem.,9: 4921-4926 (2011).
[21] Zhu J., Bienaymé H., (Eds.) “Multicomponent Reactions”, Wiley-VCH: Weinheim, 33–75 (2005).
[23] Rouhi A.M., Traditional Methods Thrive Because Numerous Hurdles, Including Tough Luck, Slow Down the Commercialization of Catalytic Processes, Chem. Eng. News, 82: 47-62 (2004).
[24] Kolb H.C., Finn M.G., Sharpless K.B., Click Chemistry: Diverse Chemical Function from a Few Good Reactions, Angew. Chem. Int., 40: 2004-2021 (2001).
[26] Shaabani A., Maleki A., Mofakham H., Moghimi-Rad J., A Novel One-Pot Pseudo-Five-Component Synthesis of 4,5,6,7-Tetrahydro-1H-1,4-diazepine-5-carboxamide Derivatives, J. Org. Chem., 73: 3925-3927 (2008).
[27] Shaabani A., Maleki A., Mofakham H., Khavasi H.R., Novel Isocyanide-Based Three-Component Synthesis of 3,4-Dihydroquinoxalin-2-amine Derivatives, J. Comb. Chem., 10: 323-326 (2008).
[28] Shaabani A., Maleki A., Mofakham H., Novel Multicomponent One-Pot Synthesis of Tetrahydro-1H-1,5-benzodiazepine-2-carboxamide Derivatives, J. Comb. Chem., 10: 595-598 (2008).
[29] Shaabani A., Maleki A., Mofakham H., Khavasi H.R., Novel Isocyanide-Based Three-Component One-Pot Synthesis of Cyanophenylamino-acetamide Derivatives, J. Comb. Chem., 10: 883-885 (2008).
[30] Shaabani A., Maleki A., Mofakham H., A Novel Synthesis of Highly Substituted Imidazo[1,5-a]pyrazine Derivatives by 3-CR/2-CR Sequence, Mol. Divers., 13: 63-67 (2009).
[31] Shaabani A., Mofakham H., Maleki A., Hajishaabanha F., Novel Isocyanide-Based One-Pot Multicomponent Syntheses of Tetrahydrobenzo[b][1,4]oxazepine and Malonamide Derivatives, J. Comb. Chem., 12: 630-632 (2010).
[32] Shaabani A., Maleki A., Hajishaabanha F., Mofakham H., Seyyedhamzeh M., Mahyari M., Novel Syntheses of Tetrahydrobenzodiazepines and Dihydropyrazines via Isocyanide-Based Multicomponent Reactions of Diamines, J. Comb. Chem., 12: 186-190 (2010).
[35] (a) Hajishaabanha F., Shaabani S., Shaabani A., Synthesis of Furan-Fused Quinoxaline Tetracyclic Scaffolds via A Three-Component Isocyanide-Based Reaction, Res. Chem. Intermed., 42: 4109-4120 (2016).
        (b) Shaabani A., Ghadari R., Rezayan A. H., Synthesis of Functionalized Coumarins, Iranian Journal of Chemistry and Chemical Engineering (IJCCE), 30: 19-22 (2011);
        (c) Shaabani A., Farhangi E., Shaabani S., A Rapid Combinatorial Library Synthesis of Benzazolo[2,1-b]quinazolinones and Triazolo[2,1-b]quinazolinones, Iranian Journal of Chemistry and Chemical Engineering (IJCCE), 32: 3-10 (2013).
[36] Banaszynski L.A., Liu C.W., Wandless T.J., Characterization of the FKBP Rapamycin FRB Ternary Complex, J. Am. Chem. Soc., 127: 4715-4721 (2005).
[37] (a) Rostovtsev V.V., Green L.G., Fokin V.V., Sharpless K. B., A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes, Angew. Chem. Int. Ed., 41: 2596-2599 (2002);
        (b) Himo F., Lovell T., Hilgraf R., Rostovtsev V. V., Noodleman L., Sharpless K. B., Fokin V. V., Copper(I)-Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates, J. Am. Chem. Soc., 127: 210-216 (2005).
         (c) Amblard F., Cho J. H., Schinazi R. F., Cu(I)-Catalyzed Huisgen Azide-Alkyne 1,3-Dipolar Cycloaddition Reaction in Nucleoside, Nucleotide, and Oligonucleotide Chemistry, Chem. Rev., 109: 4207–4220 (2009).