Cyclic Peptidomimetics and Pseudopeptides from Multicomponent Reactions

  • Ludger A. WessjohannEmail author
  • Cristiano R. B. Rhoden
  • Daniel G. Rivera
  • Otilie Eichler Vercillo
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 23)


Multicomponent reactions (MCRs) that provide in the final product amides are suitable to produce peptides and peptide-like moieties. The Passerini and Staudinger reactions provide one amide bond, and the Ugi-four-component reaction generates two amides from three or even four (or more) components, respectively. The Ugi-reaction thus is most important to produce peptides and peptoids while the Passerini reaction is useful to generate depsipeptoid moieties. In order to produce cyclic peptides and pseudopeptides, the linear peptidic MCR products have to be cyclized, usually with the help of bifunctional or activatable building blocks. Orthogonal but cyclizable secondary functionalities that need no protection in isonitrile MCRs commonly include alkenes (for ring closing metathesis), azide/alkyne (for Huisgen click reactions) or dienes and enoates (Diels-Alder) etc. If MCR-reactive groups are to be used also for the cyclisation, monoprotected bifunctional building blocks are used and deprotected after the MCR, e.g. for Ugi reactions as Ugi-Deprotection-Cyclisation (UDC). Alternatively one of the former building blocks or functional groups generated by the MCR can be activated. Most commonly these are activated amides (from so-called convertible isonitriles) which can be used e.g. for Ugi-Activation-Cyclisation (UAC) protocols, or most recently for a simultaneous use of both strategies Ugi-Deprotection/Activation-Cyclisation (UDAC). These methods mostly lead to small, medicinally relevant peptide turn mimics. In an opposing strategy, the MCR is rather used as ring-closing reaction, thereby introducing a (di-)peptide moiety. Most recently these processes have been combined to use MCRs for both, linear precursor synthesis and cyclisation. These multiple MCR approaches allow the most efficient and versatile one pot synthesis of macrocyclic pseudopeptides known to date.


Cyclopeptides Depsipeptides Peptoids Macrocycles Diketopiperazines Benzodiazepines Ugi-reaction Polycyclic compounds Orthogonal reactivity Sequential reactions Iteration Bifunctional building blocks Medium sized rings Beta-turn motif 


  1. 1.
    Davies JS (2003) J Pept Sci 9:471–501CrossRefGoogle Scholar
  2. 2.
    Wessjohann LA, Ruijter E, Rivera DG, Brandt W (2005) Mol Divers 9:171–186CrossRefGoogle Scholar
  3. 3.
    Lambert JN, Mitchell JP, Roberts KD (2001) J Chem Soc Perkin Trans 1 471–484CrossRefGoogle Scholar
  4. 4.
    Gulevich AV, Shpilevaya IV, Nenajdenko VG (2009) Eur J Org Chem 22:3801–3808CrossRefGoogle Scholar
  5. 5.
    Brandt W, Haupt VJ, Wessjohann LA (2010) Cheminformatic analysis of biologically active macrocycles, Curr Top Med Chem, in printGoogle Scholar
  6. 6.
    Wessjohann LA, Andrade CKZ, Vercillo OE, Rivera DG (2007) In: Attanasi OA, Spinelli D (eds) Targets in heterocyclic systems: chemistry and properties. Royal Society of Chemistry, Cambridge, pp 24–53Google Scholar
  7. 7.
    Adessi C, Soto C (2002) Curr Med Chem 9:963CrossRefGoogle Scholar
  8. 8.
    Arbor S, Kao J, Wu Y, Marshall GR (2008) Biopolymers 3:384–393CrossRefGoogle Scholar
  9. 9.
    Xiao Q, Pei D (2007) J Med Chem 50:3132–3137CrossRefGoogle Scholar
  10. 10.
    Rezai T, Bock JE, Zhou MV, Kalyanaraman C, Lockey RS, Jacobson MP (2006) J Am Chem Soc 128:14073–14080CrossRefGoogle Scholar
  11. 11.
    Kessler H (1982) Angew Chem Int Ed Engl 21:512–523CrossRefGoogle Scholar
  12. 12.
    Wipf P (1995) Chem Rev 95:2115–2134CrossRefGoogle Scholar
  13. 13.
    Hamada Y, Shioiri T (2005) Chem Rev 105:4441–4482CrossRefGoogle Scholar
  14. 14.
    Pomilio AB, Battista ME, Vitale AA (2006) Curr Org Chem 10:2075–2121CrossRefGoogle Scholar
  15. 15.
    Marcaccini S, Torroba T (2005) In: Zhu J, Bienaymé H (eds) Multicomponent reactions. Wiley, Weinheim, pp 33–75, Chapter 2 (cf. also other chapters of this book)CrossRefGoogle Scholar
  16. 16.
    Dömling A (2006) Chem Rev 106:17–89CrossRefGoogle Scholar
  17. 17.
    Fischer PM (2003) J Pept Sci 9:9–35CrossRefGoogle Scholar
  18. 18.
    Dinsmore CJ, Beshore DC (2002) Tetrahedron 58:3297–3312CrossRefGoogle Scholar
  19. 19.
    Martins MB, Carvalho I (2007) Tetrahedron 63:9923–9932CrossRefGoogle Scholar
  20. 20.
    Szardenings AK, Antonenko V, Campbell DA, De Francisco N, Ida S, Shi L, Sharkov N, Tien D, Wang Y, Navre M (1999) J Med Chem 42:1348–1357CrossRefGoogle Scholar
  21. 21.
    Bryant SD, Balboni G, Guerrini R, Salvadori S, Tomatis R, Lazarus LH (1997) Biol Chem 378:107–114CrossRefGoogle Scholar
  22. 22.
    Houston DR, Synstad B, Eijsink VGH, Stark MJR, Eggleston IM, van Aalten MF (2004) J Med Chem 47:5713–5720CrossRefGoogle Scholar
  23. 23.
    Byun H-G, Zhang H, Mochizuki M, Adachi K, Shizuri Y, Lee W-J, Kim S-K (2003) J Antibiot 56:102–106CrossRefGoogle Scholar
  24. 24.
    Fdhila F, Vázquez V, Sánchez JL, Riguera R (2003) J Nat Prod 66:1299–1301CrossRefGoogle Scholar
  25. 25.
    Abraham W-R (2005) Drug Des Rev 2:13Google Scholar
  26. 26.
    Funabashi Y, Horiguchi T, Iinum S, Tanida S, Harada S (1994) J Antibiot 47:1202–1218CrossRefGoogle Scholar
  27. 27.
    Gellerman G, Hazan E, Kovaliov M, Albeck A, Shatzmiler S (2009) Tetrahedron 65:1389–1396CrossRefGoogle Scholar
  28. 28.
    Cain JP, Mayorov AV, Hruby V (2006) J Bioorg Med Chem Lett 16:5462–5467CrossRefGoogle Scholar
  29. 29.
    Pedro B, Mamedova L, Jacobson KA (2005) Org Biomol Chem 3:2016–2025CrossRefGoogle Scholar
  30. 30.
    Souers AJ, Ellman JA (2001) Tetrahedron 57:7431–7448CrossRefGoogle Scholar
  31. 31.
    Jainta M, Nieger M, Bräse S (2008) Eur J Org Chem 5418Google Scholar
  32. 32.
    Stark T, Hofmann T (2005) J Agric Food Chem 53:7222–7231CrossRefGoogle Scholar
  33. 33.
    Hulme C, Cherrier M-P (1999) Tetrahedron Lett 40:5295–5299CrossRefGoogle Scholar
  34. 34.
    Hulme C, Morrissette MM, Volz FA, Burns CJ (1998) Tetrahedron Lett 39:1113–1116CrossRefGoogle Scholar
  35. 35.
    El Kaim L, Gageat M, Gaultier L, Grimaud L (2007) Synlett 56:500–502CrossRefGoogle Scholar
  36. 36.
    Santra S, Andreana P (2007) Org Lett 9:5035–5038CrossRefGoogle Scholar
  37. 37.
    Rhoden CRB, Westerman B, Wessjohann LA (2008) Synthesis 2077–2082Google Scholar
  38. 38.
    Bruttomesso AC, Eiras J, Ramírez JA, Galagovsky LR (2009) Tetrahedron Lett 50:4022–4024CrossRefGoogle Scholar
  39. 39.
    Hulme C, Chappeta S, Dietrich J (2009) Tetrahedron Lett 50:4054–4057CrossRefGoogle Scholar
  40. 40.
    Rhoden CRB, Rivera DG, Kreye O, Bauer AK, Westermann B, Wessjohann LA (2009) J Comb Chem 11:1078–1082CrossRefGoogle Scholar
  41. 41.
    Kreye O, Westermann B, Wessjohann LA (2007) Synlett 3188–3192Google Scholar
  42. 42.
    Venkatesan N, Kim BH (2002) Curr Med Chem 9:2243–2270CrossRefGoogle Scholar
  43. 43.
    Myers AC, Kowalski JA, Lipton MA (2004) Bioorg Med Chem Lett 14:5219–5222CrossRefGoogle Scholar
  44. 44.
    Zega A (2005) Curr Med Chem 12:589–597Google Scholar
  45. 45.
    Piliero PJ (2004) Drugs Today 40:901–912CrossRefGoogle Scholar
  46. 46.
    Sañudo M, Marcaccini S, Basurto SJ, Torroba T (2006) J Org Chem 71:4578–4584CrossRefGoogle Scholar
  47. 47.
    Cuny G, Bois-Choussy M, Zhu J (2004) J Am Chem Soc 126:14474–14484CrossRefGoogle Scholar
  48. 48.
    Bonnaterre F, Bois-Choussy M, Zhu J (2006) Org Lett 8:4351–4354CrossRefGoogle Scholar
  49. 49.
    Kalinski C, Umkehrer M, Ross G, Kolb J, Burdack C, Hiller W (2006) Tetrahedron Lett 47:3423–3426CrossRefGoogle Scholar
  50. 50.
    Horton DA, Bourne GT, Smythe ML (2003) Chem Rev 103:893–930CrossRefGoogle Scholar
  51. 51.
    Herpin TF, Van Kirk KG, Salvino JM, Yu ST, Labaudinière RF (2000) J Comb Chem 2:513–521CrossRefGoogle Scholar
  52. 52.
    Carlier PR, Zhao H, MacQuarrie-Hunter SL, De Guzman JC, Hsu DC (2006) J Am Chem Soc 128:15215–15220CrossRefGoogle Scholar
  53. 53.
    Joseph CG, Wilson KR, Wood MS, Sorenson NB, Phan DV, Xiang Z, Witek RM, Haskell-Luevano C (2008) J Med Chem 51:1423–1431CrossRefGoogle Scholar
  54. 54.
    Ramajayam R, Girdhar R, Yadav MR (2007) Mini Rev Med Chem 7:793–812CrossRefGoogle Scholar
  55. 55.
    Butini S, Gabellieri E, Huleatt PB, Campiani G, Franceschini S, Brindisi M, Ros S, Coccone SS, Fiorini I, Novellino E, Giorgi G, Gemma S (2008) J Org Chem 73:8458–8468CrossRefGoogle Scholar
  56. 56.
    Blakeney JS, Reid RC, Le GT, Fairlie DP (2007) Chem Rev 107:2960–3041CrossRefGoogle Scholar
  57. 57.
    Butler MS (2005) Nat Prod Rep 22:162–195CrossRefGoogle Scholar
  58. 58.
    Evans BE, Bock MG, Rittle KE, DiPardo RM, Whitter WL, Veber DF, Anderson PS, Freidinger RM (1986) Proc Natl Acad Sci USA 83:4918–4922CrossRefGoogle Scholar
  59. 59.
    Faggi C, Marcaccini S, Pepino R, Pozo MC (2002) Synthesis 2756–2760Google Scholar
  60. 60.
    Marcaccini S, Miliciani M, Pepino R (2005) Tetrahedron Lett 46:711–713CrossRefGoogle Scholar
  61. 61.
    Sañudo M, García-Valverde M, Marcaccini S, Delgado JJ, Rojo J, Torroba T (2009) J Org Chem 74:2189–2192CrossRefGoogle Scholar
  62. 62.
    Akritopoulou-Zanze I, Gracias V, Djuric SW (2004) Tetrahedron Lett 45:8439–8441CrossRefGoogle Scholar
  63. 63.
    Golebiowski A, Jozwik J, Klopfenstein R, Colson A, Grieb AL, Russell AF, Rastogi VL, Diven CF, Portlock D, Chen J (2002) J Comb Chem 4:584–590CrossRefGoogle Scholar
  64. 64.
    Golebiowski A, Klopfenstein R, Shao X, Chen JJ, Colson A-O, Grieb AL, Russell AF (2000) Org Lett 2:2615–2617CrossRefGoogle Scholar
  65. 65.
    Oikawa M, Naito S, Sasaki M (2006) Tetrahedron Lett 47:4763–4767CrossRefGoogle Scholar
  66. 66.
    Banfi L, Basso A, Guanti G, Riva R (2003) Tetrahedron Lett 44:7655–7658CrossRefGoogle Scholar
  67. 67.
    Dietrich SA, Banfi L, Basso A, Damonte G, Guanti G, Riva R (2005) Org Biomol Chem 3:97–106CrossRefGoogle Scholar
  68. 68.
    Dechantsreiter MA, Planker E, Matha B, Lohof E, Hoelzemann G, Jonczyk A, Goodman SL, Kessler H (1999) J Med Chem 42:3033–3040CrossRefGoogle Scholar
  69. 69.
    Wessjohann LA, Ruijter E (2005) Top Curr Chem 243:137–184Google Scholar
  70. 70.
    Wessjohann LA, Ruijter E (2005) Mol Divers 9:159–169CrossRefGoogle Scholar
  71. 71.
    Wessjohann LA, Rivera DG, Vercillo OE (2009) Chem Rev 109:796–814CrossRefGoogle Scholar
  72. 72.
    Bauer SM, Armstrong RW (1999) J Am Chem Soc 121:6355–6366CrossRefGoogle Scholar
  73. 73.
    Bowers MM, Carroll P, Joullié MM (1989) J Chem Soc Perkin Trans 1, 857–865CrossRefGoogle Scholar
  74. 74.
    Joullié MM, Nutt RF (1985) In: Pelletier SW (ed) Alkaloids: chemical and biological perspectives, vol 3. Wiley, New York, 3:113ppGoogle Scholar
  75. 75.
    Gournelis DC, Laskaris GG, Verpoorte R (1997) Nat Prod Rep 14:75–82CrossRefGoogle Scholar
  76. 76.
    Cristau P, Vors J-P, Zhu J (2001) Org Lett 3:4079–4082CrossRefGoogle Scholar
  77. 77.
    Cristau P, Vors J-P, Zhu J (2003) Tetrahedron 59:7859–7870CrossRefGoogle Scholar
  78. 78.
    Cristau P, Vors J-P, Zhu J (2006) QSAR Comb Sci 25:519–526CrossRefGoogle Scholar
  79. 79.
    De Greef M, Abeln S, Belkasmi K, Dömling A, Orru RVA, Wessjohann LA (2006) Synthesis 3997–4004Google Scholar
  80. 80.
    Beck B, Larbig G, Mejat B, Magnin-Lachaux M, Picard A, Herdtweck E, Dömling A (2003) Org Lett 5:1047–1050CrossRefGoogle Scholar
  81. 81.
    Pirali T, Tron GC, Zhu J (2006) Org Lett 8:4145–4148CrossRefGoogle Scholar
  82. 82.
    Sun X, Janvier P, Zhao G, Bienaymé H, Zhu J (2001) Org Lett 3:877–880CrossRefGoogle Scholar
  83. 83.
    Janvier P, Sun X, Bienaymé H, Zhu J (2002) J Am Chem Soc 124:2560–2567CrossRefGoogle Scholar
  84. 84.
    Zhao G, Sun X, Bienaymé H, Zhu J (2001) J Am Chem Soc 123:6700–6701CrossRefGoogle Scholar
  85. 85.
    Bughin C, Zhao G, Bienaymé H, Zhu J (2006) Chem Eur J 12:1174–1184CrossRefGoogle Scholar
  86. 86.
    Hebach C, Kazmaier U (2003) Chem Comm 5:596–597CrossRefGoogle Scholar
  87. 87.
    Kazmaier U, Hebach C, Watzke A, Maier S, Mues H, Huch V (2005) Org Biomol Chem 3:136–145CrossRefGoogle Scholar
  88. 88.
    Bughin G, Masson G, Zhu J (2007) J Org Chem 72:1826–1829CrossRefGoogle Scholar
  89. 89.
    Pirali T, Tron GC, Masson G, Zhu J (2007) Org Lett 9:5275–5278CrossRefGoogle Scholar
  90. 90.
    Faure S, Hjelmgaard T, Roche SP, Aitken DJ (2009) Org Lett 11:1167–1170CrossRefGoogle Scholar
  91. 91.
    Owens TD, Araldi GL, Nutt RF, Semple JE (2001) Tetrahedron Lett 42:6271–6274CrossRefGoogle Scholar
  92. 92.
    Failli A, Immer H, Götz MD (1979) Can J Chem 57:3257–3261CrossRefGoogle Scholar
  93. 93.
    Vercillo OE, Andrade CKZ, Wessjohann LA (2008) Org Lett 10:205–208CrossRefGoogle Scholar
  94. 94.
    Vercillo OE, Andrade CKZ, Wessjohann LA. UnpublishedGoogle Scholar
  95. 95.
    Vercillo OE (2007) Ugi reaction on the cyclopeptoids construction: Synthesis of a potencial inhibitor of Tat/TAR complex of HIV-1 virus. PhD thesis, Universidade de Brasília, BrasilGoogle Scholar
  96. 96.
    Wessjohann LA, Rivera DG, Coll F (2006) J Org Chem 71:7521–7526CrossRefGoogle Scholar
  97. 97.
    Leon F, Rivera DG, Wessjohann LA (2008) J Org Chem 73:7162–7167CrossRefGoogle Scholar
  98. 98.
    Michalik D, Schaks A, Wessjohann LA (2007) Eur J Org Chem 149–157Google Scholar
  99. 99.
    Westermann B, Michalik D, Schaks A, Kreye O, Wagner C, Merzweiler K, Wessjohann LA (2007) Heterocycles 73:863–872CrossRefGoogle Scholar
  100. 100.
    Rivera DG, Wessjohann LA (2006) J Am Chem Soc 128:7122–7123CrossRefGoogle Scholar
  101. 101.
    Rivera DG, Wessjohann LA (2009) J Am Chem Soc 131:3721–3723CrossRefGoogle Scholar
  102. 102.
    Nikulinkov M, Tsirulnikov S, Kysil V, Ivachtchenko A, Krasavin M (2009) Synlett 260–262Google Scholar
  103. 103.
    Da Settimo F, Taliani S, Trincavelli ML, Montali M, Martini C (2007) Curr Med Chem 14:2680–2701CrossRefGoogle Scholar
  104. 104.
    Whiting PJ (2006) Curr Opin Pharmacol 6:24–29CrossRefGoogle Scholar
  105. 105.
    Atack JR (2005) Expert Opin Investig Drugs 14:601–618CrossRefGoogle Scholar
  106. 106.
    Banfi L, Basso A, Damonte G, De Pellegrini F, Galatini A, Guanti G, Monfardini I, Riva R, Scapolla C (2007) Bioorg Med Chem Lett 17:1341–1345CrossRefGoogle Scholar
  107. 107.
    Wessjohann LA, Voigt B, Rivera DG (2005) Angew Chem Int Ed 44:4785–4790CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Ludger A. Wessjohann
    • 1
    Email author
  • Cristiano R. B. Rhoden
    • 1
    • 2
  • Daniel G. Rivera
    • 1
    • 3
  • Otilie Eichler Vercillo
    • 1
    • 4
  1. 1.Department of Bioorganic ChemistryLeibniz Institute of Plant BiochemistryHalle (Saale)Germany
  2. 2.UNIFRASanta MariaBrasil
  3. 3.University of HavanaHavanaCuba
  4. 4.University of BrasiliaBrasiliaBrasil

Personalised recommendations