Solid-Phase Peptide Synthesis

  • Mare Cudic
  • Gregg B. Fields
Part of the Springer Protocols Handbooks book series (SPH)

1. Introduction

Peptides play a central role in numerous biological and physiological processes. They also may be critical for research endeavors in the post-genomic and proteomic era that is characterized by a vast array of new predicted protein sequences. To elucidate the biological function of putative proteins it is important to have facile access to their synthesis. Today we have almost routine technologies for the chemical synthesis of small peptides and proteins, and have made significant progress toward the synthesis of larger proteins via chemoselective ligation (1, 2, 3, 4, 5) and expressed protein ligation (6, 7, 8). Although these new approaches are impressive and have been employed successfully for the synthesis of many proteins, general protein chemical synthesis is still not routine and there are still many challenges that remain to be confronted.

Methods for synthesizing peptides are divided conveniently into two categories: solution and solid-phase. Classical solution...


Hydrogen Fluoride Fmoc Group Fmoc Chemistry Native Chemical Ligation Anhydrous Hydrogen Fluoride 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Borgia JA, Fields GB (2000) Chemical synthesis of proteins. Trends Biotech 18:243–251Google Scholar
  2. 2.
    Dawson PE, Kent SBH (2000) Synthesis of native proteins by chemical ligation. Annu Rev Biochem 69:923–960PubMedGoogle Scholar
  3. 3.
    Miranda IP, Alewood PF (2000) Challenges for protein chemical synthesis in the 21st century: bridging genomics and proteomics. Biopolymers (Peptide Sci) 55:217–226Google Scholar
  4. 4.
    Tam JP, Xu J, Eom KD (2001) Methods and strategies of peptide ligation. Biopolymers (Peptide Sci) 60:194–205Google Scholar
  5. 5.
    Kimmerlin T, Seebach D (2005) “100 years of peptide synthesis”: ligation methods for peptide and protein synthesis with applications to β-peptide assemblies. J Peptide Res 65:229–260Google Scholar
  6. 6.
    Muir TW, Sondhi D, Cole PA (1998) Expressed protein ligation: A general method for protein engineering. Proc Natl Acad Sci USA 95:6705–6710PubMedGoogle Scholar
  7. 7.
    Muir TW (2003) Semisynthesis of proteins by expressed protein ligation. Annu Rev Biochem 72:249–289PubMedGoogle Scholar
  8. 8.
    David R, Richter MPO, Beck-Sickinger A (2004) Expressed protein ligation: Method and application. Eur J Biochem 271:663–677PubMedGoogle Scholar
  9. 9.
    Erickson BW, Merrifield RB (1976) Solid-phase peptide synthesis in The Proteins Vol II 3rd Ed (Neurath, H., and Hill, R. L., Eds.) pp 255–527, Academic Press, New YorkGoogle Scholar
  10. 10.
    Barany G, and Merrifield RB (1979) Solid-phase peptide synthesis. In: Gross E, Meienhofer J (eds) The Peptides Vol 2. Academic Press, New York, pp 1–284Google Scholar
  11. 11.
    Stewart JM, Young JD (1984) Solid Phase Peptide Synthesis 2nd edn, Pierce Chemical Co., Rockford, ILGoogle Scholar
  12. 12.
    Merrifield B (1986) Solid phase synthesis. Science 232:341–347PubMedGoogle Scholar
  13. 13.
    Barany G, Kneib-Cordonier N, Mullen DG (1987) Solid-phase peptide synthesis: a silver anniversary report. Int J Peptide Protein Res 30:705–739Google Scholar
  14. 14.
    Kent SBH (1988) Chemical synthesis of peptides and proteins: Annu Rev Biochem 57:957–989PubMedGoogle Scholar
  15. 15.
    Atherton E, Sheppard RC (1989) Solid phase peptide synthesis: a practical approach. IRL Press, Oxford, U.K.Google Scholar
  16. 16.
    Fields GB, Noble RL (1990) Solid phase peptide synthesis utilizing 9-fluorenyl-methoxycarbonyl amino acids. Int J Peptide Protein Res 35:161–214Google Scholar
  17. 17.
    Fields GB (1997) Solid-phase peptide synthesis: methods in enzymology 289. Academic Press, Orlando, FLGoogle Scholar
  18. 18.
    Sakakibara S (1999) Chemical synthesis of proteins in solution. Biopolymers (Peptide Sci) 51:279–296Google Scholar
  19. 19.
    Albericio F (2000) Orthogonal protecting groups for Nα-amino and C-terminal carboxyl functions in solid-phase peptide synthesis. Biopolymers (Peptide Sci) 55:123–139Google Scholar
  20. 20.
    Anderson L, Blomberg L, Flegel M, Lepsa L, Nilsson B, Verlander M (2000) Large-scale synthesis of peptides. Biopolymers (Peptide Sci) 55:227–250Google Scholar
  21. 21.
    Fields GB, Lauer-Fields JL, Liu R-q, Barany G (2001) Principles and practice of solid-phase peptide synthesis. In: Grant GA (ed) Synthetic peptides: a user's guide, 2nd edn; W.H. Freeman & Co., New York, pp 93–219Google Scholar
  22. 22.
    Albericio F (2004) Developments in peptide and amide synthesis. Curr Opinion Chem Biol 8:211–221Google Scholar
  23. 23.
    Merrifield RB (1963) Solid phase peptide synthesis I: synthesis of a tetrapeptide, J Am Chem Soc 85:2149–2154Google Scholar
  24. 24.
    Angeletti RH, Bonewald LF, Fields GB (1997) Six-year study of peptide synthesis. Meth Enzymol 289:697–717PubMedGoogle Scholar
  25. 25.
    Remmer HA, Fields GB (2000) Chemical synthesis of peptides. In: Reid RE (ed) Peptide and protein drug analysis. Marcel Dekker, Inc., New York, pp 133–169Google Scholar
  26. 26.
    Sarin VK, Kent SBH, Merrifield RB (1980) Properties of swollen polymer networks: solvation and swelling of peptide-containing resins in solid-phase peptide synthesis. J Am Chem Soc 102:5463–5470Google Scholar
  27. 27.
    Live D, Kent SBH (1982) Fundamental aspects of the chemical applications of cross-linked polymers. In: Mark JE (ed) Elastomers and rubber elasticity. American Chemical Society, Washington, DC, pp 501–515Google Scholar
  28. 28.
    Arshady R, Atherton E, Clive DLJ, Sheppard RC (1981) Peptide synthesis, part 1: preparation and use of polar supports based on poly(dimethylac rylamide). J Chem Soc Perkin Trans I: 529–537Google Scholar
  29. 29.
    Hellermann H, Lucas HW, Maul J, Pillai VNR, Mutter M (1983) Poly(ethylene glycol)s grafted onto crosslinked polystyrenes, 2: multidetachably anchored polymer systems for the synthesis of solubilized peptides. Makromol Chem 184:2603–2617Google Scholar
  30. 30.
    Zalipsky S, Albericio F, Barany G (1985) Preparation and use of an aminoethyl polyethylene glycol-crosslinked polystyrene graft resin support for solid-phase peptide synthesis. In: Deber CM, Hruby VJ, Kopple KD (eds) Peptides: structure and function. Pierce Chemical Co., Rockford, IL, pp 257–260Google Scholar
  31. 31.
    Bayer E, Rapp W (1986) New polymer supports for solid–liquid-phase peptide synthesis. In: Voelter W, Bayer E, Ovehinnikov YA, Ivanov VT (eds) Chemistry of peptides and proteins, Vol 3 Walter de Gruyter & Co., Berlin, pp 3–8Google Scholar
  32. 32.
    Bayer E, Albert K, Willisch H, Rapp W, Hemmasi B (1990) 13C NMR relaxation times of a tripeptide methyl ester and its polymer-bound analogues. Macromolecules 23:1937–1940Google Scholar
  33. 33.
    Zalipsky S, Chang JL, Albericio F, Barany G (1994) Preparation and applications of polyethylene glycol-polystyrene graft resin supports for solid-phase peptide synthesis. Reactive Polymers 22:243–258Google Scholar
  34. 34.
    Meldal M (1992) PEGA – a flow stable polyethylene-glycol dimethyl acrylamide copolymer for solid-phase synthesis. Tetrahedron Lett 33:3077–3080Google Scholar
  35. 35.
    Roice M, Johannsen I, Meldal M (2004) High capacity poly(ethylene glycol) based amino polymers for peptide and organic synthesis. QSAR Comb Sci 23:662–673Google Scholar
  36. 36.
    Garcia-Martin F, Quintanar-Audelo M, Garcia-Ramos Y, Cruz LJ, Gravel C, Furic R, Cote S, Tulla-Puche J, Albericio F (2006) ChemMatrix, a poly(ethylene glycol)-based support for the solid-phase synthesis of complex peptides. J Comb Chem 8:213–220PubMedGoogle Scholar
  37. 37.
    Kempe M, Barany G (1996) CLEAR: a novel family of highly cross-linked polymeric supports for solid-phase peptide synthesis. J Am Chem Soc 118:7083–7093Google Scholar
  38. 38.
    Niederhafner P, Sebestik J, Jezek J (2005) Peptide dendrimers. J Peptide Sci 11:757–788Google Scholar
  39. 39.
    Alsina J, Albericio F (2003) Solid-phase synthesis of C-terminal modified peptides. Biopolymers (Peptide Sci) 71:454–477Google Scholar
  40. 40.
    Meldal M (1997) Properties of solid supports. Meth Enzymol 289:83–104PubMedGoogle Scholar
  41. 41.
    Barany G, Kempe M (1997) The context of solid-phase synthesis. In: Czarnik AW, DeWitt SH (eds) A Practical guide to combinatorial chemistry. American Chemical Society, Washington, D.C., pp 51–97Google Scholar
  42. 42.
    Kent SBH, Parker KF (1988) The chemical synthesis of therapeutic peptides and proteins. In: Masshak DR, Liu DT (eds) Banbury report 29: therapeutic peptides and proteins: assessing the new technologies. Cold Spring Harbor, New York, pp 3–16Google Scholar
  43. 43.
    Wallace CJA, Mascagni P, Chait BT, Collawn JF, Paterson Y, Proudfoot AEI, Kent SBH (1989) Substitutions engineered by chemical synthesis at three conserved sites in mitochondrial cytochrome c. J Biol Chem 264:15199–15209PubMedGoogle Scholar
  44. 44.
    Suzuki K, Nitta K, Endo N (1975) Suppression of diketopiperazine formation in solid phase peptide synthesis. Chem Pharm Bull 23:222–224Google Scholar
  45. 45.
    Schnölzer M, Alewood P, Jones A, Alewood D, Kent SBH (1992) In situ neutralization in Boc-chemistry solid phase peptide synthesis: rapid, high yield assembly of difficult sequences. Int J Peptide Protein Res 40:180–193Google Scholar
  46. 46.
    Carpino LA, Han GY (1972) The 9-fluorenylmethoxycarbonyl amino-protecting group. J Org Chem 37:3404–3409Google Scholar
  47. 47.
    Carpino LA (1987) The 9-fluorenylmethyloxycarbonyl family of base-sensitive amino-protecting groups. Acc Chem Res 20:401–407Google Scholar
  48. 48.
    O'Ferrall RAM, Slae S (1970) β-elimination of 9-fluorenylmethanol in aqueous solution: An E1cB mechanism. J Chem Soc (B): 260–268Google Scholar
  49. 49.
    O'Ferrall RAM (1970) β-elimination of 9-fluorenylmethanol in solutions of metha-nol and t-butyl alcohol. J Chem Soc (B): 268–274Google Scholar
  50. 50.
    O'Ferrall RAM (1970) Relationships between E2 and E1cB mechanisms of β-elimination. J Chem Soc (B): 274–277Google Scholar
  51. 51.
    Fields GB (1994) Methods for removing the Fmoc group. In: Pennington MW, Dunn BM (eds) Methods in molecular biology, Vol. 35: peptide synthesis protocols. Humana Press Inc., Totowa, NJ, pp 17–27Google Scholar
  52. 52.
    Wade JD, Bedford J, Sheppard RC, Tregear GW (1991) DBU as an Nα-deprotect-ing reagent for the fluorenylmethoxycarbonyl group in continuous flow solid-phase peptide synthesis. Peptide Res 4:194–199Google Scholar
  53. 53.
    Fields CG, Mickelson DJ, Drake SL, McCarthy JB, Fields GB (1993) Melanoma cell adhesion and spreading activities of a synthetic 124-residue triple-helical “mini-collagen”. J Biol Chem 268:14,153–14,160Google Scholar
  54. 54.
    Meldal M, Svensen I, Breddam K, Auzanneau FI (1994) Portion-mixing peptide libraries of quenched fluorogenic substrates for complete subsite mapping of endo-protease specificity. Proc Natl Acad Sci USA 91:3314–3318PubMedGoogle Scholar
  55. 55.
    Carreno C, Mendez ME, Kim YD, Kim HJ, Kates SA, Andreu D, Albericio F (2000) Nsc and Fmoc Nα-amino protection for solid-phase peptide synthesis: a parallel study. J Pept Res 56:63–69PubMedGoogle Scholar
  56. 56.
    Okada Y, Iguchi S (1988) Amino acid and peptides, part 19: synthesis of β-1- and β-2-adamantyl aspartates and their evaluation for peptide synthesis. J Chem Soc Perkin Trans I:2129–2136Google Scholar
  57. 57.
    Tam JP, Riemen MW, Merrifield RB (1988) Mechanisms of aspartimide formation: the effects of protecting groups, acid, base, temperature and time. Peptide Res 1:6–18Google Scholar
  58. 58.
    Karlström A, Undén A (1996) A new protecting group for aspartic acid that minimizes piperidine-catalyzed aspartimide formation in Fmoc solid phase peptide synthesis. Tetrahedron Lett 37:4243–4246Google Scholar
  59. 59.
    Bolin DR, Wang CT, Felix AM (1989) Preparation of N-t-butyloxy-carbonyl-Oω-9-fluorenylmethyl esters of asparatic and glutamic acids. Org Prep Proc Int 21:67–74Google Scholar
  60. 60.
    Albericio F, Nicolas E, Rizo J, Ruiz-Gayo M, Pedroso E, Giralt E (1990) Convenient syntheses of fluorenylmethyl-based side chain derivatives of glutamic and aspartic acids, lysine, and cysteine. Synthesis: 119–122Google Scholar
  61. 61.
    Al-Obeidi F, Sanderson DG, Hruby VJ (1990) Synthesis of (β- and γ-fluorenylme-thyl esters of respectively Nα-Boc-L-aspartic acid and Nα-Boc-L-glutamic acid. Int J Peptide Protein Res 35:215–218Google Scholar
  62. 62.
    Belshaw PJ, Mzengeza S, Lajoie GA (1990) Chlorotrimethylsilane mediated formation of ω-allyl esters of aspartic and glutamic acids. Synth Commun 20:3157–3160Google Scholar
  63. 63.
    Lyttle MH, Hudson D (1992) Allyl based side-chain protection for SPPS. In: Smith JA, Rivier JE (eds) Peptides chemistry and biology Escom, Leiden, The Netherlands, pp 583–584Google Scholar
  64. 64.
    Chan WC, Bycroft BW, Evans DJ, White PD (1995) A novel 4-aminobenzyl ester-based carboxy-protecting group for synthesis of atypical peptides by Fmoc-But solid phase chemistry. J Chem Soc Chem Commun: 2209–2210Google Scholar
  65. 65.
    Erickson BW, Merrifield RB (1973) Acid stability of several benzylic protecting groups used in solid-phase peptide synthesis: rearrangement of O-benzyltyrosine to 3-benzyltyrosine. J Am Chem Soc 95:3750–3756PubMedGoogle Scholar
  66. 66.
    Yamashiro D, Li CH (1973) Protection of tyrosine in solid-phase peptide synthesis. J Org Chem 38:591–592PubMedGoogle Scholar
  67. 67.
    Albericio F, Barany G, Fields GB, Hudson D, Kates SA, Lyttle MH, Solé NA (1993) Allyl-based orthogonal solid-phase peptide synthesis. In: Schneider CH, Eberle AN (eds) Peptides 1992. Escom, Leiden, The Netherlands, pp 191–193Google Scholar
  68. 68.
    Bycroft BW, Chan WC, Chhabra SR, Hone ND (1993) A novel lysine-protecting procedure for continuous flow solid phase synthesis of branched peptides. J Chem Soc Chem Commun: 778–779Google Scholar
  69. 69.
    Fields CG, Lovdahl CM, Miles AJ, Matthias-Hagen VL, Fields GB (1993) Solid-phase synthesis and stability of triple-helical peptides incorporating native collagen sequences. Biopolymers 33:1695–1707PubMedGoogle Scholar
  70. 70.
    Grab B, Miles AJ, Furcht LT, Fields GB (1996) Promotion of fibroblast adhesion by triple-helical peptide models of type I collagen-derived sequences. J Biol Chem 271:12,234–12,240Google Scholar
  71. 71.
    Xu Q, Zheng J, Cowburn D, Barany G (1996) Synthesis and characterization of branched phosphopeptides: prototype consolidated ligands for SH(32) domains. Lett Peptide Sci 3:31–36Google Scholar
  72. 72.
    Chhabra SR, Hothi B, Evans DJ, White PD, Bycroft BW, Chan WC (1998) An appraisal of new variants of Dde amine protecting group for solid phase peptide synthesis. Tetrahedron Lett 39:1603–1606Google Scholar
  73. 73.
    Aletras A, Barlos K, Gatos D, Koutsogianni S, Mamos P (1995) Preparation of the very acid-sensitive Fmoc-Lys(Mtt)-OH. Int J Peptide Protein Res 45:488–500Google Scholar
  74. 74.
    Fujino M, Wakimasu M, Kitada C (1981) Further studies on the use of multi-substituted benzenesulfonyl groups for protection of the guanidino function of arginine. Chem Pharm Bull 29:2825–2831Google Scholar
  75. 75.
    Green J, Ogunjobi OM, Ramage R, Stewart ASJ, McCurdy S, Noble R (1988) Application of the NG-(2,2,5,7,8-pentamethylchroman-6 sulphonyl) derivative of Fmoc-arginine to peptide synthesis. Tetrahedron Lett 29:4341–4344Google Scholar
  76. 76.
    Carpino LA, Shroff H, Triolo SA, Mansour ESME, Wenschuh H, Albericio F (1993) The 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group (Pbf) as arginine side chain protectant. Tetrahedron Lett 34:7829–7832Google Scholar
  77. 77.
    Jones JH, Ramage WI, Witty MJ (1980) Mechanism of racemization of histidine derivatives in peptide synthesis. Int J Peptide Protein Res 15:301–303Google Scholar
  78. 78.
    Riniker B, Sieber P (1988) Problems and progress in the synthesis of histidine-con-taining peptides. In: Penke B, Torok A (eds) Peptides: chemistry, biology, interactions with proteins. Walter de Gruyter & Co., Berlin, pp 65–74Google Scholar
  79. 79.
    Ishiguro T, Eguchi C (1989) Unexpected chain-terminating side reaction caused by histidine and acetic anhydride in solid-phase peptide synthesis. Chem Pharm Bull 37:506–508PubMedGoogle Scholar
  80. 80.
    Kusunoki M, Nakagawa S, Seo K, Hamana T, Fukuda T (1990) A side reaction in solid phase synthesis: Insertion of glycine residues into peptide chains via Nim -> Nα transfer. Int J Peptide Protein Res 36:381–386Google Scholar
  81. 81.
    Forest M, Fournier A (1990) BOP reagent for the coupling of pGlu and Boc-His(Tos) in solid phase peptide synthesis. Int J Peptide Protein Res 35:89–94Google Scholar
  82. 82.
    Atherton E, Cammish LE, Goddard P, Richards JD, Sheppard RC (1984) The Fmoc-polyamide solid phase method: new procedures for histidine and arginine. In: Ragnarsson U (ed) Peptides 1984 Almqvist & Wiksell Int., Stockholm, pp 153–156Google Scholar
  83. 83.
    Sieber P, Riniker B (1987) Protection of histidine in peptide synthesis: a reassessment of the trityl group. Tetrahedron Lett 28:6031–6034Google Scholar
  84. 84.
    Mojsov S, Mitchell AR, Merrifield RB (1980) A quantitative evaluation of methods for coupling asparagine. J Org Chem 45:555–560Google Scholar
  85. 85.
    Gausepohl H, Kraft M, Frank RW (1989) Asparagine coupling in Fmoc solid phase peptide synthesis. Int J Peptide Protein Res 34:287–294Google Scholar
  86. 86.
    Sieber P, Riniker B (1990) Side-chain protection of asparagine and glutamine by trityl: Application to solid-phase peptide synthesis. In: Epton R (ed) Innovation and perspectives in solid phase synthesis. Solid Phase Conference Coordination, Ltd., Birmingham, U.K, pp 577–583Google Scholar
  87. 87.
    Sieber P, Riniker B (1991) Protection of carboxamide functions by the trityl residue: Application to peptide synthesis. Tetrahedron Lett 32:739–742Google Scholar
  88. 88.
    Fields GB, Carr SA, Marshak DR, Smith AJ, Stults JT, Williams LC, Williams KR, Young JD (1993) Evaluation of peptide synthesis as practiced in 53 different laboratories. In: Angeletti RH (ed) Techniques in protein chemistry I V. Academic Press, San Diego, pp 229–238Google Scholar
  89. 89.
    Franzén H, Grehn L, Ragnarsson U (1984) Synthesis, properties, and use of Nin-Boc-tryptophan derivatives. J Chem Soc Chem Commun: 1699–1700Google Scholar
  90. 90.
    White P (1992) Fmoc-Trp(Boc)-OH: A new derivative for the synthesis of pep-tides containing tryptophan. In: Smith JA, Rivier JE (eds) Peptides: Chemistry and Biology Escom, Leiden, The Netherlands, pp 537–538Google Scholar
  91. 91.
    Fields CG, Fields GB (1993) Minimization of tryptophan alkylation following 9-fluorenylmethoxycarbonyl solid-phase peptide synthesis. Tetrahedron Lett 34:6661–6664Google Scholar
  92. 92.
    Choi H, Aldrich JV (1993) Comparison of methods for the Fmoc solid-phase synthesis and cleavage of a peptide containing both tryptophan and arginine. Int J Peptide Protein Res 42:58–63Google Scholar
  93. 93.
    Photaki I, Taylor-Papadimitriou J, Sakarellos C, Mazarakis P, Zervas L (1970) On cysteine and cystine peptides, part V: S-trityl- and S-diphenylmethylcysteine and -cysteine peptides. J Chem Soc (C): 2683–2687Google Scholar
  94. 94.
    Munson MC, García-Echeverria C, Albericio F, Barany G (1992) S-2,4,6-Trimethoxybenzyl (Tmob): a novel cysteine protecting group for the Nα-9-fluorenyl-methoxycarbonyl (Fmoc) strategy of peptide synthesis. J Org Chem 57:3013–3018Google Scholar
  95. 95.
    Nishio H, Kimura T, Sakakibara S (1994) Side reaction in peptide synthesis: Modification of tryptophan during treatment with mercury(II) acetate/2-mercapto-ethanol in aqueous acetic acid. Tetrahedron Lett 35:1239–1242Google Scholar
  96. 96.
    Kenner GW, Galpin IJ, Ramage R (1979) Synthetic studies directed towards the synthesis of a lysozyme analog. In: Gross E, Meienhofer J (eds) Peptides: structure and biological function. Pierce Chemical Co., Rockford, IL, pp 431–438Google Scholar
  97. 97.
    Albericio F, Hammer RP, García-Echeverría C, Molins MA, Chang JL, Munson MC, Pons M, Giralt E, Barany G (1991) Cyclization of disulfide-containing pep-tides in solid-phase synthesis. Int J Peptide Protein Res 37:402–413Google Scholar
  98. 98.
    Edwards WB, Fields CG, Anderson CJ, Pajeau TS, Welch MJ, Fields GB (1994) Generally Applicable, Convenient Solid-Phase Synthesis and Receptor Affinities of Octreotide Analogs. J Med Chem 37:3749–3757PubMedGoogle Scholar
  99. 99.
    Albericio Fea, Annis I, Royo M, Barany G (2000) Preparation and handling of peptides containing methionine and cysteine. In: Chan WC, White PD (eds) Fmoc solid phase peptide synthesis. Oxford University Press, Oxford, pp 77–114Google Scholar
  100. 100.
    Marder O, Albericio F (2003) Industrial application of coupling reagents in pep-tides. Chim Oggi 21:35–40Google Scholar
  101. 101.
    Hachmann J, Lebl M (2006) Search for optimal coupling reagent in multiple peptide synthesizer. Biopolymers (Peptide Sci) 84:340–347Google Scholar
  102. 102.
    Rich DH, Singh J (1979) The carbodiimide method. In: Gross E, Meienhofer J (eds). The peptides, Vol 1 Academic Press, New York, pp 241–314Google Scholar
  103. 103.
    Merrifield RB, Singer J, Chait BT (1988) Mass spectrometric evaluation of synthetic peptides for deletions and insertions. Anal Biochem 174:399–414PubMedGoogle Scholar
  104. 104.
    König W, Geiger R (1970) Eine neue methode zur synthese von peptiden: Aktivierung der carboxylgruppe mit dicyclohexylcarbodiimid unter zusatz von 1-hydroxy-benzotriazolen. Chem Ber 103:788–798PubMedGoogle Scholar
  105. 105.
    König W, Geiger R (1973) N-hydroxyverbindungen als katalysatoren für die ami-nolyse aktivierter ester. Chem Ber 106:3626–3635Google Scholar
  106. 106.
    Abdelmoty I, Alberici F, Carpino LA, Foxman BM, Kates SA (1994) Structural studies of reagents for peptide bond formation: crystal and molecular structures of HBTU and HATU. Lett Peptide Sci 1:57–67Google Scholar
  107. 107.
    Dourtoglou V, Gross B, Lambropoulou V, Zioudrou C (1984) O-benzotriazolyl-N,N,N′,N′,-tetramethyluronium hexafluorophosphate as coupling reagent for the synthesis of peptides of biological interest. Synthesis: 572–574Google Scholar
  108. 108.
    Fournier A, Wang CT, Felix AM (1988) Applications of BOP reagent in solid phase peptide synthesis: advantages of BOP reagent for difficult couplings exemplified by a synthesis of [Ala15]-GRF(1–29)-NH2. Int J Peptide Protein Res 31:86–97Google Scholar
  109. 109.
    Ambrosius D, Casaretto M, Gerardy-Schahn R, Saunders D, Brandenburg D, Zahn H (1989) Peptide analogues of the anaphylatoxin C3a: synthesis and properties. Biol Chem Hoppe-Seyler 370:217–227PubMedGoogle Scholar
  110. 110.
    Gausepohl H, Kraft M, Frank R (1989) In situ activation of Fmoc-amino acids by BOP in solid phase peptide synthesis. In: Jung G, Bayer E (eds). Peptides 1988 Walter de Gruyter & Co., Berlin, pp 241–243Google Scholar
  111. 111.
    Seyer R, Aumelas A, Caraty A, Rivaille P, Castro B (1990) Repetitive BOP coupling (REBOP) in solid phase peptide synthesis: luliberin synthesis as model. Int J Peptide Protein Res 35:465–472Google Scholar
  112. 112.
    Fields CG, Lloyd DH, Macdonald RL, Otteson KM, Noble RL (1991) HBTU activation for automated Fmoc solid-phase peptide synthesis. Peptide Res 4:95–101Google Scholar
  113. 113.
    Knon R, Trzeciak A, Bannwarth W, Gillessen D (1991) 1,1,3,3-Tetramethyluronium compounds as coupling reagents in peptide and protein chemistry. In: Giratt E, Andreu (eds) Peptides 1990. Escom, Leiden, The Netherlands, pp 62–64Google Scholar
  114. 114.
    Carpino LA, El-Faham A, Minor CA, Albericio F (1994) Advantageous applications of azabenzotriazole (triazolopyridine)-based coupling reagents to solid-phase peptide synthesis. J Chem Soc Chem Commun: 201–203Google Scholar
  115. 115.
    Hudson D (1988) Methodological implications of simultaneous solid-phase peptide synthesis 1: Comparison of different coupling procedures. J Org Chem 53:617–624Google Scholar
  116. 116.
    Sabatino G, Mulinacci B, Alcaro MC, Chelli M, Rovero P, Papini AM (2002) Assessment of new 6-Cl-HOBt based coupling reagents for peptide synthesis. Lett Peptide Sci 9:119–123Google Scholar
  117. 117.
    Gausepohl H, Pieles U, Frank RW (1992) Schiffs base analog formation during in situ activation by HBTU and TBTU. In: Smith JA, Rivier JE (eds) Peptides chemistry and biology Escom, Leiden, The Netherlands, pp 523–524Google Scholar
  118. 118.
    Story SC, Aldrich JV (1992) A resin for the solid phase synthesis of protected peptide amides using the Fmoc chemical protocol. Int J Peptide Protein Res 39:87–92Google Scholar
  119. 119.
    Coste J, Le-Nguyen D, Castro B (1990) PyBOP: a new peptide coupling reagent devoid of toxic by-product. Tetrahedron Lett 31:205–208Google Scholar
  120. 120.
    Carpino LA, Xia J, Zhang C, El-Faham A (2004) Organophosphorus and nitro-substituted sulfonate esters of 1-hydroxy-7-azabenzotriazole as highly efficient fast-acting peptide coupling reagents. J Org Chem 69:62–71PubMedGoogle Scholar
  121. 121.
    Li J, Jiang X, Ye YH, Fan C, Romoff T, Goodman M (1999) 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT): a new coupling reagent with remarkable resistance to racemization. Org Lett 1:91–93PubMedGoogle Scholar
  122. 122.
    Yo YH, Li H, Jiang X (2004) DEPBT as an efficient coupling reagent for amide bond formation with remarkable resistance to racemization. Biopolymers (Peptide Sci) 80:172–178Google Scholar
  123. 123.
    Kisfaludy L, Löw M, Nyéki O, Szirtes T, Schön I (1973) Die verwendung von pen-tafluorophenylestern bei peptid-synthesen. Justus Liebigs Ann Chem: 1421–1429Google Scholar
  124. 124.
    Penke B, Baláspiri L, Pallai P, Kovács K (1974) Application of pentafluoroph-enyl esters of Boc-amino acids in solid phase peptide synthesis. Acta Phys Chem 20:471–476Google Scholar
  125. 125.
    Kisfaludy L, Schön I (1983) Preparation and applications of pentafluoroph-enyl esters of 9-fluorenylmethyloxycarbonyl amino acids for peptide synthesis. Synthesis: 325–327Google Scholar
  126. 126.
    Green M, Berman J (1990) Preparation of pentafluorophenyl esters of Fmoc protected amino acids with pentafluorophenyl trifluoroacetate. Tetrahedron Lett 31:5851, 5852Google Scholar
  127. 127.
    Atherton E, Cameron LR, Sheppard RC (1988) Peptide synthesis, part 10: Use of pentafluorophenyl esters of fluorenylmethoxycarbonylamino acids in solid phase peptide synthesis. Tetrahedron 44:843–857Google Scholar
  128. 128.
    Hudson D (1990) Methodological implications of simultaneous solid-phase peptide synthesis: A comparison of active esters Peptide Res 3:51–55Google Scholar
  129. 129.
    Fields CG, Fields GB, Noble RL, Cross TA (1989) Solid phase peptide synthesis of [15N]-gramicidins A, B, and C and high performance liquid chromatographic purification. Int J Peptide Protein Res 33:298–303Google Scholar
  130. 130.
    Harrison JL, Petrie GM, Noble RL, Beilan HS, McCurdy SN, Culwell AR (1989) Fmoc chemistry: Synthesis, kinetics, cleavage, and deprotection of arginine-con-taining peptides. In: Hugli TE (ed) Techniques in Protein Chemistry. Academic Press, San Diego, pp 506–516Google Scholar
  131. 131.
    Geiser T, Beilan H, Bergot BJ, Otteson KM (1988) Automation of solid-phase pep-tide synthesis. In: Schlesinger DH (ed) Macromolecular sequencing and synthesis: selected methods and applications. Alan R. Liss, Inc., New York, pp 199–218Google Scholar
  132. 132.
    König W, Geiger R (1970) Racemisierung bei peptidsynthesen. Chem Ber 103:2024–2033PubMedGoogle Scholar
  133. 133.
    Carpino LA, Sadat-Aalaee D, Chao HG, DeSelms RH (1990) ((9-Fluorenylmet-hyl)oxy)carbonyl (Fmoc) amino acid fluorides: convenient new peptide coupling reagents applicable to the Fmoc/tert-butyl strategy for solution and solid-phase syntheses. J Am Chem Soc 112:9651–9652Google Scholar
  134. 134.
    Carpino LA, Mansour ESME (1992) Protected β- and γ-aspartic and -glutamic acid fluorides. J Org Chem 57:6371–6373Google Scholar
  135. 135.
    Wenschuh H, Beyermann M, Krause E, Brudel M, Winter R, Schümann M, Carpino LA, Bienert M (1994) Fmoc amino acid fluorides: convenient reagents for the solid-phase assembly of peptides incorporating sterically hindered residues. J Org Chem 59:3275–3280Google Scholar
  136. 136.
    Wenschuh H, Beyermann M, Haber H, Seydel JK, Krause E, Bienert M, Carpino LA, El-Faham A, Albericio F (1995) Stepwise automated solid phase synthesis of naturally occurring peptaibols using Fmoc amino acid fluorides. J Org Chem 60:405–410Google Scholar
  137. 137.
    Carpino LA, El-Faham A (1995) Tetramethylfluoroformamidinium hexafluoro-phosphate: a rapid-acting peptide coupling reagent for solution and solid-phase peptide synthesis. J Am Chem Soc 117:5401–5402Google Scholar
  138. 138.
    Carpino LA, Ionescu D, El-Faham A, Beyermann M, Henklein P, Hanay C, Wenschuh H, Bienert M (2003) Complex Polyfluoride Additives in Fmoc-Amino Acid Fluoride Coupling Processes. Enhanced Reactivity and Avoidance of Stereomutation. Org Lett 5:975–977PubMedGoogle Scholar
  139. 139.
    Schnölzer M, Kent SBH (1992) Constructing proteins by dovetailing unprotected synthetic peptides. Science 256:221–225PubMedGoogle Scholar
  140. 140.
    Muir TW, Dawson PE, Kent SBH (1997) Protein synthesis by chemical ligation of unprotected peptides in aqueous solution. Meth Enzymol 289:266–298PubMedGoogle Scholar
  141. 141.
    Dawson PE, Kent SBH (1993) Convenient total synthesis of a 4-helix TASP molecule by chemoselective ligation. J Am Chem Soc 115:7263–7266Google Scholar
  142. 142.
    Williams MJ, Muir TW, Ginsberg MH, Kent SBH (1994) Total chemical synthesis of a folded β-sandwich protein domain: an analog of the tenth fibronectin type 3 module. J Am Chem Soc 116:10,797–10,798Google Scholar
  143. 143.
    Baca M, Muir TW, Schnölzer M, Kent SBH (1995) Chemical ligation of cysteine-containing peptides: synthesis of a 22 kDa tethered dimer of HIV-1 protease. J Am Chem Soc 117:1881–1887Google Scholar
  144. 144.
    Canne LE, Walker SM, Kent SBH (1995) A general method for the synthesis of thioester resin linkers for use in the solid phase synthesis of peptide-a-thioacids. Tetrahedron Lett 36:1217–1220Google Scholar
  145. 145.
    Muir TW, Williams MJ, Ginsberg MH, Kent SBH (1994) Design and chemical synthesis of a neoprotein structural model for the cytoplasmic domain of a multi-subunit cell-surface receptor: integrin αIIbβ3 (platelet GPIIb-IIIa). Biochemistry 33:7701–7708PubMedGoogle Scholar
  146. 146.
    Nefzi A, Sun X, Mutter M (1995) Chemoselective ligation of multifunctional peptides to topological templates via thioether formation for TASP synthesis. Tetrahedron Lett 36:229–230Google Scholar
  147. 147.
    McCafferty DG, Slate CA, Nakhle BM, Graham J, HD, Austell TL, Vachet RW, Mullis BH, Erickson BW (1995) Engineering of a 129-residue tripod protein by chemoselective ligation of proline-II helices. Tetrahedron 51:9859–9872Google Scholar
  148. 148.
    Englebretsen DR, Garnham BG, Bergman DA, Alewood PF (1995) A novel thioether linker: chemical synthesis of a HIV-1 protease analogue by thioether ligation. Tetrahedron Lett 36:8871–8874Google Scholar
  149. 149.
    Ramage R, Biggin GW, Brown AR, Comer A, Davison A, Draffan L, Jiang L, Morton G, Robertson N, Shaw KF, Tennant G, Urquhart K, Wilken J (1996) Methodology for chemical synthesis of proteins. In: Epton R (ed) Innovation and perspectives in solid phase synthesis & combinatorial libraries 1996. Mayflower Scientific, Kingswinford, UK, pp 1–10Google Scholar
  150. 150.
    Li X, Kawakami T, Aimoto S (1998) Direct preparation of peptide thioesters using an Fmoc solid-phase method. Tetrahedron Lett 39:8669–8672Google Scholar
  151. 151.
    Clippingdale AB, Barrow CJ, Wade JD (2000) Peptide thioester preparation by Fmoc solid phase peptide synthesis for use in native chemical ligation. J Peptide Sci 6:225–234Google Scholar
  152. 152.
    Bu XZ, Xie G Y, Law CW, Guo ZH (2002) An improved deblocking agent for direct Fmoc solid-phase synthesis of peptide thioesters. Tetrahedron Lett 43:2419–2422Google Scholar
  153. 153.
    Gross CM, Lelievre D, Woodward CK, Barany G (2005) Preparation of protected peptidyl thioester intermediates for native chemical ligation by Nα-9-fluorenyl-methoxycarbonyl (Fmoc) chemistry: considerations of side-chain and backbone anchoring strategies, and compatible protection for N-terminal cysteine. J Peptide Res 65:395–410Google Scholar
  154. 154.
    Ingenito R, Bianchi E, Fattori D, Pessi A (1999) Solid-phase synthesis of peptide C-terminal thioesters by Fmoc/t-Bu chemistry. J Am Chem Soc 121:11,369–11,374Google Scholar
  155. 155.
    Shin Y, Winans KA, Backes BJ, Kent SBH, Ellman JA, Bertozzi CR (1999) Fmoc-based synthesis of peptide-thioesters: applications to the total chemical synthesis of a glycoprotein by native chemical ligation. J Am Chem Soc 121:11,684–11,689Google Scholar
  156. 156.
    Quaderer R, Hilvert D (2001) Improved synthesis of C-terminal peptide thioesters on “safety-catch” resins using LiBr/THF. Org Lett 3:3181–3184PubMedGoogle Scholar
  157. 157.
    Camarero JA, Hackel BJ, Yoreo JJD, Mitchell AR (2004) Fmoc-based synthesis of peptide thioesters using an aryl hydrazine support. J Org Chem 69:4145–4151PubMedGoogle Scholar
  158. 158.
    Alasina J, Yokum TS, Albericio F, Barany G (1999) Backbone amide linker (BAL) strategy for Nα-9-fluorenylmethoxycarbonyl solid-phase synthesis of unprotected peptide p-nitroanilide and thioesters. J Org Chem 64:8761–8769Google Scholar
  159. 159.
    Brask J, Albericio F, Jensen KJ (2003) Fmoc solid-phase synthesis of peptide thioesters by masking as trithioorthoesters. Org Lett 5:2951–2953PubMedGoogle Scholar
  160. 160.
    Swwinnen D, Hilvert D (2000) Facile, Fmoc-compatible solid-phase synthesis of peptide C-terminal thioesters. Org Lett 2:2439–2442Google Scholar
  161. 161.
    Sewing A, Hilvert D (2001) Fmoc-compatible solid-phase peptide synthesis of long C-terminal peptide thioesters. Angew Chem Int Ed 40:3395–3396Google Scholar
  162. 162.
    Tuchscherer G (1993) Template assembled synthetic proteins: condensation of a multifunctional peptide to a topological template via chemoselective ligation. Tetrahedron Lett 34:8419–8422Google Scholar
  163. 163.
    Rose K (1994) Facile synthesis of homogeneous artificial proteins. J Am Chem Soc 116:30–33Google Scholar
  164. 164.
    Rao G, Tam JP (1994) Synthesis of peptide dendrimer. J Am Chem Soc 116:6975–6976Google Scholar
  165. 165.
    Spetzler JG, Tam JP (1995) Unprotected peptides as building blocks for branched peptides and peptide dendrimers. Int J Peptide Protein Res 45:78–85Google Scholar
  166. 166.
    Shao J, Tam JP (1995) Unprotected peptides as building blocks for the synthesis of peptide dendrimers with oxime, hydrazone, and thiazolidine linkages. J Am Chem Soc 117:3893–3899Google Scholar
  167. 167.
    Tam JP, Spetzler JC (1997) Multiple antigen peptide system. Meth Enzymol 289:612–637PubMedGoogle Scholar
  168. 168.
    Dawson PE, Muir TW, Clark-Lewis I, Kent SBH (1994) Synthesis of proteins by native chemical ligation. Science 266:776–779PubMedGoogle Scholar
  169. 169.
    Dawson PE, Churchill MJ, Ghadiri MR, Kent SBH (1997) Modulation of reactivity in native chemical ligation through the use of thiol additives. J Am Chem Soc 119:4325–4329Google Scholar
  170. 170.
    Johnson ECB, Kent SBH (2006) Insights into the mechanism and catalysis of the native chemical ligation reaction. J Am Chem Soc 128:6640–6646PubMedGoogle Scholar
  171. 171.
    Hackeng TM, Griffin JH, Dawson PE (1999) Protein synthesis by native chemical ligation: Expanded scope by using straightforward methodology. Proc Natl Acad Sci USA 96:10,068–10,073Google Scholar
  172. 172.
    Camarero JA, Pavel J, Muir TW (1998) Chemical synthesis of a circular protein domain: Evidence for folding-assisted cyclization. Angew Chem Int Ed 37:347–349Google Scholar
  173. 173.
    Camarero JA, Muir TW (1999) Biosynthesis of a head-to-tail cyclized protein with improved biological activity. J Am Chem Soc 121:5597–5598Google Scholar
  174. 174.
    Beligere GS, Dawson PE (1999) Conformationally assisted protein ligation using C-terminal thioester peptides. J Am Chem Soc 121:2633–6333Google Scholar
  175. 175.
    Liu CF, Tam JP (1994) Peptide segment ligation strategy without use of protecting groups. Proc Natl Acad Sci USA 91:6574–6588Google Scholar
  176. 176.
    Tam JP, Yu Q, Miao Z (1999) Orthogonal ligation strategies for peptide and protein. Biopolymers (Peptide Sci) 51:311–332Google Scholar
  177. 177.
    Beligere GS, Dawson PE (1999) Synthesis of a three zinc finger protein, Zif268, by native chemical ligation. Biopolymers (Peptide Sci) 51:363–369Google Scholar
  178. 178.
    Canne LE, Botti P, Simon RJ, Chen Y, Dennis EA, Kent SBH (1999) Chemical protein synthesis by solid phase ligation of unprotected peptide segments. J Am Chem Soc 121:8720–8727Google Scholar
  179. 179.
    Canne LE, Ferré-D'Amaré AR, Burley SK, Kent SBH (1995) Total chemical synthesis of a unique transcription factor-related protein: cMyc-Max. J Am Chem Soc 117:2998–3007Google Scholar
  180. 180.
    Quaderer R, Sewing A, Hilvert D (2001) Selenocysteine-mediated native chemical ligation. Helv Chim Acta 84:1197–1206Google Scholar
  181. 181.
    Gieselman MD, Xie L, van der Donk WA (2001) Synthesis of selenocysteine-containing peptide by native chermical ligation. Org Lett 3:1331–1334PubMedGoogle Scholar
  182. 182.
    Canne LE, Bark SJ, Kent SBH (1996) Extending the applicability of native chemical ligation. J Am Chem Soc 118:5891–5896Google Scholar
  183. 183.
    Offer J, Dawson PE (2000) N-2-mercaptobenzylamine-assisted chemical ligation. Org Lett 2:23–26PubMedGoogle Scholar
  184. 184.
    Offer J, Boddy CNC, Dawson PE (2000) Extending synthetic access to proteins with a removable acyl transfer auxilliary. J Am Chem Soc 124:4642–4646Google Scholar
  185. 185.
    Nilsson BL, Kiessling LL, Raines RT (2000) Staudinger ligation: a peptide from a thioster and azide to form a peptide. Org Lett 2:1939–1941PubMedGoogle Scholar
  186. 186.
    Saxon E, Armstrong JI, Bertozzi CR (2000) A “traceless” Staudinger ligation for chemoselective synthesis of amide bonds. Org Lett 2:2141–2143PubMedGoogle Scholar
  187. 187.
    Nilsson BL, Kiessling LL, Raines RT (2001) High-yielding Staudinger ligation of a phosphothioster and azide to form a peptide. Org Lett 3:9–12PubMedGoogle Scholar
  188. 188.
    Soellner MB, Nilsson BL, Raines RT (2002) Staudinger ligation of alpha-azido acids retains stereochemistry. J Org Chem 67:4993–4996PubMedGoogle Scholar
  189. 189.
    Nilsson BL, Hondal RJ, Soellner MB, Raines RT (2003) Protein assembly by orthogonal chemical ligation methods. J Am Chem Soc 125:5268–5269PubMedGoogle Scholar
  190. 190.
    Tam JP, Merrifield RB (1987) Strong acid deprotection of synthetic peptides: Mechanisms and methods. In: Udenfriend S, Meienhofer J (eds) The peptides, Vol 9. Academic Press, New York, pp 185–248Google Scholar
  191. 191.
    Yajima H, Fujii N, Funakoshi S, Watanabe T, Murayama E, Otaka A (1988) New strategy for the chemical synthesis of proteins. Tetrahedron 44:805–819Google Scholar
  192. 192.
    Nomizu M, Inagaki Y, Yamashita T, Ohkubo A, Otaka A, Fujii N, Roller PP, Yajima H (1991) Two-step hard acid deprotection/cleavage procedure for solid phase peptide synthesis. Int J Peptide Protein Res 37:145–152Google Scholar
  193. 193.
    Akaji K, Fujii N, Tokunaga F, Miyata T, Iwanaga S, Yajima H (1989) Studies on peptides CLXVIII: syntheses of three peptides isolated from horseshoe crab hemocytes, tachyplesin I, tachyplesin II, and polyphemusin I. Chem Pharm Bull 37:2661–2664Google Scholar
  194. 194.
    Jaeger E, Thamm P, Knof S, Wünsch E, Löw M, Kisfaludy L (1978) Nebenreaktionen bei peptidsynthesen III: synthese und charakterisierung von Nin-tert-butylierten tryptophan-derivaten. Hoppe-Seyler's Z Physiol Chem 359:1617–1628PubMedGoogle Scholar
  195. 195.
    Jaeger E, Thamm P, Knof S, Wünsch E (1978) Nebenreaktionen bei peptidsynthe-sen IV: charakterisierung von C- und C,N-tert-butylierten tryptophan-derivaten. Hoppe-Seyler's Z Physiol Chem 359:1629–1636PubMedGoogle Scholar
  196. 196.
    Löw M, Kisfaludy L, Jaeger E, Thamm P, Knof S, Wünsch E (1978) Direkte tert-butylierung des tryptophans: Herstellung von 2,5,7-tri-tert-butyltryp-tophan. Hoppe-Seyler's Z Physiol Chem 359:1637–1642PubMedGoogle Scholar
  197. 197.
    Löw M, Kisfaludy L, Sohár P (1978) tert-Butylierung des tryptophan-indolringes während der abspaltung der tert-butyloxycarbonyl-gruppe bei peptidsynthesen. Hoppe-Seyler's Z Physiol Chem 359:1643–1651PubMedGoogle Scholar
  198. 198.
    Masui Y, Chino N, Sakakibara S (1980) The modification of tryptophyl residues during the acidolytic cleavage of Boc-groups I: studies with Boc-tryptophan. Bull Chem Soc Jpn 53:464–468Google Scholar
  199. 199.
    Sieber P (1987) Modification of tryptophan residues during acidolysis of 4-methoxy-2,3,6-trimethylbenzenesulfonyl groups: Effects of scavengers. Tetrahedron Lett 28:1637–1640Google Scholar
  200. 200.
    King DS, Fields CC, Fields GB (1990) A cleavage method which minimizes side reactions following Fmoc solid phase peptide synthesis. Int J Peptide Protein Res 36:255–266Google Scholar
  201. 201.
    Riniker B, Hartmann A (1990) Deprotection of peptides containing Arg(Pmc) and tryptophan or tyrosine: elucidation of by-products. In: Rivier JE, Marshall GR (eds) Peptides: chemistry, structure and biology. Escom, Leiden, The Netherlands, pp 950–952Google Scholar
  202. 202.
    Riniker B, Kamber B (1989) Byproducts of Trp-peptides synthesized on a p-benzyloxybenzyl alcohol polystyrene resin. In: Jung G, Bayer E (eds) Peptides 1988. Walter de Gruyter & Co., Berlin, pp 115–117Google Scholar
  203. 203.
    Gesellchen PD, Rothenberger RB, Dorman DE, Paschal JW, Elzey TK, Campbell CS (1990) A new side reaction in solid-phase peptide synthesis: Solid support-dependent alkylation of tryptophan. In: Rivier JE, Marshall GR (eds) Peptides: chemistry structure and biology. Escom, Leiden, The Netherlands, pp 957–959Google Scholar
  204. 204.
    Albericio F, Kneib-Cordonier N, Biancalana S, Gera L, Masada RI, Hudson D, Barany G (1990) Preparation and application of the 5-(4-(9-fluorenylmethyloxy carbonyl)aminomethyl-3,5-dimethoxyphenoxy)valeric acid (PAL) handle for the solid-phase synthesis of C-terminal peptide amides under mild conditions. J Org Chem 55:3730–3743Google Scholar
  205. 205.
    Fields CG, VanDrisse VL, Fields GB (1993) Edman degradation sequence analysis of resin-bound peptides synthesized by 9-fluorenylmethoxycarbonyl chemistry. Peptide Res 6:39–47Google Scholar
  206. 206.
    Stierandová A, Sepetov NF, Nikiforovich G V, Lebl M (1994) Sequence-dependent modification of Trp by the Pmc protecting group of Arg during TFA deprotection. Int J Peptide Protein Res 43:31–38Google Scholar
  207. 207.
    Jaeger E, Remmer HA, Jung G, Metzger J, Oberthür W, Rücknagel KP, Schäfer W, Sonnenbichler J, Zetl I (1993) Nebenreaktionen bei peptidsynthesen V: O-sulfonierung von serin und threonin während der abspaltung der Pmc- und Mtr-schutzgruppen von argininresten bei Fmoc-festphasen-synthesen. Biol Chem Hoppe-Seyler 374:349–362PubMedGoogle Scholar
  208. 208.
    Solé NA, Barany G (1992) Optimization of solid-phase synthesis of [Ala8]-dynorphin A. J Org Chem 57:5399–5403Google Scholar
  209. 209.
    Gisin BF, Merrifield RB (1972) Carboxyl-catalyzed intramolecular aminolysis: a side reaction in solid-phase peptide synthesis. J Am Chem Soc 94:3102–3106PubMedGoogle Scholar
  210. 210.
    Pedroso E, Grandas A, de las Heras X, Eritja R, Giralt E (1986) Diketopiperazine formation in solid phase peptide synthesis using p-alkoxybenzyl ester resins and Fmoc-amino acids. Tetrahedron Lett 27:743–746Google Scholar
  211. 211.
    Albericio F, Barany G (1985) Improved approach for anchoring Nα-9-fluorenyl-methyloxycarbonylamino acids as p-alkoxybenzyl esters in solid-phase peptide synthesis. Int J Peptide Protein Res 26:92–97Google Scholar
  212. 212.
    Gairi M, Lloyd-Williams P, Albericio F, Giralt E (1990) Use of BOP reagent for the suppression of diketopiperazine formation in Boc/Bzl solid-phase peptide synthesis. Tetrahedron Lett 31:7363–7366Google Scholar
  213. 213.
    Ueki M, Amemiya M (1987) Removal of 9-fluorenylmethyloxycarbonyl (Fmoc) group with tetrabutylammonium fluoride. Tetrahedron Lett 28:6617–6620Google Scholar
  214. 214.
    Barlos K, Gatos D, Hondrelis J, Matsoukas J, Moore GJ, Schäfer W, Sotiriou P (1989) Darstellung neuer säureempfindlicker harze vom sek.-alkohol-typ und ihre anwendung zur synthese von peptiden. Liebigs Ann Chem: 951–955Google Scholar
  215. 215.
    Barlos K, Gatos D, Kallitsis J, Papaphotiu G, Sotiriu P, Wenqing Y, Schäfer W (1989) Darstellung geschützter peptid-fragmente unter einsatz substituierter triphenylmethyl-harze. Tetrahedron Lett 30:3943–3946Google Scholar
  216. 216.
    Bodanszky M, Kwei JZ (1978) Side reactions in peptide synthesis VII: Sequence dependence in the formation of aminosuccinyl derivatives from β-benzyl-aspartyl peptides. Int J Peptide Protein Res 12:69–74Google Scholar
  217. 217.
    Bodanszky M, Tolle JG, Deshmane SS, Bodanszky A (1978) Side reactions in peptide synthesis VI: A reexamination of the benzyl group in the protection of the side chains of tyrosine and aspartic acid. Int J Peptide Protein Res 12:57–68Google Scholar
  218. 218.
    Nicolás E, Pedroso E, Giralt E (1989) Formation of aspartimide peptides in Asp-Gly sequences. Tetrahedron Lett 30:497–500Google Scholar
  219. 219.
    Kenner GW, Seely JH (1972) Phenyl esters for C-terminal protection in peptide synthesis. J Am Chem Soc 94:3259–3260PubMedGoogle Scholar
  220. 220.
    Schön I, Colombo R, Csehi A (1983) Effect of piperidine on benzylaspartyl pep-tides in solution and in the solid phase. J Chem Soc Chem Commun: 505–507Google Scholar
  221. 221.
    Yang Y, Sweeney WV, Scheider K, Thörnqvist S, Chait BT, Tam JP (1994) Aspartimide formation in base-driven 9-fluorenylmethoxycarbonyl chemistry. Tetrahedron Lett 35:9689–9692Google Scholar
  222. 222.
    Lauer JL, Fields CG, Fields GB (1995) Sequence dependence of aspartimide formation during 9-fluorenylmethoxycarbonyl solid-phase synthesis. Lett Peptide Sci 1:197–205Google Scholar
  223. 223.
    Dölling R, Beyermann M, Haenel J, Kernchen F, Krause E, Franke P, Brudel M, Bienert M (1994) Piperidine-mediated side product formation for Asp(OBut)-containing peptides. J Chem Soc Chem Commun: 853–854Google Scholar
  224. 224.
    Wade JD, Mathieu MN, Macris M, Tregear GW (2000) Base-induced side reactions in Fmoc-solid phase peptide synthesis: Minimization by use of piperazine as Nα-deprotection reagent. Lett Peptide Sci 7:107–112Google Scholar
  225. 225.
    Quibell M, Owen D, Packman LC, Johnson T (1994) Suppression of piperidine-mediated side product formation for Asp(OBut)-containing peptides by the use of N-(2-hydroxy-4-methoxybenzyl) (Hmb) backbone amide protection. J Chem Soc Chem Commun: 2343–2344Google Scholar
  226. 226.
    Cebrián J, Domingo V, Reig F (2003) Synthesis of peptide sequences related to thrombospondin: Factors affecting aspartimide by-product formation. J Pept Res 62:238–244PubMedGoogle Scholar
  227. 227.
    Atherton E, Hardy PM, Harris DE, Matthews BH (1991) Racemization of C-terminal cysteine during peptide assembly. In: Giralt E, Andreu D (eds) Peptides 1990. Escom, Leiden, The Netherlands, pp 243–244Google Scholar
  228. 228.
    Angell YM, Alsina J, Albericio F, Barany G (2002) Practical protocols for stepwise solid-phase synthesis of cysteine-containing peptides. J Pept Res 60:292–299PubMedGoogle Scholar
  229. 229.
    Fujiwara Y, Akaji K, Kiso Y (1994) Racemization-free synthesis of C-terminal cysteine-peptide using 2-chlorotrityl resin. Chem Pharm Bull 42:724–726PubMedGoogle Scholar
  230. 230.
    Fields CG, Fields GB (1994) Solvents for solid-phase peptide synthesis. In: Pennington MW, Dunn BM (eds) Methods in molecular biology Vol 35: peptide synthesis protocols. Humana Press, Inc., Totowa, NJ, pp 29–40Google Scholar
  231. 231.
    Sarin VK, Kent SBH, Mitchell AR, Merrifield RB (1984) A general approach to the quantitation of synthetic efficiency in solid-phase peptide synthesis as a function of chain length. J Am Chem Soc 106:7845–7850Google Scholar
  232. 232.
    Pickup S, Blum FD, Ford WT (1990) Self-diffusion coefficients of Bocamino acid anhydrides under conditions of solid phase peptide synthesis. J Polym Sci A: Polym Chem 28:931–934Google Scholar
  233. 233.
    Live DH, Kent SBH (1983) Correlation of coupling rates with physico-chemical properties of resin-bound peptides in solid phase synthesis. In: Hruby VJ, Rich DH (eds) Peptides: structure and function. Pierce Chemical Co., Rockford, ILGoogle Scholar
  234. 234.
    Mutter M, Altmann KH, Bellof D, Flörsheimer A, Herbert J, Huber M, Klein B, Strauch L, Vorherr T, Gremlich HU (1985) The impact of secondary structure formation in peptide synthesis. In: Deber CM, Hruby VJ, Kopple KD (eds) Peptides: structure and function. Pierce Chemical Co., Rockford, IL, pp 397–405Google Scholar
  235. 235.
    Ludwick AG, Jelinski LW, Live D, Kintanar A, Dumais JJ (1986) Association of peptide chains during Merrifield solid-phase peptide synthesis: a deuterium NMR study. J Am Chem Soc 108:6493–6496Google Scholar
  236. 236.
    Narita M, Kojima Y (1989) The β-sheet structure-stabilizing potential of twenty kinds of amino acid residues in protected peptides. Bull Chem Soc Jpn 62:3572–3576Google Scholar
  237. 237.
    Yamashiro D, Blake J, Li CH (1976) The use of trifluoroethanol for improved coupling in solid-phase peptide synthesis. Tetrahedron Lett: 1469–1472Google Scholar
  238. 238.
    Narita M, Umeyama H, Yoshida T (1989) The easy disruption of the β-sheet structure of resin-bound human proinsulin C-peptide fragments by strong electron-donor solvents. Bull Chem Soc Jpn 62:3582–3586Google Scholar
  239. 239.
    Fields GB, Otteson KM, Fields CG, Noble RL (1990) The versatility of solid phase peptide synthesis. In: Epton R (ed) Innovation and perspectives in solid phase synthesis. Solid Phase Conference Coordination, Ltd., Birmingham, UK, pp 241–260Google Scholar
  240. 240.
    Fields GB, Fields CG (1991) Solvation effects in solid-phase peptide synthesis. J Am Chem Soc 113:4202–4207Google Scholar
  241. 241.
    Stewart JM, Klis WA (1990) Polystyrene-based solid phase peptide synthesis: The state of the art. In: Epton R (ed) Innovation and perspectives in solid phase synthesis. Solid Phase Conference Coordination, Ltd., Birmingham, UK, pp 1–9Google Scholar
  242. 242.
    Thaler A, Seebach D, Cardinaux F (1991) Lithium-salt effects in peptide synthesis, part II: improvement of degree of resin swelling and of efficiency of coupling in solid-phase synthesis. Helv Chim Acta 74:628–643Google Scholar
  243. 243.
    Tam J P, Lu YA (1995) Coupling difficulty associated with interchain clustering and phase transition in solid phase peptide synthesis. J Am Chem Soc 117:12,058–12,063Google Scholar
  244. 244.
    Atherton E, Woolley V, Sheppard RC (1980) Internal association in solid phase peptide synthesis: Synthesis of cytochrome C residues 66–104 on polyamide supports. J Chem Soc Chem Commun: 970–971Google Scholar
  245. 245.
    Atherton E, Sheppard RC (1985) Detection of problem sequences in solid phase synthesis. In: Deber CM, Hruby VJ, Kopple KD (eds) Peptides: structure and function. Pierce Chemical Co., Rockford, IL, pp 415–418Google Scholar
  246. 246.
    Bedford J, Hyde C, Johnson T, Jun W, Owen D, Quibell M, Sheppard RC (1992) Amino acid structure and “difficult sequences” in solid phase peptide synthesis. Int J Peptide Protein Res 40:300–307Google Scholar
  247. 247.
    Hyde C, Johnson T, Sheppard RC (1992) Internal aggregation during solid phase peptide synthesis: dimethyl sulfoxide as a powerful dissociating solvent. J Chem Soc Chem Commun:1573–1575Google Scholar
  248. 248.
    Miranda LP, Alewood PF (1999) Accelerated chemical synthesis of peptides and small proteins. Proc Natl Acad Sci USA 96:1181–1186PubMedGoogle Scholar
  249. 249.
    Zhang L, Goldhammer C, Henkel B, Panhaus G, Zuehl F, Jung G, Bayer E (1994) “Magic mixture,” a powerful solvent system for solid-phase synthesis of difficult peptides. In: Epton R (ed) Innovation and perspectives in solid phase synthesis 1994. Mayflower Worldwide, Ltd., Birmingham, UK, pp 711–716Google Scholar
  250. 250.
    Johnson T, Quibell M, Owen D, Sheppard RC (1993) A reversible protecting group for the amide bond in peptides: use in the synthesis of ‘difficult sequences’. J Chem Soc Chem Commun: 369–372Google Scholar
  251. 251.
    Hyde C, Johnson T, Owen D, Quibell M, Sheppard RC (1994) Some ‘difficult sequences’ made easy: a study of interchain association in solid-phase peptide synthesis. Int J Peptide Protein Res 43:431–440Google Scholar
  252. 252.
    Miranda LP, Meutermans WDF, Smythe ML, Alewood PF (2000) An activated O -> N acyl transfer auxiliary: Efficient amide-backbone substitution of hindered “difficult” peptides. J Org Chem 65:5460–5468PubMedGoogle Scholar
  253. 253.
    Tickler AK, Clippingdale AB, Wade JD (2004) Amyloid-β as a “difficult sequence” in solid phase peptide synthesis. Protein Pept Lett 11:377–384PubMedGoogle Scholar
  254. 254.
    Yu HM, Chen ST, Wang KT (1992) Enhanced coupling efficiency in solid-phase peptide synthesis by microwave irradiation. J Org Chem 57:4781–4784Google Scholar
  255. 255.
    Erdelyi M, Gogoll A (2002) Rapid microwave-assisted solid phase peptide synthesis. Synthesis: 1592–1596Google Scholar
  256. 256.
    Ferguson JD (2003) Focused microwave instrumentation from CEM corporation. Mol Div 7:281–286.Google Scholar
  257. 257.
    Murray, J. K., and Gellman, S. H. (2005) Application of microwave irradiation to the synthesis of 14-helical β-peptides Org Lett 7:1517–1520PubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Mare Cudic
    • 1
  • Gregg B. Fields
    • 1
  1. 1.Department of Chemistry and BiochemistryFlorida Atlantic UniversityBoca Raton

Personalised recommendations