The 9-Fluorenylmethoxycarbonyl (Fmoc) Group in Chemical Peptide Synthesis – Its Past, Present, and Future
Wenyi Li
A , Neil M. O’Brien-Simpson A , Mohammed Akhter Hossain B C D and John D. Wade B C D
A Bio21 Institute and Melbourne Dental School, University of Melbourne, Melbourne, Vic. 3010, Australia.
B Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Vic. 3010, Australia.
C School of Chemistry University of Melbourne, Melbourne, Vic. 3010, Australia.
D Corresponding authors. Email: akhter.hossain@florey.edu.au; john.wade@florey.edu.au
Wenyi Li received his doctoral degree in 2016 from The University of Melbourne under the supervision of Professors John D. Wade and Frances Separovic. His doctoral thesis on antimicrobial peptide development won the Graham Johnston Best Thesis Award from the RACI, Australia. From 2016 to 2018, he was based at the Leibniz Institute of Molecular Pharmacology, Germany, where he was partially supported as a Leibniz-DAAD postdoctoral fellow working on protein semisynthesis and chemical ligation. In 2018, he returned to The University of Melbourne to work on antibacterial polymers and peptides in the groups of Professors Neil M. O’Brien-Simpson and Greg Qiao. |
Neil M. O’Brien-Simpson graduated from Edinburgh Napier University in 1992 with a B.Sc. degree with honours in science and management studies. He moved to Australia and completed a Ph.D. in peptide-polymer vaccines in 1998 at The University of Melbourne. He is currently a professor and his research interests include antimicrobial peptides/materials, nanoparticles for peptide and vaccine delivery, and bacterial outer membrane vesicles-host interactions. He has several editorial duties and is the current president of the Peptide Users Group of the Royal Australian Chemical Institute. |
Mohammed Akhter Hossain received his Ph.D. degree in 2001 from the Tokyo Institute of Technology, where he worked on chemosensors based on cyclodextrin-peptide conjugates with Professor Akihiko Ueno. After that, he was a postdoctoral fellow at the Josef Fourier University in France. In 2005, he joined the Florey Institute of Neuroscience and Mental Health in Melbourne, Australia, where his research interests involve the design and synthesis of novel insulin and relaxin peptidomimetics, and β-amyloid peptides. He is currently a Florey Principal Research Fellow and head of the Insulin Peptides Laboratory. |
John D. Wade obtained his Ph.D. degree in 1979 at Monash University, Australia, on the structural basis of the diabetogenic action of growth hormones. He received a Nuffield Foundation Fellowship to Cambridge, UK, to undertake post-doctoral studies in the laboratory of Dr R. C. Sheppard at the MRC Laboratory of Molecular Biology on the development of the Fmoc-solid phase peptide synthesis methodology. In 1983, he returned to Melbourne at the invitation of the now Florey Institute of Neuroscience and Mental Health, University of Melbourne, where he heads the Laboratory of Peptide and Protein Chemistry. His interests are in solid phase peptide synthesis of large, complex, functionalized, and often multi-chain peptides. Professor Wade is an NHMRC of Australia Principal Research Fellow and a Fellow of both the Royal Australian Chemical Institute and the Royal Society of Chemistry. |
Australian Journal of Chemistry 73(4) 271-276 https://doi.org/10.1071/CH19427
Submitted: 3 September 2019 Accepted: 9 October 2019 Published: 22 November 2019
Journal Compilation © CSIRO 2020 Open Access CC BY-NC-ND
Abstract
The chemical formation of the peptide bond has long fascinated and challenged organic chemists. It requires not only the activation of the carboxyl group of an amino acid but also the protection of the Nα-amino group. The more than a century of continuous development of ever-improved protecting group chemistry has been married to dramatic advances in the chemical synthesis of peptides that, itself, was substantially enhanced by the development of solid-phase peptide synthesis by R. B. Merrifield in the 1960s. While the latter technology has continued to undergo further refinement and improvement in both its chemistry and automation, the development of the base-labile 9-fluorenylmethoxycarbonyl (Fmoc) group and its integration into current synthesis methods is considered a major landmark in the history of the chemical synthesis of peptides. The many beneficial attributes of the Fmoc group, which have yet to be surpassed by any other Nα-protecting group, allow very rapid and highly efficient synthesis of peptides, including ones of significant size and complexity, making it an even more valuable resource for research in the post-genomic world. This review charts the development and use of this Nα-protecting group and its adaptation to address the need for more green chemical peptide synthesis processes.
References
[1] M. Bergmann, L. Zervas, Ber. Dtsch. Chem. Ges. 1932, 65, 1192.| Crossref | GoogleScholarGoogle Scholar |
[2] L. A. Carpino, J. Am. Chem. Soc. 1957, 79, 98.
| Crossref | GoogleScholarGoogle Scholar |
[3] R. B. Merrifield, J. Am. Chem. Soc. 1963, 85, 2149.
| Crossref | GoogleScholarGoogle Scholar |
[4] J. Meienhofer, Biopolymers 1981, 20, 1761.
| Crossref | GoogleScholarGoogle Scholar |
[5] L. A. Carpino, G. Y. Han, J. Am. Chem. Soc. 1970, 92, 5748.
| Crossref | GoogleScholarGoogle Scholar |
[6] E. Atherton, H. Fox, D. Harkiss, C. J. Logan, R. C. Sheppard, B. J. Williams, J. Chem. Soc. Chem. Commun. 1978, 537.
| Crossref | GoogleScholarGoogle Scholar |
[7] C.-D. Chang, J. Meienhofer, Int. J. Pept. Protein Res. 1978, 11, 246.
| Crossref | GoogleScholarGoogle Scholar | 649259PubMed |
[8] M. Beyermann, J. Pept. Sci. 2019, 25, e3168.
| Crossref | GoogleScholarGoogle Scholar | 30989739PubMed |
[9] E. Atherton, J. D. Wade, J. Pept. Sci. 2019, 25, e3171.
| Crossref | GoogleScholarGoogle Scholar | 30989738PubMed |
[10] L. A. Carpino, G. Y. Han, J. Am. Chem. Soc. 1970, 92, 5748.
| Crossref | GoogleScholarGoogle Scholar |
[11] M. Tessier, F. Albericio, E. Pedroso, A. Grandas, R. Eritja, E. Giralt, C. Granier, J. Van Rietschoten, Int. J. Pept. Protein Res. 1983, 22, 125.
| Crossref | GoogleScholarGoogle Scholar | 6885246PubMed |
[12] G. F. Sigler, W. D. Fuller, N. C. Chaturvedi, M. S. Verlander, Biopolymers 1983, 22, 2157.
| Crossref | GoogleScholarGoogle Scholar |
[13] L. A. Carpino, G. Y. Han, J. Org. Chem. 1972, 37, 3404.
| Crossref | GoogleScholarGoogle Scholar |
[14] G. B. Fields, R. L. Noble, Int. J. Pept. Protein Res. 1990, 35, 161.
| Crossref | GoogleScholarGoogle Scholar | 2191922PubMed |
[15] L. A. Carpino, Acc. Chem. Res. 1987, 20, 401.
| Crossref | GoogleScholarGoogle Scholar |
[16] R. C. Sheppard, J. Pept. Sci. 2003, 9, 545.
| Crossref | GoogleScholarGoogle Scholar |
[17] G. I. Tesser, I. C. Balvert-Geers, Int. J. Pept. Protein Res. 1975, 7, 295.
| Crossref | GoogleScholarGoogle Scholar | 241727PubMed |
[18] R. B. Merrifield, A. E. Bach, J. Org. Chem. 1978, 43, 4808.
| Crossref | GoogleScholarGoogle Scholar |
[19] C. G. J. Verhart, G. I. Tesser, Recl. Trav. Chim. Pays Bas 1988, 107, 621.
| Crossref | GoogleScholarGoogle Scholar |
[20] P. M. Balse, G. Han, V. J. Hruby, H. J. Kim, J. Pept. Res. 2000, 56, 70.
| Crossref | GoogleScholarGoogle Scholar | 10961541PubMed |
[21] R. Ramage, J. Green, M. R. Florence, in Peptides – Chemistry and Biology (Ed. G. R. Marshall) 1988, pp. 157–158 (ESCOM: Leiden).
[22] C.-D. Chang, M. Waki, M. Ahmad, J. Meienhofer, E. O. Lundell, J. D. Huag, Int. J. Pept. Protein Res. 1980, 15, 59.
| 7358458PubMed |
[23] E. Atherton, C. J. Logan, R. C. Sheppard, J. Chem. Soc. Perkin Trans. 1 1981, I, 538.
| Crossref | GoogleScholarGoogle Scholar |
[24] E. Atherton, C. Bury, R. C. Sheppard, B. J. Williams, Tetrahedron Lett. 1979, 20, 3041.
| Crossref | GoogleScholarGoogle Scholar |
[25] M. Ueki, M. Amemiya, Tetrahedron Lett. 1987, 28, 6617.
| Crossref | GoogleScholarGoogle Scholar |
[26] J. D. Wade, M. N. Mathieu, M. Macris, G. W. Tregear, Lett. Pept. Sci. 2000, 7, 107.
[27] J. D. Wade, J. Bedford, R. C. Sheppard, G. W. Tregear, Pept. Res. 1991, 4, 194.
| 1823190PubMed |
[28] S. A. Kates, N. A. Solé, M. Beyermann, G. Barany, F. Albericio, Pept. Res. 1996, 9, 106.
| 8875589PubMed |
[29] A. K. Tickler, C. J. Barrow, J. D. Wade, J. Pept. Sci. 2001, 7, 488.
| Crossref | GoogleScholarGoogle Scholar | 11587187PubMed |
[30] D. M. Szantai-Kis, C. R. Walters, T. M. Barrett, E. M. Hoang, E. J. Petersson, Synlett 2017, 1789.
| Crossref | GoogleScholarGoogle Scholar |
[31] E. Kitas, R. Knorr, A. Trzeciak, W. Bannwarth, Helv. Chim. Acta 1991, 74, 1314.
| Crossref | GoogleScholarGoogle Scholar |
[32] J. L. Lauer, C. G. Fields, G. B. Fields, Lett. Pept. Sci. 1995, 1, 197.
| Crossref | GoogleScholarGoogle Scholar |
[33] J. Offer, M. Quibell, T. Johnson, J. Chem. Soc., Perkin Trans. 1 1996, 175.
| Crossref | GoogleScholarGoogle Scholar |
[34] T. Michels, R. Dölling, U. Haberkorn, W. Mier, Org. Lett. 2012, 14, 5218.
| Crossref | GoogleScholarGoogle Scholar | 23025410PubMed |
[35] K. Ralhan, V. G. KrishnaKumar, S. Gupta, RSC Adv. 2015, 5, 104417.
| Crossref | GoogleScholarGoogle Scholar |
[36] C.-C. Chen, B. Rajagopal, X. Y. Liu, K. L. Chen, Y.-C. Tyan, F. Lin, P.-C. Lin, Amino Acids 2014, 46, 367.
| Crossref | GoogleScholarGoogle Scholar | 24306456PubMed |
[37] M. L. Di Gioia, P. Costanzo, A. De Nino, L. Maiuolo, M. Nardi, F. Olivito, A. Procopio, RSC Adv. 2017, 7, 36482.
| Crossref | GoogleScholarGoogle Scholar |
[38] O. F. Luna, J. Gomez, C. Cárdenas, F. Albericio, S. H. Marshall, F. Guzmán, Molecules 2016, 21, 1542.
| Crossref | GoogleScholarGoogle Scholar |
[39] J. Hachmann, M. Lebl, J. Comb. Chem. 2006, 8, 149.
| Crossref | GoogleScholarGoogle Scholar | 16529506PubMed |
[40] V. Rodriguez, H. Pineda, N. Ardila, D. Insuasty, K. Cárdenas, J. Román, M. Urrea, D. Ramírez, R. Fierro, Z. Rivera, J. García, Int. J. Peptide Res. Ther. 2019.,
| Crossref | GoogleScholarGoogle Scholar |
[41] J. Lopez, S. Pletscher, A. Aemissegger, C. Bucher, F. Gallou, Org. Process Res. Dev. 2018, 22, 494.
| Crossref | GoogleScholarGoogle Scholar |
[42] L. Bergkamp, N. Herbatschek, Rev. Eur. Comp. Int. Environ. Law 2014, 23, 221.
| Crossref | GoogleScholarGoogle Scholar |
[43] Y. E. Jad, G. A. Acosta, T. Govender, H. G. Kruger, A. El-Faham, B. G. de la Torre, F. Albericio, ACS Sustain. Chem.& Eng. 2016, 4, 6809.
| Crossref | GoogleScholarGoogle Scholar |
[44] Y. E. Jad, T. Govender, H. G. Kruger, A. El-Faham, B. G. de la Torre, F. Albericio, Org. Process Res. Dev. 2017, 21, 365.
| Crossref | GoogleScholarGoogle Scholar |
[45] A. Isidro-Llobet, M. N. Kenworthy, S. Mukherjee, M. E. Kopach, K. Wegner, F. Gallou, A. G. Smith, F. Roschangar, J. Org. Chem. 2019, 84, 4615.
| Crossref | GoogleScholarGoogle Scholar | 30900880PubMed |
[46] V. Agouridas, O. El Mahdi, V. Diemer, M. Cargoët, J. M. Monbaliu, O. Melnyk, Chem. Rev. 2019, 119, 7328.
| Crossref | GoogleScholarGoogle Scholar | 31050890PubMed |
[47] X. Liu, R. P. B. Emes, K. A. Jollifee, Aust. J. Chem. 2017, 70, 201.
| Crossref | GoogleScholarGoogle Scholar |
[48] E. C. Browne, S. J. Langford, B. M. Abbott, Aust. J. Chem. 2012, 65, 539.
| Crossref | GoogleScholarGoogle Scholar |
