See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/281478549

Peptide Coupling Reactions

Article  in  Journal of Molecular Pharmaceutics & Organic Process Research · January 2015

DOI: 10.4172/2329-9053.1000e119

CITATIONS READS

2 2,753

1 author:

Fernando Albericio
University of KwaZulu-Natal
1,200 PUBLICATIONS   28,176 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

drug development View project

[Antibiotics] Special Issue "Antibiotic Resistance: From the Bench to Patients" View project

All content following this page was uploaded by Fernando Albericio on 04 January 2016.

The user has requested enhancement of the downloaded file.

 Khattab et al., J Mol Pharm Org Process Res 2015, 3:1
Molecular Pharmaceutics & http://dx.doi.org/10.4172/2329-9053.1000e119

Organic Process Research

Editorial Open Access

Peptide Coupling Reactions

Khattab NS1, El-Faham A1,2*, and Albericio F2-7
1
Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, 12321 Alexandria, Egypt
2
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
3
Institute for Research in Biomedicine (IRB), Barcelona Science Park, Baldiri Reixac 10, Barcelona 08028, Spain
4
CIBER-BBN, Networking Centre for Address, Baldiri Reixac 10, 08028-Barcelona, Spain
5
Department of Organic Chemistry, University of Barcelona, Martí i Franqués 1-11, Barcelona 08028, Spain
6
School of Chemistry & Physics, University of KwaZulu-Natal, Durban 4001, South Africa
7
School of Chemistry, Yachat Tech, Yachay City of Knowledge, 100119-Urcuqui, Ecuador

Peptide bond formation is a nucleophilic substitution reaction

OXt F
of an amino group (nucleophile) at a carboxyl group involving a N N
tetrahedral intermediate. Furthermore, the peptide coupling reaction N N

must be performed under mild conditions, and preferably at room X PF6 O

PF6
temperature. Activation of the carboxyl component is achieved by the X = O (6a-g)
DMFH, 8
introduction of electron accepting moieties [1]. Carboxyl components X = S (7a,b)

can be activated as acyl halides, acyl azides, acylimidazoles, anhydrides, O

N X N F F
esters etc. There are different ways of coupling reactive carboxyl N N
N
derivatives with an amine [2]. Y N Y N F F
Xt = O F
In recent years, peptide-coupling reactions have significantly Y = CH, HDMB, 6a HDMS, 6f HDMPfp, 6g
advanced in accord with the development of new peptide-coupling Y = N, HDMA, 6b X = H, Y = Cl, 6-HDMCB; 6c
X = S, Y = CH, HDTMB, 7a X = H, Y = CF3, 6-HDMFB; 6d
reagents and their application to both solution and solid- phase X = S, Y = N, HDTMA, 7b X = N, Y = H, 4-HDMA; 6e
synthesis [3,4]. The formerly techniques of carbodiimide is being
replaced with iminium/uronium derivatives 1-5 [5-21] (Figure 1). Figure 2: Structure of morpholine-based coupling reagents.

Later, El-Faham and Albericio [22] reported a new family of

coupling reagents based on the modification of the structures of the
carbocation skeleton moiety, which feature relatively high reactivity HO
N
and low racemization during peptide bond formation [22]. Very COOEt COOEt CN N O O
HO N HO N HO N
recently, El-Faham and Albericio [23] extended their work taking an CN
HO N
O O
COOEt CN CN
N-containing 6-membered ring structure containing O, S, and N-CH3 11a 11b 11c 11d 11e
for synthesis of novel coupling reagents [24] (Figure 2).
Recent reports confirmed the explosive properties of HOBt Figure 3: Structure of oximes to replace of HOBt.

derivatives [25]. Accordingly, El-Faham and Albericio [25-26]

reported the new additives as well as their uronium salts derivatives
as replacement for HOBt and HOAt derivatives (Figures 3 and 4).
Among these entire additives Oxyma [26] (Figure 3) and its uronium
salt COMU (Figure 4) showed an excellent replacement for HOBt and
its analogues [26,27].
More recently, we have reported 5-(hydroxyimino)-1,3-
dimethylpyrimidine-2,4,6 (1H,3H,5H)-trione (Oxyma-B) as an
excellent additive for the suppression of racemization during peptide
synthesis [27]. Oxyma-B, has the same structure future for the carbonyl
moiety in which the oxime group is flanked between the two carbonyl
group as in HONM. In addition, Oxyma-B performs better as a
racemization suppressor than Oxyma Pure and even better than HOAt
in both stepwise and segment coupling in solid- and solution-phase
peptide synthesis [28]. Lately,a new class of O-form uronium-type
coupling reagents derived from Oxyma-B were introduced TOMBU
and COMBU (Figure 5) [29].

R3
Me PF 6 Me OX
PF6 PF6 PF6
Me N N N SbCl6
N R2 N
OX OX OX OX R1
Me N N N N
R1, R2 = alkyl, aryl
Me Me R3 = H, alkyl, aryl *Corresponding author: El-Faham A, Chemistry Department, Faculty of Science,
1
2 3 4 5 Alexandria University, P.O. Box 426, Ibrahimia, 12321 Alexandria, Egypt, E-mail:
aymanel_faham@hotmail.com

N X N
O Received February 07, 2015; Accepted February 09, 2015; Published February
N N
N
15, 2015
Y N Y N

X = O Citation: Khattab NS, El-Faham A, Albericio F (2015) Peptide Coupling Reactions.

Y = CH,, HBTU, 1a X = H, Y = Cl, HCTU; 1c J Mol Pharm Org Process Res 3: e119. doi: 10.4172/2329-9053.1000e119
HSTU, 1f
Y = N, HATU, 1b X = H, Y = CF3, HFTU; 1d
X = N, Y = H, 4-HATU; 1e
Copyright: © 2015 Khattab NS, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
Figure 1: Structure of symmetric imininum/uronium salts coupling reagents. unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited

J Mol Pharm Org Process Res

ISSN: 2329-9053 JMPOPR, an open access journal Volume 3 • Issue 1 • 1000e119
Citation: Khattab NS, El-Faham A, Albericio F (2015) Peptide Coupling Reactions. J Mol Pharm Org Process Res 3: e119. doi: 10.4172/2329-
9053.1000e119

Page 2 of 2

13. Wijkmans JCHM, Blok FAA, Van der Marel GA, Van Boom JH, Bloemhoff
Me Me Me O O W (1995) CF3-NO2-PyBOP: a new and highly efficient coupling reagent for
N N Me N N N N
Me Me N N
Me N-methyl amino acids. Tetrahedron Lett 36: 4643-4646.
OXt PF6 Me OXt PF6 OXt
PF6
OXt PF6 14. Carpino LA, El-Faham A, Albericio F (1995) Efficiency in Peptide Coupling:
12a-f 13a-f 14a-f 15a-i 1-Hydroxy-7-azabenzotriazole vs 3, 4-Dihydro-3-hydroxy-4-oxo-1,2,3-
benzotriazine. J Org Chem 60: 3561-3564.
N 15. Klose J, El-Faham A, Henklein P, Carpino LA, Bienert, M (1999) Addtion of
COOEt COOEt CN O O
N HOAt Dramatically Improve the Effectiveness of Pentafluorophenyl-Based
N N N N
CN COOEt CN CN
O O Coupling Reagents. Tetrahedron Lett 40: 2045-2048.
Xt = a b c d e
16. Chen SQ, Xu JC (1992) A new coupling reagent for peptide synthesis.
N Benzotriazolvyloxy-bis (pyrroltdino)-carbonium hexaflouorophosphate (BBC).
N N
N O N N
N Tetrahedron Lett 33: 647-650.
Cl N
N N N

h i
17. Carpino LA, El-Faham A (1994) Effect of Tertiary Bases on O-Benzotri-
f g
azolyluronium Salt-Induced Peptide Segment Coupling. J Org Chem 59: 695-
Figure 4: Structures of oximino and benzotriazolo uronium salt. 698.

18. Carpino LA, Xia J, El-Faham A (2004) 3-Hydroxy-4-oxo-3, 4-dihydro-5-

azabenzo-1,2,3-triazene. J Org Chem 69: 54-61.

19. Carpino LA, Henklein P, Foxman BM, Abdelmoty I, Costisella B et al. (2001)
The Solid and Solution Structure of HAPyU. J Org Chem 66: 5245-5247.

20. Li P, Xu JC (2000) New and Highly Efficient Immonium Type Peptide Coupling
Reagents: Synthesis, Mechanism and Application. Tetrahedron 56: 4437-4445

21. Li P, Xu JC (2000) HOBt and HOAt-derived immonium salts: new and highly
efficient coupling reagents for peptide synthesis. Tetrahedron Lett 41: 721-724.

22. El-Faham A, Khattab ShN, Abdul-Ghani M, Albericio F (2006) Design and

Synthesis of New Immonium-Type Coupling Reagents. Eur J Org Chem 1563-
1573.

23. El-Faham A, Albericio F (2007) Novel Proton Acceptor Immonium-Type

Figure 5: Structure of Oxyma-B 16 and its uronium salts TOMBU 17 and
Coupling Reagents: Application in Solution and Solid Phase Peptide Synthesis.
COMBU 18.
Org Lett 9: 4475-4477.
References 24. Faham A, Albericio F (2008) Morpholine-Based Immonium and
1. Montalbetti CAGN, Falque V (2005) Amide bond formation and peptide Halogenoamidinium Salts as Coupling Reagents in Peptide Synthesis. J Org
coupling. Tetrahedron 61: 10827-10852. Chem 73: 2731-1737.

2. El-Faham A, Albericio F (2011) Peptide Coupling Reagents, More than a Letter 25. Wehrstedt KD, Wandrey PA, Heitkamp D (2005) Explosive properties of
Soup. Chem Rev 111: 6557-6602. 1-hydroxybenzotriazoles. J Hazard Mater 126: 1-3.

3. Albericio F, Carpino LA (1997) Methods Enzymol: Solid Phase Peptide 26. Subiros-Funosas R, Prohens R, Barbas R, El-Faham A, Albericio F (2009)
Synthesis Fields, Academic Press, Orlando 289: 104-126. Oxyma: an efficient additive for peptide synthesis to replace benzotriazole-
based HOBt and HOAt with a lower risk of explosión. Chem Eur J 15: 9394-
4. Albericio F, Kates SA (2000) In Solid-Phase Synthesis, A Practical Guide, 9403.
Marcel Dekker, New York 275-330
27. El-Faham A, Subirós-Funosas R, Prohens R, Albericio F (2009) COMU, a Safer
5. Albericio F, Chinchilla R, Dodsworth DJ, Najera C (2001) New Trends in and More Effective Replacement for Benzotriazole-based Uronium Coupling
Peptide Coupling Reagents. Org Prep Proced Int 33: 203-303. Reagents. Chem Eur J 15: 9404-9416.
6. Humphrey JM, Chamberlin AR (1997) Chemical Synthesis of Natural Product 28. Jad YE, Khattab ShN, Govender Th, Kruger HG, El-Faham A, et al. (2014)
Peptides: Coupling Methods for the Incorporation of Noncoded Amino Acids Oxyma-B, an Excellent Racemization Suppressor. Org and Bio Chem 12:
into Peptides. Chem Rev 97: 2243-2266. 8379-8385.
7. Valeur E, Bradley M (2009) Amide bond formation: beyond the myth of coupling 29. Jad YE, Khattab ShN, de la Torre BG, Govender Th, Kruger HG, et al. (2014)
reagents. Chem Soc Rev 38: 606-631. TOMBU and COMBU as novel uronium-type peptide coupling reagents derived
from Oxyma-B. Molecules 19: 18953-18965.
8. König W, Geiger RA (1970) New method for the synthesis of peptides:
activation of the carboxyl group with dicyclohexylcarbodiimide and
1-hydroxybenzotriazoles. Chem Ber 103: 788-798. Submit your next manuscript and get advantages of OMICS
9. Carpino LA (1993) 1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling Group submissions
additive. J Am Chem Soc 115: 4397-4398.
Unique features:
10. Knorr R, Trzeciak A, Bannwarth W, Gillessen D (1989) New coupling reagents
• User friendly/feasible website-translation of your paper to 50 world’s leading languages
in peptide chemistry. Tetrahedron Lett 30: 1927-1930.
• Audio Version of published paper
11. Abdelmoty I, Albericio F, Carpino LA, Forman BM, Kates SA (1994) Structural • Digital articles to share and explore
studies of reagents for peptide bond formation: Crystal and molecular structures Special features:
of HBTU and HATU. Lett Pept Sci 1: 57-67.
• 400 Open Access Journals
12. Dourtoglou V, Ziegler JC, Gross B (1978) O-Benzotriazolyl-N,N- • 30,000 editorial team
tetramethyluronium hexafluorophosphate: a new and effective reagent for • 21 days rapid review process
peptide coupling. Tetrahedron Lett: 1269-1272. • Quality and quick editorial, review and publication processing
• Indexing at PubMed (partial), Scopus, EBSCO, Index Copernicus and Google Scholar etc
• Sharing Option: Social Networking Enabled
Citation: Khattab NS, El-Faham A, Albericio F (2015) Peptide Coupling • Authors, Reviewers and Editors rewarded with online Scientific Credits
Reactions. J Mol Pharm Org Process Res 3: e119. doi: 10.4172/2329- • Better discount for your subsequent articles
9053.1000e119 Submit your manuscript at: http://www.omicsonline.org/submission/

J Mol Pharm Org Process Res

ISSN: 2329-9053 JMPOPR, an open access journal Volume 3 • Issue 1 • 1000e119

View publication stats