Khattab et al., J Mol Pharm Org Process Res 2015, 3:1 http://dx.doi.org/10.4172/2329-9053.1000e119
Molecular Pharmaceutics & 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 of an amino group (nucleophile) at a carboxyl group involving a tetrahedral intermediate. Furthermore, the peptide coupling reaction must be performed under mild conditions, and preferably at room temperature. Activation of the carboxyl component is achieved by the introduction of electron accepting moieties [1]. Carboxyl components can be activated as acyl halides, acyl azides, acylimidazoles, anhydrides, esters etc. There are different ways of coupling reactive carboxyl derivatives with an amine [2]. In recent years, peptide-coupling reactions have significantly advanced in accord with the development of new peptide-coupling reagents and their application to both solution and solid- phase synthesis [3,4]. The formerly techniques of carbodiimide is being replaced with iminium/uronium derivatives 1-5 [5-21] (Figure 1). 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 and low racemization during peptide bond formation [22]. Very recently, El-Faham and Albericio [23] extended their work taking an N-containing 6-membered ring structure containing O, S, and N-CH3 for synthesis of novel coupling reagents [24] (Figure 2). Recent reports confirmed the explosive properties 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)-1,3dimethylpyrimidine-2,4,6 (1H,3H,5H)-trione (Oxyma-B) as an excellent additive for the suppression of racemization during peptide
Me PF 6 Me N OX Me N Me
N N
1
OX
Y
N
X N
Y = CH,, HBTU, 1a Y = N, HATU, 1b
Y
R3 N N
PF6 OX
N N
R2 N
X = H, Y = Cl, HCTU; 1c X = H, Y = CF3, HFTU; 1d X = N, Y = H, 4-HATU; 1e
5
N O
HSTU, 1f
Figure 1: Structure of symmetric imininum/uronium salts coupling reagents.
J Mol Pharm Org Process Res ISSN: 2329-9053 JMPOPR, an open access journal
N
N
X PF6 X = O (6a-g) X = S (7a,b)
Y
N O
PF6
DMFH, 8
N
Xt =
F
N
X
N
N
N
Y
O N
F
N
F
F
F F
O Y = CH, HDMB, 6a HDMS, 6f X = H, Y = Cl, 6-HDMCB; 6c Y = N, HDMA, 6b X = S, Y = CH, HDTMB, 7a X = H, Y = CF3, 6-HDMFB; 6d X = S, Y = N, HDTMA, 7b X = N, Y = H, 4-HDMA; 6e
HDMPfp, 6g
Figure 2: Structure of morpholine-based coupling reagents.
HO HO N 11a
COOEt CN
HO N 11b
COOEt COOEt
HO N
CN CN
11c
HO N
N CN
11d
N
O
O O
O
11e
Figure 3: Structure of oximes to replace of HOBt.
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].
SbCl6
O N
OXt
OX R1
R1, R2 = alkyl, aryl R3 = H, alkyl, aryl
4
3
2
N
X =
Me PF6 N OX N Me
PF6
N
*Corresponding author: El-Faham A, Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, 12321 Alexandria, Egypt, E-mail:
[email protected] Received February 07, 2015; Accepted February 09, 2015; Published February 15, 2015 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 Copyright: © 2015 Khattab NS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
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: 10.4172/23299053.1000e119
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Me
Me N Me OXt PF6
Me N
Me
Me N
Me
N
O
N PF6
N OXt
PF6
PF6
14. Carpino LA, El-Faham A, Albericio F (1995) Efficiency in Peptide Coupling: 1-Hydroxy-7-azabenzotriazole vs 3, 4-Dihydro-3-hydroxy-4-oxo-1,2,3benzotriazine. J Org Chem 60: 3561-3564.
15a-i
14a-f
13a-f
13. Wijkmans JCHM, Blok FAA, Van der Marel GA, Van Boom JH, Bloemhoff W (1995) CF3-NO2-PyBOP: a new and highly efficient coupling reagent for N-methyl amino acids. Tetrahedron Lett 36: 4643-4646.
O
N
OXt
OXt
12a-f
Me N
N COOEt
N
CN a
Xt =
N
COOEt
N
COOEt
f
N
CN c
b N
N
CN
O
N
O O
CN
N N
N h
N N
O e
d
N
g
O
N
N
Cl
N
i
Figure 4: Structures of oximino and benzotriazolo uronium salt.
15. Klose J, El-Faham A, Henklein P, Carpino LA, Bienert, M (1999) Addtion of HOAt Dramatically Improve the Effectiveness of Pentafluorophenyl-Based Coupling Reagents. Tetrahedron Lett 40: 2045-2048. 16. Chen SQ, Xu JC (1992) A new coupling reagent for peptide synthesis. Benzotriazolvyloxy-bis (pyrroltdino)-carbonium hexaflouorophosphate (BBC). Tetrahedron Lett 33: 647-650. 17. Carpino LA, El-Faham A (1994) Effect of Tertiary Bases on O-Benzotriazolyluronium Salt-Induced Peptide Segment Coupling. J Org Chem 59: 695698. 18. Carpino LA, Xia J, El-Faham A (2004) 3-Hydroxy-4-oxo-3, 4-dihydro-5azabenzo-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 15631573.
Figure 5: Structure of Oxyma-B 16 and its uronium salts TOMBU 17 and COMBU 18.
References
23. El-Faham A, Albericio F (2007) Novel Proton Acceptor Immonium-Type Coupling Reagents: Application in Solution and Solid Phase Peptide Synthesis. Org Lett 9: 4475-4477.
1. Montalbetti CAGN, Falque V (2005) Amide bond formation and peptide coupling. Tetrahedron 61: 10827-10852.
24. Faham A, Albericio F (2008) Morpholine-Based Immonium and Halogenoamidinium Salts as Coupling Reagents in Peptide Synthesis. J Org Chem 73: 2731-1737.
2. El-Faham A, Albericio F (2011) Peptide Coupling Reagents, More than a Letter Soup. Chem Rev 111: 6557-6602.
25. Wehrstedt KD, Wandrey PA, Heitkamp D (2005) Explosive properties of 1-hydroxybenzotriazoles. J Hazard Mater 126: 1-3.
3. Albericio F, Carpino LA (1997) Methods Enzymol: Solid Phase Peptide Synthesis Fields, Academic Press, Orlando 289: 104-126.
26. Subiros-Funosas R, Prohens R, Barbas R, El-Faham A, Albericio F (2009) Oxyma: an efficient additive for peptide synthesis to replace benzotriazolebased HOBt and HOAt with a lower risk of explosión. Chem Eur J 15: 93949403.
4. Albericio F, Kates SA (2000) In Solid-Phase Synthesis, A Practical Guide, Marcel Dekker, New York 275-330 5. Albericio F, Chinchilla R, Dodsworth DJ, Najera C (2001) New Trends in Peptide Coupling Reagents. Org Prep Proced Int 33: 203-303.
27. El-Faham A, Subirós-Funosas R, Prohens R, Albericio F (2009) COMU, a Safer and More Effective Replacement for Benzotriazole-based Uronium Coupling Reagents. Chem Eur J 15: 9404-9416.
6. Humphrey JM, Chamberlin AR (1997) Chemical Synthesis of Natural Product Peptides: Coupling Methods for the Incorporation of Noncoded Amino Acids into Peptides. Chem Rev 97: 2243-2266.
28. Jad YE, Khattab ShN, Govender Th, Kruger HG, El-Faham A, et al. (2014) Oxyma-B, an Excellent Racemization Suppressor. Org and Bio Chem 12: 8379-8385.
7. Valeur E, Bradley M (2009) Amide bond formation: beyond the myth of coupling reagents. Chem Soc Rev 38: 606-631.
29. Jad YE, Khattab ShN, de la Torre BG, Govender Th, Kruger HG, et al. (2014) 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. 9. Carpino LA (1993) 1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive. J Am Chem Soc 115: 4397-4398. 10. Knorr R, Trzeciak A, Bannwarth W, Gillessen D (1989) New coupling reagents in peptide chemistry. Tetrahedron Lett 30: 1927-1930. 11. Abdelmoty I, Albericio F, Carpino LA, Forman BM, Kates SA (1994) Structural studies of reagents for peptide bond formation: Crystal and molecular structures of HBTU and HATU. Lett Pept Sci 1: 57-67. 12. Dourtoglou V, Ziegler JC, Gross B (1978) O-Benzotriazolyl-N,Ntetramethyluronium hexafluorophosphate: a new and effective reagent for peptide coupling. Tetrahedron Lett: 1269-1272. Citation: Khattab NS, El-Faham A, Albericio F (2015) Peptide Coupling Reactions. J Mol Pharm Org Process Res 3: e119. doi: 10.4172/23299053.1000e119
J Mol Pharm Org Process Res ISSN: 2329-9053 JMPOPR, an open access journal
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