3
enkephalin pentapeptide,31 where two glycine residues are
replaced by the hindered α,α-disubstituted amino acid (Aib). This
modification leads to difficult coupling of the second Aib residue
and therefore the formation of des-Aib tetrapeptide (H-Tyr-Aib-
Phe-Leu-NH2) as a major side-product.28 Standard Fmoc-SPPS
protocols were employed. The purity of the crude product
obtained with Oxyma-T was higher than that produced using
HOBt and at a similar level to that attained with HOAt. However,
Oxyma-T yielded less pure product when compared to that of
OxymaPure (Table 3).
6
7
8
König, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
Sabatino, G.; Mulinacci, B.; Alcaro, M. C.; Chelli, M.;
Rovero, P.; Papini, A. M. Peptides 2002: Proceedings of the Twenty-
Seventh European Peptide Symposium, Aug. 31-Sept. 6, Sorrento,
Italy, 2002.
9
Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D.
Tetrahedron Lett. 1989, 30, 1927.
10
Lett. 1994, 35, 2279.
11
Carpino, L. A.; El-Faham, A.; Albericio, F. Tetrahedron
Marder, O.; Shvo, Y.; Albericio, F. Chim. Oggi-Chem.
Today 2002, 20, 37.
Table 3. Percentage purity of the pentapeptide (H-Tyr-Aib-Aib-Phe-
Leu-NH2) a
12
Coste, J.; Le-Nguyen, D.; Evin, G.; Castro, B. Tetrahedron
Entry
Coupling reagent
DIC/HOBtc
Pentapeptide (%)
des-Aib (%)b
80.6
Lett. 1990, 31, 205.
13
Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F.
1
2
3
4
18.9
55.0
71.8
43.8
J. Chem. Soc., Chem. Commun. 1994, 201.
14
Subiros-Funosas, R.; Moreno, J. A.; Bayo-Puxan, N.; Abu-
DIC/HOAtc
45.0
Rabeah, K.; Ewenson, A.; Atias, D.; Marks, R. S.; Albericio, F.
Chim. Oggi-Chem. Today 2008, 26, 10.
DIC/OxymaPure
DIC/Oxyma-Td
28.2
15
Wehrstedt, K. D.; Wandrey, P. A.; Heitkamp, D. J.
46.1
Hazard. Mater. 2005, A126, 1.
16
1499.
17
El-Faham, A.; Albericio, F. Eur. J. Org. Chem. 2009,
a
Fmoc-RinkAmide-AM-PS resin, DMF as a solvent, and 1 h coupling
times were generally used, except for the Aib–Aib coupling (1 h double
coupling). b Deletion tetrapeptide (des-Aib) was identified by peak overlap in
HPLC with an authentic sample obtained on the solid phase. The crude H-
Tyr-Aib-Aib-Phe-Leu-NH2 was analyzed by reverse-phase HPLC using a
linear gradient of 5–95% CH3CN (0.1% TFA)/H2O (0.1% TFA) over 30 min,
flow rate 0.3 mL/min, detection at 220 nm, and an YMC-Triart C18 (3μm,
Subirós-Funosas, R.; Prohens, R.; Barbas, R.; El-Faham,
A.; Albericio, F. Chem.--Eur. J. 2009, 15, 9394.
18 Khattab, S. N.; Subiros-Funosas, R.; El-Faham, A.;
Albericio, F. ChemistryOpen 2012, 1, 147.
19
20
21
Itoh, M. Bull. Chem. Soc. Jpn. 1973, 46, 2219.
Izdebski, J. Pol. J. Chem. 1979, 53, 1049.
El-Faham, A.; Funosas, R. S.; Prohens, R.; Albericio, F.
c
3.0 × 150 mm) column. tR = 17.5 (pentapeptide), 17.9 (des-Aib) min. Data
from ref 17. d des-Tyr,Aib (2.5%) and des-Tyr (5.9%) were also observed.
Chem.--Eur. J. 2009, 15, 9404.
22
23
El-Faham, A.; Albericio, F. J. Pept. Sci. 2010, 16, 6.
Subiros-Funosas, R.; Khattab, S. N.; Nieto-Rodriguez, L.;
In summary, we report the addition of Oxyma-T, a new
benzotriazole-free coupling reagent, to the arsenal of peptide
coupling agents. It has a similar structure to that of HONM and
Oxyma-B, but without an ester moiety. It shows good solubility
in DMF. The performance of Oxyma-T was superior to that of
HOBt but inferior to that of HOAt and OxymaPure. Given its
features, we propose that Oxyma-T has applications in solid- and
solution-phase peptide synthesis, as well as in manual and
automated synthesis.
El-Faham, A.; Albericio, F. Aldrichim. Acta 2013, 46, 21.
24 Collins, J. M.; Porter, K. A.; Singh, S. K.; Vanier, G. S.
Org. Lett. 2014, 16, 940.
25
Dutta, J.; Ramesh, S.; Radebe, S. M.; Somboro, A. M.;
Torre, B. G.; Kruger, H. G.; Essack, S. Y.; Albericio, F.; Govender,
T. Int. J. Pept. Res. Ther. 2014, 21, 13.
26
Org. Chem. 2010, 2010, 3641.
27
El-Faham, A.; Subirós-Funosas, R.; Albericio, F. Eur. J.
Although, harsh conditions were used in order to force the
undesired side-reaction involving the ester moiety: mixing the amino
component in the presence of OxymaPure (10 equiv.) for 12 h or
microwave heating of the amino component with OxymaPure (10
equiv.) at 80 °C for 10 min in DMF or NMP, we did not observed the
side-reaction. For experimental details, see ref. 17.
Acknowledgments
This work was funded in part by the South-African National
Research Foundation (NRF), the University of KwaZulu-Natal
(South Africa), and the Generalitat de Catalunya (2014 SGR
137) and MEC (CTQ2015-67870-P). Additionally, the authors
thank the Deanship of Scientific Research at King Saud
University for funding this work through the Prolific Research
Group Program (PRG-1437-33; Saudi Arabia). Finally, the
authors thank Y. Luxembourg (Luxembourg Bio Technologies
Ltd) for his continuous support of this study.
28
Jad, Y. E.; Khattab, S. N.; de la Torre, B. G.; Govender, T.;
Kruger, H. G.; El-Faham, A.; Albericio, F. Org. Biomol. Chem.
2014, 12, 8379.
29
Jad, Y. E.; Acosta, G. A.; Khattab, S. N.; de la Torre, B.
G.; Govender, T.; Kruger, H. G.; El-Faham, A.; Albericio, F. Org.
Biomol. Chem. 2015, 13, 2393.
30
Elsawy, M. A.; Hewage, C.; Walker, B. J. Pept. Sci. 2012,
18, 302.
31
Acosta, G. A.; del Fresno, M.; Paradis-Bas, M.; Rigau-
References and notes
DeLlobet, M.; Cote, S.; Royo, M.; Albericio, F. J. Pept. Sci. 2009,
15, 629.
1
Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61,
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Supplementary Material
2
3
4
5
Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447.
Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
El-Faham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557.
Subirós-Funosas, R.; Albericio, F.; El-Faham, A. In N-
Supplementary data containing experimental details, NMR,
HRMS and HPLC can be found in the online version.
Hydroxylamines for Peptide Synthesis; John Wiley & Sons, Ltd,
2009.