- Peptide synthesis beyond DMF: THF and ACN as excellent and friendlier alternatives
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To date, DMF has been considered as the only solvent suitable for peptide synthesis. Here we demonstrate the capacity of THF and ACN, which are friendlier solvents than DMF, to yield the product in higher purity than DMF. Using various peptide models, both THF and ACN reduced racemization in solution-phase and solid-phase synthesis when compared with DMF. Moreover, the use of ACN and THF in the solid-phase peptide synthesis of hindered peptides, such as Aib-enkephalin pentapeptide and Aib-ACP decapeptide, in combination with a complete polyethylene glycol resin (ChemMatrix), gave a better coupling efficiency than DMF. This journal is
- Jad, Yahya E.,Acosta, Gerardo A.,Khattab, Sherine N.,De La Torre, Beatriz G.,Govender, Thavendran,Kruger, Hendrik G.,El-Faham, Ayman,Albericio, Fernando
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- Oxyma-T, expanding the arsenal of coupling reagents
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Herein, we report a new oxime-based additive (Oxyma-T) with a similar structure to HONM and Oxyma-B for use in peptide synthesis. Oxyma-T produces less racemization than HOBt, HOAt, OxymaPure, and Oxyma-B during the stepwise solution-phase synthesis of Z-Phg-Pro-NH2. Moreover, it exhibits superior coupling efficiency in comparison to HOBt during the SPPS of an Aib-enkephalin pentapeptide. Racemization during segment coupling follows the order: HOBt?>?Oxyma-T?>?OxymaPure?>?HOAt?>?Oxyma-B.
- Jad, Yahya E.,de la Torre, Beatriz G.,Govender, Thavendran,Kruger, Hendrik G.,El-Faham, Ayman,Albericio, Fernando
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- TOMBU and COMBU as novel uronium-type peptide coupling reagents derived from oxyma-b
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Here we describe two novel uronium salts, TOMBU and COMBU, derived from the recently described Oxyma-B for use in peptide bond synthesis. These coupling reagents are more stable than COMU in DMF. Furthermore, using various peptide synthetic models in solu
- Jad, Yahya E.,Khattab, Sherine N.,De La Torre, Beatriz G.,Govender, Thavendran,Kruger, Hendrik G.,El-Faham, Ayman,Albericio, Fernando
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- BOP-OXy, BOP-OBt, and BOP-OAt: Novel organophosphinic coupling reagents useful for solution and solid-phase peptide synthesis
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Stand-alone coupling reagents derived from bis(2-oxo-3-oxazolidinyl) phosphorodiamidic chloride show efficient performance in solution and SPPS. In particular, the Oxyma Pure (Luxembourg Biotech., Tel Aviv, Israel) derivative shows the additional advantag
- El-Faham, Ayman,Khattab, Sherine N.,Subiros-Funosas, Ramon,Albericio, Fernando
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- Addition of HOAt dramatically improves the effectiveness of pentafluorophenyl-based coupling reagents
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In the course of comparing the effectiveness of several HOAt- and HOPfp- derived coupling reagents by cyclization and segment condensation of model sequences, using HPLC to follow the time course and to determine the outcome in terms of oligomerization an
- Klose,El-Faham,Henklein,Carpino,Bienert
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- EDC·HCl and potassium salts of oxyma and oxyma-b as superior coupling cocktails for peptide synthesis
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Nowadays, DIC is the most widely used carbodiimide for solid-phase peptide synthesis, while EDC·HCl is mostly used only for solution-phase synthesis. In this paper, we report new coupling cocktails containing EDC·HCl in combination with potassium salts of OxymaPure and Oxyma-B (i.e., K-Oxyma and K-Oxyma-B, respectively). These reagent cocktails gave spectacular purity compared to DIC/classical N-hydroxylamine derivatives in the solid-phase peptide synthesis of the Aib-enkephaline (Aib = 2-aminoisobutyric acid) pentapeptide (H-Tyr-Aib-Aib-Phe-Leu-NH2), a hindered peptide. Furthermore, we found that the EDC·HCl/K-Oxyma combination can be used with DMF, THF, or MeCN as the solvent. The optimized cocktail gave less racemization than benzotriazole derivatives, but slightly more than OxymaPure and Oxyma-B during stepwise solution-phase peptide synthesis. We have shown that combinations of rather simple and green reagents, such as EDC·HCl and the potassium salt of OxymaPure or Oxyma-B, give unique results in terms of yield and low levels of racemization. We envisage a broad application of these reagents in solid-phase and solution synthesis, and especially in the preparation of peptide-based nanomaterials.
- Jad, Yahya E.,Khattab, Sherine N.,De La Torre, Beatriz G.,Govender, Thavendran,Kruger, Hendrik G.,El-Faham, Ayman,Albericio, Fernando
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- PyOxP and PyOxB: The Oxyma-based novel family of phosphonium salts
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Recent studies described the great impact of a non-benzotriazolic family of coupling reagents based on ethyl 2-cyano-2-(hydroxyimino)acetate, Oxyma, as a powerful coupling methodology for peptide synthesis. Here we present the synthesis and evaluation of the derived phosphonium salts O-[(1-cyano-2-ethoxy- 2-oxoethylidene)amino]-oxytri(pyrrolidin-1-yl) phosphonium hexafluorophosphate (PyOxP) and tetrafluoroborate (PyOxB). Both coupling reagents exhibited higher capacity to suppress racemization in various peptide models and enhanced solubility in DMF and DCM than benzotriazole-based reagents. In addition, the hexafluorophosphate analog PyOxP, combined excellent stability with outstanding efficiency in the assembly of demanding penta and decapeptides that include consecutive Aib residues. Cyclization models revealed the advantages of PyOxP, which rendered a higher percentage of cyclic material than other known potent phosphonium salts.
- Subiros-Funosas, Ramon,El-Faham, Ayman,Albericio, Fernando
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experimental part
p. 3665 - 3673
(2010/09/06)
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- A novel family of onium salts based upon isonitroso meldrum's acid proves useful as peptide coupling reagents
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A new family of uronium salts (HTMU, HMMU, and HDmPyMU) based on isonitroso Meldrum's acid (HONM) are reported as stand-alone coupling reagents. Amide bond formation with the use of these reagents occurred more quickly than that with other uronium salts as a result of the presence of a neighboring group effect with a cyclic structure. Thus, these novel onium salts were often more effective in the acylation of poor nucleophiles and in the control of optical purity than related Oxyma- and benzotriazole-based reagents. Among the HONM derivatives, HMMU showed the best performance in reducing racemization and assembling demanding sequences such as the Aib-ACP decapeptide or analogues of Leu-enkephalin pentapeptide, Furthermore, the scope and limitations of the use of HONM as an additive in combination with carbodiimides is discussed.
- El-Faham, Ayman,Subiros-Funosas, Ramon,Albericio, Fernando
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scheme or table
p. 3641 - 3649
(2010/09/03)
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- Ethyl 2-Cyano-2-(hydroxyimino)acetate (Oxyma): An efficient and convenient additive used with tetramethylfluoroformamidinium hexafluorophosphate (TFFH) to replace 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt) during peptide synthesis
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The appropriateness of ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma) as a substitute for benzotriazole-based additives, for use in the TFFH approach for peptide synthesis, is discussed in terms of its capacity to control racemization, its coupling efficiency in difficult couplings either for stepwise or segment coupling in solution- and solid-phase coupling. In addition, Boc-based solution-phase peptide synthesis and its stability in the presence of growing peptide chains were studied. Oxyma displayed remarkable results in terms of racemization depression together with impressive coupling efficiency in both solution- and solid-phase synthesis. Furthermore, Oxyma suggests a lower risk of explosion than HOBt and HOAt.
- Khattab, Sherine N.
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experimental part
p. 1374 - 1379
(2011/02/23)
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- Oxyma: An efficient additive for peptide synthesis to replace the benzotriazole-based HOBt and HOAt with a lower risk of explosion
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Oxyma [ethyl 2-cyano-2-(hydroxyimino)acetate] has been tested as an additive for use in the carbodiimide approach for formation of peptide bonds. Its performance in relation to those of HOBt and HOAt, which have recently been reported to exhibit explosive properties, is reported. Oxyma displayed a remarkable capacity to inhibit racemization, together with im-pressive coupling efficiency in both automated and manual synthesis, superior to those of HOBt and at least comparable to those of HOAt, and surpassing the latter coupling agent in the more demanding peptide models. Stability assays showed that there was no risk of capping the resin under standard coupling conditions. Finally, calorimetry assays (DSC and ARC) showed decomposition profiles for benzotriazolebased additives that were consistent with their reported explosivities and suggested a lower risk of explosion in the case of Oxyma.
- Subiros-Funosas, Ramon,Prohens, Rafei,Barbas, Rafael,El-Faham, Ayman,Albericio, Fernando
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scheme or table
p. 9394 - 9403
(2010/04/28)
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- COMU: A safer and more effective replacement for benzotriazole-based uronium coupling reagents
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We describe a new family of uronium-type coupling reagents that differ in their iminium moieties and leaving groups. The presence of the morpholino group in conjunction with an oxime derivative-especially ethyl 2-cy ano-2- (hydroxyimino) acet ate (Oxyma)-had a marked influence on the solubilities, stabilities, and reactivities of the reagents. Finally, the new uronium salt derived from Oxyma (COMU) performed extremely well in the presence of only 1 equiv of base, thereby confirming the effect of the hydrogen bond acceptor in the reaction. COMU also showed a less hazardous safety profile than the benzotriazolebased HDMA and HDMB, which exhibited unpredictable autocatalytic decompositions. Furthermore, the Oxyma moiety contained in COMU suggests a lower risk of explosion than in the case of the benzotriazole derivatives.
- El-Faham, Ayman,Funosas, Ramon Subiros,Prohens, Rafel,Albericio, Fernando
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scheme or table
p. 9404 - 9416
(2010/04/03)
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- Morpholine-based immonium and halogenoamidinium salts as coupling reagents in peptide synthesis
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(Chemical Equation Presented) Here we describe a new family of N-form immonium-type coupling reagents that differ in their carbocation skeleton structure. The N-methylpiperazine derivative failed to form immonium salts, while the thiomorpholine derivative did not give better results than the coupling reagents currently used. The presence of the morpholine had a marked influence on the solubility and stability as well as the reactivity of the reagent. Finally, the fluoroamidinium salt performed extremely well in the presence of only 1 equiv of base, thereby confirming the effect of the proton acceptor in the reaction.
- El-Faham, Ayman,Albericio, Fernando
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p. 2731 - 2737
(2008/09/19)
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- Novel proton acceptor immonium-type coupling reagents: Application in solution and solid-phase peptide synthesis
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(Chemical Equation Presented) A novel proton acceptor coupling reagent shows superiority to those described previously. The oxygen in the carbocation moiety confers more solubility to the reagent. Furthermore, it enhances coupling yields and decreases racemization, allowing the use of 1 equiv of base.
- El-Faham, Ayman,Albericio, Fernando
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p. 4475 - 4477
(2008/03/12)
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- S-(2-Pyrimidinyl)- and S-(2-(4,6-dimethylpyrimidinyl))-1,1,3,3- tetramethylthiouronium hexafluorophosphates: Novel reagents for in situ peptide coupling
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Two new reagents for in situ peptide coupling based on the 2-mercaptopyrimidine core have been developed. The readily prepared thiouronium salts were found to promote both peptide and segment coupling efficiently with low racemization/epimerization levels
- Garner, Philip,?e?eno?lu, ?zge,ümit Kaniskan
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p. 483 - 486
(2007/10/03)
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- Organophosphorus and Nitro-Substituted Sulfonate Esters of 1-Hydroxy-7-azabenzotriazole as Highly Efficient Fast-Acting Peptide Coupling Reagents
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Organophosphorus esters 9, 10, 14, and 15 prepared via reaction of diethyl- and diphenylphosphoryl chloride, di(o-tolyl)phosphinyl chloride, and 2,8-dimethylphenoxaphosphinyl chloride with HOAt are excellent coupling reagents for peptide synthesis which are generally superior to their uronium/guanidinium analogues and HOBt- or HODhbt-derived phosphate ester counterparts in minimizing loss of configuration during segment coupling. The phosphinyl analogues are more shelf-stable than the phosphoryl systems. The new reagents have been tested in segment couplings leading to two tripeptides (20, 21) and a hexapeptide 22. Outstanding utility is also shown for the solid-phase assembly of the ACP decapeptide. Similar results were obtained with the 2- and 4-nitro- and 2,4-dinitrophenylsulfonyl esters derived from HOAt.
- Carpino, Louis A.,Xia, Jusong,Zhang, Chongwu,El-Faham, Ayman
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- 3-Hydroxy-4-oxo-3,4-dihydro-5-azabenzo-1,2,3-triazene
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The known but long-neglected compound HODhat was shown to be in certain situations a useful peptide coupling additive. Uronium and phosphonium salts with HODhat built into the system were also useful stand-alone coupling reagents. Comparisons with related additives and coupling reagents showed that the new systems were sometimes more and sometimes less effective than previously described systems in the case of stepwise and segment couplings. Applications to assembly of the model decapeptide ACP showed that HDATU was far more effective than HDTU and more effective than HATU under some conditions.
- Carpino, Louis A.,Xia, Jusong,El-Faham, Ayman
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- Comparison of the effects of 5- and 6-HOAt on model peptide coupling reactions relative to the cases for the 4- and 7-isomers
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(equation presented) Synthesis of 5- and 6-HOAt has completed the full set of the four HOAt isomers derived from HOBt by insertion of a single nitrogen atom in the benzenoid nucleus. Comparison of the reactivity of all four isomers in model peptide coupling reactions has confirmed the unique character of the 7-isomer in promoting selectivity and maintaining configuration at the reactive carboxylic acid residue.
- Carpino, Louis A.,Imazumi, Hideko,Foxman, Bruce M.,Vela, Michael J.,Henklein, Peter,El-Faham, Ayman,Klose, Jana,Bienert, Michael
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p. 2253 - 2256
(2007/10/03)
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- The diisopropylcarbodiimide/1-hydroxy-7-azabenzotriazole system: Segment coupling and stepwise peptide assembly
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For a group of model peptide segments, coupling reactions carried out via solution or solid phase techniques have demonstrated the advantages of the system DIC/HOAt over DIC/HOBt and in addition for systems involving other selected carbodiimides and substituted HOBt derivatives bearing electron- withdrawing substituents. Very little, if any, loss of configuration occurred in DCM regardless of the additive used, although the relative order of efficiency was similar in solvents such as DMF in which more extensive epimerization resulted. In application of DIC/HOAt to stepwise peptide assembly by solid phase techniques, it was found that the hindered pyridine base collidine enhanced the step involving preactivation of the carboxylic acid residue in contrast to the normal situation in which bases such as DIEA, NMM, or non-hindered pyridine bases inhibit this step. These results led to development of a stepwise procedure for peptide assembly in which collidine is added to enhance activation and subsequently DIEA is added to enhance coupling.
- Carpino, Louis A.,El-Faham, Ayman
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p. 6813 - 6830
(2007/10/03)
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- Peptide coupling in the presence of highly hindered tertiary amines
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Previously, 2,4,6-trimethylpyridine (collidine), due to steric shielding around the N-atom, was found to be an efficient base for effecting peptide segment coupling via azabenzotriazole-based onium-style coupling reagents. A number of even more highly hin
- Carpino, Louis A.,Ionescu, Dumitru,El-Faham, Ayman
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p. 2460 - 2465
(2007/10/03)
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