N‐Hydroxylamines for Peptide Synthesis

Abstract

peptide‐coupling reactions have significantly advanced in accord with the development of new N‐hydroxylamines as additives used in peptide synthsis, which has been covered in a number of valuable reviews. In this Chapter we focus on the development of the N ‐hydroxylamines as additives for peptide synthesis, properties, synthesis, general comparison between different N ‐hydroxylamines, their uses in the synthesis of phosphonium, uronium/iminium salts , active esters, phosphate and sulfonate coupling reagents, polymer bond N ‐hydroxylamines, as well as their applications in peptide synthesis.

Peptide synthesis beyond DMF: THF and ACN as excellent and friendlier alternatives

“…30 The tripeptide models H-Gly-Ser-Phe-NH 2 7 and H-Gly-Cys-Phe-NH 2 8 were manually assembled by stepwise solid-phase synthesis using 5 min preactivation and Ser(tBu) and Cys(Trt) as protecting group for 7 and 8, respectively. 22,31,32 Again, THF and ACN achieved greater suppression of racemization than DMF in both cases. In order to demonstrate the efficiency of THF and ACN in 15 peptide synthesis, Aib-enkephaline pentapeptide 9 was used as a model for solid-phase peptide synthesis.…”

“…In this study, we chosea DIC (N,N′-diisopropylcarbodiimide)mediated coupling method in combination with HOBt1 (1hydroxybenzotriazole, the most classical benzotriazole additive), 20 HOAt2 (1-hydroxy-7-azabenzotriazole, the most 5 reactive and expensive additive), 21 OxymaPure3 (ethyl 2-cyano-2-(hydroxyimino)acetate, which showedsuperiority in all cases to HOBt and in many cases the same performance asHOAt) 22,23 or Oxyma-B 4 (5-(hydroxyimino)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione, which showed superiority in 10 racemization suppression in comparison to HOBt1 and even HOAt2 and OxymaPure3). 24 The key parameters used to evaluate the effect of solvent on the 15 coupling reaction are racemization and coupling performance.…”

“…In order to demonstrate the efficiency of THF and ACN in 15 peptide synthesis, Aib-enkephaline pentapeptide 9 was used as a model for solid-phase peptide synthesis. 22,25,26,33 Misincorporation of one Aib residue to give (des-Aib) is the most important side reaction, which is caused by the sterically hindered nature of the Aib residue. Therefore, a clear difference between 20 the performances of coupling potency in different solventswill be achieved.…”

Synthesis of tumor necrosis factor α for use as a mirror-image phage display target

“…Ultimately, the most effective solution was to directly suppress aspartimide formation during SPPS. Addition of 0.1 M Oxyma Pure to the Fmoc deprotection solution 51 effectively prevented aspartimide formation, providing a sufficiently pure C-terminal segment that did not require additional HPLC purification (Fig. 2).…”

Oxyma-T, expanding the arsenal of coupling reagents

“…It also exhibited improved coupling efficiencies compared to HOBt in the SPPS of a sterically hindered Aib-enkephalin pentapeptide; but with inferior crude purity than HOAt and OxymaPure. 28 Herein, we report a new additive, namely Oxyma-T (15), a derivative of 1,3-diethyl-2-thiobarbituric acid (14). This additive is considered to belong to the same family as HONM and Oxyma-B, as it is a six-membered cyclic oxime with two carbonyl groups and without an ester moiety in its structure.…”