Synthesis and Application of N‐Hydroxylamine Derivatives as Potential Replacements for HOBt

Abstract

Several heterocycles containing N-hydroxylamine were prepared and tested as coupling additives to replace the use of N-hydroxybenzotriazole (HOBt) derivatives. On the basis of our results on coupling yield and racemization-suppressing properties, we propose N-hydroxyindolin-2-one and 6-

BOP‐OXy, BOP‐OBt, and BOP‐OAt: novel organophosphinic coupling reagents useful for solution and solid‐phase peptide synthesis

“…Method A: The product was obtained as a white solid, mp 178-181°C, in 2.3 g (65.0%) yield. 1 General Method for the Racemization Experiments Using the New Phosphonic Derivatives (BOP-Cl, BOP-OBt, BOP-OAt, BOP-OXy, and BOP-NOXy derivatives) [28,33,35,36,45] Some 0.125 mmol of an acid (Z-Phg-OH, Z-Gly-Phe-OH, or Z-Phe-Val-OH) and (20 μl) 0.125 mmol BOP-Cl, BOP-OBt, BOP-OAt, BOP-OXy, and BOP-NOXy were dissolved in 2 ml DMF at 0°C. Then, 0.125 mmol of H-Pro-NH 2 was added.…”

“…HOBt and its more potent aza derivative HOAt are being discontinued for safety reasons [31]. Oxyma Pure does not show that problem, and it has been shown to be superior in all cases to HOBt and even in many cases with the same performance than HOAt [28,[32][33][34][35][36][37][38][39][40]. In addition, the derivative of the amide counterpart, N-Oxyma (12) [41], was also prepared.…”

“…In particular, the Oxyma Pure (Luxembourg Biotech., Tel Aviv, Israel) derivative shows the additional advantage of being highly soluble in DMF and even fairly soluble in CH 3 CN, which can extend its use for the synthesis of complex peptides. These new stand-alone coupling reagents have the advantage of not bearing any counteranion such as PF 6 or BH 4 , whose presence can jeopardize the purification of final peptides prepared in solution.Synthesis of H-Tyr-Aib-Aib-Phe-Leu-NH 2 (20) in solid phase [28,33,35,36,45] The pentapeptide H-Tyr-Aib-Aib-Phe-Leu-NH 2 (20) was prepared following a published procedure. The synthesis was carried out in a plastic syringe that was attached to a vacuum manifold so as to effect rapid removal of reagents and solvent.…”

“…Synthesis of H-Tyr-Aib-Aib-Phe-Leu-NH 2 (20) in solid phase [28,33,35,36,45] The pentapeptide H-Tyr-Aib-Aib-Phe-Leu-NH 2 (20) was prepared following a published procedure. The synthesis was carried out in a plastic syringe that was attached to a vacuum manifold so as to effect rapid removal of reagents and solvent.…”

Oxyma-T, expanding the arsenal of coupling reagents

“…Our group has evaluated a number of N-hydroxylamine derivatives obtained from N-hydroxylamine-containing heterocyclic compounds or oximes. [16][17][18] Of these, OxymaPure (10) which was first introduced by Itoh 19 and Izdebski 20 during the 1970's, initially found only few applications in peptide synthesis. Four decades later, COMU (11) a novel and efficient peptide coupling reagent based on OxymaPure, was reported.…”