Design and Synthesis of New Immonium‐Type Coupling Reagents

Abstract

A new family of immonium-type coupling reagents is described here. The differences in the carbocation skeletons of these reagents can be correlated with differences in stability and thus reactivity. The dihydroimidazole derivatives are highly unstable to air, whereas the salts derived from dimethylamine are the most stable and the pyrrolidino derivatives are of intermediate stability. These results should be taken into account mainly when coupling reagents are depositedThe activation of a carboxylic acid for the formation of an amide bond is usually carried out using the so-called peptide coupling reagents.[2] During the last decade there has been an evolution in the development of new activation methods and their application to both solution and solidScheme 1.[ ‡] For abbreviations see ref.[ in open vessels, such in some automatic synthesizers. As regards both coupling yield and retention of configuration, HOAt derivatives have been confirmed to be superior to those of HOBt in all cases. For peptides containing hindered residues, fluoroformamidinium salts are more convenient than the HOAt-based reagents.

A Novel Family of Onium Salts Based Upon Isonitroso Meldrum's Acid Proves Useful as Peptide Coupling Reagents

“…[1,8] Recently, an alternative pathway to enhance coupling efficiency by modifying the carbon skeleton of uronium salts has been reported. [9] Later, the incorporation of a hydrogen-bond acceptor in the iminium part was studied, showing superiority to those described earlier. [10] Oxygen in the iminium moiety confers the reagent more solubility, enhances coupling yields, and decreases racemization, thereby allowing the use of only 1 equiv.…”

TOMBU and COMBU as Novel Uronium-Type Peptide Coupling Reagents Derived from Oxyma-B

“…Uronium salts 17 and 18, both based on Oxyma-B, were prepared following a reported method [18,19,21,22,27].Thus, for instance the reaction of N,N-dimethylcarbamoyl chloride (19) with (20) renders dimethylmorpholineurea (21). This compound was then treated with oxalyl chloride to yield the corresponding chloride salt, which was stabilized by the formation of a PF6 salt (23).…”

Peptide Coupling Reactions

“…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-CH 3 for synthesis of novel coupling reagents [24] (Figure 2).…”