Uronium coupling reagents

El-Faham A, Funosas RS, Prohens R, Albericio F (2009) CO MU A safer and more effective replacement for benzotriazole-based uronium coupling reagents. Chem Eur J 15 9404-9416... 

Another family of coupling reagents frequently used with the Fmoc method is related to A-hydroxybenzotriazole and A-hydroxy 7-azabenzotriazole but also incorporates phosphonium or amidinium groups. The latter can exist in either the O-(uronium) or A-(guanidinium) forms.48 Both can effect coupling. The former are more reactive but isomerize to the latter. Which form is present depends on the protocol of preparation, including the amine used and the time before addition of the carboxylic acid 49 The... 

Scheme 13.77. Phosphonium, Uronium, and Guanidinium Coupling Reagents...

FIGURE 2.28 An aid to deciphering the constitution of coupling reagents from their abbreviations. HBPyU and HAPyU correspond to incorrect names of the compounds because U = uronium = OC+N2 includes the nitrogen atoms of the pyrrolidine rings. The substitutents on each nitrogen are tetramethylene. 

O-ACYL AND A/-ACYL N -OXIDE FORMS OF 1 -HYDROXYBENZOTRIAZOLE ADDUCTS AND THE URONIUM AND GUANIDINIUM FORMS OF COUPLING REAGENTS... 

LA Carpino, H Imazumi, A El-Faham, FJ Ferrer, C Zhang, Y Lee, BM Foxman, P Henklein, C Hanay, C Miigge, H Wenschuh, J Klose, M Beyermann, M Bienert. The uronium/guanidinium peptide coupling reagents finally the true uronium salts. Angew Chem Inti Edn 41, 442, 2002. 

Historically, the methods used for ring closure of linear precursor peptides via amide bond formation evolved in parallel to the methods applied in segment condensations from the azide and active ester procedures to the use of coupling reagents such as DCC in the presence of additives, or of the more recently developed phosphonium and uronium/gua-nidinium reagents. In all cases the choice of method is mainly dictated by the epimerization problem when chiral amino acids act as the carboxy component in the cyclization reaction, and by other side reactions. 

The reactivity of uronium- (and phosphonium-) based coupling reagents is mainly determined by the type of activated acid derivative formed during activation (see Figure 13.2). Unlike phosphonium salts, uronium salts can react with amines to yield guanidines [84]. This side reaction can interfere with amide formation if more uronium salt than carboxylic acid is used. Illustrative examples of the use of uronium salts are listed in Table 13.6. 

PAL-PEG resin, Fmoc amino acids and coupling reagent N,N -diisopropylethylamine (DIPEA) and fhbcnzotriazolc-/V,/V,Ar,Ar-tetramct.hyl-uronium-hexafluoro-phosphate (HBTU) (Advanced ChemTech, Louisville, KY). 

A. Carpino, H. Imazumi, A. El-Faham, F. J. Ferrer, C. Zhang, Y. Lee, B. M. Foxman, P. Henklein, C. Hanay, C. Miigge, H. Wenschuh, The uronium/guanidinium peptide coupling reagents finally the true uronium salts. Angew. Chem. Int. Edn. 2002 41 442-445. 

Figure 15 Uronium/guanidinium and iminium-based coupling reagents.

For the coupling reaction with phosphonium and uronium/guanidinium reagents an intermediate formation of the acyloxyonium salts (Scheme 5) is postulated which in the presence of the oxyanion of 1,2,3-benzotriazol-l-ol or 7-aza-l,2,3-benzotriazol-l-ol generate the related active esters 15 as the predominant transient species for aminolysis.f ... 

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