Carboxylic function activation, during peptide synthesis

Such condensation reactions are also promoted by certain trTvalent phosphorus compounds, e.g. triphenyl phosphite (2) or diphenyl ethylphosphonite (3), or to a lesser extent by pFosphonate esters, e.g. diphenyl n-butylphosphonate (3). "Bates reagent," p-oxobi s[tri s(cTi methyl ami no)phosphoni urn] bi s-tetra-f1uoroborate (2) may also be used to activate the carboxyl function towards amide bond formation during peptide synthesis (4) and to bring about the Beckmann rearrangement of ketoximes (F). 

The scheme of classical peptide SPS is shown in Fig. 2.1. The first step is the attachment of the first amino acid onto the resin, usually via the carboxylic group with both the amino and the side-chain functions of the a-amino acid protected (step 1). The inverse strategy, where the amino group would be linked to the resin and the carboxyl would be protected, has seldom been used because extensive racemization occurs during repeated resin-bound carboxylate activations (3) this limits the accessibility of C-terminal modified peptides that are biologically relevant. However, several recent reports (4-7) describe the SP modification of the peptide C-terminus using the more reliable C-to-N direction for peptide synthesis. 

Merrifield s original idea was based on the general scheme of stepwise condensation of N-protected amino acids to the first one, which is linked with its carboxyl function by an ester bond to the insoluble polymer support. This way of solid phase peptide synthesis resulted from the well-known risk of racemization during activation of peptidic carboxyl components, which is minimized in activated amino acid derivatives, N-acylated by urethane-type protecting groups [40] (Fig. 7). Depending on the chosen method, the C-terminal activation of N-protected peptides tends to racemize a certain amount of the material because of the possible formation of an oxazolinone intermediate [41] (Fig. 8). 

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