Peptide synthesis with benzisoxazolium salts-II. Activation chemistry of 2-ethyl-7-hydroxybenzisoxazolium fluroborate; Coupling chemistry of 3-acyloxy-2-hydroxy-N-ethylbenzamides

Article abstract of DOI:10.1016/S0040-4020(01)97371-5

Mechanistic aspects of the application of 2-ethyl-7-hydroxybenzisoxazolium fluoroborate, 1, to peptide synthesis are presented. Optimal conditions are described for the formation of 3-acyloxy-2-hydroxy-N-ethylbenzamides, 2, from 1 and peptide acids. Amines are found to react with esters, 2, as their 2-oxyanion conjugate bases. Racemization in model systems is found to occur via oxazolones, and the low racemizing tendency of the esters, 2, is shown to result from a unique internal buffering effect. In the preceding paper,¹ we have outlined the reasoning which led us to synthesize the 2-ethyl-7-hydroxybenzisoxazolium cation, 1, and the evidence which establishes the active esters, 2, as products of the reactions of 1 with carboxylic acid anions. In the following paper,² we report results of the application of this reaction to the synthesis of simple amino acid derivatives. In this paper, we describe the known practical features of the activation sequence 1→2, carried out with the model, carbobenzoxyglycine, and salient features of the coupling sequence, 2→amide, carried out with a variety of peptide derivatives. Evidence relevant to the mechanisms of coupling and racemization for the esters 2 is described.