Isoxazolium salts, peptide

The smooth conversion of the enol acetate (151) into an A -acyl derivative (152) under extremely mild conditions points to the high acylating capacity of these esters. This cleavage of isoxazolium salts is also caused by other anions of carboxylic acids, and thus they can be readily converted to reactive enol esters. A very convenient and specific synthesis of peptides due to Woodward et is based on... 

This isoxazolium salt (10 g.) (obtained from the Aldrich Chemical Company, Inc.) was dissolved in 45 ml. of aqueous 1 M hydrochloric acid and reprecipitated by the slow addition with swirling of 400 ml. of acetone. The salt was collected, washed with 300 ml. of acetone, and dried overnight at 25° under reduced pressure (< 1 min.) to give a fluffy product, m.p. 206-208° (decomp.). An isomeric salt, A-ethyl-5-phenylisoxazolium-4 -sulfonate, which may be obtained by the usual synthetic procedure,2 is also useful in peptide synthesis. 

In a survey of the methods used for peptido synthesis in 1968, the isoxazolium salt method was used in 7% of the examples surveyed J. H. Jones in Amino Acids, Peptides, and Proteins, Vol. 2, The Chemical Society, London, 1970, p. 145. 

Isoxazolium salts, such as the well-known Woodward s Reagent K , have found significant use as reagents in the preparation of activated enol esters suitable for peptide coupling reactions. Since this aspect of isoxazole chemistry has been extensively surveyed, this topic will not be treated in further detail here (B-74MI11601). 

When recent advances in the chemistry of isoxazoles were reviewed by Kochetkov and Sokolov1 in this Series in 1963 (and by Quilico2 in 1962), the main features of isoxazole chemistry had been established. Since then some important new discoveries have been made, but probably the most significant advances have concerned the exploitation of the known features of their chemistry in synthesis. Particularly noteworthy developments include the further application of the cycloaddition of nitrile oxides in the synthesis of isoxazoles (Section II,C and D), the use of isoxazolium salts in peptide synthesis (Section III,B,2), syntheses involving the products of reductive cleavage of isoxazoles as intermediates (Section III,D and E) and annelation reactions via deprotonation of alkylisoxazoles (Section 1II,E). 

Isoxazolium salts are even more susceptible than isoxazoles to attack by nucleophiles. It was discovered in the early years of this century that 3-unsubstituted isoxazolium salts were cleaved by a variety of mild reagents, including even carboxylate ions in aqueous solution.1,165 However, it was not until much later that the Harvard group were able to elucidate details of the structures of the products and the routes by which they are formed, and to exploit the reactions, notably in peptide synthesis. 

The application of isoxazolium salts as reagents for activating carbonyl groups in peptide synthesis is based on this reaction [85]. 

Since the soon extremely popular DCC method was proposed by John C. Sheehan, Professor of Chemistry at the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts, it was not too surprising that Robert B. Woodward (Plate 50), Professor at Harvard University, a rival of MIT in the same town, after earlier flirts with peptide chemistry (p. 37) tried to develop another, perhaps even more spectacular method of coupling. In 1961 Woodward and his coworkers announced, in two short papers [43], the preparation and use of a new coupling reagent, an isoxazolium salt ... 

Based on this reaction is the application of isoxazolium salts as COOH-activating reagents in peptide synthesis [303]. 

This reagent is a dehydrating agent which has been used much less for peptide bond formation than the carbodiimides. Reaction first occurs with a carboxylate function after base catalyzed decomposition of the isoxazolium salt ... 

Peptide Coupling Reagent. Woodward s reagent K reacts with an / -protected amino acid, under mild conditions, in the presence of a tertiary amine to form an enol ester intermediate, e.g. (1). This enol ester acylates an amino acid ester or peptide to afford the elongated peptide derivative (eq 1). The isoxazolium salt is not soluble in organic solvents, but as it reacts with a carboxyl group in the presence of a tertiary amine the reaction mixture clears. 

The isoxazolium salt has been used in the synthesis of other difficult peptide structures. A peptidoglycan has been obtained in good yield by this procedure (eq 5). ... 

Some examples of the isoxazolium ions which have been tried as peptide coupling reagents are compounds 56-59. The sulfonium inner salt 56 (Woodward s Reagent K) is widely used because the by-product (60) in Scheme 10 is water soluble it is stated to be superior to diimides as far as racemization is concerned.168,170,171 (V-Arylisoxazolium salts such as 57... 

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