2-Alkoxy-5(4H)-oxazolones from N-alkoxycarbonylamino acids and their implication in carbodiimide-mediated reactions in peptide synthesis

Abstract

Reaction of N-ethyl,N′-(γ-dimethylaminopropyl)-carbodiimide- HCl with one equiv. of N-tert-butoxycarbonyl-L-valine (3a) in dichloromethane at 23 °C gives, besides the symmetrical anhydride (5a), the optically pure 2-tert-butoxy-4-isopropyl-5(4H)-oxazolone (4a) which can be obtained in 50% yield under selected conditions. The 2-benzyloxycarbonyl-4-isopropyl-5(4H)-oxazolone (4b) is similarly obtainable from N-benzyloxycarbonyl-L-valine (3b). Anhydrous acid converts 4a to the oxazolidinedione. Simple preparations of the N-carboxyanhydrides of valine and isoleucine have been devised from these reactions. Compound 4 reacts with 3 to give 5. Compound 4 reacts with an amino acid ester to give the optically pure peptide even in the presence of salts, but partial racemization occurs for reactions in the presence of a tertiary amine. Evidence for the implication of 2-alkoxy-5(4H)-oxazolones in the couplings of N-alkoxycarbonylamino acids is presented. Compound 4a has been isolated in 6–11% yield from carbodiimide-mediated reactions of 3a with itself or amino acid methyl esters which have been terminated before completion.