The synthesis of novel heterocyclic substituted α-amino acids; further exploitation of α-amino acid alkynyl ketones as reactive substrates

Abstract

A series of novel non-proteinogenic heterocyclic substituted α-amino acids derived from L-aspartic acid have been synthesised using the alkynyl ketone functionality as a versatile building block. Condensation of (S)-2-tert-butoxycarbonylamino-4-oxohex-5-ynoic acid tert-butyl ester 4 with enamines 5, 6, phenylhydrazine, hydroxylamine and phenyl azide has led to the generation of pyridines 9, 10, pyrazolines 11a/b, isoxazoles 12a/b, and triazole 13, respectively in moderate to excellent yields. Acid deprotection of the initial adducts afforded the desired heterocyclic substituted α-amino acids as their TFA salts or in the form of the zwitterions themselves after ion-exchange chromatography. The enantiomeric purity of a representative selection of these products were greater than 98% ee as verified by derivatisation to the corresponding Mosher’s amides and subsequent ¹⁹F NMR spectroscopy.