Synthesis of amino acid derivatives substituted in the backbone with stable isotopes for application in peptide synthesis

Abstract

Starting from the corresponding precursors, 1 and 2, the two well known procedures for asymmetric synthesis of amino acids, those of Schollkopf and Oppolzer, were compared for the preparation of [1,2-¹³C₂,¹⁵N]-labelled (substituted) Boc-leucine enantiomers. Although both gave the final products in comparable overall yields, analysis of optical purity by two independent chromatographic methods revealed that the two procedures differed considerably in this respect. The enantiomeric excess found was 97.2–97.4 and 99.7%, respectively. As a consequence, the latter method was preferred for the synthesis of a number of additional backbone-labelled Boc-derivatives of the three proteinogenic amino acids alanine, phenylalanine and tyrosine, including such deuteriated in the amino acid side-chain. These derivatives exemplify precursors suitable for chemical synthesis of specifically backbone-labelled peptides and should allow greater exploitation of the properties of the ¹³C and, especially, the ¹⁵N nuclei in structural studies.