Facilitation of Peptide Synthesis by the Use of 4-Picolyl Esters: Synthesis of Val⁵–Angiotensin II

Abstract

THE simplified procedure for peptide synthesis in which a basic “handle”, incorporated into the C-terminal residue, facilitates the extraction of the growing peptide after each coupling step^1–3 has now been examined in a synthesis of Val⁵–angiotensin II. The basic “handle” was provided by the 4-picolyl ester of the C-terminal phenylalanine; this group can conveniently be removed by catalytic hydrogenation or by electrolytic reduction (unpublished work of D. Stevenson and W. B. Watkins). An analogous method using p-dimethylarninoazobenzyl esters has recently been reported⁴. The synthetic scheme is shown in Fig. 1. Coupling reactions (using 1.05–3.0 M proportions of acylating agent) were continued until no unchanged amino-component could be detected by thin-layer chromatography (limit of detection, 0.1 per cent); the histidine and arginine residues were incorporated by means of dicyclohexylcarbodiimide. The basic coupling product was extracted into 2 N-citric acid solution, except in the final stage, when the product was taken up on sulpho-ethyl-‘Sephadex’ saturated with 3-bromopyridine². So effective were these simple separations that at every step the crude protected peptide was chromatographically pure (in at least four solvents) and had satisfactory elemental analysis. The overall yield of protected octapeptide (based on L-phenylalanine 4-picolyl ester dihydrobromide) was 34 per cent.