A new generation of reversible backbone-amide protection for the solid phase synthesis of difficult sequences

A versatile safety catch backbone-amide protection system (1, 2) has been developed to inhibit interchain aggregation during solid phase peptide synthesis. The strategy utilises the Nα-Fmoc derivative of an N-(3-methylsulfinyl-4-methoxy-6-hydroxybenzyl) (SiMB, 2) substituted amino acid (5b), a group which exhibits excellent all round coupling kinetics. The value of these improved derivatives is demonstrated through the syntheses of leucine enkephalinamide (9) and the well known ‘difficult sequence’ from the acyl carrier protein, residues (65–74) (10) via standard uronium activation and pentafluorophenyl ester chemistry.