Efficient acylation of the N-terminus of highly hindered C(alpha)(alpha)-disubstituted amino acids via amino acid symmetrical anhydrides.

[reaction: see text] Fmoc amino acid symmetrical anhydrides are efficient and readily available reagents for acylation of the N-terminus of highly hindered C(alpha)(alpha)-dialkylated alpha-amino acids. Comparison of a variety of coupling protocols showed that the symmetrical anhydride method always provided the superior results. This method was successfully applied to the solid-phase synthesis of a peptide containing three alpha(alpha)AAs at alternating positions.