Resins for the Synthesis of C-Terminal Modified Peptides

Hydroxymethylbenzoic acid (HMBA) is a useful and versatile benzyl ester derived linker, completely resistant to acids (even to liquid HF) but easily cleavable by a variety of nucleophilic reagents to give access to peptides with diverse C-terminal functionalities.^(1-3) Because the HMBA resin is TFA stable, on-resin side-chain deprotection can also be achieved. Peptide acids are obtained by saponification.^{(2, 3)} Ammonolysis or amminolysis provides primary or secondary amides.^(2-4) Peptide alcohols can be synthesized by boron hydride reduction-cleavage procedure of the C-terminal benzyl ester. Reductive cleavage is effected rapidly using LiBH₄ in THF.⁽⁵⁾ Transesterification of the peptide resin benzyl ester linkage releases peptide esters. Tertiary amines may serve as catalysts, but better results are described employing either KCN^{(6, 7)} or LiBr/1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).⁽⁸⁾ Hydrazinolysis of peptidyl resins provides protected peptide hydrazides, precursors for subsequent fragment condensations via azide coupling.⁽⁹⁾ Coupling of the first amino acid residue is accomplished employing either carbodiimide/dimethylaminopyridine (DMAP) in dichloromethane,⁽¹⁰⁾ 2,6-dichlorobenzoyl chloride/pyridine in dimethylformamide,⁽¹¹⁾ or 1-(2-mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole (MSNT) in the presence of N-methylimidazole.^{(12, 13)}