Hydroxymethylbenzoic acid, HMBA

Linkers cleavable by nucleophiles include the safety-catch linker [13, 14], hydrazino benzoyl linker [15, 16] and 4-hydroxymethylbenzoic acid (HMBA) [14, 17] (Table 1). All three linkers can provide fully protected peptides, and as the HMBA and hydrazinobenzoyl linkers are acid-stable, the peptide side-chains can be deprotected prior to release of the peptide. The HMBA linker is a versatile but less often used linker for Fmoc-SPPS. Varying the nucleophile employed in the cleavage cocktail a wide range of C-terminal modified peptides can be obtained primary amide (NH3 in methanol) [18,19], hydrazides (5 % NH2NH2 in DMF) [20], acids (0.1 M aqueous NaOH) [21], and methyl esters (5 % DIEA, 5 % MeOH in DMF at 50 °C) [22] (Fig. 1). 

Figure 4.1 Major oxidation intermediates from pX to TA. p-HMBA is p-hydroxymethylbenzoic acid, and 4-CBA is 4-carboxybenzaldehyde. Cat. Co-Mn-Br.

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