This study demonstrates effective cleavage of HMPB using hexafluoroisopropanol, suggesting new methods for peptide synthesis.
Hexafluoroisopropanol (HFIP) is widely used as a hydrogen-bond donor solvent. Here, we demonstrate that 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB), a commonly used linker for generating C-terminal carboxylic acid peptides, cleaves from solid support at HFIP concentrations as low as 20% in DCM. The resulting yields are comparable to concentrated trifluoroacetic acid (TFA) cleavage conditions. This reactivity is attributed to an added resonance structure, enabled by a para-methoxy substituent, which potentially stabilizes the benzylic carbocation intermediate during cleavage.
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Desgagné et al. (2025) studied this question.
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