Orthogonal Cleavage of the HMPB Linker from Solid Support Using HFIP
Michael Desgagné1, Dennis A Kutateladze1, Bradley L Pentelute1,2,3,4
1Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Abstract:
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 the solid support at HFIP concentrations as low as 20% in dichloromethane. The resulting yields are comparable to concentrated trifluoroacetic acid cleavage conditions. This reactivity is attributed to an added resonance structure, enabled by a p-methoxy substituent, which potentially stabilizes the benzylic carbocation intermediate during cleavage.
