Backbone Amide Linker in Solid-Phase Synthesis

A comprehensive survey of the Backbone Amide Linker (BAL) chemical methodology, which extends beyond applications in peptide chemistry, is provided. The theories used in the implementation of BAL chemistry include attaching the aromatic aldehyde to the support and perform the reductive amination (RA) on-resin. A direct strategy for measuring of reactions on the trialkoxybenzyl BAL handle is provided by introduction of a 13C label at the aldehyde moiety used to monitor reactions leading to BAL-carbamate formation. The OHBAL linker is attached to the solid phase via a Sieber linker, allowing the release of the entire substrate-BAL adduct by treatment with trifluoroacetic acid-DCM (TFA-DCM). A way to extend the peptide C-terminally from the BAL-anchored residue is described to access peptides with C-termini labile to nucleophiles.