Modification of peptide side chains, either to add a label to trace the peptide in subsequent applications or to modify the characteristics of the peptide, is one of the current challenges of peptide synthesis.
RS Giri, SR Manne, G Dolai, et al. recently published a report that they could use FeCl3 in DCM to cleave the t-butyl esters on the side chains of Asp and Glu residues while the peptide was still attached to Rink amide resin. They subsequently modified these residues by forming a variety of esters, amides, and a thioester. Alloc groups and allyl esters were stable to this treatment.
The scope of this method needs to be studied. Presumably, t-Bu protected Ser and Thr side chains will be stable, but this should be verified. The stabilities of Lys(Boc) and Arg(Pbf) also need to be determined. Further, will FeCl3 cleave peptides from Wang resin?
This is not the first report of using Lewis acids to hydrolize t-butyl esters. WD Lubell and co-workers have reported using ZnBr2 in DCM to hydrolize t-butyl esters. They found N-Boc and N-trityl groups were also labile. E Marcantoni, M Massaccesi and E Terrregiani selectively hydrolyzed t-butyl esters in the presence of N-Boc groups using NaI with CeCl3 in refluxing acetonitrile.
These reports are interesting for as yet, there are only limited choices for selective deprotection of Asp or Glu sidechains. With further studies to determine the limitations of these Lewis acid promoted reactions, they could play an important role in peptide synthesis.