Masked side-chain aldehyde amino acids for solid-phase synthesis and ligation

The masked aldehyde amino acid Fmoc-Hyl(Boc-oxazolidine) 1, has been synthesized from the parent amino acid in five steps (3 pots). The employed protection scheme renders 1 well suited for standard Fmoc-based solid-phase assembly of peptides and similar structures, including TFA-based deprotections. The resulting peptides possess a side-chain 1,2-amino alcohol, and post-TFA treatment, periodate oxidation of the unprotected peptide unmasks the aldehyde function. The given order of transformations circumvents the known, problematic release of reactive aldehydes in TFA solution. The post-TFA generated peptide aldehydes have been utilized in model chemo-selective ligations, with formation of hydrazone constructs. Additionally, Fmoc-Hyl(Alloc-oxazolidine) 10 was synthesized, and used for on-resin aldehyde generation and hydrazone transformation