Palladium as a Golden Additive in Chemical Protein Synthesis

Despite great advances in chemical and semi-synthesis of proteins there are several challenges remain to be solved. One of these is the need for practical protecting groups for the synthesis of uniquely modified proteins.¹ Thiazolidine (Thz) and Acetamidomethyl (Acm) protecting groups are widely utilized in peptide and protein synthesis, however, the reaction time and the harsh conditions of their removal limit their utilities. Developing optimal removal conditions for theses protecting groups remains a challenge. We have recently reported that water-soluble palladium (II) complexes² are excellent reagents for rapid unmasking of Thz under NCL conditions.³ Moreover, palladium (II) complexes are also able to rapidly remove propargyloxycarbonyl (Proc) protecting group from the N-terminal Cys in a similar efficiency.³ The utility of these conditions was exemplified in the efficient total chemical synthesis of Lys34-ubiquitinated H2B (H2BK34Ub),³ neddlyated peptides,³ Tyr57-phosphorylated H2A (H2AY57p)⁴ and methylated/acetylated H3 analogues for different biochemical studies.⁵ Based on these finding, we have also developed a new approach to control polypeptide structure by introducing a cleavable backbone thiazolidine linkage in peptides and proteins.⁶ For the first time we have demonstrated also the rapid and efficient Acm removal using palladium (II) complexes in fully aqueous medium and applied it in the synthesis of ubiquitin like protein (UBL-5).⁷

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