Efficient Reagent-Saving Method for the N‑Terminal Labeling of Bioactive Peptides with Organometallic Carboxylic Acids by Solid-Phase Synthesis

Labeling
of biomolecules with organometallic moieties holds great
promise as a tool for chemical biology and for the investigation of
biochemical signaling pathways. Herein, we report a robust and reproducible
synthetic strategy for the synthesis of ruthenocenecarboxylic acid,
giving the acid in 53% overall yield. This organometallic label was
conjugated via solid-phase peptide synthesis in near-quantitative
yield to a number of different biologically active peptides, using
only 1 equiv of the acid and coupling reagents, thereby avoiding wasting
the precious organometallic acid. This optimized method of stoichiometric
N-terminal acylation was then also successfully applied to conjugating
ferrocenecarboxylic acid and a novel organometallic ReI(CO)3 complex, showing the generality of the synthetic
procedure.