Biomimetic approaches to gas phase peptide chemistry: combining selective binding motifs with reactive carbene precursors to form molecular mousetraps

Biomimetic reagents capable of selectively forming non-covalent complexes and initiating intermolecular reactions with peptides in the gas phase are presented. In the present work, 18-crown-6 ether (18C6) is utilized to bind specifically to various protonated primary amines, including the protonated side chain of lysine. The use of multiple crown ethers is shown to be an efficient method for enhancing the binding energy, which is a critical factor influencing the success of these reagents. The binding energy must exceed any reaction barriers to the desired chemistry, otherwise simple dissociation of the complex occurs. Two reagents containing acidic and transition metal binding functionalities, respectively, designed to selectively cleave peptide bonds, are synthesized and tested experimentally. A third class of reagent designed to covalently attach to peptides utilizing carbene insertion chemistry is also presented. The results demonstrate that combining the recognition and binding powers of 18C6 with an easily activated diazo group allows for the efficient generation of a highly reactive carbene within a non-covalent complex. Intermolecular insertion reactions initiated by the carbene can transform these non-covalent complexes into covalently bound molecules. Electrospray ionization mass spectrometry and density functional theory (DFr) are utilized to evaluate these intermolecular insertion reactions. The results from experiments with several small molecules and peptides are presented. These diazo-based reagents prove to be highly versatile molecules capable of binding to, and with appropriate activation, becoming covalently attached to virtually any molecule that contains a primary amine. For this reason, we have dubbed them "molecular mousetraps." (C) 2003 Elsevier Science B.V All rights reserved.