Researchers in the field of bioconjugate chemistry have long needed well-defined ligation strategies that can be rationally and effectively used for orthogonal and selective binding of specific small molecule and biological targets under a wide range of conditions. Requirements for efficient bioconjugation strategies generally include high levels of functional group tolerance, compatibility with water and environmentally benign solvents, and efficient conversions (in terms of reaction times and yields). Reactions that adhere to the principles of "click chemistry," introduced by Sharpless and co-workers in 2001, are ideal candidates for bioconjugation applications. Surprisingly, current synthetic methodologies for accessing the aryl azides, thiols and isothyocyanates, which can be used as precursors for "click" bioconjugation are limited to synthetic strategies that generally have harsh conditions and low functional group tolerance. The ultimate goal of this work is devoted to the development of efficient catalytic methodologies for the conversion of functionalized aryl halides to molecules useful for highly specific bioconjugation processes. Specifically, we will focus on catalytic C-N and C-S bond formations using the highly active Group 10 (Ni, Pd, Pt) based N-heterocyclic carbene (NHC) catalytic manifold. These NHC ligands will feature large steric bulk and hemilabile moieties, which will enforce a mononuclear, electron-rich metal site, crucial for high catalytic activity. The scope of the proposed catalytic functionalizations will include important functional motifs, such as azides, thiols, and isothiocyanates. Successful establishment of the reactive intermediates and optimized conditions for the catalytic reaction cycle will enable us to develop an efficient protocol for late-stage introduction of highly-active functional groups within commonly used homo- and hetero-bifunctional protein crosslinking agents, conjugating fluorescent probes, and other bioorthogonal reagents.
Development of new functional targets for bioconjugation will further our understanding in protein-protein interactions and live cell imaging, which is crucial t the development of new methods for disease treatments. The proposed methodology will also impact facile production of new building blocks for pharmaceuticals, containing nitrogen- and sulfur-based building blocks via more practical and safe routes.
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