Metal Catalyzed CN and CS Bond Forming Reactions for Bioconjugation Targets

描述（申请人提供）：生物偶联化学领域的研究人员一直需要明确的连接策略，以便在广泛的条件下合理有效地用于特定小分子和生物靶点的正交和选择性结合。对高效生物偶联策略的要求通常包括高水平的官能团耐受性，与水和环境无害溶剂的相容性，以及高效的转化（就反应时间和产率而言）。遵循Sharpless和他的同事在2001年提出的“点击化学”原理的反应，是生物偶联应用的理想候选者。令人惊讶的是，目前用于获取可作为“点击”生物偶联前体的芳基叠氮化物，硫醇和异thyocyanates的合成方法仅限于通常具有苛刻条件和

DESCRIPTION (provided by applicant): 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.