Site-Selective Catalysts for Organic Synthesis

描述（由申请人提供）：多功能有机分子在疾病的化学治疗中起着不可或缺的作用。合成化学在为研究人员和医生提供他们所需的生物活性物质方面发挥着关键作用。绝大多数的这些合成工作严重依赖于含有多个反应基团的多官能结构上的反应位点的选择性衍生化。到目前为止，这项任务的主要策略是重复使用“保护性基团”。“根据定义，保护基团掩盖了一个位点的反应性，同时允许反应在另一个位点发生。然而，保护基是低效的-它们需要引入反应，裂解反应，并且这两个步骤通常以低于100%的产率进行。在时间、试剂、废物去除和所需产物的总产率方面的成本是巨大的。在不使用保护基团的情况下选择性地官能化多官能结构中非常相似的位点的能力将显著提高合成化学家组装复杂目标的效率。同时，提高效率将减少综合努力的成本和环境压力。然而，还没有关于这一问题的系统的、普遍的解决办法的报告。在许多圈子里，这个问题被认为是难以解决的。我们打算追求一个系统的计划，针对多官能分子的位点选择性官能化。我们的方法将取决于手性催化剂，执行对映体和区域选择性反应的发展。在催化过程中，我们将研究将位点选择性磷酸化，酰化和脱氧。我们发现的催化剂将来自合理设计的催化剂库，以及我们实验室开发的组合库。该催化剂的效用将通过磷酸肌醇家族中的复杂多官能目标的定向合成来证明。此外，这些新的催化剂将被应用于合成天然产物样库，通过选择性修饰的重要的多功能天然产物的生物医学意义。最终结果将是选择性合成复杂生物活性化合物的新工具，以及用于生物筛选的重要样品。

DESCRIPTION (provided by applicant): Polyfunctional organic molecules play an integral role in the chemotherapeutic treatment of disease. Synthetic chemistry plays a key role in providing researchers and physicians with the biologically active substances they require. The overwhelming majority of these synthesis efforts depends critically on the selective derivatization of reactive sites on polyfunctional structures containing multiple reactive groups. The dominant strategy for this task to date is the repetitive use of "protective groups." Protective groups, by definition, mask the reactivity of one site while allowing reactions to take place at another site. Yet, protective groups are inefficient - they require a reaction to be introduced, a reaction to be cleaved, and both of these steps usually proceed in less than 100% yield. The costs in terms of time, reagents, waste removal and overall yields of desired products are tremendous. The capacity to selectively functionalize very similar sites in polyfunctional structures without the use of protecting groups would dramatically improve the efficiency with which synthetic chemists assemble complex targets. Simultaneously, improved efficiency would reduce the cost and environmental stress of synthesis efforts. Yet, systematic, general solutions to this problem have not been reported. In many circles, the problem is represented as intractable. We intend to pursue a systematic program targeted at the site-selective functionalization of polyfunctional molecules. Our approach will depend on the development of chiral catalysts that perform enantio- and regioselective reactions. Among the catalytic processes we will study will be site-selective phosphorylation, acylation and deoxygenation. The catalysts we discover will be derived from both rationally designed catalyst libraries, as well as from combinatorial libraries developed in our lab. The utility of the catalysts will be demonstrated through the target-oriented syntheses of complex polyfunctional targets in the phosphoinositide family. In addition, these new catalysts will be applied to the synthesis of natural product-like libraries through the selective modification of important polyfunctional natural products of demonstrated biomedical significance. The end result will be both new tools for the selective synthesis of complex biologically active compounds, as well as important samples for use in biological screens.