Site-Selective Catalysts for Organic Synthesis

描述（申请人提供）：多功能有机分子在疾病的化疗治疗中发挥着不可或缺的作用。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起着关键作用。这些合成努力的绝大多数都依赖于含有多个反应基团的多官能团结构上反应位点的选择性衍生化。迄今为止，这项任务的主要策略是重复使用“保护组”。顾名思义，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，保护基团是低效的——它们需要一个反应被引入，一个反应被裂解，而这两个步骤通常都不到100%的产率。在时间、试剂、废物清除和所需产品的总体产量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功能化多功能结构中非常相似的位点的能力将大大提高合成化学家组装复杂目标的效率。同时，提高效率将减少合成工作的成本和环境压力。然而，对这个问题的系统的、普遍的解决办法还没有报道。在许多圈子里，这个问题被认为是难以解决的。我们打算对多功能分子的选择性功能化进行系统的研究。我们的方法将取决于进行对映和区域选择性反应的手性催化剂的发展。在催化过程中，我们将研究位点选择性磷酸化，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。催化剂的用途将通过靶向合成磷酸肌肽家族中复杂的多功能靶标来证明。此外，这些新型催化剂将通过选择性修饰具有生物医学意义的重要多功能天然产物，应用于天然产物类文库的合成。最终结果将成为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.