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起着不可或缺的作用。合成化学在为研究人员和内科医生提供他们所需的生物活性物质方面发挥着关键作用。这些合成工作中的绝大多数都依赖于含有多个活性基团的多官能团结构上的活性中心的选择性衍生化。到目前为止，这项任务的主导战略是重复使用“保护团体”。根据定义，保护性基团掩盖了一个部位的反应性，同时允许另一个部位发生反应。然而，保护基团是低效的-它们需要引入反应，需要裂解反应，并且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收率方面的成本都是巨大的。在多功能结构中选择性地将非常相似的位置功能化而不使用保护基团的能力将极大地提高合成化学家组装复杂靶标的效率。同时，效率的提高将减少合成工作的成本和环境压力。然而，对这一问题的系统、普遍的解决方案还没有报道。在许多圈子里，这个问题被描绘成难以解决的问题。我们打算进行一个系统的计划，目标是多功能分子的位置选择性官能化。我们的方法将依赖于执行对映体和区域选择性反应的手性催化剂的开发。在我们将研究的催化过程中，将包括定点选择性磷酸化、酰化和脱氧。我们发现的催化剂既来自合理设计的催化剂库，也来自我们实验室开发的组合库。这些催化剂的用途将通过以目标为导向的磷脂酰肌醇家族中复杂多功能目标的合成来展示。此外，这些新型催化剂还将通过对具有生物医学意义的重要的多功能天然产物进行选择性修饰，应用于天然产物类库的合成。最终的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.