Site-Selective Catalysts for Organic Synthesis

描述(申请人提供)：多功能分子在疾病的化疗治疗中发挥着重要作用。有机合成领域是制药科学的先锋，它既提供了用于筛选生物靶标的小分子，也提供了最终用于工业规模药物合成的高效过程。很大一部分药物候选合成依赖于包含许多这样的位点的分子内独特的反应位点的选择性官能化。因此，发生不良副作用的风险是极端的。到目前为止，处理这种情况的主导战略是使用“保护团体”。保护性团体的效率本来就很低。它们需要一个安装步骤，一个额外的拆卸步骤，并且这些步骤通常都不会100%地发生，不会浪费，也不会损失时间。此外，从根本上讲，保护基团是有机合成中一系列悬而未决的问题。保护基团掩盖了一个反应部位，同时允许化学作用在另一个部位发生。在合成有机化学中更直接的挑战将是在竞争的反应性面前实现所需的反应性，而不是低效地应用这种面具。工具的开发--即催化剂--将允许多功能分子中非常相似的位置的选择性官能化，这将是向前迈出的重要一步。虽然在一些圈子里，我们的目标被认为是棘手的，但我们已经启动了一个项目，记录了一个潜在的新战略。这对两种复杂分子的从头合成都有重要意义。此外，药物验证的、结构复杂的天然产品的无保护基团修饰的影响也非常令人兴奋。天然产物令人惊叹的生物活性指导了一代又一代合成有机化学家。然而，臭名昭著的是，许多制药公司正在淡化对天然产品发现和药物开发努力的重视。一个主要原因是结构复杂，这既阻碍了有效的综合，也阻碍了直接模拟生成。通过针对天然产物的直接、高效和无保护基团的操纵，我们努力引入新的工具，帮助它们在学术和工业实验室中进行探索，使人们能够高效地获得新的和以其他方式无法获得的生物活性类似物。

DESCRIPTION (provided by applicant): Polyfunctional molecules play an important role in the chemotherapeutic treatment of disease. The field of organic synthesis resides in the vanguard of pharmaceutical science, delivering both the small molecules for screening against biological targets, and ultimately the efficient processes for drug synthesis on an industrial scale. A large fraction of drug candidate syntheses depends on the selective functionalization of unique reactive sites within molecules that contain many such sites. Thus, the risk of undesired side reactions is extreme. To date, the dominant strategy to handle this situation is the use of "protective groups." Protective groups are inherently inefficient. They require a step for installation, an additional step for removal, and neither of these steps generally occurs in 100% yield, with no waste, nor loss of time. Furthermore, from a fundamental standpoint, protective groups bely a host of unsolved problems in organic synthesis. Protective groups mask one reactive site, while allowing chemistry to occur at another. The more direct challenge in synthetic organic chemistry would be to achieve the desired reactivity, in the face of competing reactivity, without the inefficient application of such a mask. The development of tools - i.e., catalysts - that would allow the selective functionalization of very similar sites within polyfunctional molecules would constitute a major step forward. While the goal is, in some circles, viewed as intractable, we have initiated a program that has documented a potentially new strategy. The implications for both de novo syntheses of complex molecules are significant. Moreover, the implications of the protective group-free modification of pharmaceutically proven, structurally complex natural products is also highly exciting. The amazing biological activity of natural products has guided generations of synthetic organic chemists. Yet, notoriously, many pharmaceutical companies are de-emphasizing natural products discovery and drug development efforts. A major reason is the structural complexity that prevents both efficient synthesis, and straightforward analog generation. By taking aim at the direct, efficient and protecting group-free manipulation of natural products, we endeavor to introduce new tools that may assist in their exploration in both academic and industrial laboratories, enabling efficient access to novel and otherwise inaccessible biologically active analogs.