Scalable Synthesis and New Bond Disconnections

作者声明：Phil S. 项目摘要/摘要 长期以来，天然产品作为民间药物一直具有社会价值，即使在现代，许多 FDA批准的药物仍在从自然界中发现的萜类和生物碱中提取。生物医学 研究也受益于天然产品，因为以前未知的作用机制是 在研究这些化合物在人类体内经历的独特生化途径时发现的 尸体。此外，对这些结构多样的化合物的全合成的努力已经 不断地为化学家提供挑战，这反过来又导致了研究的建立 学术和工业环境中的课程。自成立以来，我们的实验室一直是 追求并成功地实现了具有标志性的萜类和天然产物的全合成 生物碱家族。这些合成已经确定了化学文献中的空白，我们有 随后解决了这一问题。这一研究项目的产品--新的综合战略，史无前例 转化和新试剂-反过来又使得合成更多的天然产品和 与药物相关的基序，从而完成了发现的催化循环。我们寻求复制这一点 当前提案的成功：所述项目将以复杂的天然产品为目标，以确定 化学方法论的缺点，同时设计出人们普遍感兴趣的方法， 然后对它们在合成复杂分子中的实用性进行了评估。 这项提议分为三个部分，首要目标是产生化学物质 超越天然产物合成最初目标的知识。第一部分勾勒出 计划后期氧化，以有效地合成复杂的萜类和生物碱天然产物。这个 提案的第二部分认为，电化学可以是一种实用、廉价、无毒和 各种化学问题的可扩展解决方案，其中天然产物的N-H键的二聚化 合成，用于药物开发的杂芳烃氟化，以及用于 提出了萜烯类骨架的功能化方法。最后，第三部分说明了通用的 烯烃衍生的碳心自由基生成C-C和C-N键的反应性 不切实际的或不可能创造的。由此产生的程序将用于建造综合体 和空间受阻的药物主题，这将有助于扩大化学空间和 加快药物化学的发现。值得注意的是，我们已经建立了许多合作 研究将要合成的产品的生物学特性，验证和现场测试新产品 方法，并将试剂商业化，以便在学术和工业环境中广泛采用。

BARAN, PHIL S. PROJECT SUMMARY/ABSTRACT Natural products have long held societal value as folk medicines, and even in this modern era, many FDA-approved drugs are still being derived from terpenes and alkaloids found in nature. Biomedical research has also benefited from natural products, as previously unknown mechanisms of action have been discovered while studying the unique biochemical pathways that these compounds undergo in the human body. Furthermore, endeavors in the total synthesis of these architecturally diverse compounds have continuously provided chemists with challenges, which in turn have led to the establishement of research programs in both academic and industrial environments. Ever since its inception, our laboratory has been pursuing, and has succeeded in, the total synthesis of iconic natural products in both the terpene and alkaloid families. These syntheses have identified gaps in the chemical literature, which we have subsequently addressed. The products of this research program—new synthetic strategies, unprecedented transformations and novel reagents—have in turn enabled the synthesis of even more natural products and pharmaceutically relevant motifs, thus completing a catalytic cycle of discovery. We seek to replicate this success with the current proposal: the described projects will target complex natural products to identify shortcomings in chemical methodology, while simultaneously devising methods of widespread interest, followed by the assessment of their practicality in the synthesis of complex molecules. This proposal is organized into three parts with the overarching goal of generating chemical knowledge that transcends the original objective of natural product synthesis. The first section delineates plans for late-stage oxidation to efficiently synthesize complex terpene and alkaloid natural products. The second portion of the proposal argues that electrochemistry can be a practical, inexpensive, non-toxic, and scalable solution to a variety of chemistry problems, wherein dimerization of N–H bonds for natural product synthesis, heteroarene fluorination for pharmaceutical development, and allylic oxidation for the functionalization of terpene-type frameworks are presented. Lastly, the third section illustrates the versatile reactivity of olefin-derived, carbon-centered radicals to forge C–C and C–N bonds that are otherwise impractical or impossible to create. The resulting procedures will be utilized in the construction of complex and sterically encumbered pharmaceutical motifs, which will serve to expand chemical space and accelerate discovery in medicinal chemistry. Notably, we have already established numerous collaborations to study the biological properties of the products that will be synthesized, to validate and field-test new methods, and to commercialize reagents for widespread adoption in both academic and industrial settings.