Scalable Synthesis and New Bond Disconnections

菲尔·巴兰 项目概要/摘要 天然产品作为民间药物长期以来一直具有社会价值，即使在这个现代时代， FDA批准的药物仍然来自自然界中发现的萜烯和生物碱。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已经被发现。 在研究这些化合物在人体内的独特生化途径时发现的 身体此外，在这些结构上不同的化合物的全合成方面的努力已经取得了进展。 不断为化学家提供挑战，这反过来又导致了研究的建立 在学术和工业环境中的计划。自成立以来，我们的实验室一直 追求，并已成功地，在萜烯和 生物碱家族这些合成已经确定了化学文献中的空白， 随后处理。这项研究计划的产物-新的合成策略，前所未有的 转化和新试剂-反过来又使得能够合成更多的天然产物， 药物相关的基序，从而完成发现的催化循环。我们试图复制这种 目前提案的成功：所述项目将针对复杂的天然产品， 化学方法的缺点，同时设计出广泛关注的方法， 然后评估它们在合成复杂分子中的实用性。 该提案分为三个部分，其总体目标是产生化学品， 超越天然产物合成的原始目标的知识。第一部分描述了 后期氧化高效合成复杂萜类和生物碱类天然产物的方案。的 该提案的第二部分认为，电化学可以是一种实用、廉价、无毒， 一个可扩展的解决方案，以各种化学问题，其中N-H键的二聚天然产物 合成，用于药物开发的杂芳烃取代，以及用于 功能化的term类型的框架。最后，第三部分说明了通用的 烯烃衍生的碳中心自由基形成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设复杂的 和空间阻碍的药物基序，这将有助于扩大化学空间， 加速药物化学的发现值得注意的是，我们已经建立了许多合作关系， 研究将要合成的产品的生物特性，验证和实地测试新的 方法，并将试剂商业化以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.