Scalable Synthesis and New Bond Disconnections

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批准的药物仍然是从自然界中发现的萜类和生物碱中提取的。 生物医学研究也受益于天然产品，这在以前是未知的 在研究独特的生化途径时，已经发现了作用机制。 这些化合物在人体内所经历的。此外，还努力在全合成方面做出努力 这些结构多样的化合物不断地给化学家们带来挑战， 这反过来又导致了学术和工业领域的研究计划的建立 环境。自成立以来，我们的实验室一直在探索，并取得了成功， 萜类和生物碱家族中标志性天然产物的全合成。这些 合成已经确定了化学文献中的空白，我们随后解决了这一问题。 这项研究计划的产品-新的综合战略，前所未有的转变 和新的试剂-反过来又使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 将这种成功复制到当前的提案中：所描述的项目将以Complex Natural为目标 产品识别化学方法学中的缺陷，同时设计 普遍感兴趣的方法，然后评估它们在综合中的实用性 复杂的分子。在接下来的五年里，我们的实验室将产生化学知识 这超越了天然产物合成的最初目标。我们将高效地专注于 以理想为目标合成复杂的天然产物。我们还将开发有用的方法 用于合成和药物化学。由此产生的程序将用于施工 复杂的药物主题，这将有助于扩大化学空间和加速 药物发现中的发现。值得注意的是，我们已经建立了许多合作关系，以 研究将要合成的产品的生物学特性，以进行验证和现场测试 新的方法，并将试剂商业化，以便在学术和 工业背景。最后，我们将重点介绍合成材料的战略应用和发展。 有机电化学方法，其中C-H氧化介体的发展 介绍了官能化、羰基的去饱和化和还原交叉偶联。

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 establishment 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. For the next five years our laboratory will generate chemical knowledge that transcends the original objective of natural product synthesis. We will focus on efficiently synthesize complex natural products aiming for ideality. We will also develop of useful methods for synthesis and medicinal chemistry. The resulting procedures will be utilized in the construction of complex pharmaceutical motifs, which will serve to expand chemical space and accelerate discovery in drug discovery. 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. Lastly, we will focus on strategic applications and development of synthetic organic electrochemical methods, wherein the development of oxidative mediators for C-H functionalization, desaturation of carbonyls, and reductive cross-couplings are presented.