Scalable Synthesis and New Bond Disconnections

 描述（由申请人提供）：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，许多FDA批准的药物仍然来源于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物，因为在研究这些化合物在人体中经历的独特生化途径时发现了以前未知的作用机制。此外，这些结构上不同的化合物的全合成的努力不断为化学家提供挑战，这反过来又导致了在学术和工业环境中建立研究计划。自成立以来，我们的实验室一直在追求，并已成功地在萜烯和生物碱家族的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，我们随后对此进行了讨论。该研究项目的产物--新的合成策略、前所未有的转化和新型试剂--反过来又使更多天然产物和药学相关基序的合成成为可能，从而完成了发现的催化循环。我们试图复制这一成功与目前的建议：所描述的项目将针对复杂的天然产物，以确定化学方法的缺点，同时设计广泛感兴趣的方法，然后评估其在复杂分子合成中的实用性。 该提案被组织成三个部分，其总体目标是产生超越天然产物合成的原始目标的化学知识。第一部分描绘了后期氧化的计划，以有效地合成复杂的萜烯和生物碱天然产物。该提案的第二部分认为，电化学可以是一个实用的，廉价的，无毒的，和可扩展的解决方案，以各种化学问题，其中N-H键的二聚化天然产物合成，杂芳烃的药物开发，和烯丙基氧化的功能化的term型框架。最后，第三部分说明了烯烃衍生的碳中心自由基的通用反应性，以形成否则不切实际或不可能产生的C-C和C-N键。由此产生的程序将被用于构建复杂的和空间阻碍的药物基序，这将有助于扩大化学空间和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，以研究将要合成的产品的生物学特性，验证和现场测试新方法，并将试剂商业化，以便在学术和工业环境中广泛采用。

 DESCRIPTION (provided by applicant): 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.