Scalable Synthesis and New Bond Disconnections

可扩展的合成和新的键断裂

基本信息

批准号：
9891858
负责人：
PHIL S BARAN
金额：
$ 118.42万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

项目摘要

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.

描述（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，即使在当今时代，许多 FDA 批准的药物仍然源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。，因为在研究这些化合物在人体内经历的独特生化途径时发现了以前未知的作用机制。此外，这些结构多样的化合物的全合成努力不断给化学家带来挑战。自成立以来，我们的实验室一直致力于萜烯和生物碱家族中标志性天然产物的全合成，并已成功实现这些合成。我们随后解决了化学文献中的空白，该研究计划的产品——新的合成策略、前所未有的转化和新颖的试剂——反过来又使得更多天然产物和药物相关基序的合成成为可能，从而完成了催化循环。我们寻求通过当前的提案复制这一成功：所描述的项目将针对复杂的天然产物，以确定化学方法学的缺点，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。该提案分为三个部分，其总体目标是产生超越天然产物合成最初目标的化学知识。第一部分描述了后期氧化的计划，以有效合成复杂的萜烯和生物碱天然产物。该提案认为，电化学可以成为解决各种化学问题的实用、廉价、无毒且可扩展的解决方案，但用于天然产物合成的 N-H 键二聚、用于药物开发的杂芳烃氟化以及用于功能化的烯丙基氧化最后，第三部分介绍了烯烃衍生的碳中心自由基形成 C-C 和 C-N 键的多功能反应性。由此产生的程序将用于构建复杂且空间阻碍的药物基序，这将有助于扩大化学空间并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来研究其生物学特性。即将合成的产品，以验证和现场测试新方法，并将试剂商业化以在学术和工业环境中广泛采用。