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（由适用提供）：天然产品长期以来一直保持社会价值作为民间药物，即使在这个现代时代，许多经FDA批准的药物仍来自于自然界中发现的萜烯和生物碱。生物医学研究也从天然产物中受益，因为在研究这些化合物在人体中经历的独特生化途径时，已经发现了以前未知的作用机制。此外，在这些建筑上多样的化合物的总合成中，努力继续为化学家带来挑战，这又导致在学术和工业环境中建立了研究计划。自成立以来，我们的实验室就一直在追求并成功地进入了萜烯和生物碱家族中标志性天然产品的完全合成。这些合成已经确定了我们随后解决的化学文献中的差距。该研究计划的新综合策略，前所未有的转化和新型试剂又可以依次综合更天然产品和药理学相关的基序，从而完成了发现的催化循环。我们试图通过当前的提案来复制这一成功：所述项目将针对复杂的天然产品来识别化学方法论的缺点，同时同样地设计了宽度感兴趣的方法，然后评估其在合成复杂分子的实践中。该提议分为三个部分，其总体目标是产生超越天然产品合成原始目标的化学知识。第一部分描述了晚期氧化计划，以有效合成复杂的萜烯和生物碱天然产物。提案论点的第二部分是，电化学可以是针对各种化学问题的实用，廉价，无毒且可扩展的解决方案，其中N-H键在天然产物合成中的N-H键，用于制药的杂种氟化，用于药物开发的杂烯氟化，以及用于Terpene-typeworks的功能化的作用。最后，第三部分说明了烯烃衍生的，以碳为中心的自由基对C-C和C-N键的多功能反应性，这些反应性原本是不切实际或无法创建的。由此产生的程序将用于建造复杂且具有空间的药物基序，该图案将有助于扩大化学空间并加速医学化学中的发现。值得注意的是，我们已经建立了许多合作的合作，以研究将合成的产品的生物学特性，验证和现场测试新方法，并将在学术和工业环境中采用宽度的试剂进行商业化。