Scalable Synthesis and New Bond Disconnections

可扩展的合成和新的键断裂

• 批准号: 9677411
• 负责人: PHIL S BARAN
• 金额: $ 9.62万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9677411
• 关键词: Address; Adoption; Alkaloids; Alkenes; Architecture; Biochemical Pathway; Biological; Biomedical Research; Breathing; Carbon; Chemicals; Chemistry; Collaborations; Complex; Development; Dimerization; Drug Industry; Electrochemistry; Environment; FDA approved; Family; Fluorine; Folk Medicine; Goals; Human body; Hydrogen Bonding; Industrialization; Knowledge; Laboratories; Literature; Methodology; Methods; Modernization; Natural Products; Nature; Organic Chemistry; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Procedures; Property; Reagent; Research; Scientist; Source; Terpenes; Transcend; cost; field study; interest; novel; oxidation; programs; scaffold; success

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.

巴兰，菲尔·S。 项目摘要/摘要 天然产品长期以来一直保持社会价值作为民间药物，甚至在这个现代时代，许多 FDA批准的药物仍来自自然界中发现的萜烯和生物碱。生物医学 研究也从天然产品中受益，因为以前未知的作用机理已经 在研究这些化合物在人类中经历的独特生化途径时发现 身体。此外，这些建筑上多样的化合物的总合成的努力具有 不断为化学家提供挑战，这又导致了研究的建立 学术和工业环境中的计划。自成立以来，我们的实验室一直是 追求并已经成功地是在萜烯和 生物碱家庭。这些合成已经确定了化学文献中的差距，我们已经有 随后解决。该研究计划的产品 - 新合成策略，前所未有的 转化和新颖的试剂 - 反过来又可以合成更多天然产品， 药物相关的基序，从而完成了发现的催化循环。我们试图复制这个 当前建议的成功：所描述的项目将针对复杂的天然产品以识别 化学方法论的缺点，同时设计了宽度兴趣的方法， 然后在复杂分子的合成中评估其实践。 该提议分为三个部分，其总体目标是产生化学 超越天然产品合成的原始目标的知识。第一部分描述 晚期氧化物的计划有效合成复杂的萜烯和生物碱天然产物。这 该提案的第二部分认为，电化学可以是一种实用，廉价，无毒的，并且 可扩展解决各种化学问题的解决方案，其中N – H键的自然产物二聚化 合成，杂种氟化药物开发的氟化和用于耕种 提出了萜烯型框架的功能化。最后，第三部分说明了多功能 烯烃衍生的，以碳为中心的自由基对CC和C – N键的反应性 不切实际或不可能创建。由此产生的程序将用于复杂的构建 和宽带的药物图案，将有助于扩大化学空间和 加速医学化学发现。值得注意的是，我们已经建立了许多合作 研究将合成的产品的生物学特性，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采用宽度。