Scalable Synthesis and New Bond Disconnections

可扩展的合成和新的键断裂

• 批准号: 10164654
• 负责人: PHIL S BARAN
• 金额: $ 109.42万
• 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10164654
• 关键词: Address; Adoption; Alkaloids; Architecture; Biochemical Pathway; Biological; Biomedical Research; Breathing; Chemicals; Collaborations; Complex; Development; Drug Industry; Environment; FDA approved; Family; Folk Medicine; Human body; Industrialization; Knowledge; Laboratories; Literature; Mediator of activation protein; Methodology; Methods; Modernization; Natural Products; Nature; Organic Chemistry; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Procedures; Property; Reagent; Research; Scientist; Source; Synthesis Chemistry; Terpenes; Transcend; cost; drug discovery; field study; interest; novel; programs; scaffold; success

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.

项目概要/摘要 天然产物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物，这是以前未知的 在研究独特的生化途径时发现了作用机制 这些化合物在人体内发生。此外，在全合成方面的努力 这些结构多样的化合物不断给化学家带来挑战， 这反过来又导致了学术和工业研究项目的建立 环境。自成立以来，我们实验室一直追求并取得了成功， 萜烯和生物碱家族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，我们随后解决了这些空白。 该研究项目的产品——新的合成策略，前所未有的转变 和新颖的试剂——反过来又使得更多天然产物的合成成为可能 药学相关的基序，从而完成发现的催化循环。我们力求 通过当前提案复制这一成功：所描述的项目将针对复杂的自然 产品来识别化学方法的缺点，同时设计 广泛感兴趣的方法，然后评估其在合成中的实用性 的复杂分子。未来五年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。我们将专注于高效 合成复杂的天然产物，追求理想。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 复杂的药物基序，这将有助于扩大化学空间并加速 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 研究将要合成的产品的生物特性，以进行验证和现场测试 新方法，并将试剂商业化以在学术和学术界广泛采用 工业环境。最后，我们将重点关注合成材料的战略应用和开发 有机电化学方法，其中C-H氧化介体的开发 介绍了官能化、羰基去饱和和还原交叉偶联。