Accessing New Chemical Space via Organic Synthesis

通过有机合成进入新的化学空间

• 批准号: 10170385
• 负责人: GARY A MOLANDER
• 金额: $ 60.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170385
• 关键词: 3-Dimensional; Address; Amaze; Area; Carbon; Catalysis; Chemicals; Chemistry; Coupling; DNA; Development; Disease; Grant; Human; Hybrids; Industrialization; Knowledge; Libraries; Methods; Molecular; Organic Synthesis; Process; Research; Research Project Summaries; Sampling; Science; Scientist; Structure; System; Technology; Transcend; base; cost; drug discovery; innovation; invention; novel; screening; small molecule; tool

PROJECT SUMMARY The research outlined within this proposal will establish new knowledge in the following three areas: 1) Access to novel borazine structures will be explored, and the usefulness of these isosteres of all-carbon systems for predictable, highly selective, polyfunctionalization of valuable core structures will be demonstrated. 2) Photoredox/Ni dual catalysis for cross-coupling of sp3- hybridized centers was pioneered in our group. These are transformative processes that have, in an elegant and practical manner, provided the necessary tools to open vast new areas of 3D chemical space through late-stage cross-coupling in highly functionalized substructures. Continued innovation will focus on three subtopics: further expansion of the photoredox/Ni dual catalysis, application of photoredox for application to novel radical transformations, and the invention of novel radical/polar crossover transformations based on photoredox chemistry. 3) As a result of progress made within the scope of current grants, an amazing new opportunity to expand our chemistry has arisen that will provide transformational new tools for drug discovery. Methods developed in the group are being applied to DNA Encoded Library (DEL) synthesis, a technology that possesses the capability to sample easily four to five orders of magnitude more chemical space, less expensively, than any other available high-throughput, small molecule screening methods. It is widely acknowledged that the major hurdle to full implementation of DEL technology is the development of robust, versatile, DNA-compatible chemistry, which is currently exceedingly limited in scope and application. The chemistry outlined in this proposal addresses this critical gap, and thus has the capability to revolutionize the drug discovery process.

项目摘要 本提案中概述的研究将在以下三个方面建立新的知识 领域：1）将探索获得新的环硼氮烷结构，以及这些结构的有用性。 用于可预测的、高选择性的、多官能化的有价值的 将展示核心结构。2)光氧化还原/Ni双催化交叉偶联sp3- 混合中心在我们组是首创的。这些都是变革性的过程， 以一种优雅而实用的方式，提供了必要的工具，以开辟广阔的3D新领域。 通过在高度官能化的子结构中的后期交叉偶联来控制化学空间。 持续的创新将集中在三个子课题：进一步扩大光氧化还原/镍双 催化、光氧化还原在新型自由基转化中的应用，以及 发明了基于光氧化还原化学的新型自由基/极性交叉转化。第三章 由于在目前赠款范围内取得的进展， 扩展我们的化学已经出现，这将为药物发现提供变革性的新工具。 该小组开发的方法正在应用于DNA编码库（DEL）合成， 技术，拥有的能力很容易采样四到五个数量级以上， 化学空间，更便宜，比任何其他可用的高通量，小分子 筛选方法普遍承认，全面执行《公约》的主要障碍是： DEL技术是稳健的、多功能的、DNA相容的化学的发展， 目前在范围和应用上非常有限。这份提案中概述的化学物质 填补了这一关键空白，从而有能力彻底改变药物发现 过程