Iterative Csp3 Cross Coupling for Natural Products Synthesis

用于天然产物合成的迭代 Csp3 交叉耦合

• 批准号: 1955838
• 负责人: Martin Burke
• 金额: $ 45万
• 依托单位: University of Illinois at Urbana-Champaign
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1955838&HistoricalAwards=false
• 关键词: Iterative; Csp3; Cross; Coupling; Natural

With this Award, the Chemical Synthesis Program of the NSF Division of Chemistry is supporting the research of Professor Martin D. Burke at The University of Illinois at Urbana-Champaign (UIUC) who works with undergraduate and graduate students to develop strategies and methods for the Lego-like synthesis of small organic molecules. Such small molecules have many applications that positively impact society, these include serving as medicines, biological probes, crop protectants, fertilizers, and materials such as light-harvesting organophotovoltaics. The discovery and development of small molecules with new and/or improved functions is challenging and slow. This is because most small molecules are prepared using customized synthetic routes that require many person hours and a high level of specialist expertise. The Burke group is pioneering an alternate approach where most small molecules can be made using a common Lego-like platform. This platform has been automated, and non-specialists can assemble a wide range of small molecules using a bounded set of building blocks and cross-coupling reactions. This modularization and automation of the process of small molecule synthesis is saving time and resources, and expanding the range of people who can participate in the process of discovering molecular solutions to some of the most challenging problems facing society. In order to further expand the range of small molecules accessible by this platform, Professor Burke and his students are now developing novel methods for the assembly of small molecule building blocks. The broader impacts of this project include leveraging the relatability of Lego-like small molecule synthesis to inspire high school chemistry students to engage in the molecule making process through “3D printing” their own organic molecules.The continued development of new methods for cross-coupling of three-dimensional “sp3” carbon atoms, especially forming Csp3-Csp3 bonds or those flanked by adjacent heteroatoms, represents a roadmap toward generalized, automated, building block-based small molecule synthesis. As a means to efficiently access sp3-rich and topologically complex polyketide natural products, palladium catalyzed cross-coupling reactions are being developed to enable the coupling of Csp3 boronic acids possessing beta-oxygens with a specific focus on avoiding non-productive elimination of beta-heteroatoms. New electronically and sterically tuned phosphine ligands as well as directing group strategies will be employed as a means to efficiently access polyketide-like frameworks through cross-coupling. Complementary methods not using transition metals are also investigated as a means to access Csp3-Csp3 cross couplings and interrogate their potential to form adjacent stereocenters. These methods are evaluated for their capacity to access polyketide chemical space through the automated building block-based synthesis of three stereochemically complex center natural products. This research stimulates the identification of new and more robust ligands which can reversibly attenuate boron reactivity to enable the iteration of such Csp3 cross-coupling reactions. These research activities yield powerful new avenues to access stereospecific Csp3 cross-coupling though manual and automated chemical synthesis. This research program also contributes to the training of undergraduate and graduate students in the concepts and practice of next generation chemical synthesis, and inspires high school students to participate in the molecular innovation process.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

凭借该奖项，美国国家科学基金会化学部的化学合成项目正在支持伊利诺伊大学厄巴纳-香槟分校 (UIUC) 教授 Martin D. Burke 的研究，该教授与本科生和研究生合作，开发类似乐高积木的有机小分子合成策略和方法。这种小分子具有许多对社会产生积极影响的应用，包括用作药物、生物探针、农作物保护剂、肥料以及光捕获有机光伏等材料。具有新的和/或改进的功能的小分子的发现和开发具有挑战性且缓慢。这是因为大多数小分子是使用定制的合成路线制备的，需要大量的工时和高水平的专业知识。伯克小组正在开创一种替代方法，其中大多数小分子可以使用通用的乐高式平台来制造。该平台已经自动化，非专业人士可以使用一组有界的构建块和交叉偶联反应来组装各种小分子。 小分子合成过程的模块化和自动化节省了时间和资源，并扩大了参与发现社会面临的一些最具挑战性问题的分子解决方案过程的人员范围。为了进一步扩大该平台可利用的小分子范围，伯克教授和他的学生现在正在开发组装小分子构件的新方法。该项目更广泛的影响包括利用乐高式小分子合成的相关性，激发高中化学学生通过“3D打印”自己的有机分子来参与分子制造过程。三维“sp3”碳原子交叉耦合的新方法的不断发展，特别是形成Csp3-Csp3键或两侧有相邻杂原子的键，代表了 通用化、自动化、基于构建块的小分子合成路线图。作为有效获取富含 sp3 且拓扑复杂的聚酮化合物天然产物的一种方法，人们正在开发钯催化的交叉偶联反应，以实现具有 β-氧的 Csp3 硼酸的偶联，特别是避免β-杂原子的非生产性消除。新的电子和空间调谐膦配体以及导向基团策略将被用作通过交叉偶联有效获得类聚酮化合物框架的手段。还研究了不使用过渡金属的补充方法作为获取 Csp3-Csp3 交叉耦合并探究它们形成相邻立构中心的潜力的方法。通过基于构建单元的自动化合成三种立体化学复杂的中心天然产物，评估这些方法进入聚酮化合物化学空间的能力。这项研究促进了新的、更强大的配体的识别，这些配体可以可逆地减弱硼的反应性，从而能够重复进行此类 Csp3 交叉偶联反应。这些研究活动为通过手动和自动化学合成实现立体特异性 Csp3 交叉偶联提供了强大的新途径。该研究项目还有助于对本科生和研究生进行下一代化学合成概念和实践的培训，并激励高中生参与分子创新过程。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Stereospecific Csp 3 Suzuki–Miyaura Cross-Coupling That Evades β-Oxygen Elimination

避免β-氧消除的立体特异性 Csp 3 Suzuki–Miyaura 交叉偶联

• DOI: 10.1021/acscatal.2c03245
• 发表时间: 2022
• 期刊: ACS Catalysis
• 影响因子: 12.9
• 作者: LaPorte, Antonio J.;Shi, Yao;Hein, Jason E.;Burke, Martin D.
• 通讯作者: Burke, Martin D.