Iterative Csp3 Cross Coupling for Natural Products Synthesis

通过这一奖项，美国国家科学基金会化学部化学合成计划支持伊利诺伊大学香槟分校(UIUC)马丁·D·伯克(Martin D.Burke)教授的研究，他与本科生和研究生一起开发类似乐高的有机小分子合成策略和方法。这种小分子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、作物保护剂、化肥和诸如捕光有机光伏等材料。具有新的和/或改进的功能的小分子的发现和开发是具有挑战性的和缓慢的。这是因为大多数小分子都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。伯克团队正在开创一种替代方法，在这种方法中，大多数小分子可以使用常见的乐高平台来制造。这个平台已经自动化，非专业人士可以使用一组有限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，并扩大了能够参与发现解决社会面临的一些最具挑战性问题的分子解决方案的人员范围。为了进一步扩大这个平台可以接触到的小分子的范围，伯克教授和他的学生现在正在开发组装小分子积木的新方法。该项目的更广泛影响包括利用乐高类小分子合成的相关性来启发高中生通过“3D打印”他们自己的有机分子来从事分子制造过程。三维“SP3”碳原子交叉偶联的新方法的持续发展，特别是形成Csp3-Csp3键或那些相邻杂原子侧翼的方法，代表了通用化、自动化、基于积木的小分子合成的路线图。作为一种有效地获得富含sp3和拓扑结构复杂的聚酮类天然产物的手段，正在开发钯催化的交叉偶联反应，以使具有β-氧基的CSP3硼酸能够偶联，并特别关注避免非生产性地消除β-杂原子。新的电子和空间调谐的膦配体以及导向基团策略将被用作通过交叉偶联有效地获得聚酮类骨架的手段。不使用过渡金属的互补方法也被研究为获得Csp3-Csp3交叉偶联和询问它们形成相邻立体中心的可能性的一种手段。通过三种立体化学复杂中心天然产物的自动构建块合成，评估了这些方法访问聚酮化学空间的能力。这项研究促进了新的和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，从而使这种Csp3交叉偶联反应能够迭代。这些研究活动产生了通过手动和自动化学合成获得立体特异性Csp3交叉偶联的强大新途径。该研究计划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优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.