Enantioselective Formation of All-Carbon Quaternary Centers via Pi-Allylic Rearrangements of N-Alloc Enamines and Ynamides

通过 N-Alloc 烯胺和 Ynamides 的 Pi 烯丙基重排对映选择性形成全碳四元中心

• 批准号: 1800487
• 负责人: Matthew Cook
• 金额: $ 45万
• 依托单位: Montana State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1800487&HistoricalAwards=false
• 关键词: Enantioselective; Formation; Carbon; Quaternary; Centers

With this award, the Chemical Synthesis Program of the Division of Chemistry is supporting the research of Professor Matthew Cook of the Department of Chemistry and Biochemistry at Montana State University. Professor Cook is studying new catalytic reactions that produce molecules containing a carbon atom bound to four other carbon atoms. Such carbons atoms are called "all-carbon quaternary centers". These carbons can possess a property known as "chirality" or "handedness". Chiral molecules, like human hands, are not superimposable on their mirror images. The two-handed forms of such molecules (like the left hand or the right hand) can be difficult to generate selectively. This is even more so in the case of compounds that bear all-carbon quaternary centers. Roughly 10% of the 200 top selling pharmaceuticals contain chiral all-carbon quaternary centers; however, none can be synthesized entirely in a laboratory. Instead, they are formed from naturally occurring sources. Professor Cook addresses this problem by developing new palladium-catalyzed methods that can selectively form chiral, all-carbon quaternary centers with a preference for one handed form over the other. Professor Cook also works closely with Professor Neufeldt, also at Montana State University, to investigate the mechanism of theses reactions so they can be further improved and optimized. This project provides excellent preparation for graduate and undergraduate students in future careers in STEM fields, in either academia or industry. Professor Cook also works on an outreach program to introduce K-12 school students living in Montana's rural areas (including a large Native American population) to practical science and modern instrumentation, with the aim of fostering their interests in STEM subjects and improving their enrollment rates at college.Professor Cook is exploring the use of new pi-allylic rearrangement chemistry to generate stereogenic all-carbon quaternary centers with high levels of stereoselectivity. He is adopting two approaches, both of which utilize N-alloc carbamates that undergo a decarboxylative rearrangement to generate the requisite stereocenter. These methods overcome the major challenge in pi-allyl chemistry in acyclic systems, efficiently controlling E/Z selectivity in the nucleophile. By utilizing N-alloc enamines, which are much more configurationally stable than their enolate analogs, geometric fidelity can be retained. This allow catalyst control to dictate the stereochemical outcome. Another strategy being pursued uses N-alloc ynamides, which generate ketenimines following a pi-allylic rearrangement. These ketenimine intermediates then undergo a subsequent sigmatropic rearrangement, nucleophilic addition, or a second pi-allylic rearrangement to generate an all-carbon stereocenter. These ketenimine intermediates are chiral but undergo epimerization, and are being used in dynamic kinetic resolution reactions. Detailed mechanistic studies of both of these reactions are being conducted experimentally and computationally in collaboration with Professor Sharon Neufeldt at Montana State.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.

有了这个奖项，化学系的化学合成计划支持蒙大拿州立大学化学和生物化学系的马修·库克教授的研究。库克教授正在研究新的催化反应，这种反应可以产生含有一个碳原子和四个碳原子结合的分子。这种碳原子被称为“全碳季中心”。 这些碳可以具有称为“手性”或“手性”的性质。手性分子，就像人手一样，不能在它们的镜像上重叠。这种分子的双手形式（如左手或右手）可能难以选择性地产生。 这在具有全碳季中心的化合物的情况下更是如此。在200种最畅销的药物中，大约有10%含有手性全碳季中心;然而，没有一种可以完全在实验室中合成。相反，它们是由自然发生的来源形成的。 Cook教授通过开发新的钯催化方法来解决这个问题，该方法可以选择性地形成手性全碳季中心，其中一种手性形式优于另一种。库克教授还与同样在蒙大拿州立大学工作的Neufeldt教授密切合作，研究这些反应的机理，以便进一步改进和优化。 该项目为研究生和本科生在STEM领域未来的职业生涯提供了良好的准备，无论是学术界还是工业界。 库克教授还致力于一项外展计划，向生活在蒙大拿州农村地区的K-12学校学生介绍（包括大量美洲原住民）到实用科学和现代仪器，，旨在培养他们对STEM学科的兴趣，提高他们的大学入学率。Cook教授正在探索使用新的π-烯丙基重排化学来生成立体异构的全-具有高水平立体选择性的碳季中心。他采用了两种方法，这两种方法都利用N-异丙氨基甲酸酯进行脱羧重排，以产生必要的立体中心。这些方法克服了非环状体系中π-烯丙基化学的主要挑战，有效地控制了亲核试剂中的E/Z选择性。通过利用构型比它们的烯醇化物类似物稳定得多的N-阿洛碳烯胺，可以保持几何保真度。 这允许催化剂控制决定立体化学结果。另一种策略是使用N-异丙酰亚胺，其在π-烯丙基重排后产生烯酮亚胺。这些烯酮亚胺中间体然后经历随后的σ转移重排、亲核加成或第二次π-烯丙基重排以产生全碳立构中心。这些烯酮亚胺中间体是手性的，但经历差向异构化，并且被用于动态动力学拆分反应。这两种反应的详细机理研究正在与蒙大拿州立大学的Sharon Neufeldt教授合作进行实验和计算。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估。