Structure Based Development of Organic Reactions

基于结构的有机反应进展碱金属和极少量的阳离子金属稳定剂，如硼、锌、钛和铂，是目前有机合成中应用最广泛的有机金属试剂。然而，关于它们的解决方案和固态结构仍然有许多悬而未决的问题。这项建议的具体目标1旨在加强我们对这类试剂的聚集状态、配位数、连接配体的几何构型和密切结构特征的了解。该项目的结果将为开发新试剂和优化现有试剂的立体选择性提供模型。该项目的第二个具体目标是设计合成和表征新的试剂，并利用我的实验室将制备的新型手性聚合物试剂开发不对称合成方法。新聚合物的设计将基于我实验室的活性中间体的结构主题。将设计新的设备，并制定方案，从生长、分类和操作极端活性、极潮湿和极温度敏感的有机金属化合物，为通过X射线衍射分析对其进行表征做准备。因此，将开发一种高通量晶体筛选设备和方案，以模拟已被证明非常成功地高通量制备大分子蛋白质晶体的方案。广泛影响：立体选择性是合成纯的手性化合物的基础。在新试剂和催化剂的设计中，结构细节对于立体选择性的优化尤为重要。投机性和未经证实的结构性假设通常被用于这一目的。然而，对这些试剂的紧密结构的了解仍然非常不完整，与这些试剂在实践中的广泛和成功使用不相称。尽管如此，令人鼓舞的是，这些试剂的结构与它们的反应性之间有很好的相关性。因此，我提出了一个旨在获得结构信息的研究计划，这些信息将被用于制备新的手性聚合物，并提高制备新化合物的效率。具体到这一建议是对硼烯醇化试剂和手性锂酰胺碱的关注。我们开发的新试剂将被优化用于手性分子的合成，这些分子被用作催化剂和更大分子的构建块。该项目的成功直接和积极地影响了新材料、纳米结构、聚合物和大宗有机化学品的发现和制备效率。我的研究小组中的所有学生都发展了有机合成、光谱分析、层析和X射线衍射分析方面的专业知识，主要侧重于获得在化学、材料或生物化学研究实验室继续独立研究所需的技能。我与布朗大学正在进行的计划合作，积极招募学生参加这个项目，这些计划包括领导力联盟(少数族裔本科生)、NSF教练补助金(理科研究生女性)、UTRA(本科教学和研究)、WISE(科学与工程本科女性)和贝克曼基金会(本科生研究培训)计划。我特别高兴的是，我们在接纳通过领导力联盟和WISE计划确定的少数族裔女本科生方面取得了成功。

AbstractStructure Based Development of Organic ReactionsAlkali metal and a very few additional cationic metal stabilized reagents such as boron, zinc, titanium and platinum are the most widely utilized organometallic reagents in organic synthesis today. However, many unanswered questions concerning their solution and solid-state structures remain. Specific aim 1 of this proposal is designed to enhance our understanding of the aggregation state, the coordination number, the geometry of attached ligands, and the intimate structural features of such reagents. Results of this project will provide models for use in developing new reagents and in optimizing the stereoselectivity of extant reagents. The second specific aim of this project is designed to synthesize and characterize new reagents and to develop asymmetric synthetic methodology utilizing new chiral polymeric reagents that will be prepared in my lab. The design of new polymers will be based upon structure motifs of reactive intermediates from my lab. New equipment will be designed and protocols developed from growing, sorting and manipulating extremely reactive, extremely moisture sensitive and extremely temperature sensitive organometallic compounds in preparation for their characterization by x-ray diffraction analysis. Hence, a high throughput crystal screening apparatus and protocol will be developed in analogy to the protocols that have proven highly successful for high throughput preparation of macromolecular protein crystals.Broader Impact: Stereoselectivity is the basis for synthesizing pure, chiral chemical compounds. Structural details are especially important for the optimization of stereoselectivity in the design of new reagents and catalysts. Speculative and unproven structural postulates typically have been utilized for this purpose. However knowledge of the intimate structure of these reagents remains woefully incomplete and is not commensurate with the widespread, successful use of these reagents in practice. Nonetheless it is encouraging that there is a very good correlation between the structures of these reagents and their reactivity. Hence, I propose a research program designed to obtain structural information that will be utilized to prepare new chiral polymers and to improve the efficiency with which new chemical compounds are prepared. Specific to this proposal is a focus on boron enolate reagents and chiral lithium amide bases. New reagents that we develop will be optimized for the synthesis of chiral molecules utilized as catalysts and as building blocks for larger molecules. Success of this project directly and positively affects the efficiency with which new materials, nanostructures, polymers, and bulk organic chemicals are discovered and prepared. All students in my research group develop expertise in organic synthesis, spectroscopic analyses, chromatography and x-ray diffraction analysis with a major emphasis on acquiring the skills necessary to continue independent research in a chemical, materials or biochemical research laboratory. I actively recruit students to participate in this program in collaboration with ongoing initiatives at Brown University including the Leadership Alliance (minority undergraduates), NSF COACH grant (graduate women in science), UTRA (undergraduate teaching and research), WISE (undergraduate women in science & engineering) and Beckman Foundation (undergraduate research training) programs. I am especially pleased with success we have had in the inclusion of minority, female undergraduates identified through the Leadership Alliance and WISE programs.