Structure Based Development of Organic Reactions

摘要碱金属及硼、锌、钛、铂等极少数阳离子金属稳定试剂是当今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有许多悬而未决的问题。本提案的具体目标1旨在增强我们对这些试剂的聚集状态、配位数、附着配体的几何形状以及内部结构特征的理解。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合成和表征新试剂，并利用新的手性聚合物试剂开发不对称合成方法，这些试剂将在我的实验室中制备。新聚合物的设计将基于我实验室中反应性中间体的结构基序。将设计新的设备，并制定新的方案，从生长，分类和操作极端活性，极端湿度敏感和极端温度敏感的有机金属化合物，准备通过x射线衍射分析进行表征。因此，将开发一种高通量晶体筛选装置和方案，类似于已被证明非常成功的高通量制备大分子蛋白质晶体的方案。更广泛的影响：立体选择性是合成纯手性化合物的基础。在设计新试剂和催化剂时，结构细节对优化立体选择性尤为重要。推测性和未经证实的结构假设通常被用于这一目的。然而，这些试剂的内部结构的知识仍然是可悲的不完整，是不相称的广泛，成功地使用这些试剂在实践中。尽管如此，令人鼓舞的是，这些试剂的结构和它们的反应性之间有很好的相关性。因此，我提出了一项研究计划，旨在获得结构信息，用于制备新的手性聚合物，并提高制备新化合物的效率。具体到这个建议是关注硼烯酸盐试剂和手性锂酰胺碱。我们开发的新试剂将被优化用于手性分子的合成，用作催化剂和大分子的构建块。这个项目的成功直接和积极地影响着新材料、纳米结构、聚合物和散装有机化学品的发现和制备效率。我研究小组的所有学生都在有机合成、光谱分析、色谱和x射线衍射分析方面发展专业知识，重点是获得在化学、材料或生化研究实验室继续独立研究所必需的技能。我积极招募学生参加这个项目，并与布朗大学正在进行的项目合作，包括领导力联盟（少数族裔本科生）、美国国家科学基金会（NSF） COACH资助（理科研究生）、UTRA（本科教学和研究）、WISE（理科和工程专业本科女性）和贝克曼基金会（本科研究培训）项目。我特别高兴的是，通过领导力联盟和WISE项目，我们成功地吸纳了少数族裔和女性本科生。

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.