Advancing Enantioselective Carbanion Chemistry Through Complex Molecule Synthesis

在化学系化学合成项目的支持下，加州大学圣巴巴拉分校的Armen Zakarian教授将研究利用碳（带负电荷的碳）进行高选择性和复杂转化的合成方法。该提案将利用设计胺基选择性地生成和反应来自医学相关支架的碳，从而以高度选择性的方式形成重要的键。这些方法的重要性和力量将在生物活性复合物分子的合成中得到证明。拟议中的研究将改进化学家获取具有挑战性分子的方式，应用范围从医药到材料研究。它还将成为从高中到研究生各级学生培训的宝贵平台。这种立体控制合成化学方面的专业培训将有助于培养具有合成专业知识的未来劳动力，以解决化学/生物界面的问题，并对医学、制药和新材料等领域产生长期影响。根据该奖项，Zakarian小组将应用易于获得的手性锂酰胺碱（CLAs）的组装化学来开发羰基和杂环衍生碳离子的立体选择性转化。虽然这种与烯醇化物的反应有先例，但由CLAs介导的非烯醇化碳离子的应用有更有限的先例，并且仍然不发达。该项目将推进这两种类型的转换，可以以模块化格式呈现具有高对映性，区域性和非对映性的多个立体中心的构建。将该方法应用于石蒜科生物碱和异二聚双吲哚生物碱布西甘碱A和双亮果碱A的合成中，将在复杂分子合成的严格背景下对所提出方法的实用性进行测试，以确认其作为有机合成中富集对映体中间体的实际来源的可靠性和可扩展性。该奖项反映了美国国家科学基金会的法定使命，并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，被认为值得支持。

With the support of the Chemical Synthesis program in the Division of Chemistry, Professor Armen Zakarian of the University of California, Santa Barbara will study synthetic methods for leveraging carbanions, carbons with a negative charge, in highly selective and complex transformations. The proposal will leverage designer amine bases for the selective generation and reaction of the carbanions derived from medicinally relevant scaffolds, leading to important bond formations in a highly selective fashion. The importance and power of these methods will be demonstrated in the synthesis of biologically active complex molecules. The proposed research will improve the way chemists access challenging molecules, with applications from medicinal to materials research. It will also serve as an invaluable platform for the training of students at all levels, from high school to graduate students. Such specialized training in stereocontrolled synthetic chemistry will help to produce the future workforce with synthetic expertise to tackle problems at the chemistry/biology interface with longer term implications for fields such as medicine, pharmaceuticals and new materials.Under this award, the Zakarian group will apply the assembly chemistry of readily accessible chiral lithium amide bases (CLAs) to the development of stereoselective transformations with carbonyl and heterocycle-derived carbanions. While such reactions with enolates have precedent, applications of non-enolate carbanions mediated by CLAs have much more limited precedent and remain underdeveloped. This project will advance both types of these transformations, which can be rendered towards the construction of multiple stereocenters with high enantio-, regio-, and diastereocontrol in a modular format. Applications of this methodology in the synthesis of alkaloids of Lycopodium family and heterodimeric bisindole alkaloids bousigonine A and bisleuconothine A will subject the utility of the proposed methods to the test in the rigorous context of complex molecule synthesis, so as to confirm their reliability and scalability as a practical source of enantioenriched intermediates for organic synthesis.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.