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教授将研究在高度选择性和复杂的转化中利用碳负离子（带负电荷的碳）的合成方法。该提案将利用设计师胺碱来选择性地产生和反应来自医学相关支架的碳负离子，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杂分子的合成中得到证明。拟议的研究将改善化学家获得具有挑战性的分子的方式，应用范围从医药到材料研究。它还将成为培训从高中到研究生的各级学生的宝贵平台。这种立体控制合成化学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/生物学界面的问题，对医学，制药和新材料等领域具有长期影响。Zakarian小组将应用易于获得的手性氨基锂碱（CLA）的组装化学涉及用羰基和杂环衍生的碳负离子进行立体选择性转化的发展。虽然与烯醇化物的这种反应有先例，但由CLA介导的非烯醇化碳负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这些转换，这可以呈现对高对映体，区域和非对映体控制的模块化格式的多个立体中心的建设。该方法学在石松属生物碱和异二聚体双吲哚生物碱bousigonothine A和bisleuconothine A的合成中的应用将使所提出的方法的实用性在复杂分子合成的严格背景下经受测试，以确认其作为有机合成对映体富集中间体的实际来源的可靠性和可扩展性。该奖项反映了NSF的法定使命，并已被视为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，

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.