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阿门·扎卡里安教授将研究在高选择性和复杂的转化中利用碳负离子的合成方法。该提案将利用设计胺类碱选择性地生成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威力将在生物活性复杂分子的合成中得到证明。这项拟议的研究将改善化学家获取具有挑战性的分子的方式，应用范围从药物到材料研究。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方面的专门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/生物界面上的问题，这些问题对医药、制药和新材料等领域具有长期影响。根据这一奖项，扎卡里安小组将把易于获得的手性锂酰胺碱(CLAS)的组装化学应用于开发具有羰基和杂环衍生碳负离子的立体选择性转化。虽然这种与烯醇酸盐的反应已经有了先例，但Clas介导的非烯醇碳负离子的应用更是有限的先例，而且仍然不发达。该项目将推进这两种类型的转换，可用于以模块化格式建造具有高度对映、区域和非对映控制的多个立体中心。将这一方法学应用于石松属生物碱和异二聚体双吲哚生物碱的合成，将在严格的复杂分子合成的背景下对所提出的方法的实用性进行测试，以确认它们作为有机合成的富对映体中间体的实用来源的可靠性和可扩展性。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.