Stereoselective Assembly of Oxindole Alkaloid Natural Products

有了这个奖项，化学系的化学合成计划支持教授布兰登L。阿什菲尔德在圣母大学。获奖提案的重点是开发新方法，以解决复杂的高价值分子靶标合成中的关键挑战。主要目标是开发一套新的工具，使获得生物相关的生物碱天然产物中存在的核心分子支架。总体战略的重点是利用一个单一的碳成分的反应性，可从容易获得的前体访问各种各样的相关目标。该建议的一个关键方面是将研究成果纳入本科生实验室介绍和研究生合成方法设计和开发培训。本科生和研究生更有可能追求化学高级学位和职业生涯中的研究和发现时，提出了针对具体目标的教学方法对化学教育。结合基于目标的教学，因为它涉及特定化学功能的分子组装，而不是传统的以反应为中心的实验室设计，是该项目更广泛影响的核心。尽管5元碳环和杂环在天然产物化学和化学生物学中无处不在，用于组装具有柔性位点特异性官能化能力的高度取代的环的可靠方法的数量相对有限。该项目的重点是开发生物碱框架的新合成策略，通过设计和实施（4+1）-和（4+3）-环加成来解决小分子构建中的几个关键的长期挑战。具体目标包括：1）采用缩甲醛（4+1）-环加成反应对映选择性合成螺吡咯烷羟吲哚骨架; 2）对映选择性缩甲醛（4+3）-环加成反应合成威威特吲哚啉酮生物碱的环庚烷羟吲哚核心;和3）通过扩大可用乙烯基烯酮的结构多样性立体选择性构建螺环戊烯酮羟吲哚。该设计的实施使得能够获得具有中心5元环或7元环的各种多环支架。为此，该项目解决了与以下方面相关的挑战：1）5元和7元环的会聚组装，具有提供碳和N-杂环框架的灵活性，2）构建具有近端功能的关键立体碳用于后续操作，以及3）控制相对和绝对立体化学。这些环框架在医学相关目标中的流行突出了这项工作在化学生物学和治疗学开发中的科学广泛影响。此外，本研究的长期意义在于其对工艺流程化学和生物正交反应开发等领域的C-C和C-N键组装的影响。开发的综合方法构成了实验室教学的连贯教学方法的基础，这将广泛影响各级STEM教育工作。通过强调目标分析，而不是反应介绍，在概念层面的理解和复杂分子合成的应用之间实现了凝聚力。该奖项反映了NSF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 this Award, the Chemical Synthesis Program of the Division of Chemistry is supporting the research of Professor Brandon L. Ashfeld at the University of Notre Dame. The awarded proposal is focused on the development of new methods that address critical challenges in the synthesis of complex, high value molecular targets. The primary objective is to develop a suite of new tools that enable access to the core molecule scaffolds present in biologically relevant alkaloid natural products. The overarching strategy focuses on exploiting the reactivity of a single carbon component attainable from readily available precursors for accessing a diverse array of related targets. A key aspect of this proposal is the integration of research findings in the laboratory introduction of undergraduates and the training of graduate students in synthetic methods design and development. Undergraduate and graduate students are more likely to pursue advanced degrees in chemistry and careers in research and discovery when presented with a target-specific pedagogical approach toward chemical education. The incorporation of target-based instruction as it pertains to the molecular assembly of specific chemical functionality, rather than the traditional reaction-centered lab design prevalent today, is central to the broader impacts of this project.Despite the ubiquitous presence of 5-membered carbocycles and heterocycles in natural products chemistry and chemical biology, the number of reliable methods for the assembly of highly substituted rings with flexible site-specific functionalization capabilities is relatively limited. This project focuses on the development of new synthetic strategies toward alkaloid frameworks that address several key long-standing challenges in small molecule construction through the design and implementation of (4+1)- and (4+3)-cycloadditions. Specific objectives include the 1) the enantioselective synthesis of the spiropyrrolidine oxindole scaffold employing a formal (4+1)- cycloaddition; 2) enantioselective formal (4+3)-cycloaddition synthesis of the cycloheptane oxindole core of the welwitindolinone alkaloids; and 3) the stereoselective construction of spirocyclopentenone oxindoles by expanding the architectural diversity of available vinyl ketenes. Implementation of this design enables access to various polycyclic scaffolds bearing a central 5- or 7-membered ring. Toward that end, this project addresses challenges associated with the 1) convergent assembly of both 5- and 7-membered rings with the flexibility to provide carbo- and N-heterocyclic frameworks, 2) construction of a key stereogenic carbon with proximal functionality for subsequent manipulations, and 3) control of relative and absolute stereochemistry. The prevalence of these ring frameworks in translationally relevant targets highlights the scientific broader impacts of this work in chemical biology and therapeutics development. Additionally, the long-range significance of this study is its impact on C–C and C–N bond assembly in fields such as process flow chemistry and bioorthogonal reaction development. The synthetic methods developed form the basis for a cohesive pedagogical approach to laboratory instruction that will broadly impact STEM education efforts at all levels. By emphasizing target analysis, rather than reaction introduction, a cohesiveness between comprehension at the conceptual level and application to the synthesis of complex molecules is to be achieved.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.