Stereoselective Assembly of Oxindole Alkaloid Natural Products

通过这个奖项，化学系的化学合成项目支持圣母大学的布兰登·l·阿什菲尔德教授的研究。该提案的重点是开发新方法，以解决复杂、高价值分子靶点合成中的关键挑战。主要目标是开发一套新工具，使其能够获得存在于生物相关生物碱天然产物中的核心分子支架。总体战略的重点是利用从现成的前体中获得的单一碳组分的反应性，以获取各种相关目标。本建议的一个关键方面是整合实验室的研究成果，向本科生介绍合成方法的设计和开发，并培养研究生。本科和研究生更有可能追求更高的化学学位，并从事研究和发现方面的职业，如果化学教育有特定目标的教学方法。结合目标为基础的教学，因为它与特定化学功能的分子组装有关，而不是传统的以反应为中心的实验室设计，这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普遍存在，但用于组装具有灵活位点特异性功能化能力的高取代环的可靠方法数量相对有限。本项目侧重于开发新的生物碱框架合成策略，通过设计和实现(4+1)-和(4+3)-环加成来解决小分子结构中几个长期存在的关键挑战。具体目标包括：1)采用正式的(4+1)-环加成法对映选择性合成螺吡咯烷氧吲哚支架；2)威氏吲哚酮类生物碱环庚烷氧吲哚核的对映选择性正(4+3)-环加成合成；3)通过扩大现有乙烯基酮的结构多样性，立体选择性地构建螺环戊酮氧吲哚。这种设计的实现使人们能够接触到各种多环支架，这些支架的中心有一个5元环或7元环。为此，该项目解决了以下方面的挑战：1)5元环和7元环的聚合组装，提供碳和n杂环框架的灵活性；2)具有近端功能的关键立体碳的构建，以供后续操作；3)相对和绝对立体化学的控制。这些环框架在翻译相关靶标中的普遍存在，突出了这项工作在化学生物学和治疗学发展中的科学广泛影响。此外，本研究的长远意义在于其对C-C和C-N键组装在工艺流程化学和生物正交反应开发等领域的影响。开发的综合方法构成了实验室教学的凝聚力教学方法的基础，将广泛影响各级STEM教育的努力。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一种凝聚力。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 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.