Stereoselective Assembly of Oxindole Alkaloid Natural Products

羟吲哚生物碱天然产物的立体选择性组装

• 批准号: 1956170
• 负责人: Brandon Ashfeld
• 金额: $ 43万
• 依托单位: University of Notre Dame
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1956170&HistoricalAwards=false
• 关键词: Stereoselective; Assembly; Oxindole; Alkaloid; Natural

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.

凭借该奖项，化学系的化学合成项目正在支持圣母大学 Brandon L. Ashfeld 教授的研究。获奖提案的重点是开发新方法，解决复杂、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工具，能够获取生物相关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可从现成的前体中获得的单一碳成分的反应性，以获取各种相关目标。该提案的一个关键方面是将研究成果整合到本科生的实验室介绍和研究生合成方法设计和开发的培训中。当采用针对特定目标的化学教育教学方法时，本科生和研究生更有可能攻读化学高级学位以及研究和发现职业。结合基于目标的指令，因为它涉及特定化学功能的分子组装，而不是当今流行的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。尽管天然产物化学和化学生物学中普遍存在五元碳环和杂环，但用于组装具有灵活位点特异性的高度取代环的可靠方法有很多 功能化能力相对有限。该项目重点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长期存在的几个关键挑战。具体目标包括 1) 采用正式的 (4+1)-环加成反应对映选择性合成螺吡咯烷羟吲哚支架； 2) welwitindolinone生物碱的环庚烷羟吲哚核心的对映选择性形式(4+3)-环加成合成； 3）通过扩展可用乙烯基烯酮的结构多样性来立体选择性地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元或7元环的各种多环支架。为此，该项目解决了与以下相关的挑战：1) 5 元环和 7 元环的聚合组装，具有提供碳和 N 杂环框架的灵活性，2) 构建具有用于后续操作的邻近功能的关键立体碳，以及 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凸显了这项工作在化学生物学和治疗学开发中的科学更广泛的影响。此外，这项研究的长期意义在于它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统一教学方法的基础，它将广泛影响各个级别的 STEM 教育工作。通过强调目标分析而不是反应引入，可以实现概念层面的理解和复杂分子合成应用之间的凝聚力。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Controlling phase separation behavior of thermo-responsive ionic liquids through the directed distribution of anionic charge

• DOI: 10.1016/j.molliq.2022.119401
• 发表时间: 2022-05
• 期刊: Journal of Molecular Liquids
• 影响因子: 6
• 作者: Eva M. Gulotty;Sidharth Sanadhya;Zachary D. Tucker;Saeed S. Moghaddam;B. Ashfeld

Front Cover: Rational Design and Identification of Harmine‐Inspired, N ‐Heterocyclic DYRK1A Inhibitors Employing a Functional Genomic In Vivo Drosophila Model System (ChemMedChem 4/2022)

封面：采用功能性基因组体内果蝇模型系统对 Harmine 启发的 N-杂环 DYRK1A 抑制剂进行合理设计和鉴定 (ChemMedChem 4/2022)

• DOI: 10.1002/cmdc.202200066
• 发表时间: 2022
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: Huizar, Francisco J.;Hill, Harrison M.;Bacher, Emily P.;Eckert, Kaitlyn E.;Gulotty, Eva M.;Rodriguez, Kevin X.;Tucker, Zachary D.;Banerjee, Monimoy;Liu, Haining;Wiest, Olaf
• 通讯作者: Wiest, Olaf

High-precision vapor pressure measurement apparatus with facile and inexpensive construction

结构简单且廉价的高精度蒸汽压测量装置

• DOI: 10.1088/1361-6501/ac5135
• 发表时间: 2022
• 期刊: Measurement Science and Technology
• 影响因子: 2.4
• 作者: Bhagwat, Rohit;Sanadhya, Sidharth;Gulotty, Eva;Tucker, Zachary;Ashfeld, Brandon;Moghaddam, Saeed
• 通讯作者: Moghaddam, Saeed

Thermodynamic Descriptors of Sensible Heat Driven Liquid-Liquid Phase Separation

• DOI: 10.1016/j.molliq.2022.119440
• 发表时间: 2022-05
• 期刊: Journal of Molecular Liquids
• 影响因子: 6
• 作者: Sidharth Sanadhya;Zachary D. Tucker;Eva M. Gulotty;William Boggess;B. Ashfeld;S. Moghaddam

Utilizing Ionic Liquids as Bifunctional Reagents for the Ionothermal Synthesis of Uranyl Compounds

• DOI: 10.1021/acs.cgd.3c00976
• 发表时间: 2023-10-10
• 期刊: CRYSTAL GROWTH & DESIGN
• 影响因子: 3.8
• 作者: Felton，Daniel E.;Kohlgruber，Tsuyoshi A.;Burns，Peter C.
• 通讯作者: Burns，Peter C.