Asymmetric Formal [4+1]-Cycloadditions for the Stereoselective Assembly of Quaternary Stereogenic Centers

四元立体中心立体选择性组装的不对称形式[4 1]-环加成

• 批准号: 1665440
• 负责人: Brandon Ashfeld
• 金额: $ 42万
• 依托单位: University of Notre Dame
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1665440&HistoricalAwards=false
• 关键词: Asymmetric; Formal; 4+1; Cycloadditions; Stereoselective

The Chemical Synthesis Program of the Chemistry Division supports the project by Professor Brandon L. Ashfeld. Professor Ashfeld is a faculty member in the Department of Chemistry and Biochemistry at the University of Notre Dame, and is developing new synthetic methods that enable construction of functionalized heterocyclic and carbocyclic frameworks that contain very difficult to synthesize tetrasubstituted carbons. Cyclic systems that contain tetrasubstituted (or quaternary) carbons are found in a great number of molecules used in biological and materials science settings. Yet in spite of their importance, these ring systems remain difficult to synthesize, especially if they need to be constructed as a single "right-handed" or left-handed" mirror image in order to control molecular interactions with a biological system. To address this issue, Professor Ashfeld and his students are developing new methods for constructing both the hetero- and carbocyclic systems and the highly hindered quaternary carbons they contain. These methods take advantage of a transition metal catalyzed formal [4+1]-cycloaddition between a single carbon unit and a polarized four atom substrate. The catalyst used is chiral so that the reaction affords predominately one mirror image of the product. The project outcomes are broadly impacting the disciplines of synthetic and physical organic, organometallic, medicinal, and materials chemistry both in terms of the methods developed and the products generated. The scientific goals of the project integrate seamlessly with the education/outreach pursuits through the implementation of a target-based pedagogical philosophy toward STEM education at the secondary and post-secondary levels. These educational efforts are being complimented by Professor Ashfeld's contributions to the Upward Bound College Preparatory program in South Bend Indiana that serve to extend the program's reach beyond his labs to the larger community.Quaternary stereogenic carbons and carbo- and heterocycles are pervasive architectures across numerous facets of academic and industrial chemical research. Despite the ubiquitous presence of 5-membered carbocycles and heterocycles in medicinal chemistry (e.g., CNS drugs, analgesics, antibiotics, etc.) and materials science (e.g., ionic liquids, high energy materials, etc.), the number of reliable methods for the assembly of highly substituted rings with flexible site-specific functionalization capabilities is relatively limited. Additionally, the synthesis of quaternary carbon centers is far from trivial, and to do so with control of absolute stereochemistry remains a significant obstacle in target-directed synthesis. Using the biologically active spirooxindole alkaloids as a motivating template for design, this project concurrently addresses these challenges through the development of a transition metal-catalyzed, formal [4+1]-cycloaddition for the fragment coupling of a diazo compound with a vinyl ketene to access cyclopentenones bearing a neighboring quaternary center, and vinyl isocyanates to construct the N-heterocyclic counterpart. By employing a well-defined chiral ligand-metal complex, assembly of the quaternary ring stereogenic carbon in a stereocontrolled fashion while acting as a point of spiro-attachment en route to numerous oxindole alkaloids, is tenable. Due to the chemoselective nature of the transition metal catalyst and relatively mild reaction conditions, this retrosynthetic disconnect is broadly applicable to a diverse array of synthetic targets. Completion of this study will ultimately lead to improved synthetic efficiency toward these important molecular scaffolds, and lay the keystone for long term significance in stereoselective quaternary carbon and carbo/heterocycle formation. The educational plan will integrate our findings in the training of graduate students in their approach toward synthesis, and the introduction of undergraduates to synthetic methods in laboratory offerings. The incorporation of a target-based approach toward molecule construction, such as quaternary carbon and heterocycle synthesis with tangible applications (i.e. pharmacophores), rather than the traditional reaction-centered lab design prevalent today, is an immediate goal. Graduate and undergraduates alike will gain a better appreciation for reaction design, and the discovery of new chemical reactivity, if their focus is on a series of specified target functionalities that are translational in nature.

化学学部的化学合成项目支持布兰登·l·阿什菲尔德教授的项目。Ashfeld教授是圣母大学化学与生物化学系的一名教员，他正在开发新的合成方法，能够构建含有很难合成的四取代碳的功能化杂环和碳环框架。含有四取代（或四元）碳的循环系统在生物和材料科学设置中使用的大量分子中发现。然而，尽管它们很重要，这些环系统仍然很难合成，特别是如果它们需要被构建为单一的“右手”或“左手”镜像，以控制分子与生物系统的相互作用。为了解决这个问题，Ashfeld教授和他的学生正在开发新的方法来构建杂环和碳环系统以及它们所含的高度阻碍的季碳。这些方法利用过渡金属催化的形式[4+1]-环加成在单碳单元和极化的四原子底物之间。所使用的催化剂是手性的，因此反应主要产生产物的一个镜像。项目成果对合成和物理有机、有机金属、药物和材料化学的学科产生了广泛的影响，包括开发的方法和产生的产品。该项目的科学目标通过在中学和大专阶段实施以目标为基础的STEM教育教学理念，与教育/推广追求无缝结合。这些教育努力受到Ashfeld教授对印第安纳州南本德向上大学预科项目的贡献的赞扬，该项目将该项目的范围从他的实验室扩展到更大的社区。在学术和工业化学研究的许多方面，第四纪立体碳和碳杂环是普遍的结构。尽管在药物化学（如中枢神经系统药物、镇痛药、抗生素等）和材料科学（如离子液体、高能材料等）中普遍存在5元碳环和杂环，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。此外，季碳中心的合成远非微不足道，并且在控制绝对立体化学的情况下进行合成仍然是靶向合成的一个重大障碍。利用具有生物活性的螺烷吲哚生物碱作为设计的激励模板，该项目同时解决了这些挑战，通过开发过渡金属催化，正式的[4+1]环加成，用于重氮化合物与乙烯基烯酮的片段偶联，以获得具有邻近四元中心的环戊烯酮，以及乙烯基异氰酸酯来构建n -杂环对应物。通过使用一种定义明确的手性配体-金属配合物，以立体控制的方式组装第四环立体碳，同时作为许多氧吲哚生物碱的螺旋附着点，是成立的。由于过渡金属催化剂的化学选择性和相对温和的反应条件，这种反合成断开广泛适用于各种合成目标。本研究的完成将最终提高这些重要分子支架的合成效率，并为立体选择性季碳和碳杂环形成的长期意义奠定基础。教育计划将把我们的发现整合到研究生的合成方法训练中，并在实验室课程中向本科生介绍合成方法。结合基于靶标的分子构建方法，如具有实际应用（即药效团）的季碳和杂环合成，而不是今天流行的传统以反应为中心的实验室设计，是一个直接的目标。如果研究生和本科生将重点放在一系列具有转化性质的特定目标功能上，他们将对反应设计和新化学反应性的发现有更好的理解。

项目成果

(4+1)-Cycloadditions Exploiting the Biphilicity of Oxyphosphonium Enolates and RhII/PdII-Stabilized Metallocarbenes for the Construction of Five-Membered Frameworks

• DOI: 10.1055/s-0040-1706009
• 发表时间: 2021-01
• 期刊: Synlett
• 影响因子: 2
• 作者: Zachary D. Tucker;B. Ashfeld

Transition metal-free strategies for the stereoselective construction of spirocyclopropyl oxindoles

• DOI: 10.1016/j.tet.2019.130692
• 发表时间: 2020-01-24
• 期刊: TETRAHEDRON
• 影响因子: 2.1
• 作者: Bacher, Emily P.;Ashfeld, Brandon L.
• 通讯作者: Ashfeld, Brandon L.

Combined Scaffold Evaluation and Systems‐Level Transcriptome‐Based Analysis for Accelerated Lead Optimization Reveals Ribosomal Targeting Spirooxindole Cyclopropanes

• DOI: 10.1002/cmdc.201900266
• 发表时间: 2019-09
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: Kevin X. Rodriguez;Erin N. Howe;E. Bacher;M. Burnette;Jennifer L. Meloche;J. Meisel;P. Schnepp;Xuejuan Tan;Mayland Chang;J. Zartman;Siyuan Zhang;B. Ashfeld

A Phosphorus(III)‐Mediated (4+1)‐Cycloaddition of 1,2‐Dicarbonyls and Aza‐ o ‐Quinone Methides to Access 2,3‐Dihydroindoles

• DOI: 10.1002/hlca.201900192
• 发表时间: 2019-12
• 期刊: Helvetica Chimica Acta
• 影响因子: 1.8
• 作者: Kaitlyn E. Eckert;Antonio J. Lepore;B. Ashfeld