Dearomatization of Planar Aromatic Cores into Three-Dimensional Scaffolds with Defined Stereochemistry

平面芳香核脱芳构化成具有明确立体化学的三维支架

• 批准号: 10700834
• 负责人: Kathleen M Sicinski
• 金额: $ 6.95万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-06 至 2025-09-05
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700834
• 关键词: 3-Dimensional; Alkenes; Alkylation; Amination; Anti-Bacterial Agents; Antifungal Agents; Biological; Carbon; Chemistry; Complex; Cytochrome P450; DNA Sequence Alteration; Data; Development; Directed Molecular Evolution; Engineering; Enzymes; Goals; Hemeproteins; Iridium; Iron; Knowledge; Laboratories; Libraries; Methods; Mixed Function Oxygenases; Molecular; Naphthols; Natural Selections; Nature; Organic Synthesis; Outcome; Palladium; Periodicity; Planet Earth; Process; Property; Protein Engineering; Reaction; Reporting; Rhodium; Route; Scandium; Side; Structure; Testing; Therapeutic; Transition Elements; Variant; Viral; Work; aqueous; carbene; catalyst; chemical reaction; mimic natural products; nitrene; novel; pharmacophore; scaffold; stereochemistry; success; two-dimensional; wasting

Abstract Naphthalenones are bicyclic scaffolds found in many natural and synthetic compounds which display diverse biological activities and serve as building blocks to access more complex molecules. Naphthalenones have been successfully synthesized via dearomatization of naphthols with simultaneous installation of new C–C or C–X bonds. Formation of these new quaternary centers with stereoselective control has proven to be a synthetic challenge and commonly requires use of expensive, rare, or toxic transition metals. In few cases where earth abundant iron or organic catalysts are utilized, enantioselective control and/or yield are compromised. Biocata- lysts provide a great alternative for a more sustainable synthetic route which operate under mild conditions, generate enantioenriched products, reduce side products, and achieve high substrate selectivity. Through itera- tive rounds of genetic mutation and natural selection, enzymes can evolve to catalyze new-to-nature reactions. Herein, I propose to engineer an alternative catalytic route to synthesize chiral naphthalenones utilizing the di- verse library of hemoproteins developed by the Arnold group. This work will be achieved through engineering and evolving hemoproteins for (i) dearomative amination of 2-naphthols by nitrene insertion, (ii) dearomatization of 2-naphthols by carbene insertion, and (iii) further functionalization of naphthalenone core scaffolds by stereo- specific biocatalytic reactions. These reactions will be the first of its kind to be characterized in hemoproteins. The products of these reactions will feature new quaternary carbon centers and will expand current mechanistic knowledge of the robust hemoproteins and their abilities to tame reactive carbenes and nitrenes for highly en- antioselective reactions. This work will explore new methods to access substituted polycyclic structures in a facile and sustainable approach expanding the synthetic feasibility of biologically relevant naphthalenones. The biocatalytic method generated in this proposal will begin to elucidate new strategies for dearomatization and allow for transformation of many readily available 2-dimensional aromatic feedstocks into intricate pharmaco- phores.

抽象的 萘酮是在许多天然和合成化合物中发现的双环支架，其表现出多种特征 生物活性并作为获取更复杂分子的构建块。萘酮类已 通过萘酚脱芳构化并同时安装新的 C–C 或 C–X 成功合成 债券。这些具有立体选择性控制的新四元中心的形成已被证明是一种合成方法 挑战，通常需要使用昂贵、稀有或有毒的过渡金属。在极少数情况下，地球 使用丰富的铁或有机催化剂，对映选择性控制和/或产率受到损害。生物目录- lysts 为在温和条件下操作的更可持续的合成路线提供了一个很好的替代方案， 生成对映体富集的产物，减少副产物，并实现高底物选择性。通过迭代- 经过一轮轮的基因突变和自然选择，酶可以进化来催化新的自然反应。 在此，我建议设计一种替代催化路线，利用二元合成手性萘酮。 由阿诺德小组开发的血红素蛋白 verse 文库。这项工作将通过工程来实现 和进化血红素蛋白用于（i）通过氮宾插入对2-萘酚进行脱芳香胺化，（ii）脱芳香化 2-萘酚通过卡宾插入，以及（iii）通过立体-萘酮核心支架的进一步功能化 特定的生物催化反应。这些反应将是第一个在血红素蛋白中进行表征的反应。 这些反应的产物将具有新的季碳中心，并将扩展当前的机制 了解强大的血红素蛋白及其驯服反应性卡宾和氮宾以获得高效率的能力 抗选择性反应。这项工作将探索在a中获取取代多环结构的新方法 简便且可持续的方法扩大了生物相关萘酮的合成可行性。这 该提案中产生的生物催化方法将开始阐明脱芳构化和 允许将许多容易获得的二维芳香族原料转化为复杂的药物 信号。