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.

摘要 萘酮是存在于许多天然和合成化合物中的双环支架，它们表现出不同的 生物活性，并作为获得更复杂分子的构建块。萘酮类化合物已被 同时安装新的C-C或C-X的萘酚脱芳构化合成 债券。用立体选择性控制形成这些新的四元中心已被证明是一种合成的 这是一种挑战，通常需要使用昂贵、稀有或有毒的过渡金属。在少数情况下，地球 使用大量的铁或有机催化剂，会影响对映体选择性控制和/或产率。Biocata- 赖斯为在温和条件下运行的更可持续的合成路线提供了一个很好的替代方案， 生成富含对映体的产物，减少副产物，实现高底物选择性。通过伊特拉- 经过几轮基因突变和自然选择，酶可以进化为催化适应大自然的反应。 在这里，我建议设计一种替代的催化路线来合成手性萘酮类化合物。 阿诺德小组开发的血红素蛋白文库。这项工作将通过工程来完成 以及用于(I)2-萘酚的硝基插入脱芳胺化，(Ii)脱芳构化的进化血球蛋白 通过卡宾插入对2-萘酚进行官能化，以及(Iii)通过立体构象进一步官能化萘酮核心支架。 特定的生物催化反应。这些反应将是同类反应中第一个以血红素蛋白为特征的反应。 这些反应的产物将以新的季碳中心为特征，并将扩展现有的机理 了解强健的血色素蛋白及其驯服反应性卡宾和硝烯的能力，以获得高能量. 抗选择性反应。这项工作将探索新的方法来访问取代的多环结构在一个 简便和可持续的方法，扩大了生物相关的萘酮的合成可行性。这个 本提案中产生的生物催化方法将开始阐明脱芳构化和 允许将许多现成的二维芳烃原料转化为复杂的制药- 凤凰城。