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: 10464808
• 负责人: Kathleen M Sicinski
• 金额: $ 6.72万
• 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/10464808
• 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 Products; Natural Selections; Nature; Organic Synthesis; Outcome; Palladium; Planet Earth; Process; Property; Protein Engineering; Reaction; Reporting; Rhodium; Route; Scandium; Side; Structure; Testing; Therapeutic; Transition Elements; Variant; Viral; Work; aqueous; base; carbene; catalyst; chemical reaction; 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 萘烯酮是许多天然和合成化合物中发现的生物支架，它们显示多样 生物活动并用作访问更复杂分子的基础。萘甲烯酮已经存在 通过简单安装新的C – C或C – X来成功合成萘酚。 债券。这些新的第四纪中心具有立体选择控制已被证明是合成的 挑战和通常需要使用昂贵，稀有或有毒的过渡金属。在少数情况下 利用丰富的铁或有机催化剂，对映选择性控制和/或产量受到损害。 biocata- LYST为在轻度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法 产生映射的产品，减少侧产品并达到高底物选择性。通过itera- 基因突变和自然选择的综合，酶可以演变为催化新的对天然反应。 在本文中，我建议设计一种替代的催化途径，以合成手性萘甲烯酮 阿诺德组开发的血蛋白诗歌库。这项工作将通过工程来实现 （i）通过氮插入对2-萘酚的善良胺化的进化血蛋白，（ii）亲爱的疗法 卡宾插入的2-萘酚，以及（iii）立体声的萘酮核心支架进一步官能化 特定的生物催化反应。这些反应将是在血op蛋白中表征的第一个反应。 这些反应的产品将具有新的第四纪碳中心，并将扩大电流机械 了解强大的血蛋白及其能力驯服反应性碳和硝酸盐的能力 抗离选择性反应。这项工作将探索新方法，以访问在 便捷而可持续的方法，扩大了与生物学相关的萘烯酮的合成可行性。 本提案中产生的生物催化方法将开始阐明新的策略，以实现尊贵的策略和 允许将许多容易获得的二维原料转换为复杂的药物 孔。