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