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

摘要 萘酮类化合物是一种存在于许多天然和合成化合物中的双环骨架， 生物活性，并作为构建模块，以获得更复杂的分子。萘酮一直是 通过萘酚的脱芳构化并同时安装新的C-C或C-X成功合成 债券这些新的具有立体选择性控制的季中心的形成已被证明是合成的。 挑战，通常需要使用昂贵的、稀有的或有毒的过渡金属。在少数情况下， 使用了大量的铁或有机催化剂，对映选择性控制和/或产率受到损害。Biocata- 裂解物为在温和条件下操作的更可持续的合成路线提供了很好的选择， 生成对映体富集产物，减少副产物，实现高底物选择性。通过itera- 经过五轮的基因突变和自然选择，酶可以进化成催化新的自然反应。 在此，我建议设计一种替代的催化路线来合成手性萘酮， 由Arnold小组开发的血红素蛋白的韵文库。这项工作将通过工程实现 和进化血红素蛋白用于（i）通过氮烯插入使2-萘酚脱芳构化，（ii）脱芳构化 的2-萘酚的卡宾插入，和（iii）进一步官能化的萘酮核心骨架的立体- 特定的生物催化反应。这些反应将是第一次在血红素蛋白中进行表征。 这些反应的产物将具有新的季碳中心，并将扩展当前的机理。 强大的血红素蛋白质的知识和他们的能力，驯服反应卡宾和氮烯的高度en. 反选择性反应这项工作将探索新的方法来获得取代的多环结构， 简单和可持续的方法，扩大生物相关的萘酮的合成可行性。的 在这个提议中产生的生物催化方法将开始阐明脱芳构化的新策略， 允许将许多容易获得的二维芳族原料转化为复杂的药理学原料， 佛勒斯

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.