Dearomative Functionalization with Arenophiles

项目总结 小的、含杂原子的复杂分子是与生物相关的常见基序，并且 在药物化学中非常受欢迎，但它们通常也很难获得。有选择地转换 芳香族化合物可以提供一种更直接的途径来达到这种理想的目标；然而，许多挑战 与脱芳烃官能化相关的反应使这些类型的反应普遍不发达。这个 拟议的研究努力通过弥合脱芳构化和烯烃类型之间的差距来满足这一需求 化学反应。从根本上说，这个提议的目标是从简单的芳香族中获得理想的结构主题 通过使用小分子-亲芳烃-开发脱芳官能化来合成化合物，这种化合物的形式 在芳烃底物上实现类似烯烃的反应。具体地说，在这项提案中，我们描述了几种除臭剂 基于催化1，2-和1，4-去官能化以及环化的非活化芳烃的研究进展。 这些转变将提供独特的脱节，并为复杂的准备打开新的视野 小分子。例如，我们在自下而上的化学合成2-DOS方面取得了良好的进展 氨基糖苷类抗生素对映体选择性1，2-氢胺化简苯。这一战略将起到作用 氨基半胱醇核心修饰的氨基糖苷类化合物文库的制备和研究 获得其他开发较少的衍生物，如基于2-DOF的抗生素。此外，我们还提出了一项延期 用于杂芳烃底物的亲芳烃脱芳烃反应。令人信服的初步数据表明 几个成熟的烯烃反应，如二羟基化、还原和环氧化，现在可以 转化为吡啶的脱芳官能化。此外，过渡金属催化的过程 涉及吡啶-亲芳烃加合物将使各种官能化的快速合成成为可能 杂环化合物。虽然直接官能化(杂环)芳香族化合物的传统方法 提供有限的官能化选项，并受到过度反应或分解的阻碍，亲芳烃- 基于策略允许有选择地和可控地引入各种功能复杂性。最后，这一点 Approach提供了既难以通过现有方法合成又具有互补性的产品 到通过化学或生物除臭过程获得的。 总体而言，与芳香族的通用脱芳烃功能化平台的开发具有 通过提供对制药、农业和材料科学产生深远影响的潜力 从简单易得的芳烃中方便地获得具有定制性质的复杂小分子。

PROJECT SUMMARY Small, heteroatom-containing complex molecules are common motifs of biological relevance and are highly desired in medicinal chemistry, but they are also often difficult to access. Selective transformations of aromatic compounds could provide a more direct route to such desirable targets; however, the many challenges associated with dearomative functionalization have left these types of reactions widely underdeveloped. The proposed research strives to address this need by bridging the gap between dearomatization and alkene-type chemistry. Fundamentally, the goal of this proposal is to access desirable structural motifs from simple aromatic compounds by developing dearomative functionalizations using small molecules – arenophiles – that formally enable olefin-like reactions on arene substrates. Specifically, in this proposal, we describe several dearomative approaches on non-activated arenes based on catalytic 1,2- and 1,4-difunctionalizations as well as annulations. These transformations will provide unique disconnections and open new horizons for the preparation of complex small molecules. For example, we have made good progress in bottom-up chemical synthesis of 2-DOS aminoglycoside antibiotics using enantioselective 1,2-hydroamination of simple benzene. This strategy will serve the preparation and study of a library of aminoglycosides that are modified at the aminocyclitol core, and grant access to other less-explored derivatives, such as 2-DOF-based antibiotics. Moreover, we propose an extension of arenophile-based dearomatizations to heteroaromatic substrates. Compelling preliminary data demonstrate that several well-established olefin reactions, such as dihydroxylation, reduction, and epoxidation, can now be translated into dearomative functionalization of pyridines. Additionally, transition-metal-catalyzed processes involving pyridine-arenophile adducts will enable a rapid synthesis of a diverse range of functionalized heterocyclic compounds. While traditional approaches to directly functionalize (hetero)aromatic compounds provide limited functionalization options and are hampered by overreaction or decomposition, the arenophile- based strategy permits the selective and controlled introduction of a variety of functional complexity. Finally, this approach provides products that are both challenging to synthesize via existing methods and are complementary to those acquired through chemical or biological dearomative processes. Overall, the development of a general dearomative functionalization platform with arenophiles has the potential to make a profound impact on the pharmaceutical, agricultural, and materials sciences by providing expedient access to complex small molecules with tailored properties from simple and readily available arenes.