Dearomative Functionalization with Arenophiles

亲仁体的脱芳香功能化

• 批准号: 10444505
• 负责人: David Sarlah
• 金额: $ 33.33万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444505
• 关键词: Achievement; Address; Agriculture; Alkenes; Aminoglycoside Antibiotics; Aminoglycosides; Antibiotics; Area; Aromatic Compounds; Benzene; Biological; Biology; Chemicals; Chemistry; Collaborations; Complex; Core Grant; Data; Development; Drug Design; Family member; Goals; Grant; Heterocyclic Compounds; In Situ; Laboratories; Left; Libraries; Logic; Mediating; Medicine; Methods; Molecular; Natural Products; Organic Synthesis; Outcome; Pathway interactions; Pharmaceutical Chemistry; Pharmacologic Substance; Play; Preparation; Process; Production; Property; Reaction; Reagent; Research; Role; Route; Science; Series; Transition Elements; Translating; Visible Radiation; adduct; base; bioactive natural products; chemical synthesis; cycloaddition; design; drug discovery; materials science; novel; pharmacophore; piperidine; programs; pyridine; small molecule

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.

项目摘要 小的、含杂原子的复杂分子是生物相关性的常见基序， 它们在药物化学中是非常理想的，但它们也常常难以获得。选择性转化 芳香族化合物可以提供更直接的途径达到这些理想的目标;然而，许多挑战 与脱芳香官能化相关的反应使得这些类型的反应广泛地不发达。的 拟议的研究致力于通过弥合脱芳构化和烯烃型之间的差距来解决这一需求 化学.从根本上说，这项建议的目标是从简单的芳香族化合物中获得理想的结构基序， 化合物通过使用小分子--芳亲物--开发脱芳官能化， 能够在芳烃底物上进行类似烯烃的反应。具体地说，在这个建议中，我们描述了几种脱芳香剂， 基于催化1，2-和1，4-双官能化以及环化的非活化芳烃的方法。 这些转变将提供独特的断开，并为复杂的制备打开新的视野。 小分子。例如，我们在2-DOS的自底向上化学合成方面取得了良好的进展 使用简单苯的对映选择性1，2-氢化胺化的氨基糖苷类抗生素。这一战略将有助于 在氨基环醇核心修饰的氨基糖苷类化合物库的制备和研究， 获得其他较少开发的衍生物，如2-DOF抗生素。此外，我们还提出了一个扩展 的芳醚基脱芳构化为杂芳族底物。令人信服的初步数据表明， 几种成熟的烯烃反应，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，过渡金属催化过程 涉及吡啶-亲芳烃加合物将使得能够快速合成多种官能化的 杂环化合物。虽然直接官能化（杂）芳族化合物的传统方法 提供有限的官能化选择，并受到过度反应或分解的阻碍，亲芳烃- 基于的策略允许有选择地和有控制地引入各种功能复杂性。最后 方法提供的产品既难以通过现有方法合成，又具有互补性 通过化学或生物脱芳香过程获得的那些。 总的来说，用亲芳烃化合物开发通用脱芳烃官能化平台具有以下优点： 通过提供对制药，农业和材料科学产生深远影响的潜力 从简单和容易获得的芳烃中方便地获得具有定制性质的复杂小分子。