Dearomative Functionalization with Arenophiles

项目总结 家长基金的工作目标是提供新的化学转化和策略。 这将选择性地引入功能性，从而极大地扩展了脱芳烃化学工具箱。 小的、含杂原子的复杂分子是生物(以及 药物和农用化学品)相关性，在药物化学中非常受欢迎，但它们也是 通常很难接近。芳香族化合物的选择性转化可以提供一条更直接的途径 这种理想的目标；然而，与脱芳烃官能化相关的许多挑战已经留下 这些类型的反应普遍不发达。我们努力通过弥合以下差距来满足这一需求 脱芳构化和烯烃化学。从根本上说，该提案的目标是访问所需的结构 通过开发使用小分子的脱芳官能化来从简单的芳香族化合物中提取基元- 亲芳烃-能够使分离的烯烃在芳烃底物中发生反应。此外，爱芳者，在 结合过渡金属催化，为亲核取代提供独特的活性底物 反应，并可以快速合成各种氨基官能化脂环化合物。 我们已经准备了一系列有效的抗癌天然产品和抗生素，目前正在准备 用于SAR研究的类似物，以及设计具有改进的药代动力学特性的前药。这个 从本副刊购买的仪器，UHPLC-MS，将使我们能够高度分析这些 并将极大地促进这些研究。

PROJECT SUMMARY The objective of the work of the parent grant is to provide new chemical transformations and strategies that will selectively introduce functionality and, consequently, greatly expand the dearomative chemical toolbox. Small, heteroatom-containing complex molecules are common motifs of biological (as well as pharmaceutical and agrochemical) 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. We strive to address this need by bridging the gap between dearomatization and alkene 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 enable reactions of isolated alkenes in an arene substrate. Additionally, arenophiles, in combination with transition metal catalysis, provide uniquely reactive substrates for nucleophilic substitution reactions, and could enable the rapid synthesis of a diverse range of aminofunctionalized alicyclic compounds. We have prepared a series of potent anticancer natural products and antibiotics and are currently preparing analogues for SAR studies as well as designing prodrugs with improved pharmacokinetics properties. The instrument, UHPLC-MS, to be purchased by funds from this Supplement will allow us for analysis of these highly polar compounds and will greatly facilitate these studies.