Dearomative Functionalization with Arenophiles

亲仁体的脱芳香功能化

• 批准号: 10794085
• 负责人: David Sarlah
• 金额: $ 17.59万
• 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/10794085
• 关键词: Address; Agrochemicals; Alkenes; Antibiotics; Area; Aromatic Compounds; Biological; Catalysis; Chemicals; Chemistry; Complex; Drug Kinetics; Funding; Goals; Left; Natural Products; Pharmaceutical Chemistry; Pharmacologic Substance; Preparation; Prodrugs; Property; Reaction; Route; Series; Transition Elements; Work; analog; anti-cancer; bioactive natural products; design; improved; instrument; nucleophilic substitution; parent grant; small molecule

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.

项目摘要 母公司赠款的工作目标是提供新的化学转化和战略 这将选择性地引入官能度，并因此极大地扩展了脱芳族化合物的工具箱。 小的、含杂原子的复杂分子是生物学（以及 药物和农业化学）相关性，并且在药物化学中是高度期望的，但它们也是 往往难以接近。芳香族化合物的选择性转化可以提供更直接的途径， 然而，与脱芳构化官能化相关的许多挑战已经离开了这些期望的目标。 这种反应还没有得到广泛的发展。我们努力通过弥合以下方面的差距来满足这一需求： 脱芳构化和烯烃化学。从根本上说，这项建议的目标是获得理想的结构， 基序从简单的芳香族化合物通过开发脱芳香官能化使用小分子- 亲芳烃化合物-其能够使芳烃底物中的孤立烯烃反应。此外，arenophiles，在 与过渡金属催化剂结合，为亲核取代提供独特的反应性底物 反应，并可以使各种各样的氨基官能化的脂环族化合物的快速合成。 我们准备了一系列强效抗癌天然产物和抗生素，目前正在准备 类似物的SAR研究以及设计具有改善的药代动力学性质的前药。的 仪器，UHPLC-MS，将由本补充基金购买，将使我们能够分析这些高度 极性化合物，将大大促进这些研究。