A New General Strategy for Pyridine Functionalization via Dearomatized Intermediates

通过脱芳构中间体进行吡啶功能化的新通用策略

• 批准号: 10532161
• 负责人: Andrew McNally
• 金额: $ 29.81万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532161
• 关键词: ADME Study; Acids; Acylation; Aldehydes; Alkenes; Ammonium; Biological; Carbon; Cell Respiration; Chemicals; Chemistry; Complex; Coupling; Cyclization; Drug Design; Drug Receptors; Electronics; Electrons; FDA approved; Goals; Hydrazines; Hydrogen Bonding; Hydroxylamine; Imines; Intercept; Ions; Isotopes; Mediating; Medicine; Metabolic; Metals; Methods; Modernization; Nitrogen; Oxides; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Process; Property; Reaction; Research; Resistance; Salts; Series; Solubility; Structure; Structure-Activity Relationship; System; Technology; Toxicology; Variant; adduct; aqueous; clinical candidate; design; drug candidate; drug development; drug discovery; drug standard; functional group; halogenation; manufacturing cost; novel therapeutics; operation; physical property; piperidine; programs; pyridine; receptor binding; scaffold; small molecule; targeted treatment; tool

Project Abstract. The goal of this project is to introduce a new synthetic strategy to functionalize pyridine heterocycles. Pyridines are the second most common nitrogen heterocycle found in FDA approved drugs, an unsurprising fact because of their propensity for hydrogen bonding and suite of valuable physiochemical properties such as aqueous solubility, net polarity, and resistance to oxidative metabolism. Synthetic methods to directly and selectively functionalize pyridines are critical in drug discovery efforts because drug-developers require variation in positional selectivity, various carbon- and heteroatom bearing groups on the scaffold a wide variance in their steric and electronic properties. However, general approaches to transform pyridine C–H bonds into valuable derivatives are lacking. In this proposal, we outline a dearomatization strategy by converting pyridines into Zincke imine and iminium adducts. In effect, these adducts make pyridines react like a series of alkenes rather than an aromatic system and thus open up the plethora of reactions associated with olefins that were previously ineffective on pyridines themselves. We will show that pyridines can now participate in numerous processes, such as halogenation, reaction with sp2-carbon electrophiles radical reactions that were either not viable or operated under extreme reaction conditions. The processes will occur with exclusive control of regioselectivity for the 3-position of Zincke intermediates and are also switchable to the 5-position based on the Zincke adduct's structure. The ring-opening-functionalization-ring-closing is sequencable into one-pot processes in many cases. We will also use the Zincke platform to access pyridine isotopologs for ADME studies and new methods to form N–oxides. We plan to employ this strategy for simple building block pyridines, drug-like intermediates and for late-stage functionalization of complex pyridine-containing drugs.

项目摘要。 该项目的目标是引入一种新的合成策略来官能化吡啶杂环。 是 FDA 批准的药物中发现的第二常见的氮杂环，这一事实并不令人惊讶，因为 它们的氢键倾向和一系列有价值的理化性质，例如水性 溶解度、净极性和抗氧化代谢的直接和选择性合成方法。 吡啶的功能化对于药物发现工作至关重要，因为药物开发人员需要在 位置选择性，支架上各种含碳和杂原子的基团在其性能上存在很大差异 然而，将吡啶 C-H 键转化为有价值的通用方法。 在该提案中，我们概述了将吡啶转化为锌的脱芳构化策略。 实际上，这些加合物使吡啶像一系列烯烃而不是烯烃那样发生反应。 芳香系统，从而开启了以前与烯烃相关的大量反应 对吡啶本身无效 我们将证明吡啶现在可以参与许多过程， 例如卤化、与sp2-碳亲电试剂的反应自由基反应，这些反应要么不可行，要么 该过程将在区域选择性的独家控制下进行。 用于 Zincke 中间体的 3 位，也可根据 Zincke 加合物的 5 位切换 在许多情况下，开环-官能化-闭环顺序地形成一锅法。 我们还将使用 Zincke 平台获取吡啶同位素，用于 ADME 研究和形成新方法 我们计划将这种策略用于简单的结构单元吡啶、类药物中间体和 复杂的含吡啶药物的后期功能化。