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: 10344085
• 负责人: Andrew McNally
• 金额: $ 29.91万
• 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/10344085
• 关键词: ADME Study; Acids; Acylation; Aldehydes; Alkenes; Ammonium; Biological; Carbon; Cell Respiration; Chemicals; Chemistry; Complex; Coupling; Drug Design; Drug Receptors; Electrons; FDA approved; Fluorine; 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; base; clinical candidate; cost; design; drug candidate; drug development; drug discovery; drug standard; functional group; halogenation; 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。 该项目的目的是引入一种新的合成策略，以使吡啶杂环的功能化。吡啶 是FDA批准的药物中第二个最常见的氮杂环，这是一个毫不奇怪的事实，因为 它们具有氢键和有价值的物理化学特性（例如水）的倾向 溶解度，净极性和对氧化代谢的抗性。合成方法直接和选择性地 功能化吡啶在药物发现工作中至关重要，因为药物开发者需要变化 位置选择性，脚手架上的各种碳和杂原子轴承基团有很大的差异 空间和电子特性。但是，将吡啶C – H键变成价值的一般方法 缺乏衍生物。在此提案中，我们通过将吡啶转换为锌来概述了亲爱的策略 亚胺和亚胺加合物。实际上，这些加合物使吡啶类似于一系列烷烃，而不是 芳香系统，因此打开了与以前是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-碳电力的反应反应是不可行或 在极端反应条件下进行操作。这些过程将通过对监管仪的独家控制进行 对于锌中间体的3位，也可以基于锌加合物的5位切换到5位 结构。在许多情况下，开环官能化的闭合环闭合可以对单盘过程进行测序。 我们还将使用Zincke平台访问吡啶同位素学以进行ADME研究和新方法以形成 N氧化物。我们计划将此策略用于简单的构件吡啶，类似毒品的中间体以及 复杂含吡啶的药物的晚期功能化。