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。 本项目的目标是介绍一种新的合成策略来官能化吡啶杂环。吡啶 是FDA批准药物中第二常见的氮杂环，这并不奇怪，因为 它们的氢键倾向和一套有价值的理化性质，如水溶性， 溶解性、净极性和抗氧化代谢性。合成方法直接和选择性地 官能化吡啶在药物发现工作中是关键，因为药物开发者需要改变 位置选择性，支架上的各种含碳和杂原子的基团在它们的位置上有很大的差异。 空间和电子性质。然而，将吡啶C-H键转化为有价值的 缺少衍生品。在这个建议中，我们概述了一个脱芳构化战略，通过将吡啶转化为锌 亚胺和亚胺鎓加合物。实际上，这些加合物使吡啶的反应像一系列烯烃，而不是一系列烯烃。 芳族体系，从而打开了与烯烃相关的大量反应， 对吡啶本身无效。我们将展示吡啶类现在可以参与许多过程， 例如卤化、与sp2-碳亲电试剂反应、或者不可行或者 在极端反应条件下操作。这些过程将在区域选择性的排他性控制下进行 对于Zincke中间体的3-位，并且基于Zincke加合物的 结构在许多情况下，开环-官能化-闭环可顺序化为一锅法。 我们还将使用Zincke平台来获得用于ADME研究的吡啶同位素，并使用新的方法来形成 氮氧化物我们计划将这种策略应用于简单的吡啶类结构单元、药物样中间体和 复杂的含吡啶药物的后期功能化。