Preparative Radical Chemistry for Biomedical Research

生物医学研究的制备自由基化学

• 批准号: 8795737
• 负责人: PHIL S BARAN
• 金额: $ 51.73万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8795737
• 关键词: Air; Alkylation; Area; Biological; Biomedical Research; Chemicals; Chemistry; Coupling; Development; Disadvantaged; Discipline; Food; Halogens; Health; Heterocyclic Compounds; Human; Hydrogen; Kinetics; Life; Malignant Neoplasms; Mediating; Medicine; Metals; Methodology; Methods; Nitrogen; One-Step dentin bonding system; Organism; Pharmaceutical Chemistry; Pharmacologic Substance; Procedures; Property; Reaction; Reagent; Research; Salts; Science; Series; Skeleton; Societies; Solubility; Solvents; Technology; Temperature; Therapeutic; Time; Transition Elements; Water; Zinc; alkyl group; appendage; aqueous; base; catalyst; cost; cryogenics; fighting; functional group; improved; insight; interest; process optimization; programs; small molecule; trend; user-friendly

DESCRIPTION (provided by applicant): Arenes and heteroarenes form the basis of living organisms and, as a consequence, are ubiquitous in pharmaceuticals and other biologically active compounds. Although there has been sustained interest in (hetero)arene functionalization, ever-growing time and cost constraints of discovery chemistry still demand the development of rapid, efficient and operationally trivial procedures. As this presents an immense task, this proposal will focus on the appendage of fluoroalkyl and alkyl groups onto (hetero)arenes (i.e., C-H to C-C transformations). Many methods are currently available for (hetero)arene functionalization, each of them presenting advantages and disadvantages. Although "programmed" C-C bond formations such as halogen-metal exchange/electrophilic trap, nucleophilic aromatic substitution and cross-coupling methodology are vital in all aspects of chemistry, these methods require the use of pre-functionalized (typically halogenated) (hetero)arenes, thus adding extra steps to the synthesis. In this regard, one-step methods are more attractive, however, hydrogen-metal exchange/electrophilic trap, electrophilic aromatic substitution and C-H activation methodology all present drawbacks as well, such as the use of highly acidic/basic reagents, cryogenic conditions, or expensive transition metal catalysts. These drawbacks can be potentially overcome by using a radical-based functionalization strategy: recent results have shown that zinc bis(difluoromethanesulfinate) can generate difluoromethyl radicals, which can add to a variety of heterocycles at room temperature under open air. Building upon these results, this proposal aims to generate a series of user-friendly, shelf-stable zinc bis(alkanesulfinate) reagents. These reagents will be made widely accessible and their reactions will be optimized from the vantage point of operational simplicity. This proposal is organized into three parts: 1) the first section details the synthesis of zinc bis(fluoroalkanesulfinate) reagents for direct (hetero)arene fluoroalkylation; 2) the second part outlines the development of zinc bis(alkanesulfinate) reagents for (hetero)arene alkylation, as well as the bis- functionalization of hetero(arene)s using a sequential addition strategy; and 3) the final section describes kinetic analysis to guide the optimization process and to elucidate solvent effects on regioselectivity. While these three objectives will be investigated in parallel, they will all contribute in establishing reactivity trends of zinc bis(alkanesulfinate) reagents. Generating an armamentarium of these stable reagents and user- friendly procedures would accelerate discovery in medicinal chemistry, food chemistry, agrochemistry, and other chemical and scientific disciplines.

说明书(申请人提供)：芳烃和杂芳烃构成了生物体的基础，因此，它们普遍存在于药物和其他生物活性化合物中。尽管人们对(杂化)芳烃功能化一直很感兴趣，但发现化学日益增长的时间和成本限制仍然要求开发快速、高效和操作简单的过程。由于这是一项艰巨的任务，本提案将侧重于将氟烷基和烷基附加到(杂环)芳烃上(即C-H到C-C转化)。目前有许多方法可用于(杂化)芳烃功能化，每一种方法都有优缺点。尽管“程序化”的C-C键形成，如卤素-金属交换/亲电陷阱、亲核芳香族取代和交叉偶联方法在化学的各个方面都是至关重要的，但这些方法需要使用预官能化(通常是卤代)(杂化)芳烃，从而增加了合成的额外步骤。在这方面，一步法更有吸引力，然而，氢-金属交换/亲电陷阱法、亲电取代芳香族取代法和C-H活化法也都存在缺点，如使用高酸/碱性试剂、低温条件或昂贵的过渡金属催化剂。这些缺点可以通过使用基于自由基的官能化策略来克服：最近的研究结果表明，双(二氟甲基亚磺酸锌)可以产生二氟甲基自由基，这些自由基可以在室温和露天条件下添加到各种杂环上。在这些结果的基础上，这项提议旨在生产一系列用户友好、货架稳定的双(烷基磺酸锌)试剂。这些试剂将被广泛使用，其反应将从操作简单的角度进行优化。本建议分为三个部分：1)第一部分详细介绍了用于直接(杂环)芳烃氟烷基化反应的双(氟烷基亚磺酸锌)试剂的合成；2)第二部分概述了用于(杂环)芳烃烷基化反应的双(烷基)亚磺酸锌试剂的发展，以及采用顺序加成策略对杂环(芳烃)S的双官能化反应；以及3)最后一部分描述了动力学分析，以指导优化过程并阐明溶剂对区域选择性的影响。虽然这三个目标将同时进行调查， 它们都将有助于确定双(烷基亚磺酸锌)试剂的反应趋势。建立这些稳定试剂和用户友好的程序将加速在药物化学、食品化学、农业化学和其他化学和科学学科中的发现。