Preparative Radical Chemistry for Biomedical Research

生物医学研究的制备自由基化学

基本信息

批准号：
8996063
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2017-01-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：芳烃和杂芳烃形成生物体的基础，因此在药物和其他生物活性化合物中普遍存在。尽管人们对（杂）芳烃官能化一直感兴趣，但发现化学不断增长的时间和成本限制仍然需要开发快速、高效且操作简单的程序。由于这是一项艰巨的任务，该提案将重点关注将氟烷基和烷基附加到（杂）芳烃上（即 C-H 到 C-C 转化）。目前有许多方法可用于（杂）芳烃官能化，每种方法都有优点和缺点。尽管“程序化”C-C 键形成（例如卤素-金属交换/亲电陷阱、亲核芳族取代和交叉偶联方法）在化学的各个方面都至关重要，但这些方法需要使用预官能化（通常是卤化）（杂）芳烃，从而为合成添加了额外的步骤。在这方面，一步法更有吸引力，然而，氢-金属交换/亲电捕获、亲电芳族取代和C-H活化方法也都存在缺点，例如使用强酸性/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：最近的结果表明，双（二氟甲亚磺酸）锌可以产生二氟甲基自由基，该自由基可以在室温下露天加成到各种杂环中。基于这些结果，该提案旨在产生一系列用户友好、货架稳定的双（链烷亚磺酸）锌试剂。这些试剂将被广泛使用，并且它们的反应将从操作简单性的角度进行优化。该提案分为三个部分：1）第一部分详细介绍了用于直接（杂）芳烃氟烷基化的双（氟代烷亚磺酸）锌试剂的合成； 2）第二部分概述了用于（杂）芳烃烷基化的双（烷亚磺酸）锌试剂的开发，以及使用顺序加成策略的杂（芳烃）的双官能化； 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研究，它们都将有助于确定双（链烷亚磺酸）锌试剂的反应趋势。生成这些稳定试剂和用户友好程序的装备将加速药物化学、食品化学、农业化学以及其他化学和科学学科的发现。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bioconjugation by native chemical tagging of C-H bonds.

DOI：
10.1021/ja407739y
发表时间：
2013-09-04
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Zhou Q;Gui J;Pan CM;Albone E;Cheng X;Suh EM;Grasso L;Ishihara Y;Baran PS
通讯作者：
Baran PS

A simple litmus test for aldehyde oxidase metabolism of heteroarenes.

DOI：
10.1021/jm4017976
发表时间：
2014-02-27
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
O'Hara F;Burns AC;Collins MR;Dalvie D;Ornelas MA;Vaz AD;Fujiwara Y;Baran PS
通讯作者：
Baran PS

Radical C-H functionalization of heteroarenes under electrochemical control.

DOI：
10.1002/anie.201407948
发表时间：
2014-10-27
期刊：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
影响因子：
16.6
作者：
O'Brien, Alexander G.;Maruyama, Akinobu;Inokuma, Yasuhide;Fujita, Makoto;Baran, Phil S.;Blackmond, Donna G.
通讯作者：
Blackmond, Donna G.

Simple sulfinate synthesis enables C-H trifluoromethylcyclopropanation.

DOI：
10.1002/anie.201406622
发表时间：
2014-09-08
期刊：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
影响因子：
16.6
作者：
Gianatassio, Ryan;Kawamura, Shuhei;Eprile, Cecil L.;Foo, Klement;Ge, Jason;Burns, Aaron C.;Collins, Michael R.;Baran, Phil S.
通讯作者：
Baran, Phil S.

Mechanistic Insights into Two-Phase Radical C-H Arylations.