Late-stage C-H functionalization and C-C/N coupling enabled by new strategies for electrochemically-controlled radical formation
电化学控制自由基形成的新策略实现了后期C-H功能化和C-C/N耦合
基本信息
- 批准号:10663182
- 负责人:
- 金额:$ 36.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAlkylationAminationAminesCarboxylic AcidsCatalysisChloridesComplementComplexCouplingDecarboxylationDedicationsElectrochemistryElectrolysesElectron TransportEpoxy CompoundsEthersEventGoalsHydrogen BondingInterceptLigandsMediatingMetalsMethodologyModificationNatural ProductsOrganic SynthesisOrganometallic ChemistryOxidantsPharmacologic SubstancePhysiologic pulsePredispositionPreparationReactionReagentResearchResearch ProposalsSiteSystemTechniquesTherapeutic AgentsWorkcatalystcostnext generationnovel therapeuticsoxidationprograms
项目摘要
Project Summary
The proposed research seeks to develop metal-catalyzed C–C and C–N bond-forming methodologies that
streamline organic synthesis by leveraging the unique control that electrochemistry provides over electron trans-
fer events. In particular, this work will develop synthetic methodologies based on dual-catalyst systems. One
catalyst is electrochemically activated to mediate the formation of alkyl radicals, while a second catalyst selec-
tively activates the complementary substrate to effect coupling with the electrogenerated radicals.
The long-term goal of this program is to establish electrochemistry as a standard synthetic strategy in a way
that complements the successful integration of photoredox catalysis into organic synthesis: another dual-catalyst
system that relies on one catalyst to promote electron transfer and a second to mediate bond-forming reactions.
The proposed research relies on the merger of multiple scientific fields to develop next-generation methodologies
in organic synthesis. The Sevov team has a unique combination of expertise in synthetic methodology, mecha-
nistic organometallic chemistry, and homogeneous electrochemistry that will lead to new synthetic strategies
that impact both the rate of discovery and large-scale synthesis of new therapeutic agents. These strategies and
the targeted transformations of the proposal are summarized below:
Goal 1. to develop C–C and C–N coupling reactions with alkyl electrophiles: Electrochemically-driven
cross-coupling will be developed using a dual-catalyst system that allows each substrate to be activated by a
distinct catalyst. Dedicated electrocatalysts will be developed that mediate formation of alkyl radicals from alkyl
halides or ethers/epoxides. The radical intermediates will be intercepted and functionalized by co-catalysts that
exclusively (i) activate aryl chlorides and ethers to form alkyl arenes, (ii) mediate C–N coupling from high-valent
complexes to form amines, or (iii) utilize chiral nonracemic ligands to enable enantioselective C–C/N coupling.
Goal 2. to develop C(sp3)–H bond alkylation/arylation and amination: Aliphatic C–H bond activation will be
accomplished via directed H-atom abstraction (HAA) from a tethered aryl radical. Aryl radicals will be generated
by electroreduction of Ni(II)aryl intermediates to form low-valent organonickel(I) complexes that are susceptible
to Ni–C bond homolysis. Radical relay by HAA from the aryl directing group to the alkyl side-chain provides
access to an activated aliphatic site for C–X coupling.
Goal 3. to develop decarboxylative functionalization of carboxylic acids: The first of two complementary
approaches will investigate pulsed-electrolysis techniques to enable decarboxylation at potentials that are mild
and compatible with catalysts for selective C-C/N/X of the resulting alkyl radicals. A second approach will utilize
electrocatalysts that are photoactive upon oxidation at mild potentials. Photoexcitation of the oxidized species
will transiently generate a high energy oxidant that can effect oxidative decarboxylation to form alkyl radicals.
项目概要
拟议的研究旨在开发金属催化的 C-C 和 C-N 键形成方法,
通过利用电化学对电子反式提供的独特控制来简化有机合成
fer 事件。特别是,这项工作将开发基于双催化剂系统的合成方法。一
催化剂被电化学激活以介导烷基自由基的形成,而第二种催化剂则选择
主动激活互补底物以实现与电产生的自由基的偶联。
该计划的长期目标是以某种方式将电化学建立为标准合成策略
补充了光氧化还原催化在有机合成中的成功整合:另一种双催化剂
该系统依靠一种催化剂来促进电子转移,另一种催化剂来介导成键反应。
拟议的研究依赖于多个科学领域的合并来开发下一代方法
在有机合成中。 Sevov 团队在合成方法学、机械学等方面拥有独特的专业知识组合。
本质有机金属化学和均相电化学将带来新的合成策略
这会影响新治疗药物的发现速度和大规模合成。这些策略和
该提案的目标改造概述如下:
目标 1. 开发与烷基亲电子试剂的 C-C 和 C-N 偶联反应:电化学驱动
交叉偶联将使用双催化剂系统进行开发,该系统允许每个底物被
独特的催化剂。将开发专用电催化剂来介导从烷基形成烷基自由基
卤化物或醚/环氧化物。自由基中间体将被助催化剂拦截并官能化,
仅 (i) 活化芳基氯和醚形成烷基芳烃,(ii) 介导高价键的 C-N 偶联
配合物形成胺,或 (iii) 利用手性非外消旋配体实现对映选择性 C-C/N 偶联。
目标 2. 开发 C(sp3)–H 键烷基化/芳基化和胺化:脂肪族 C–H 键活化
通过从束缚的芳基中直接提取氢原子(HAA)来完成。会产生芳基自由基
通过电还原 Ni(II) 芳基中间体形成易受影响的低价有机镍 (I) 配合物
Ni-C 键均裂。 HAA 从芳基导向基团到烷基侧链的自由基中继提供了
访问活化的脂肪族位点进行 C-X 偶联。
目标 3. 开发羧酸的脱羧功能化:两个互补的第一个
方法将研究脉冲电解技术,以在温和的电位下实现脱羧
并与所得烷基的选择性 C-C/N/X 催化剂相容。第二种方法将利用
在温和电位下氧化时具有光活性的电催化剂。氧化物质的光激发
将瞬时产生高能氧化剂,可实现氧化脱羧形成烷基自由基。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Persistent organonickel complexes as general platforms for Csp2-Csp3 coupling reactions.
- DOI:10.1038/s41557-024-01528-7
- 发表时间:2024-04
- 期刊:
- 影响因子:21.8
- 作者:Long P. Dinh;Hunter F Starbuck;Taylor B. Hamby;Matthew J. LaLama;C. Q. He;D. Kalyani;C. Sevov
- 通讯作者:Long P. Dinh;Hunter F Starbuck;Taylor B. Hamby;Matthew J. LaLama;C. Q. He;D. Kalyani;C. Sevov
Mediator-Enabled Electrocatalysis with Ligandless Copper for Anaerobic Chan-Lam Coupling Reactions.
- DOI:10.1021/jacs.1c02103
- 发表时间:2021-04-28
- 期刊:
- 影响因子:15
- 作者:Walker BR;Manabe S;Brusoe AT;Sevov CS
- 通讯作者:Sevov CS
Synergistic Catalyst-Mediator Pairings for Electroreductive Cross-Electrophile Coupling Reactions.
- DOI:10.1021/acscatal.1c05144
- 发表时间:2022-01
- 期刊:
- 影响因子:12.9
- 作者:Jordan L S Zackasee;Samir Al Zubaydi;Blaise L Truesdell;C. Sevov
- 通讯作者:Jordan L S Zackasee;Samir Al Zubaydi;Blaise L Truesdell;C. Sevov
Controlling Ni redox states by dynamic ligand exchange for electroreductive Csp3-Csp2 coupling.
- DOI:10.1126/science.abo0039
- 发表时间:2022-04-22
- 期刊:
- 影响因子:56.9
- 作者:Hamby, Taylor B.;LaLama, Matthew J.;Sevov, Christo S.
- 通讯作者:Sevov, Christo S.
Catalyst-controlled functionalization of carboxylic acids by electrooxidation of self-assembled carboxyl monolayers.
- DOI:10.1038/s41467-022-28992-4
- 发表时间:2022-03-14
- 期刊:
- 影响因子:16.6
- 作者:Hintz HA;Sevov CS
- 通讯作者:Sevov CS
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Christo Sevov其他文献
Christo Sevov的其他文献
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{{ truncateString('Christo Sevov', 18)}}的其他基金
Late-stage C-H functionalization and C-C/N coupling enabled by new strategies for electrochemically-controlled radical formation
电化学控制自由基形成的新策略实现了后期C-H功能化和C-C/N耦合
- 批准号:
10453666 - 财政年份:2020
- 资助金额:
$ 36.55万 - 项目类别:
Late-stage C-H functionalization and C-C/N coupling enabled by new strategies for electrochemically-controlled radical formation
电化学控制自由基形成的新策略实现了后期C-H功能化和C-C/N耦合
- 批准号:
10222733 - 财政年份:2020
- 资助金额:
$ 36.55万 - 项目类别:
Late-stage C-H functionalization and C-C/N coupling enabled by new strategies for electrochemically-controlled radical formation
电化学控制自由基形成的新策略实现了后期C-H功能化和C-C/N耦合
- 批准号:
10028826 - 财政年份:2020
- 资助金额:
$ 36.55万 - 项目类别:
Late stage C-H functionalization and C-C/N coupling enabled by new strategies for electrochemically-controlled radical formation
电化学控制自由基形成的新策略实现了后期C-H功能化和C-C/N耦合
- 批准号:
10388445 - 财政年份:2020
- 资助金额:
$ 36.55万 - 项目类别:
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