Nickel-Catalyzed Radical Mechanisms: Informing Cross-Coupling for Synthesizing Non-Canonical Biomolecules.
Nickel-Catalyzed Radical Mechanisms: Informing Cross-Coupling for Synthesizing Non-Canonical Biomolecules.
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DOI：
10.1021/acs.accounts.3c00588
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发表时间：
2023-12-19
影响因子：
18.3
通讯作者：
Diao T
中科院分区：
文献类型：
--
作者：
Dawson GA;Spielvogel EH;Diao T
镍在促进选择性自由基化学方面表现突出，在金属酶催化和现代交叉偶联反应中发挥着关键作用。自由基是非极性和中性的，与生物分子中常见的亲核和碱性官能团表现出正交性反应。利用这种兼容性，我们深入研究了镍催化的自由基途径在合成非规范多肽和碳水化合物中的应用，这对化学生物学研究和药物发现至关重要。我们以前描述了一种顺序还原机制，该机制解释了交叉亲电偶联反应中的化学选择性。这个催化循环从镍(I)介导的烷基卤化物生成自由基开始，然后被镍(II)络合物捕获碳自由基，最后以还原消除结束。这些步骤与镍催化的交叉偶联反应、光氧化还原反应和电催化反应的机理建议相一致。在这里，我们介绍了我们对涉及自由基的每个步骤的见解，包括引发、传播、终止，以及动力学的细微差别、选择性的起源和配体效应。C(SP3)亲电体与低价镍自由基中间体通过单电子氧化加成生成自由基，为立体聚合和交叉亲电偶联提供了基础。我们的电分析研究阐明了一种协同的卤素原子提取机制，其中电子转移与卤化物解离相耦合。利用这一途径，我们开发了镍催化的脱氢丙氨酸的立体选择性自由基加成反应，促进了非正则多肽的合成。在这一应用中，手性配体通过镍-烯酸酯中间体的不对称质子化来调节立体化学结果。镍(II)对烷基的捕获扩大了交叉偶联的范围，通过形成高价镍(III)促进了还原消除，并控制了化学和立体选择性。我们发现，镍(II)-芳基以7-9千卡/摩尔的势垒有效地捕获自由基，然后快速还原消除。相反，镍(II)-烷基捕获自由基形成镍(III)物种，这通过EPR光谱进行了表征。然而，随后的缓慢还原消除导致了最小的产物形成。观察到的高非对映选择性的自由基捕获激发了对C-芳基和C-酰基糖基化反应的研究。我们开发了一种氧化还原助剂，它很容易与天然碳水化合物偶联，并在光氧化还原激活时产生糖基自由基。镍催化的糖基与溴代芳烃和羧酸的交叉偶联导致了多种非天然糖苷的形成，这些糖苷可以促进药物开发。对定义明确的d8-镍配合物的化学计量研究显示了促进还原消除的方法，包括配体缔合、氧化和氧化加成。在最后一节中，我们讨论了辅助配体对有机镍中间体的电子结构和氧化还原活性的影响。合成了一系列低价镍自由基络合物，并对其电子结构进行了表征，得到了配体氧化还原活性与配位几何构型相关的假设。我们的数据表明，配体氧化还原活性的变化可以改变反应中间产物的氧化还原电位，从而潜在地改变催化反应的机理。此外，添加剂和溶剂的配合可以通过调节配体的氧化还原活性来稳定催化过程中的镍自由基，这与已知的催化条件是一致的。
Nickel excels at facilitating selective radical chemistry, playing a pivotal role in metalloenzyme catalysis and modern cross-coupling reactions. Radicals, being nonpolar and neutral, exhibit orthogonal reactivity to nucleophilic and basic functional groups commonly present in biomolecules. Harnessing this compatibility, we delve into the application of nickel-catalyzed radical pathways in the synthesis of noncanonical peptides and carbohydrates, critical for chemical biology studies and drug discovery. We previously characterized a sequential reduction mechanism that accounts for chemoselectivity in cross-electrophile coupling reactions. This catalytic cycle begins with nickel(I)-mediated radical generation from alkyl halides, followed by carbon radical capture by nickel(II) complexes, and concludes with reductive elimination. These steps resonate with mechanistic proposals in nickel-catalyzed cross-coupling, photoredox, and electrocatalytic reactions. Herein, we present our insights into each step involving radicals, including initiation, propagation, termination, and the nuances of kinetics, origins of selectivity, and ligand effects. Radical generation from C(sp3) electrophiles via one-electron oxidative addition with low-valent nickel radical intermediates provides the basis for stereoconvergent and cross-electrophile couplings. Our electroanalytical studies elucidate a concerted halogen atom abstraction mechanism, where electron transfer is coupled with halide dissociation. Using this pathway, we have developed a nickel-catalyzed stereoselective radical addition to dehydroalanine, facilitating the synthesis of noncanonical peptides. In this application, chiral ligands modulate the stereochemical outcome through the asymmetric protonation of a nickel-enolate intermediate. The capture of the alkyl radical by nickel(II) expands the scope of cross-coupling, promotes reductive elimination through the formation of high-valent nickel(III) species, and governs chemo- and stereoselectivity. We discovered that nickel(II)-aryl efficiently traps radicals with a barrier ranging from 7 to 9 kcal/mol, followed by fast reductive elimination. In contrast, nickel(II)-alkyl captures radicals to form a nickel(III) species, which was characterized by EPR spectroscopy. However, the subsequent slow reductive elimination resulted in minimal product formation. The observed high diastereoselectivity of radical capture inspired investigations into C-aryl and C-acyl glycosylation reactions. We developed a redox auxiliary that readily couples with natural carbohydrates and produces glycosyl radicals upon photoredox activation. Nickel-catalyzed cross-coupling of the glycosyl radical with bromoarenes and carboxylic acids leads to diverse non-natural glycosides that can facilitate drug discovery. Stoichiometric studies on well-defined d8-nickel complexes have showcased means to promote reductive elimination, including ligand association, oxidation, and oxidative addition. In the final section, we address the influence of auxiliary ligands on the electronic structure and redox activity of organonickel intermediates. Synthesis of a series of low-valent nickel radical complexes and characterization of their electronic structures led us to a postulate that ligand redox activity correlates with coordination geometry. Our data reveal that a change in ligand redox activity can shift the redox potentials of reaction intermediates, potentially altering the mechanism of catalytic reactions. Moreover, coordinating additives and solvents may stabilize nickel radicals during catalysis by adjusting ligand redox activity, which is consistent with known catalytic conditions.
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影响因子：
15
作者：
Dawson, Gregory A.;Lin, Qiao;Neary, Michelle C.;Diao, Tianning
通讯作者：
Diao, Tianning
影响因子：
37.8
作者：
Day, Craig S. S.;Renteria-Gomez, Angel;Martin, Ruben
通讯作者：
Martin, Ruben
影响因子：
15
作者：
Diccianni, Justin B.;Katigbak, Joseph;Diao, Tianning
通讯作者：
Diao, Tianning
DOI：
10.1126/science.aaf7230
发表时间：
2017-04-14
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Choi J;Fu GC
通讯作者：
Fu GC
影响因子：
2.8
作者：
Day, Craig S.;Ton, Stephanie J.;McGuire, Ryan T.;Foroutan-Nejad, Cina;Martin, Ruben
通讯作者：
Martin, Ruben