Reactivity of biarylazacyclooctynones in copper-free click chemistry.
Reactivity of biarylazacyclooctynones in copper-free click chemistry.
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DOI：
10.1021/ja3000936
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发表时间：
2012-06-06
影响因子：
15
通讯作者：
Bertozzi, Carolyn R.
中科院分区：
文献类型：
--
作者：
Gordon, Chelsea G.;Mackey, Joel L.;Jewett, John C.;Sletten, Ellen M.;Houk, K. N.;Bertozzi, Carolyn R.
环辛炔与叠氮化物的 1,3-偶极环加成反应也称为“无铜点击化学”，是一种生物正交反应，在生物发现中具有广泛应用。这种反应的动力学对于动态过程的研究至关重要，特别是在活体受试者中。在这里，我们使用密度泛函理论（DFT）畸变/相互作用过渡态模型，通过实验测量和计算研究，系统分析了应变和电子对环辛炔与叠氮化物反应性的影响。我们特别关注二芳基氮杂环辛炔酮 (BARAC)，因为它与叠氮化物的反应速度比任何其他已报道的环辛炔更快，并且其模块化合成有助于快速获得类似物。我们发现，BARAC 芳环上的取代基可以通过电子效应改变计算的环加成过渡态相互作用能，或通过空间效应改变计算的畸变能。实验数据证实，BARAC芳环的电子扰动对反应速率影响不大，而过渡态的空间位阻可以显着延迟反应。根据这些结果，我们分析了一系列环辛炔的炔键角（使用 X 射线晶体学测定）与反应性（通过实验二阶速率常数量化）之间的关系。我们的结果表明炔键角减小与环辛炔反应性增加之间存在相关性。最后，我们获得了结构和计算数据，揭示了 BARAC 中心内酰胺的构象与化合物反应性之间的关系。总的来说，这些结果表明，畸变/相互作用模型与键角分析相结合将能够预测环辛炔反应性并合理设计无铜点击化学的新试剂。
The 1,3-dipolar cycloaddition of cyclooctynes with azides, also called “copper-free click chemistry”, is a bioorthogonal reaction with widespread applications in biological discovery. The kinetics of this reaction are of paramount importance for studies of dynamic processes, particularly in living subjects. Here we performed a systematic analysis of the effects of strain and electronics on the reactivity of cyclooctynes with azides through both experimental measurements and computational studies using a density functional theory (DFT) distortion/interaction transition state model. In particular, we focused on biarylazacyclooctynone (BARAC) because it reacts with azides faster than any other reported cyclooctyne and its modular synthesis facilitated rapid access to analogues. We found that substituents on BARAC’s aryl rings can alter the calculated transition state interaction energy of the cycloaddition through electronic effects or the calculated distortion energy through steric effects. Experimental data confirmed that electronic perturbation of BARAC’s aryl rings has a modest effect on reaction rate, whereas steric hindrance in the transition state can significantly retard the reaction. Drawing on these results, we analyzed the relationship between alkyne bond angles, which we determined using X-ray crystallography, and reactivity, quantified by experimental second-order rate constants, for a range of cyclooctynes. Our results suggest a correlation between decreased alkyne bond angle and increased cyclooctyne reactivity. Finally, we obtained structural and computational data that revealed the relationship between the conformation of BARAC’s central lactam and compound reactivity. Collectively, these results indicate that the distortion/interaction model combined with bond angle analysis will enable predictions of cyclooctyne reactivity and the rational design of new reagents for copper-free click chemistry.
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影响因子：
46.2
作者：
Jewett JC;Bertozzi CR
通讯作者：
Bertozzi CR
影响因子：
4
作者：
Dehnert, Karen W.;Beahm, Brendan J.;Huynh, Thinh T.;Baskin, Jeremy M.;Laughlin, Scott T.;Wang, Wei;Wu, Peng;Amacher, Sharon L.;Bertozzi, Carolyn R.
通讯作者：
Bertozzi, Carolyn R.
影响因子：
4.7
作者：
Hong, Vu;Steinmetz, Nicole F.;Manchester, Marianne;Finn, M. G.
通讯作者：
Finn, M. G.
影响因子：
5.2
作者：
Ess, Daniel H.;Jones, Gavin O.;Houk, K. N.
通讯作者：
Houk, K. N.
DOI：
10.1073/pnas.0707090104
发表时间：
2007-10-23
影响因子：
11.1
作者：
Baskin, Jeremy M.;Prescher, Jennifer A.;Bertozzi, Carolyn R.
通讯作者：
Bertozzi, Carolyn R.