Origin of Orthogonality of Strain-Promoted Click Reactions.
Origin of Orthogonality of Strain-Promoted Click Reactions.
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DOI：
10.1002/chem.201501727
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发表时间：
2015-08-24
期刊：
影响因子：
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通讯作者：
Gräter F
中科院分区：
文献类型：
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作者：
Wagner JA;Mercadante D;Nikić I;Lemke EA;Gräter F
由于新的相互正交反应的发现，生物分子的位点特异性标记正在迅速发展。量子化学研究也增加了我们对它们的相对速率的理解，尽管到目前为止这些都是基于高度简化的反应物。在这里，我们研究了一组菌株促进的n-丙基叠氮、3-苄基四氮和3-苄基-6-甲基四氮与环烯/炔的咔嗒型环加成反应，我们的目标是解决反应物的所有相关结构细节。我们的计算包括用于附加标签和生物分子的必要处理，因为它们可以严重影响反应的立体化学和电子需求。我们利用密度泛函理论系统地计算了轨道间隙、激活能和畸变能，并确定了验证的实验速率。我们的结果挑战了当前这类反应的逆向电子需求范式。我们发现，在环炔的三键旁边，无处不在的手柄可以将Diels-Alder型连接转换为正常的电子需求，我们称之为SPINEDAC反应。四氮上的给电子取代基可以提高正常需求，但也会增加扭曲惩罚。因此，把手的存在和同分异构体结构决定了反应速度和区域选择性。我们的发现可以直接用于工程真正的环加成点击化学生物标记。
Site-specific labeling of biomolecules is rapidly advancing due to the discovery of novel mutually orthogonal reactions. Quantum chemistry studies have also increased our understanding of their relative rates, although these have until now been based on highly simplified reactants. Here we examine a set of strain-promoted click-type cycloaddition reactions of n-propyl azide, 3-benzyl tetrazine and 3-benzyl-6-methyl tetrazine with cyclooctenes/ynes, in which we aim to address all relevant structural details of the reactants. Our calculations have included the obligatory handles used to attach the label and biomolecule as these can critically influence the stereochemistry and electron demand of the reaction. We systematically computed orbital gaps, activation and distortion energies using density functional theory and determined experimental rates for validation. Our results challenge the current paradigm of the inverse electron demand for this class of reactions. We found that the ubiquitous handles, when next to the triple bond of cyclooctynes, can switch the Diels–Alder type ligations to normal electron demand, a class we term as SPINEDAC reactions. Electron donating substituents on tetrazine can enhance normal demand but also increase distortion penalties. The presence and isomeric configuration of handles thus determine the reaction speed and regioselectivity. Our findings can be directly utilized in engineering genuine cycloaddition click chemistries for biological labeling.