Control and Design of Mutual Orthogonality in Bioorthogonal Cycloadditions
Control and Design of Mutual Orthogonality in Bioorthogonal Cycloadditions
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DOI：
10.1021/ja309241e
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发表时间：
2012-10-31
影响因子：
15
通讯作者：
Houk, K. N.
中科院分区：
文献类型：
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作者：
Liang, Yong;Mackey, Joel L.;Houk, K. N.
叠氮-二苯并环辛炔和反式-环辛烯-四氮杂环加成反应均具有生物正交性和相互正交性：在生理条件下，反式环辛烯衍生物更倾向于与四嗪类化合物反应，而二苯并环辛炔类衍生物与叠氮类化合物反应，但不与四嗪类化合物反应。报道了用于确定这种特殊选择性的来源的密度泛函理论计算，并提出了指导发现新的正交环加成反应的设计原则。预测了两种新的生物正交试剂甲基环丙烯和3，3，6，6-四甲基硫代环庚炔在叠氮环加成和四氮杂环加成反应中的相互正交性。
The azide-dibenzocyclooctyne and trans-cyclooctene-tetrazine cycloadditions are both bioorthogonal and mutually orthogonal: trans-cyclooctene derivatives greatly prefer to react with tetrazines rather than azides, while dibenzocyclooctyne derivatives react with azides but not with tetrazines under physiological conditions. DFT calculations used to identify the origins of this extraordinary selectivity are reported, and design principles to guide discovery of new orthogonal cycloadditions are proposed. Two new bioorthogonal reagents, methylcyclopropene and 3,3,6,6-tetramethylthiacycloheptyne, are predicted to be mutually orthogonal in azide and tetrazine cycloadditions.