ABSTRACT
Inverse electron demand Diels–Alder reactions have gained comprehensive attraction in recent years. Accordingly, the synthetic approaches for one of the coupling partners, namely s-tetrazine, have been extensively investigated. Generally, the main synthetic method of s-tetrazine relied on the condensation of two nitriles to give the corresponding symmetric/asymmetric tetrazines with moderate to excellent yields. However, the practical synthesis route and commercial/synthetic availability of the feedstock nitriles are still elusive. It is therefore probably worth summarizing the existing methods and typical biological applications that have been demonstrated in recent years. In brief, this overview will be split into three parts. First, we will summarize the typical approaches toward the synthesis of s-tetrazines till now. Then, we will provide the representative bio-orthogonal reactions by the combination of s-tetrazines with unsaturated compounds under physiological conditions. Eventually, we will propose a direction for the practical and efficient synthesis of s-tetrazine.
Acknowledgments
RW thanks Huazhong University of Science and Technology for the start-up funding. R.W. thanks “100 Talents Program” Youth Project of Hubei Province for financial support. R.W. also thanks China Postdoctoral Science Foundation (No. 217877 to J.Z.Z.) for financial support. Supported by the Fundamental Research Funds for the Central Universities (S.W.) is greatly appreciated. Dr. Hanqing Dong (Arvinas, Inc.) is appreciated during the preparation of this manuscript.