molecules Article Concise Synthesis of Functionalized Cyclobutene Analogues for Bioorthogonal Tetrazine Ligation Jiayu Sun 1,†, Jie Li 1,†, Hongbao Sun 1,†, Chunling Li 2,3,* and Haoxing Wu 1,* 1 Department of Radiology, West China Hospital, Sichuan University, Guo Xue Xiang 37, Chengdu 610041, China;
[email protected] (J.S.);
[email protected] (J.L.);
[email protected] (H.S.) 2 Department of Neurosurgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China 3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China * Correspondence:
[email protected] (C.L.);
[email protected] (H.W.); Tel.: +86-028-65261615 (H.W.) † These authors contributed equally to this work. Abstract: Novel bioorthogonal tools enable the development of new biomedical applications. Here we report the concise synthesis of a series of aryl-functionalized cyclobutene analogues using com- mercially available starting materials. Our study demonstrates that cyclobutene acts as a small, strained dienophile to generate stable substrates suitable for bioorthogonal tetrazine ligation. Keywords: functionalized cyclobutene analogues; concise synthesis; tetrazine ligation; bioorthogo- nal chemistry 1. Introduction Citation: Sun, J.; Li, J.; Sun, H.; Li, C.; Wu, H. Concise Synthesis of Tetrazine has attracted increasing attention since the emergence of bioorthogonal Functionalized Cyclobutene chemistry [1–4]. Recent clinical trials have highlighted the biomedical usefulness of the Analogues for Bioorthogonal Tetrazine bioorthogonal reaction between tetrazine and dienophiles, an inverse electron demand Ligation. Molecules 2021, 26, 276. Diels–Alder (IEDDA) reaction [5–8]. A wide range of dienophiles, each with different https://doi.org/molecules26020276 advantages and limitations, have been developed as IEDDA substrates for various research purposes.