Strain-promoted reaction of 1,2,4-triazines with bicyclononynes.
Strain-promoted reaction of 1,2,4-triazines with bicyclononynes.
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DOI：
10.1002/chem.201502397
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发表时间：
2015-10-05
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影响因子：
--
通讯作者：
Webb ME
中科院分区：
文献类型：
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作者：
Horner KA;Valette NM;Webb ME
1,2,4,5-四嗪类化合物与双克隆酮类化合物之间的逆电按需diols - alder环加成反应（SPIEDAC）是最快的生物正交反应之一。然而，1,2,4,5-四嗪的合成是复杂的，并且可能涉及挥发性试剂。1,2,4-三嗪类化合物在高温下也能与无环和未张力的亲二烯试剂发生环加成反应，但它们与张力炔的反应尚未被描述。我们假设1,2,4-三嗪会在低温下与应变炔反应，因此在体外或体内标记实验中提供了四嗪环加成反应的替代方法。我们描述了一种1,2,4-三嗪-3-丙氨酸衍生物的合成，与氟酰甲基氧羰基（Fmoc）合成多肽的策略完全兼容，并证明了它在37°C下与应变双环壬炔的反应，其反应速率与叠氮化物与相同底物的反应速率相当。三嗪基丙氨酸的合成路线很容易适应其他探针分子的后期功能化，因此1,2,4-三嗪- spiedac具有替代四嗪环加成的潜力，可用于细胞和生化研究。
Strain-promoted inverse electron-demand Diels–Alder cycloaddition (SPIEDAC) reactions between 1,2,4,5-tetrazines and strained dienophiles, such as bicyclononynes, are among the fastest bioorthogonal reactions. However, the synthesis of 1,2,4,5-tetrazines is complex and can involve volatile reagents. 1,2,4-Triazines also undergo cycloaddition reactions with acyclic and unstrained dienophiles at elevated temperatures, but their reaction with strained alkynes has not been described. We postulated that 1,2,4-triazines would react with strained alkynes at low temperatures and therefore provide an alternative to the tetrazine cycloaddition reaction for use in in vitro or in vivo labelling experiments. We describe the synthesis of a 1,2,4-triazin-3-ylalanine derivative fully compatible with the fluorenylmethyloxycarbonyl (Fmoc) strategy for peptide synthesis and demonstrate its reaction with strained bicyclononynes at 37 °C with rates comparable to the reaction of azides with the same substrates. The synthetic route to triazinylalanine is readily adaptable to late-stage functionalization of other probe molecules, and the 1,2,4-triazine-SPIEDAC therefore has potential as an alternative to tetrazine cycloaddition for applications in cellular and biochemical studies.