Department of Chemistry and Biomolecular Sciences, Centre for Chemical and Synthetic Biology, University of Ottawa, 150 Louis-Pasteur, Ottawa, Ontario, Canada K1N 6N5.
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
ACS Chem Biol. 2023 Nov 17;18(11):2430-2438. doi: 10.1021/acschembio.3c00491. Epub 2023 Oct 18.
The reactions of nitrones with cyclooctadiynes were studied to establish the relative rates of sequential reactions and to determine the limits and scope of this bioorthogonal chemistry. We have established the second-order rate constants for the consecutive additions of a variety of nitrones onto diyne and studied the structure-activity relationships via Hammett plots. Results show that the addition of the second nitrone to the monointermediate occurs significantly faster than the first, with both reactions being faster than analogous reactions with azides. Computational chemistry supports these observations. The rate of second addition increases with electron-deficient nitrones, as demonstrated by a large rho value of 2.08, suggesting that the reaction rate can be controlled by nitrone selectivity. To further investigate the kinetic parameters of the reaction, dinitrone monomers containing cyclic and diaryl-nitrones were designed for use in oligomerization applications. Oligomerization was used as a probe to test the limits of the reactivity and attempt to isolate monocycloaddition products. The oligomer formed from a cyclic nitrone reacts faster, and detailed MALDI mass spectrometry analysis shows that monoaddition products exist only transiently and are not isolatable. These studies inform on the scope and limits of this chemistry in a variety of applications. We successfully demonstrated bacterial cell wall labeling using heterogeneous dual cycloadditions involving nitrone and azide dipoles, where the nitrone was the faster reacting partner on the bacterial cell surface.
我们研究了硝酮与环辛二炔的反应，以确定连续反应的相对速率，并确定这种生物正交化学的限制和范围。我们已经确定了各种硝酮连续加成到二炔上的二级速率常数，并通过哈米特图研究了结构-活性关系。结果表明，第二个硝酮与单中间体的加成速度明显快于第一个，这两个反应都比类似的与叠氮化物的反应快。计算化学支持这些观察结果。第二个加成的速率随着缺电子硝酮的增加而增加，这由 2.08 的大 rho 值证明，表明反应速率可以通过硝酮的选择性来控制。为了进一步研究反应的动力学参数，设计了含有环状和二芳基硝酮的二硝酮单体，用于聚合应用。聚合反应被用作探针来测试反应性的极限并试图分离单环加成产物。由环状硝酮形成的低聚物反应更快，详细的 MALDI 质谱分析表明，单加成产物仅短暂存在且不可分离。这些研究为这种化学在各种应用中的范围和限制提供了信息。我们成功地使用涉及硝酮和叠氮二极体的异质双重环加成来证明了细菌细胞壁标记，其中硝酮在细菌细胞壁表面是更快反应的反应物。
