Department of Chemical Sciences, University of Naples Federico II, Via Cintia 21, Naples I-80126, Italy.
Department of Chemistry "Giacomo Ciamician", University of Bologna, Via S. Giacomo 11, Bologna I-40126, Italy.
J Org Chem. 2022 Apr 1;87(7):4580-4589. doi: 10.1021/acs.joc.1c02911. Epub 2022 Mar 10.
The addition of thiol compounds to -quinones, as exemplified by the biologically relevant conjugation of cysteine to dopaquinone, displays an anomalous 1,6-type regiochemistry compared to the usual 1,4-nucleophilic addition, for example, by amines, which has so far eluded intensive investigations. By means of an integrated experimental and computational approach, herein, we provide evidence that the addition of glutathione, cysteine, or benzenethiol to 4-methyl--benzoquinone, modeling dopaquinone, proceeds by a free radical chain mechanism triggered by the addition of thiyl radicals to the -quinone. In support of this conclusion, DFT calculations consistently predicted the correct regiochemistry only for the proposed thiyl radical-quinone addition pathway. These results would prompt a revision of the commonly accepted mechanisms for thiol--quinone conjugation and stimulate further work aimed at assessing the impact of the free radical processes in biologically relevant thiol-quinone interactions.
将巯基化合物添加到苯醌中，例如将半胱氨酸与多巴醌进行生物相关的缀合，与通常的亲核 1,4-加成（例如通过胺）相比，表现出异常的 1,6-区域化学，这迄今为止一直回避了深入研究。通过综合的实验和计算方法，本文提供了证据表明，谷胱甘肽、半胱氨酸或苯硫醇与 4-甲基-对苯醌（模拟多巴醌）的加成是通过硫自由基加成到 -醌引发的自由基链机制进行的。支持这一结论的是，DFT 计算仅对于所提出的硫自由基-醌加成途径一致地预测了正确的区域化学。这些结果将促使对常见的巯基-醌缀合机制进行修订，并激发进一步的工作，旨在评估自由基过程对生物相关的巯基-醌相互作用的影响。
