Preparation and mechanistic studies of 2-substituted Bisthiazolidines by imine exchange.
Preparation and mechanistic studies of 2-substituted Bisthiazolidines by imine exchange.
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DOI：
10.1002/ejoc.201901677
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发表时间：
2020-03-08
影响因子：
2.8
通讯作者：
Mahler G
中科院分区：
文献类型：
--
作者：
Martínez V;Villamil V;Duarte D;Saiz C;Davyt D;Fontana C;Veiga N;Mahler G
双噻唑烷(BTZ)是被认为是青霉素类似物的双环化合物，它能全面抑制金属-β-内酰胺酶(MBLS)，并增强β-内酰胺对耐药细菌的活性。在这里，我们提出了一种新的方法，通过醛交换制备2-取代的双噻唑烷。用该方法合成了13个新的双噻唑烷类化合物，产率从31%到75%不等。该反应基于能够交换侧链的原位亚胺的形成。根据核磁共振实验对反应中间体进行了研究，在反应混合物中检测到了关键的亚胺1b-II。此外，还进行了密度泛函计算分析，以深入了解反应机理，从而揭示了合成路线中不同的途径及其活化障碍。结果表明，最有利的途径是通过I)N辅助N-C键裂解和II)硫醇介导的5内触发环化和C-N键裂解形成噻唑烷1b-III。与之前报道的证据相反，亚胺的化合作用被认为是一种合理的途径而被丢弃。最后，1b-III与醛2a通过亚胺离子1b-V反应生成自行车4a。
Bisthiazolidines (BTZ) are bicyclic compounds considered penicillin analogs that inhibit the full range of Metallo-β-Lactamases (MBLs) and potentiate β-lactam activity against resistant bacteria. Herein we present a new methodology to prepare 2-substituted bisthiazolidines by aldehyde exchange. Thirteen new bisthiazolidines were prepared using this methodology, with yields ranged from 31 to 75%. The reaction is based on in situ imines formation, which are able to exchange side chains. The reaction intermediates were studied based on NMR experiments and a key imine 1b-II could be detected in the reaction mixture. Furthermore, a DFT computational analysis was performed to gain insights into the reaction mechanism, allowing us to unveil the different pathways and their activation barriers within the synthetic route. The results suggest that the most favorable route involve the formation of the thiazolidine 1b-III by i) a N-assisted N-C bond cleavage, and ii) a thiol-mediated 5 endo-trig cyclization followed by a C-N bond cleavage. In contrast with previously reported evidence, the imine metathesis was discarded as a plausible pathway. Finally, the reaction of 1b-III with aldehyde 2a leads to bicycle 4a via the iminium ion 1b-V.
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影响因子：
5.6
作者：
Labute, Paul
通讯作者：
Labute, Paul
影响因子：
12.9
作者：
Aljuhani, Maha A.;Barman, Samir;Basset, Jean-Marie
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作者：
Saiz, Cecilia;Villamil, Valentina;Mahler, Graciela
通讯作者：
Mahler, Graciela
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作者：
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Gonzalez, Mariano M.;Kosmopoulou, Magda;Mojica, Maria F.;Castillo, Valerie;Hinchliffe, Philip;Pettinati, Ilaria;Brem, Juergen;Schofield, Christopher J.;Mahler, Graciela;Bonomo, Robert A.;Llarrull, Leticia I.;Spencer, James;Vila, Alejandro J.
通讯作者：
Vila, Alejandro J.