Departamento de Química Orgánica I, Centro de Investigación y Estudios Avanzados "Lucio Lascaray", Facultad de Farmacia, University of the Basque Country, UPV/EHU Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
Molecules. 2022 Jun 5;27(11):3624. doi: 10.3390/molecules27113624.
A study on the reactivity of 3-amino α,β-unsaturated γ-lactam derivatives obtained from a multicomponent reaction is presented. Key features of the substrates are the presence of an endocyclic α,β-unsaturated amide moiety and an enamine functionality. Following different synthetic protocols, the functionalization at three different positions of the lactam core is achieved. In the presence of a soft base, under thermodynamic conditions, the functionalization at C-4 takes place where the substrates behave as enamines, while the use of a strong base, under kinetic conditions, leads to the formation of C-5-functionalized γ-lactams, in the presence of ethyl glyoxalate, through a highly diastereoselective vinylogous aldol reaction. Moreover, the nucleophilic addition of organometallic species allows the functionalization at C-3, through the imine tautomer, affording γ-lactams bearing tetrasubstituted stereocenters, where the substrates act as imine electrophiles. Taking into account the advantage of the presence of a chiral stereocenter in C-5 substituted γ-lactams, further diastereoselective transformations are also explored, leading to novel bicyclic substrates holding a fused γ and δ-lactam skeleton. Remarkably, an example of a highly stereoselective formal [3+3] cycloaddition reaction of chiral γ-lactam substrates is reported for the synthesis of 1,4-dihidropyridines, where a non-covalent attractive interaction of a carbonyl group with an electron-deficient arene seems to drive the stereoselectivity of the reaction to the exclusive formation of the isomer. In order to unambiguously determine the substitution pattern resulting from the diverse reactions, an extensive characterization of the substrates is detailed through 2D NMR and/or X-ray experiments. Likewise, applications of the substrates as antiproliferative agents against lung and ovarian cancer cells are also described.
本文研究了多组分反应得到的 3-氨基α,β-不饱和γ-内酰胺衍生物的反应性。底物的关键特征是存在环内α,β-不饱和酰胺部分和烯胺官能团。根据不同的合成方案，在酰胺核心的三个不同位置实现了官能团化。在软碱存在下，在热力学条件下，在 C-4 处发生官能团化，其中底物表现为烯胺，而在强碱存在下，在动力学条件下，通过高度非对映选择性的乙烯基醇醛反应，在乙基乙二醛存在下，形成 C-5 官能化的γ-内酰胺。此外，亲核试剂加成允许通过亚胺互变异构体在 C-3 处进行官能团化，得到带有四取代立体中心的γ-内酰胺，其中底物作为亚胺亲电试剂。考虑到 C-5 取代的γ-内酰胺中存在手性立体中心的优势，还探索了进一步的非对映选择性转化，得到了含有稠合γ和δ-内酰胺骨架的新型双环底物。值得注意的是，报告了手性γ-内酰胺底物的高度立体选择性的[3+3]环加成反应的实例，用于合成 1,4-二氢吡啶，其中羰基与缺电子芳烃之间的非共价吸引相互作用似乎驱动反应的立体选择性，有利于形成异构体。为了明确确定不同反应产生的取代模式，通过二维 NMR 和/或 X 射线实验详细描述了底物的广泛表征。同样，还描述了底物作为抗肺癌和卵巢癌细胞的抗增殖剂的应用。
