Douchez Antoine, Geranurimi Azade, Lubell William D
Département de Chimie , Université de Montréal , C.P.6128, Succursale Centre-Ville , Montréal H3C 3J7 , Canada.
Acc Chem Res. 2018 Oct 16;51(10):2574-2588. doi: 10.1021/acs.accounts.8b00388. Epub 2018 Oct 5.
γ,δ-Unsaturated ketones, so-called homoallylic ketones, have served as versatile building blocks for the synthesis of a variety of heterocycles, carbocycles, natural products, and reactive intermediates. Procured by a variety of processes, including conjugate addition of vinyl organometallic reagents to unsaturated ketones, allylation of silyl enol ethers, and rearrangements, homoallylic ketones are often synthesized by step-intensive methods. The cascade addition of 2 equiv of vinyl Grignard reagent to a carboxylate was reported by the Lubell laboratory in 2003 to give effective access to homoallylic ketones from a variety of aromatic, aliphatic, and α-amino methyl esters. Employing readily accessible vinyl magnesium halides in the presence of a catalytic amount of copper salt, this cascade reaction provides high yields of homoallylic ketones with minimal side product by a process featuring the assembly and collapse of a tetrahedral intermediate with expulsion of alkoxide ion, followed by conjugate addition to the resulting enone. Application of the cascade reaction to the synthesis of various homoallylic ketones has provided versatile building blocks for the synthesis of targets for different applications. For example, by employing (hetero)aryl di- and tricarboxylates as precursors, copper-catalyzed cascade additions have provided donor-acceptor and star-shaped monomers for optical-electronic materials. Amino ester starting materials have given homoallylic ketones for the synthesis of various peptidomimetics, including heteroarylalanines, hydroxyethylene isoesters, and diazepinone turn mimics. Moreover, anthranilate has served as building block to prepare various pyrrole, quinoline, benzodiazepine, and benzotriazepine heterocyles. In addition, cascade additions on hydroxyprolinates have given access to bipyrrole precursors of the prodigiosin family of natural products. In the interest to highlight the utility of the copper-catalyzed cascade addition of vinyl Grignard reagents to carboxylates, this Account provides details on the broad scope of substrates that deliver homoallylic ketone products as well as an overview of the wide range of applications in which this method may impact including materials and peptide science, heterocycle and natural product synthesis, and medicinal chemistry.
γ,δ-不饱和酮，即所谓的高烯丙基酮，已成为合成各种杂环、碳环、天然产物和反应中间体的通用构建单元。通过多种方法制备，包括将乙烯基有机金属试剂共轭加成到不饱和酮上、硅烯醇醚的烯丙基化以及重排反应，高烯丙基酮通常通过多步合成方法制备。2003年，卢贝尔实验室报道了将2当量的乙烯基格氏试剂级联加成到羧酸盐上，从而能够从各种芳香族、脂肪族和α-氨基甲酯有效地制备高烯丙基酮。在催化量的铜盐存在下，使用易于获得的乙烯基卤化镁，这种级联反应通过一个以四面体中间体的组装和分解并排出醇盐离子为特征的过程，随后对生成的烯酮进行共轭加成，以高收率得到高烯丙基酮且副产物最少。将级联反应应用于各种高烯丙基酮的合成，为不同应用目标的合成提供了通用的构建单元。例如，通过使用（杂）芳基二羧酸酯和三羧酸酯作为前体，铜催化的级联加成反应为光电子材料提供了供体-受体和星形单体。氨基酯起始原料得到了用于合成各种肽模拟物的高烯丙基酮，包括杂芳基丙氨酸、羟基乙烯异酯和二氮杂环庚三酮转角模拟物。此外，邻氨基苯甲酸酯已用作构建单元来制备各种吡咯、喹啉、苯并二氮杂卓和苯并三氮杂卓杂环。此外，对羟基脯氨酸酯的级联加成反应得到了灵菌红素家族天然产物的联吡咯前体。为了突出铜催化的乙烯基格氏试剂级联加成到羧酸盐的实用性，本综述详细介绍了能生成高烯丙基酮产物的广泛底物范围，以及该方法可能产生影响的广泛应用概述，包括材料和肽科学、杂环和天然产物合成以及药物化学。
