Matsukuma Kakeru, Tayu Masanori, Itai Ryota, Imai Kotaro, Ohrui Sayaka, Saito Nozomi
Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588, Japan.
J Org Chem. 2025 Jul 25;90(29):10454-10464. doi: 10.1021/acs.joc.5c01232. Epub 2025 Jul 15.
Multicomponent reactions, which involve the reaction of three or more components in a single step to efficiently produce a new molecular structure, have received growing attention in a range of research areas. In this study, four- and five-component reactions incorporating alkenes, carboxylic acids, alkyl radicals, and nitriles are developed for the imidoalkylation of alkenes with perfect regioselectivity. More specifically, this approach involves a photoredox reaction based on a catalytic indirect reductive quenching system. Various drug molecules and amino acids were demonstrated to be compatible substrates for this reaction, thereby enabling the synthesis of multifunctionalized derivatives. Notably, five individual components were assembled with perfect regioselectivity via the reaction of a radical species in the presence of a polarity-matched alkene. Mechanistic studies and density functional theory calculations suggested that this multicomponent reaction involves a cascade of Ritter-type substitutions and Mumm rearrangements. This method exhibits immense potential for use in the creation of structurally diverse and biologically relevant molecules with defined connectivities, thereby holding promise for applications in drug discovery and materials science.
多组分反应涉及三种或更多种组分在一步反应中高效生成新的分子结构，在一系列研究领域中受到越来越多的关注。在本研究中，开发了包含烯烃、羧酸、烷基自由基和腈的四组分和五组分反应，用于烯烃的亚胺烷基化反应，具有完美的区域选择性。更具体地说，该方法涉及基于催化间接还原猝灭体系的光氧化还原反应。各种药物分子和氨基酸被证明是该反应的兼容底物，从而能够合成多功能化衍生物。值得注意的是，在极性匹配的烯烃存在下，通过自由基物种的反应，五个单独的组分以完美的区域选择性组装在一起。机理研究和密度泛函理论计算表明，这种多组分反应涉及一系列 Ritter 型取代和 Mumm 重排。该方法在创建具有确定连接性的结构多样且与生物学相关的分子方面具有巨大潜力，因此在药物发现和材料科学中的应用前景广阔。
