Synthesis of Dragmacidin D via Direct C–H Couplings

Dragmacidin D, an emerging biologically active marine natural product, has attracted attention as a lead compound for treating Parkinson’s and Alzheimer’s diseases. Prominent structural features of this compound are the two indole–pyrazinone bonds and the presence of a polar aminoimidazole unit. We have established a concise total synthesis of dragmacidin D using direct C–H coupling reactions. Methodological developments include (i) Pd-catalyzed thiophene–indole C–H/C–I coupling, (ii) Pd-catalyzed indole–pyrazine N-oxide C–H/C–H coupling, and (iii) acid-catalyzed indole–pyrazinone C–H/C–H coupling. These regioselective catalytic C–H couplings enabled us to rapidly assemble simple building blocks to construct the core structure of dragmacidin D in a step-economical fashion.

德拉马克定D(Dragmacidin D)是一种新兴的生物活性海洋天然产物，作为治疗帕金森病与阿尔茨海默病的先导化合物受到广泛关注。该化合物的显著结构特征为拥有两个吲哚-吡嗪酮键，以及一个极性氨基咪唑单元。我们开发了一条简洁的德拉马克定D全合成路线，采用直接C-H偶联反应作为核心策略。本次方法学开发涵盖以下内容：(i) 钯(Pd)催化的噻吩-吲哚C-H/C-I偶联反应；(ii) 钯(Pd)催化的吲哚-吡嗪N-氧化物C-H/C-H偶联反应；(iii) 酸催化的吲哚-吡嗪酮C-H/C-H偶联反应。这些区域选择性催化C-H偶联反应使得我们能够快速组装简单结构砌块，以步骤经济性的方式构建德拉马克定D的核心结构。