抄録
The search for natural products in marine and terrestrial environments has led to the discovery of a number of biologically active bis(indole)alkaloids, which include the bioactive marine natural product family of dragmacidins. Dragmacidin D (1: Figure 1), which is known as a potent inhibitor of serine-threonine protein phosphatases, has also attracted attention as a lead compound for treating Parkinson's, Alzheimer's and Huntington's diseases. Additionally, two structural isomers of this molecule are known, named dragmacidins E (2) and F (3). Prominent structural features of these compounds are two indole-azine bonds and a complex aminoimidazole moiety. To conquer these unique structures and to study their interesting bioactivity, many synthetic organic chemists have been trying to synthesize 1 and its analogues. However, only Stoltz and coworkers have successfully synthesized these molecules (1 and 3) thus far, using the Suzuki-Miyaura cross-coupling reactions as key steps. Palladium-catalyzed cross-coupling reactions of arylmetal compounds with aryl halides are the most reliable method for C-C bond construction in organic synthesis. However, a fair number of steps would be required to utilize this strategy in the synthesis of dragmacidins, since the aromatic coupling partners must be pre-functionalized. Therefore, our group set out to construct 1 in a concise fashion, which features the direct arylation of C-H bonds without pre-functionalization. In conclusion, the total synthesis of dragmacidin D(1) was achieved, including a newly developed direct arylation strategy which involves an oxidative C3-selective indole-azine (N-oxide) C-H/C-H coupling reaction, aβ-selective thiophene-indole C-H/C-X coupling reaction, and an indole-pyrazinone C-H/C-H coupling reaction.
