Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan

[Synthetic studies on natural products with aromatic nitrogen heterocycles based on development of the methods for the formation of aryl carbon-nitrogen bond].

PMID 24088350


Total syntheses of yatakemycin, PDE-II, dictyodendrins, and heptaphylline are described. This article focuses on the formation of aryl carbon-nitrogen bonds by two methods: first by an aromatic amination reaction using a combination of CuI and CsOAc, and then by a benzyne-mediated one-pot cyclization-functionalization sequence. The aryl amination reaction shows a high functional group compatibility and applicability for highly hindered substrates. The utility of this reaction has been fully demonstrated through a total synthesis of yatakemycin, which features the regioselective ring opening of (S)-epichlorohydrin with 2,6-dibromophenyllithium species and the efficient deprotection of benzyl groups of aryl benzyl ether with BCl3 in the presence of pentamethylbenzene. The copper-mediated aryl amination reaction was applied to a one-pot double aryl amination for facile access to the highly substituted pyrroloindole skeleton, which led to a concise total synthesis of PDE-II. A highly efficient total synthesis of dictyodendrins A-E was accomplished by the development of a novel benzyne-mediated one-pot indoline formation/cross-coupling sequence for the construction of a highly substituted key indoline intermediate. Peripheral substituents were introduced onto this intermediate in a modular fashion to complete the total synthesis of dictyodendrins A-E. The utility of the one-pot benzyne-mediated cyclization-functionalization reaction was demonstrated by the total synthesis of carbazole alkaloid, heptaphylline.