Development of new reaction method utilized metallic characteristics. Application to the synthesis of biological active compound.

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Novel indium-mediated radical cyclization reactions of aliphatic iodoalkynes have been studied. Treatment of iodoalkynes with a catalytic amount of In and I_2 promotes atom-transfer 5-exo-cyclization to give five-membered alkenyl iodides. In contrast, reaction with In and I_2 yields reductive 5-exo-cyclization products via the same 5-exo-cyclization. Both processes are most likely initiated by low-valent indium species. To demonstrate versatility of these reactions, optically active HIV protease inhibitors were synthesized by this reductive cyclization method. Among them, several products, which contain a hydroxyethylamine dipeptide isostere as a transition state-mimicking substructure, proved to possess potent activity against a wide spectrum of HIV strains including multi-drug-resistant variants.The first efficient methods for stereoselective synthesis of various (E)-, (Z)-, and disubstituted 3-alkylideneoxindoles via radical cyclization reactions were investigated using tandem In-mediated carbometallation and palladium-catalyzed cross-coupling reaction. The proper combination of substrates and reaction conditions is important for good yields. The key step is the first stereoselective carboindation reaction using the strong coordination ability of an indium cation to the amide carbonyl oxygen. We applied this method to the synthesis of TMC-95A precursor.