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

研究了新型铟离子介导的脂肪族碘代炔自由基环化反应。用催化量的In和I_2处理碘代炔，促进原子转移5-外环化，得到五元烯基碘。与此相反，与In和I_2的反应通过相同的5-外环化产生还原性5-外环化产物。这两个过程最有可能引发的低价铟物种。为了证明这些反应的通用性，通过这种还原环化方法合成了光学活性的HIV蛋白酶抑制剂。其中，含有羟乙胺二肽电子等排体作为过渡态模拟亚结构的几种产物被证明对包括多药耐药变异体在内的广谱HIV毒株具有有效活性。和二取代的3-亚烷基羟吲哚通过自由基环化反应进行了研究，使用串联的In介导的碳甲烷和钯催化的交叉-偶联反应底物和反应条件的适当组合对于良好的产率是重要的。关键步骤是利用铟阳离子对酰胺羰基氧的强配位能力进行第一次立体选择性碳茚化反应。我们将此方法应用于TMC-95 A前体的合成。

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.