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Synthesis of Cyclobutane-Fused Tetracyclic Scaffolds via Visible-Light Photocatalysis for Building Molecular Complexity
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-01-13 , DOI: 10.1021/jacs.9b12129 Martins S Oderinde 1 , Edna Mao 1 , Antonio Ramirez 2 , Joseph Pawluczyk 1 , Christine Jorge 3 , Lyndon A M Cornelius 1 , James Kempson 1 , Muthalagu Vetrichelvan 4 , Manivel Pitchai 4 , Anuradha Gupta 4 , Arun Kumar Gupta 4 , Nicholas A Meanwell 1 , Arvind Mathur 1 , T G Murali Dhar 1
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-01-13 , DOI: 10.1021/jacs.9b12129 Martins S Oderinde 1 , Edna Mao 1 , Antonio Ramirez 2 , Joseph Pawluczyk 1 , Christine Jorge 3 , Lyndon A M Cornelius 1 , James Kempson 1 , Muthalagu Vetrichelvan 4 , Manivel Pitchai 4 , Anuradha Gupta 4 , Arun Kumar Gupta 4 , Nicholas A Meanwell 1 , Arvind Mathur 1 , T G Murali Dhar 1
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We describe the synthesis through visible-light photocatalysis of novel functionalized tetracyclic scaffolds that incorporate a fused azabicyclo[3.2.0]heptan-2-one motif, which are structurally interesting cores with potential in natural product synthesis and drug discovery. The synthetic approach involves an intramolecular [2+2] cycloaddition with concomitant dearomatization of the heterocycle via an energy transfer process promoted by an iridium-based photosensitizer, to build a complex molecular archi-tecture with three stereogenic centers from relatively simple, achiral precursors. These fused azabicyclo[3.2.0]heptan-2-one-based tetracycles were obtained in high yield (generally >99%) and with excellent diastereoselectivity (>99:1). The late-stage derivatization of a bromine-substituted, tetracyclic indoline derivative with alkyl groups, employing a mild Negishi C-C bond forming protocol as a means of increasing structural diversity, provides additional modularity that will enable the delivery of valuable building blocks for medicinal chemistry. DFT calculations were used to compute the T1-S0 free energy gap of the ole-fin-tethered precursors and also to predict their reactivities based on triplet state energy transfer and transition state energy feasi-bility.
中文翻译：
通过可见光光催化合成环丁烷稠合四环支架以构建分子复杂性
我们描述了通过可见光光催化合成新型功能化四环支架，这些支架结合了一个融合的氮杂双环 [3.2.0] 庚烷-2-one 基序，这些基序是结构有趣的核心，在天然产物合成和药物发现中具有潜力。合成方法涉及分子内 [2+2] 环加成反应，同时通过铱基光敏剂促进的能量转移过程使杂环脱芳构化，以从相对简单的非手性前体构建具有三个立体中心的复杂分子结构。这些基于稠合氮杂双环[3.2.0]庚烷-2-one的四环以高产率（通常> 99％）和优异的非对映选择性（> 99：1）获得。具有烷基的溴取代的四环二氢吲哚衍生物的后期衍生化，采用温和的 Negishi CC 键形成方案作为增加结构多样性的一种手段，提供了额外的模块化，能够为药物化学提供有价值的构建模块。DFT 计算用于计算烯烃系链前驱体的 T1-S0 自由能隙，并基于三重态能量转移和过渡态能量可行性预测其反应性。
更新日期：2020-01-13
中文翻译：
通过可见光光催化合成环丁烷稠合四环支架以构建分子复杂性
我们描述了通过可见光光催化合成新型功能化四环支架，这些支架结合了一个融合的氮杂双环 [3.2.0] 庚烷-2-one 基序，这些基序是结构有趣的核心，在天然产物合成和药物发现中具有潜力。合成方法涉及分子内 [2+2] 环加成反应，同时通过铱基光敏剂促进的能量转移过程使杂环脱芳构化，以从相对简单的非手性前体构建具有三个立体中心的复杂分子结构。这些基于稠合氮杂双环[3.2.0]庚烷-2-one的四环以高产率（通常> 99％）和优异的非对映选择性（> 99：1）获得。具有烷基的溴取代的四环二氢吲哚衍生物的后期衍生化，采用温和的 Negishi CC 键形成方案作为增加结构多样性的一种手段，提供了额外的模块化，能够为药物化学提供有价值的构建模块。DFT 计算用于计算烯烃系链前驱体的 T1-S0 自由能隙，并基于三重态能量转移和过渡态能量可行性预测其反应性。
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