Boryl Radicals Enabled a Three-Step Sequence to Assemble All-Carbon Quaternary Centers from Activated Trichloromethyl Groups

The construction of diversely substituted all-carbon quaternary centers has been a longstanding challenge in organic synthesis. Methods that add three alkyl substituents to a simple C(sp3) atom rely heavily on lengthy multiple processes, which usually involve several preactivation steps. Here, we describe a straightforward three-step sequence that uses a range of readily accessible activated trichloromethyl groups as the carbon source, the three C-Cl bonds of which are selectively functionalized to introduce three alkyl chains. In each step, only a single C-Cl bond was cleaved with the choice of an appropriate Lewis base-boryl radical as the promoter. A vast range of diversely substituted all-carbon quaternary centers could be accessed directly from these activated CCl3 trichloromethyl groups or by simple derivatizations. The use of different alkene traps in each of the three steps enabled facile collections of a large library of products. The utility of this strategy was demonstrated by the synthesis of variants of two drug molecules, whose structures could be easily modulated by varying the alkene partner in each step. The results of kinetic and computational studies enabled the design of the three-step reaction and provided insights into the reaction mechanisms.

构建多样取代的全碳季碳中心一直是有机合成领域的一项长期挑战。向一个简单的C(sp3)原子添加三个烷基取代基的方法在很大程度上依赖冗长的多步过程，这通常涉及几个预活化步骤。在此，我们描述了一个直接的三步反应序列，该序列使用一系列容易获得的活化三氯甲基作为碳源，其三个C - Cl键被选择性地官能化以引入三个烷基链。在每一步中，通过选择合适的路易斯碱 - 硼基自由基作为促进剂，只有一个C - Cl键被断裂。大量多样取代的全碳季碳中心可以直接从这些活化的CCl3三氯甲基获得，或者通过简单的衍生化得到。在三步中的每一步使用不同的烯烃捕获剂能够轻松收集大量的产物库。通过合成两种药物分子的变体证明了该策略的实用性，其结构可以通过改变每一步中的烯烃伙伴轻松调节。动力学和计算研究的结果使三步反应的设计成为可能，并为反应机理提供了见解。