铜催化的烷基卤代烃与烯基硼酸酯立体汇聚式不对称自由基交叉偶联反应

       手性烯烃广泛存在于天然产物和药物分子中，并且是合成化学中重要的合成单元，因此手性烯烃的合成引起了广泛重视。 传统构建手性烯烃的方法主要通过手性原料的官能团转化获取，例如手性炔烃的加氢反应和手性醛的 Wittig 反应等。 因此， 通过没有手性或外消旋的起始原料实现催化不对称合成是一类更加直接和高效的方法。 在这方面，利用廉价的过渡金属催化外消旋烷基卤代烃与有机金属试剂的立体汇聚式 C(sp3)-C 交叉偶联反应是合成手性分子的有力工具。 其中，烷基卤代烃与烯基金属试剂的立体汇聚式自由基 C(sp3)-C(sp2)是一种很有吸引力的构建手性烯烃的策略。 目前的方法严重依赖于对空气/水分敏感的烯基锌、硅、锆和镁试剂的使用。相比之下，烯基硼酸酯是一类易制备、对空气/水分稳定的、 并与许多官能团兼容的烯基亲核试剂。 因此，发展烷基卤代烃与烯基硼酸酯的不对称自由基 C(sp3)–C(sp2)交叉偶联，从而构建手性烯烃类化合物具有非常重要的研究意义。

       该论文中， 我们首先对合成手性烯烃的不对称催化方法进行了简单的综述，总结了目前合成手性烯烃的一些策略，并给出它们相应尚未解决的问题。 之后我们阐述了通过设计新型 Hemilabile N,N,N 手性阴离子配体（具有强和弱的配位基团，呈现“半不稳定性”），来实现铜催化烷基卤代烃与烯基硼酸酯的立体汇聚式 不对称自由基 交叉偶联反应。 新设计的Hemilabile N,N,N 配体在反应启动时，利用三齿配位模式的强还原性使反应经历自由基机制从而易于产生前手性中间体，并基于三齿配位模式使得铜中心处于配体饱和，抑制烯基硼自身偶联副反应；在手性控制时，通过双齿配位模式更好地实现高活性自由基对映选择性控制。 烯烃的转化突出了它在合成各种手性骨架(如醇、羧酸和酯)中的合成潜力。 它可以进一步通过连续的 C-H 溴化/交叉偶联过程，应用于生物活性分子的后期官能化。

       总之， 我们实现了一种铜催化的烷基卤代烃与烯基硼酸酯立体汇聚式自由基 C(sp3)-C(sp2)交叉偶联反应。该反应包括大量的苄溴和杂环苄溴，以及乙烯基、单/二取代的烯基硼酸酯， 超过 45 个底物（ee 值最高可达>99%） 的手性烯烃化合物的构建， 具有广泛的官能团多样性。

 

Chiral alkenes are important structure motifs in natural products and pharmaceuticals, and are also valuable synthetic intermediates in organic chemistry. Therefore, great afforts has been devoted towards their synthesis. Traditionally, chiral alkenes are mainly obtained from the transformation of chiral starting materials, such as hydrogenation of chiral alkynes, Wittig reaction of chiral aldehydes, etc. In this context, the catalytic asymmetric synthesis represents an appealing tool and has attracted great attention since no chiral starting materials are needed. In this aspect, the earth-abundant transition metal-catalyzed enantioconvergent C(sp3)–C cross-coupling of racemic alkyl halides with organometallic reagents represents a powerful tool in the synthesis of chiral molecules. Among others, the enantioconvergent radical C(sp3)-C(sp2) cross-coupling of alkyl halides with alkenylmetallic reagents represents an appealing strategy to access chiral alkenes. The current methods rely heavily on the utilization of alkenyl zinc, silicon, zirconium, and magnesium reagents, which are generally sensitive towards air/moisture and need cautious storage in solution. In comparison, alkenylboronate esters are air-/moisture-stable, easily accessible, and compatible with many functional groups. Therefore, the development of a practical enantioconvergent C(sp3)-C(sp2) coupling of alkyl halides with alkenylboronate esters is highly desirable.

In this thesis, we firstly introduced the reported catalytic asymmetric synthesis of chiral alkenes and summarized the unsolved problems of the known strategies. Afterwards, we described our efforts in developing a copper-catalyzed enantioconvergent radical cross-coupling of alkyl halides with alkenylboronate esters. Key to the success is rational design of hemilabile N,N,N-ligands. Thus, the newly designed ligand could promote the radical cross-coupling process and suppress the homocoupling of alkenlyboronate esters in the tridentate form. Meanwhile, it also delivers the excellent enantiocontrol over highly reactive alkyl radicals in the bidentate form. Straightforward transformations highlight its synthetic potential in the synthesis of various chiral building blocks, such as alcohols, carboxylic acids, and esters. It can be further applied in the late-stage functionalization of bioactive molecules via a sequential C–H bromination/cross-coupling process.

In sum, we have described a copper-catalyzed enantioconvergent radical C(sp3)–C cross-coupling of alkyl halides with alkenylboronate esters for expedient synthesis of chiral alkenes. More than 45 examples have been demonstrated in up to >99% ee. The reaction covers a number of benzyl and heterobenzyl bromides, as well as vinyl-, mono/di-substituted alkenylboronate esters with broad functional group diversity.
 

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