武汉大学周强辉/程鸿刚/湖北工业大学张谦JACS:基于钯/手性降冰片烯协同催化的去对称化策略实现立体发散性构建氧杂季碳手性中心

图1. TOC (图片来源于JACS)

摘要：

Oxa-quaternary carbon centers are prevalent in bioactive natural products and pharmaceuticals. However, the development of general and practical methods to construct these oxa-quaternary carbon stereocenters remains a formidable challenge. Herein, we report a desymmetrization strategy for the construction of oxa-quaternary carbon stereocenters based on palladium/chiral norbornene cooperative catalysis. With readily available aryl iodides and prochiral 2’-bromo-aryl-substituted tertiary alcohols as the building blocks, a wide variety of 6H benzo[c]chromenes bearing an oxa-quaternary carbon stereocenter and a versatile C−Br bond are expediently prepared in a highly enantioselective manner (43 examples, up to 99% e.e.). Notably, both enantiomers can be stereodivergently obtained through a simple switch of the same configurated chiral NBE cocatalysts. The synthetic utility of this method is demonstrated by a successful scale-up experiment and diverse late-stage structural modifications through the facile elaboration of the common C−Br bond of the obtained chiral 6H-benzo[c]chromene products. In addition to the experimental studies, DFT calculations are performed to elucidate the reaction mechanism, the origin of enantiodiscrimination, and enantioselectivity inversion in this desymmetrization process.

研究背景：

图2. 研究背景及本策略 (图片来源于JACS)

研究内容：

图3. 条件优化 (图片来源于JACS)

图4. 前手性芳基化试剂2底物范围 (图片来源于JACS)

图5. 芳基碘代物1底物范围 (图片来源于JACS)

图6. 合成应用 (图片来源于JACS)

图7. DFT计算 (图片来源于JACS)

总结：

In summary, we have developed an intriguing desymmetrization method enabled by Pd/NBE* cooperative catalysis for the enantioselective construction of oxa-quaternary carbon stereocenters. A wide range of 6H-benzo[c]chromene products bearing an oxa-quaternary carbon stereocenter and a versatile C−Br bond are expediently prepared in a highly enantioselective manner (43 examples, up to 99% e.e.). Notably, both enantiomers can be stereodivergently obtained through a simple switch of the same configurated chiral NBE cocatalysts. Other features of this method include readily available starting materials (both aryl iodides and the prochiral arylating reagents), high step economy, and scalability. Moreover, the obtained chiral 6H-benzo[c]chromene products contain a versatile C−Br bond, which can be facilely utilized for diverse late-stage structural modifications. In addition to the experimental studies, DFT calculations were performed to elucidate the reaction mechanism, the origin of enantiodiscri mination and enantioselectivity inversion in this desymmetri zation process.

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