Meng Fanke’s group at the State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences has been working on the study of cobalt-catalyzed enantioselective reactions. They have developed a series of cobalt-catalyzed enantioselective hydrofunctionalization of cyclopropenes (Angew. Chem. Int. Ed. 2019, 58, 11049 –11053, Angew. Chem. Int. Ed. 2021, 60, 2694-2698). Recently, they promoted the activation of the allylic C-H bond through the strong coordination of Co(I) and unsaturated C-C bonds, and generated nucleophilic allyl cobalt intermediates chemoselectivity, which were combined with aldehydes and -ketoesters undergo regio, diastereo, and enantioselective addition reactions (Cell Reports Physical Science 2021, DOI: 10.1016/j.xcrp.2021.100406).

 

Transition-metal-catalyzed enantioselective hydrofunctionalization is one of the most efficient strategies for rapid and diverse synthesis of chiral compounds. The introduction of specific groups can be avoided in advance through metal-catalyzed selective activation of allylic C-H bonds, and sensitive organometallic reagents can be efficiently prepared, thereby shortening the synthesis route and improving the synthesis efficiency. Transition-metal-catalyzed enantioselective allylic C-H functionalization reactions that generate electrophilic allyl metal intermediates through C-H bond activation and allyl radical intermediates have been developed, but how to produce nucleophilic allyl metal intermediates through enantioselective activation of allylic C-H bonds has not been reported yet. Enantioenriched homoallyl alcohols are common existence in drug molecules and natural products. Therefore, it is necessary to construct a new method of enantioenriched homoallyl alcohols by allylic C-H bonds activation strategy, which generate nucleophilic allyl metal intermediates and in situ add to carbonyl compounds. 

 

Meng Fanke’s group discovered that Me-Co(I) complexes were produced by in-situ reduction, which performed oxidative addition to the allylic C-H bonds to produce allyl Co(III) intermediates through the metal center coordination with olefins. After the methanes were eliminated, nucleophilic allyl Co(I) intermediate were produced. The chem-, regio-, diastereo-, and enantio-selectivity of the reaction can be accurately controlled by adjusting ligands. In addition, the reaction has high yield, wide substrate applicability and tolerance with a variety of sensitive functional groups. Both allylbenzene and 1,4-diene substrates can be suitable for the reaction. Both aldehydes and -ketoesters can be converted to functionalized enantioenriched homoallyl alcohols which were difficult to obtain by other methods in one step. Mechanism studies implied that the cleavage of C-H bond was not rate-limiting step; when there are both -methylstyrene and allylbenzene in the molecule, allylbenzene can be converted chemoselectively; C-Co bond produced by the activation of C-H bond was not enantioselective or chiral center was racemized during isomerization of C-Co bond. The products can undergo subsequent functional groups conversion and can construct bioactive molecules efficiently. This method has been applied to the formal enantioselective synthesis of lithospermic acid and the enantioselective total synthesis of dihydrodehydrodiconiferyalcohol.

 

This work was completed by Zhang Haiyan and Huang Jun. The research was funded by the National Natural Science Foundation of China, the Shanghai Municipal Science and Technology Commission, the Chinese Academy of Sciences, the Shanghai Institute of Organic Chemistry, and the State Key Laboratory of Organometallic Chemistry.

 

Cobalt-catalyzed enantioselective allylic C-H functionalization