Chiral cis-hydrobenzofurans represent a unique motif existing in numerous natural products. One of the most straightforward and powerful ways to construct such a framework is the catalytic asymmetric desymmetrization of cyclohexadienones. In recent years, significant efforts were mainly focused on the application of chiral organocatalysts in intramolecular Stetter and RauhutCurrier reactions , however with a limited substrate scope.

 

Recently, Guo-Qiang Lin and co-workers at CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, realized the rhodium-catalyzed asymmetric arylative cyclization of cyclohexadienone-containing 1,6-enynes through tandem arylrhodation/conjugate addition reaction, thus providing optically pure cis-hydrobenzofurans with high to excellent yields ( up to 99%) and excellent enantioselectivities (up to 99% ee). The cyclization products were further transformed to interesting chiral frameworks of some natural products, thus demonstrating the utility of the products.

 

Rh-Catalyzed asymmetric arylative cyclization of cyclohexadienone-containing 1,6-enynes. (Imaged by LIN Guo-Qiang)

 

Subsequently, this team has achieved the first Cu-catalyzed asymmetric borylative cyclization of cyclohexadienone-containing 1,6-enynes through a tandem process: selective -borylation of propargylic ether and subsequent conjugate addition to cyclohexadienone. The reaction proceeds with excellent regioselectivity and enantioselectivity to afford an optically pure cis-hydrobenzofuran framework bearing alkenylboronate and enone substructures. Furthermore, the resulting bicyclic products could be converted to bridged and tricyclic ring structures. This method extends the realm of Cu-catalyzed asymmetric tandem reactions using bis(pinacolato)diboron.

 

 

Cu-Catalyzed asymmetric borylative cyclization of cyclohexadienone-containing 1,6-enynes. (Imaged by LIN Guo-Qiang)

 

Very recently, the same team has also established the tunable arylative cyclizations of cyclohexadienone-containing 1,6-enynes via rhodium(III)-catalyzed C−H activation of O-substituted N-hydroxybenzamides. The use of different O-substituents, i.e. O-Piv or O-Me, on the directing group allows the formation of either tetracyclic isoquinolones through N-Michael addition process or hydrobenzofurans through C-Michael addition process. Mechanistic investigations of these two cascade reactions clearly indicated that the C-H bond cleavage process was involved in the turnover-limiting step. This is the first example of RhIII-catalyzed arylative cyclization reaction of 1,6-enynes, and the results extend the application realm of Cp*Rh(III)-catalyzed C−H activation cascade reaction (J. Am. Chem. Soc. 2014, 136, 15607).

 

 

 

Tunable arylative cyclization of 1,6-enynes triggered by RhIII-catalyzed CH activation. (Imaged by LIN Guo-Qiang)

 

This project was sponsored by National Science Foundation of China, Ministry of Science and Technology of China, Chinese Academy of Science, and the Science and Technology Commission of the Shanghai Municipality.