Benzo-Fused-Ring Toolbox Based on Palladium/Norbornene Cooperative Catalysis: Methodology Development and Applications in Natural Product Synthesis.

ConspectusBenzo-fused skeletons are ubiquitous in agrochemicals, medicines, natural products, catalysts, and other organic function materials. The assembly of these skeletons in an efficient manner is an actively explored field in organic synthesis. Palladium/norbornene (Pd/NBE) cooperative catalysis is a powerful tool for the expeditious assembly of polysubstituted arenes through bis-functionalization of the ortho and ipso positions of aryl iodides in one operation. Owing to the efforts of Lautens, Catellani, and others, an array of Pd/NBE-promoted annulations for the syntheses of diversified benzo-fused rings have been developed. However, these methods have not been broadly applied in total synthesis yet.Our group is interested in efficient and practical total synthesis of biologically active molecules. In the past 7 years, we have been devoted to the development of new annulation strategies for the assembly of common benzo-fused skeletons through Pd/NBE-promoted reactions of aryl iodides with novel bifunctional reagents. In this Account, we summarize our laboratory's systematic efforts in this direction. First, readily available epoxides and aziridines were exploited as versatile bifunctional alkylating reagents, which enables quick assembly of a series of valuable benzo-fused heterocycles, including isochromans, dihydrobenzofurans, 1,3--tetrahydroisoquinolines (THIQs), 1,3--THIQs, etc. Second, a convergent access to 5-7-membered benzo-fused carbocycles (including indanes and tetrahydronaphthalenes) was developed by Pd/NBE-promoted annulation of aryl iodides with simple olefinic alcohol-containing alkylating reagents. Third, a Pd/NBE-promoted annulation between aryl iodides and cyclohexanone-containing amination reagents was developed for the construction of benzo-fused N-containing bridged scaffolds. Thus, we have established a practical and versatile toolbox for the quick assembly of diversified benzo-fused skeletons. These new annulation reactions are of high chemo-, regio-, and stereoselectivities with good step and atom economy. Moreover, they are able to rapidly increase molecular complexity from simple building blocks. Finally, their synthetic value has been demonstrated by immediate adoption in several efficient total syntheses of medicines and complex natural products. Compared to conventional synthetic logics, the Pd/NBE-promoted annulation toolbox allows the development of highly convergent strategies, which significantly improves the overall synthetic efficiency.We believe the results presented in this Account will have significant implications beyond our research. It can be envisaged that new Pd/NBE-promoted annulations as well as new applications in complex total synthesis will be revealed in the near future.