Enantioselective Assembly of Ferrocenes with Axial and Planar Chiralities via Palladium/Chiral Norbornene Cooperative Catalysis.

The preparation of ferrocenes with both axial and planar chiralities poses a considerable challenge. Herein, we report a strategy for the construction of both axial and planar chiralities in a ferrocene system via palladium/chiral norbornene (Pd/NBE*) cooperative catalysis. In this domino reaction, the first established axial chirality is dictated by Pd/NBE* cooperative catalysis, while the latter planar chirality is controlled by the preinstalled axial chirality through a unique axial-to-planar diastereoinduction process. This method exploits readily available ortho-ferrocene-tethered aryl iodides (16 examples) and the bulky 2,6-disubstituted aryl bromides (14 examples) as the starting materials. Five- to seven-membered benzo-fused ferrocenes with both axial and planar chiralities (32 examples) are obtained in one step with constantly high enantioselectivities (>99% e.e.) and diastereoselectivities (>19:1 d.r.).

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-cis-tetrahydroisoquinolines (THIQs), 1,3-trans-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.

A Modular Approach for Diversity-Oriented Synthesis of 1,3-trans-Disubstituted Tetrahydroisoquinolines: Seven-Step Asymmetric Synthesis of Michellamines†B and C.

1,3-trans-Disubstituted tetrahydroisoquinoline (THIQ) is a common heterocyclic structural unit of naphthylisoquinoline alkaloids. The assembly of this structural unit is not trivial, which constitutes a substantial challenge in the total synthesis of naphthylisoquinoline alkaloids and related pharmaceuticals. Herein, we report a modular and convergent method for the rapid assembly of 1,3-trans-disubstituted THIQ frameworks through a three-component Catellani reaction and a AuI -catalyzed cyclization/reduction cascade. With widely available simple aryl iodides, aziridines and (triisopropylsilyl)acetylene as the building blocks, this method paves a practical way for the diversity-oriented synthesis of 1,3-trans-disubstituted THIQs. Based on this new method, concise syntheses of an analogue of the new drug mevidalen and four naphthylisoquinoline alkaloids have been accomplished, demonstrating the broad synthetic utility of this approach.