Asymmetric total synthesis of kopsia alkaloids

kopsia indole alkaloids are isolated from various Kopsia (Apocynaceae) species, which are mainly distributed in Southeast Asia, India, and China and have been used to treat rheumatoid arthritis, tonsillitis, pharyngitis, and edema as a folk medicine. Their impressive types of biological activity and unique cage-like polycyclic skeleton have piqued the interest of synthetic community, and Magnus, MacMillan, Ma and Qin groups et al have achieved total synthesis of kopsia alkaloids.

Dawei Ma group from Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences has focused on total synthesis of kopsia alkaloids for several years. In 2013, they accomplished the first asymmetric total synthesis of N-decarbomethoxymethyl chanofruticosinate with iodine-mediated oxidative coupling of indole (Angew. Chem., Int. Ed. 2013, 52, 12988).

Recently, Ma group has finished three kopisa alkaloids on the basis of organocatalytic asymmetric Michael addition (Angew.Chem. Int. Ed. 2018, 57, 10207.). Obviously, In terms of the synthetic challenge, these alkaloids feature a rigid cage-like system as well as multiple all-carbon quaternary stereocenters, the construction of which is considered to be one of the most difficult challenges in synthetic organic chemistry. The 3,3-disubstituted carbazolones with C20 quaternary stereocenter have been well recognized as valuable building blocks for assembling Kopia indole alkaloids while they behave as less active vinylogous amide and their assembling was full of challenge. Until now, asymmetric synthesis of these chiral synthons was only accomplished by enantioselective Pd-catalyzed decarboxylative allylation of racemic-keto esters by Lupton and Shao groups simultaneously. However, it needed expensive palladium catalyst and ligand with strict reaction condition. To solve this problem, Ma group has discovered a modified Takemoto thiourea catalyst enabling formation all-carbon quaternary stereocenter in high yield with excellent enantioselectivity via efficient Michael addition of carbozolones with 2-chloroacrylonitrile. Subsequently, a Mn(III)-mediated oxidative cyclization was developed to install the cage-like core architecture. Three kopsia alkaloids (5,22-dioxokopsane, kopsinidine C and dimethoxycarbonyl-kopsin) have been accomplished by late stage SmI2-mediated reductive coupling and ketol rearrangement. The present work provides a new strategy to asymmetric total synthesis of kopsia alkaloids and gives an alternative method to construct the indole C3 quaternary stereocenter.


These projects were sponsored by Chinese Academy of Sciences and National Natural Science Foundation of China.

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