Sun Y, Chen P, Zhang D, Baunach M, Hertweck C, Li A * Shanghai Institute of Organic
Chemistry, P. R. of China and Leibniz Institute for Natural Product Research and Infection
Biology, Jena, Germany
Bioinspired Total Synthesis of Sespenine.
Angew. Chem. Int. Ed. 2014;
53: 9012-9016
Key words
sespenine - indole sesquiterpenoids - aza-Prins recation - Friedel–Crafts reaction
- radical cascades - Nysted olefination
Significance
Sespenine is a rare and architecturally complex indole sesquiterpenoid that was isolated
from an endophyte in 2011. Biosynthetically, sespenine may be formed from a structurally
simpler indole precursor by oxidation of the indole C3 position followed by a cationic
cascade involving an aza-Prins/Friedel–Crafts reaction and a subsequent fragmentation.
Ang Li and co-workers now report the first total synthesis of sespenine. Their strategy
relies on a titanium-mediated radical cascade for quick access to a key intermediate
and an elegant implementation of the cationic cascade described above.
Comment
The synthesis commences with acetate A, which is converted into α,β-epoxy ester B in seven steps. Titanium(III)-mediated radical cyclization of B furnishes allylic alcohol C, which is oxidized and protected to give enone D. Key intermediate G is prepared via 1,4-addition of indole E and Nysted olefination using reagent F. Oxidation of G with Oxone affords H as a 2.7:1 mixture of epimers. The major and desired product undergoes the crucial
sequence of aza-Prins/Friedel–Crafts reaction and fragmentation to give J, presumably via the intermediacy of I. Two additional steps then complete the synthesis of sespenine.
