C-H functionalization of 2-alkyl tryptamines: direct assembly of azepino[4,5-]indoles and total synthesis of ngouniensines.

The Pictet-Spengler type condensation of tryptamine derivatives and aldehydes or ketones is a classic reaction, and has been previously applied to assemble indole-annulated 5-, 6- and 8-membered heterocyclic rings. In this work, we further expand the synthetic scope of this reaction to the 7-membered azepino[4,5-]indole skeleton through the direct C-H functionalization of 2-alkyl tryptamines, in which the non-activated methylene group participates in a 7-membered ring formation with aldehydes. By combining this unprecedented ring-forming process with a second C-H olefination at the same carbon, the concise total synthesis of natural products ngouniensines is achieved, demonstrating the synthetic potential of the developed chemistry in simplifying retrosynthetic disconnections.