New strategies for the synthesis of azepine-containing alkaloids

Abstract

The Stemona alkaloids are an important family of natural products which have received attention due to their unique chemical structure and important biological properties. The stemona family members contain the 4-azaazulene substructure (1): stenine[,] stemoamide[,] croomine[,] stemonamide[,] parvistemoline[],-- The importance of the 4-azaazulene ring system has attracted the attention of many synthetic groups in recent years. We have developed a concise approach to functionalized azaazulene systems which employs an intramolecular asymmetric Heck reaction (AHR) of an endocyclic enamide as the key bond-forming step. The enamide Heck precursors are prepared by in situ acylation of the corresponding 7-membered imine with (Z)-3-bromopropenoyl chloride. Imines of this type are generated by deprotection of readily available N-formyl enamides with Grignard reagents. [ ]-- Stenine is a member of the stenine group of Stemona alkaloids which has been of interest to synthetic chemists in recent years. To date, three total syntheses have been completed by Chen, Wipf and Morimoto. Our synthetic strategy involves a Diels-Alder cyclization between a fumarate ester and a diene of type 2. Model studies were conducted and it was found that for R = H and Pr a single isomer (3) was obtained in moderate to good yield (51-87%). This route also allows for the possibility of an asymmetric synthesis with the use of chiral auxilaries (R₂ = R*). Diels-Alder cyclization of diene 2 (R = H) with N-phenylmaleimide, unexpectedly led to the exo product, which may be the result of thermodynamic equilibration via epimerization. [ ]--