Electrophilic-Induced Cyclization Reaction of Hexahydroindolinone Derivatives and Its Application toward the Synthesis of (±)-Erysotramidine

A convenient synthesis of variously substituted octahydroindolo[7a,1a]-isoquinolinones has been
achieved by an acid-induced cyclization of hexahydroindolinones bearing tethered phenethyl groups.
The formation of a single lactam diastereomer is the result of the stereoelectronic preference for
axial attack by the aromatic ring onto the initially formed N-acyliminium ion from the least hindered
side. Additional experiments showed that a variety of hexahydroindolinones containing tethered
π-bonds undergo a related acid-induced cyclization reaction. Treatment of the 3-methylbut-3-enyl-substituted hexahydroindolinone with acid furnished a 3:1 mixture of isomeric octahydropyrido[2,1-i]indolinones in near-quantitative yield. Interestingly, cyclization of the closely related 1-(3-methoxybut-3-enyl)-substituted hexahydroindolin-one afforded a pyrrolo[3,2,1-ij]quinolinone as the
exclusive product. With this system, initial protonation takes place on the more nucleophilic enol
ether π-bond and the resulting carbonium ion undergoes a subsequent cyclization with the enamido
π-bond to give the observed product. The electrophilic promoted cyclizations were extended to include
the related hexahydro[1]pyrindinone and 1H-quinolinone systems. An NBS-promoted intramolecular
electrophilic aromatic substitution reaction of 1-[2-(3,4-dimethoxyphenyl)ethyl]-1,4,5,6-tetrahydroindolinone was used to assemble the tetracyclic core of the erythrinone skeleton. The resulting
cyclized product was transformed into (±)-erysotramidine in three additional steps.