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

• Published in: Journal of organic chemistry Vol. 69; no. 24; pp. 8209 - 8218
• Main Authors: Padwa, Albert, Lee, Hyoung Ik, Rashatasakhon, Paitoon, Rose, Mickea
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.11.2004; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Cyclization; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Heterocyclic Compounds, 4 or More Rings - chemical synthesis; Indoles - chemical synthesis; Indoles - chemistry; Lactams - chemistry; Molecular Structure; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; Stereoisomerism; AZA-COPE REARRANGEMENTS; N-ACYLIMINIUM IONS; ASYMMETRIC-SYNTHESIS; ERYTHRINA ALKALOIDS; DIELS-ALDER REACTION; EFFICIENT SYNTHESIS; BIOMIMETIC ALKALOID SYNTHESES; FORMAL TOTAL-SYNTHESIS; INDOLE ALKALOIDS; OXIDATIVE RADICAL CYCLIZATION; Intramolecular reaction; Organic synthesis; Alkaloid; Catalytic reaction; Electrophilic substitution; Angular nitrogen heterocycle; Homogeneous catalysis; Aromatic compound; Tetracyclic compound; Aromatic substitution; N-Bromosuccinimide
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo048647f

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.