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

Abstract

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 pi-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 pi-bond and the resulting carbonium ion undergoes a subsequent cyclization with the enamido pi-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.

Scaffold Diversity from N-Acyliminium Ions

“…Among numerous methods for assembly of the erythrinane tetracyclic core, , a two-step sequence comprises ketone alkylation with N -substituted iodoacetamides to give hydroxyl lactam substrates 304 , 307 , and 310 , followed by NAI cyclization to give tetracyclic scaffolds, such as compounds 305 , 308 , and furan-fused compounds 311 , which Padwa and co-workers have studied extensively (Scheme ). , …”

β-Phenylethylamines and the isoquinoline alkaloids

“…Allylic oxidation of 208a by selenium dioxide and formic acid gave the formate ester 208b, which was converted into the alcohol 208c and then methylated to (±)-erysotramidine 209. 133 In an alternative approach, the simple erythrinanes 212a and 212b were synthesised in a one-step process by treating homoveratrylamine and homopiperonylamine respectively with trimethylaluminium, followed by the enol acetate of the ketoester 204b, the process being represented as a domino reaction proceeding through 210 and 211. 134 Other, stepwise, routes to the erythinane skeleton have also been reported.…”

Intramolecular Acylal Cyclisation (IAC) as an Efficient Synthetic Strategy towards the Total Synthesis of Erythrina Alkaloid Derivatives

“…[6,7] Nearly all methods focus on one of two routes to generate the three aliphatic rings, either via a single cyclisation, or via a simultaneous tandem cyclisation approach. [7][8] However, despite the reported potent biological activities, there has been a surprising lack reports on structural variation of the tetracyclic core.…”

“…[5] All members of the Erythrina family possess a distinctive tetracyclic spironamine core and can be classified by variations of the D ring, into three sub-classes with aromatic, heteroaromatic or unsaturated lactone types as shown ( Figure 1). [6] As a result of their potent biological activity and challenging structural features, the synthesis of the Erythrina alkaloid core has attracted significant attention over a number of years via a variety of approaches, which have included radical and Pummerer mediated syntheses, intramolecular condensation and Diels-Alder reactions to name but a few. [6,7] Nearly all methods focus on one of two routes to generate the three aliphatic rings, either via a single cyclisation, or via a simultaneous tandem cyclisation approach.…”

“…[6] As a result of their potent biological activity and challenging structural features, the synthesis of the Erythrina alkaloid core has attracted significant attention over a number of years via a variety of approaches, which have included radical and Pummerer mediated syntheses, intramolecular condensation and Diels-Alder reactions to name but a few. [6,7] Nearly all methods focus on one of two routes to generate the three aliphatic rings, either via a single cyclisation, or via a simultaneous tandem cyclisation approach. [7][8] However, despite the reported potent biological activities, there has been a surprising lack reports on structural variation of the tetracyclic core.…”