2,3-Bis(phenylsulfonyl)-1,3-butadiene as a reagent for the synthesis of the azatricyclic core of (+/-)-halichlorine.

An efficient stereocontrolled route to the azatricyclic core of an advanced halichlorine intermediate is described. Reaction of the oxime derived from 2-(oxo-cyclopentyl)acetic acid ethyl ester with 2,3-bis(phenylsulfonyl)-1,3-butadiene gives rise to a 7-oxa-1-azanorbornane cycloadduct in high yield. The formation of the bicyclic isoxazolidine arises from conjugate addition of the oxime onto the diene to afford a transient nitrone that then undergoes an intramolecular dipolar cycloaddition. Treatment of the cycloadduct with 5% Na/Hg results in reductive nitrogen-oxygen bond cleavage to furnish a spirocyclic piperidinone, which was further elaborated to an advanced intermediate employed in an earlier synthesis of halichlorine.

Application of cross-conjugated heteroaromatic betaines to the synthesis of the schizozygane alkaloid (+/-)-strempeliopine.

An efficient stereocontrolled route to the isoschizozygane alkaloid core has been developed utilizing an intramolecular 1,4-dipolar cycloaddition of a cross-conjugated heteroaromatic betaine. The resulting cycloadduct undergoes loss of COS, and further reduction delivers a 5a-azaacenaphthylene intermediate that was transformed into the isoschizozygane skeleton upon treatment with acid. A variation of this tactic was then employed for a synthesis of the hexacyclic framework of the shizozygane alkaloid (+/-)-strempeliopine. The key step of the synthesis corresponds to an intramolecular 1,4-dipolar cycloaddition of a heteroaromatic betaine across a tethered 4-((2-nitrophenyl)but-3-enyl) side chain. Catalytic reduction of the nitro group followed by reaction with NBS resulted in the formation of the required pentacyclic indoline framework of the target alkaloid. Closure of the final ring of the shizozygane skeleton was carried using an oxidative cyclization.

An approach to the isoschizozygane alkaloid core using a 1,4-dipolar cycloaddition of a cross-conjugated heteroaromatic betaine.

[reaction: see text] A new strategy for the synthesis of the isoschizozygane alkaloid core has been developed that is based on a 1,4-dipolar cycloaddition reaction of a cross-conjugated heteroaromatic betaine. The resulting cycloadduct undergoes loss of COS, and further reduction delivers a 5a-aza-acenaphthylene intermediate that was transformed into the isoschizozygane skeleton upon treatment with acid.

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 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.

Efficient synthesis of (+/-)-erysotramidine using an NBS-promoted cyclization reaction of a hexahydroindolinone derivative.

An NBS-promoted intramolecular electrophilic aromatic substitution reaction of a hexahydroindolinone derivative was used to assemble the tetracyclic core of the erythrinane skeleton. The resulting cyclized product was transformed into (+/-)-erysotramidine in three additional steps. The cyclization reaction is also successful using variously substituted aryl and furanyl bicyclic lactams under acidic conditions. [reaction: see text]

Synthetic studies toward sarain A. Formation of the western macrocyclic ring.

Starting with the tricyclic core 2b, annulation to form the 13-membered western ring of sarain A has been achieved to afford the macrocycle 30a by initial construction of the sterically congested quaternary center at C-3, followed by elaboration of the C-3 side-chain and ring-closing olefin metathesis. Also included is a parallel conversion of tricycle 2c to macrocycle 30b containing a functionalized side-chain at N-1 suitable for attachment of the eastern macrocyclic ring.

Radical fragmentation of omega-bromoalkyl cyclobutanones. A modular approach to eight-membered carbocycles.

[reaction: see text] An eight-membered ring was conveniently appended onto a cycloalkene carboxylate by employing a facile radical cyclization-fragmentation reaction of an omega-bromoalkyl spirocyclobutanone, which was readily accessible by the Kulinkovich cyclopropanation and subsequent electrophilic addition to a 3-bromoalkyl acetal.