Nitropyrrolins A-E, cytotoxic farnesyl-α-nitropyrroles from a marine-derived bacterium within the actinomycete family Streptomycetaceae.

Five new farnesyl-α-nitropyrroles, nitropyrrolins A-E (1-5), were isolated from the saline culture of the marine actinomycete strain CNQ-509. This strain belongs to the "MAR4" group of marine actinomycetes, which have been demonstrated to be a rich source of hybrid isoprenoid secondary metabolites. The structures of the nitropyrrolins are composed of α-nitropyrroles with functionalized farnesyl groups at the C-4 position. These compounds are the first examples of naturally occurring terpenyl-α-nitropyrroles. Chemical modifications, including one-step acetonide formation from an epoxide, and application of the modified Mosher method provided the full stereostructures and absolute configurations of these compounds. Several of the nitropyrrolins, nitropyrrolin D in particular, are cytotoxic toward HCT-116 human colon carcinoma cells, but show weak to little antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).

Acid-promoted cyclization reactions of tetrahydroindolinones. Model studies for possible application in a synthesis of selaginoidine.

The synthesis of various substituted bicyclic lactams by an acid-induced Pictet-Spengler reaction of tetrahydroindolinones bearing tethered heteroaromatic rings is presented. The outcome of the cyclization depends on the position of the furan tether, tether length, nature of the tethered heteroaromatic ring, and the substituent group present on the 5-position of the tethered heteroaryl group. A one-pot procedure was developed to efficiently prepare tetrahydroindolinones containing tethered furan rings. In a typical example, the reaction of furanyl azide 26 with n-Bu3P delivered iminophosphorane 27, which was allowed to react with a 1-alkyl-(2-oxocyclohexyl)acetic acid to provide the desired furanyl-substituted tetrahydroindolinone system 29. Treatment of 29 with trifluoroacetic acid afforded the tetracyclic lactam skeleton 30 found in the alkaloid (+/-)-selaginoidine.

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.

Triflic anhydride mediated cyclization of 5-hydroxy-substituted pyrrolidinones for the preparation of alpha-trifluoromethylsulfonamido furans.

The reaction of alpha-angelica lactone with alkylamines under aqueous conditions afforded 5-hydroxy-5-methylpyrrolidinones in high yield. When the reaction was carried out under anhydrous conditions, the only products obtained were the corresponding 4-oxopentanoic acid amides. Treatment of either class of compound with triflic anhydride (Tf(2)O) in pyridine resulted in the formation of various substituted sulfonamidofurans. The suggested mechanism involves initial formation of an iminium ion which is subsequently transformed into a transient imino triflate. Cyclization of the highly electrophilic imine onto the oxygen atom of the adjacent carbonyl group generates an imino dihydrofuran intermediate. This species reacts further with another equivalent of Tf(2)O to give the observed product. The nature of the Lewis acid used was found to affect the outcome of the cyclization reaction. In certain cases, the sulfonamide furan was utilized as a cycloaddition substrate for the synthesis of indolines and related heterocyclic systems.

Several convenient methods for the synthesis of 2-amido substituted furans.

Several new methods for the synthesis of differently substituted 2-amidofurans are described. The thermolysis of furan-2-carbonyl azide results in a Curtius rearrangement and the resulting furanyl isocyanate was trapped with various organometallic reagents. A second method consists of a C-N cross-coupling reaction of a bromo-substituted furan with various amides, carbamates, and lactams. The CuI-catalyzed cross-coupling reaction between furanyl bromides and amides furnished 2- and 3-substituted amidofurans in 45-95% yield. The third protocol used involves the reaction of cyclic carbinol amides with triflic anhydride. The reaction proceeds under very mild conditions to provide alpha-(trifluoromethyl)sulfonamido-substituted furans in high yield. The resulting iminium ion derived from the reaction of the hydroxy pyrrolidinone with Tf(2)O undergoes a facile ring opening as a consequence of the adjacent hydroxyl group to produce an imino triflate intermediate. Subsequent cyclization of this highly electrophilic imine with the oxygen atom of the adjacent carbonyl group leads to an imino dihydrofuran that reacts further with another equivalent of Tf(2)O to give the observed product.