Noncanonical Cation−π Cyclizations of Alkylidene β-Ketoesters: Synthesis of Spiro-fused and Bridged Bicyclic Ring Systems

Abstract

Three cation−π cyclization cascades initiated at alkylidene β-ketoesters bearing pendent alkenes are described. Depending upon the alkene substitution pattern and the reaction conditions employed, it is possible to achieve selective synthesis of the three different types of products, including 1-halo-3-carbo­methoxy­cyclo­hexanes, spiro-fused tricyclic systems, and [4.3.1] bridged bicyclic ring systems. All three reactions begin with 6-endo addition of an olefin to the alkylidene β-ketoester electrophile, followed by one of three different cation capture events.

Facile generation of bridged medium-sized polycyclic systems by rhodium-catalysed intramolecular (3+2) dipolar cycloadditions

“…The readily available chiral compound 4 46 underwent a diastereoselective aldol reaction with aldehyde 5 47 followed by TIPS protection of the resulting hydroxyl group to give compound 6 . Reduction of 6 with NaBH 4 and subsequent oxidation provided 7 in 55% overall yield (20 g scale).…”

Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones

“…In parallel, we synthesized the 3,5-dimethoxyphenyl chalcone 10 (Scheme 3) by reaction of the 1-(3,5-dihydroxyphenyl)ethan-1-one 27 with methyl iodide to provide the ketone 28 [33], whose reaction with pyrimidine-5-carbaldehyde afforded the chalcone 10 (64% yield). Additionally, in this case, the α-COOCH3 chalcone was synthesized through the transformation of the ketone 28 into the methylpropionate 29 [34], and further reaction A second set of modifications involved the incorporation as ring B of different pyridines instead of the 5-pyrimidinyl of the prototype 9. To this end, the ketone 11 was reacted with different aldehydes (21)(22)(23) in the presence of Ba(OH) 2 , using a mixture of methanol and water at rt, to yield the chalcones 24-26 (Scheme 2).…”

“…In parallel, we synthesized the 3,5-dimethoxyphenyl chalcone 10 (Scheme 3) by reaction of the 1-(3,5-dihydroxyphenyl)ethan-1-one 27 with methyl iodide to provide the ketone 28 [33], whose reaction with pyrimidine-5-carbaldehyde afforded the chalcone 10 (64% yield). Additionally, in this case, the α-COOCH3 chalcone was synthesized through the transformation of the ketone 28 into the methylpropionate 29 [34], and further reaction Scheme 2. Reagents and conditions: (a) Ba(OH) 2 , methanol/water, rt, 2-7 h, 32-73% yield.…”

“…In parallel, we synthesized the 3,5-dimethoxyphenyl chalcone 10 (Scheme 3) by reaction of the 1-(3,5-dihydroxyphenyl)ethan-1-one 27 with methyl iodide to provide the ketone 28 [33], whose reaction with pyrimidine-5-carbaldehyde afforded the chalcone 10 (64% yield). Additionally, in this case, the α-COOCH 3 chalcone was synthesized through the transformation of the ketone 28 into the methylpropionate 29 [34], and further reaction of this methyl ester with pyrimidine-5-carbaldehyde afforded the α-COOCH 3 chalcone 30. On the other hand, as will be later shown in the molecular modeling studies, one of the methoxy groups of the chalcone 10 seems to be pointing towards the lower part of the NES-binding cleft that lodges the aliphatic chain of leptomycin B.…”

“…Scheme 3. Reagents and conditions: (a) as described in[33]: MeI, Cs2CO3, DMF, 80 °C, 1 h; (b) pyrimidine-5-carbaldehyde, Ba(OH)2, methanol/water, rt, 16 h, 32-64% yield; (c) as described in[34]: dimethyl carbonate, NaH, 1,4-dioxane, 70 °C, 3 h; (d) pyrimidine-5-carbaldehyde, piperidine, AcOH, 70 °C, 16 h, 39% yield; (e) (i) as described in[35]: MeI, Cs2CO3, DMF, rt, 16 h, (ii) 2-bromoethylmethyl ether, Cs2CO3, DMF, 80 °C, 1 h, 77% yield; (f) (i) as described in[35]: MeI, Cs2CO3, DMF, rt, 16 h; (ii) 3,3-dimethylallyl bromide, Cs2CO3, DMF, 80 °C, 1 h, 75% yield.…”