Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity.

A novel one-pot [3+2]-cycloaddition reaction of (E)-3-arylidene-1-phenyl-succinimides, cyclic 1,2-diketones (isatin, 5-chloro-isatin and acenaphtenequinone), and diverse α-aminoacids such as 2-phenylglycine or sarcosine is reported. The reaction provides succinimide-substituted dispiropyrrolidine derivatives with high regio- and diastereoselectivities under mild reaction conditions. The stereochemistry of these N-heterocycles has been confirmed by four X-ray diffraction studies. Several synthetized compounds show higher inhibition on acetylcholinesterase (AChE) than butyrylcholinesterase (BChE). Of the 17 synthesized compounds tested, five exhibit good AChE inhibition with IC50 of 11.42 to 22.21 µM. A molecular docking study has also been undertaken for compound 4n possessing the most potent AChE inhibitory activity, disclosing its binding to the peripheral anionic site of AChE enzymes.

Highly diastereoselective construction of novel dispiropyrrolo[2,1-a]isoquinoline derivatives via multicomponent 1,3-dipolar cycloaddition of cyclic diketones-based tetrahydroisoquinolinium N-ylides.

In the quest for new heterocyclic scaffolds exhibiting potentially biological activities for medicinal chemistry, a multicomponent 1,3-dipolar cycloaddition reaction of tetrahydroisoquinolinium N-ylides, generated in situ from cyclic diketones and isoquinoline, and (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones has been developed. This route provides workable access to dispiropyrrolo[2,1-a]isoquinoline-fused pyrrolidine-2,5-diones bearing two adjacent spiro-carbons. An unprecedented regioselectivity was observed in this 1,3-dipolar cycloaddition, leading to the construction of a novel dispirooxindole skeleton. The structure and relative stereochemistry of the spiranic adducts have been confirmed by three X-ray diffraction studies. To reinforce the observed regio- and stereoselectivity of the [3+2] cycloaddition, calculations using the DFT approach at the B3LYP/6-31G(d,p) level were carried out. It was found that this reaction affords the kinetic products.

Regio- and Stereoselective Synthesis of Spiropyrrolizidines and Piperazines through Azomethine Ylide Cycloaddition Reaction.

A series of original spiropyrrolizidine derivatives has been prepared by a one-pot three-component [3 + 2] cycloaddition reaction of (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones, l-proline, and the cyclic ketones 1H-indole-2,3-dione (isatin), indenoquinoxaline-11-one and acenaphthenequinone. We disclose an unprecedented isomerization of some spiroadducts leading to a new family of spirooxindolepyrrolizidines. Furthermore, these cycloadducts underwent retro-1,3-dipolar cycloaddition yielding unexpected regioisomers. Upon treatment of the dipolarophiles with in situ generated azomethine ylides from l-proline or acenaphthenequinone, formation of spiroadducts and unusual polycyclic fused piperazines through a stepwise [3 + 3] cycloaddition pathway is observed. The stereochemistry of these N-heterocycles has been confirmed by several X-ray diffraction studies. Some of these compounds exhibit extensive hydrogen bonding in the crystalline state. To enlighten the observed regio- and stereoselectivity of the [3 + 2] cycloaddition, calculations using the DFT approach at the B3LYP/6-31G(d,p) level were carried out. It was found that this reaction is under kinetic control.