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

Abstract

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.

Spiropyrrolizidine and piperazine derivatives: Synthesis and evaluation on kras expression levels in human colon cancer cells

“…The VLA9 (7) sample contained 3 products (6.6, 7.6 and 9.1 min) and the presence of 3. The potential for the creation of three spiropyrrolizidine isomers in the 1,3-dipolar cycloaddition was previously reported by Haddad et al 77 The azomethine ylide formation between 4 and 5 can interconvert between the W-shape and the S-shape during the in situ reaction (Figure. 2.2.3.1).…”

“…The formation of UNBC152 (7) was the result of a 1,3-dipolar cycloaddition reaction between an azomethine ylide (6) and (2E)-2-(2-bromobenzylidine)-1-indanone (3), which is a popular synthetic route towards the regio-and stereoselective formation of 5-membered ring heterocycles. 77 The synthesis began with a reaction between ʟ-proline ( The formation of the azomethine ylide is key to the success of the 1,3-dipolar cycloaddition. Once generated, it reacts with (2E)-2-(2-bromobenzylidene)-1-indanone (3), as shown in Figure. 2.2.2.2., to form UNBC152 (7) in a concerted fashion.…”

“…This finding was not congruent with the report by Haddad, who indicated that only two fused dispiropiperazines will form from the dimerization reaction. 77 Although it is true that there would be steric hinderance between the naphthalene ring and the pyrrolidine, making the formation of 8ʹ and 9ʹ unfavorable, this does not mean the regioisomers are impossible to form in small quantity under different reaction conditions (Figure. Three column purifications were performed and a total of 686 mg of crude material was processed. Since the 1 ethyl acetate: 2 hexanes system was able to separate a yellow and an orange compound on TLC, the system was then adapted for column purification (Figure. The low percent yield after this step was not surprising considering there were multiple other peaks in the HPLC chromatogram of VLB133 (8/9, Figure. were seen from the HPLC traces of VLB165-1, VLB159-1, VLB188-1 and VLB189-1 ( Figure. 2.2.6.7).…”

“…However, as reported by Haddad et al in 2015, two ylide intermediates can cyclize together to form the fused piperazines 8 and 9 as side-products of the main 1,3-dipolar cycloaddition reaction. 77 Originally, 8/9 (VLA25) was synthesized as a control to test side-by-side with UNBC152-3 (7). At the initial stages of the project, HPLC-MS was not available, and I had no access to higher detailed analyses.…”

“…Creation of the third regioisomer was hypothesized to be due to a retro-1,3-dipolar cycloaddition and subsequent cycloreversion. 77 Since VLA9 (7) contained three peaks of the 534 mass, it was hypothesized that main two regioisomers were formed through the main reaction. The third product would then be formed by the cycloreversion mechanism.…”