1,3-Dipolar cycloaddition of isatin-derived azomethine ylides with 2H- azirines: stereoselective synthesis of 1,3- diazaspiro[bicyclo[3.1.0]hexane]oxindoles Anikó Angyal a,b , András Demjén a , Veronika Harmat c , János Wölfling b , László G. Puskás a , Iván Kanizsai a, * a AVIDIN Ltd., Alsó kikötő sor 11/D, Szeged, H-6726, Hungary; b Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720, Szeged, Hungary; c Eötvös Loránd University, Institute of Chemistry, Laboratory of Strucutral Chemistry and Biology, Pázmány P. sétány 1/A, H-1117, Budapest, Hungary. Tel.: +36-62/202107; fax: +36-62/202108; e-mail: i.kanizsai@avidinbiotech.com Introduction Spiroheterocycles containing oxindole scaffold are regarded as a growing field of interest due to their highly pronounced biological and pharmaceutical activity, 1 particularly the spiro-oxindolopyrrolidine framework, which constitutes the core unit of numerous alkaloids and pharmaceutics. 2 Among the known synthetic strategies, 3 the 1,3- dipolar cycloaddition (1,3-DC) of isatin-derived azomethine ylides with dipolarophiles has been proved to be the main tool for the construction of spirocyclic oxindoles. 4 In terms of dipolarophiles, a considerable amount of alkenes 5 and alkynes 6 have been subjected to 1,3-DC leading to the formation of various spiro-oxindolopyrrolidines and - pyrrolines. In contrast, the assembly of analogous spiro- oxindoloimidazolidines by the utilization of imines as dipolarophiles is scarcely explored. 7-9 Additionally, the few reported efforts mainly focus on the synthesis of dispirooxindole derivatives, exploiting the reaction of an electron-deficient isatin-derived ketimine with an azomethine ylide generated from isatin and amines/α- aminoacids (Scheme 1a). 7 Other approaches involve a different route for the in situ formation of the azomethine ylide, employing diazooxindoles, amines and aldehydes as starting materials. 8 An alternative protocol, established recently by Shi’s group, relies on the three-component reaction of isatin-derived imines, amino-ester and aldehydes via phosphoric acid catalyzed 1,3-DC and enables the construction of the spiro-oxindoloimidazolidine scaffold with a different regiochemical outcome (Scheme 1b). 9 Although the scope of 1,3-DC in the synthesis of spirocyclic oxindoles has been broadened by various dipolarophiles, to the best of our knowledge, the utilization of 2H-azirines as dipolarophiles in cycloaddition reactions of isatin-derived azomethine ylides have not been studied yet. Scheme 1. Synthesis of spiro-oxindoloimidazolidines As a continuation of our interest in constructing aziridine-based heterocycles, ref we report here the first synthesis of 1,3-diazaspiro[bicyclo[3.1.0]hexane]oxindole framework through the one-pot three-component reaction of isatins, α-amino acids and 2H-azirines in a diastereo- and regioselective manner (Scheme 1c). Results and discussion At the outset of the study, the feasibility of the azirine-based 1,3-DC was investigated by performing the model three component reaction of isatin (1a), D-(-)-2- phenylglycine (2a) and (±)-ethyl 3-methyl-2H-azirine-2- carboxylate (3a) in polar solvents at room temperature (Table 1, entries 1‒5). To our delight, the cycloaddition proceeded smoothly in DMSO and led to desired endo-