1,3-Dipolar Cycloaddition of 3-Chromonyl-Substituted Glycine Imino Esters with Arylidenes and in situ Diastereodivergent via Retrocycloaddition Mohammed F. Radwan, [a] Elghareeb E. Elboray,* [a, b, c] Hemat M. Dardeer, [a] Yusuke Kobayashi, [b] Takumi Furuta, [b] Shohei Hamada, [b] Toshifumi Dohi, [c] and Moustafa F. Aly* [a] ThispaperisdedicatedinmemoryoflateProf.RonaldGrigg,whopassedawayon10thJanuary2021. Abstract: 1,3-Dipolar cycloaddition through insitu generation of azomethine ylide provides a straightforward and critically important sustainable approach for access to diverse pyrroli- dine chemical space. Herein, we developed a metal-free AcOH-activated 1,3-dipolar cycloaddition protocol that per- mits the synthesis of uncommon pyrrolidine cycloadducts with excellent diastereoselectivity. The challenging substrates of 3-formylchromone, glycine ester.HCl and arylidene dipolar- ophile were reacted in the presence of AcONa, which played a dual role as a base and AcOH source, to deliver firstly endo- cycloadduct. Under prolonged reaction time at room temper- ature or heating; the endo-adduct underwent diastereodiver- gent via a sequence of retro-cycloaddition, stereomutation of the generated syn-dipole into anti-dipole and recycloaddi- tion; to furnish the scarcely known exo’-cycloadduct with high diastereodivergency. The reaction worked well with a broad range of substrates and the stereochemistry of the obtained cycloadducts was determined without ambiguity using NMR- and X-ray analysis. Experimental and theoretical DFT calculation studies were performed to support the proposed reaction mechanism and elucidate the key role of AcOH in the process which seems more beneficial than other transition metal-catalyzed processes. Introduction Pyrrolidine ring is the main constituent of proline amino acid and is identified as a privileged structure in synthetic and medicinal chemistry including natural products, pharmaceut- icals and agrochemicals (Figure 1). [1–4] The broad therapeutic applications have designated the pyrrolidine skeleton to be the most frequently used five-membered aromatic and nonaro- matic ring system found in marketed drugs. [1,5] The constrained skeleton of pyrrolidine gives proline amino acid unique conformational features to be a major target for potential molecular engineered modifications. [6a] Therefore, designing molecules with more constrained frameworks will deliver derivatives with improved potency and selectivity. [6] Substitu- tion of the pyrrolidine ring is expected to give more constrain to the ring, particularly with the construction of a quaternary stereocenter. Numerous processes have been established for the syn- thesis of various pyrrolidine derivatives. [7] Among these meth- ods, azomethine ylide generation and then [3 + 2] cycloaddition with an appropriate dipolarophile has emerged as a powerful, direct, and highly atom-economic strategy for the construction of diverse pyrrolidine skeletons with up to four adjacent stereogenic centers. [8] Several tactics including organocatalytic, metal and metal-free conditions have been developed to obtain the related pyrrolidine cycloadducts in high stereoselective fashions. Stereodivergent synthesis of pyrrolidine cycloadducts is a remarkable topic of interest with particular limitation to metal-catalyzed processes, which allow the synthesis of regio-, diastereo-, and enantio-divergent cycloadducts by simple alterations of the metal salt, ligand or by treating with base. [9] The majority of these metal-catalyzed reactions are oriented only to the selective synthesis of either endo- or exo-diaster- eomers. Whereas the other diastereomers (endo’ and exo’) are still very rare. Arai et al. used Ni(OAc) 2 /imidazoline-aminophenol combination to diverge the common synthesis of endo-adducts into the uncommon exo’-cycloadducts. [10] Whilst Huang and coworkers achieved the exo’-products via Cu(OAc) 2 /(S)-tol- BINAP catalyzed the synthesis of exo-cycloadducts followed by base promoted epimerization of C-2 centre. [11] Our previous work on the insitu generation of azomethine ylide under AcOH-catalyzed conditions showed unique reac- tivity and stereoselectivity of the 1,3-dipolar cycloaddition process (Scheme 1). [12] Similar to the well-established metal- [a] M.F.Radwan,Dr.E.E.Elboray,Dr.H.M.Dardeer,Prof.Dr.M.F.Aly Departmentofchemistry,FacultyofScience SouthValleyUniversity Qena,Egypt E-mail: e.elboray@sci.svu.edu.eg mosfaly51@yahoo.com [b] Dr. E. E. Elboray, Dr. Y. Kobayashi, Prof. Dr. T. Furuta, Dr. S. Hamada DepartmentofPharmaceuticalChemistry KyotoPharmaceuticalUniversity Kyoto607-8414,Japan [c] Dr.E.E.Elboray,Prof.Dr.T.Dohi CollegeofPharmaceuticalSciences UniversityRitsumeikanUniversity 1-1-1,Nojihigashi,KusatsuShiga525-8577,Japan Supporting information for this article is available on the WWW under https://doi.org/10.1002/asia.202300215 Research Article doi.org/10.1002/asia.202300215 www.chemasianj.org ChemAsianJ. 2023, 18, e202300215 (1 of 11) © 2023 Wiley-VCH GmbH