Pyrrolidine-2,3,4-tricarboxylic anhydrides: I. Organocatalytic synthesis and fusion of pyrrole ring by the action of p-fluorobenzylamine

Abstract

N-Boc-glycine effectively catalyzes 1,3-dipolar cycloaddition of maleic anhydride to N-benzylidene α-amino acid esters, which leads to the formation of pyrrolidine-2,3,4-tricarboxylic anhydrides. The subsequent opening of the anhydride fragment in the adducts by the action of p-fluorobenzylamine is regioselective, and it involves recyclization to produce polysubstituted octahydropyrrolo [3,4-b]pyrroles. The newly synthesized fused pyrrolidines inhibit enzymatic activity of thrombin (factor IIA) in vitro.Consecutive and/or joint modification of the above functional groups in molecules I could lead to various complex low-molecular organic compounds. Heterocyclic anhydrides I are isostructural to cantharidin (II, R = Me) and norcantharidin (II, R = H). Cantharidin is produced as protecting agent by various beetle species, and it exhibits a broad spectrum of antitumor activity and inhibits serine/threonine protein phosphatases; the same is also typical of its synthetic analog, norcantharidin [1]. Opening of the anhydride ring in compounds II and their analogs by the action of nitrogenPolyfunctional organic compounds attract considerable interest from the viewpoint of creation of combinatorial libraries for biological screening. Pyrrolidine-2,3,4-tricarboxylic acid 3,4-anhydrides I may be regarded as promising molecular structures possessing various functional groups. Compounds like I contain three functional groups: a secondary amino group, anhydride fragment, and carboxy (ester) group. centered nucleophiles gives dicarboxylic acid monoamides or imides which show modified biological activity as compared to parent compounds [1,2]. The goal of the present work was to develop an effective procedure for the synthesis of heterocyclic anhydrides I, examine their reactions with primary amines, and test the products thus obtained for inhibitory activity toward thrombin (factor IIA).Functionalized pyrrolidines I can be synthesized by 1,3-dipolar cycloaddition of maleic anhydride to azomethine ylides A as shown in Scheme 1.