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A Facile Three-Step Synthetic Pathway to Fused Bicyclic Hydantoins Using Selenocyclization Step
Published: 31 October 2013 by MDPI in The 17th International Electronic Conference on Synthetic Organic Chemistry session General Organic Synthesis
Abstract: Sequential 5-alkenyl hydantoin and pyrrolidine ring-forming reactions have been applied in the synthesis of conformationally constrained fused bicyclic scaffold. These novel compounds share the structural complexity characteristic of certain alcaloid natural products and represent a source of chemical diversity that complements more traditional classes of heterocyclic compounds of interest as potential pharmaceutical agents. They are assembled in only three-step reaction sequence from two variable building blocks (readily available β-ketoesters and alkenyl halides) by combining Bucherer-Bergs reaction with a final selenium-promoted intramolecular cyclization as a key step. Chemoselectivity of bicyclic hydantoin formation is strongly influenced by experimental factors such as the solvent and the use of additives. The reaction is regiospecific giving only five-membered fused bicyclic hydantoins in good to excellent yields stemming from the nucleophilic attack of the nitrogen atom to cyclic selenuranium ion intermediate during the cyclization step. Formation of this sole regioisomer proceed via favorable 5-exo-trig ring closure process. The separable diastereomeric mixture are obtained. The products with bridgehead substituents and phenylseleno groups in cis relationships were formed predominantly. The reaction tolerates a variety of substitution on double bond. Furthermore, the presence of substituents in C-5 and N-3 position open up capability of generating a broad structural diversity. This methodology would be extended to access six-membered ring systems.
Keywords: hydantoins, selenocyclization, ketoesters, alkenyl halides,