PAPER: Improvement of TADDOLate-TiCl2-catalyzed 1,3-dipolar nitrone cycloaddition reactions by substitution of the oxazolidinone auxiliary of the alkene with succinimide

Jensen, K. B.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A.

J. Org. Chem. 1997, 62, 2471–2477.

Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark


A significant improvement of metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions of acyclic nitrones with alpha,beta-unsaturated carbonyl compounds is described using succinimide as a new auxiliary for the alpha,beta-unsaturated carbonyl moiety. In the absence of a catalyst, N-crotonoylsuccinimide reacts with C,N-diphenylnitrone to give the endo-isoxazolidine, whereas in the presence of 10 mol % TiCl(2)(i-PrO)(2) the exo-product is obtained. Four different TiCl(2)-TADDOLate complexes have been tested as catalysts for the 1,3-dipolar cycloaddition reactions, and the most successful catalyst was applied (5 mol %) in a series of reactions between two different alkenoylsuccinimides and three different nitrones. The crude products containing an N-acylsuccinimide moiety were converted directly into the corresponding carboxamides upon treatment with hydrazine. The 1,3-dipolar cycloaddition reactions proceed with a high degree of exo-selectivity, often >90% de, which is an improvement compared with previous experiments performed using the oxazolidinone auxiliary for the alkenoyl moiety. Furthermore, the enantioselectivities are also improved compared with previous work, and ee up to 73% is obtained, which is the highest ee found for these metal-catalyzed exo-selective 1,3-dipolar cycloaddition reactions. The ee can be improved to >90% by recrystallization. The absolute structure of the 1,3-dipolar cycloaddition adduct is determined on the basis of the X-ray crystal structure of a compound with a known configuration. On the basis of this knowledge of the absolute structure of the product the mechanism of the reaction is briefly discussed.

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