One-pot synthesis of conformationally restricted spirooxindoles. Martha S. Morales-Ríos, Daphne E. González-Juárez, Ernesto Rivera-Becerril, Oscar R. Suárez-Castillo, Pedro Joseph-Nathan. DOI: http://dx.doi.org/10.1016/j.tet.2007.05.009
Diastereomeric three-, five- and six-membered spirocycloalkyloxindoles were successfully synthesized in a rapid and convenient manner from readily accessible starting materials in moderate to high yields using 1-methyl-3-acetonitriloxindole after a one-pot base-mediated double-alkylation strategy. It was found that the diastereoselection is dependent on the reaction conditions and the spirocycloalkyl ring size, with the 3R?,8R? diastereomers being thermodynamically favored under the basic reaction conditions for three- and five-membered rings, and the 3R?,8S? diastereomer in the case of six-membered rings, as predicted by DFT calculations. The relative stereochemistry was supported by 2D NMR spectra and X-ray crystal structural analysis. The conformational rigidity of the spirocycloalkyloxindoles in solution was established based on NMR experimental and theoretical DFT approaches.