Enantioselective BINOL-Phosphoric Acid Organocatalyzed Vinylogous Mannich-Type Reaction Involving Isatin

Substituted oxindoles continue to be recognized as important compounds of interest for drug discovery. 2-Oxindoles, especially 3,3-disubstituted or spiro-fused, feature in a large number of natural and non-natural pharmaceutically relevant compounds [1]. Going on with our interest in the asymmetric synthesis of 3,3-disubstituted oxindoles [2], we are developing an asymmetric BINOL-derived phosphoric acid catalyzed vinylogous Mannich-type reaction [3]. Using isatin as carbonyl moiety, we are going to obtain enantiomerically enriched 3-aminooxindole butenolide derivatives. The application of such reaction to ketimines remains to date largely unexplored due to the steric challenge inherent in the stereocontrolled formation of a quaternary stereocenter consecutive with a bulky tertiary one. Reaction of trimethylsilyloxyfurans with various preformed isatin-derived imines allowed us to access a small family of highly functionalized compounds in high yields and enantiomeric excesses. To demonstrate the synthetic utility of such Mannich-type adducts, increasing the number of achievable compounds, post-transformation reactions are presently in progress. The assignment of the absolute and relative configuration through X-ray diffraction is currently underway on selected compounds, as well as computational studies aimed to explain the stereochemical outcome of this organocatalyzed process. [1] 1. Singh, G.S.; Desta, Z.Y. Chem. Rev. 2012, 112, 6104. [2] Lesma, G.; Meneghetti, F. Belstein J. Org. Chem. 2014, 10, 1383. [3] Mahalau, M.; List, B. Angew. Chem. Int. Ed. 2013, 52, 518. Bhaskara Rao V.U., Jadhav P.A., Org. Lett., 2014, 16, 648; Hayashi M., Nakamura S., Angew. Chem. Int. Ed., 2013, 52, 5557; Shy Y.H., Wang Z., Tetrahedron, 2012, 68, 3649.