Organocatalytic Vinylogous Mannich Reaction of Silyloxy Furan with Isatin-derived Benzhydryl-Ketimines

Optically active -amino--unsaturated carbonyl compounds, particularly those bearing the -butenolide skeleton, are receiving attention due to their broad application in the synthesis of biologically active compounds. The vinylogous Mannich-type reaction of imines with a dienolate equivalent, such as trimethylsiloxyfuran (TMSOF), is a useful mean to prepare -butenolide derivatives bearing an amine functionality. Metal complexes and organocatalysts promote efficiently asymmetric vinylogous Mannich (AVM) reactions of aldimines, affording optically active -amino--unsaturated carbonyl compounds in high yields and enantiomeric excesses. Application of the AVM reaction to ketimines is more challenging, due to the lower reactivity of ketimines compared with aldimines and to the steric challenge inherent in the stereocontrolled formation of a quaternary stereocenter consecutive with a bulky tertiary one. As part of our interest in the asymmetric synthesis of 3,3-disubstituted oxindole derivatives and related spiro-compounds, herein we report the BINOL-derived phosphoric acid-catalyzed asymmetric synthesis of quaternary 3-aminooxindole butenolides via a AVM reaction, consisting in the enantioselective addition of TMSOF to isatin-derived ketimines. We began our investigation using the unprecedented N-diphenylmethyl ketimine 1a (R1 = Bn, R2 = H, Scheme). Reaction of 1a with TMSOF, initially carried out in THF at room temperature, in the presence of the protic cosolvent MeOH, afforded the corresponding 3-aminooxindole butenolide 3a in 84% yield. From subsequent reaction conditions screening, the temperature proved to be a key parameter for the asymmetric induction. Carrying out the reaction at - 40 oC, with catalyst 2a, both anti and syn diastereoisomers could be recovered in almost equal quantities (80% overall yield), showing excellent enantioselectivities (ee anti up to 90%, ee syn up to 92%). The substrate scope of the AVM reaction has then been surveyed, by evaluating differently N-substituted isatins and the presence of substituents at 5- or 6-position of the isatin nucleus, as well as the potentiality of post-transformation reactions. The assignment of the absolute and relative configuration is currently underway on selected compounds, as well as computational studies aimed to explain the stereochemical outcome of this organocatalyzed process. (a) Lesma, G.; Meneghetti, F.; Sacchetti, A.; Stucchi, M.; Silvani, A. Belstein J. Org. Chem. 2014, 10, 1383-1389. (b) Sacchetti, A.; Silvani, A.; Gatti, F. G.; Lesma, G.; Pilati, T.; Trucchi, B. Org. Biomol. Chem. 2011, 9, 5515-5522. (c) Lesma, G.; Landoni, N.; Sacchetti, A.; Silvani, A. Tetrahedron 2010, 66, 4474-4478. (d) Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009, 74, 4537-4541.