Highly diastereoselective entry into chiral spirooxindole-based 4-methyleneazetidines via formal [2+2] annulation reaction

We describe here a diastereoselective, DABCO-catalyzed reaction of allenoates with chiral N-tert-butanesulfinyl ketimines derived from isatin

Organocatalytic access to enantioenriched spirooxindole-based 4-methyleneazetidines

This work describes the synthesis of enantioenriched spiro compounds, incorporating the azetidine and the oxindole motifs. The preparation relies on a formal [2 + 2] annulation reaction of isatin-derived N-tert-butylsulfonyl ketimines with allenoates. The asymmetric induction is secured by an organocatalytic strategy, exploiting a bifunctional cinchona-type \uce\ub2-isocupridine-based catalyst. Some post-transformation products, including unexpected spiropyrroline and 3,3-disubstituted oxindole derivatives, are also presented

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

Optically active \uf064-amino-\uf061\uf02c\uf062-unsaturated carbonyl compounds, particularly those bearing the \uf067-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 \uf067-butenolide derivatives bearing an amine functionality. Metal complexes and organocatalysts promote efficiently asymmetric vinylogous Mannich (AVM) reactions of aldimines, affording optically active \uf064-amino-\uf061\uf02c\uf062-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

Highly Diastereoselective DABCO-catalyzed Synthesis of Spirooxindole-based 4-methyleneazetidines via Formal [2+2] Annulation Reaction

The strained four-membered ring system of azetidines occurs as a structural motif in several natural products and pharmaceutical agents.1 Despite the interest in azetidin-2-ones, in general azetidines have received much less attention compared to their lower and higher homologues, and their application in drug discovery programs is not so common, with only a few spirocyclic azetidine scaffolds proposed as new potential lead compounds.2 Our long-standing interest in the asymmetric synthesis of 3,3-disubstituted oxindoles derivatives,3 combined with the growing interest in hybrid drugs as therapeutic agents, inspired us to connect the two pharmacologically relevant moieties in a spiro arrangement. Relying on our previous experience with isatin-derived ketimines,3b we considered the formal [2+2] annulation reactions of such compounds with allenoates as a practical and direct strategy to obtain highly functionalized chiral spirooxindole-based 4-methyleneazetidines with a high level of atom-economy. Since Shi's pioneer work,4 additional examples of such [2+2] annulations were reported, both on electron-deficient aldimines and ketimines.5 However, to the best of our knowledge, no diastereoselective strategies employing chiral imines have been described for the preparation of methyleneazetidines. Herein we demonstrate the suitability of chiral, isatin-derived tert-butanesulfinyl ketimines for reaction with allenoates, applying this reaction to the synthesis of unprecedented, enantiopure spirooxindole-based 4-methyleneazetidines. Some post-transformation reactions were also performed to increase the number of useful compounds and to show the versatility of these scaffolds. Further research aimed to establish these compounds as possible lead compounds for drug discovery programs is currently underway. References: 1 A. Brandi, S. Cicchi, F. M. Cordero, Chem. Rev. 2008, 108, 3988-4035. 2 M. L\ufcthy, M. C. Wheldon, C. Haji-Cheteh, M. Atobe, P. S. Bond, P. O\u2019Brien, R. E. Hubbard, I. J. S. Fairlamb, Bioorg. Med. Chem. 2015, 23, 2680-2694. 3 (a) M. Stucchi, G. Lesma, F. Meneghetti, G. Rainoldi, A. Sacchetti, A. Silvani, J. Org. Chem. 2016, 81, 1877-1884. (b) G. Lesma, F. Meneghetti, A. Sacchetti, M. Stucchi, A. Silvani, Belstein J. Org. Chem. 2014, 10, 1383-1389. (c) A. Sacchetti, A. Silvani, F. G. Gatti, G. Lesma, T. Pilati, B. Trucchi, Org. Biomol. Chem. 2011, 9, 5515-5522. (d) G. Lesma, N. Landoni, A. Sacchetti, A. Silvani, Tetrahedron, 2010, 66, 4474-4478. (e) G. Lesma, N. Landoni, T. Pilati, A. Sacchetti, A. Silvani, J. Org. Chem. 2009, 74, 4537-4541. 4 G. L. Zhao, J. W. Huang, M. Shi, Org. Lett. 2003, 5, 4737-4739. 5 (a) L. J. Yang, S. Li, S. Wang, J. Nie, J. A. Ma, J. Org. Chem. 2014, 79, 3547-3558. (b) J. B. Denis, G. Masson, P. Retailleau, J. Zhu, Angew. Chem. Int. Ed. 2011, 50, 5356-5360. (c) B. S. Santos, A. L. Cardoso, A. Matos Beja, M. Ramos Silva, J. A. Paix\ue3o, F. Palacios, T. M. V. D. Pinho e Melo, Eur. J. Org. Chem. 2010, 17, 3249-3256

Palladium-Catalyzed Cascade to Benzoxepins by Using Vinyl-Substituted Donor-Acceptor Cyclopropanes

A palladium‐catalyzed intermolecular cascade (4+3) cyclocondensation of salicylaldehydes and vinylcyclopropanes is reported. A key feature of the reaction is the use of a phosphonate group as an acceptor moiety on the cyclopropane, exploiting its propensity to undergo olefination with aldehydes. Subsequent O‐allylation enabled the formation of a range of substituted benzoxepinsWith a novel chiral ligand, the products were obtained in generally good yield and with reasonable enantioselectivity

Palladium‐Catalyzed Cascade to Benzoxepins by Using Vinyl‐Substituted Donor–Acceptor Cyclopropanes

A palladium‐catalyzed intermolecular cascade (4+3) cyclocondensation of salicylaldehydes and vinylcyclopropanes is reported. A key feature of the reaction is the use of a phosphonate group as an acceptor moiety on the cyclopropane, exploiting its propensity to undergo olefination with aldehydes. Subsequent O‐allylation enabled the formation of a range of substituted benzoxepinsWith a novel chiral ligand, the products were obtained in generally good yield and with reasonable enantioselectivity