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. Lüthy, M. C. Wheldon, C. Haji-Cheteh, M. Atobe, P. S. Bond, P. O’Brien, 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. Paixão, F. Palacios, T. M. V. D. Pinho e Melo, Eur. J. Org. Chem. 2010, 17, 3249-3256.
Highly Diastereoselective DABCO-catalyzed Synthesis of Spirooxindole-based 4-methyleneazetidines via Formal [2+2] Annulation Reaction / G. Rainoldi, M. Faltracco, L. Lo Presti, A. Silvani, G. Lesma. ((Intervento presentato al convegno International Symposium on Emerging Frontiers in Organic Synthesis tenutosi a London nel 2016.
|Titolo:||Highly Diastereoselective DABCO-catalyzed Synthesis of Spirooxindole-based 4-methyleneazetidines via Formal [2+2] Annulation Reaction|
|Data di pubblicazione:||17-ott-2016|
|Parole Chiave:||Diasteroselective Synthesis; Spirooxindole; Organocatalysis|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Enti collegati al convegno:||Royal Society of Chemistry|
|Citazione:||Highly Diastereoselective DABCO-catalyzed Synthesis of Spirooxindole-based 4-methyleneazetidines via Formal [2+2] Annulation Reaction / G. Rainoldi, M. Faltracco, L. Lo Presti, A. Silvani, G. Lesma. ((Intervento presentato al convegno International Symposium on Emerging Frontiers in Organic Synthesis tenutosi a London nel 2016.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|