1,721,225 research outputs found
Organocatalytic Vinylogous Mannich Reaction of Silyloxy Furan with Isatin-derived Benzhydryl-Ketimines
No full textOptically 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
Highly Diastereoselective DABCO-catalyzed Synthesis of Spirooxindole-based 4-methyleneazetidines via Formal [2+2] Annulation Reaction
No full textThe 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
Joining MCRs, Drug Discovery and Organocatalysis: Synthesis of Novel 3,3-Spirooxindoles Fused with Thiazolidines as New Potentially Bioactive Molecules
No full text2-Oxindoles, especially 3,3-disubstituted or spiro-fused derivatives, are recognized as highly relevant compounds for drug discovery. In particular, a great interest appeared towards oxindole-based thiazolidine compounds1 as antitumor agents, for the inhibition of the p53-MDM2 protein-protein interaction.
As part of our interest2 in multicomponent reactions (MCRs), we turned our attention to the almost unexplored Asinger reaction3 to form a thiazoline ring fused to the oxindole scaffold. Subsequently, this intermediate was subjected to a Joullié-Ugi 3-CR to give the target products in a highly efficient sequence. This combination of two sequential MCRs allowed us to synthesize a highly diverse library of spiro[indoline-3,2'-thiazolidin]-2-one derivatives.
Finally, to enhance our work, we are developing an asymmetric organocatalytic approach for the synthesis of Asinger intermediates.
References
1 Bertamino A.; Soprano M.; Musella S.; Rusciano M.R.; Sala M.; Vernieri E.; Di Sarno V.; Limatola A.; Carotenuto A.; Cosconati S.; Grieco P.; Novellino E.; Illario M.; Campiglia P.; Gomez-Monterrey I. J. Med. Chem., 2013, 56, 5407-5421.
2 Stucchi M.; Lesma G.; Meneghetti F.; Rainoldi G.; Sacchetti A.; Silvani A. J. Org. Chem., 2016, 81, 1877-1884.
3 Asinger F. Angew. Chem., 1956, 68, 377
Joining Drug Discovery and MCRs: New Spiro[indoline-3,2'-thiazolidin]-2-one Derivatives as Potentially Bioactive Anticancer Compounds
No full text2-Oxindoles, especially 3,3-disubstituted and spiro-fused derivatives, are widely recognized as highly relevant compounds for drug discovery. In particular, spirooxindole-fused thiazolidines have recently aroused great interest as promising anticancer agents, acting by inhibition of the p53-MDM2 protein-protein interaction.
1. As part of our interest in multicomponent reactions (MCRs) applied to the synthesis of oxindole-based compounds,2 we report a novel synthetic approach towards the title compounds based on two sequential MCRs. Starting from isatin derivatives 1, ammonia (2) and mercaptoacetaldehyde (3), spirooxindole-fused 3-thiazolines 4 were easily obtained by means of the underutilized Asinger reaction.3 Intermediates 4 were then subjected to a diastereoselective Joullié-Ugi reaction, which afforded products 7 in high yields, the diastereoisomers being readily separable by flash chromatography. Both MCRs display a broad substrate scope, allowing us to quickly generate a diverse library of compounds 7, for which R1-R4 substituents could be varied extensively.
Evaluation of the antiproliferative activity and p53-MDM2 protein-protein interaction inhibition of the entire library is currently underway, as well as docking studies to understand the binding mode of the most promising representatives of this novel class of lead compounds.
1. Bertamino A.; Soprano M.; Musella S.; Rusciano M.R.; Sala M.; Vernieri E.; Di Sarno V.; Limatola A.; Carotenuto A.; Cosconati S.; Grieco P.; Novellino E.; Illario M.; Campiglia P.; Gomez-Monterrey I. J. Med. Chem., 2013, 56, 5407-5421.
2. Stucchi M.; Lesma G.; Meneghetti F.; Rainoldi G.; Sacchetti A.; Silvani A. J. Org. Chem., 2016, 81, 1877-1884; de Graaff C., Ruijter E., Orru R., Chem. Soc. Rev., 2012, 41, 3969-4009.
3. Asinger F. Angew. Chem., 1956, 68, 377
An efficient enantioselective approach to cyclic beta-amino acid derivatives via olefin metathesis reactions
No full textThe asymmetric synthesis of polyfunctionalized piperidine-and pyrrolidine-based scaffolds, specifically designed for the preparation of cyclic, conformationally constrained beta-amino acids, is realized combining a biocatalytic access to a versatile chiral building block with a wide range of transformations based on olefin metathesis
New chiral diamino ligands as sparteine analogues. Application to the palladium-catalyzed kinetic oxidative resolution of 1-phenyl ethanol
No full textNovel chiral 9-keto-bispidines were investigated as ligands in the palladium-catalyzed kinetic oxidative resolution (KOR) of 1-phenyl ethanol. The ligands were easily prepared by means of a two-step synthetic sequence starting from commercially available products
The spiropiperidine-3,3 '-oxindole scaffold: a type II beta-turn peptide isostere
Full text linkAn unprecedented chiral spiropiperidine oxindole system quaternary 3-aminooxindole and relying on a ring closing acts as an highly constrained Freidinger gamma-lactam, adopting assessed by modelling and spectroscopical studies. was synthesized starting from enantiopure metathesis as the key step. This compound a type II beta-turn conformation in solution, as (C) 2010 Elsevier Ltd. All rights reserved
Synthesis and conformational analysis of benzimidazole-based reverse turn mimics
No full textNew benzimidazole-based tetrapeptide mimics were synthesized and their conformational features were studied by NMR and molecular modeling techniques. All the analyses led to the conclusion that a β-turn is stabilized in both 2 and 3. Since values of the torsion angles do not allow an univocal definition of the β-turn type, structures 2 and 3 could be assigned to the generic type IV classification
A new spirocyclic proline-based lactam as efficient type II' b-turn inducing peptidomimetic
No full textA new proline-based spirotricyclic lactam is reported as an efficient type II′ β-turn inducing peptidomimetic. After investigations of the reverse turn properties by computational techniques, the scaffold has been synthesized by a straightforward sequence relying on a key RCM reaction for the construction of the spirocyclic lactams ring. For its conformational properties, the scaffold can be considered a privileged structure to be employed as a mimic of the β-turn motif of the potent antibiotic Gramicidin S
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