102,004 research outputs found
A JOURNEY IN THE ORGANOCATALYSED AND MULTICOMPONENT SYNTHESIS OF 3,3-DISUBSTITUTED AND SPIRO-OXINDOLES
Get PDF2-Oxindoles, especially those 3,3-disubstituted or spiro-fused to other cyclic frameworks, continue to be recognized as valuable compounds for drug discovery. They are present in a large number of natural and unnatural compounds with important biological activities and serve as key intermediates for the synthesis of many kinds of drug candidates.1 In particular, spirooxindoles, having cyclic structures fused at the C3 carbon, move away from the flat heterocycles encountered in many drug discovery programs. For this reason, they are of special interest, being able to potentially provide improved physicochemical properties in their interaction with biological systems.2 As more examples of the enantiospecific biological activity are identified, efficient and reliable asymmetric synthesis of such compounds becomes more and more valuable. In this context, the identification of asymmetric methods that achieve high stereoselectivity in the synthesis of heterocyclic compounds, in particular bearing tetrasubstituted or spiro-stereocenters, remains challenging.
In this context, my research was aimed to the synthesis of oxindole-based libraries, exploiting protocols at the cutting edge of synthetic chemistry, such as MCRs and organocatalysis.
Considering the great attention around optically active δ-amino-α,β-unsaturated carbonyl compounds as important building blocks in the synthesis of biologically active compounds,3 for my first project I focused my attention on the synthesis of 3-amino-3-(5-oxo-2,5-dihydrofuran-2-yl)indolin-2-ones derivatives via a BINOL-based phosphoric acids organocatalyzed vinylogous Mannich-type reaction.4
The desired products were obtained in general good yields and high enantiomeric excesses considering the challenge in the formation of a quaternary stereocenter consecutive with a bulky tertiary one. The stereochemistry of the final products was assigned by chemical correlation with respect to a reported compound5 and the stereochemical outcome was also rationalized by computational study.
Moreover, I studied the Biginelli reaction, a three component cyclocondensation between alkyl acetoacetates, urea and a carbonyl compound, as a practical method for the synthesis of biologically important 3,4-dihydropyrimidine-2(1H)-ones.6
In particular, BINOL-phosphoric acids have been used in the development of the first enantioselective organocatalyzed multicomponent Biginelli-like reaction applied to a ketone, allowing to obtain a small library of spiro[indoline-pyrimidine]-dione derivatives in good yields and enantioselectivity.7
During the second year, I focused my attention on the synthesis of 2-oxindoles spiro-fused with four- and five-membered rings.
Considering the recent medicinal chemists' interest in oxindole-based thiazolidine compounds as antitumor agents for the inhibition of the p53-MDM2 PPI,8 a novel synthetic approach towards spirooxindole-fused thiazolidines has been developed, based on two sequential multicomponent reactions (MCRs), namely the Asinger and two different Ugi-type reactions, Joullié-Ugi 3-CR and azido-Ugi 3-CR.9,10
The traditional Asinger 4-MCR11 allows to synthesize the thiazoline scaffold by treating a ketone with sulfur and ammonia with high atom economy. However, considerable more flexible is the “resynthesis protocol” in which an α-sulfanyl-carbonyl compound is directly used.12
The first part of the project involved the development of an Asinger-type reaction using isatin as the oxo component. After a screening of reaction conditions, the best parameters were selected to perform the substrate scope synthesizing different spirooxindole-fused 3-thiazolines in good yields.13
Spirooxindole-fused 3-thiazolines bearing an hydrogen as substituent on the double bond proved to be useful for the application of sequential MCRs. By application of Joulliè-Ugi and azido-Ugi reactions respectively, two small families of spiro-[indoline-3,2’-thiazolidine] derivatives were obtained in good yields and high diasteroselectivity.14
Another project developed during the second year was focused on the azetidine moiety. This strained four-membered ring system occurs as a structural motif in several natural products and pharmaceutical agents.15 Despite the interest in azetidin-2-ones, azetidines have received much less attention compared to their lower and higher homologues.16
Considering my interest in the synthesis of spirooxindoles derivatives, combined with the growing interest in hybrid drugs as therapeutic agents, I planned to connect the two pharmacologically relevant moieties, oxindole and azetidine, in a spiro arrangement. To do this, the formal [2+2] annulation reaction17 of isatins with allenoates has been considered as a practical and direct strategy to obtain highly functionalized chiral spirooxindole-based 4-methyleneazetidines with a high level of atom-economy.18 After a screening of reaction conditions, the best parameters were selected to extend the substrate scope obtaining different spirooxindole-fused 4-methyleneazetidines in good yield and excellent diasteroselectivity.
Considering the increasing interest for the development of catalytic asymmetric synthesis, I spent the third year in the development of a more efficient asymmetric cinchona-based organocatalyzed approach for the synthesis of enantiomerically enriched spirooxindole-fused 4-methyleneazetidines. After a deep screening of catalysts and reaction conditions, best parameters were applied to the reaction scope obtaining spirooxindole-fused 4-methyleneazetidines in good yields and enatiomeric ratios.19
In conclusion, during my PhD, I synthesized six different 3,3-disubstituted and spirooxindole-based scaffolds using innovative approaches.
In some cases, novel asymmetric organocatalyzed methodologies have been developed leading to enantiomerically enriched products. In other cases, more relevance was given to the multicomponent synthetic strategy for the rapid construction of highly functionalized scaffolds for drug discovery programs. Indeed, some of these compounds are under biological evaluation in collaborations with Merck (Pharma).
References:
1. Singh G. et al. Chem. Rev. 2012, 112, 6104.
2. Yang C. et al. Org. Biomol. Chem. 2015, 13, 4869.
3. Ruan S.T. et al. Org. Lett. 2011, 13, 4938.
4. Rainoldi G. et al. Org. Biomol. Chem. 2016, 14, 7768.
5. Rao V. U. B. et al. Org. Lett., 2014, 16, 648.
6. Goss J. et al. J. Org. Chem. 2008, 73, 7651.
7. Stucchi M. et al. J. Org. Chem. 2016, 81, 1877.
8. Bertamino A. et al. J. Med. Chem. 2013, 56, 5407.
9. Katsuyama A. et al. Org. Lett. 2016, 18, 2552;
10. Nenajdenko G. et al. Eur. J. Org. Chem. 2013, 6379.
11. Asinger F. Angew. Chem. 1956, 68, 377.
12. Keim, W. and Offermanns, H. Angew. Chem. Int. Ed. 2007, 46, 6010.
13. Rainoldi G. et al. Synlett 2016, 27, 2831.
14. Rainoldi G. et al. ACS Comb. Sci. 2017, Just Accepted.
15. Brandi A. et al. Chem. Rev. 2008, 108, 3988.
16. Orr S. T. M. et al. ACS Med. Chem. Lett. 2015, 6, 156.
17. Shi M. et al. J. Org. Chem. 2005.
8. Rainoldi G. et al. Chem. Commun. 2016, 52, 11575.
19. Rainoldi G. et al. Molecules 2017, 22, 2016
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
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
Muscle fatigue induced by two different resistance: elastic tubing versus weight machine
No full textOrganocatalytic 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
Individuazione degli itinerari Origine-Destinazione di maggior interesse per la sperimentazione
No full textRelazione per il Ministero dei Trasport
Organocatalytic vinylogous Mannich reaction of trimethylsiloxyfuran with isatin-derived benzhydryl-ketimines
No full textA family of chiral quaternary 3-aminooxindole butenolides has been synthesized by BINOL-derived phosphoric acid-catalyzed addition of trimethylsiloxyfuran to isatin-derived ketimines. Such a vinylogous Mannich-type reaction was found to produce diastereoisomeric butenolides in good yields and in most cases high enantiomeric excesses. The configurational assignment of the obtained products was safely performed by chemical correlation. A computational study of the transition state allowed rationalizing the obtained stereochemical outcome, highlighting the possible binding modes of the catalyst-imine-nucleophile transition complex
Enantioselective organocatalyzed multicomponent Biginelli- and Ugi-like reactions involving isatin
No full textThe reactions at the C-3 carbonyl group of isatins transform them into 2-oxindole derivatives, featuring in a large number of compounds with biological activities.1 Going on with our interest in the asymmetric synthesis of 3,3-disubstituted oxindoles2 we are exploring the applicability of organocatalysis, particularly chiral Brønsted acid catalysis,3 in the multicomponent Biginelli- and Ugi-like reactions involving isatin as the carbonyl component. The application of such reactions to ketimines remains to date largely unexplored, due to the hard challenge inherent in the stereocontrolled formation of a quaternary stereogenic center. The Biginelli-like reaction, employing urea and various β-dicarbonyl compounds besides isatin, allowed us to obtain a small library of chiral spiro(indoline-pyrimidine)-diones derivatives (1) in high yields and acceptable enantiomeric excesses. Post-condensation reactions have been performed, increasing the number of potentially useful compounds. On the other hand, starting from isatin-derived imines and isocyanoacetamides, we applied an Ugi-like reaction, affording unprecedented, chiral 3-(amino)-3-(oxazol-2-yl)indolin-2-ones derivatives (2) in good yields. For both reactions, the assignment of the absolute configuration at the new oxindole C-3 stereocenter, as well as computational studies in order to explain the stereochemical outcome, are currently underway.
References:
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
Rischio di incendio nelle gallerie ferroviarie: elaborazione di piani di emergenza esterna
No full textNelle procedure di analisi del rischio comunemente adottate risultano poco approfonditi gli aspetti relativi a quanto una corretta gestione delle emergenze in caso di incendio in una galleria ferroviaria contribuisca alla mitigazione del rischio. Il presente studio ha elaborato una procedura che, attraverso un approccio multidisciplinare, consente la valutazione, in modo coerente alle tecniche di analisi del rischio comunemente adottate, di aspetti connessi a una corretta gestione dei soccorsi. Le analisi che ne sono conseguite hanno permesso di individuare le interdipendenze tra i differenti soggetti chiamati a concorrere nella mitigazione del rischio e a ottenere indicazioni utili alla redazione di Piani di Emergenza EsternaAbstract
Common risk analysis does not focus on mitigation measures as results from a
proper emergencies management of fire in railway tunnels. The present study has
developed a multidisciplinary approach, that evaluates rescue management
procedures, according to commonly adopted risk analysis techniques. The results
of the present study indicate:
- interdependencies among the different stakeholders involved in risk mitigation;
- useful guideline for the redaction of emergency plan for railway tunnels’
fire
- …
