A JOURNEY IN THE ORGANOCATALYSED AND MULTICOMPONENT SYNTHESIS OF 3,3-DISUBSTITUTED AND SPIRO-OXINDOLES

2-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.