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

Abstract

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,…