Development and application of novel multicomponent reactions using (a)alfa-acidic isocyanides
The research described in this thesis deals with: i) the exploitation of the a-acidity of isocyanides in the development of new multicomponent reactions; ii) the application of such MCRs for the synthesis of NHC complexes; and iii) the C–2 functionalisation of 2 imidazolines as a route towards libraries of potential p53-MDM2 interaction inhibitors. In Chapter 2, the translation of Schöllkopf’s aldol type chemistry with a-isocyanoacetates to a novel multicomponent synthesis of 2H-2-imidazolines is described. The scope of this MCR is further explored in Chapter 3 by the use of 9-isocyanofluorene and p-nitrobenzyl isocyanide as well as functionalised amines and aldehydes. Also the application of ketones instead of aldehydes and the influence of chiral inputs are addressed. Differences in reactivity of the employed isocyanides are explained using high level Density Functional Theory (DFT) calculations. Chapter 4 contains a review on the history, structure, reactivity and synthesis of NHCs and their metal complexes. Furthermore, the use of 2H-2-imidazolines prepared with our MCR in the synthesis of unprecedented types of NHC complexes is displayed. This procedure allows the variation of all substituents of the NHC ligands. The NHC-transition metal complexes are characterised using NMR, IR and X-ray crystal structures. Chapter 5 starts with a comprehensive overview of the role of the p53 tumour suppressor and its interaction with MDM2, its natural inhibitor and regulator. Then, a recently discovered class of p53-MDM2 interaction inhibitors called Nutlins is introduced and our synthetic efforts towards Nutlin analogues via the C–2 functionalisation of 2H-2-imidazolines are described. The first part of Chapter 6 is an introduction to conformationally constrained peptides as ß-turn mimics. The next part deals with the discovery of a new MCR involving the reaction of in situ generated azadienes with a-isocyanoacetates, in which the versatile isocyano group is preserved. The products, 3-isocyano-3,4-dihydropyridones can be regarded as Freidinger type lactams suited for additional multicomponent chemistry, possibly leading to new ß-turn mimics. In the final Chapter of this thesis, a retrospection on the different topics described in this thesis is presented. Finally, some proposals for the future elaboration of the different projects are displayed. Some parts of this thesis have been published or will be published in the near future.