Stereoselective synthesis of heterocycles as intermediates of biologically active compounds

The aim of this thesis was to investigate the synthesis of enantiomerically enriched heterocycles and dehydro-β-amino acid derivatives which can be used as scaffolds or intermediates of biologically active compounds, in particular as novel αvβ3 and α5β1 integrin ligands. The starting materials of all the compounds here synthesized are alkylideneacetoacetates. Alkylidene derivates are very usefull compounds, they are usually used as unsaturated electrophiles and they have the advantage of introducing different kind of functionality that may be further elaborated. In chapter 1, regio- and stereoselective allylic amination of pure carbonates is presented. The reaction proceeds via uncatalyzed or palladium-catalyzed conditions and affords enantiopure dehydro-β-amino esters that are useful precursor of biologically active compounds. Chapter 2 illustrates the synthesis of substituted isoxazolidines and isoxazolines via Michael addition followed by intramolecular hemiketalisation. The investigation on the effect of the Lewis acid catalysis on the regioselectivity of the addition it also reported. Isoxazolidines and isoxazolines are interesting heterocyclic compounds that may be regarded as unusual constrained -amino acids or as furanose mimetics. The synthesis of unusual cyclic amino acids precursors, that may be envisaged as proline analogues, as scaffolds for the design of bioactive peptidomimetics is presented in chapter 3. The synthesis of 2-substituted-3,4-dehydropyrrole derivatives starting from allylic carbonates via a two step allylic amination/ring closing metathesis (RCM) protocol is carried out. The reaction was optimized by testing different Grubbs’ catalysts and carbamate nitrogen protecting groups. Moreover, in view of a future application of these dehydro-β-amino acids as central core of peptidomimetics , the malonate chain was also used to protect nitrogen prior to RCM. Finally, chapter 4 presents the synthesis of two novel different classes of integrin antagonists, one derived from dehydro-β-amino acid prepared as described in chapter 1 and the other one has isoxazolidines synthesized in chapter 2 as rigid constrained core. Since that these compounds are promising RGD mimetics for αvβ3 and α5β1 integrins, they have been submitted to biological assay. and to interpret on a molecular basis their different affinities for the αvβ3 receptor, docking studies were performed using Glide program.

Synthesis and aplication of linear and macrocyclic nitrogen ligand

Linear and macrocyclic nitrogen ligands have been found wide application during the years. Nitrogen has a much strong association with transition-metal ions because the electron pair is partucularly available for complexing purposes. We started our investigation with the synthesis of new chiral perazamacrocycles containing four pyrrole rings. This ligand was synthesized by the [2+2]condensation of (R,R)-diaminocyclohexane and dipirranedialdehydes and was tested, after a complexation with Cu(OAc)2, in Henry reactions. The best yields (96%) and higher ee’s (96%) were obtained when the meso-substituent on the dipyrrandialdehyde was a methyl group. The positive influence of the pyrrole-containing macrocyclic structure on the efficiency/enantioselectivity of the catalytic system was demonstrated by comparison with the Henry reactions performed using analogous ligands. Henry product was obtain in good yield but only 73% of ee, when the dialdehyde unit was replaced by a triheteroaromatic dialdehye (furan-pyrrol-furan). Another well known macrocyclic ligand is calix[4]pyrrole. We decided to investigate, in collaboration with Neier’s group, the metal-coordinating properties of calix[2]pyrrole[2]pyrrolidine compounds obtained by the reduction of calix[4]pyrrole. We focused our attention on the reduction conditions, and tested different Pd supported (charcoal, grafite) catalysts at different condition. Concerning the synthesis of linear polyamine ligands. We focused our attention to the synthesis of 2-heteroaryl- and 2,5-diheteroarylpyrrolidines. The reductive amination reaction of diarylketones and aryl-substitutedketo-aldehydes with different chiral amines was exploited to prepare a small library of diastereo-enriched substituted pyrrolidines. We have also described a new synthetic route to 1,2-disubstituted 1,2,3,4-tetrahydropyrrole[1,2-a]pyrazines, which involves the diastereoselective addition of Grignard reagents to chiral oxazolidines. The best diastereoselectivity (98:2) was dependent on the nature of both the chiral auxiliary, (S)-1-phenylglycinol, and the nature of the organometallic reagent (MeMgBr).

Catalytic processes for the transformation of ethanol into acetonitrile

This thesis deals with the transformation of ethanol into acetonitrile. Two approaches are investigated: (a) the ammoxidation of ethanol to acetonitrile and (b) the amination of ethanol to acetonitrile. The reaction of ethanol ammoxidation to acetonitrile has been studied using several catalytic systems, such as vanadyl pyrophosphate, supported vanadium oxide, multimetal molibdates and antimonates. The main conclusions are: (I) The surface acidity must be very low, because acidity catalyzes several undesired reactions, such as the formation of ethylene, and of heavy compounds as well. (II) Supported vanadium oxide is the catalyst showing the best catalytic behaviour, but the role of the support is of crucial importance. (III) Both metal molybdates and antimonates show interesting catalytic behaviour, but are poorly active, and probably require harder conditions than those used with the V oxide-based catalysts. (IV) One key point in the reaction network is the rate of reaction between acetaldehyde (the first intermediate) and ammonia, compared to the parallel rates of acetaldehyde transformation into by-products (CO, CO2, HCN, heavy compounds). Concerning the non-oxidative process, two possible strategies are investigated: (a) the ethanol ammonolysis to ethylamine coupled with ethylamine dehydrogenation, and (b) the direct non-reductive amination of ethanol to acetonitrile. Despite the good results obtained in each single step, the former reaction does not lead to good results in terms of yield to acetonitrile. The direct amination can be catalyzed with good acetonitrile yield over catalyst based on supported metal oxides. Strategies aimed at limiting catalyst deactivation have also been investigated.