Chiral 1,5-disubstituted 1,2,3-triazoles-versatile tools for foldamers and peptidomimetic applications

1,4- A nd 1,5-Disubstituted triazole amino acid monomers have gained increasing interest among peptidic foldamers, as they are easily prepared via Cu- A nd Ru-catalyzed click reactions, with the potential for side chain variation. While the latter is key to their applicability, the synthesis and structural properties of the chiral mono-or disubstituted triazole amino acids have only been partially addressed. We here present the synthesis of all eight possible chiral derivatives of a triazole monomer prepared via a ruthenium-catalyzed azide alkyne cycloaddition (RuAAC). To evaluate the conformational properties of the individual building units, a systematic quantum chemical study was performed on all monomers, indicating their capacity to form several low energy conformers. This feature may be used to effect structural diversity when the monomers are inserted into various peptide sequences. We envisage that these results will facilitate new applications for these artificial oligomeric compounds in diverse areas, ranging from pharmaceutics to biotechnology

Glycerol derivatives in the hydrogen autotransfer reaction - Development of C-C and C-N bond forming reactions

Glycerol (1,2,3-propanetriol) is obtained as a byproduct in the biodiesel industry. In the quest for more sustainable starting materials for organic synthesis, glycerol with its three alcohol functionalities is a promising candidate. Hydrogen autotransfer is a catalytic method that allows for the direct substitution of alcohols with a variety of nucleophiles to form new carbon-carbon and carbon-heteroatom bonds. In this work we have aimed at developing such procedures employing amine and enolate nucleophiles using glycerol derivatives as electrophiles. In the first part of this thesis, the coupling reaction of 1,3-propanediol with acetophenone was investigated. A mixture of alkylation products consisting of 1-phenylpentan-1-one and small amounts of 1-phenylbutan-1-one and propiophenone was obtained using [Ir(cod)Cl]2/PPh3 as the catalyst. In addition, transfer hydrogenation of acetophenone as well as the product 1-phenylbutan-1-one occurred in parallel. A maximum of 43% conversion of the starting material was obtained in these studies and the highest selectivity for alkylated product was 90%. The complexity of the product mixture is a result of the combination of a weak nucleophile that can act as hydrogen acceptor, as well as the basic conditions, allowing base-promoted E1cB elimination and retro-aldol reaction to occur. The use of anthranilamide, a slightly stronger nucleophile without the possibility of transfer hydrogenation, proved more successful with a 50% conversion using [Cp*IrCl2]2 as the catalyst. In the second part of this work, the amination of protected glycerol derivatives was examined. DL-Isopropylideneglycerol was aminated using [Ru(p-cymene)Cl2]2/dppf as the catalyst in quantitative conversion. A series of three aminated isopropylideneglycerol derivatives were prepared in good isolated yields. Deprotection of amino isopropylidenglycerol was achieved quantitatively under acidic conditions. Initial tests on the amination of the obtained amino diol gave low yields of diaminated product, preferably on the secondary alcohol. Amination of the secondary alcohol in 1,3-O-benzylideneglycerol was achieved using [Ru(p-cymene)Cl2]2/DPEPhos as the catalyst, with a moderate conversion of 55%. We are currently working on optimizing these initial results. Keywords: Glycerol, Sustainable precursors, Organic synthesis, Hydrogen autotransfer, Alkylation, Aminatio

Valorisation of Renewable Building Blocks via Transition Metal Catalysis – Glycerol- and Amino Acid Derived Compounds in Hydrogen Borrowing and RuAAC Reactions

To a large extent, organic building blocks are today obtained from petroleum-based products. From an environmental point of view, biomass-derived compounds are more sustainable alternatives to such oil-derived molecules. The 12 principles of green chemistry describe how chemical processes can be improved in terms of sustainability. With some of these principles as guidelines, this thesis considers the upgrading of renewable glycerol- and amino acid-derived compounds using two different atom economic catalytic reactions: the hydrogen borrowing reaction, and the ruthenium-catalysed azide-alkyne cycloaddition (RuAAC) reaction. First, the glycerol derivatives solketal and 1,3-propanediol were investigated as starting materials in organic transformations using hydrogen borrowing methodology. Solketal was aminated with a set of secondary amines as well as sterically hindered primary amines, yielding the corresponding amino glycerol derivatives in good to excellent yields, using [Ru(p-cymene)Cl2]2 as the catalyst. Deprotection of the acetal gave the free amino diol, and this reaction sequence was used to synthesise the antitussive agent dropropizine in two steps from solketal. Furthermore, the iridium-catalysed α-alkylation of acetophenone with 1,3-propanediol was investigated. A mixture of products was obtained in moderate yields when using [Ir(cod)Cl]2 as the catalyst, while the selectivity could be improved by instead utilising an iridium-carbene complex as the catalyst. Hydrogen transfer methodology was also employed in the synthesis of chromanone scaffolds from 2’-hydroxyacetophenone and an alcohol. Brief mechanistic insight was gained considering the two reaction types via deuterium-labelling experiments and computational techniques, respectively.In addition, chiral triazole δ-amino acids were constructed via a RuAAC reaction for the construction of foldamers. Eight chiral triazoles were synthesized in good yields. Computational conformational studies revealed that the synthesised monomers had several low energy conformations that could be part of a well-defined three-dimensional foldameric structure.Finally, the RuAAC reaction was used in combination with a hydrogen borrowing cyclisation reaction for the construction of 1,5-fused triazole piperazines from a simple amino acid derived azide. A set of 14 different triazoles were synthesised in moderate to excellent yields, and 7 of these triazoles were successfully cyclised to give the desired 1,5-fused triazoles in two steps

Selective cleavage of 3,5-bis-(trifluoromethyl)benzylcarbamate by SmI2-Et3N-H2O

A novel electron poor protection group for amines has been developed. It undergoes rapid cleavage by SmI2-Et3N-H2O and its orthogonality towards the regular benzyl carbamate group (CBz) under reductive or transfer hydrogenolytic conditions is reported