Le pyrrole est un hétérocycle souvent présent dans les produits naturels et les composés biologiquement actifs. Son étude intensive en synthèse organique est donc d'un grand intérêt. Ainsi, la première réaction acido-catalysée de pyrroles sur des nitrones, reportée par notre équipe, a conduit selon les conditions expérimentales employées, soit aux 2,2-bis(pyrrolyl)alcanes symétriques, soit aux N-benzylhydroxylamines pyrroliques de façon sélective. Les N-hydroxylamines pyrroliques sont des composés intéressants et ont été le point de départ des deux études méthodologiques développées dans ce manuscrit. Les bis(pyrrolyl)alcanes non symétriques ont pu être synthétisés efficacement et avec une bonne diversité, en une étape, par réaction entre des N-hydroxylamines pyrroliques et des pyrroles. La méthode a aussi permis la préparation de ter(pyrrolyl)alcanes symétriques et non symétriques. Une application de cette méthodologie a été la préparation de marqueurs de fluorescence F-Bodipy® non symétriques. Ces derniers ont été obtenus pour la première fois et avec de bons rendements, directement à partir de 2,2'-bis(pyrrolyl)alcanes non symétriques. De plus, un F-Bodipy® présentant une chiralité axiale a pu être synthétisé. Nous avons également étudié l'accès aux acides a-N-hydroxyaminés, analogues N-hydroxylés des acides a-aminés. Une réaction hautement diastéréosélective entre le pyrrole et une nitrone cyclique chirale a donné accès à une hydroxylamine pyrrolique. Une séquence en trois étapes a permis d'obtenir un a-N-hydroxyamino ester avec un bon rendement et un bon excès énantiomère de 80%. La méthode a ensuite été appliquée à d'autres hétéroaromatiques pyrroliques, indoliques et furaniques. Aucun acide a-N-hydroxaminé comportant l'un de ces hétérocycles n'était décrit précédemment dans la littérature. Les rendements globaux obtenus sont bons (36-62%) et les excès énantiomères peuvent atteindre des valeurs ≥ 98%.

Yaku’amide A (YA) is a linear anticancer peptide that is rich in bulky dehydroamino acids (ΔAAs) and β-hydroxyamino acids (β-OHAAs). In our recent total synthesis of YA, we featured a one-pot anti dehydration–azide reduction–O→N acyl transfer process for the stereospecific construction of Z- and E- ∆Ile residues. Despite previous total syntheses and our efforts, the synthesis of YA remains lengthy. Via computational studies, we identified two analogue peptides that closely resemble the conformation of YA. The use of simpler and symmetrical bulky ΔAAs such as dehydrovaline (ΔVal) and dehydroethylnorvaline (ΔEnv) as surrogates of ∆Ile, along with azlactone chemistry for their incorporation, significantly decreased the overall number of synthetic steps. Biological studies revealed that our analogues exhibited very similar activity to that of the natural product YA, demonstrating their suitability as mimics and consistency with our computational model. Despite its utility in the construction of YA analogues, azlactone chemistry is sluggish and moderate to low yielding. For this reason, we have explored strategies to streamline the synthesis of peptides containing Z-dehydroaminobutyric acid (∆Abu), ∆Val, and Z-dehydrophenylalanine (∆Phe). The key process is to form the alkene moiety via elimination of a β-sulfonium or β-OHAA embedded within a peptide, avoiding the need to form the alkene moiety via azlactone-dipeptide dehydration and bypassing sluggish amidation/ring opening steps. β-sheet disruption of Tau-model hexapeptides is a key type of inhibition for modulating Alzheimer’s disease progression. Previous studies replaced key residues with proline, due to its rigidity and lack of amide proton, to inhibit β-sheet formation. Similar to proline, ∆AAs are also known for their rigidity and ability to favor other conformations (e.g. β-hairpin, 310-helix) along with increasing peptide half-life. We have incorporated ∆Abu, ∆Val and dehydrocyclohexylglycine (∆Chg) in a highly aggregative hexapeptide sequence, using previously studied methods, to assess their capabilities as putative β-sheet breakers and to stabilize against proteolysis. Studies are continuing.

This dissertation primarily covers the impact of bulky ,-dehydroamino acids on the proteolytic stability and enhanced folding of -hairpins. It partly describes the progress towards the total synthesis of yakuamide A, a potent anticancer peptide with an IC50 value of 14 ng/mL against leukemia cells. Proteins and peptides are a very attractive source of potential medicinal agents as they can target various protein“protein interactions that are implicated in several diseases and disorders. The global sales of peptide drugs in 2013 were estimated to be about $28 billion and are constantly rising at an appreciable rate. However, peptide drugs have a short plasma half-life because of their susceptibility to proteolysis. Multiple approaches have been discovered to overcome this shortcoming, but there is still an urgent need for better peptidomimetics to increase the stream of peptides entering the pharmaceutical market. Here, it has been demonstrated that the incorporation of a bulky ,-dehydroamino acid in the turn regions of -hairpins can substantially increase their proteolytic stability and folding. Insertion of a dehydrovaline (ΔVal) residue at the i+1 position imparted ca. 7-fold increase in proteolytic resistance and ca. 15% increase in folding when compared to the parent peptide. Since the insertion of a bulky ,-dehydroamino acid into the turn regions of -hairpins can promote proteolytic stability without perturbing the secondary structures, it is believed that this novel approach is very promising in stabilizing bioactive turn-containing peptides for therapeutic use.Yakuamide A is a medium-sized peptide that contains several bulky dehydroamino acids, -hydroxyamino acids and unique N- and C-termini. It has an unprecedented anticancer profile, and potent bioactivity, hence it was imperative to accomplish its total synthesis to elicit its unique mode of action and biological target. More efficient methods were developed to synthesize bulky dehydroamino acids and -hydroxyamino acids. A regioselective base-free aminohydroxylation was developed for the synthesis of -hydroxyamino acids. The major focus was the three-step synthesis of the N-terminal acyl group from a known compound by a one-pot indium-catalyzed cross-Claisen condensation/reduction and the synthesis of (2S,3R)--hydroxyisoleucine, and racemic -hydroxyisoleucine, which are the precursors of E- and Z-dehydroisoleucine.