Doctor of Philosophy (PhD), Science / A concise stereo-selective synthesis of a protected form of APTO 1, an unusual amino acid component of microsclerodermin C 2, was undertaken. Sequential Sharpless Asymmetric Aminohydroxylation (AA) and Asymmetric Dihydroxylation (AD) reactions were used to introduce the chiral amino and hydroxyl groups. Specific directing groups were chosen to ensure high regio- and enantio-selectivity in these reactions. The target compound was reached in a linear reaction sequence of fourteen steps. The strategy was designed to generate common intermediates which could be used to access analogous amino acid fragments in other microsclerodermins. A protected form of AETD 3, from microsclerodermin E, was synthesised via a late-stage common intermediate. Initial studies into the modification of the sequence to allow access to AMPTD 4 and 10-methyl AMPTD 5 were made.

Doctor of Philosophy (PhD), Science / A concise stereo-selective synthesis of a protected form of APTO 1, an unusual amino acid component of microsclerodermin C 2, was undertaken. Sequential Sharpless Asymmetric Aminohydroxylation (AA) and Asymmetric Dihydroxylation (AD) reactions were used to introduce the chiral amino and hydroxyl groups. Specific directing groups were chosen to ensure high regio- and enantio-selectivity in these reactions. The target compound was reached in a linear reaction sequence of fourteen steps. The strategy was designed to generate common intermediates which could be used to access analogous amino acid fragments in other microsclerodermins. A protected form of AETD 3, from microsclerodermin E, was synthesised via a late-stage common intermediate. Initial studies into the modification of the sequence to allow access to AMPTD 4 and 10-methyl AMPTD 5 were made.

Nos travaux ont porté sur la mise au point de synthèse de nouveaux dérivés β-substitués β-hydroxy aspartates : Inhibiteurs du transport du glutamate dans le système nerveux centrale (SNC). Ces analogues d'aspartates ont été caractérisés par différentes méthodes spectroscopiques (RMN-1H, RMN-13C et HRMS) et leur pureté énantiomérique a été confirmée par analyses HPLC chirale et des mesures de pouvoir rotatoire. Ce manuscrit est organisé en trois chapitres : la première partie présente un point bibliographique sur le système glutamatergique dans le SNC, en rappelant les différents récepteurs et transporteurs du glutamate dans ce système ainsi leurs agonistes et antagonistes spécifiques.Puis, nous avons décrit un aperçu sur les différentes synthèses de dérivés aspartates β-substitués et leurs activités inhibitrices vers les transporteurs du Glu dans le SNC.Afin d'avoir une grande diversité dans la structure les dérivés β-substitués β-hydroxy aspartates et réduire le temps de préparation et le nombre d'étapes de synthèse, nous avons développé dans la troisième partie de ce manuscrit deux stratégies originales et récentes pour préparer des dérivés -substitués -hydroxy aspartates via une aminohydroxylation asymétrique de Sharpless, qui est considérée comme l'étape clé dans cette synthèse.Enfin, Les résultats préliminaires de tests biologiques sur les dérivés β-substitués β-hydroxy aspartates protégés montrent que ces composés ne présentent aucune toxicité vers les cellules nerveuses de l'hippocampe de rat. L'étude de la cytotoxicité et l'activité inhibitrice de dérivés β-substitués β-hydroxy aspartates totalement déprotégés vis à vis du transport du glutamate dans le SNC sont actuellement en cours. / Our work focused on the development of synthesis of originals β-substituted β-hydroxy aspartates derivatives: Inhibitors of glutamate transport in the central nervous system (CNS).These analogs of aspartate have been characterized by various spectroscopic methods (1H-NMR, 13C-NMR and HRMS) and their enantiomeric purity was confirmed by chiral HPLC analysis and D measurement.This manuscript is organized into three chapters: the first part presents a bibliographical point of the glutamatergic system in CNS, recalling the different receptors and glutamate transporters in this system and their specific agonists and antagonists.Then, we described an overview of the various syntheses of β-substituted aspartates derivatives and their inhibitory activities toward glutamate transporters in CNS.In order, to have a great diversity in the structure of β-substituted β-hydroxy aspartates derivatives and reduce preparation time and the number of synthetic steps, we have developed in the third part of this manuscript two recent and original strategies for prepare β-substituted β-hydroxy aspartates derivatives via asymmetric aminohydroxylation Sharpless, who is considered the key step in this synthesis. Finally, preliminary results of biological tests on optically pure aspartates derivatives showed no toxicity to nerve cells of the rat hippocampus. The study of the inhibitory activity of these derivatives towards transport of glutamate in CNS is currently underway.

This thesis describes the development of new osmium-mediated methodologies providing novel applications through the use of a third generation of reoxidant for osmium. Chapter 1, The introduction: Summary of past and present methodologies towards the synthesis of the 1,2 amino alcohol motif. Chapter 2, Intramolecular processes: The studies of the tethered aminohydroxylation (TA) of amide and urea derivatives are being investigated. Chapter 3, Investigations towards an intermolecular process: The transposition of the TA methodology to an intermolecular process and the requirements involved are discussed. The role of acetamide is being investigated. Chapter 4, Successful transition to an intermolecular process: Amino acid derivatives became for the first time possible nitrogen sources and were efficiently employed through osmium-mediated reaction to afford interesting biological scaffolds. Chapter 5, Experimental: Full experimental procedures and characterisation of compounds are reported. References: A complete list of citations employed in the previous five chapters is provided. Appendix: Full documentation of X-ray crystal structures, key NMR spectra and HPLC traces is provided.

Two different research projects are described in this dissertation. The first one focuses on microwave-promoted iminyl radical cyclization for the formation of azaheterocycles which are embedded within numerous pharmaceuticals and biologically active natural products (such as clindamycin, eletriptan, moxiflaxin, etc.). We are quite interested in this project because of the significance of nitrogen-containing heterocycles as pharmaceuticals and organocatalysts combined with the need for safe, simple, and economical means of constructing them. We have successfully developed an efficient one-step synthesis of 2-acylpyrroles and diastereoselective dihydropyrroles from readily available oxime ether substrates. This remarkably efficient and environmentally friendly methodology should be useful for rapid and easy preparation of potent drugs containing pyrrolidine ring systems. The second project focuses on the total synthesis of yaku'amide A. The natural compound, isolated from a marine sponge in 2010, is a medium-sized peptide that contains bulky dehydroamino acids. It has an excellent IC50 value (14 ng/mL) against leukemia cells, making it a promising anticancer agent. Because of the unique anticancer profile, potent bioactivity, and limited supply, the natural product was attractive to us for an efficient synthesis and mechanistic investigation. We have devised more efficient strategies compared to Inoue's methods for the synthesis of bulky ∆AAs and their incorporation into peptides, which are innovative and will allow us to synthesize yaku'amide A rapidly and conveniently. A one-pot sequence consisting Martin sulfurane mediated anti dehydration, azide reduction, and O→N acyl transfer was developed for the construction of E- and Z-dehydroisoleucine-containing peptides. We also developed a three-step synthesis of N-terminal acyl group involving a one-pot indium-catalyzed cross-Claisen condensation/reduction from a known compound. The most hindered coupling reaction of pentapeptide acid and nanapeptide amine in the late stage is accomplished. Our total synthesis of yaku'amide A can be completed in 19 longest linear steps and 66 total steps. Further identification of yaku'amide A for elucidation of its biological target and mode of action will be explored, which will open up new avenues in the fight against cancer.

Yaku'amide A shows a unique inhibitory profile against a series of 39 human cancer cell lines (JFCR39). In our efforts to synthesize yaku'amide A, we have optimized our regioselective base-free aminohydroxylation method with a series of nitrogen sources, developed a chiral reagent-mediated aminohydroxylation strategy and chemoselective deprotections of the resulting aminohydroxylation product, and explored a stereospecific E2 dehydration and O-N acyl transfer sequence. In addition, we have prepared the right-hand tetrapeptide and the NTA subunit. For our bulky α,β-dehydroamino acids project, we have developed strategies to incorporate α,β-dehydroamino acids such as ΔVal and ΔEnv into small synthetic peptides via Solid Phase Peptide Synthesis (SPPS). We have also prepared two analogues of a monomeric helical peptide with 13 residues.

The synthetic progress towards yaku'amide A is described. The study leads to development of new synthetic methodologies. Base-free regioselective aminohydroxylation is convenient to deliver β-tert-hydroxyamino acids. A sequence consisting of alkylative esterification, Martin sulfurane mediated anti dehydration, a tandem azide reduction-O→N acyl transfer allows the rapid access of E- and Z-dehydroisoleucine-containing peptides from β-tert-hydroxyisoleucine derivatives. Those methods are effective in constructing complicated peptides and advanced subunits of yaku'amide A.

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.