Conformationally constrained ligands and their flexible analogues were prepared as inhibitors of the Grb2 SH2 domain in order to study the structural and energetic effects of ligand preorganization in protein-ligand interactions. The compounds were prepared by using trans-cyclopropane-containing amino acid mimics, macrocyclization, or [alpha,alpha]-disubstituted amino acid residues. All trans-cyclopropane containing peptides were more potent than their corresponding succinate containing analogues due to an enthalpic advantage. Surprisingly, the binding of constrained peptides to the domain was entropically disfavored relative to their flexible controls. Effects of proton transfer and desolvation as being the source of the unprecedented entropic penalty for the constrained ligands relative to their respective controls were precluded, and X-ray crystallographic studies revealed that the binding conformations for the respective cyclopropane and succinate containing ligands were similar. This led us to believe that differential changes in protein dynamics may occur upon binding of the constrained and flexible ligands, which could contribute to the observed binding energetics. Two 23-membered macrocyclic ligands were slightly more potent than their corresponding linear controls. The amino acids used to link the N- and C-termini of the linear peptides to form the macrocycles were found to affect the energetics of binding. In one case, the 23-membered macrocycle was more potent than its control due to an entropic advantage, whereas the other 23-membered macrocycle was more potent than its control because it benefited from an enthalpic advantage. [alpha,alpha]-Disubstituted and [alpha]-monosubstituted residues that varied in hydrophobic character were incorporated into Grb2 SH2 domain binding tripeptides, and binding became more favorable as nonpolar surface area increased only for the set of tripeptides possessing cyclic [alpha,alpha]-disubstituted residues. The increase in affinity was due to an increasing enthalplic term, whereas the entropy of binding became less favorable. A total synthesis of (±)-lycopladine A was achieved in five steps from known compounds. The tricyclic core of the natural product was prepared utilizing a novel two-step sequence comprising a conjugate addition of a metalated picoline derivative followed by an intramolecular enolate arylation. It was demonstrated that the natural product existed in a solvent dependent equilibrium with its isomeric lactol. / text

Total synthesis of the pyrrolizidine alkaloid NP25302: (+)-NP25302 is an unusual vinylogous urea containing pyrrolizidine alkaloid shown to exhibit cell adhesion inhibition. It was envisaged that this natural product could be accessed by a novel 5-endo-dig cyclisation to construct the pyrrolizidine core, and a Curtius rearrangement to install the vinylogous urea motif. This methodology was first tested on a model system, furnishing nor-NP25302 from L-proline in 12 steps and 9% overall yield. The total synthesis of (±)-NP25302 was completed in 9 steps and 26% overall yield from ethyl 2-nitropropionate using similar methodology. Studies into the stereospecificity of the Au(I)-catalysed cyclisation of monoallylic diols: During the synthesis of (+)-isoaltholactone in the Robertson group, the key Au(I)-catalysed cyclisation was observed to occur with some stereospecificity. Further investigations were therefore conducted into the stereochemical outcome of this reaction using stereodefined allylic alcohols, and from the combined results a mnemonic was proposed to predict the stereochemistry of the products of this reaction. Studies into the total synthesis of ascospiroketals A and B: Investigations were conducted into the total synthesis of the recently isolated natural products ascospiroketals A and B. A second generation synthesis was used to construct advanced intermediates 1 and 2.

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In 2004, the polyketide natural product, chamuvarinin (72) was isolated by Laurens et al. from the roots of Uvaria chamae, a member of the Annonaceae plant family. This unique tetrahydropyran containing acetogenin displayed potent levels of cytotoxic activity against the KB 3-1 cell line with an ED50 value of 0.8 nM. Upon initial isolation the relative and absolute stereochemical assignment of chamuvarinin (72) was unable to be readily achieved through ¹H and ¹³C NMR analysis. The initial synthetic route described herein has enabled the relative and absolute stereochemical determination of chamuvarinin (72) through the first total synthesis completed in 20 longest linear steps in 1.5% overall yield. A revised synthetic strategy towards chamuvarinin (72) was completed in 17 longest linear steps in 2.2% overall yield. The revised route facilitated the assembly of non-natural chamuvarinin-like analogues and their trypanocidal and cytotoxic activities have been assessed. The synthesis of these analogues has formed the basis of a more focussed study through the design and synthesis of simplified triazole (295), isoxazole (325) and butenolide triazole (305) analogues as potential Trypanosoma brucei (causative agent in African Sleeping sickness) inhibitors.

No description available.

The aplyronines are a family of 24-membered macrolides of polyketide origin, isolated from the Japanese sea hare Aplysia kurodai. They exhibit an exceptional biological activity profile, acting through an actin and tubulin dual-targeting mechanism, with subnanomolar growth inhibitory potency against a diverse range of cancer cell lines. These characteristics render the aplyronines ideal payloads for antibody-drug conjugates but their prohibitively low natural abundance calls for an efficient total synthesis to overcome the supply issue. This dissertation describes the efforts towards developing a second-generation Paterson synthesis of the macrocyclic core of the aplyronines, focused on improving the scalability and selectivity of key transformations. Chapter 1 details the isolation, biological background and previous synthetic efforts towards the aplyronines to illustrate their therapeutic potential and the challenges associated with material sourcing by chemical synthesis. Chapter 2 presents the existing body of work on the aplyronine project within the Paterson group, highlighting the lessons learned over the past two decades and shortcomings to be addressed. Chapter 3 discusses a revised protecting group strategy towards the C1-C27 macrocyclic alcohol 159 with fewer manipulation steps. A refined reaction sequence featuring titanium aldol methodology and an enzymatic desymmetrisation process delivered multigram stocks of the C15-C27 aldehyde 161 upon scale- up, testifying to the robustness of the devised route. Synthesis of the C1-C14 northern fragment 253 closely followed the existing boron aldol approach with optimisation of the C11-C12 alkylation step, geared towards enhancing the regioselectivity. Chapter 4 describes the coupling of the two major fragments using an Horner-Wadsworth-Emmons reaction to assemble the C1-C27 backbone of the cyclic aplyronine core and suitably adjusted endgame steps to enable a one-step oxidative unmasking of the macrolactonisation sites. The first-generation intermediate 159 was accessed via site-specific Yamaguchi esterification and orthogonal deprotection of the C27 allyl carbonate. Discussion in Chapter 5 includes the appendage of the C28-C34 side chain 118, prepared by the known sequence, and suggestions for the future direction of the second-generation route with the outlook of linker appendage for the purposes of antibody-drug conjugate development.

La synthèse totale de la N1999-A2 représente un défi synthétique qui a intéressé plusieurs grandes équipes spécialisées dans ce domaine. L’approche synthétique envisagée repose sur le savoir-faire du laboratoire. Elle permet de former le cœur diènediyne dans les dernières étapes de la synthèse. Nous avons réussi à réaliser le premier couplage des deux synthons clefs, une avancée majeure dans le cadre de notre approche synthétique. Ce travail a aussi permis le développement de nouvelles méthodologies. Notamment les couplages croisés au palladium avec un nouveau type de partenaire électrophile stable : les nosylates d’aryle ou vinyle. Cette découverte permettra de compenser l’instabilité de plusieurs intermédiaires synthétiques clefs (triflates d’énol). / The total synthesis of N1999-A2 is a synthetic challenge which mobilized several renown groups specialized in this field. Our group is also interested in the construction of this complex molecule. Our strategy is based on the know-how of our laboratory. The considered synthetic approach permits the formation of the dienediyne core at the lasts steps of the synthesis. We managed to achieve the first coupling of the two key building blocks. This is a major advance in our synthetic approach. This project also allowed the development of new synthetic methodologies. In particular the palladium catalyzed cross-coupling reactions with aryl and vinyl nosylates, novel stable and reactive electrophilic partners. This discovery will allow us to bypass the extreme instability of several key intermediates (enol triflates).

Le travail présenté dans ce manuscrit consiste à développer une voie de synthèse originale visant les alcaloïdes de type Lycorine, composés naturels isolés de plantes de la famille des Amaryllidaceae, possédant des activités anticancéreuses prometteuses. La réaction clé de métathèse tandem ène-yne-ène a été explorée avec succès, permettant un accès rapide au cœur hexahydroindole des Lycorines. Le développement de nouvelles méthodes synthétiques autour de composés de type N-sulfinylthioimidate a été réalisé ; leur synthèse efficace en trois étapes, leur fonctionnalisation en position α par des halogénures d'alkyles ou des aldéhydes, ainsi que leur réduction ménagée en aldimines α-chirales hautement fonctionnalisées ont été étudiés. Ces aldimines représentent des intermédiaires clés avancés pour la synthèse de divers membres de la famille des Lycorines : la synthèse totale des α et γ-Lycorane a donc été réalisée ; la synthèse de composés mono-hydroxylés tels que la Fortucine et la Kirkine est en cours d'étude. / The work reported in this manuscript concerns the development of an original synthetic strategy towards Lycorine-type alkaloids, natural products isolated from the plants of the Amaryllidaceae family, owning promising antitumoral activities. The tandem metathesis key step ene-yne-ene was explored with success, offering a quick access to the Lycorine hexahydroindole core. The development of new synthetic methods around N-sulfinylthioimidates was performed: the settings up of their efficient synthesis in three steps, their α-functionalization with halide alkyles or aldehydes, as well as their reduction in α-chiral aldimines highly functionalised were studied. These aldimines represent advanced key intermediates for the synthesis of several members of the Lycorine family: we achieved the total synthesis of α and γ-Lycorane; the synthesis of mono-hydroxylated compounds such as Fortucine and Kirkine is on going.

Organosulfur compounds have been used by humans for centuries and played a pivotal role in shaping our history. The chemistry presented herein deals primarily with three distinct organic transformations involving organosulfur species. The three transformations are used in tandem to complete the synthesis of natural products. The first chapter examines a new diastereoselective alkylation reaction of sulfenate anions with stereoinduction provided by chiral amino iodides. A series of β-amino sulfoxides are accessed in good yields and selectivities from alkylations with the corresponding lithium arene- and E-1-alkenesulfenate anions. The relative reactivity of different electrophiles towards a selection of lithium sulfenate anions was also evaluated by performing competition experiments. In the second chapter 1,2-dibromotetrachloroethane (C2Br2Cl4) was evaluated as a more economical halogenating agent for the in-situ Ramberg-Bäcklund rearrangement (RBR). A series of trans-stilbenoids were successfully synthesized using this protocol in excellent yields. The new RBR system also worked well for dialkyl and cyclic substrates, but the reaction was plagued by polyhalogenation for hexyl benzyl sulfone. The methodology was extended to the formal total synthesis of natural polyphenol E-resveratrol. Chapter three investigates asymmetric aza-Michael reactions of chiral β-amino sulfoxides/sulfones to synthesize thiomorpholine S-oxides and S,S-dioxides, respectively. Remarkably, cyclizations of the β-amino sulfoxides provide the trans- 3,5-substituted heterocycles, while the β-amino sulfones provide the complementary cis-3,5-substituted heterocycles. The aza-Michael chemistry was exploited along with the sulfenate and RBR protocols to access two ant venom alkaloids. / NSERC

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