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Thesis advisor: Kian L. Tan / Scaffolding ligand, 14, was designed to direct the hydroformylation of 1,2 disubstituted alkenes, such that the aldehyde forms at the carbon distally from the directing group. The ligand has the ability to form reversible covalent bonds with the substrate and bind to the metal to achieve high conversion, regio- and diastereoselectivity of homoallylic alcohol products. / Thesis (MS) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / The metal-catalyzed diboration of alkenes has gained fame as a practical methodology for use in the stereoselective construction of complex organic molecules and synthetic building blocks. The created carbon-boron bonds have tremendous versatility and can easily be manipulated into carbon-carbon or carbon-heteroatom bonds. Unfortunately, metal-catalyzed diborations often suffer from limitations such as substrate specificity. To address these issues, we investigated diboration reactions in the absence of transition-metal catalysts. Herein is presented a transition-metal-free, diastereoselective diboration methodology utilizing alkenyl alcohols as substrates. Allylic alcohols can be treated with an organolithium base and bis(pinacolato)diboron to generate 1,2,3-triols upon oxidation. Most studies were done on homoallylic alcohols, which can be performed using a carbonate base and an alcohol additive. This methodology has many strengths, such as a wide substrate scope and high levels of diastereoselectivity. Further investigations into product functionalization and synthetic applications will be pursued in due time. / Thesis (MS) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

No description available.

Thesis advisor: James P. Morken / This dissertation describes the development of four metal-catalyzed carbon-carbon bond forming methods. The first project presented is a palladium-catalyzed proparyl-allyl cross-coupling which proceeds via a kinetic resolution to give enantioenriched 1,5-enynes. Next the asymmetric rhodium-catalyzed hydroformylation of 1-alkenes is described. This reaction delivers synthetically useful a-chiral aldehydes in up to 98:2 er and up to 15:1 branched to linear ratio. The development of a unique nickelcatalyzed asymmetric Kumada coupling of cyclic sulfates is presented. Mechanistic studies reveal the reaction proceeds via an SN2 oxidative addition of a chiral nickelcomplex. Finally, a-Substituted allyl bis(boronic) esters, which are derived from 1,2-diboration of 1,3-dienes are shown to undergo allylation and subsequent Suzuki coupling with aldehydes tethered to sp2 electrophiles. The carbocycle products obtained bear three contiguous stereocenters and were used as intermediates in the synthesis of complex molecules. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Recent years have seen an expansion beyond the more druggable biological targets into novel areas of biological space. However, drug discovery campaigns against these challenging targets have been afflicted with low hit rates during screening campaigns and high levels of candidate attrition during clinical trials. Subsequent studies have looked to explore the underlying factors to these challenges and have identified the lack of scaffold diversity and poor physicochemical properties in screening libraries as the leading causes. In an attempt to address this issue drug discovery strategies such as fragment-based drug discovery and lead-oriented synthesis have been developed which control and direct the compound properties within screening libraries towards relevant areas of chemical space. In addition, strategies such as diversity oriented synthesis aim to synthesise structurally complex and diverse compounds, expanding screening collections into previously under-explored areas of chemical space. This thesis reports the development of a step-efficient, modular and highly adaptable synthetic route for the synthesis of partially saturated bicyclic heteroaromatic scffolds (Figure i). The designed route takes advantage of the large chiral pool provided by amino acids, with each scaffold synthesised in just 4-6 steps from these readily available enantiopure starting materials. The mild conditions allow for excellent functional group tolerance, thus enabling the incorporation of growth vectors for chemical elaboration from the outset, a strong advantage in the drug discovery process. Overall, 29 partially saturated bicyclic heteroaromatic compounds were synthesised based around 7 different scaffolds. These demonstrated a number of possible areas for diversifation both on and around the scaffold, including variation of functional groups (Figure i, red), double (cis-diastereoisomers) and single (R2- and R3-positions) substitution patterns, variation of the 5-membered heterocycle (Figure i, green) and increased size of the saturated ring (Figure i, blue). Furthermore, careful selection of the substituents, heterocycle and size of the saturated ring would enable the synthesis of screening libraries within the constraints of fragment-like, lead-like or drug-like structures. The final library has been incorporated into the Diamond XChem high-throughput crystallography program and initial screening has identified a weakly binding hit for Activin A.

Hydrogenation of "largely unfunctionalized" alkenes has been an active area of research for about a decade. Many catalysts have been prepared but we noticed that comparatively few substrates have been studied and none of these hydrogenations provided useful chirons for the organic synthesis area. That motivated us to investigate asymmetric hydrogenations of chiral acyclic alkenes, which are seldom used for hydrogenations and usually the reactions are fully substrate controlled. It emerged that such reactions could provide a concise entry points into chirons that can be used to prepare many natural products. Asymmetric hydrogenations of functionalized, but not coordinatively functionalized, alkenes have been used to prepare several chirons for syntheses ofpolyketide natural products using our N,carbene Crabtree's catalyst analog. Starting from optically active starting materials (eg Roche esters, lactic acid, glyceraldehyde dimethyl ketals, amino acids), highly optically active chiral alkenes can be made in several steps with high yield. With the iridium catalyzed asymmetric hydrogenations, chiral ethers, 1,3-hydroxymethyl chiron, alpha-methyl-beta-hydroxy-gamma-methyl chiron, alpha-methyl-gamma-alkyl-gamma-amino acid can be obtained with high stereoselectivities. With those well developed methodologies, (-)-dihydromyoporone, (-)-spongidepsin, (-)-invictolide have been prepared with high efficiency. Not like the vinyl acetate, which can be hydrogenated quite well with many Rh catalysts, the alkyl vinyl ether does not have a coordination functional group nearby, hence it is a difficult substrate for asymmetric hydrogenation and there are relatively few iv reports. Also the simple alkyl enol ether is quite acid sensitive and the Pfatlz's type N,PIr catalysts cannot hydrogenate the simple alkyl enol ethers well under the standard hydrogenation conditions. We explored many alkyl enol ethers and found some of them can be hydrogenated efficiently (50 bar H2, 1 mol percent N,carbene-Ir catalyst, 25 degree C) with high enantioselectivities (up to 98 percent ee). This study led us to suspect that more protons were produced when N,P-Ir catalyst precursors were used relative to the corresponding carbene catalyst since the former only gave complex mixture when being used. DF calculations and several other experiments supported this postulation.

Le travail présenté dans ce manuscrit concerne la synthèse du fragment C12-C25 de la Thuggacine A, macrolide antibiotique, par deux voies de synthèse. La première voie de synthèse nous a permis de créer 4 des 5 centres stéréogéniques à partir du (R)-glycéraldéhyde acétonide. L'étape-clé d'induction asymétrique a montré que les 3 centres C18 à C20 présentent une configuration relative syn présente dans la Thuggacine A mais que les centres C17-C18 sont anti-configurés, configuration confirmée par cristallographie du composé 84. Les faibles rendements ainsi qu'un contrôle insuffisant de la diastéréosélectivité de ces 4 centres asymétriques nous ont conduit à étudier une stratégie de synthèse alternative. La deuxième voie de synthèse nous a permis d'obtenir le fragment C13-C25 en 10 étapes linéaires et avec un très bon contrôle de la stéréochimie des 5 centres stéréogéniques créés. Les 4 centres asymétriques C-17 à C-20 ont été construits grâce à deux réactions d'aldolisations type Evans, tandis que l'addition d'un allényl-stannane a permis l'introduction stéréosélective du centre C-16. / The herein presented study is concerned by the synthesis of the C12-C25 fragment of Thuggacine A, a potent antibiotic macrolide, through two distinct synthetic pathways. The first synthetic pathway enabled us to form 4 among 5 stereogenic centers from (R)-glyceraldehyde acetonide. The key induction asymmetric step showed that the 3 chiral centers C18-C20 were formed with a syn-configuration as in Thuggacine A and the C17-C18 stereocenters were anti-configurated, a result confirmed by X-ray cristallography of compound 84. Low yields and low diastereocontrol of these four chiral centers led us to envisage an alternative synthetic strategy. The second synthetic pathway enabled us ti obtain the C13-C25 fragment within ten linear steps and a high diastereocontrol of the five required stereogenic centers. The 4 chiral centers C-17 to C-20 were formed through two Evans's aldolization steps while the stereochemistry of the C16 center was secured by an allenyl-stannane homologation.

Faculty of Science; School of Chemistry; PhD Thesis / The synthesis of nitrogen containing ring systems has been one of the interests of this research group at the University of the Witwatersrand for a long time. These systems form part of a group of compounds called alkaloids, whose structural diversity is rivalled only by their distribution in nature. A small sub-set of the alkaloids is the fused 5 and 6 membered bicyclic frames with nitrogen at one bridgehead. Having developed a unique method of synthesising these indolizidine alkaloids, we examined various aspects of this methodology and there remained one crucial question – what is the best way to control the stereochemical outcome of the ring-forming steps? This project looks at this question from the view of a model natural product, the indolizidine alkaloids (+)- and (–)-tashiromine. The synthesis of tashiromine and related compounds was examined using chiral auxiliaries such as the Oppolzer sultam and the Evans oxazolidinone, as well as the use of chirally modified reductants. The efficacies of the chiral auxiliaries were studied using molecular modelling techniques, and certain modifications were suggested from these results.

Yes / Fused cyclobutanes are found in a range of natural products and formation of these motifs in a straightforward and easy manner represents an interesting synthetic challenge. To this end we investigated an intramolecular variant of the thermal enamine [2 + 2] cyclisation, developing a diastereoselective intramolecular enamine [2 + 2] cyclisation furnishing δ lactone and lactam fused cyclobutenes in good yield and excellent diastereoselectivity. / The work was funded by Yorkshire Cancer Research