Alzheimer’s disease (AD), a progressive age-related neurodegenerative disorder is characterized by impairments in memory and cognitive functions. The two main pathogenic hallmarks associated with the progression of this multifactorial disease include accumulation of amyloid-beta (Aβ) plaques and the deterioration of the cholinergic system in the brain. Using cost-effective synthetic procedures, mono-, di-, and tri- substituted sym-triazine derivatives incorporating acetylcholine substrate analogues and aromatic phenyl moieties were synthesized for the targeted modulation of Aβ aggregation and acetylcholinesterase (AChE) activity. A subset of these sym-triazines demonstrated dual inhibition of Aβ fibrillization and AChE hydrolytic activity in vitro studies. These highly effective compounds were also shown to be well tolerated by differentiated human neuronal cells in cell viability tests. These novel compounds have the potential to undergo future in vivo pharmaceutical analysis and have a positive impact on the quality of life of the people living with this devastating disease and their caretakers.

In 2006, an amphoteric molecule containing both an aldehyde and an unprotected amine was reported in the Yudin group by Dr. Ryan Hili. The unprotected aziridine aldehyde exists as homochiral dimers. Furthermore, due to the reversibility of the hemiacetal formation, the free aldehyde is available to undergo a wide array of reactions including an Ugi multicomponent reaction to give the final peptide macrocycle. Thus far, the mechanistic pathway involved in the Ugi reaction between S-trans aziridine aldehyde dimer and L-amino acids in the presence of tert-butyl isocyanide has given high diastereoselectivity whereas low diastereoselectivity is observed if the aziridine dimer is of the opposite stereochemistry. Herein, preliminary results show that a S-cis aziridine aldehyde with either a D or L-secondary amino acid gives high diastereoselectivity showing that the reaction is under Felkin-Ahn control.

Rhodium-catalyzed hydroacylation is a powerful and atom-economical method for synthesizing ketones from aldehydes and olefins. Despite this, a narrow scope of reactive substrates has limited the utility and broad application of this transformation. Efforts towards the development of new classes of reactive substrates have focused on the use of oxygen- and sulfur-containing olefins, which have enabled various modes of reactivity and thus allowed access to novel types of hydroacylation products. In addition to reactivity, a key to the success of these transformations is the control of regio-, stereo-, and chemoselectivity. In combination with substrate structure, strategies in enantioselective catalysis and metal-organic cooperative catalysis have been applied to achieve requisite reactivity and selectivity when required. A variety of products, such as medium-sized heterocycles, branched sulfur-containing and β-hydroxy ketones, and ketones bearing quaternary carbon centres have been synthesized via hydroacylation using these strategies. A method for preparing polyelectrolyte-stabilized palladium nanoparticles and their use in Suzuki coupling reactions have also been developed.

This work can be separated into two parts; the first will encompass chapters one and two, which discuss the use of the Catellani reaction to access different heterocycles. The second part will encompass the remaining chapters and deals with stereoselective reactions of arynes. Chapter one outlines the development of a general and high yielding synthesis of the phenanthridine nucleus via a palladium-catalyzed domino reaction of aryl iodides with N-H or N-trimethylsilyl imines. This strategy was applied in a succinct synthesis of benzo[c]phenanthridine alkaloids nitidine and NK109. Chapter two details the development of a Catellani-type reaction of aryl iodides with 2H-azirines. Conditions were found to selectively provide access to either the indole nucleus or unusual dihydroimidazoles. The yields of the products ranged from moderate to good, however, the success of the reaction is highly dependent on the structure of the 2H-azirine. A mechanism was proposed involving oxidative addition of the azirine to generate an azaalyl intermediate. In Chapter three the foray into the area of aryne chemistry begins. A stereoselective nickel- catalyzed [2+2+2] cycloaddition of 1,6-enynes with aryne intermediates was developed. Attempts were made at the development of an asymmetric variant of the reaction, however, only low enantiomeric excess was observed. Good diastereoselectivity could be obtained when an allylic substituent was present. The yields of the products ranged from moderate to excellent. However, the yields vary greatly and in a number of cases the reactions were unsuccessful. Finally, in chapter four the development of a general and high yielding annulation strategy for the synthesis of various carbo- and heterocycles, based on an intramolecular aryne ene reaction is described. It was found that the geometry of the olefin is crucial to the success of the reaction and it that regioselective hydrogen migration occurs. Furthermore, the electronic nature of the aryne was found to be important to the success of the reaction. Deuterium labeling studies and DFT calculations provided insight into the reaction mechanism. The data suggested a concerted asynchronous transition state, resembling a nucleophilic attack on the aryne. This strategy was successfully applied to the formal synthesis of the ethanophenanthridine alkaloid (±)-crinine. In a similar vein, preliminary results demonstrating an intramolecular, formal [2+2] cycloaddition of an aryne with an S, O-ketene acetal to give interesting tricyclic benzocyclobutene products are disclosed.

The development of new, improved methods for forming carbon–carbon and carbon–heteroatom bonds is the basic goal in synthetic organic chemistry. In the Lautens group, many recent advances have been made using late transition metals such as rhodium and palladium. One such research project involves the synthesis of indoles through tandem C–N and C–C coupling reactions using gem-dibromoolefin starting materials, and this area serves as a starting point for the research described. Chapter 1 describes a method by which the tandem use of gem-dibromoolefins can be halted to give intramolecular monocoupling reactions, maintaining one of the carbon–bromine bonds which can serve as a useful handle for further functionalization. The use of copper as a catalyst is key to this reaction, as it features a unique mechanism for carbon–heteroatom bond formation. Benzofurans and benzothiophenes can be prepared by this method. Chapter 2 describes the synthesis of 2-bromoindoles using an intramolecular Buchwald–Hartwig amination of gem-dibromoolefins. It is found that the products are more reactive towards palladium(0) than the starting material, and the use of a bulky phosphine ligand which facilitates reversible oxidative addition is required. This represents one of the first catalytic applications of this step in synthesis. Chapter 3 further explores the concept of reversible oxidative addition in a novel carbohalogenation reaction of alkenes. Aryl iodides tethered to alkenes are treated with a palladium(0) catalysts, which can undergo the basic steps of oxidative addition, carbopalladation, and novel sp2 carbon–iodine reductive elimination. This process is remarkably simple in concept, and is a waste-free, atom economically method for preparing new carbon–carbon bonds. Chapter 4 discusses various limitations to the carbohalogenation methodology, and seeks to overcome these problems. The use of aryl bromide starting materials can be accomplished by adding an iodide source to the reaction, allowing halide exchange of palladium(II) intermediates to occur. Intermolecular and asymmetric variants are also explored. Computational studies are discussed which reveal useful mechanistic details of the catalytic cycle, and this information is used in the development of novel phosphine ligands.

A range of N-H alkynylaziridines were prepared from amphoteric unprotected aziridine aldehydes without protecting-group manipulation. Unprotected alpha -amino allenes can be obtained from these strained propargyl amines via a 9-BBN mediated hydride transfer. Further transformation of alpha -amino allenes to 2,4,6-trisubstituted pyridines was realized. We also developed another class of amphoteric molecules – alpha-boryl aldehydes, equipped with the tetrahedral MIDA boryl group. A wide range of boryl-substituted building blocks or functionalized boronic acid derivatives have been accessed from these bench-stable alpha-borylcarbonyl compounds. Further chemoselective transformations of these alpha-boryl aldehyde derived building blocks have been conducted, where alph-boryl isocyanates, alpha-aminoboronic acids, acylboronates, and borylated heterocycles were achieved through the decarboxylative functionalization of alpha-borylcarboxylic acids.

Transition metal-catalyzed olefin hydroacylation represents an atom-economical approach for the synthesis of valuable ketone products. To date, the intermolecular variant of this reaction suffers from several drawbacks, which include limited substrate scope, poor reactivity and/or regioselectivity for non-activated, non-chelating alkene substrates, and competitive reductive decarbonylation pathways that lead to catalyst decomposition. Herein, we report the linear-selective intermolecular hydroacylation of a wide range of electronically diverse olefins with salicylaldehydes employing catalyst loadings as low as 2 mol%. A unique reactivity profile is observed for the chiral C2-symmetric phosphoramidite ligand employed in our catalyst system, and thus, we outline progress made towards the synthesis of new phosphoramidite ligands. We have applied our methodology in the total synthesis of nine octaketide natural products belonging to the dothiorelone, cytosporone, and phomopsin families. Due to recent reports demonstrating the anticancer activity of cytosporone B (Csn-B), we will also discuss progress towards the synthesis of Csn-B analogues.

In 2006, an amphoteric molecule containing both an aldehyde and an unprotected amine was reported in the Yudin group by Dr. Ryan Hili. The unprotected aziridine aldehyde exists as homochiral dimers. Furthermore, due to the reversibility of the hemiacetal formation, the free aldehyde is available to undergo a wide array of reactions including an Ugi multicomponent reaction to give the final peptide macrocycle. Thus far, the mechanistic pathway involved in the Ugi reaction between S-trans aziridine aldehyde dimer and L-amino acids in the presence of tert-butyl isocyanide has given high diastereoselectivity whereas low diastereoselectivity is observed if the aziridine dimer is of the opposite stereochemistry. Herein, preliminary results show that a S-cis aziridine aldehyde with either a D or L-secondary amino acid gives high diastereoselectivity showing that the reaction is under Felkin-Ahn control.

Alzheimer’s disease (AD), a progressive age-related neurodegenerative disorder is characterized by impairments in memory and cognitive functions. The two main pathogenic hallmarks associated with the progression of this multifactorial disease include accumulation of amyloid-beta (Aβ) plaques and the deterioration of the cholinergic system in the brain. Using cost-effective synthetic procedures, mono-, di-, and tri- substituted sym-triazine derivatives incorporating acetylcholine substrate analogues and aromatic phenyl moieties were synthesized for the targeted modulation of Aβ aggregation and acetylcholinesterase (AChE) activity. A subset of these sym-triazines demonstrated dual inhibition of Aβ fibrillization and AChE hydrolytic activity in vitro studies. These highly effective compounds were also shown to be well tolerated by differentiated human neuronal cells in cell viability tests. These novel compounds have the potential to undergo future in vivo pharmaceutical analysis and have a positive impact on the quality of life of the people living with this devastating disease and their caretakers.

Doctor of Philosophy / Department of Chemistry / Stefan Kraft / Highly toxic aromatic halogenated compounds such as PCB’s, PCDF’s and PCDD’s act as persistent organic pollutants and can bio-accumulate. These compounds are highly stable to oxidation, reduction and thermal degradation. Current remediation technologies are expensive and can cause the formation of even more toxic byproducts. It is clear that an environmentally friendly and inexpensive remediation technology is required. Our goal was the synthesis of dehalogenation catalysts incorporating aromatic side arms for the pre-concentration of the substrates to the catalysts. We envisioned that aromatic side arms would allow the aggregation of catalyst and substrate to form a pre-complex that would enhance rates of dehalogenation. Rapid and stereochemically predictable synthesis of N and C functionalized nickel cyclam complexes were a priority for this project. Synthesis of N-functionalized cyclam molecules and subsequent metal incorporation proceeds smoothly to form trans(III) nickel cyclam complexes. However longer reaction times, initiation periods and short catalyst lifetimes made these complexes unsuitable for long-term study. Cyclization of dipeptides and tetrapeptides using a metal template in basic conditions led to the formation of cyclopeptide nickel complexes with stereochemistry retained from the peptide precursors. Free cyclopeptides could be isolated from the nickel complexes by treatment with HCl. Cyclopeptides are reduced to the cyclam molecules via a LAH reduction in low to moderate yields. Nickel incorporation into the cyclam molecules produced C-functionalized nickel catalysts with stereochemical integrity maintained throughout the synthesis. Intermolecular CH-π interactions can be seen in the solid state for the nickel cyclam complexes with aromatic side arms. Reduction data show that the C-functionalized catalysts do not show improved rates of reduction for several aromatic substrates but small rate enhancements are observed for the reduction of chloronaphthalene over the unfunctionalized catalyst.