Ph.D. Chemistry

Permanent URI for this collectionhttps://hdl.handle.net/10464/2239

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Open Access
Towards the total synthesis of semi-synthetic opiate species and presilphiperfolan-1-ol.
(Brock University) Wicks, Christopher; Department of Chemistry
The synthesis of 10-keto opiates is underscored by the urgent need of novel κ-selective opioid agonists that offer comparable analgesic effects to their alkaloid precursors while limiting the risks of physical dependency. While there have been multiple syntheses of oxycodone reported, there has been only one total synthesis of 10-keto-oxycodone to date. Inspired by previous work from the Fukuyama group we investigated a functional group-based approach to oxycodone and 10-keto-oxycodone highlighted by a key oxidative dearomatization step. Efforts made towards this end with be discussed herein. Presilphiperfolanols constitute a family of sesquiterpenes that can undergo further rearrangement to afford a diverse array of terpenoid skeletons due to the ring strain that is inherent to their carbocyclic framework. This structurally complex family of natural products is unique owing to their highly compact tricyclo[5.3.1.04,11]undecane sesquiterpene skeleton that bears five contiguous stereocenters, two all-carbon quaternary centers, and a tertiary hydroxy group. To date, only three natural presilphiperfolanols have been isolated: presilphiperfolan-1β-ol, presilphiperfolan-8α-ol, and presilphiperfolan-9α-ol. In addition to being important biosynthetic precursors, these natural products have also been found to exhibit antimicrobial activity and insecticidal properties. Of particular interest is presilphiperfolan-1β-ol, which has been previously synthesized by Stoltz in the first asymmetric synthesis of a presilphiperfolanol, and subsequently by Tiefenbacher in a semi-synthesis involving supramolecular catalysis. Unlike the approaches by Stoltz and Tiefenbacher, our group has discovered a highly efficient tandem gold (I) catalyzed 5-exo-dig and formal [4+2] cyclization that affords direct access to this tricyclo[5.3.1.04,11]undecane sesquiterpene skeleton. This method has the added benefit of generating 3 of the 5 requisite stereocenters found within the target in a single transformation. Efforts towards the completion of the total synthesis of presilphiperfolan-1-ol will be discussed herein. Experimental and spectral data are provided for all newly synthesized compounds.
Open Access
Synthesis and Reactivity of Diimino-N-Heterocyclic Carbene Supported Tetrylones
(Brock University) Segizbayev, Medet; Department of Chemistry
The work described in this thesis is focused on the preparation of a series of novel tetrylones stabilized by diimino-N-heterocyclic carbene followed by studies on their reactivity. In the pursuit of dimNHC-supported stannylone III-6, attempts to isolate free dimNHC ligand IV-19 before its reaction with a tin reagent proved challenging. Conventional deprotonation of imidazolium salt III-7 led to undesired rearrangement product III-10. Facing difficulties in isolating free dimNHC III-8, alternative routes were explored. An effective solution involved using bis(trimethylsilyl)amido chlorotin(II), SnCl[N(SiMe3)2], which generated dimNHC ligand III-8 in-situ. This process simultaneously incorporated the (Sn+-Cl) fragment at the central carbene position, forming cationic stannylene III-14. The subsequent reduction of III-14 with excess potassium graphite resulted in the desired stannylone III-6. The reactivity studies of dimNHC-supported germylone IV-6 were expanded. Germylone IV-6 reacts with azides N3R (R=SiMe3 or p-tolyl) to furnish the first examples of germanium π-complexes IV-10 and IV-11. Reaction of IV-10 with tetrachloro-o-benzoquinone results in the net transfer of a germanium atom and formation of the free diimino-guanidine ligand IV-13. Germylone IV-6 reacts with B(C6F5)3 to give the zwitterionic borate V-7. This compound can be converted into the hydroborate V-8 and further into germylene-borane V-4. Compound V-4 is a Ge/B analogue of Stephan’s FLP parent P/B compound (C6H2Me3)2P-C6F4-B(C6F5)2 but unlike the latter cannot split dihydrogen. Moreover, attempts to prepare a Ge/B analogue of the zwitterion (C6H2Me3)2HP-C6F4-BH(C6F5)2 by protonation of borate V-8 resulted in immediate elimination of H2. A synthetic approach for dimNHC-supported silylone VI-9 involved utilizing the adduct of dimNHC with ZnCl2 VI-11. The adduct VI-11 was prepared by trapping the in-situ formed dimNHC IV-19 with a Lewis acid (ZnCl2). Subsequent exchange between the dimNHC →ZnCl2 adduct VI-11 and the IPr→SiCl2 silylene VI-12 resulted in the formation of the novel dimNHC-supported silylene VI-13. Finally, VI-13 was successfully reduced to yield the desired dimNHC-supported silylone VI-9. Later, we found that dimNHC IV-19 could be directly prepared from imidazolium salt VI-10 by deprotonation with IPr, serving as a Lewis acid-free base. IV-19 is the first isolable diimino carbene. Upon heating IV-19 in toluene, it cleanly converted to the aromatic C-C bond activation product IV-17. With dimNHC IV-19, we established an alternative synthetic route to silylone VI-9 using ligand IV-19 and HSiCl3 as starting reagents.
Open Access
Transition Metal-Free Hydrosilylation and Hydroboration of Unsaturated Carbon-Heteroatom Bonds
(Brock University) Clarke, Joshua A.; Department of Chemistry
The hydrosilylation or hydroboration of unsaturated C-O and C-N bonds yields valuable reagents and intermediates for organic synthesis. Traditionally, these reactions have been carried out by transition metal catalysts which are generally expensive and toxic, or stoichiometric reagents which produce a significant amount of waste. As such, transition metal-free catalytic alternatives have steadily gained popularity as a more sustainable alternative. This thesis presents the use of cheap and readily available simple alkali metal bases such as KOtBu and nBuLi as powerful catalysts for the reduction of carbonyls and imines. Notably, aldehydes can be selectively obtained through the reduction of tertiary amides and esters, and amines can be produced from nitriles using a similar method. These conversions have previously been relegated to the domain of late transition metal catalysts. Variation of the silane or borane was found to be highly influential in adjusting the chemoselectivity. For example, in the conversion of amides to aldehydes, use of (EtO)3SiH resulted in overreduction to the amine product, whereas (EtO)2MeSiH allowed for selective reduction to the aldehyde equivalent. In this work, we discuss our investigations into the scope and selectivity of this straightforward yet effective system. Additionally, we introduce a new approach for achieving long-term precise control of reaction conditions at low temperatures.
Open Access
Programing strand displacement reaction pathways using small molecular DNA binders
(Brock University) Xu, Junpeng; Department of Chemistry
DNA has been used in nature as carriers of heredity information for billions of years. The last four decades have witnessed the success of DNA nanotechnology, an interdisciplinary research area in which DNA is used as a synthetic engineering tool rather than a carrier of genetic information. The growth of DNA nanotechnology crosses the boundaries between physics, chemistry, biology and computer science and enables DNA to function as an electronic component, substrate, drug delivery vector and data storage unit. The hybridization of DNA strictly follows the by Watson-Crick rule; thus, DNA base pairs are the most reliable and predictable building block in the true nanometer range. New methods and designs for controlling DNA hybridization have always provided the most essential momentum for the development of DNA nanotechnology. When small molecules bind to the double helical structure of DNA, either through intercalation or minor groove binding, the stability and functionality of DNA may be significantly altered, which is a fundamental basis for many therapeutic and sensing applications. Herein, we reveal, for the first time, that small molecular DNA binders may also be used to program the reaction pathways of toehold-mediated DNA strand displacement, an elementary building block in DNA nanotechnology.
Open Access
Synthesis of unnatural analogues of narciclasine: Chemoenzymatic synthesis of 2-epi-1-hydroxymethylnarciclasine
(Brock University) Bedard, Korey; Department of Chemistry
An approach to the synthesis of novel C-1 analogues of narciclasine has been developed. The synthesis relies on chemoenzymatic dihydroxylation of an arene, Stille coupling, and an intramolecular Heck reaction to affect key transformations. The synthesis of the targeted C-1 analogues addresses a gap in literature where few narciclasine analogues have been prepared, with no C-1 homologues existing to date. The synthetic route to 2-epi-1-hydroxymethylnarciclasine, as well as a possible route to several other derivatives, is described in detail. Experimental and spectral data are provided for all newly synthesized compounds.
Open Access
Synthesis of C-1 Homologues of Narciclasine
(Brock University) Habaz, Lihi; Department of Chemistry
This thesis describes current progress towards the total synthesis of C1-homologues of the Amaryllidaceae alkaloid narciclasine (1), a powerful anticancer agent which suffers from a poor solubility profile. A 15-step chemoenzymatic total synthesis of C-1 carboxymethyl narciclasine (248) was accomplished. A key step in this convergent synthesis is the formation of the C ring syn-diol moiety via the chemoenzymatic dihydroxylation of ortho-dibromobenzene to provide the corresponding cis-dihydrodiene diol as a single enantiomer, which constitutes an efficient method of generating chiral substrates from readily available commercial materials. The dense A ring functionalities are derived from another commercially available unit; ortho-vanillin, via previously established protocols. Further key steps involve a nitroso Diels-Alder reaction and an intramolecular Heck reaction. The C-1 homologue that was prepared, 248, was then tested for its biological activity against natural narciclasine as the positive control. Experimental and spectral data are provided for all novel compounds.
Open Access
Synthesis and Reactivity of Low Valent Silicon and Phosphorus Compounds
(Brock University) Baradzenka, Aliona; Department of Chemistry
The research described in this thesis is focused on studying the use of phosphinoamidinato ligand NP (NP = [ArNC(Ph)NPiPr2]– (Ar = 2,6-iPr2C6H3)) to stabilize low-valent main group element compounds. Reduction of silane (NP)SiCl3 by magnesium allows for the high-yield preparation of base-stabilized disilylene [(NP)Si-]2. Although it is stable at room temperature, upon heating it rearranges via intermolecular N-P activation into an N,Si-heterocyclic silylene supported by a phosphine donor. The reactivity of [(NP)Si-]2 in the single bond activation of pinacolborane, phenylsilane and diphenylphosphine was tested. Additionally, the phosphidosilylene (NP)SiPPh2 that is formed in the last reaction was found to perform P-P coupling when reacted with diphenylphosphine. Experimental pursuits were taken to elucidate the mechanism of formation of disilylene [(NP)Si-]2, and some insights into its fluxionality in solution were obtained. Disilylene [(NP)Si-]2 was reacted with Si(II) and Ge(II) chlorides to yield the products of tetrylene insertion into the Si-Si bond, the low-valent compounds [(NP)Si-Si(Cl)2-Si(NP)], [(NP)Si(Cl)2Si-Si(NP)] and [(NP)Si(Cl)2Ge-Si(NP)]. Compound [(NP)Si-Si(Cl)2-Si(NP)] is the kinetic product of the direct insertion of SiCl2 fragment into Si-Si bond of [(NP)Si-]2. The thermodynamic product of the insertion of silicon dichloride is disilylene [(NP)Si(Cl)2Si-Si(NP)] that is the consequence of migration of chlorides to terminal Si center. The reaction of [(NP)Si-]2 with GeCl2 produced only one compound [(NP)Si(Cl)2Ge-Si(NP)] that is a rear example of germylene-silylene. Interaction of [(NP)Si-]2 with SiCl4 and SiHCl3 produced a new example of acyclic disilyl silylene. Reduction of (NP)PCl2 with potassium graphite allowed isolation of the base-stabilized phosphinidene (NP)P. Its reactivity was studied. The use of substrates with E-H bonds like pinacolborane, phenylsilane and diphenylphosphine yielded compounds (NP)Bpin (pin = (OC(CH3)2)2) and NPH, (NP)SiH2Ph and NPH, NPH-P-PPh2, respectively, which are the result of N-P and E-H bond metathesis. Upon reaction with tetrachlorobenzoquinone both phosphorus atoms of phosphinidene (NP)P underwent oxidation. (NP)P reacted with benzaldehyde and phenylisocyanate as a phospha-Wittig reagent. Additionally, (NP)P was transformed into phosphinidene oxide (NP)P=O, iminophosphine (NP)P=Np-Tol and phosphinidene sulfide (NP)P=S. Transient (NP)P=O and (NP)P=Np-Tol were captured by para-tolyl isocyanate to form compound (NP)P(N,N-(Np-Tol)2CO). All the compounds were fully characterized by NMR and for most of them single crystal X-ray structure was obtained.
Open Access
Enzymatic Studies of Bromocyclohexadienediols & Semi-synthesis of Narciclasine Analogues
(Brock University) Goulart Stollmaier, Juana; Department of Chemistry
This thesis describes two projects: • cis-Diene bromo diol obtained from the microbial oxidation of bromobenzene was used as a substrate for lipase-catalyzed acylation and epoxidation reactions. The model studies showed that the regiochemistry of the acylation is solvent dependent. The chemoenzymatic epoxidation followed the expected regiochemistry when compared to the chemical epoxidation with m-CPBA, but with the unexpected formation of bromoconduritol-C, an important intermediate whose electrochemical reduction led to the short synthesis of (-)-conduritol-C. • A detailed description is given to the studies of conversion of natural narciclasine to its C-1 enol derivative, followed by the attempted conversion of this material to its triflate, in order to conduct cross-coupling at the C-1 position. However, it resulted in a triflate at C-6 that was successfully coupled with several functionalities. All compounds were fully deprotected and subjected to evaluation of biological activity. Only one derivative showed moderate activity as compared to those of narciclasine and pancratistatin. Spectral and physical data are provided for all new compounds.
Open Access
Reactivity of a Low Valent Gallium Compound
(Brock University) Kassymbek, Aishabibi; Department of Chemistry
The work described in this thesis is conducted to expand the reactivity of the β-diketiminate gallium(I) compound, NacNacGa (NacNac=[ArNC(Me)HC(Me)NAr]−, Ar=2,6-iPr2C6H3). The reactivity of NacNacGa towards various unsaturated compounds is studied. In particular, reaction between NacNacGa and phenyl isothiocyanate resulted in the oxidative addition of the C=S bond under ambient conditions, leading to the isolation cyclization product NacNacGa(κ2-S2CNPh) and sulfide isocyanide-bridged dimer (NacNacGa)2(μ-S)(μ-CNPh). Additionally, a [1+4] cycloaddition with a conjugated aldehyde (methacrolein) and a [1+2+3] cycloaddition with isocyanate and carbodiimide are presented. The oxidative cleavage of P=S bond of triphenylphosphine sulfide at increased temperatures gave the previously reported sulfide bridged gallium dimer. In situ oxidation of NacNacGa in the presence of substrates featuring donor sites led to the C-H activation reactions. As such, C-activation of pyridine N-oxide, pyridine, cyclohexanone, DMSO, and Et3P=O by a transient NacNacGa=O resulting in the corresponding gallium hydroxides is demonstrated. DFT calculations suggested initial formation of adducts between substrates and NacNacGa=O followed by a C-H bond abstraction from the substrate. Similarly, a transient gallium imide NacNacGa=NSiMe3, generated from the reaction of NacNacGa with trimethylsilyl azide, is shown to cleave C-H bonds of pyridine, cyclohexanone, ethyl acetate, DMSO, and Et3P=O with the formation of gallium amides. In an attempt to isolate a gallium alkylidene, NacNacGa was treated with trimethylsilyl(diazomethane). Instead, a monomeric gallium nitrilimine and a metalated diazomethane were obtained. The gallium nitrilimine undergoes 1,3-addition reaction with phenylsilane and catecholborane forming gallium hydrazonides. Its reaction with diborane resulted in the formal nitrene insertion into the B-B bond to produce a gallium diborylamide. DFT calculations revealed intermediate gallium alkylidene formation from the reaction of NacNacGa with diazomethane that upon reaction with the second equivalent of diazomethane leads to a gallium nitrilimine.
Open Access
Design of Redox-active Ligands: In Pursuit of Stable Radicals, their Complexes, and Assembly of Paramagnetic Coordination Clusters.
(Brock University) Bonanno, Nico Matteo; Department of Chemistry
This thesis describes the design, synthesis, properties, and coordination chemistry of redoxactive ligands. This thesis also explores new ways of expanding our ligand systems, in order to improve their binding capacities. We accomplished this by utilizing familiar redox-active moieties and structures to those published previously in our group, but with enhanced topological capacities and predictable structural outcomes. Chapter 1 begins with a general outline of the fundamental principles that govern organic radicals including; their reactivity, their properties and applications, and how these can be applied to the design of ligands for polynuclear assembly. Chapter 2 starts with a brief overview of arylazo ligands and the synthesis of a new hydrazone substituted phenalenol ligand (2.1). In the following section (2.2) we use this ligand to produce homoleptic ligand mixed-valence complexes featuring trivalent cobalt and iron metals. The chapter is concluded (2.3) with the synthesis of a new ditopic aryl-azo ligand and its cobalt coordination chemistry involving a neutral tetra-radical/tetra-nuclear molecular grid featuring valence tautomerism. Chapter 3 begins with the design and synthesis of a new ditopic diamino phenol ligand, which was found to oxidize to a neutral stable phenoxyl radical (3.1-3.2). The solution properties, which include reversible pi-dimerization of this stable radical are also described (3.3), and later the substitution chemistry of this new ligand is explored (3.4). In chapter 4, we describe the coordination chemistry of this new ditopic aminophenol ligand, which includes assembly into several coordination clusters involving copper (4.2), iron (4.3), nickel (4.4), and zinc (4.5). These coordination clusters feature the ligand in a variety of oxidation states; including rare examples of dianion “aminyl” radical clusters. In chapter 5, we begin with a description of a new synthetic derivative which can be used for the construction of larger tetratopic or asymmetric diamino phenol ligands. In 5.2 we describe the synthesis of a tetratopic aminophenol ligand along with its reactivity and aerial oxidation to a tri-phenoxyl radical. In 5.3, we conclude the thesis with the use of an asymmetric diamino phenol ligand and it’s Cu(II/III) coordination chemistry, which displayed unique reactivity with molecular oxygen.
Open Access
Reactivity of Aluminum Carbenoid with Unsaturated Substrates
(Brock University) Dmitrienko, Anton; Department of Chemistry
Reactivity patterns of the β-diketiminate aluminum(I) complex NacNacAl towards a variety of unsaturated molecules were determined. Reaction of NacNacAl with one equivalent of benzophenone affords η2(C,O) adduct III-2 that undergoes cyclization reactions with benzophenone (III-3), aldimine (III-4), quinoline (III-5), pyridine (III-6), phenyl nitrile (III-7), trimethylsilyl azide (III-8), and a saturated cyclic thiourea (III-9). The latter reacted via unusual C−N cleavage. Analogous η2-coordination products were prepared with p-tolyl benzoate (IV-6), N,N-dimethylbenzamide (IV-9) and (1‐phenylethylidene)aniline (IV-13). Addition of pyridine to such species results in [2+2] cycloaddition products analogous to III-6, except for the case of p‐tolyl benzoate when a migration of the alkoxy group from the ester moiety accompanied by hydrogen transfer from pyridine preserves the aromaticity within the latter. Chemoselective couplings between aliphatic ketones and pyridine were exemplified by reactions with non-enolizable (1R)-(‒) fenchone and enolizable yet sterically encumbered isophorone. The reaction with the CH‐acidic ketone (1R) (+) camphor afforded a hydrido alkoxide (IV-11) as the result of enolization. Whereas the reaction of NacNacAl with (1R)‐(−)‐fenchone in the absence of pyridine led to CH activation in the isopropyl group of the NacNac ligand. NacNacAl demonstrated diverse reactivity in reactions with N‐heterocycles. 4 Dimethylaminopyridine induces rearrangement of NacNacAl by deprotonation of backbone methyl group of the ligand. C−H activation of the methyl group of 4‐picoline produced a species with a reactive terminal methylene. Reaction of NacNacAl with 3,5 lutidine led to the cleavage of the sp2 C−H bond (4‐position). Another reactivity mode was observed for quinoline, which undergoes 2,2′‐coupling. Finally, a reaction of NacNacAl with phthalazine produced a product of the N−N bond cleavage. NacNacAl reacted with a series of polycyclic aromatic hydrocarbons via [4+1] cycloaddition. While a reaction with anthracene was irreversible, with the formation of products of activation of the lateral and central rings, reactions with phenanthrene, triphenylene, and fluoranthene were reversible. Heating reaction mixtures at 90 °C yielded dialuminum hydride VI-6. Mechanistic studies showed that the reaction proceeds via dissociation of polycycles with the release of NacNacAl that undergoes further intermolecular transformations. All novel complexes were characterized by spectroscopic methods and X-ray diffraction analysis for most of them.
Open Access
Dynamic DNA Nanotechnology for Probing Single Nucleotide Variants and DNA Modifications
(Brock University) Wang, Guan; Department of Chemistry
In the last decades, various DNA hybridization probes have been developed that attempt to conquer the challenge of single-nucleotide-variants (SNVs) detection. Even though a powerful toolbox including the toehold-exchange reaction, the dynamic ‘sink’ design, and the polymerase chain reaction (PCR) has been built, it still faces practical problems. For example, the natural DNA is usually in double-stranded form whereas most hybridization probes aim for single-stranded targets; the concentration of extracted DNA samples is totally unknown thus may lay outside the optimal design of probes/primers. To achieve ultra-high sensitivity and specificity, expensive and sophisticated machines such as digital droplet PCR and next-generation-sequencing may be inapplicable in rural areas. Therefore, the quantitative PCR method is still the gold standard for clinical tests. Thus motivated, my PhD career was mainly focused on the fundamental understanding of the challenges in SNVs discrimination and developing robust, versatile, and user-friendly probes/strategies. In this thesis, Chapter 1 provides a general introduction of dynamic DNA nanotechnology and its representative applications in discriminating SNVs. Chapter 2 to 4 describe three completed projects that aim to understand the thermodynamic and kinetic properties of strand displacement reactions and to circumvent the challenges of discriminating SNVs through finely tuned probes/assays.
Open Access
Synthesis of Cyclopropenium-Appended Organocatalysts and Applications
(Brock University) Smajlagic, Ivor; Department of Chemistry
Enclosed within this dissertation is the development and application of multiple cyclopropenium-containing compounds formally belonging to two closely-related classes of organocatalysts, namely thioureas and squaramides. The former catalyst, coined as a thiourea-cyclopropenium, is deployed in pyranylation reactions of alcohols and phenols, as well as Friedel–Crafts alkylation, while the latter—a squaramide-cyclopropenium catalyst—targets oxime ether bond formation. Accompanying these innovative synthetic methodologies are comprehensive experimental and computational mechanistic studies that work in synergy to delineate numerous key features, all of which provide valuable information with respect to understanding the multifaceted nature of catalysis. Experimental and spectral data are provided for all new compounds.
Open Access
Approaches towards C-10-hydroxylated analogues of narciclasine
(Brock University) Ticli, Vincenzo; Department of Chemistry
Discussed in this thesis is the synthesis of a C10-benzyloxy unnatural derivative of narciclasine. The described approach involves the use of homochiral cyclohexadiene diols, products of the biocatalytic transformation of aromatic compounds, as precursors to ring C, and of highly oxygenated aromatic molecules to construct ring A. The document also reports a detailed account of the protocols studied for the intramolecular formation of ring B. Experimental data and spectral data are provided for the novel compounds.
Open Access
Stereoselective Synthesis of N-Propargyl Alkynes and Axial Chiral N-Allenes with Epimeric Imidazolone Auxiliaries
(Brock University) Sechi, Maria Laura; Department of Chemistry
This thesis describes the synthesis of an N-propargyl pyrroloimidazolone chiral auxiliary/directing group with syn or anti stereochemistry derived from L-proline hydantoin and its diastereoselective lithiation for the synthesis of central chiral alkynes and axial chiral allenamides. Lithiation followed by quench with alkylating electrophiles or aldehydes/ketones gives access to chiral propargyl or allene derivatives respectively, both in high diastereomeric ratio (>95:5 dr). Use of the anti epimer of the aforementioned imidazolone chiral auxiliary results in the reversal of stereochemistry at the propargyl position of the products, again with high diastereoselectivity. This conclusion was confirmed by the synthesis and comparison of the solely central chiral alkynes from both the syn and anti series, obtained via acid-induced elimination of the labile silyloxy protecting group. Therefore, this method allows for the preparation of both enantiomeric propargyl products without the need to prepare additional starting materials from more expensive unnatural D-proline. X-Ray analysis of an allene derivative confirmed that lithiation of the syn pyrroloimidazolone followed by direct quench with prochiral benzaldehydes led to axial chiral allenamides in high selectivity (>95:5 dr) with atypical stereochemistry of the resulting benzylic alcohol. Lithiation followed by transmetalation to a titanium triisopropoxide intermediate before benzaldehyde quench gave epimeric allenamides with opposite stereochemistry at the benzylic alcohol. Density Functional Theory (DFT) computational modelling explained this reversal of stereochemistry at the benzylic position as arising from stereofacial attack in 6,5-bicyclic or 6-membered transition states in the lithium or titanium series, respectively.
Open Access
Investigating the Cluster Chemistry of α-Methyl-2-pyridine methanol (mpmH) with Select 3d Ions
(Brock University) Abbasi, Parisa; Department of Chemistry
This thesis describes an investigation of the coordination chemistry of the potentially chiral bridging, chelating ligand, α-methyl-2-pyridinemethanol (mpmH) with select 3d ions for the discovery of polynuclear clusters with single molecule magnet (SMM) properties. Chapter 1 introduces the theory of molecular magnetism, SMMs and the concepts of chiral SMMs, magnetochiral dichroism and multiferroics. In Chapter 2, two NiII clusters, {Ni8} and {Ni18} prepared from rac-mpmH are reported. The {Ni8} cluster crystallizes in a trapezoidal prismatic topology and contains tetrazolate ligands that are formed via a metal-assisted click reaction. The molecular structure of the second {Ni18} cluster is highly disordered comprising of eight edge-sharing cubane subunits. Dc magnetic susceptibility measurements reveal dominant ferromagnetic interactions down to ~18 K, stabilizing spin states with large values, whereas at T < 18 K the antiferromagnetic contribution results in the population of smaller, but appreciable non-zero spin states. Ac magnetic susceptibility measurements confirm the presence of two relaxation processes at two temperature regimes that is extremely rare for a 3d-metal based SMM. The first at low temperature (5 K) is attributed to conventional SMM behavior with τ0 = 3.26 × 10-10 s and Ueff = 11 K. The origin of high temperature (15 K) relaxation process with a large Ueff = 381 K and τ0 = 2.7 × 10-15 s is less clear, but tentatively assigned to spin-glass properties. In Chapter 3, the synthesis and structure of a large mixed-valence [MnII2MnIII28MnIV] polynuclear cluster with a closed cage-like conformation is presented. Ac magnetic susceptibility measurements show the compound is an SMM with Ueff of 58 K, that is large for a 3d cluster, and a τ0 = 3 × 10−8 s. Chapter 4 describes the coordination chemistry of racemic and chiral-mpmH with CuII and FeIII, where the synthesis and magnetostructural properties of a chiral {Cu4} tetramer, a non-chiral 1-D chain, as well as a chiral {Fe6} and a non-chiral{Fe8} cluster are reported. Dc magnetic susceptibility measurements on all four complexes reveal the presence of dominant antiferromagnetic exchange interactions affording S = 0 spin ground states at low temperature that precludes the observation of any SMM behavior.
Open Access
Chemoenzymatic Formal Total Syntheses of Tetrodotoxin and an Approach to Daphenylline
(Brock University) Baidilov, Daler; Department of Chemistry
This thesis describes chemoenzymatic formal total syntheses of tetrodotoxin and a concise synthetic approach to daphenylline. Advanced intermediates for the syntheses of tetrodotoxin reported by the groups of Fukuyama, Alonso, and Sato were prepared. Key steps included toluene dioxygenase-mediated dihydroxylation of either iodobenzene or benzyl acetate and a [4+2] hetero-Diels-Alder cycloaddition/Kornblum–DeLaMare rearrangement sequence to construct a common enone intermediate. The resulting key enone was transformed into Fukuyama's intermediate in four steps, into Alonso's intermediate in six steps, and into Sato's intermediate in seven steps. Fukuyama’s route employed a highly stereoselective allyl cyanate-to-isocyanate rearrangement to install the nitrogen atom at C8a. This protocol was also successfully applied in designing a synthetic avenue to daphenylline. The ABC tricyclic skeleton of daphenylline was successfully constructed in just eight steps starting from readily available (S)-carvone.
Open Access
Magnetically Interesting Coordination Complexes Based on Macrocyclic Ligands
(Brock University) Ras Ali, Zineb; Department of Chemistry
The synthesis and study of select 3d and/or 4f coordination complexes prepared from crown ether and Schiff-base dual compartmental macrocycles are described herein, working towards the discovery and study of new families of macrocyclic-based single molecule magnets (SMMs). Chapter 1 introduces the general theory of magnetism, molecular magnetism and SMMs and provides the reader with a brief overview of the relevant coordination chemistry of the two families of macrocycles. In Chapter 2, two 15-crown-5 complexes [Ln(NO3)3(OH2)2(MeOH)], (where Ln(III) = Tb (I) and Dy (II)) have been prepared and characterized. X-ray diffraction studies reveal the two complexes crystallize as 1-D chains. Variable temperature ac magnetic susceptibility studies reveal that (II) is an SMM with two effective energy barriers, Ueff = 26 K (18 cm−1); τ0 = 4.10 × 10−7 s and Ueff = 41 K (29 cm−1); τ0 = 1.35 × 10−8 s, whereas ab initio studies suggest that the observation of slow relaxation of magnetization in the Tb complex (I) is hindered by the presence of rapid quantum tunneling mechanisms (QTM). Solid state photoluminescence measurements reveal the two complexes have well-resolved f–f transitions, where a Gaussian fit of the fine structure of the highest-energy emission band for the Dy(III) complex allows the Stark splitting of the ground state to be determined. In Chapter 3, select Ln(III) complexes with benzo and dibenzo 15-crown-5 macrocycles were synthesized and characterized. Reaction of Dy(III) together with benzo 15-crown-5 afforded a unique [Dy(OH2)8]3+ complex (III), where the hydrated Dy(III) cation is fully encapsulated within a supramolecular cage formed by three benzo 15-crown-5 macrocycles. Interestingly, the close to perfect square antiprismatic geometry of the 4f ion enhances its axial anisotropy, which suppresses quantum tunnelling mechanisms (QTM) in the ground and first excited states, resulting in the observation of SMM behavior in zero dc field. For this system the magnetic data were further supported by solid-state photoluminescence and ab initio studies, The introduction of a second benzene ring into the organic framework of the macrocycle increases its rigidity, where on coordination to Dy(III), affords the partially encapsulated complex (IV), which displays slow relaxation of magnetisation, consistent with SMM properties. In Chapter 4, the coordination chemistry of a dual compartmental Schiff-base macrocycle H2L3 containing O3O2 and N3O2 cavities was explored together with select 3d and 4f ions. In the first part of this chapter, the coordination chemistry of H2L3 with 3d metal ions is presented, where in the presence of NaOH, the Na(I) ions reside in the O3O2 cavity and the 3d ions occupy the second N3O2 cavity. Three coordination complexes containing Cu(II), Zn(II), and Mn(II) ions were prepared and characterized. The Cu(II), and Zn(II) complexes are monomeric with molecular formulae [CuNa(L3b)ClCH3OH]‧6H2O (V) and [ZnNa(L3b)(CH3COO)(CH3OH)]‧H2O (VI) respectively, while the Mn(II) complex crystallizes as a trimer with stoichiometry [Mn3Na2(L3)2(CH3COO)4]·5.75CH3OH·0.5H2O (VII). For complexes (V) and (VI), nucleophilic addition of the NH of the N3O2 cavity to the carbon atom of the adjacent imine results in a contraction of the N3O2 cavity and the formation of a five-membered imidazoline ring to afford the modified ligand L3b.The magnetic properties of (V) and (VII) are also reported. In the second part of this chapter, coordination of the macrocycle to select 4f ions in the absence of any base afforded the mononuclear complexes [Dy(H2L3)(H2O)2(CH3OH)2]Cl3·CH3OH, (VIII), and [Ln(H2L3)(H2O)3(CH3OH)] Cl3, where Ln(III) = Tb (IX), Er (X), and Gd (XI), in which the Ln(III) ion is coordinated in the O3O2 cavity. Magneto-structural studies on these complexes reveal that the Dy complex has a slightly different structure than the other three complexes, however all four 4f ions crystallize with square antiprismatic geometries, where only the Dy(III) complex (VIII) displays SMM properties.
Open Access
Synthesis and Derivatization of Amaryllidaceae Constituents – Narciclasine and Pancratistatin
(Brock University) Lapinskaite, Ringaile; Department of Chemistry
This thesis describes the synthesis and derivatization of narciclasine and pancratistatin. A detailed description is given to the total formal synthesis of pancratistatin through a reductive transposition approach and the total and semi-syntheses of 2-epi-narciclasine and its discovery as a new natural product. The last part of this work focuses on the search for a divergent approach to access C-1 narciclasine and C-1-pancratistatin derivatives from natural narciclasine. Experimental and spectral data are provided for the new compounds.
Open Access
Synthesis and Reactivity of Main Group Complexes for Applications in Small Molecule Activation
(Brock University) Nguyen, Minh Tho; Department of Chemistry
The work described in this thesis is focused on the preparation of a series of novel main group complexes, featuring unusual structural and bonding situations, and the study of their reactivity toward small molecules. The new zinc complexes dimphZnBu (V-2) and dimphZnCl2Li(THF)3 (V-3), supported by a diiminophenyl (dimph) ligand were prepared. The reaction of complex V-3 with LiHBEt3 resulted in hydride transfer to the C=N imine group to give an unusual zinc dimer (V-7). The latter transformation occurs via formation of compound (ɳ1(C),ĸ1(N)- 2,6-(2,6-iPr2C6H3N=CH)2C6H3)2Zn (V-5) which can be also accessed by reduction of V-7 with KC8. Diiminophenyl (dimph) proved to be an excellent ligand platform to stabilise a low-valent phosphorus centre. The resultant compound dimphP (VI-2), which can be rationalised as an imino-stabilised phosphinidene or benzoazaphopshole, shows remarkable chemical stability toward water and oxygen. VI-2 reacts with excess strong acid HCl to generate the P(III) chloride (dimHph)PCl (VI-6). Surprisingly, substitution of the chloride under some nucleophilic (KOBut) and electrophilic conditions (Me3SiOTf) regenerates the parent compound VI-2 by proton removal from the weakly acidic CH2N position. A related species (dimH2ph)P (VI-10) is produced upon thermal rearrangement of the hydride (dimHph)PH (VI-9). The molecular structure and reactivity of compounds VI-2 and other related compounds are also discussed. The reduction of the O,C,O-chelated phosphorus (III) chloride (VI-16) ( O,C,O = 2,6-bis[(2,6-diisopropyl)phenoxyl]phenyl) with KC8 or PMe3 resulted in the formation of a cyclic three-membered phosphorus compound (VI-18). The intermediacy of phosphinidene VI-17 was confirmed by trapping experiments and a VT 31P{1H} NMR study. The reaction of in-situ generated phosphinidene with either PhSiH3 or HBpin resulted in the formation of an unprecedented phosphine (VI-23). The treatment of VI-16 with two equivalents of DippNHC carbene led to ArP(Cl)NHC product (VI-24). The germylone dimNHCGe (dimNHC = diimino N-Heterocyclic Carbene, VII-8) was successfully prepared by the reduction of germanium cation (VII-7) with KC8. The molecular structure of VII-8 was unambiguously established, using NMR spectroscopy and single-crystal X-ray diffraction analysis. The reactivity of VII-8 was investigated. VII-8 is inactive towards butadiene but undergoes an oxidative cyclization with tetrachloro-o-benzoquinone to give a tetragermanium derivative. VII-8 undergoes oxidation addition of CH3I and PhI, followed by an unusual migration of the Me and Ph groups from germanium to the carbene ligand. Related chemistry takes place upon protonation with dry HCl, which results in the migration of the hydride to the carbene ligand.

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