Browsing by Author "Back, Thomas G."
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Item Open Access A new, concise synthesis of the brassinosteroids castasterone and brassinolide(1992) Blazecka, Peter G.; Back, Thomas G.Item Open Access A novel route to 4-quinolones and an enantioselective total synthesis of virantmycin(2004) Wulff, Jeremy Earle; Back, Thomas G.Item Open Access An investigation of chirality transfer in <2,3> sigmatropic rearrangements and syn-eliminations of chiral selenoxides(1993) Jones, John Howard; Back, Thomas G.Item Embargo An investigation of chirality transfer in [2,3] sigmatropic rearrangements and syn-eliminations of chiral selenoxides(1993) Jones, John Howard; Back, Thomas G.Item Open Access Applications of unsaturated sulfones to the synthesis of indoles, carbazoles and other heterocycles(2001) Taylor, Jerry; Back, Thomas G.Item Open Access Asymmetric reactions with camphorseleno chiral auxilliaries(1998) Nan, Siqiao; Back, Thomas G.Item Open Access Benzylisoquinoline Alkaloid Biosynthesis in Sacred Lotus (Nelumbo nucifera)(2022-08-29) Menendez Perdomo, Ivette M.; Facchini, Peter J.; Ng, Kenneth K.S.; Yeaman, Samuel J.; Back, Thomas G.; Ober, Dietrich, O.Benzylisoquinoline alkaloids (BIA) constitute a family of plant specialized metabolites comprising numerous bioactive compounds. BIA metabolism has been extensively studied in the opium poppy and related species in the Ranunculales order, but limited research has been conducted in non-model plants. Sacred lotus (Nelumbo nucifera), in the order Proteales, is an ancient aquatic plant rich in proaporphine, aporphine, and bisbenzylisoquinoline alkaloids, with a prevalence of unusual R-enantiomers. However, BIA biosynthetic genes and cognate enzymes in this plant remain unknown.Considering the proposed monophyletic origin of BIA biosynthesis in Angiosperms and sacred lotus’ reported alkaloid profile, opium poppy’s well-established pathways could be envisaged as a blueprint to predict the corresponding biosynthetic genes in N. nucifera. This thesis describes the isolation and characterization of several genes involved in Nelumbo’s BIA metabolism, including those purportedly encoding for norcoclaurine synthase, O- and N-methyltransferases, proaporphine synthase, bisbenzylisoquinoline synthase, and aporphine methylenedioxy bridge synthase. Through a combination of in vitro assays with recombinant enzymes and plant total protein extracts and organ-specific correlational analysis between transcript levels and alkaloid content, we demonstrate that NnOMT1 acts as the main 6-O-methyltransferase (favoring the conversion of (R)-norcoclaurine), whereas NnOMT5 and NnOMT7 are non-stereospecific 7-O-methyltransferases acting on several 1-benzylisoquinolines. Additionally, in vivo assays performed in engineered yeast strains allowed the preliminary characterization of three novel P450 catalysts, NnCYP80Q1 acting as a proaporphine synthase (R-stereospecific intramolecular C-C phenol coupling), NnCYP80Q2 as a bisbenzylisoquinoline synthase (R-stereospecific intermolecular C-O phenol coupling), and NnCYP719A22, the aporphine methylenedioxy bridge synthase. Furthermore, we describe how the absence of 3'-hydroxylase activity radically changes the alkaloid profile in Proteales versus Ranunculales.In addition, via in vivo deuterium labeling experiments, this work provides the first empirical evidence to support that L-tyrosine is the primary precursor for lotus BIA. Based on a consistent absence of norcoclaurine synthase activity for the recombinant enzyme candidates and plant total protein extracts, we suggest that a non-enzymatic spontaneous Pictet-Spengler condensation of dopamine and 4-hydroxyphenylacetaldehyde produces racemic norcoclaurine in lotus, in opposition to the enzyme-catalyzed (S)-norcoclaurine formation in the Ranunculales. These results support a possible convergent evolution of BIA biosynthesis in sacred lotus.Item Open Access Cycloadditions of acetylenic sulfones in solution and on solid supports(2008) Gao, Detian; Back, Thomas G.Item Open Access Design, Synthesis and Evaluation of Novel Organoselenium Antioxidants(2016-02-03) McNeil, Nicole Mary Ryan; Back, Thomas G.; Sutherland, Todd; Ling, Chang-ChunGlutathione peroxidase is an antioxidant selenoenzyme that protects against oxidative stress by reducing peroxides in the presence of glutathione, a tripeptide thiol. Under certain circumstances, such as ischemic reperfusion, this protective mechanism can be overwhelmed. There is a need for potential therapeutics that mimic the function of this selenoenzyme that could be administered during abnormal levels of oxidative stress. Organoselenium compounds can function as antioxidants by catalytically reducing peroxides in the presence of thiols. The design, synthesis and evaluation of novel organoselenium compounds as glutathione peroxidase mimetics is the main focus of the work presented in this thesis. Of particular interest is the synthesis of water-soluble compounds. Two main strategies were investigated, the addition of hydroxymethyl groups or the PEGylation of known glutathione peroxidase mimetics. The addition of hydroxymethyl groups to cyclic seleninate esters and half aromatic half aliphatic selenides resulted in increased polarity of the compounds but only moderate catalytic activity. During the synthesis of these catalysts, an unexpected rearrangement was observed and the mechanism was thoroughly investigated. PEGylated compounds based on the half aromatic half aliphatic selenides were synthesized and demonstrated superior catalytic activity. With several novel organoselenium catalysts in hand, a water-based assay was desired for their evaluation. A D2O-based NMR assay was developed, validated and subsequently used to evaluate the novel organoselenium catalysts. In addition to using organoselenium compounds as glutathione peroxidase mimetics, oxidation catalysis is also possible when hydrogen peroxide is used as a stoichiometric oxidant. The observation of unusual kinetics associated with several cyclic seleninate esters, suggested that these catalysts could not only oxidize thiols to disulfides but could further oxidize disulfides to thiolsulfinates. Based on this observation, a new methodology for the oxidation of disulfides to thiolsulfinates using cyclic seleninate esters and hydrogen peroxide as a stoichiometric oxidant was developed. Finally, a spirodioxyselenurane was investigated using variable-temperature NMR and computational methods. This compound displayed unexpected proton NMR behaviour and a computational investigation into the effects of activated vibrational modes on chemical shift determined that the experimental observations were a result of temperature-dependent chemical shifts and not from dynamic exchange processes.Item Open Access Desulfurization with nickel boride(1992) Yang, Kexin; Back, Thomas G.Item Open Access Item Embargo Exploration of Pomalidomide for Heterobifunctional Protein Degraders: From Chemistry to Application(2023-04-04) Brownsey, Duncan Keith; Derksen, Darren J.; Van Humbeck, Jeffrey F.; Back, Thomas G.; Ling, Chang-Chun; Williams, Florence J.Targeted protein degradation (TPD) has recently come to the forefront of chemical biology and medicinal chemistry as a means to disrupt protein function by selective degradation. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that exemplify TPD technology. One of the most widely used E3 ligase ligands in PROTAC development is pomalidomide which make up 46% of all CRBN-targeting PROTACs. This work explores the chemistry of pomalidomide: first by improving the synthesis of pomalidomide derivatives, second by application in new protein degraders of p300, and then third by characterizing the fluorescent properties of pomalidomide. The improved synthesis of pomalidomide derivatives via an SNAr pathway was began by identification and avoidance of the formation of dimethyl pomalidomide, an undesired byproduct. This led to greatly enhanced yields of compounds that can be used to build new pomalidomide containing PROTACs. As well, differences in the reactivity of amines used to create pomalidomide derivatives were exploited to produce PROTACs in one-pot reactions, which in some instances, exceeded the yields of multistep syntheses used in the literature. Secondly, new degraders of the protein target p300 were prepared using a known p300 ligand A-485, outlining a new strategy to create PROTACs. To verify that linker attachment onto A-485 was amenable to PROTAC function, biotin conjugates were installed and verified using immunoprecipitation blots. A library of A-485-pomalidomide conjugates were then prepared and tested for their p300 degradation capability, which showed a general trend that the PROTACs with longer linkers were more effective degraders. Finally, the fluorescent properties of pomalidomide derivatives were explored. In aqueous solutions, pomalidomide emits visible light with a maximum at ~530 nm upon excitation at 420 nm. This emission was characterized and a library of pomalidomide PROTACs were synthesized and tested in vitro with osteosarcoma cells. In vitro fluorescence microscopy imaging of the pomalidomide library showed trends with linker structure. Relationships between fluorescence, target degradation and calculated partition coefficients were then explored.Item Open Access Morita-baylis-hillman reactions and cyclizations of aldimines and activated diene systems(2006) Sorbetti, Jovina; Back, Thomas G.Item Open Access Novel preparations and applications of unsaturated sulfones and sulfonates(1990) Muralidharan, Raman K.; Back, Thomas G.Item Open Access One-Pot Synthesis of Aryl Selenonic Acids and some Unexpected Byproducts(ASC Publications, 2021-07-16) Sands, Kai N.; Gelfand, Benjamin S.; Back, Thomas G.The synthesis of aryl selenonic acids was achieved from diverse aryl bromides via a one-pot method involving metalation, selenation and oxidation with hydrogen peroxide, followed by ion exchange to afford the pure products in 77-90% yield. An o-hydroxymethyl derivative was found to dehydrate readily, affording the first example of a cyclic selenonic ester, while two minor byproducts were isolated and shown by x-ray crystallography to be mixed salts of aryl selenonic acids with either the corresponding aryl seleninic or selenious acid.Item Open Access Organoselenium compounds as glutathione peroxidase mimetics and catalysts for synthetically useful oxidation reactions(2010) Mercier, Eric Alain; Back, Thomas G.Item Open Access Preparation and reactions of some novel azasteroids and their n-chloro derivatives(1988) Brunner, Kurt; Back, Thomas G.Item Open Access Reactions of diazo compounds with selenoesters and selenium (II) electrophiles: preparation of selenium (II) compounds by silicon-selenium metathesis(1986) Kerr, Russell G. (Russell Greig), 1959-; Back, Thomas G.Item Open Access Ring-expansions of tertiary a-vinylamines via novel aza-cope rearrangements(2009) Weston, Mitchell Hugh; Back, Thomas G.Item Open Access Studies on synthesizing nitrogen heterocycles for acetylenic sulfones using an iterative cyclization protocol: synthesis of (+/-)-myrtine(2004) Lim, Vania; Back, Thomas G.