Thompson, Alison

Permanent URI for this collectionhttps://hdl.handle.net/10222/27742

Alison Thompson

Professor

Faculty of Science Killam Professor 2012-2017

Email: Alison.Thompson@dal.ca

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A mild synthetic route to α-nitroso diaryl pyrroles (Postprint)
(2024) Brown, Emily B.; Gapare, Rosinah Liandrah; Campbell, Jacob W.; Alkaş, Adil; Sequeira, Steve; Hilborn, James W.; Greening, Sarah M.; Robertson, Katherine N.; Thompson, Alison
A new synthetic method to access α-nitroso pyrroles is presented. This method utilises the nitrosonium salt NOBF4, enabling short reaction times (<10 minutes) and avoiding the harsh acidic conditions usually associated with pyrrole nitrosation. Application of this procedure to diarylated pyrroles yielded several novel nitroso-pyrroles. Modifications to the method, through exclusion of air and inclusion of a mild base, allowed for the nitrosation of pyrroles bearing aryl groups substituted with electron-donating groups. Attempts to nitrosylate pyrroles bearing alkyl substituents resulted in the formation of a dimeric material composed of a pyrrolic unit and a 2-hydroxyimino-protected 1,5-dihydro-2H-pyrrol-2-one.
Open Access
BODIPYs with Chalcogenophenes at Boron: Synthesis and Properties. Postprint
(J. Org. Chem., 2023-07-13) Campbell, J.W.; Tung, M.T.; Robertson, K.N.; Beharry, A.A.; Thompson, A.
Reported herein are the synthesis and characterization of BODIPYs bearing heterocycles at boron. To synthesize this series, various chalcogenophenes (furan, thiophene, selenophene, and tellurophene) were lithiated and then used as nucleophiles to attack the boron center of a parent F-BODIPY. Compounds in the series were compared with respect to their photophysical and structural properties, and trends were discussed. By virtue of the “heavy atom effect”, as the mass of the heterocycle appended to the BODIPY core increases, compounds exhibit a higher singlet oxygen quantum yield. The BODIPY with tellurophene at boron exhibits the highest quantum yield (ΦΔ = 0.68) in the series and reduced emission (Φf = 0.01).
Open Access
Bridging and Conformational Control of Porphyrin Units through Non-Traditional Rigid Scaffolds
(2019-11-07) Grover, Nitika; Locke, Gemma M.; Flanagan, Keith J.; Beh, Michael H. R.; Thompson, Alison; Senge, Mathias O.
Connecting two porphyrin units in a rigid linear fashion, without any undesired electron delocalization or communication between the chromophores, remains a synthetic challenge. Herein, a broad library of functionally diverse multi-porphyrin arrays that incorporate the non-traditional rigid linker groups cubane and bicyclo[1.1.1]pentane (BCP) is described. A robust, reliable, and versatile synthetic procedure was employed to access porphyrin-cubane/BCPporphyrin arrays, representing the largest non-polymeric structures available for cubane/BCP derivatives. These reactions demonstrate considerable substrate scope, from utilization of small phenyl moieties to large porphyrin rings, with varying lengths and different angles. To control conformational flexibility, amide bonds were introduced between the bridgehead carbon of BCP/cubane and the porphyrin rings. Through varying the orientation of the substituents around the amide bond of cubane/BCP, different intermolecular interactions were identified through single crystal X-ray analysis. These studies revealed non-covalent interactions that are the first-of-their-kind including a unique iodine-oxygen interaction between cubane units. These supramolecular architectures indicate the possibility to mimic a protein structure due to the sp3 rigid scaffolds (BCP or cubane) that exhibit the essential conformational space for protein function while simultaneously providing amide bonds for molecular recognition.
Open Access
Synthesis, properties and reactivity of BCl2 aza-BODIPY complexes and salts of the aza-dipyrrinato scaffold
(Royal Society of Chemistry, 2020-02-25) Diaz-Rodriguez, Roberto M.; Burke, Luke; Robertson, Katherine N.; Thompson, Alison
The synthesis and characterisation of the BCl2-chelated complexes of both archetypal aza-dipyrrin sub- types are presented. A stepwise halogen exchange, leading to a mixed-halide Cl–B–F intermediate, is implicated in the conversion of F-aza-BODIPYs to Cl-aza-BODIPYs upon treatment with BCl3. The utility of the Cl-aza-BODIPY scaffold to facilitate substitutions at boron is demonstrated under mild conditions through treatment with aryl Grignard reagents. Additionally, the lability of the B–Cl bond enables facile removal of the BCl2 group, i.e. deprotection of F-aza-BODIPYs, under aqueous conditions. Three aza- dipyrrin HX salts were also synthesised and characterised. The pKa of the protonated aza-dipyrrin was determined to be 4, thereby providing insight regarding the storage and stability of such species.
Open Access
Bridging and Conformational Control of Porphyrin Units through Non-Traditional Rigid Scaffolds
(Wiley, 2019-11) Grover, Nitika; Locke, Gemma M.; Flanagan, Keith J.; Beh, Michael H. R.; Thompson, Alison; Senge, Mathias O.
Connecting two porphyrin units in a rigid linear fashion, without any undesired electron delocalization or communication between the chromophores, remains a synthetic challenge. Herein, a broad library of functionally diverse multi-porphyrin arrays that incorporate the non-traditional rigid linker groups cubane and bicyclo[1.1.1]pentane (BCP) is described. The reactions demonstrate wide substrate scope, from utilization of small phenyl to large porphyrin rings, with varying lengths and different angles. To control conformational flexibility, amide bonds were introduced between the bridgehead carbon of BCP/cubane and the porphyrin rings. Through varying the orientation of the substituents around the amide bond of cubane/BCP, different intermolecular interactions were identified
Open Access
Bis[Pyrrolyl Ru(II)] Triads: a New Class of Photosensitizers for Metal-Organic Photodynamic Therapy
(2020) Smithen, Deborah A.; Monro, Susan; Pinto, Mitch; Roque III, John; Diaz- Rodriguez, Roberto M.; Yin, Huimin; Cameron, Colin G.; Thompson, Alison; McFarland, Sherri A.
A new family of ten dinuclear Ru(II) complexes based on the bis[pyrrolyl Ru(II)] triad scaffold, where two Ru(bpy)2 centers are separated by a variety of organic linkers, was prepared to evaluate the influence of the organic chromophore on the spectroscopic and in vitro photodynamic therapy (PDT) properties of the compounds. The bis[pyrrolyl Ru(II)] triads absorbed strongly throughout the visible region, with several members having molar extinction coefficients (e) ≥104 at 600–620 nm and longer. Phosphorescence quantum yields (Fp) were generally less than 0.1% and in some cases undetectable. The singlet oxygen quantum yields (FD) ranged from 5% to 77% and generally correlated with their photocytotoxicities toward human leukemia (HL-60) cells regardless of the wavelength of light used. Dark cytotoxicities varied ten-fold, with EC50 values in the range of 10– 100 μM and phototherapeutic indices (PIs) as large as 5,400 and 260 with broadband visible (28 J cm-2, 7.8 mW cm-2) and 625-nm red (100 J cm-2, 42 mW cm-2) light, respectively. The bis[pyrrolyl Ru(II)] triad with a pyrenyl linker (5h) was especially potent, with an EC50 value of 1 nM and PI >27,000 with visible light and subnanomolar activity with 625-nm light (100 J cm-2, 28 mW cm- 2). The lead compound 5h was also tested in a tumor spheroid assay using the HL60 cell line and exhibited greater photocytotoxcicity in this more resistant model (EC50=60 nM and PI>1,200 with 625-nm light) despite a lower dark cytotoxicity. The in vitro PDT effects of 5h extended to bacteria, where submicromolar EC50 values and PIs >300 against S. mutans and S. aureus were obtained with visible light. This activity was attenuated with 625-nm red light, but PIs were still near 50. The ligand-localized 3ππ* state contributed by the pyrenyl linker of 5h likely plays a key role in its phototoxic effects toward cancer cells and bacteria.
Open Access
Synthesis of sulfenyl dipyrroles via reaction of a-free pyrroles with thionyl chloride
(2020-09) Beh, Michael H. R.; Smith, Craig D.; Robertson, Katherine N.; Thompson, Alison
Open Access
Facile Deprotection of F-BODIPYs using Methylboronic Acid
(2020) Smith, Craig D.; Thompson, Alison
4,4-Difluoro-4-bora-3a,4a-diaza-s-indacenes (F-BODIPYs) are deprotected through removal of the –BF2 moiety upon treatment with methylboronic acid. The tolerance of various substitution patterns about the dipyrrinato core is demonstrated via the deprotection of thirteen F-BODIPYs and an F-aza-BODIPY. Work-up with aq. HBr affords the desired dipyrrin HBr salt in quantitative yield without need for purification.
Open Access
Synthesis and reactivity of 2-thionoester pyrroles: a route to 2-formyl pyrroles
(RSC Advances, 2019) Kim, Min Joon; Gaube, Sophie M.; Beh, Michael H. R.; Smith, Craig D.; Thompson, Alison
2-Functionalised pyrroles exhibit considerable synthetic utility. Herein, the synthesis and reactivity of 2-thionoester (-C(S)OR) pyrroles is reported. 2-Thionoester pyrroles were synthesized using a Knorr-type approach from aliphatic starting materials. 2-Thionoester pyrroles were reduced to the corresponding 2-formyl pyrroles, or the deuterated formyl variant, in one step using Raney nickel, thereby removing the need for the much-utilized hydrolysis/decarboxylation/formylation steps that are typically required to convert Knorr-type 2-carboxylate pyrroles into 2-formyl pyrroles. 2-Thionoester pyrroles proved tolerant of typical functional group interconversions for which the parent 2-carboxylate pyrroles have become known.
Open Access
The Photodecarboxylation of Substituted Naphthylmethyl Arylacetate Esters: Synthesis of Naphthylarylethanes
(2019) Hilborn, James W.; Moya-Barrios, Reinaldo; Thompson, Alison
The synthesis of naphthylarylethanes via the photodecarboxylation of naphthylmethyl arylacetate esters is reported where the aryl group is able to stabilize a charge transfer reaction. The reaction proceeds via intramolecular charge transfer from the donor to acceptor thereby enhancing a pathway to produce, within the solvent cage, the desired diarylethane products. These in-cage naphthylarylethanes are produced in good yields, in a single photochemical step, with the use of cyclohexane as solvent providing optimal yields.
Open Access
Classifying donor strengths of dipyrrinato/aza-dipyrrinato ligands
(2019) Diaz-Rodriguez, Roberto M.; Robertson, Katherine N.; Thompson, Alison
A parameter is reported by which to use 13C NMR chemical shifts to measure and predict the donor capabilities of N^N dipyrrinato and aza-dipyrrinato ligands chelating in L^X fashion. The results enable the rationalisation of the properties of these ligands and their complexes, as well as enable rational design incorporating both steric and electronic considerations when tuning to effect desired applications. Complexes containing these ligands are prevalent due to their desirable photophysical properties such as high chemical stability, resistance to photodegradation, strong absorbance, and ease of chemical modifiability.
Open Access
Step-wise synthetic approach is necessary to access g-conjugates of folate: folate-conjugated prodigiosenes
(2019) Figliola, Carlotta; Marchal, Estelle; Groves, Brandon R.; Thompson, Alison
Despite the vast literature that describes reacting folic acid with a pharmacophore, this route is ineffective in providing the correct regioisomer of the resulting conjugate. We herein present a step-wise route to the preparation of nine folate conjugates of the tripyrrolic prodigiosene skeleton. The strict requirement for step-wise construction of the folate core is demonstrated, so as to achieve conjugation at only the desired γ-carboxylic acid and thus maintain the acarboxylic site for folate receptor (FRa) recognition. Linkages via ethylenediamine, polyethylene glycol and glutathione are demonstrated.
Open Access
Synthesis of Prodigiosene-Estrogen Conjugates: optimization of protecting group strategies and anticancer properties
(Canadian Journal of Chemistry, 2015) Marchal, Estelle; Uddin, Md. Imam; Hawco, Cassandra L. A.; Thompson, Alison
The tripyrrolic prodigiosene skeleton was conjugated to several estrogen ligands. The conjugation was achieved via an ester linker that proved to be unusually sensitive to hydrolysis during synthesis. This work describes the determination of an appropriate protecting group for the hydroxy groups of the estrogen linker. The anticancer properties of the target prodigiosene-estrogen conjugates were evaluated against breast cancer cells and some show selectivity for ER+ breast cancer cell lines.
Open Access
Regioselective Substituent Effects upon the Synthesis of Dipyrrins from 2-Formyl Pyrroles
(Canadian Journal of Chemistry, 2018) Beh, Michael; Figliola, Carlotta; Lund, Kate-Lyn A. R.; Kajetanowicz, Aleksandra K.; Johnsen, Ann E.; Aronitz, Elise M.; Thompson, Alison
The synthesis of symmetric α-free meso-H-dipyrrin hydrobromides from 5-H-2-formyl pyrroles was investigated. The self-condensation produces regioisomeric dipyrrins through the adoption of two mechanistic pathways. The key difference between the two pathways lies in which position of the pyrrole directs nucleophilic attack. Through a systematic study involving various substituted and/or isotopically labelled 5-H-2-formyl pyrroles, we herein provide evidence to suggest that not only do two mechanistic pathways exist but that the steric bulk of the substituent adjacent to the 5-unsubstituted position influences which pathway dominates.
Open Access
Synthesis of symmetric meso-H dipyrrin hydrobromides from 2-formyl pyrroles
(Synlett, 2014) Lund, Kate-lyn A.R.; Thompson, Alison
The reaction of 2-formyl pyrroles in acidic methanol gives the corresponding symmetric, meso-H 4,6-dipyrrin hydrobromides. This convenient strategy involves initial deformylation under the acidic conditions, followed by immediate in situ reaction of the resulting α-free pyrrole with the remaining 2-formyl pyrrole in solution to give the dipyrrin hydrobromide salt in good yield.
Open Access
The Use of Tin (IV) Chloride to Selectively Cleave Benzyl Esters over Benzyl Ethers and Benzyl Amines
(Canadian Journal of Chemistry, 2014) Baker, Alexander E. G.; Marchal, Estelle; Lund, Kate-lyn A.R.; Thompson, Alison
Benzyl esters are cleaved upon reaction with SnCl4, resulting in isolation of the corresponding carboxylic acid. Importantly, benzyl ethers, amines and amides do not undergo debenzylation under these conditions, nor do a variety of other common protecting groups for alcohols, thereby rendering SnCl4 selective amongst Lewis acids. The scope, tolerance and limitations of the strategy are demonstrated through the analysis of several multi-functional substrates, including those bearing Cbz groups.
Open Access
Antimicrobial Activity of Non-natural Prodigiosenes
(RSC Advances, 2013) Marchal, E.; Uddin, Md. I.; Smithen, D. A.; Hawco, C. L.A.; Lanteigne, M.; Overy, D. P.; Kerr, R. G.; Thompson, A.
Tripyrrolic prodigiosenes, derivatives of the natural product prodigiosin, have been produced via multi-step synthesis beginning with 2-formyl pyrroles bearing various functionalities at the 4-position. Two tin complexes are also reported, and these feature a prodigiosene ligand bearing a conjugated benzyl-ester. Antimicrobial activities of prodigiosenes are evaluated against Gram positive and Gram negative bacterial strains, as well as a yeast.
Open Access
Activation and Deprotection of F-BODIPYs using Boron Trihalides
(2014) Lundrigan, Travis; Cameron, T. Stanley; Thompson, Alison
The activation of F-BODIPYs with boron trihalides, followed by treatment with a nuclephile, effects facile substitution at boron; using water as the nucleophile promotes deprotective removal of the–BF2 moiety and thereby production of the corresponding 10 parent dipyrrin salt in quantitative yield under extremely mild conditions.
Open Access
Synthesis and Characterization of Pyrrolyldipyrrin F-BODIPYs
(Photochemical and Photobiological Sciences, 2018) Greening, Sarah M.; Robertsonb, Katherine N.; Thompson, Alison
A series of synthetic analogs of the tripyrrolic natural product prodigiosin were complexed with boron trifluoride to generate the corresponding F-BODIPYs. The maximum wavelengths of absorption and emission of the pyrrolyldipyrrin F-BODIPYs was tuned through variation of the substituents about the pyrrolyldipyrrinato core. The limited variation of substituents on the C-ring did not significantly affect absorption and emission. However, variation on the B-ring and A-ring resulted in a corresponding red-shift in absorption and emission reaching maximum wavelengths of 600 nm. The presence of electron donating substituents on the B-ring caused a decrease in the Stokes’ shift, while the presence of electron-withdrawing substituents caused an increase, ranging from 3-25 nm. Stokes shifts were solvent-dependant for some compounds. The inclusion of a dimethylamino group resulted in photo-induced electron transfer and thus quenched fluorescence which was restored upon protonation.
Open Access
Photo-induced Anticancer Activity and Singlet Oxygen Production of Prodigiosenes
(2018) Savoie, Huguette; Figliola, Carlotta; Marchal, Estelle; Crabbe, Bry W.; Hallett-Tapley, Geniece L.; Boyle, Ross W.; Thompson, Alison
The photo-induced cytotoxicity of prodigiosenes is reported. One prodigiosene represents a synthetic analogue of the natural product prodigiosin, and two are conjugated to molecules that target the estrogen receptor (ER). A comparison of incubation and irradiation frameworks for the three prodigiosenes is reported, with activity against ER- and ER+ lines explored. Furthermore, the ability of the three prodigiosenes to photosensitise the production of singlet oxygen is demonstrated, shedding mechanistic light onto possible photodynamic therapeutic effects of this class of tripyrroles.