Publications
99 results found
Kuimova MK, Kubankova M, Lopez Duarte, et al., 2017, Probing supramolecular protein assembly using covalently attached fluorescent molecular rotors, Biomaterials, Vol: 139, Pages: 195-201, ISSN: 1878-5905
Changes in microscopic viscosity and macromolecular crowding accompany the transition of proteins from their monomeric forms into highly organised fibrillar states. Previously, we have demonstrated that viscosity sensitive fluorophores termed ‘molecular rotors’, when freely mixed with monomers of interest, are able to report on changes in microrheology accompanying amyloid formation, and measured an increase in rigidity of approximately three orders of magnitude during aggregation of lysozyme and insulin. Here we extend this strategy by covalently attaching molecular rotors to several proteins capable of assembly into fibrils, namely lysozyme, fibrinogen and amyloid-β peptide (Aβ(1–42)). We demonstrate that upon covalent attachment the molecular rotors can successfully probe supramolecular assembly in vitro. Importantly, our new strategy has wider applications in cellulo and in vivo, since covalently attached molecular rotors can be successfully delivered in situ and will colocalise with the aggregating protein, for example inside live cells. This important advantage allowed us to follow the microscopic viscosity changes accompanying blood clotting and during Aβ(1–42) aggregation in live SH-SY5Y cells. Our results demonstrate that covalently attached molecular rotors are a widely applicable tool to study supramolecular protein assembly and can reveal microrheological features of aggregating protein systems both in vitro and in cellulo not observable through classical fluorescent probes operating in light switch mode.
St John-Campbell S, White AJP, Bull JA, 2017, Single operation palladium catalysed C(sp3)–H functionalisation of tertiary aldehydes: investigations into transient imine directing groups, Chemical Science, Vol: 8, Pages: 4840-4840, ISSN: 2041-6539
Simple amine and diamine derivatives can promote the palladium catalysed direct -C–H arylation of aliphatic aldehydes via transient imine formation. Trifluoroacetate was shown to be crucial in promoting the reaction. Sub-stoichiometric quantities of simple N-tosylethylenediamine was shown to form a bidentate directing group with an imine linkage. Isolation of an unsymmetrical palladacyle has shown different potential binding modes of the secondary NTs coordinating group by single crystal X-ray diffraction analysis, suggestive of a hemilabile ligand.
Sherin PS, Lopez-Duarte I, Dent MR, et al., 2017, Visualising the membrane viscosity of porcine eye lens cells using molecular rotors, CHEMICAL SCIENCE, Vol: 8, Pages: 3523-3528, ISSN: 2041-6520
The plasma membranes of cells within the eye lens play an important role in metabolite transport within the avascular tissue of the lens, maintaining its transparency over the entire lifespan of an individual. Here we use viscosity-sensitive ‘molecular rotors’ to map the microscopic viscosity within these unusual cell membranes, establishing that they are characterised by an unprecedentedly high degree of lipid organisation.
Shimolina LE, Izquierdo MA, Lopez-Duarte I, et al., 2017, Imaging tumor microscopic viscosity in vivo using molecular rotors, Scientific Reports, Vol: 7, ISSN: 2045-2322
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- Citations: 69
Tota A, Zenzola M, Chawner SJ, et al., 2017, Synthesis of NH-sulfoximines from sulfides by chemoselective one-pot N- and O-transfers, CHEMICAL COMMUNICATIONS, Vol: 53, Pages: 348-351, ISSN: 1359-7345
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- Citations: 131
Davis OA, Croft RA, Bull JA, 2016, Synthesis of substituted 1,4-dioxenes through O–H insertion and cyclization using keto-diazo compounds, Journal of Organic Chemistry, Vol: 81, Pages: 11477-11488, ISSN: 1520-6904
1,4-Dioxenes present interesting potential as synthetic intermediates, and as unusual motifs for incorporation into biologically active compounds. Here, an efficient synthesis of functionalized 1,4-dioxenes is achieved in two steps through a ruthenium catalyzed O–H insertion and base mediated C–O cyclization strategy. From keto-diazo compounds, O–H insertion with bromohydrins, followed by enolization results in cyclization by O–alkylation of the keto-enolate, with excellent selectivity. A variety of substituted bromohydrins and anion-stabilizing functional groups in the diazo-component are tolerated, to afford novel functionalized dioxenes. The use of enantioenriched -bromohydrins provides enantioenriched 1,4-dioxenes.
Croft RA, Mousseau JJ, Choi C, et al., 2016, Structurally Divergent Lithium Catalyzed Friedel-Crafts Reactions on Oxetan-3-ols: Synthesis of 3,3-Diaryloxetanes and 2,3-Dihydrobenzofurans, Chemistry - A European Journal, Vol: 22, Pages: 16271-16276, ISSN: 0947-6539
The first examples of 3,3-diaryloxetanes are prepared in a lithium-catalyzed and substrate dependent divergent Friedel–Crafts reaction. para-Selective Friedel–Crafts reactions of phenols using oxetan-3-ols afford 3,3-diaryloxetanes by displacement of the hydroxy group. These constitute new isosteres for benzophenones and diarylmethanes. Conversely, ortho-selective Friedel–Crafts reactions of phenols afford 3-aryl-3-hydroxymethyl-dihydrobenzofurans by tandem alkylation–ring opening; the outcome of the reaction diverging to structurally distinct products dependent on the substrate regioselectivity. Further reactivity of the oxetane products is demonstrated, suitable for incorporation into drug discovery efforts.
Bull JA, Croft RA, Davis OA, et al., 2016, Oxetanes: Recent Advances in Synthesis, Reactivity and Medicinal Chemistry, Chemical Reviews, Vol: 116, Pages: 12150-12233, ISSN: 1520-6890
The 4-membered oxetane ring has been increasingly exploited for its behaviors, i.e. influence on physicochemical properties as a stable motif in medicinal chemistry, and propensity to undergo ring opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivatives. This review takes an overview of the literature for the synthesis of oxetane derivatives, concentrating on advances in the last 5 years up to the end of 2015. These methods are clustered by strategy for preparation of the ring (Sections 3 and 4), and further derivatisation of preformed oxetane-containing building blocks (Sections 5-7). Examples of the use of oxetanes in medicinal chemistry are reported, including a collation of oxetane derivatives appearing in recent patents for medicinal chemistry applications. Finally examples of oxetane derivatives in ring opening and ring expansion reactions are described.
Zenzola M, Doran R, Degennaro L, et al., 2016, Transfer of Electrophilic NH Using Convenient Sources of Ammonia: Direct Synthesis of NH Sulfoximines from Sulfoxides, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 55, Pages: 7203-7207, ISSN: 1433-7851
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- Citations: 141
Affron DP, Bull JA, 2016, Palladium-Catalyzed Directed C(sp<SUP>3</SUP>)-H Arylation of Saturated Heterocycles at C-3 Using a Concise Optimization Approach, EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Vol: 2016, Pages: 139-149, ISSN: 1434-193X
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- Citations: 57
Morgan KF, Doran R, Croft RA, et al., 2015, 2-Sulfinyl-oxetanes: Synthesis, stability and reactivity, Synlett, Vol: 27, Pages: 106-110, ISSN: 1437-2096
The synthesis of 2-sulfinyl oxetanes is described by a C–C bond forming cyclisation strategy. Oxetanes bearing electron poor aryl sulfoxides are shown to be viable targets using this strategy. We report investigations into the sulfoxide magnesium exchange on 2-sulfinyl oxetanes, which resulted in products formed via ligand exchange and ligand coupling pathways. The sulfinyl-oxetanes can be readily oxidised to the sulfonyl-oxetanes.
Dent M, Lopez-Duarte I, Bull J, et al., 2015, Imaging patterns in lipid membranes through the use of molecular rotors, EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS, Vol: 44, Pages: S107-S107, ISSN: 0175-7571
Bull JA, Boultwood T, Affron DA, 2015, Studies on the synthesis of α−iodoaziridines and improved conditions for the synthesis of alkyl-α-iodoaziridines using ClMgCHI2, Tetrahedron, Vol: 71, Pages: 4949-4957, ISSN: 0040-4020
α-Iodoaziridines are unusual motifs and intriguing structures for further functionalisation of the intact aziridine. The preparation of N-protected α-iodoaziridines is achieved through an addition-cyclisation reaction of LiCHI2 with imines. The effects of varying the N-group and using different carbenoids are investigated. Excellent cis-stereochemistry is achieved, except for N-carbamates containing aryl groups. Using the mixed carbenoid LiCHICl, the iodide leaving group is selected for cyclisation affording chloroaziridines only, as a cis/trans mixture. More convenient and higher yielding conditions for the preparation of alkyl N-Ts α-iodoaziridines are developed, using ClMgCHI2. Additionally, the formation of the problematic primary alkyl α-iodoaziridines is achieved.
Zenzola M, Doran R, Luisi R, et al., 2015, Synthesis of Sulfoximine Carbamates by Rhodium-Catalyzed Nitrene Transfer of Carbamates to Sulfoxides, Journal of Organic Chemistry, Vol: 80, Pages: 6391-6399, ISSN: 1520-6904
Sulfoximines are of considerable interest for incorporation into medicinal compounds. A convenient synthesis of N-protected sulfoximines is achieved, under mild conditions, by rhodium-catalyzed transfer of carbamates to sulfoxides. The first examples of 4-membered thietane-oximines are prepared. Sulfoximines bearing Boc and Cbz groups are stable to further cross coupling reactions, and readily deprotected. This method may facilitate the preparation of NH-sulfoximines providing improved (global) deprotection strategies, which is illustrated in the synthesis of methionine sulfoxide (MSO).
Davis OA, Bull JA, 2015, Recent Advances in the Synthesis of 2-Substituted Oxetanes, SYNLETT, Vol: 26, Pages: 1283-1288, ISSN: 0936-5214
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- Citations: 30
Morgan KF, Hollingsworth IA, Bull JA, 2015, Studies on the Synthesis, Stability and Conformation of 2-Sulfonyl-Oxetane Fragments, Organic and Biomolecular Chemistry, Vol: 13, Pages: 5265-5272, ISSN: 1477-0520
2-(Arylsulfonyl)oxetanes have been prepared as new structural motifs of interest for medicinal chemistry. These are designed to fit within fragment space and be suitable for screening in fragment based drug discovery, as well as being suitable for further elaboration or incorporation into drug-like compounds. The oxetane ring is constructed through an efficient C–C bond forming cyclisation which allows the incorporation of a wide range of aryl-sulfonyl groups. Furthermore, biaryl-containing compounds can be accessed through Suzuki-Miyaura coupling from halogenated derivatives. With a number of oxetane containing fragment compounds available, their pH stability was assessed, indicating good half-life values for mono-substituted aryl sulfonyl oxetanes across the pH range (1 to 10). Solubility and metabolic stability data is also reported. Finally, the conformation of the fragments is assessed computationally, providing an indication of possible binding orientations.
Dent MR, Lopez-Duarte I, Dickson CJ, et al., 2015, Imaging phase separation in model lipid membranes through the use of BODIPY based molecular rotors, PHYSICAL CHEMISTRY CHEMICAL PHYSICS, Vol: 17, Pages: 18393-18402, ISSN: 1463-9076
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- Citations: 73
Davis OA, Croft RA, Bull JA, 2015, Synthesis of diversely functionalised 2,2-disubstituted oxetanes: fragment motifs in new chemical space, CHEMICAL COMMUNICATIONS, Vol: 51, Pages: 15446-15449, ISSN: 1359-7345
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- Citations: 45
Davis OA, Bull JA, 2014, Synthesis of Di-, Tri-, and Tetrasubstituted Oxetanes by Rhodium-Catalyzed O-H Insertion and C-C Bond- Forming Cyclization, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 53, Pages: 14230-14234, ISSN: 1433-7851
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- Citations: 48
Affron DP, Davis OA, Bull JA, 2014, Regio- and Stereospecific Synthesis of C-3 Functionalized Proline Derivatives by Palladium Catalyzed Directed C(sp<SUP>3</SUP>)-H Arylation, ORGANIC LETTERS, Vol: 16, Pages: 4956-4959, ISSN: 1523-7060
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- Citations: 120
Lopez-Duarte I, Thanh TV, Izquierdo MA, et al., 2014, A molecular rotor for measuring viscosity in plasma membranes of live cells, CHEMICAL COMMUNICATIONS, Vol: 50, Pages: 5282-5284, ISSN: 1359-7345
Boultwood T, Bull JA, 2014, Stereospecific Functionalization of Iodoaziridines via Unstabilized Aziridinyllithiums Generated by Iodine-Lithium Exchange, ORGANIC LETTERS, Vol: 16, Pages: 2740-2743, ISSN: 1523-7060
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- Citations: 12
Morgan KF, Hollingsworth IA, Bull JA, 2014, 2-(Aryl-sulfonyl)oxetanes as designer 3-dimensional fragments for fragment screening: synthesis and strategies for functionalisation, CHEMICAL COMMUNICATIONS, Vol: 50, Pages: 5203-5205, ISSN: 1359-7345
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- Citations: 46
Boultwood T, Affron DA, Bull JA, 2014, Synthesis and Purification of Iodoaziridines Involving Quantitative Selection of the Optimal Stationary Phase for Chromatography, J. Vis. Exp., Vol: 87
The highly diastereoselective preparation of cis-N-Ts-iodoaziridines through reaction of diiodomethyllithium with N-Ts aldimines is described. Diiodomethyllithium is prepared by the deprotonation of diiodomethane with LiHMDS, in a THF/diethyl ether mixture, at -78 °C in the dark. These conditions are essential for the stability of the LiCHI2 reagent generated. The subsequent dropwise addition of N-Ts aldimines to the preformed diiodomethyllithium solution affords an amino-diiodide intermediate, which is not isolated. Rapid warming of the reaction mixture to 0 °C promotes cyclization to afford iodoaziridines with exclusive cis-diastereoselectivity. The addition and cyclization stages of the reaction are mediated in one reaction flask by careful temperature control.Due to the sensitivity of the iodoaziridines to purification, assessment of suitable methods of purification is required. A protocol to assess the stability of sensitive compounds to stationary phases for column chromatography is described. This method is suitable to apply to new iodoaziridines, or other potentially sensitive novel compounds. Consequently this method may find application in range of synthetic projects. The procedure involves firstly the assessment of the reaction yield, prior to purification, by 1H NMR spectroscopy with comparison to an internal standard. Portions of impure product mixture are then exposed to slurries of various stationary phases appropriate for chromatography, in a solvent system suitable as the eluent in flash chromatography. After stirring for 30 min to mimic chromatography, followed by filtering, the samples are analyzed by 1H NMR spectroscopy. Calculated yields for each stationary phase are then compared to that initially obtained from the crude reaction mixture. The results obtained provide a quantitative assessment of the stability of the compound to the different stationary phases; hence the optimal can be selected. The choice of basic alumina, modified to a
Boultwood T, Affron DP, Trowbridge AD, et al., 2013, Synthesis of C-Iodo-N-Tosyl-Aziridines using Diiodomethyllithium: Reaction Optimization, Product Scope and Stability, and a Protocol for Selection of Stationary Phase for Chromatography, J. Org. Chem., ISSN: 0022-3263
The preparation of C-iodo-N-Ts-aziridines with excellent cis-diastereoselectivity has been achieved in high yields by the addition of diiodomethyllithium to N-tosylimines and N-tosylimine–HSO2Tol adducts. This addition-cyclization protocol successfully provided a wide range of cis-iodoaziridines, including the first examples of alkyl-substituted iodoaziridines, with the reaction tolerating both aryl imines and alkyl imines. An ortho-chlorophenyl imine afforded a β-amino gem-diiodide under the optimized reaction conditions due to a postulated coordinated intermediate preventing cyclization. An effective protocol to assess the stability of the sensitive iodoaziridine functional group to chromatography was also developed. As a result of the judicious choice of stationary phase, the iodoaziridines could be purified by column chromatography; the use of deactivated basic alumina (activity IV) afforded high yield and purity. Rearrangements of electron-rich aryl-iodoaziridines have been promoted, selectively affording either novel α-iodo-N-Ts-imines or α-iodo-aldehydes in high yield.
Davis OA, Hughes M, Bull JA, 2013, Copper-Catalyzed N-Arylation of 2-Imidazolines with Aryl Iodides, J. Org. Chem., Vol: 78, Pages: 3470-3475
The first copper-catalyzed N-arylation of 2-imidazolines is described. The reaction affords compounds with desirable lead-like characteristics in high yield with practical simplicity under inexpensive, “ligand-free” conditions. The cross coupling was successful with electron-rich and electron-poor aromatic iodides. Substrates bearing halides, esters, nitriles, and free hydroxyls are well tolerated, providing reactive handles for further functionalization, as are pyridines. In addition, the regioselective N-arylation of a 4-substituted imidazoline is reported
Hughes M, Boultwood T, Zeppetelli G, et al., 2013, Palladium-Catalyzed Cross-Coupling of Aziridinyl-Metal Species, Generated by Sulfinyl-Magnesium Exchange, with Aryl Bromides: Reaction Optimization, Scope, and Kinetic Investigations, J. Org. Chem., Vol: 78, Pages: 844-854
A series of novel, highly substituted N-PMP aziridines have been accessed in high yields by palladium-catalyzed cross-coupling of intact aziridines. The cross-coupling employed aryl bromides and tertiary organometallic aziridines, generated from sulfinyl aziridines by sulfinyl–magnesium exchange and transmetallation to the aziridinyl-zinc with zinc chloride. A wide range of electron rich and electron poor aryl bromides were utilized to afford the functionalized aziridine products as single diastereoisomers with retention of configuration at the reacting center. Assessment of the reaction kinetics showed zero-order in both the aziridine species and the aryl bromide. This indicated that the rate-determining step was reductive elimination from the palladium (II) species bearing both the aziridine and aryl groups, to form the hindered C-C bond. The intermediate aziridinyl zinc species underwent a progressive, background degradation that led to a plateau in yield and afforded reduced yields in substrates with ortho-substituted aryl groups, which are less reactive due to the additional steric demands.
Bull JA, Boultwood T, Taylor TA, 2012, Highly cis-selective synthesis of iodo-aziridines using diiodomethyllithium and in situ generated N-Boc-imines, Chemical Communications, Vol: 48, Pages: 12246-12248
The first preparation of iodoaziridines is described. The addition of diiodomethyllithium to N-Boc-imines affords these novel aziridines in high yields. The reaction proceeds in one-pot via a highly diastereoselective cyclisation of an amino gem-diiodide intermediate.
Bull JA, 2012, Catalytic Enantioselective Synthesis of Secondary Alkylboronate Building Blocks With and Without Metals, Angew. Chem. Int. Ed., Vol: 51, Pages: 8930-8932
With or without you: Chiral secondary alkylboronates can now be accessed by highly enantioselective catalytic methods including conjugate addition under metal-free conditions with an NHC catalyst, and also iridium-catalyzed hydrogenation. These methods reinforce the potential of secondary alkylboronates as ideal and universal chiral building blocks for bond formation to sp3 carbon atoms.
Bull JA, Mousseau JJ, Pelletier G, et al., 2012, Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition to N-Activated Pyridines, Chemical Reviews, Vol: 112, Pages: 2642-2713
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