153 results found
Nielsen C, White AJP, Sale D, et al., 2019, Hydroarylation of Alkenes by protonation/Friedel-Crafts Trapping – HFIP-Mediated Access to Per-Aryl Quaternary Stereocentres
<jats:p><div><p>Upon treatment with a combination of HFIPand a strong Brønsted acid, alkenes behave as Brønsted bases and protonate to givecarbocations which can be trapped by electron rich arenes. The reaction constitutesa Friedel-Crafts (FC) hydroarylation which proceeds with Markovnikovselectivity and is orthogonal to traditional metal catalyzed processes. Theproducts contain polyarylated quaternary carbon atoms which are difficult toobtain <i>via</i> alternative methods. Intermoleculartransfer hydrogenation andhydrothiolation are also demonstrated. </p></div></jats:p>
Cryer AM, Chan C, Eftychidou A, et al., 2019, Tyrosine kinase inhibitor gold nanoconjugates for the treatment of non-small cell lung cancer, ACS Applied Materials and Interfaces, Vol: 11, Pages: 16336-16346, ISSN: 1944-8244
Gold nanoparticles (AuNPs) have emerged as promising drug delivery candidates that can be leveraged for cancer therapy. Lung cancer (LC) is a heterogeneous disease that imposes a significant burden on society, with an unmet need for new therapies. Chemotherapeutic drugs such as afatinib (Afb), which is clinically approved for the treatment of epidermal growth factor receptor positive LC, is hydrophobic and has low bioavailability leading to spread around the body, causing severe side effects. Herein, we present a novel afatinib-AuNP formulation termed Afb-AuNPs, with the aim of improving drug efficacy and biocompatibility. This was achieved by synthesis of an alkyne-bearing Afb derivative and reaction with azide functionalized lipoic acid using copper catalyzed click chemistry, then conjugation to AuNPs via alkylthiol-gold bond formation. The Afb-AuNPs were found to possess up to 3.7-fold increased potency when administered to LC cells in vitro and were capable of significantly inhibiting cancer cell proliferation, as assessed by MTT assay and electric cell-substrate impedance sensing respectively. Furthermore, when exposed to Afb-AuNPs, human alveolar epithelial type I-like cells, a model of the healthy lung epithelium, maintained viability and were found to release less pro-inflammatory cytokines when compared to free drug, demonstrating the biocompatibility of our formulation. This study provides a new platform for the development of non-traditional AuNP conjugates which can be applied to other molecules of therapeutic or diagnostic utility, with potential to be combined with photothermal therapy in other cancers.
Ferris T, Carroll L, Mease RC, et al., 2019, Iodination of terminal alkynes using KI/CuSO4 – A facile method with potential for radio-iodination, Tetrahedron Letters, Vol: 60, Pages: 936-939, ISSN: 0040-4039
Herein, we report an efficient new method for the iodination of terminal alkynes using stoichiometric KI and CuSO4 in a mix of acetonitrile and acetate buffer that holds promise for further development into a method for radio-iodination.
Boddy AJ, Cordier C, Goldberg K, et al., 2019, Acid-mediated ring-expansion of 2,2-disubstituted azetidine carbamates to 6,6-disubstituted 1,3-oxazinan-2-ones, Organic Letters, Vol: 21, Pages: 1818-1822, ISSN: 1523-7052
The ring expansion of 2-ester-2-aryl-azetidine carbamates can be achieved using Brønsted acids to form 6,6-disubstituted 1,3-oxazinan-2-ones. The reaction is rapid at room temperature with Boc or Cbz derivatives, and proceeds with excellent yield (up to 96%) and broad substrate scope. Derivatives of drug compounds and natural products are incorporated. The combina-tion of this ring expansion in a 3-step N–H insertion/cyclization/expansion (NICE) sequence is applied to directly access medicinally relevant scaffolds from acyclic precursors.
Boddy A, Affron D, Cordier C, et al., 2019, Rapid assembly of saturated nitrogen heterocycles in one-pot: Diazo–heterocycle ‘stitching’ by N–H insertion and cyclization, Angewandte Chemie International Edition, Vol: 58, Pages: 1458-1462, ISSN: 1521-3757
Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2-disubstituted azetidines, pyrrolidines, piperidines and azepanes bearing ester and diverse aryl substituents. A one-pot rhodium catalyzed N–H insertion and cyclization sequence uses diazo compounds to stitch together linear 1,m-haloamines (m = 2 to 5) to rapidly assemble 4-, 5-, 6- and 7-membered saturated nitrogen heterocycles in excellent yields. Over fifty examples are demonstrated, including with diazo compounds derived from biologically active compounds. The products can be functionalized to afford alpha,alpha-disubstituted amino acids and applied to fragment synthesis.
Nielsen CD-T, Mooij WJ, Sale D, et al., 2019, Reversibility and reactivity in an acid catalyzed cyclocondensation to give furanochromanes - a reaction at the "oxonium-Prins' vs. "ortho-quinone methide cycloaddition' mechanistic nexus, Chemical Science, Vol: 10, Pages: 406-412, ISSN: 2041-6520
Herein we report a combined experimental and computational investigation of the acid catalyzed cyclocondensation reaction between styrenyl homoallylic alcohols and salicylaldehyde to form furanochromanes. We disclose a previously unreported isomerisation of the ‘unnatural’ trans-fused products to the diastereomeric ‘natural’ cis-fused congeners. Notwithstanding the appeal of assuming this corresponds to endo to exo isomerisation of Diels–Alder (D–A) adducts via concerted retro-cycloaddition/cycloaddition reactions of an in situ generated ortho-quinone methide with the styrenyl alkene, our combined Hammett/DFT study reveals a stepwise Prins-like process via discrete benzylic carbocation intermediates for all but the most electron deficient styrenes. As these reactions fortuitously lie at the intersection of these two mechanistic manifolds, it allows us to propose an experimentally determined indicative ρ+ value of ca. −3 as marking this nexus between a stepwise Prins-type pathway and a concerted cycloaddition reaction. This value should prove useful for categorising other reactions formally involving ‘ortho-quinomethides’, without the need for the extensive computation performed here. Logical optimisation of the reaction based upon the mechanistic insight led to the use of HFIP as an additive which enables exclusive formation of ‘natural’ cis-fused products with a ∼100-fold reaction rate increase and improved scope.
Nielsen CD-T, Abas H, Spivey AC, 2018, Stereoselective reactions of ortho-quinone methide and ortho-quinone methide imines and their utility in natural product synthesis, SYNTHESIS, Vol: 50, Pages: 4008-4018, ISSN: 0039-7881
Herein presented is a review of the reactivity and synthetic utility of ortho-quinone methides and ortho-quinone methide imines. These versatile intermediates have received significant attention in the literature and new methods for their preparation and reaction as well as recent applications in total synthesis are discussed.
Griffiths K, Tsipis AC, Kumar P, et al., 2017, 3d/4f Coordination Clusters as Cooperative Catalysts for Highly Diastereoselective Michael Addition Reactions, INORGANIC CHEMISTRY, Vol: 56, Pages: 9563-9573, ISSN: 0020-1669
Michael addition (MA) is one of the most well studied chemical transformation in synthetic chemistry. Here, we report the synthesis and crystal structures of a library of 3d/4f coordination clusters (CCs) formulated as [ZnII2YIII2L4(solv)X(Z)Y] and study their catalytic properties toward the MA of nitrostyrenes with barbituric acid derivatives. Each CC presents two borderline hard/soft Lewis acidic ZnII centers and two hard Lewis acidic YIII centers in a defect dicubane topology that brings the two different metals into a proximity of ∼3.3 Å. Density functional theory computational studies suggest that these tetrametallic CCs dissociate in solution to give two catalytically active dimers, each containing one 3d and one 4f metal that act cooperatively. The mechanism of catalysis has been corroborated via NMR, electron paramagnetic resonance, and UV–vis. The present work demonstrates for the first time the successful use of 3d/4f CCs as efficient and high diastereoselective catalysts in MA reactions.
Abas H, Linsdall SM, Mamboury M, et al., 2017, Total Synthesis of (+)-Lophirone H and Its pentamethyl ether utilizing an oxonium-prins cyclization, Organic Letters, Vol: 19, Pages: 2486-2489, ISSN: 1523-7052
The first total synthesis of (+)-lophirone H (1) and its pentamethyl ether 29, featuring an oxonium–Prins cyclization/benzylic cation trapping reaction, is described.
Murray JI, Flodén NJ, Bauer A, et al., 2017, Kinetic Resolution of 2-Substituted Indolines by N -Sulfonylation using an Atropisomeric 4-DMAP- N -oxide Organocatalyst, Angewandte Chemie, Vol: 129, Pages: 5854-5858, ISSN: 0044-8249
The first catalytic kinetic resolution by N‐sulfonylation is described. 2‐Substituted indolines are resolved (s=2.6–19) using an atropisomeric 4‐dimethylaminopyridine‐N‐oxide (4‐DMAP‐N‐oxide) organocatalyst. Use of 2‐isopropyl‐4‐nitrophenylsulfonyl chloride is critical to the stereodiscrimination and enables facile deprotection of the sulfonamide products with thioglycolic acid. A qualitative model that accounts for the stereodiscrimination is proposed.
Murray JI, Floden NJ, Bauer A, et al., 2017, Kinetic resolution of 2-substituted indolines by N-sulfonylation using an atropisomeric 4-DMAP-N-oxide organocatalyst, Angewandte Chemie International Edition, Vol: 56, Pages: 5760-5764, ISSN: 1433-7851
The first catalytic kinetic resolution by N-sulfonylation is described. 2-Substituted indolines are resolved (s=2.6–19) using an atropisomeric 4-dimethylaminopyridine-N-oxide (4-DMAP-N-oxide) organocatalyst. Use of 2-isopropyl-4-nitrophenylsulfonyl chloride is critical to the stereodiscrimination and enables facile deprotection of the sulfonamide products with thioglycolic acid. A qualitative model that accounts for the stereodiscrimination is proposed.
Frampton CS, Murray JI, Spivey AC, 2017, Crystal structure of 1-methylimidazole 3-oxide monohydrate., Acta Crystallographica Section E: Crystallographic Communications, Vol: 73, Pages: 372-374, ISSN: 2056-9890
1-Methylimidazole 3-N-oxide (NMI-O) crystallizes as a monohydrate, C4H6N2O·H2O, in the monoclinic space group P21 with Z' = 2 (mol-ecules A and B). The imidazole rings display a planar geometry (r.m.s. deviations = 0.0008 and 0.0002 Å) and are linked in the crystal structure into infinite zigzag strands of ⋯NMI-O(A)⋯OH2⋯NMI-O(B)⋯OH2⋯ units by O-H⋯O hydrogen bonds. These chains propagate along the b-axis direction of the unit cell.
Bodero O, Spivey AC, 2016, An expedient synthesis of 2-aryl-1,4-benzoxazin-3-ones via tandem Anionic cyclisation/alkylation reactions of N-Boc-O-benzyl-2-aminophenols, Synlett, Vol: 27, ISSN: 0936-5214
A one-pot, tandem anionic cyclization/alkylation reaction of N-Boc-O-benzylated-2-aminophenols to give 2-aryl-1,4-benzoxazin-3-ones is described. The Boc protecting group plays a crucial role in the process, as the tert-butoxide liberated in the cyclisation step facilitates the benzylic deprotonation necessary for the subsequent alkylation. The reaction gives expedient access to a range of substitution patterns in 1,4-benzoxazin-3-ones of potential biological relevance.
Murray JI, Spivey AC, 2016, Preparation of 1-Methylimidazole- N-oxide (NMI-O), ORGANIC SYNTHESES, Vol: 93, Pages: 331-+, ISSN: 0078-6209
Abas H, Frampton CS, Spivey AC, 2016, Diels-Alder Reactions of α-Amido Acrylates with N-Cbz-1,2-dihydropyridine and Cyclopentadiene, Journal of Organic Chemistry, Vol: 81, Pages: 9947-9956, ISSN: 1520-6904
Thermal Diels-Alder reactions of α-amido acrylates with N-Cbz-1,2-dihydropyridine and cyclopentadiene have been explored to investigate the factors influencing the endo/exo selectivity. For the dihydropyridine, steric factors allowed the diastereoselectivity to be modulated to favor either endo- or exo-ester adducts. For cyclopentadiene, the endo-ester adducts were favored regardless of steric perturbation, although catalysis by bulky Lewis acids increased the proportion of exo-ester adducts in some cases. These Lewis acids were incompatible with the dihydropyridine diene as they induced its decomposition.
Murray JI, Heckenast Z, Spivey AC, 2016, Chiral Lewis Base Activation of Acyl and Related Donors in Enantioselective Transformations (n → π*), Lewis Base Catalysis in Organic Synthesis, Pages: 457-526, ISBN: 9783527336180
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA. The role of Lewis bases in acylation reactions has been studied from both synthetic and mechanistic standpoints with a particular recent focus on enantioselective variants mediated by single enantiomer chiral Lewis bases deployed substoichiometrically. The modern-era of research into asymmetric enantioselective nucleophile-catalyzed acyl transfer using designed nucleophiles was initiated in the mid-1990s by the groups of Vedejs and Fu. This group developed chiral ferro-cenyl 4-dialkylaminopyridine derivatives first for the kinetic resolution (KR) of sec-alcohols and for an array of other transformations. Since the 1980s, the synthetic potential of enantioselective acylation has been well established in the context of fine chemical synthesis as a result of the development of biocatalytic processes that rely on hydrolytic enzymes. Cognizant that both bases and nucleophiles catalyze the acylation of alcohols using anhydrides and that alkyl phosphines in particular display weak basicity and strong nucleophilicity, Vedejs and Diver published a study of the utility of phosphines as acyl transfer catalysts.
Almond-Thynne J, Blakemore DC, Pryde DC, et al., 2016, Site-selective Suzuki-Miyaura coupling of heteroaryl halides - understanding the trends for pharmaceutically important classes, Chemical Science, Vol: 8, Pages: 40-62, ISSN: 2041-6539
Suzuki–Miyaura cross-coupling reactions of heteroaryl polyhalides with aryl boronates are surveyed. Drawing on data from literature sources as well as bespoke searches of Pfizer's global chemistry RKB and CAS Scifinder® databases, the factors that determine the site-selectivity of these reactions are discussed with a view to rationalising the trends found.
Murray JI, Spivey AC, 2015, Amines vs. N-Oxides as Organocatalysts for Acylation, Sulfonylation and Silylation of Alcohols: 1-Methylimidazole N-Oxide as an Efficient Catalyst for Silylation of Tertiary Alcohols, ADVANCED SYNTHESIS & CATALYSIS, Vol: 357, Pages: 3825-3830, ISSN: 1615-4150
Carroll L, Evans H, Spivey AC, et al., 2015, Mn-salen catalysed benzylic C-H activation for the synthesis of aryl [(18)F]CF3-containing PET probes., Chemical Communications, Vol: 51, Pages: 8439-8441, ISSN: 1364-548X
The development of a Mn-salen complex catalysed oxidative benzylic fluorination of non-activated C-H bonds using [(18)F]fluoride is described for installation of [(18)F]CHRF, [(18)F]CR2F and particularly [(18)F]CF3 containing groups in the presence of other functional groups.
Murray JI, Woscholski R, Spivey AC, 2015, Organocatalytic Phosphorylation of Alcohols Using Pyridine-N-oxide, Synlett, Vol: 26, Pages: 985-990, ISSN: 1437-2096
Murray JI, Woscholski R, Spivey AC, 2014, Highly efficient and selective phosphorylation of amino acid derivatives and polyols catalysed by 2-aryl-4-(dimethylamino)pyridine-N-oxides - towards kinase-like reactivity, CHEMICAL COMMUNICATIONS, Vol: 50, Pages: 13608-13611, ISSN: 1359-7345
Evans HL, Quang-De N, Carroll LS, et al., 2014, A bioorthogonal Ga-68-labelling strategy for rapid in vivo imaging, CHEMICAL COMMUNICATIONS, Vol: 50, Pages: 9557-9560, ISSN: 1359-7345
Evans HL, Carroll L, Aboagye EO, et al., 2014, Bioorthogonal chemistry for Ga-68 radiolabelling of DOTA-containing compounds, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, Vol: 57, Pages: 291-297, ISSN: 0362-4803
Pisaneschi F, Slade RL, Iddon L, et al., 2014, Synthesis of a new fluorine-18 glycosylated 'click' cyanoquinoline for the imaging of epidermal growth factor receptor, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, Vol: 57, Pages: 92-96, ISSN: 0362-4803
George GPC, Stevens E, Aberg O, et al., 2014, Preclinical evaluation of a CXCR4-specific Ga-68-labelled TN14003 derivative for cancer PET imaging, BIOORGANIC & MEDICINAL CHEMISTRY, Vol: 22, Pages: 796-803, ISSN: 0968-0896
Andrews KG, Spivey AC, 2013, Improving the Accuracy of Computed C-13 NMR Shift Predictions by Specific Environment Error Correction: Fragment Referencing, JOURNAL OF ORGANIC CHEMISTRY, Vol: 78, Pages: 11302-11317, ISSN: 0022-3263
Andrews KG, Frampton CS, Spivey AC, 2013, Structural assignment of a bis-cyclopentenyl--cyanohydrin formed via alkene metathesis from either a triene or a tetraene precursor, ACTA CRYSTALLOGRAPHICA SECTION C-STRUCTURAL CHEMISTRY, Vol: 69, Pages: 1207-+, ISSN: 2053-2296
Carroll L, Evans HL, Aboagye EO, et al., 2013, Bioorthogonal chemistry for pre-targeted molecular imaging - progress and prospects, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 11, Pages: 5772-5781, ISSN: 1477-0520
Bayly AR, White AJP, Spivey AC, 2013, Design and Synthesis of a Prototype Scaffold for Five-Residue -Helix Mimetics, EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Vol: 2013, Pages: 5566-5569, ISSN: 1434-193X
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