59 results found
Briggs E, Tota A, Colella M, et al., 2019, Synthesis of sulfonimidamides from sulfenamides via an alkoxy-amino-λ6-sulfanenitrile intermediate, Angewandte Chemie - International Edition, ISSN: 0570-0833
Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry, and provide attractive bioisosteres for sulfonamides. However, there remain few operationally simple methods for their preparation. Here, for the first time the synthesis of NH-sulfonimidamides is achieved directly from sulfenamides, themselves readily formed in 1 step from amines and disulfides. A highly chemoselective and one-pot NH and O transfer is developed, mediated by PhIO in iPrOH, using ammonium carbamate as the NH source, and in the presence of 1 equivalent of acetic acid. A wide range of functional groups are tolerated under the developed reaction conditions, including the functionalization of anti-depressants desipramine and fluoxetine. Additionally, the methodology is applied to the preparation of an aza-analogue of the drug probenecid, with further N-functionalization reactions exemplified on this scaffold. The reaction is shown to proceed via different and concurrent mechanistic pathways, including the formation of novel S≡N sulfanenitrile species as intermediates. Several alkoxy-amino-λ6-sulfanenitriles are prepared with different alcohols, and shown to be alkylating agents to a range of nucleophiles. Detailed mechanistic studies demonstrate the iPrOH as one source of the sulfonimidamide oxygen atom, in addition to water and acetate.
St John-Campbell S, Bull J, 2019, Intramolecular palladium(II)/(IV) catalysed C(sp3)–H arylation of tertiary aldehydes using a transient imine directing group, Chemical Communications, ISSN: 1359-7345
Palladium catalysed β-C(sp3)–H activation of tertiary aldehydes using a transient imine directing group enables intramolecular arylation to form substituted indane-aldehydes. A simple amine bearing a methyl ether (2-methoxyethan-1-amine) is the optimal TDG to promote C–H activation and reaction with an unactivated proximal C–Br bond. Substituent effects are studied in the preparation of various derivatives. Preliminary mechanistic studies identify a reversible C–H activation, product inhibition and suggest that oxidative addition is the turnover limiting step.
Antermite D, Bull J, Transition Metal-Catalyzed Directed C(sp3)–H Functionalization of Saturated Heterocycles, SYNTHESIS, ISSN: 0039-7881
Synthetic methods that can readily access saturated heterocycles with different substitution patterns and with control of stereo- and regiochemistry are of huge potential value in the development of new medicinal compounds. Directed C–H functionalization of simple and commercially available precursors offers the potential to prepare diverse collections of such valuable compounds that can probe the different available exit vectors from a ring system. Nonetheless, the presence of the Lewis basic heteroatoms makes this a significant challenge. This review covers recent advances in the catalytic C–H functionalization of saturated heterocycles, with a view to different heterocycles (N, O, S), substitution patterns and transformations.1. Introduction2 alpha-C–H Functionalization with directing group on nitrogen3 C–H Functionalization at unactivated C(3), C(4) and C(5) positions3.1 C–H Functionalization at C(3) with directing groups at C(2)3.2 C–H Functionalization at C(3), C(4) and C(5): Directing groups at C(4) and C(3)4 Transannular C–H functionalization5 Conclusion
St John-Campbell S, Bull J, 2019, Base metal catalysis in directed C(sp³)–H functionalization, Advanced Synthesis and Catalysis, ISSN: 1615-4150
Directed C(sp³)–H functionalization has made enormous progress in recent years, but has largely been restricted to catalysis using noble metals, particularly palladium. However, since 2013, there have been prominent advances that exploit the reactivity of abundant first row transition metals for a multitude of new bond formations. The use of base metal catalysis for C–H functionalization can provide huge advantages in terms of cost and sustainability compared to methods using noble metals. This review covers all examples, to end 2018, of auxiliary assisted, base metal catalyzed C(sp³)–H functionalization reactions. Successful examples are reported with Fe, Co, Ni and Cu catalysis with monodentate or bidentate directing groups for C–N, C–O, C–S and C–C bond forming reactions. This review aims to highlight the current state of this field and potential for expansion and so scope and limitations are highlighted. Notably, examples to date have required sterically activated α-disubstituted substrates, particularly propanamide derivatives with bidentate directing groups, such as 8 aminoquinoline amides. Monodentate quinoline and thioamide directing groups have also been used with Co catalysis for C–N and C–C bond formations. Mechanistic details are provided to outline the nature of the proposed organometallic intermediates and potential reaction pathways. We hope this review will stimulate further development in this growing and important field
Croft RA, Dubois M, Boddy A, et al., 2019, Catalytic Friedel-crafts reactions on saturated heterocycles and small rings for sp³-sp² coupling of medicinally relevant fragments, European Journal of Organic Chemistry, ISSN: 1099-0690
gem-Diarylheterocycles display a wide range of biological activity. Here we present a systematic study into the formation of 4- to 6-membered O- and N-heterocycles and cyclobutanes bearing the diaryl motif through a catalytic Friedel–Crafts reaction from the corresponding benzylic alcohols. 3,3-Diaryltetrahydrofurans, 4,4 diaryltetrahydropyrans, 3,3-diarylpyrrolidines, 4,4-diaryl-piperidines, as well as diarylcyclobutanes are examined, with results for 3,3-diaryloxetanes and 3,3-diarylazetidines presented for comparison. Three catalytic systems are investigated for each substrate [Ca(II), Li(I) and Fe(III)], across preinstalled aromatic groups of differing electronic character. In most cases examined, the diaryl product is obtained directly from the alcohol with good yields using the most appropriate catalyst system. In the absence of a nucleophile, the olefins from the 5- and 6-membered substrates by elimination of water are obtained under the same reaction conditions.
Green SP, Payne AD, Wheelhouse KM, et al., 2019, Diazo-Transfer Reagent 2-Azido-4,6-dimethoxy-1,3,5-triazine Displays Highly Exothermic Decomposition Comparable to Tosyl Azide, The Journal of Organic Chemistry, Vol: 84, Pages: 5893-5898, ISSN: 0022-3263
Dubois MAJ, Lazaridou A, Choi C, et al., 2019, Synthesis of 3-Aryl-3-Sulfanyl Azetidines by Iron-Catalyzed Thiol Alkylation with N-Cbz Azetidinols, The Journal of Organic Chemistry, Vol: 84, Pages: 5943-5956, ISSN: 0022-3263
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.
Boultwood T, Bull J, 2019, Synthesis of selenoaziridines: a study on stereochemical outcomes of the reaction of aziridine radicals and anions generated from iodoaziridines, ACS Omega, Vol: 4, Pages: 870-879, ISSN: 2470-1343
The synthesis of a new functional group in the form of selenyl-substituted aziridines is described. Selenoaziridines are stereoselectively prepared by functionalization of intact aziridine precursors involving radical and anionic intermediates. Radicals are generated from cis-N-Ts iodoaziridines by activation of the C–I bond using alkoxides as a source of single electrons. These form predominantly trans-substituted seleno-aziridines dependent on the size of the diselenide. cis-Aziridinyllithiums generated by Li–I exchange also react with diselenides stereospecifically to form a range of cis-selenoaziridines. Proposals for the stereochemical outcome are presented.
Boddy AJ, Affron DP, Cordier CJ, et al., 2019, Rapid Assembly of Saturated Nitrogen Heterocycles in One-Pot: Diazo-Heterocycle "Stitching" by N-H Insertion and Cyclization., Angew Chem Int Ed Engl, Vol: 58, Pages: 1458-1462
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=2-5) to rapidly assemble 4 -, 5 -, 6 -, and 7 -membered saturated nitrogen heterocycles in excellent yields. Over fifty examples are demonstrated, including examples with diazo compounds derived from biologically active compounds. The products can be functionalized to afford α,α-disubstituted amino acids and applied to fragment synthesis.
Denis C, Dubois MAJ, Voisin-Chiret AS, et al., 2019, Synthesis of 3,3-Diarylazetidines by Calcium(II)-Catalyzed Friedel-Crafts Reaction of Azetidinols with Unexpected Cbz Enhanced Reactivity, ORGANIC LETTERS, Vol: 21, Pages: 300-304, ISSN: 1523-7060
St John-Campbell S, Ou AK, Bull JA, 2018, Palladium-Catalyzed C(sp(3))-H Arylation of Primary Amines Using a Catalytic Alkyl Acetal to Form a Transient Directing Group, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 24, Pages: 17838-17843, ISSN: 0947-6539
Croft RA, Bull J, 2018, Oxetanes and Oxetan-3-ones (37.3), Science of Synthesis Knowledge Updates, Vol: 4, Pages: 379-434
Croft RA, Mousseau JJ, Choi C, et al., 2018, Oxetane ethers are formed reversibly in the lithium-catalyzed Friedel-Crafts alkylation of phenols with oxetanols: synthesis of dihydrobenzofurans, diaryloxetanes, and oxetane ethers, Tetrahedron, Vol: 74, Pages: 5427-5435, ISSN: 0040-4020
Studies on the mechanism and intermediate products in the Friedel–Crafts reaction between oxetanols and phenols are presented. Formation of O-alkylated intermediates is identified using 1H NMR spectroscopy, in a reversible formation of the kinetic oxetane ether products. An interesting relationship between the electronic nature of the nucleophile and the degree of O-alkylation is uncovered. For phenols substituted with an electron withdrawing group such as CN, oxetane ethers are the only products isolated regardless of reaction time. Increasing the electron rich nature of the phenol leads to an increased proportion of the thermodynamic C-alkylated Friedel–Crafts products after just one hour and as the sole product/s after extended reaction times. These studies have enabled a more complete catalytic cycle to be proposed. Using the same lithium catalyst and carefully selected reaction times, several examples of oxetane ethers are successfully isolated as novel bioisosteres for ester groups.
St John-Campbell S, Bull JA, 2018, Transient imines as ‘next generation’ directing groups for the catalytic functionalisation of C–H bonds in a single operation, Organic and Biomolecular Chemistry, Vol: 16, Pages: 4582-4595, ISSN: 1472-7781
C–H Functionalisation promises a paradigm shift in synthetic planning. However, the additional steps often required to install and remove directing groups currently detracts from the efficiency. The strategy of reversible installation of a directing group via an imine linkage has recently emerged, with the imine formed and hydrolysed in situ. Such transient directing groups can promote transition metal catalysed functionalisation of unactivated C–H bonds of aldehydes, ketones and amines. This approach removes additional steps usually required for covalent directing groups and can use catalytic quantities of the imine forming component. This review updates the rapidly developing field of transient directing groups for C–H functionalisation on sp2 and sp3 carbon centres, to form new C–C and C–X bonds. We focus on the structures of the transient directing groups as mono or bidentate coordinating groups for various metal catalysts.
Antermite D, Affron DP, Bull JA, 2018, Regio- and Stereoselective Palladium-Catalyzed C(sp(3))-H Arylation of Pyrrolidines and Piperidines with C(3) Directing Groups, ORGANIC LETTERS, Vol: 20, Pages: 3948-3952, ISSN: 1523-7060
Tota A, St John-Campbell S, Briggs E, et al., 2018, Highly chemoselective NH- and O-transfer to thiols using hypervalent iodine reagents: synthesis of sulfonimidates and sulfonamides, Organic Letters, Vol: 20, Pages: 2599-2602, ISSN: 1523-7052
Aryl thiols can be selectively converted to sulfonimidates or sulfonamides with 3 new S–X connections being made selectively in one-pot. Using hypervalent iodine reagents in the presence of ammonium carbamate, NH- and O-groups are transferred under mild and practical conditions. Reducing the loading of ammonium carbamate changed the product distribution, converting the sulfonimidate to the sulfonamide. Studies into the possible intermediate species are presented, suggesting that multiple pathways may be possible via sulfinate esters, or related intermediates, with each species forming the same products.
Vysniauskas A, Lopez Duarte I, Thompson AJ, et al., 2018, Surface functionalisation with viscosity-sensitive BODIPY molecular rotor, Methods and Applications in Fluorescence, Vol: 6, ISSN: 2050-6120
Surface functionalisation with viscosity sensitive dyes termed ‘molecular rotors’ can potentially open up new opportunities in sensing, for example for non-invasive biological viscosity imaging, in studying the effect of shear stress on lipid membranes and in cells, and in imaging contacts between surfaces upon applied pressure. We have functionalised microscope slides with BODIPY-based molecular rotor capable of viscosity sensing via its fluorescence lifetime. We have optimised functionalisation conditions and prepared the slides with the BODIPY rotor attached directly to the surface of glass slides and through polymer linkers of 5 kDa and 40 kDa in mass. The slides were characterised for their sensitivity to viscosity, and used to measure viscosity of supported lipid bilayers during photooxidation, and of giant unilamellar vesicles lying on the surface of the slide. We conclude that our functionalised slides show promise for a variety of viscosity sensing applications.
Croft RA, Mousseau JJ, Choi C, et al., 2018, Lithium-Catalyzed Thiol Alkylation with Tertiary and Secondary Alcohols: Synthesis of 3-Sulfanyl-Oxetanes as Bioisosteres, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 24, Pages: 818-821, ISSN: 0947-6539
Bull JA, Degennaro L, Luisi R, 2017, Straightforward Strategies for the Preparation of NH-Sulfox-imines: A Serendipitous Story, Synlett, Vol: 28, Pages: 2525-2538, ISSN: 0936-5214
© Georg Thieme Verlag Stuttgart, New York. Sulfoximines are emerging as valuable new isosteres for use in medicinal chemistry, with the potential to modulate physicochemical properties. Recent developments in synthetic strategies have made the unprotected 'free' NH-sulfoximine group more readily available, facilitating further study. This account reviews approaches to NH-sulfoximines, with a focus on our contribution to the field. Starting from the development of catalytic strategies involving transition metals, more sustainable metal-free processes have been discovered. In particular, the use of hypervalent iodine reagents to mediate NH-transfer to sulfoxides is described, along with an assessment of the substrate scope. Furthermore, a one-pot strategy to convert sulfides directly into NH-sulfoximines is discussed, with N- and O-transfer occurring under the reaction conditions. Mechanistic evidence for the new procedures is included as well as relevant synthetic applications that further exemplify the potential of these approaches. 1 Introduction 2 Strategies to Form NH-Sulfoximines Involving Transition-Metal Catalysts 3 Metal-Free Strategies to Prepare NH-Sulfoximines 4 Mechanistic Evidence for the Direct Synthesis of NH-Sulfoximines from Sulfoxides and Sulfides 5 Further Applications 6 Conclusion.
Chawner SJ, Cases-Thomas MJ, Bull JA, 2017, Divergent Synthesis of Cyclopropane-Containing Lead-like Compounds, Fragments and Building Blocks via a Cobalt Catalyzed Cyclopropanation of Phenyl Vinyl Sulfide, European Journal of Organic Chemistry, Vol: 2017, Pages: 5015-5024, ISSN: 1434-193X
Cyclopropanes provide important design elements in medicinal chemistry and are widely present in drug compounds. Here we describe a strategy and extensive synthetic studies for the preparation of a diverse collection of cyclopropane-containing fragments, lead-like compounds and building blocks exploiting a single precursor. The bifunctional cyclopropane (E/Z)-ethyl 2-(phenylsulfanyl)-cyclopropane-1-carboxylate was designed to allow derivatization through the ester and sulfide functionalities to topologically varied compounds designed to fit in desirable chemical space for drug discovery. A cobalt-catalyzed cyclopropanation of phenyl vinyl sulfide affords these scaffolds on multigram scale. Divergent, orthogonal derivatization is achieved through hydrolysis, reduction, amidation and oxidation reactions as well as sulfoxide–magnesium exchange/functionalization. The cyclopropyl Grignard reagent formed from sulfoxide exchange is stable at 0 C for >2 h, enabling trapping with various electrophiles and Pd-catalyzed Negishi cross-coupling reactions. The library prepared, as well as a further virtual elaboration, is analyzed against parameters of lipophilicity (ALogP), MW, and molecular shape using the LLAMA (Lead-Likeness and Molecular Analysis) software, to illustrate the success in generating lead-like compounds and fragments.
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
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
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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