Co-reporter:Dr. Andreas Greb;Jian-Siang Poh;Stephanie Greed;Dr. Claudio Battilocchio;Dr. Patrick Pasau;Dr. David C. Blakemore; Steven V. Ley
Angewandte Chemie 2017 Volume 129(Issue 52) pp:16829-16832
Publication Date(Web):2017/12/22
DOI:10.1002/ange.201710445
AbstractCoupling of readily available boronic acids and diazo compounds has emerged recently as a powerful metal-free carbon–carbon bond forming method. However, the difficulty in forming the unstable diazo compound partner in a mild fashion has hitherto limited their general use and the scope of the transformation. Here, we report the application of oxadiazolines as precursors for the generation of an unstable family of diazo compounds using flow UV photolysis and their first use in divergent protodeboronative and oxidative C(sp2)−C(sp3) cross-coupling processes, with excellent functional-group tolerance.
Co-reporter:Dr. Andreas Greb;Jian-Siang Poh;Stephanie Greed;Dr. Claudio Battilocchio;Dr. Patrick Pasau;Dr. David C. Blakemore; Steven V. Ley
Angewandte Chemie International Edition 2017 Volume 56(Issue 52) pp:16602-16605
Publication Date(Web):2017/12/22
DOI:10.1002/anie.201710445
AbstractCoupling of readily available boronic acids and diazo compounds has emerged recently as a powerful metal-free carbon–carbon bond forming method. However, the difficulty in forming the unstable diazo compound partner in a mild fashion has hitherto limited their general use and the scope of the transformation. Here, we report the application of oxadiazolines as precursors for the generation of an unstable family of diazo compounds using flow UV photolysis and their first use in divergent protodeboronative and oxidative C(sp2)−C(sp3) cross-coupling processes, with excellent functional-group tolerance.
Co-reporter:Fabio Lima;Dr. Upendra K. Sharma;Lars Grunenberg;Dr. Debasmita Saha;Sra Johannsen;Dr. Joerg Sedelmeier; Erik V. Van der Eycken; Steven V. Ley
Angewandte Chemie International Edition 2017 Volume 56(Issue 47) pp:15136-15140
Publication Date(Web):2017/11/20
DOI:10.1002/anie.201709690
AbstractWe report herein the use of a dual catalytic system comprising a Lewis base catalyst such as quinuclidin-3-ol or 4-dimethylaminopyridine and a photoredox catalyst to generate carbon radicals from either boronic acids or esters. This system enabled a wide range of alkyl boronic esters and aryl or alkyl boronic acids to react with electron-deficient olefins via radical addition to efficiently form C−C coupled products in a redox-neutral fashion. The Lewis base catalyst was shown to form a redox-active complex with either the boronic esters or the trimeric form of the boronic acids (boroxines) in solution.
Co-reporter:Fabio Lima;Dr. Upendra K. Sharma;Lars Grunenberg;Dr. Debasmita Saha;Sra Johannsen;Dr. Joerg Sedelmeier; Erik V. Van der Eycken; Steven V. Ley
Angewandte Chemie 2017 Volume 129(Issue 47) pp:15332-15336
Publication Date(Web):2017/11/20
DOI:10.1002/ange.201709690
AbstractWe report herein the use of a dual catalytic system comprising a Lewis base catalyst such as quinuclidin-3-ol or 4-dimethylaminopyridine and a photoredox catalyst to generate carbon radicals from either boronic acids or esters. This system enabled a wide range of alkyl boronic esters and aryl or alkyl boronic acids to react with electron-deficient olefins via radical addition to efficiently form C−C coupled products in a redox-neutral fashion. The Lewis base catalyst was shown to form a redox-active complex with either the boronic esters or the trimeric form of the boronic acids (boroxines) in solution.
Co-reporter:Claudio Bomio;Mikhail A. Kabeshov;Arthur R. Lit;Shing-Hing Lau;Janna Ehlert;Claudio Battilocchio
Chemical Science (2010-Present) 2017 vol. 8(Issue 9) pp:6071-6075
Publication Date(Web):2017/08/21
DOI:10.1039/C7SC02264F
By means of computational and experimental mechanistic studies the fundamental role of boroxines in the reaction between diazo compounds and boronic acids was elucidated. Consequently, a selective metal-free carbon–carbon homologation of aryl and vinyl boroxines using TMSCHN2, giving access to TMS-pinacol boronic ester products, was developed.
Co-reporter:Mikhail A. Kabeshov;Biagia Musio
Reaction Chemistry & Engineering (2016-Present) 2017 vol. 2(Issue 6) pp:822-825
Publication Date(Web):2017/11/29
DOI:10.1039/C7RE00164A
The continuous production of benzyl amides by anodic oxidation in flow was developed. The stability and productivity of the equipment was examined over time and monitored by means of in-line UV analysis. The applicability of the method to twelve substrates was demonstrated.
Co-reporter:C. Battilocchio;G. Iannucci;S. Wang;E. Godineau;A. Kolleth;A. De Mesmaeker;S. V. Ley
Reaction Chemistry & Engineering (2016-Present) 2017 vol. 2(Issue 3) pp:295-298
Publication Date(Web):2017/06/08
DOI:10.1039/C7RE00020K
A flow chemistry process for the synthesis of 2-substituted cyclobutanones, via [2 + 2] cycloaddition of keteneiminium salts and ethylene gas, is reported. Our approach uses rapid and mild reaction conditions to access a diverse array of products with good to excellent yield, alongside a good level of functional group compatibility.
Co-reporter:Charlotte L. Sutherell; Cynthia Tallant; Octovia P. Monteiro; Clarence Yapp; Julian E. Fuchs; Oleg Fedorov; Paulina Siejka; Suzanne Müller; Stefan Knapp; James D. Brenton; Paul E. Brennan
Journal of Medicinal Chemistry 2016 Volume 59(Issue 10) pp:5095-5101
Publication Date(Web):April 27, 2016
DOI:10.1021/acs.jmedchem.5b01997
Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors that target these proteins and display unusual binding modes involving water displacement from the KAc binding site. The best compound binds the fifth bromodomain of PB1 with a KD of 124 nM, SMARCA2B and SMARCA4 with KD values of 262 and 417 nM, respectively, and displays excellent selectivity over bromodomains other than PB1, SMARCA2, and SMARCA4.
Co-reporter:Takashi Ouchi, Robbie J. Mutton, Victor Rojas, Daniel E. Fitzpatrick, David G. Cork, Claudio Battilocchio, and Steven V. Ley
ACS Sustainable Chemistry & Engineering 2016 Volume 4(Issue 4) pp:1912
Publication Date(Web):March 16, 2016
DOI:10.1021/acssuschemeng.6b00287
A solvent-free approach to intensification of chemical processes is reported. This concept, in which reactions are carried out solvent-free, without the need for further downstream processing, was highlighted first with a full reduction of ethyl nicotinate to ethylpiperidine-3-carboxylate under continuous flow conditions. Using a small footprint reactor, a throughput of 26.4 g h–1 was achieved. Similarly, this approach was used for the telescoped two-step synthesis of 2-propyl phenol (productivity 120 g h–1) and 2-propyl cyclohexanone (productivity 30 g h–1), starting from the commercially available allyl phenol ether via Claisen rearrangement and subsequent reduction.Keywords: Claisen rearrangement; Flow chemistry; Heterogeneous hydrogenation; Process intensification; Solvent-free reactions
Co-reporter:Daniel E. Fitzpatrick, Claudio Battilocchio, and Steven V. Ley
ACS Central Science 2016 Volume 2(Issue 3) pp:131
Publication Date(Web):February 24, 2016
DOI:10.1021/acscentsci.6b00015
Technology is evolving at breakneck pace, changing the way we communicate, travel, find out information, and live our lives. Yet chemistry as a science has been slower to adapt to this rapidly shifting world. In this Outlook we use highlights from recent literature reports to describe how progresses in enabling technologies are altering this trend, permitting chemists to incorporate new advances into their work at all levels of the chemistry development cycle. We discuss the benefits and challenges that have arisen, impacts on academic–industry relationships, and future trends in the area of chemical synthesis.
Co-reporter:Steffen V. F. Hansen, Zoe E. Wilson, Trond Ulven and Steven V. Ley
Reaction Chemistry & Engineering 2016 vol. 1(Issue 3) pp:280-287
Publication Date(Web):25 Feb 2016
DOI:10.1039/C6RE00020G
A method for the generation and use of carbon monoxide in flow chemistry has been developed. By using a tube-in-tube reactor, oxalyl chloride can be conveniently and safely hydrolyzed using a NaOH solution to generate CO in the outer stream, which then passes through AF-2400 semi-permeable inner tubing to enrich a reaction stream where it is consumed. The tube-in-tube reactor allows the generation of CO under conditions which would otherwise be incompatible with the reaction conditions. In this way carbonylations can be successfully performed in flow without the use of pressurized gas cylinders. Both alkoxy- and aminocarbonylation was carried out in flow, including a 320 minute continuous run, as proof of concept.
Co-reporter:Martin Brzozowski, Matthew O’Brien, Steven V. Ley, and Anastasios Polyzos
Accounts of Chemical Research 2015 Volume 48(Issue 2) pp:349
Publication Date(Web):January 22, 2015
DOI:10.1021/ar500359m
The previous decade has witnessed the expeditious uptake of flow chemistry techniques in modern synthesis laboratories, and flow-based chemistry is poised to significantly impact our approach to chemical preparation. The advantages of moving from classical batch synthesis to flow mode, in order to address the limitations of traditional approaches, particularly within the context of organic synthesis are now well established. Flow chemistry methodology has led to measurable improvements in safety and reduced energy consumption and has enabled the expansion of available reaction conditions. Contributions from our own laboratories have focused on the establishment of flow chemistry methods to address challenges associated with the assembly of complex targets through the development of multistep methods employing supported reagents and in-line monitoring of reaction intermediates to ensure the delivery of high quality target compounds.Recently, flow chemistry approaches have addressed the challenges associated with reactions utilizing reactive gases in classical batch synthesis. The small volumes of microreactors ameliorate the hazards of high-pressure gas reactions and enable improved mixing with the liquid phase. Established strategies for gas–liquid reactions in flow have relied on plug-flow (or segmented flow) regimes in which the gas plugs are introduced to a liquid stream and dissolution of gas relies on interfacial contact of the gas bubble with the liquid phase. This approach confers limited control over gas concentration within the liquid phase and is unsuitable for multistep methods requiring heterogeneous catalysis or solid supported reagents.We have identified the use of a gas-permeable fluoropolymer, Teflon AF-2400, as a simple method of achieving efficient gas–liquid contact to afford homogeneous solutions of reactive gases in flow. The membrane permits the transport of a wide range of gases with significant control of the stoichiometry of reactive gas in a given reaction mixture. We have developed a tube-in-tube reactor device consisting of a pair of concentric capillaries in which pressurized gas permeates through an inner Teflon AF-2400 tube and reacts with dissolved substrate within a liquid phase that flows within a second gas impermeable tube.This Account examines our efforts toward the development of a simple, unified methodology for the processing of gaseous reagents in flow by way of development of a tube-in-tube reactor device and applications to key C–C, C–N, and C–O bond forming and hydrogenation reactions. We further describe the application to multistep reactions using solid-supported reagents and extend the technology to processes utilizing multiple gas reagents. A key feature of our work is the development of computer-aided imaging techniques to allow automated in-line monitoring of gas concentration and stoichiometry in real time. We anticipate that this Account will illustrate the convenience and benefits of membrane tube-in-tube reactor technology to improve and concomitantly broaden the scope of gas/liquid/solid reactions in organic synthesis.
Co-reporter:Duc N. Tran, Claudio Battilocchio, Shing-Bong Lou, Joel M. Hawkins and Steven V. Ley
Chemical Science 2015 vol. 6(Issue 2) pp:1120-1125
Publication Date(Web):07 Nov 2014
DOI:10.1039/C4SC03072A
The work takes advantage of an important feature of flow chemistry, whereby the generation of a transient species (or reactive intermediate) can be followed by a transfer step into another chemical environment, before the intermediate is reacted with a coupling partner. This concept is successfully applied to achieve a room temperature sp2–sp3 cross coupling of boronic acids with diazo compounds, these latter species being generated from hydrazones under flow conditions using MnO2 as the oxidant.
Co-reporter:Shing-Hing Lau, Alicia Galván, Rohan R. Merchant, Claudio Battilocchio, José A. Souto, Malcolm B. Berry, and Steven V. Ley
Organic Letters 2015 Volume 17(Issue 13) pp:3218-3221
Publication Date(Web):June 16, 2015
DOI:10.1021/acs.orglett.5b01307
An efficient preparation of the antimalarial drug candidate OZ439, which was obtained by integrating a machine-assisted approach with batch processes, is reported. This approach allows a rapid and cost-effective production of the key intermediates that were readily elaborated into the target molecule.
Co-reporter:Shing-Hing Lau, Samuel L. Bourne, Benjamin Martin, Berthold Schenkel, Gerhard Penn, and Steven V. Ley
Organic Letters 2015 Volume 17(Issue 21) pp:5436-5439
Publication Date(Web):October 28, 2015
DOI:10.1021/acs.orglett.5b02806
An efficient preparation of a precursor to the neprilysin inhibitor sacubitril is described. The convergent synthesis features a diastereoselective Reformatsky-type carbethoxyallylation and a rhodium-catalyzed stereoselective hydrogenation for installation of the two key stereocenters. Moreover, by integrating machine-assisted methods with batch processes, this procedure allows a safe and rapid production of the key intermediates which are promptly transformed to the target molecule (3·HCl) over 7 steps in 54% overall yield.
Co-reporter:Nuria M. Roda, Duc N. Tran, Claudio Battilocchio, Ricardo Labes, Richard J. Ingham, Joel M. Hawkins and Steven V. Ley
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 9) pp:2550-2554
Publication Date(Web):07 Jan 2015
DOI:10.1039/C5OB00019J
We have devised a room temperature process for the cyclopropanation of electron-poor olefins using unstabilised diazo compounds, generated under continuous flow conditions. This protocol was applied to a wide range of different diazo species to generate functionalised cyclopropanes which are valuable 3D building blocks.
Co-reporter:Daniela de Lucia, Oscar Méndez Lucio, Biagia Musio, Andreas Bender, Monika Listing, Sophie Dennhardt, Andreas Koeberle, Ulrike Garscha, Roberta Rizzo, Stefano Manfredini, Oliver Werz, Steven V. Ley
European Journal of Medicinal Chemistry 2015 Volume 103() pp:223-225
Publication Date(Web):20 October 2015
DOI:10.1016/j.ejmech.2015.08.050
Co-reporter:Daniela De Lucia, Oscar Méndez Lucio, Biagia Musio, Andreas Bender, Monika Listing, Sophie Dennhardt, Andreas Koeberle, Ulrike Garscha, Roberta Rizzo, Stefano Manfredini, Oliver Werz, Steven V. Ley
European Journal of Medicinal Chemistry 2015 Volume 101() pp:573-583
Publication Date(Web):28 August 2015
DOI:10.1016/j.ejmech.2015.07.011
•A new library of triazole-containing 5-lipoxygenase inhibitors was prepared.•Binding optimization of compounds was assisted with molecular docking calculations.•A clear structure–activity relationship of this family of compounds was observed.•Some of the new molecules potently suppressed 5-lipoxygenase product formation.•Cytotoxicity evaluation suggested that inhibitory activity was not due to toxicity.In this work the synthesis, structure–activity relationship (SAR) and biological evaluation of a novel series of triazole-containing 5-lipoxygenase (5-LO) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent 5-LO inhibition with IC50 of 0.2 and 3.2 μm in cell-based and cell-free assays, respectively. Optimization of binding and functional potencies resulted in the identification of compound 13d, which showed an enhanced activity compared to the parent bioactive compound caffeic acid 5 and the clinically approved zileuton 3. Compounds 15 and 16 were identified as lead compounds in inhibiting 5-LO products formation in neutrophils. Their interference with other targets on the arachidonic acid pathway was also assessed. Cytotoxicity tests were performed to exclude a relationship between cytotoxicity and the increased activity observed after structure optimization.
Co-reporter:José A. Souto, Robert A. Stockman and Steven V. Ley
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 13) pp:3871-3877
Publication Date(Web):17 Feb 2015
DOI:10.1039/C5OB00170F
A method for the continuous preparation of alcohols by hydroboration/oxidation of olefins using flow techniques is described. The process allows the isolation of up to 120 mmol h−1 of the desired alcohol in a very rapid manner with good functional group tolerance. The flow setup can be modified to perform a continuous extraction of the desired alcohol from the biphasic mixture produced by the reaction.
Co-reporter:Leandro de C. Alves, André L. Desiderá, Kleber T. de Oliveira, Sean Newton, Steven V. Ley and Timothy J. Brocksom
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 28) pp:7633-7642
Publication Date(Web):08 May 2015
DOI:10.1039/C5OB00525F
A route to enantiopure (R)-(+)-3-methyl-6-isopropenyl-cyclohept-3-enone-1, an intermediate for terpenoids, has been developed and includes a highly chemo- and regioselective Tiffeneau–Demjanov reaction. Starting from readily available (R)-(−)-carvone, this robust sequence is available on a deca-gram scale and uses flow chemistry for the initial epoxidation reaction. The stereochemistry of the addition of two nucleophiles to the carbonyl group of (R)-(−)-carvone has been determined by X-ray diffraction studies and chemical correlation.
Co-reporter:Steffen Glöckner, Duc N. Tran, Richard J. Ingham, Sabine Fenner, Zoe E. Wilson, Claudio Battilocchio and Steven V. Ley
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 1) pp:207-214
Publication Date(Web):2014/10/28
DOI:10.1039/C4OB02105C
A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from β-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide.
Co-reporter:Richard J. Ingham;Dr. Claudio Battilocchio;Daniel E. Fitzpatrick;Dr. Eric Sliwinski;Dr. Joel M. Hawkins; Steven V. Ley
Angewandte Chemie 2015 Volume 127( Issue 1) pp:146-150
Publication Date(Web):
DOI:10.1002/ange.201409356
Abstract
Performing reactions in flow can offer major advantages over batch methods. However, laboratory flow chemistry processes are currently often limited to single steps or short sequences due to the complexity involved with operating a multi-step process. Using new modular components for downstream processing, coupled with control technologies, more advanced multi-step flow sequences can be realized. These tools are applied to the synthesis of 2-aminoadamantane-2-carboxylic acid. A system comprising three chemistry steps and three workup steps was developed, having sufficient autonomy and self-regulation to be managed by a single operator.
Co-reporter:Dr. Zoe E. Wilson;Dr. Sabine Fenner ; Steven V. Ley
Angewandte Chemie 2015 Volume 127( Issue 4) pp:1300-1304
Publication Date(Web):
DOI:10.1002/ange.201410063
Abstract
Plantazolicin A, a linear decacyclic natural product, exhibits desirable selective activity against the causative agent of anthrax toxicity. The total synthesis of plantazolicin A and its biosynthetic precursor plantazolicin B was successfully achieved by an efficient, unified, and highly convergent route featuring dicyclizations to form 2,4-concatenated oxazoles and the mild synthesis of thiazoles from natural amino acids. This report represents the first synthesis of plantazolicin B and includes the first complete characterization data for both natural products.
Co-reporter: Steven V. Ley;Daniel E. Fitzpatrick;Dr. Rebecca M. Myers;Dr. Claudio Battilocchio ;Dr. Richard. J. Ingham
Angewandte Chemie International Edition 2015 Volume 54( Issue 35) pp:10122-10136
Publication Date(Web):
DOI:10.1002/anie.201501618
Abstract
In this Review we describe how the advent of machines is impacting on organic synthesis programs, with particular emphasis on the practical issues associated with the design of chemical reactors. In the rapidly changing, multivariant environment of the research laboratory, equipment needs to be modular to accommodate high and low temperatures and pressures, enzymes, multiphase systems, slurries, gases, and organometallic compounds. Additional technologies have been developed to facilitate more specialized reaction techniques such as electrochemical and photochemical methods. All of these areas create both opportunities and challenges during adoption as enabling technologies.
Co-reporter: Steven V. Ley;Daniel E. Fitzpatrick;Dr. Richard. J. Ingham ;Dr. Rebecca M. Myers
Angewandte Chemie International Edition 2015 Volume 54( Issue 11) pp:3449-3464
Publication Date(Web):
DOI:10.1002/anie.201410744
Abstract
Organic synthesis is changing; in a world where budgets are constrained and the environmental impacts of practice are scrutinized, it is increasingly recognized that the efficient use of human resource is just as important as material use. New technologies and machines have found use as methods for transforming the way we work, addressing these issues encountered in research laboratories by enabling chemists to adopt a more holistic systems approach in their work. Modern developments in this area promote a multi-disciplinary approach and work is more efficient as a result. This Review focuses on the concepts, procedures and methods that have far-reaching implications in the chemistry world. Technologies have been grouped as topics of opportunity and their recent applications in innovative research laboratories are described.
Co-reporter:Jian-Siang Poh;Dr. Duc N. Tran;Dr. Claudio Battilocchio;Dr. Joel M. Hawkins; Steven V. Ley
Angewandte Chemie International Edition 2015 Volume 54( Issue 27) pp:7920-7923
Publication Date(Web):
DOI:10.1002/anie.201501538
Abstract
A copper-catalyzed coupling reaction between flow-generated unstabilized diazo compounds and terminal alkynes provides di- and trisubstituted allenes. This extremely mild and rapid transformation is highly tolerant of several functional groups.
Co-reporter:Jian-Siang Poh;Dr. Duc N. Tran;Dr. Claudio Battilocchio;Dr. Joel M. Hawkins; Steven V. Ley
Angewandte Chemie 2015 Volume 127( Issue 27) pp:8031-8034
Publication Date(Web):
DOI:10.1002/ange.201501538
Abstract
A copper-catalyzed coupling reaction between flow-generated unstabilized diazo compounds and terminal alkynes provides di- and trisubstituted allenes. This extremely mild and rapid transformation is highly tolerant of several functional groups.
Co-reporter: Steven V. Ley;Daniel E. Fitzpatrick;Dr. Rebecca M. Myers;Dr. Claudio Battilocchio ;Dr. Richard. J. Ingham
Angewandte Chemie 2015 Volume 127( Issue 35) pp:10260-10275
Publication Date(Web):
DOI:10.1002/ange.201501618
Abstract
In diesem Aufsatz beschreiben wir, welche Konsequenzen der zunehmende Einsatz von Maschinen für organische Syntheseprogramme haben wird, wobei wir einen besonderen Schwerpunkt auf praktische Fragen des Reaktor-Designs legen. In dem sich rasch verändernden und vielschichtigen Umfeld eines Forschungslabors ist eine modulare Ausstattung erforderlich, um hohe und tiefe Temperaturen und Drücke, Enzyme, Mehrphasensysteme, Schlämme, Gase und Organometallverbindungen in Einklang zu bringen. Um spezialisierte Reaktionsverfahren wie elektrochemische und photochemische Umsetzungen zu vereinfachen, wurden weitere Techniken entwickelt. All diese Teilgebiete halten Chancen und Herausforderungen bereit.
Co-reporter: Steven V. Ley;Daniel E. Fitzpatrick;Dr. Richard. J. Ingham ;Dr. Rebecca M. Myers
Angewandte Chemie 2015 Volume 127( Issue 11) pp:3514-3530
Publication Date(Web):
DOI:10.1002/ange.201410744
Abstract
Die organische Synthese ist im Wandel begriffen: Da Forschungsetats zunehmend gekürzt werden und der Einfluss chemischer Verfahren auf die Umwelt genau geprüft wird, wird immer deutlicher, dass der effiziente Einsatz von Personal im Labor mindestens so bedeutsam ist wie die Materialverwendung. Neue Techniken und Maschinen verändern unsere Arbeitsweise, und indem die zuvor genannten Punkte — Personal und Material – erfasst werden, ermöglichen sie es Chemikern in Forschungslaboratorien, einen eher ganzheitlichen Ansatz für ihre Tätigkeit zu finden. Moderne Entwicklungen auf diesem Gebiet fördern multidisziplinäres Vorgehen mit dem Ergebnis effizienterer Arbeit. Dieser Aufsatz behandelt die Konzepte, Verfahren und Methoden, die weitreichende Implikationen für die Chemie insgesamt haben. Thematisch ist der Aufsatz nach unterschiedlichen Anwendungsmöglichkeiten gegliedert, und neuere Anwendungen in innovativen Forschungslabors werden beschrieben.
Co-reporter:Dr. Zoe E. Wilson;Dr. Sabine Fenner ; Steven V. Ley
Angewandte Chemie International Edition 2015 Volume 54( Issue 4) pp:1284-1288
Publication Date(Web):
DOI:10.1002/anie.201410063
Abstract
Plantazolicin A, a linear decacyclic natural product, exhibits desirable selective activity against the causative agent of anthrax toxicity. The total synthesis of plantazolicin A and its biosynthetic precursor plantazolicin B was successfully achieved by an efficient, unified, and highly convergent route featuring dicyclizations to form 2,4-concatenated oxazoles and the mild synthesis of thiazoles from natural amino acids. This report represents the first synthesis of plantazolicin B and includes the first complete characterization data for both natural products.
Co-reporter:Richard J. Ingham;Dr. Claudio Battilocchio;Daniel E. Fitzpatrick;Dr. Eric Sliwinski;Dr. Joel M. Hawkins; Steven V. Ley
Angewandte Chemie International Edition 2015 Volume 54( Issue 1) pp:144-148
Publication Date(Web):
DOI:10.1002/anie.201409356
Abstract
Performing reactions in flow can offer major advantages over batch methods. However, laboratory flow chemistry processes are currently often limited to single steps or short sequences due to the complexity involved with operating a multi-step process. Using new modular components for downstream processing, coupled with control technologies, more advanced multi-step flow sequences can be realized. These tools are applied to the synthesis of 2-aminoadamantane-2-carboxylic acid. A system comprising three chemistry steps and three workup steps was developed, having sufficient autonomy and self-regulation to be managed by a single operator.
Co-reporter:Mikhail A. Kabeshov, Biagia Musio, Philip R. D. Murray, Duncan L. Browne, and Steven V. Ley
Organic Letters 2014 Volume 16(Issue 17) pp:4618-4621
Publication Date(Web):August 22, 2014
DOI:10.1021/ol502201d
An expedient synthesis of the indole alkaloid nazlinine is reported. Judicious choice of flow electrochemistry as an enabling technology has permitted the rapid generation of a small library of unnatural relatives of this biologically active molecule. Furthermore, by conducting the key electrochemical Shono oxidation in a flow cell, the loading of electrolyte can be significantly reduced to 20 mol % while maintaining a stable, broadly applicable process.
Co-reporter:Claudio Battilocchio, Joel M. Hawkins, and Steven V. Ley
Organic Letters 2014 Volume 16(Issue 4) pp:1060-1063
Publication Date(Web):February 5, 2014
DOI:10.1021/ol403591c
A sustainable flow chemistry process for the hydration of nitriles, whereby an aqueous solution of the nitrile is passed through a column containing commercially available amorphous manganese dioxide, has been developed. The product is obtained simply by concentration of the output stream without any other workup steps. The protocol described is rapid, robust, reliable, and scalable, and it has been applied to a broad range of substrates, showing a high level of chemical tolerance.
Co-reporter:Jan Hartwig, Jan B. Metternich, Nikzad Nikbin, Andreas Kirschning and Steven V. Ley
Organic & Biomolecular Chemistry 2014 vol. 12(Issue 22) pp:3611-3615
Publication Date(Web):17 Apr 2014
DOI:10.1039/C4OB00662C
Continuous flow chemistry as a process intensification tool is well known. However, its ability to enable chemists to perform reactions which are not possible in batch is less well studied or understood. Here we present an example, where a new reactivity pattern and extended reaction scope has been achieved by transferring a reaction from batch mode to flow. This new reactivity can be explained by suppressing back mixing and precise control of temperature in a flow reactor set up.
Co-reporter:Takashi Ouchi, Claudio Battilocchio, Joel M. Hawkins, and Steven V. Ley
Organic Process Research & Development 2014 Volume 18(Issue 11) pp:1560-1566
Publication Date(Web):July 24, 2014
DOI:10.1021/op500208j
Here we report a process intensification study for the selective, partial, and full hydrogenation of ethyl nicotinate using a trickle bed reactor for meso-flow transformations (HEL FlowCAT). The process achieved a throughput of 1219 g d–1 (78 g h–1 of product per g of active catalyst) for the partial hydrogenation to ethyl 1,4,5,6-tetrahydropyridine-3-carboxylate, whereas the productivity for the full hydrogenation process reached a 1959 g d–1 of throughput (408 g h–1 of product per g of active catalyst) on this laboratory-scale flow chemistry platform.
Co-reporter:James A. Newby, D. Wayne Blaylock, Paul M. Witt, Richard M. Turner, Patrick L. Heider, Bashir H. Harji, Duncan L. Browne, and Steven V. Ley
Organic Process Research & Development 2014 Volume 18(Issue 10) pp:1221-1228
Publication Date(Web):September 19, 2014
DOI:10.1021/op500221s
A flow platform for preparing various aromatic scaffolds using a low-temperature fluorine-directed ortho-lithiation reaction has been successfully reconfigured to allow large-scale processing over extended reaction periods. During the course of this work several key factors have resulted in the development of new technology such as stainless steel y-piece fittings capable of hosting a thermocouple at the point of mixing which directly controls the power output of a cryogenic cooling device. These developments have enabled the continuous processing of an industrially relevant product, where adequate mixing, cooling, and exotherm control are important for successful operation. The configuration culminates in a large-scale campaign where the flow platform is utilised to process over 100 g of pure product over 7 h, in a yield of 80% after workup.
Co-reporter:James A. Newby, D. Wayne Blaylock, Paul M. Witt, Julio C. Pastre, Marija K. Zacharova, Steven V. Ley, and Duncan L. Browne
Organic Process Research & Development 2014 Volume 18(Issue 10) pp:1211-1220
Publication Date(Web):August 12, 2014
DOI:10.1021/op500213j
A flow reactor platform technology applicable to a broad range of low temperature chemistry is reported. The newly developed system captures the essence of running low temperature reactions in batch and represents this as a series of five flow coils, each with independently variable volume. The system was initially applied to the functionalization of alkynes, Grignard addition reactions, heterocycle functionalization, and heteroatom acetylation. This new platform has then been used in the preparation of a 20-compound library of polysubstituted, fluorine-containing aromatic substrates from a sequential metalation-quench procedure and can be readily adapted to provide gaseous electrophile inputs such as carbon dioxide using a tube-in-tube reactor.
Co-reporter:Claudio Battilocchio;Benjamin N. Bhawal;Rajeev Chorghade;Benjamin J. Deadman;Joel M. Hawkins
Israel Journal of Chemistry 2014 Volume 54( Issue 4) pp:371-380
Publication Date(Web):
DOI:10.1002/ijch.201300049
Abstract
A flow chemistry procedure for Sonogashira and Heck cross-coupling reactions using a low-level palladium perovskite catalyst (LaFe0.95Pd0.05O3) deposited on cerium oxide is reported. The catalyst was generated in situ at high temperature using a flow platform. The system could be applied to a wide range of functionalised substrates, allowing clean and fast delivery of the products within a few minutes (10–30 min), after scavenging with thiourea polymer (QP-TU) and sulfonic acid resin (QP-SA). The use of an in-line evaporator/solvent switching device allowed us to recover the solvent and transport the material into the following stage. The catalyst could be continuously used for at least 24 h, without any noticeable decrease in the catalytic efficiency. In one example the system was scaled to deliver 10 mmol of product.
Co-reporter:Lucie Guetzoyan, Richard J. Ingham, Nikzad Nikbin, Julien Rossignol, Michael Wolling, Mark Baumert, Nicola A. Burgess-Brown, Claire M. Strain-Damerell, Leela Shrestha, Paul E. Brennan, Oleg Fedorov, Stefan Knapp and Steven V. Ley
MedChemComm 2014 vol. 5(Issue 4) pp:540-546
Publication Date(Web):07 Mar 2014
DOI:10.1039/C4MD00007B
A combination of conventional organic synthesis, remotely monitored flow synthesis and bioassay platforms, were used for the evaluation of novel inhibitors targeting bromodomains outside the well-studied bromodomain and extra terminal (BET) family, here exemplified by activity measurements on the bromodomain of BRD9 protein, a component of some tissue-specific SWi/SNF chromatin remodelling complexes. The Frontal Affinity Chromatography combined with Mass Spectrometry (FAC-MS) method proved to be reliable and results correlated well with an independent thermal shift assay.
Co-reporter:Dr. Sean Newton;Dr. Catherine F. Carter;Dr. Colin M. Pearson;Lero deC.Alves;Dr. Heiko Lange;Dr. Praew Thansote ; Steven V. Ley
Angewandte Chemie International Edition 2014 Volume 53( Issue 19) pp:4915-4920
Publication Date(Web):
DOI:10.1002/anie.201402056
Abstract
Over the past decade, the integration of synthetic chemistry with flow processing has resulted in a powerful platform for molecular assembly that is making an impact throughout the chemical community. Herein, we demonstrate the extension of these tools to encompass complex natural product synthesis. We have developed a number of novel flow-through processes for reactions commonly encountered in natural product synthesis programs to achieve the first total synthesis of spirodienal A and the preparation of spirangien A methyl ester. Highlights of the synthetic route include an iridium-catalyzed hydrogenation, iterative Roush crotylations, gold-catalyzed spiroketalization and a late-stage cis-selective reduction.
Co-reporter:Dr. Sean Newton;Dr. Catherine F. Carter;Dr. Colin M. Pearson;Lero deC.Alves;Dr. Heiko Lange;Dr. Praew Thansote ; Steven V. Ley
Angewandte Chemie 2014 Volume 126( Issue 19) pp:5015-5020
Publication Date(Web):
DOI:10.1002/ange.201402056
Abstract
Over the past decade, the integration of synthetic chemistry with flow processing has resulted in a powerful platform for molecular assembly that is making an impact throughout the chemical community. Herein, we demonstrate the extension of these tools to encompass complex natural product synthesis. We have developed a number of novel flow-through processes for reactions commonly encountered in natural product synthesis programs to achieve the first total synthesis of spirodienal A and the preparation of spirangien A methyl ester. Highlights of the synthetic route include an iridium-catalyzed hydrogenation, iterative Roush crotylations, gold-catalyzed spiroketalization and a late-stage cis-selective reduction.
Co-reporter:Dr. Rebecca M. Myers;Daniel E. Fitzpatrick;Dr. Richard M. Turner ; Steven V. Ley
Chemistry - A European Journal 2014 Volume 20( Issue 39) pp:12348-12366
Publication Date(Web):
DOI:10.1002/chem.201402801
Abstract
Flow chemistry and continuous processing techniques are beginning to have a profound impact on the production of functional materials ranging from quantum dots, nanoparticles and metal organic frameworks to polymers and dyes. These techniques provide robust procedures which not only enable accurate control of the product material’s properties but they are also ideally suited to conducting experiments on scale. The modular nature of flow and continuous processing equipment rapidly facilitates reaction optimisation and variation in function of the products.
Co-reporter:Julio C. Pastre, Duncan L. Browne and Steven V. Ley
Chemical Society Reviews 2013 vol. 42(Issue 23) pp:8849-8869
Publication Date(Web):02 Sep 2013
DOI:10.1039/C3CS60246J
The development and application of continuous flow chemistry methods for synthesis is a rapidly growing area of research. In particular, natural products provide demanding challenges to this developing technology. This review highlights successes in the area with an emphasis on new opportunities and technological advances.
Co-reporter:Lucie Guetzoyan, Nikzad Nikbin, Ian R. Baxendale and Steven V. Ley
Chemical Science 2013 vol. 4(Issue 2) pp:764-769
Publication Date(Web):23 Nov 2012
DOI:10.1039/C2SC21850J
The flow of information between chemical and biological research can present a bottleneck in pharmaceutical research. Tools that bridge these disciplines and aid information exchange have therefore clear value. Over the last few years, both synthetic chemistry and biological screening have benefited from automation, and a seamless chemistry–biology interface is now possible. We report here on the use of flow processes to perform synthesis and biological evaluation in an integrated manner. As proof of concept, a flow synthesis of a series of imidazo[1,2-a]pyridines, including zolpidem and alpidem, was developed and connected to a Frontal Affinity Chromatography screening assay to investigate their interaction with Human Serum Albumin (HSA).
Co-reporter:Benjamin J. Deadman, Claudio Battilocchio, Eric Sliwinski and Steven V. Ley
Green Chemistry 2013 vol. 15(Issue 8) pp:2050-2055
Publication Date(Web):24 Jun 2013
DOI:10.1039/C3GC40967H
We report a convenient and efficient prototype device for evaporating, concentrating and switching solvents in continuous flow and batch processing and batch mode fashion. One of the main features of this system is the level of recyclability, whereby all solvents removed can be easily collected and reused, with reduced environmental impact.
Co-reporter:Helmut Kraus, Antoine Français, Matthew O'Brien, James Frost, Alejandro Diéguez-Vázquez, Alessandra Polara, Nikla Baricordi, Richard Horan, Day-Shin Hsu, Takashi Tsunoda and Steven V. Ley
Chemical Science 2013 vol. 4(Issue 5) pp:1989-1994
Publication Date(Web):07 Mar 2013
DOI:10.1039/C3SC50304F
An improved route to the EF fragment of the spongistatins has been developed and employed in a synthesis of spongistatin 2. The C48–C51 diene side chain, which lacks the chlorine substituent present in spongistatin 1, presented some compatibility issues during target assembly. These were overcome by implementing a late stage Stille cross coupling to construct the diene portion of the natural product.
Co-reporter:Claudio Battilocchio, Joel M. Hawkins, and Steven V. Ley
Organic Letters 2013 Volume 15(Issue 9) pp:2278-2281
Publication Date(Web):April 16, 2013
DOI:10.1021/ol400856g
A flow chemistry Meerwein–Ponndorf–Verley (MPV) reduction procedure using partially hydrated zirconium oxide via a machine-assisted approach is reported. The heterogeneous reductive system could be applied to a wide range of functionalized substrates, allowing clean and fast delivery of the alcohol products within a few minutes (6–75 min). In three examples the system was scaled to deliver 50 mmol of product.
Co-reporter:Rajeev Chorghade, Claudio Battilocchio, Joel M. Hawkins, and Steven V. Ley
Organic Letters 2013 Volume 15(Issue 22) pp:5698-5701
Publication Date(Web):October 25, 2013
DOI:10.1021/ol4027107
A flow chemistry process for the Oppenauer oxidation of benzylic secondary alcohols using partially hydrated zirconium oxide and a simple carbonyl containing oxidant such as acetone, cyclohexanone, and neopentanal is reported. The heterogeneous oxidative system could be applied to a wide range of functionalized alcohol substrates, allowing clean and fast delivery of ketone products within a few minutes between 40 and 100 °C.
Co-reporter:S. L. Bourne ;S. V. Ley
Advanced Synthesis & Catalysis 2013 Volume 355( Issue 10) pp:1905-1910
Publication Date(Web):
DOI:10.1002/adsc.201300278
Co-reporter:Mark D. Hopkin, Ian R. Baxendale and Steven V. Ley
Organic & Biomolecular Chemistry 2013 vol. 11(Issue 11) pp:1822-1839
Publication Date(Web):05 Dec 2012
DOI:10.1039/C2OB27002A
A flow-based route to imatinib, the API of Gleevec, was developed and the general procedure then used to generate a number of analogues which were screened for biological activity against Abl1. The flow synthesis required minimal manual intervention and was achieved despite the poor solubility of many of the reaction components.
Co-reporter:Benjamin J. Deadman, Mark D. Hopkin, Ian R. Baxendale and Steven V. Ley
Organic & Biomolecular Chemistry 2013 vol. 11(Issue 11) pp:1766-1800
Publication Date(Web):05 Dec 2012
DOI:10.1039/C2OB27003J
Imatinib (1), nilotinib (2) and dasatinib (3) are Bcr-Abl tyrosine kinase inhibitors approved for the treatment of chronic myelogenous leukemia (CML). This review collates information from the journal and patent literature to provide a comprehensive reference source of the different synthetic methods used to prepare the aforementioned active pharmaceutical ingredients (API's).
Co-reporter:Philip R. D. Murray, Duncan L. Browne, Julio C. Pastre, Chris Butters, Duncan Guthrie, and Steven V. Ley
Organic Process Research & Development 2013 Volume 17(Issue 9) pp:1192-1208
Publication Date(Web):August 15, 2013
DOI:10.1021/op4001548
A new enabling technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal–halogen exchange, addition, addition–elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.
Co-reporter:Julio C. Pastre, Duncan L. Browne, Matthew O’Brien, and Steven V. Ley
Organic Process Research & Development 2013 Volume 17(Issue 9) pp:1183-1191
Publication Date(Web):August 8, 2013
DOI:10.1021/op400152r
The development of a tube-in-tube reactor based on a semipermeable polymer membrane has enabled the efficient transfer of gases into liquid flow streams. In this work we describe the scalability and throughput of this reactor when applied to ammonia gas. This is made possible by a convenient titration method to rapidly assess a wide range of parameters including the liquid and gas configuration, reactor temperatures, flow rates, and solvent polarity. These data are then employed in a scaling-up process affording alkyl thioureas and are ultimately applied to a telescoped procedure leading to the anti-inflammatory agent fanetizole on a multigram scale.
Co-reporter:Claudio Battilocchio, Lucie Guetzoyan, Chiara Cervetto, Lorenzo Di Cesare Mannelli, Daniela Frattaroli, Ian R. Baxendale, Guido Maura, Antonietta Rossi, Lidia Sautebin, Mariangela Biava, Carla Ghelardini, Manuela Marcoli, and Steven V. Ley
ACS Medicinal Chemistry Letters 2013 Volume 4(Issue 8) pp:704-709
Publication Date(Web):May 22, 2013
DOI:10.1021/ml400079h
We report the biological evaluation of a class of adamantane derivatives, which were achieved via modified telescoped machine-assisted flow procedure. Among the series of compounds tested in this work, 5 demonstrated outstanding analgesic properties. This compound showed that its action was not mediated through direct interaction with opioid and/or cannabinoid receptors. Moreover, it did not display any significant anti-inflammatory properties. Experiments carried out on rat cerebrocortical purified synaptosomes indicated that 5 inhibits the P2X7-evoked glutamate release, which may contribute to its antinociceptive properties. Nevertheless, further experiments are ongoing to characterize the pharmacological properties and mechanism of action of this molecule.Keywords: 2-aminoadamantane-2-carboxylic acid; Adamantane derivatives; analgesic agents; flow chemistry; purinergic receptors;
Co-reporter:D. L. Browne;B. H. Harji;S. V. Ley
Chemical Engineering & Technology 2013 Volume 36( Issue 6) pp:959-967
Publication Date(Web):
DOI:10.1002/ceat.201200581
Abstract
There are a number of challenges that need to be overcome in order to stimulate more synthesis chemists to adopt continuous-flow chemical processing techniques. By way of example, the use of cryogenic consumables to cool reactions is impractical on scale or over extended reaction times. Here, a solution to the problem is described with the development of a convenient laboratory device that offers chemists the benefits of continuous flow processing using an accurate thermal energy transfer block which provides long-term reaction stability and is free from water ingress.
Co-reporter:Dr. Claudio Battilocchio;Benjamin J. Deadman;Dr. Nikzad Nikbin;Dr. Matthew O. Kitching; Ian R. Baxendale; Steven V. Ley
Chemistry - A European Journal 2013 Volume 19( Issue 24) pp:7917-7930
Publication Date(Web):
DOI:10.1002/chem.201300696
Abstract
Here we report the direct comparison of a conventional batch mode synthesis of Meclinertant (SR48692, 1), a neurotensin receptor-1 antagonist, with its machine-assisted flow chemistry alternative. By using these enabling tools, combined with solid-supported reagents and scavengers, many process advantages were observed. Care, however, must be taken not to convert these techniques into expensive solutions to problems that do not exist.
Co-reporter:Samuel L. Bourne;Dr. Matthew O'Brien;Sivarajan Kasinathan;Dr. Peter Koos;Dr. Päivi Tolstoy;Dennis X. Hu;Dr. Roderick W. Bates;Dr. Benjamin Martin;Dr. Berthold Schenkel; Steven V. Ley
ChemCatChem 2013 Volume 5( Issue 1) pp:159-172
Publication Date(Web):
DOI:10.1002/cctc.201200778
Abstract
Two tandem flow chemistry processes have been developed. A single palladium-catalysed Heck reaction with ethylene gas provides an efficient synthesis for functionalised styrenes. Through further elaboration the catalyst becomes multi-functional and performs a second Heck reaction providing a single continuous process for the synthesis of unsymmetrical stilbenes. In addition, the continuous, rhodium-catalysed, hydroformylation of styrene derivatives with syngas affords branched aldehydes with good selectivity. Incorporation of an in-line aqueous wash and liquid–liquid separation allowed for the ethylene Heck reaction to be telescoped into the hydroformylation step such that a single flow synthesis of branched aldehydes directly from aryl iodides was achieved. The tube-in-tube semi-permeable membrane-based gas reactor and liquid–liquid separator both play an essential role in enabling these telescoped flow processes.
Co-reporter:Richard J. Ingham, Elena Riva, Nikzad Nikbin, Ian R. Baxendale, and Steven V. Ley
Organic Letters 2012 Volume 14(Issue 15) pp:3920-3923
Publication Date(Web):July 19, 2012
DOI:10.1021/ol301673q
The development of a monolith-supported synthetic procedure is reported, taking advantage of flow processing and the superior flow characteristics of monolithic reagents over gel-phase beads, to allow facile access to an important family of 2-aminopyrimidine derivatives. The process has been successfully applied to a key precursor on route to Imatinib (Ar = 3-pyridyl, R1 = 2-methyl-5-nitrobenzyl, R2 = H).
Co-reporter:Dennis X. Hu, Matthew O’Brien, and Steven V. Ley
Organic Letters 2012 Volume 14(Issue 16) pp:4246-4249
Publication Date(Web):August 6, 2012
DOI:10.1021/ol301930h
A second-generation laboratory-scale, modular liquid–liquid separation device based on computer-controlled high-pressure pumps and a high-resolution digital camera has been invented. The diazotization of amino acids to produce valuable chiral hydroxyacids is demonstrated in flow for the first time. The use of a triple-separator system in conjuction with the developed diazotization process allows the safe and efficient production and automated isolation of multigram quantities of valuable chiral hydroxyacids.
Co-reporter:Päivi Tolstoy, Samantha X. Y. Lee, Christof Sparr, and Steven V. Ley
Organic Letters 2012 Volume 14(Issue 18) pp:4810-4813
Publication Date(Web):September 4, 2012
DOI:10.1021/ol302119j
A highly efficient and enantioselective synthesis of 3-amino-2-oxindoles through a palladium-catalyzed asymmetric intramolecular arylation of α-ketimino amides using (R)-DiFluorPhos as the coordinating ligand is reported. This report constitutes the first enantioselective palladium-catalyzed arylation of ketimines.
Co-reporter:Sean Newton;Eva Casas Arcé;Damian M. Grainger
Advanced Synthesis & Catalysis 2012 Volume 354( Issue 9) pp:1805-1812
Publication Date(Web):
DOI:10.1002/adsc.201200073
Abstract
In this update, the asymmetric homogeneous hydrogenation of a number of trisubstituted olefins utilizing the recently developed tube-in-tube gas-liquid flow reactor is described. A number of chiral iridium- and rhodium-based catalysts and other parameters such as pressure, solvent, temperature and catalyst loading were screened. The advantage of the flow set-up for rapid screening and optimization of reaction parameters is illustrated. Furthermore, a comparative study using batch conditions aided in the optimization of the flow reaction set-up. The set-up was further modified to recycle the catalyst which prolonged catalytic activity.
Co-reporter:Philippa B. Cranwell, Matthew O'Brien, Duncan L. Browne, Peter Koos, Anastasios Polyzos, Miguel Peña-López and Steven V. Ley
Organic & Biomolecular Chemistry 2012 vol. 10(Issue 30) pp:5774-5779
Publication Date(Web):21 Mar 2012
DOI:10.1039/C2OB25407G
Using a simple and accessible Teflon AF-2400 based tube-in-tube reactor, a series of pyrroles were synthesised in flow using the Paal–Knorr reaction of 1,4-diketones with gaseous ammonia. An inline flow titration technique allowed measurement of the ammonia concentration and its relationship to residence time and temperature.
Co-reporter:Tobias Brodmann, Peter Koos, Albrecht Metzger, Paul Knochel, and Steven V. Ley
Organic Process Research & Development 2012 Volume 16(Issue 5) pp:1102-1113
Publication Date(Web):November 1, 2011
DOI:10.1021/op200275d
A newly developed microscale ReactIR flow cell was used as a convenient and versatile inline analytical tool for Grignard formation in continuous flow chemical processing. The LiCl-mediated halogen/Mg exchange reaction was used for the preparation of functionalized arylmagnesium compounds from aryl iodides or bromides. Furthermore, inline IR monitoring was used for the analysis of conversion and possible byproduct formation, as well as a potential tool for elucidation of mechanistic details. The results described herein indicate that the continuous flow systems are effective for highly exothermic reactions such as the Grignard exchange reaction due to fast mixing and efficient heat transfer.
Co-reporter:Dennis X. Hu, Max Bielitza, Peter Koos, Steven V. Ley
Tetrahedron Letters 2012 Volume 53(Issue 32) pp:4077-4079
Publication Date(Web):8 August 2012
DOI:10.1016/j.tetlet.2012.05.110
A nine-step (longest linear) batch total synthesis of the cyclic hexadepsipeptide (−)-enniatin B is described. The synthesis minimizes precipitation during reaction conditions for adaptability to flow synthesis. The route was used to prepare >100 mg of the natural product.
Co-reporter:Dennis X. Hu, Peter Grice, and Steven V. Ley
The Journal of Organic Chemistry 2012 Volume 77(Issue 11) pp:5198-5202
Publication Date(Web):May 17, 2012
DOI:10.1021/jo300734r
The existence of rotamers in a solution of analyte complicates 1H NMR analysis, especially when the presence of diastereomers is also possible. Organic chemists have often responded to this problem by conducting variable-temperature (VT) NMR experiments, changing NMR solvents, or adding complexing agents. Here, with specific examples, we illustrate the use of simple yet widely overlooked chemical-exchange NMR experiments which allow the nonintrusive rapid distinguishment of rapidly equilibrating small molecules such as rotamers from nonequilibrating diastereomers.
Co-reporter:Gaël Tran, Robin Meier, Lawrence Harris, Duncan L. Browne, and Steven V. Ley
The Journal of Organic Chemistry 2012 Volume 77(Issue 24) pp:11071-11078
Publication Date(Web):November 26, 2012
DOI:10.1021/jo302052m
The presence of fluorous substituents can impart a dramatic effect on the efficacy of molecules used for a range of applications in society. Here, we describe the preparation and use of a new trifluoromethylated azomethine ylide precursor, which leads to a series of fluorinated pyrrolidine, 3-pyrroline, and pyrrole building blocks.
Co-reporter:Steven V. Ley
The Chemical Record 2012 Volume 12( Issue 4) pp:378-390
Publication Date(Web):
DOI:10.1002/tcr.201100041
Abstract
The principles of Green Chemistry are important but challenging drivers for most modern synthesis programs. To meet these challenges new flow chemistry tools are proving to be very effective by providing improved heat/mass transfer opportunities, lower solvent usage, less waste generation, hazardous compound containment, and the possibility of a 24/7 working regime. This machine-assisted approach can be used to effect repetitive or routine scale-up steps or when combined with reagent and scavenger cartridges, to achieve multi-step synthesis of complex natural products and pharmaceutical agents. DOI 10.1002/tcr.201100041
Co-reporter:James R. Frost;Dr. Colin M. Pearson;Dr. Thomas N. Snaddon;Dr. Richard A. Booth ; Steven V. Ley
Angewandte Chemie 2012 Volume 124( Issue 37) pp:9500-9505
Publication Date(Web):
DOI:10.1002/ange.201204868
Co-reporter:James R. Frost;Dr. Colin M. Pearson;Dr. Thomas N. Snaddon;Dr. Richard A. Booth ; Steven V. Ley
Angewandte Chemie International Edition 2012 Volume 51( Issue 37) pp:9366-9371
Publication Date(Web):
DOI:10.1002/anie.201204868
Co-reporter:Trine P. Petersen;Dr. Anastasios Polyzos ;Dr. Matthew O'Brien;Dr. Trond Ulven;Dr. Ian R. Baxendale; Steven V. Ley
ChemSusChem 2012 Volume 5( Issue 2) pp:274-277
Publication Date(Web):
DOI:10.1002/cssc.201100339
Co-reporter:Heiko Lange, Catherine F. Carter, Mark D. Hopkin, Adrian Burke, Jon G. Goode, Ian R. Baxendale and Steven V. Ley
Chemical Science 2011 vol. 2(Issue 4) pp:765-769
Publication Date(Web):28 Jan 2011
DOI:10.1039/C0SC00603C
In order to use segmented chemical flow processing in more complex reaction sequences, a method has been developed to precisely control the addition of reagent streams during multi-step operations. Using in-line infra-red monitoring with a new LabVIEW software application, it is possible to control additional pumps to dispense further reagents in real time based upon the concentration of reaction intermediates. This enables precise mixing with perfect timing thus greatly increasing product quality and enabling segmented chemical flow processing to be used in extended reaction sequences.
Co-reporter:Matthew O'Brien, Nicholas Taylor, Anastasios Polyzos, Ian R. Baxendale and Steven V. Ley
Chemical Science 2011 vol. 2(Issue 7) pp:1250-1257
Publication Date(Web):01 Apr 2011
DOI:10.1039/C1SC00055A
A Tube-in-Tube reactor/injector has been developed, based on a gas-permeable Teflon AF-2400 membrane, which allows both heterogeneous and homogeneous catalytic hydrogenation reactions to be efficiently carried out at elevated pressure in flow, thereby increasing the safety profile of these reactions. Measurements of the gas permeation through the tubing and uptake into solution, using both a burette method and a novel computer-assisted ‘bubble counting’ technique, indicate that permeation/dissolution follows Henry's law and that saturation is achieved extremely rapidly. The same gas-permeable membrane has also been shown to efficiently effect removal of excess unreacted hydrogen, thus enabling further downstream reaction/processing.
Co-reporter:Andrew T. Merritt, Rebecca H. Pouwer, David J. Williams, Craig M. Williams and Steven V. Ley
Organic & Biomolecular Chemistry 2011 vol. 9(Issue 13) pp:4745-4747
Publication Date(Web):19 May 2011
DOI:10.1039/C1OB05422H
A direct synthetic approach to the spiro-γ-lactone clerodane ring system has been investigated. This work builds on that of Jung and highlights the inherent difficulties associated with the otherwise obvious Diels–Alder approach.
Co-reporter:James W. Shearman, Rebecca M. Myers, James D. Brenton and Steven V. Ley
Organic & Biomolecular Chemistry 2011 vol. 9(Issue 1) pp:62-65
Publication Date(Web):15 Oct 2010
DOI:10.1039/C0OB00636J
The first total syntheses of (+)- and (−)-subereamollines A and B are reported. The enantiomeric forms of the natural products were obtained by preparative chiral HPLC separation of the corresponding racemates.
Co-reporter:Peter Koos, Ulrike Gross, Anastasios Polyzos, Matthew O'Brien, Ian Baxendale and Steven V. Ley
Organic & Biomolecular Chemistry 2011 vol. 9(Issue 20) pp:6903-6908
Publication Date(Web):27 Jul 2011
DOI:10.1039/C1OB06017A
We report on the development of a continuous flow process for the palladium catalysed methoxycarbonylation of aryl, heteroaromatic and vinyl iodides and an aryl bromide using a Teflon AF-2400 based Tube-in-Tube reactor to mediate the selective permeation of carbon monoxide into solution at elevated pressures. The low volume of pressurised gas within the reactor (5.6 mL) offers the potential for an enhanced safety profile compared to batch processes. We also present preliminary results for the use of in situFTIR to measure solution concentrations of carbon monoxide and demonstrate the use of a second reactor to effect the removal of carbon monoxide from the flow stream.
Co-reporter:Dr. Antoine Français;Dr. Antonio Leyva-Pérez;Dr. Gorka Etxebarria-Jardi;Javier Peña ;Dr. Steven V. Ley
Chemistry - A European Journal 2011 Volume 17( Issue 1) pp:329-343
Publication Date(Web):
DOI:10.1002/chem.201002380
Abstract
For over five decades, owing to their antiapoptotic activities, bongkrekic and isobongkrekic acids have generated interest from the scientific community. Here, we disclose full details of our investigation into the synthesis of isobongkrekic acid, which culminated in its first preparation and features various palladium-catalysed cross-couplings and Takai olefination reactions. Access to bongkrekic acid is also reported by this route. These syntheses involve the preparation and use of new general building blocks which could find wider applications.
Co-reporter:Dr. Anastasios Polyzos;Dr. Matthew O'Brien;Trine P. Petersen;Dr. Ian R. Baxendale ; Steven V. Ley
Angewandte Chemie International Edition 2011 Volume 50( Issue 5) pp:1190-1193
Publication Date(Web):
DOI:10.1002/anie.201006618
Co-reporter:Dr. Anastasios Polyzos;Dr. Matthew O'Brien;Trine P. Petersen;Dr. Ian R. Baxendale ; Steven V. Ley
Angewandte Chemie 2011 Volume 123( Issue 5) pp:1222-1225
Publication Date(Web):
DOI:10.1002/ange.201006618
Co-reporter:Dr. Alexer J. Oelke;Dr. Francesca Antonietti;Leonardo Bertone;Philippa B. Cranwell;Dr. David J. France;Dr. Rebecca J. M. Goss;Dr. Tatjana Hofmann;Dr. Stephan Knauer;Dr. Steven J. Moss;Paul C. Skelton;Dr. Richard M. Turner;Dr. Georg Wuitschik;Dr. Steven V. Ley
Chemistry - A European Journal 2011 Volume 17( Issue 15) pp:4183-4194
Publication Date(Web):
DOI:10.1002/chem.201003216
Abstract
Here we describe in full our investigations into the synthesis of the dimeric cyclohexapeptide chloptosin in 17 linear steps. Particularly, this work features an organocatalytic tandem process for the synthesis of the embedded piperazic acids, in which a differentially protected azodicarboxylate is used together with pyrrolidinyl tetrazole as the catalyst. The central biaryl bond is being formed by Stille coupling of two sterically demanding ortho-chloropyrroloindole fragments. The inherent flexibility of the synthetic strategy proved beneficial as the route could be adjusted smoothly during the progression of the synthesis programme.
Co-reporter:Catherine F. Carter;Dr. Heiko Lange;Dr. Daiki Sakai;Dr. Ian R. Baxendale; Steven V. Ley
Chemistry - A European Journal 2011 Volume 17( Issue 12) pp:3398-3405
Publication Date(Web):
DOI:10.1002/chem.201003148
Abstract
Diastereoselective chain-elongation reactions are important transformations for the assembly of complex molecular structures, such as those present in polyketide natural products. Here we report new methods for performing crotylation reactions and homopropargylation reactions by using newly developed low-temperature flow-chemistry technology. In-line purification protocols are described, as well as the application of the crotylation protocol in an automated multi-step sequence.
Co-reporter:Mark D. Hopkin, Ian R. Baxendale and Steven V. Ley
Chemical Communications 2010 vol. 46(Issue 14) pp:2450-2452
Publication Date(Web):05 Mar 2010
DOI:10.1039/C001550D
A concise, flow-based synthesis of Imatinib, a compound used for the treatment of chronic myeloid leukaemia, is described whereby all steps are conducted in tubular flow coils or cartridges packed with reagents or scavengers to effect clean product formation. An in-line solvent switching procedure was developed enabling the procedure to be performed with limited manual handling of intermediates.
Co-reporter:Antoine Francais, Antonio Leyva, Gorka Etxebarria-Jardi and Steven V. Ley
Organic Letters 2010 Volume 12(Issue 2) pp:340-343
Publication Date(Web):December 16, 2009
DOI:10.1021/ol902676t
The first convergent total synthesis of isobongkrekic acid is reported involving three different stereospecific palladium cross-couplings for the formation of the diene units. Access to bongkrekic acid by this route is also demonstrated. These syntheses involve the formation of several potentially general building blocks.
Co-reporter:Matthew O’Brien, Ian R. Baxendale and Steven V. Ley
Organic Letters 2010 Volume 12(Issue 7) pp:1596-1598
Publication Date(Web):March 10, 2010
DOI:10.1021/ol100322t
A flow-through chemistry apparatus has been developed which allows gases and liquids to contact via a semipermeable Teflon AF-2400 membrane. In this preliminary investigation, the concept was proven by application to the ozonolysis of a series of alkenes.
Co-reporter:ChristianH. Hornung;Bart Hallmark;MalcolmR. Mackley;IanR. Baxendale;StevenV. Ley
Advanced Synthesis & Catalysis 2010 Volume 352( Issue 10) pp:1736-1745
Publication Date(Web):
DOI:10.1002/adsc.201000139
Abstract
Herein we describe the preparation of a novel continuous flow multi-channel microreactor in which the internal surface has been functionalised with a palladium coating, enabling its use in catalytic heterogeneous liquid-phase reactions. Simple chemical deposition techniques were used to immobilise palladium(0) on the channel wall surface of a polymeric multi-capillary extrudate made from ethylene-vinyl alcohol copolymer. The Pd coating of the microcapillaries has been characterised by mass spectrometry and light and electron microscopy. The functional activity of the catalytic Pd layer was tested in a series of transfer hydrogenation reactions using triethylsilane as the hydrogen source.
Co-reporter:Catherine F. Carter, Ian R. Baxendale, John B. J. Pavey and Steven V. Ley
Organic & Biomolecular Chemistry 2010 vol. 8(Issue 7) pp:1588-1595
Publication Date(Web):10 Feb 2010
DOI:10.1039/B924309G
The continuous flow synthesis of butane-2,3-diacetal protected derivatives has been achieved using commercially available flow chemistry microreactors in concert with solid supported reagents and scavengers to provide in-line purification systems. The BDA protected products are all obtained in superior yield to the corresponding batch processes.
Co-reporter:Silvia Catalán-Muñoz;Constanze A. Müller
European Journal of Organic Chemistry 2010 Volume 2010( Issue 1) pp:183-190
Publication Date(Web):
DOI:10.1002/ejoc.200901145
Abstract
The synthesis of 3,6-dihydropyrans and 4,5-epoxytetrahydropyrans starting from enantiomerically pure β-hydroxy aldehyde (prepared by an organocatalytic aldol reaction) is described. The key step is a tandem sequence, which consists of a base-promoted conjugative addition to a vinyl onium salt, followed by either an intramolecular Wittig process to provide 3,6-dihydropyran derivatives or an intramolecular cyclisation/epoxidation process to afford 4,5-epoxytetrahydropyran scaffolds. The products obtained by this method are common substructures in polyketide natural products.
Co-reporter:Catherine F. Carter, Heiko Lange, Steven V. Ley, Ian R. Baxendale, Brian Wittkamp, Jon G. Goode and Nigel L. Gaunt
Organic Process Research & Development 2010 Volume 14(Issue 2) pp:393-404
Publication Date(Web):February 1, 2010
DOI:10.1021/op900305v
A newly developed ReactIR flow cell is reported as a convenient and versatile inline analytical tool for continuous flow chemical processing. The flow cell, operated with ATR technology, is attached directly into a reaction flow stream using standard OmniFit (HPLC) connections and can be used in combination with both meso- and microscale flow chemistry equipment. The iC IR analysis software (version 4.0) enables the monitoring of reagent consumption and product formation, aiding the rapid optimisation of procedures. Short-lived reactive intermediates can also be observed in situ, giving further mechanistic insight into complex transformations.
Co-reporter:James W. Shearman, Rebecca M. Myers, Thomas M. Beale, James D. Brenton, Steven V. Ley
Tetrahedron Letters 2010 Volume 51(Issue 37) pp:4812-4814
Publication Date(Web):15 September 2010
DOI:10.1016/j.tetlet.2010.07.016
The total syntheses of the bromotyrosine-derived natural products ianthelline, 5-bromoverongamine and JBIR-44 are described and their cytotoxic activity in a cervical cancer (HeLa) cell line and human umbilical vein endothelial cells (HUVECs) are reported.
Co-reporter:AlexerJ. Oelke Dr.;DavidJ. France Dr.;Tatjana Hofmann Dr.;Georg Wuitschik Dr. ;StevenV. Ley Dr.
Angewandte Chemie International Edition 2010 Volume 49( Issue 35) pp:6139-6142
Publication Date(Web):
DOI:10.1002/anie.201002880
Co-reporter:IanR. Baxendale Dr.;SørenC. Schou;Jörg Sedelmeier Dr.;StevenV. Ley
Chemistry - A European Journal 2010 Volume 16( Issue 1) pp:89-94
Publication Date(Web):
DOI:10.1002/chem.200902906
Co-reporter:AlexerJ. Oelke Dr.;DavidJ. France Dr.;Tatjana Hofmann Dr.;Georg Wuitschik Dr. ;StevenV. Ley Dr.
Angewandte Chemie 2010 Volume 122( Issue 35) pp:6275-6278
Publication Date(Web):
DOI:10.1002/ange.201002880
Co-reporter:Jörg Sedelmeier, Steven V. Ley and Ian R. Baxendale
Green Chemistry 2009 vol. 11(Issue 5) pp:683-685
Publication Date(Web):12 Mar 2009
DOI:10.1039/B821752A
We report the efficient reduction of a selection of ketones to the corresponding secondary alcohols using only catalytic amounts of LiOtBu in iPrOH facilitated by using a continuous flow reactor.
Co-reporter:Amanda C. Evans, Deborah A. Longbottom, Masato Matsuoka, John E. Davies, Richard Turner, Vilius Franckevičius and Steven V. Ley
Organic & Biomolecular Chemistry 2009 vol. 7(Issue 4) pp:747-760
Publication Date(Web):06 Jan 2009
DOI:10.1039/B813494D
A new and efficient desymmetrisation of succinic and glutaric cyclic meso-anhydrides is described, providing excellent yields and diastereoselectivities in most cases. Derivatisation of the desymmetrised products is demonstrated by their conversion into mono-protected 1,4-diols. General synthetic utility of the method is established by its application towards a key fragment in the total synthesis of the immunosuppressant antitumour natural product, rapamycin.
Co-reporter:Catherine F. Carter, Ian R. Baxendale, Matthew O'Brien, John B. J. Pavey and Steven V. Ley
Organic & Biomolecular Chemistry 2009 vol. 7(Issue 22) pp:4594-4597
Publication Date(Web):28 Sep 2009
DOI:10.1039/B917289K
The syntheses of butane-2,3-diacetal protected tartrate derivatives are described using continuous flow processing techniques with in-line purification and I.R. analytical protocols.
Co-reporter:Jörg Sedelmeier, ;Heiko Lange ;Ian R. Baxendale
European Journal of Organic Chemistry 2009 Volume 2009( Issue 26) pp:4412-4420
Publication Date(Web):
DOI:10.1002/ejoc.200900344
Abstract
We report a rapid microwave-assisted Sonogashira cross-coupling of aryl iodides and bromides with terminal alkynes using Pd-EnCatTM TPP30. Both electron-rich and electron-deficient aryl halides reacted smoothly with a broad variety of terminal alkynes in MeCN at 100–120 °C. The coupling products were obtained in good to excellent yields and in high purity. This reaction can be performed under copper- and DMF-free conditions and does not require an inert atmosphere. Furthermore, the encapsulated catalyst can be recovered and recycled by a simple filtration of the reaction mixture. It can be reused in further reactions with only minor decrease in activity. Additionally, we were able to produce a variety of enyne derivatives under modified conditions employing the same Pd-EnCatTM source. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Co-reporter:Alistair Boyer Dr.;GemmaE. Veitch Dr.;Edith Beckmann Dr. ;StevenV. Ley Dr.
Angewandte Chemie 2009 Volume 121( Issue 7) pp:1343-1346
Publication Date(Web):
DOI:10.1002/ange.200805395
Co-reporter:StevenV. Ley ;MilesN. Tackett Dr.;MatthewL. Maddess Dr.;JamesC. Anderson Dr.;PaulE. Brennan Dr.;MichaelW. Cappi Dr.;JagP. Heer Dr.;Céline Helgen Dr.;Masakuni Kori Dr.;Cyrille Kouklovsky Dr.;StephenP. Marsden Dr.;Joanne Norman Dr.;DavidP. Osborn Dr.;MaríaÁ. Palomero Dr.;JohnB.J. Pavey Dr.;Catherine Pinel Dr.;LesleyA. Robinson Dr.;Jürgen Schnaubelt Dr.;JamesS. Scott Dr.;ChristopherD. Spilling Dr.;Hidenori Watanabe Dr.;KieronE. Wesson Dr. ;MichaelC. Willis Dr.
Chemistry - A European Journal 2009 Volume 15( Issue 12) pp:2874-2914
Publication Date(Web):
DOI:10.1002/chem.200801656
Co-reporter:Alistair Boyer Dr.;GemmaE. Veitch Dr.;Edith Beckmann Dr. ;StevenV. Ley Dr.
Angewandte Chemie International Edition 2009 Volume 48( Issue 7) pp:1317-1320
Publication Date(Web):
DOI:10.1002/anie.200805395
Co-reporter:Alessandro Palmieri, Steven V. Ley, Kelvin Hammond, Anastasios Polyzos, Ian R. Baxendale
Tetrahedron Letters 2009 50(26) pp: 3287-3289
Publication Date(Web):
DOI:10.1016/j.tetlet.2009.02.059
Co-reporter:IanR. Baxendale Dr.;StevenV. Ley ;AndrewC. Mansfield;ChristopherD. Smith Dr.
Angewandte Chemie International Edition 2009 Volume 48( Issue 22) pp:4017-4021
Publication Date(Web):
DOI:10.1002/anie.200900970
Co-reporter:IanR. Baxendale Dr.;StevenV. Ley ;AndrewC. Mansfield;ChristopherD. Smith Dr.
Angewandte Chemie 2009 Volume 121( Issue 22) pp:4077-4081
Publication Date(Web):
DOI:10.1002/ange.200900970
Co-reporter:Marcus Baumann, Ian R. Baxendale, Laetitia J. Martin, Steven V. Ley
Tetrahedron 2009 65(33) pp: 6611-6625
Publication Date(Web):
DOI:10.1016/j.tet.2009.05.083
Co-reporter:Marcus Baumann, Ian R. Baxendale, Steven V. Ley, Nikzad Nikbin and Christopher D. Smith
Organic & Biomolecular Chemistry 2008 vol. 6(Issue 9) pp:1587-1593
Publication Date(Web):12 Mar 2008
DOI:10.1039/B801634H
The preparation and use of an azide-containing monolithic reactor is described for use in a flow chemistry device and in particular for conducting Curtius rearrangement reactions via acid chloride inputs.
Co-reporter:Marcus Baumann, Ian R. Baxendale, Steven V. Ley, Nikzad Nikbin, Christopher D. Smith and Jason P. Tierney
Organic & Biomolecular Chemistry 2008 vol. 6(Issue 9) pp:1577-1586
Publication Date(Web):12 Mar 2008
DOI:10.1039/B801631N
The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.
Co-reporter:GemmaE. Veitch;Alistair Boyer ;StevenV. Ley Dr.
Angewandte Chemie International Edition 2008 Volume 47( Issue 49) pp:9402-9429
Publication Date(Web):
DOI:10.1002/anie.200802675
Abstract
Azadirachtin has been the subject of intensive research within the scientific community ever since its isolation from the neem tree in 1968. There are now over 1000 publications relating to this natural product which cover all aspects of structural, biological and synthetic studies. Herein, we describe the worldwide synthesis efforts towards this fascinating molecule.
Co-reporter:GemmaE. Veitch;Alistair Boyer ;StevenV. Ley Dr.
Angewandte Chemie 2008 Volume 120( Issue 49) pp:9542-9570
Publication Date(Web):
DOI:10.1002/ange.200802675
Abstract
Das Azadirachtin war Gegenstand intensiver Forschungen, seit es 1968 erstmals aus dem Niembaum isoliert wurde. Über 1000 Publikationen gibt es mittlerweile, die die strukturellen, biologischen und synthetischen Aspekte dieses Naturstoffs in allen Facetten beschreiben. In diesem Aufsatz geben wir einen Überblick über die langjährigen, weltweiten Bemühungen zur Totalsynthese dieses faszinierenden Moleküls.
Co-reporter:StevenV. Ley Dr.;Antonio Abad-Somovilla Dr.;JamesC. Anderson Dr.;Carles Ayats Dr.;Rolf Bänteli Dr.;Edith Beckmann Dr.;Alistair Boyer;MariaG. Brasca Dr.;Abigail Brice;HowardB. Broughton Dr.;BrendaJ. Burke Dr.;Ed Cleator Dr.;Donald Craig Dr.;AlastairA. Denholm Dr.;RossM. Denton Dr.;Thomas Dur-Reville Dr.;LucaB. Gobbi Dr.;Michael Göbel;BrianLawrence Gray Dr.;RobertB. Grossmann Dr.;ClaireE. Gutteridge Dr.;Norbert Hahn Dr.;SarahL. Harding;DavidC. Jennens Dr.;Lynn Jennens Dr.;PeterJ. Lovell Dr.;HelenJ. Lovell Dr.;MaryL. delaPuente Dr.;HartmuthC. Kolb Dr.;Win-Jan Koot Dr.;SarahL. Maslen;CatherineF. McCusker Dr.;Amos Mattes Dr.;AndrewR. Pape Dr.;Andrea Pinto Dr.;Dinos Santafianos Dr.;JamesS. Scott Dr.;StephenC. Smith Dr.;AndrewQ. Somers Dr.;ChristopherD. Spilling Dr.;Frank Stelzer Dr.;PeterL. Toogood Dr.;RichardM. Turner Dr.;GemmaE. Veitch;Anthony Wood Dr.;Cornelia Zumbrunn Dr.
Chemistry - A European Journal 2008 Volume 14( Issue 34) pp:10683-10704
Publication Date(Web):
DOI:10.1002/chem.200801103
Abstract
We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O-alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carboncarbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5-exo-radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule.
Co-reporter:StevenV. Ley Dr.;Antonio Abad-Somovilla Dr.;JamesC. Anderson Dr.;Carles Ayats Dr.;Rolf Bänteli Dr.;Edith Beckmann Dr.;Alistair Boyer;MariaG. Brasca Dr.;Abigail Brice;HowardB. Broughton Dr.;BrendaJ. Burke Dr.;Ed Cleator Dr.;Donald Craig Dr.;AlastairA. Denholm Dr.;RossM. Denton Dr.;Thomas Dur-Reville Dr.;LucaB. Gobbi Dr.;Michael Göbel;BrianLawrence Gray Dr.;RobertB. Grossmann Dr.;ClaireE. Gutteridge Dr.;Norbert Hahn Dr.;SarahL. Harding;DavidC. Jennens Dr.;Lynn Jennens Dr.;PeterJ. Lovell Dr.;HelenJ. Lovell Dr.;MaryL. delaPuente Dr.;HartmuthC. Kolb Dr.;Win-Jan Koot Dr.;SarahL. Maslen;CatherineF. McCusker Dr.;Amos Mattes Dr.;AndrewR. Pape Dr.;Andrea Pinto Dr.;Dinos Santafianos Dr.;JamesS. Scott Dr.;StephenC. Smith Dr.;AndrewQ. Somers Dr.;ChristopherD. Spilling Dr.;Frank Stelzer Dr.;PeterL. Toogood Dr.;RichardM. Turner Dr.;GemmaE. Veitch;Anthony Wood Dr.;Cornelia Zumbrunn Dr.
Chemistry - A European Journal 2008 Volume 14( Issue 34) pp:
Publication Date(Web):
DOI:10.1002/chem.200890139
Co-reporter:Lech-Gustav Milroy Dr.;Giovanna Zinzalla Dr.;François Loiseau Dr.;Zizheng Qian;Giuseppe Prencipe;Chris Pepper Dr.;Chris Fegan Dr.;StevenV. Ley Dr.
ChemMedChem 2008 Volume 3( Issue 12) pp:1922-1935
Publication Date(Web):
DOI:10.1002/cmdc.200800265
Abstract
B-cell chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in the Western world for which no curative treatments are currently available. Purine nucleotide analogues and alkylating agents feature frequently in combination regimens to treat the malignant state, but their use has not led to any significant improvement in patient survival. Consequently, there still remains a need for alternative small-molecule chemotherapeutics. Natural products are an unparalleled source of drug leads, and an unending inspiration for the design of small-molecule libraries for drug discovery. The screening of focused libraries of natural-product-like spiroketal and fused bicyclic acetal small molecules against primary CLL cells has led to the identification of a small series of novel and potent cytotoxic agents towards primary CLL cells. The validation of the activity of these molecules is delineated through a series of synthesis and screening iterations, whereas preliminary mode of action studies positively indicate their ability to induce cell death via an apoptotic pathway with no evidence of necrosis to further support their potential as novel chemotherapeutic agents.
Co-reporter:Veit Wascholowski Dr.;Kristian Rahbek Knudsen Dr.;ClaireE.T. Mitchell Dr. ;StevenV. Ley Dr.
Chemistry - A European Journal 2008 Volume 14( Issue 20) pp:6155-6165
Publication Date(Web):
DOI:10.1002/chem.200800673
Abstract
A general enantioselective organocatalytic conjugate addition procedure of a variety of malonates to α,β-unsaturated enone systems is presented. The reaction is efficiently catalysed by the pyrrolidinyl tetrazole catalyst 1. Cyclic, acyclic and aromatic enones can be used and the reaction with ethyl malonates 3 b provides the Michael addition products in high yields with good to excellent enantioselectivities. Since only 1.5 equivalents of malonate are used as a reagent, the reaction is readily scaled and practical to operate. Furthermore, the malonate addition products can be easily mono decarboxylated without loss in enantiomeric excess by enzymatic or sodium hydroxide mediated methods.
Co-reporter:Kristian Rahbek Knudsen;John Holden;Steven V. Ley;Mark Ladlow
Advanced Synthesis & Catalysis 2007 Volume 349(Issue 4-5) pp:
Publication Date(Web):20 MAR 2007
DOI:10.1002/adsc.200600558
A versatile, fully automated flow hydrogenator has been developed that is able to perform sequential flow optimisation experiments, flow library hydrogenation, or iterative scale-up hydrogenation. The behaviour of a palladium catalyst in effecting removal of O-benzyl and N-benzyloxycarbonyl protecting groups has been investigated. Significant observations relating to maintaining optimal throughput are reported. A small library of peptidic derivatives has been deprotected in high yield and purity.
Co-reporter:Stephen P. Andrews, Malcolm M. Tait, Matthew Ball and Steven V. Ley
Organic & Biomolecular Chemistry 2007 vol. 5(Issue 9) pp:1427-1436
Publication Date(Web):2007/03/23
DOI:10.1039/B702481A
Thapsigargin is a densely oxygenated guaianolide which displays potent sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) binding affinities. The total syntheses of designed unnatural analogues of this important natural product are described. This article constitutes the chemical synthesis behind an ongoing project. Rational modifications have been made to the lactone region of thapsigargin in order to obtain derivatives for future structure–activity relationship studies.
Co-reporter:Sirirat Kumarn, Alexander J. Oelke, David M. Shaw, Deborah A. Longbottom and Steven V. Ley
Organic & Biomolecular Chemistry 2007 vol. 5(Issue 16) pp:2678-2689
Publication Date(Web):10 Jul 2007
DOI:10.1039/B708646F
A sequential, organocatalysed asymmetric reaction to access chiral 1,2-oxazines and chiral pyridazines is reported, which proceeds in moderate to good yields and good to excellent enantioselectivities.
Co-reporter:Catherine J. Smith, Francisco Javier Iglesias-Sigüenza, Ian R. Baxendale and Steven V. Ley
Organic & Biomolecular Chemistry 2007 vol. 5(Issue 17) pp:2758-2761
Publication Date(Web):19 Jul 2007
DOI:10.1039/B709043A
A new approach to the synthesis of 5-amino-4-cyanopyrazoles has been developed, utilising a novel flow microwave device. These products are then converted by a batch mode microwave process to structurally more complex dimeric and ‘mixed’ pyrazolopyrimidine structures.
Co-reporter:Christopher D. Smith, Ian R. Baxendale, Steve Lanners, John J. Hayward, Stephen C. Smith and Steven V. Ley
Organic & Biomolecular Chemistry 2007 vol. 5(Issue 10) pp:1559-1561
Publication Date(Web):2007/04/16
DOI:10.1039/B702995K
The cycloaddition of acetylenes with azides to give the corresponding 1,4-disubstituted 1,2,3-triazoles is reported using immobilised reagents and scavengers in pre-packed glass tubes in a modular flow reactor.
Co-reporter:Christopher D. Smith, Ian R. Baxendale, Geoffrey K. Tranmer, Marcus Baumann, Stephen C. Smith, Russell A. Lewthwaite and Steven V. Ley
Organic & Biomolecular Chemistry 2007 vol. 5(Issue 10) pp:1562-1568
Publication Date(Web):2007/04/16
DOI:10.1039/B703033A
The use of three orthogonally tagged phosphine reagents to assist chemical work-up via phase-switch scavenging in conjunction with a modular flow reactor is described. These techniques (acidic, basic and Click chemistry) are used to prepare various amides and tri-substituted guanidines from in situ generated iminophosphoranes.
Co-reporter:Stephen P. Andrews Dr.;Matthew Ball Dr.;Frank Wierschem Dr.;Ed Cleator Dr.;Steven Oliver Dr.;Klemens Högenauer Dr.;Oliver Simic Dr.;Alessra Antonello Dr.;Udo Hünger Dr.;Martin D. Smith Dr.;Steven V. Ley Dr.
Chemistry - A European Journal 2007 Volume 13(Issue 20) pp:
Publication Date(Web):26 JUN 2007
DOI:10.1002/chem.200790070
The first total syntheses of five thapsigargins are described by S. V. Ley et al. on page 5688 ff. These natural products are potent and selective inhibitors of sarco/endo-plasmic reticulum ATPases (SERCAs): thapsigargin-derived prodrugs have shown selective in vivo cytotoxicity against prostate tumours. So far, 17 related thapsigargin structures have been isolated from Thapsia plants, which are found naturally in parts of northern Africa, the Iberian peninsular, and regions of the Mediterranean. The backdrop of the cover illustration depicts the umbels of Thapsia villosa L. and was photographed and identified by Antonio Conejo (reproduced with permission).
Co-reporter:Ian R. Baxendale Dr.;John J. Hayward;Steven V. Ley Dr.;Geoffrey K. Tranmer Dr.
ChemMedChem 2007 Volume 2(Issue 6) pp:
Publication Date(Web):26 APR 2007
DOI:10.1002/cmdc.200700008
The pharmaceutical industry is under increasing pressure on many fronts, from investors requiring larger returns to consumer groups and health authorities demanding cheaper and safer drugs. It is also feeling additional pressure from the infringement upon its profit margins by generic drug producers. Many companies are aggressively pursuing outsourcing contracts in an attempt to counter many of the financial pressures and streamline their operations. At the same time, the productivity of the pharmaceutical industry at its science base is being questioned in terms of the number of products and the timeframes required for each company to deliver them to market. This has generated uncertainties regarding the current corporate strategies that have been adopted and the levels of innovation being demonstrated. In this essay we discuss these topics in the context of the global pharmaceutical market, investigating the basis for many of these issues and highlighting the hurdles the industry needs to overcome, especially as they relate to the chemical sciences.
Co-reporter:Stephen P. Andrews Dr.;Matthew Ball Dr.;Frank Wierschem Dr.;Ed Cleator Dr.;Steven Oliver Dr.;Klemens Högenauer Dr.;Oliver Simic Dr.;Alessra Antonello Dr.;Udo Hünger Dr.;Martin D. Smith Dr.;Steven V. Ley Dr.
Chemistry - A European Journal 2007 Volume 13(Issue 20) pp:
Publication Date(Web):16 MAY 2007
DOI:10.1002/chem.200700302
Herein we describe the total synthesis of five guaianolide natural products: thapsigargin, thapsivillosin C, thapsivillosin F, trilobolide and nortrilobolide. Prodrug derivatives of thapsigargin have shown selective in vivo cytotoxicity against prostate tumours and the need for further investigation of this phenomenon highlights the importance of these total syntheses. The first absolute stereochemical assignment of thapsivillosin C is also delineated.
Co-reporter:James A. Bull;Emily P. Balskus;Richard A. J. Horan Dr.;Martin Langner Dr.;Steven V. Ley Dr.
Chemistry - A European Journal 2007 Volume 13(Issue 19) pp:
Publication Date(Web):17 APR 2007
DOI:10.1002/chem.200700033
The bengazoles are a family of marine natural products that display potent antifungal activity and a unique structure, containing two oxazole rings flanking a single carbon atom. Total syntheses of bengazole A and B are described, which contain a sensitive stereogenic centre at this position between the two oxazoles. Additionally, the synthesis of 10-epi-bengazole A is reported. Two parallel synthetic routes were investigated, relying on construction of the 2,4-disubstituted oxazole under mild conditions and a diastereoselective 1,3-dipolar cycloaddition. Our successful route is high yielding, provides rapid access to single stereoisomers of the complex natural products and allows the synthesis of analogues for biological evaluation.
Co-reporter:Lech-Gustav Milroy;Giovanna Zinzalla Dr.;Giuseppe Prencipe;Patrick Michel Dr.;Steven V. Ley Dr.;Mekala Gunaratnam Dr.;Monica Beltran;Stephen Neidle Dr.
Angewandte Chemie 2007 Volume 119(Issue 14) pp:
Publication Date(Web):26 FEB 2007
DOI:10.1002/ange.200604688
Ein Hinweis der Natur: Kann das bicyclische Acetalgerüst, das in vielen strukturell verschiedenen, biologisch aktiven Naturstoffen vorkommt, als bevorzugtes Gerüst gelten? Einige niedermolekulare Derivate mit diesem Gerüst wurden zu potenziell oral bioverfügbaren Leitsubstanzen weiterverarbeitet, und erste biologische Tests lieferten ermutigende Ergebnisse.
Co-reporter:Alejro Diéguez-Vázquez Dr.;C.Christoph Tzschucke Dr.;WingYee Lam ;StevenV. Ley Dr.
Angewandte Chemie 2007 Volume 120( Issue 1) pp:216-219
Publication Date(Web):
DOI:10.1002/ange.200704595
Co-reporter:Gemma E. Veitch;Edith Beckmann Dr.;Brenda J. Burke Dr.;Alistair Boyer;Sarah L. Maslen;Steven V. Ley Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 40) pp:
Publication Date(Web):28 SEP 2007
DOI:10.1002/anie.200790198
The neem tree in the foreground of the cover picture is the natural source of azadirachtin, a complex molecule containing sixteen contiguous stereogenic centers, seven of which are tetrasubstituted carbon atoms. In their Communications starting on page 7629 ff., S. V. Ley et al. describe the conclusion of a long but successful journey culminating with the first synthesis of this compound following the strategy outlined. Photographs: William M. Ciesla, www.forestryimages.com; design: Alistair Boyer.
Co-reporter:Gemma E. Veitch;Edith Beckmann Dr.;Brenda J. Burke Dr.;Alistair Boyer;Sarah L. Maslen;Steven V. Ley Dr.
Angewandte Chemie 2007 Volume 119(Issue 40) pp:
Publication Date(Web):28 SEP 2007
DOI:10.1002/ange.200790198
Der Niembaum im Bildvordergrund ist die natürliche Quelle von Azadirachtin, einem komplexen Molekül mit 16 aufeinander folgenden Stereozentren, darunter sieben quartäre Kohlenstoffatome. In ihrer Zuschrift auf S. 7773 ff. beschreiben S. V. Ley et al. den Abschluss einer langen Reise, die ihren Höhepunkt in der ersten Synthese dieser Verbindung findet. Die erfolgreiche Strategie ist in die Rinde geritzt. Photographie: William M. Ciesla, www.forestryimages.com; Design: Alistair Boyer.
Co-reporter:Gemma E. Veitch;Edith Beckmann Dr.;Brenda J. Burke Dr.;Alistair Boyer;Carles Ayats Dr.;Steven V. Ley Dr.
Angewandte Chemie 2007 Volume 119(Issue 40) pp:
Publication Date(Web):30 JUL 2007
DOI:10.1002/ange.200703028
Nach 22 Jahren konnte die Totalsynthese von Azadirachtin (1) zum Abschluss gebracht werden. Die hoch konvergente Syntheseroute setzte auf eine Claisen-Umlagerung und eine radikalische Cyclisierung in den Schlüsselschritten. Die Endphase der Synthese stützte sich auf das Intermediat 2, das sowohl auf präparative Weise als auch durch Abbau von 1 erhalten werden konnte. Bn=Benzyl, TBS=tert-Butyldimethylsilyl.
Co-reporter:Gemma E. Veitch;Edith Beckmann Dr.;Brenda J. Burke Dr.;Alistair Boyer;Sarah L. Maslen;Steven V. Ley Dr.
Angewandte Chemie 2007 Volume 119(Issue 40) pp:
Publication Date(Web):30 JUL 2007
DOI:10.1002/ange.200703027
Nach 22 Jahren konnte die Totalsynthese von Azadirachtin (1) zum Abschluss gebracht werden. Die hoch konvergente Syntheseroute setzte auf eine Claisen-Umlagerung und eine radikalische Cyclisierung in den Schlüsselschritten. Die Endphase der Synthese stützte sich auf das Intermediat 2, das sowohl auf präparative Weise als auch durch Abbau von 1 erhalten werden konnte. Bn=Benzyl, TBS=tert-Butyldimethylsilyl.
Co-reporter:Matthew L. Maddess Dr.;Miles N. Tackett;Hidenori Watanabe ;Paul E. Brennan Dr.;Christopher D. Spilling Dr.;James S. Scott Dr.;David P. Osborn;Steven V. Ley
Angewandte Chemie 2007 Volume 119(Issue 4) pp:
Publication Date(Web):8 DEC 2006
DOI:10.1002/ange.200604053
Auch ein Weg: Die vorgestellte konvergente Synthese von Rapamycin (1) beruht auf einer Strategie zum Aufbau des makrocyclischen Kerns dieses ungewöhnlichen Naturstoffs durch Makroveretherung und transannulare Catechol-gestützte Dieckmann-Reaktion. Andere Studien dieses hochwirksamen kommerziell eingesetzten Immunsuppressivums enthüllen neue Zellsignalwege, die für die Krebs-Chemotherapie wichtig sind.
Co-reporter:Alejro Diéguez-Vázquez Dr.;C.Christoph Tzschucke Dr.;WingYee Lam ;StevenV. Ley Dr.
Angewandte Chemie International Edition 2007 Volume 47( Issue 1) pp:209-212
Publication Date(Web):
DOI:10.1002/anie.200704595
Co-reporter:Lech-Gustav Milroy;Giovanna Zinzalla Dr.;Giuseppe Prencipe;Patrick Michel Dr.;Steven V. Ley Dr.;Mekala Gunaratnam Dr.;Monica Beltran;Stephen Neidle Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 14) pp:
Publication Date(Web):23 FEB 2007
DOI:10.1002/anie.200604688
A clue from nature: Can the bicyclic acetal framework, which is present in many structurally diverse biologically active natural products, be considered a privileged scaffold? Scaffolds with this framework were synthesized and elaborated to give a collection of small-molecule derivatives as potential orally bioavailable lead compounds, and preliminary biological tests gave encouraging results.
Co-reporter:Matthew L. Maddess Dr.;Miles N. Tackett;Hidenori Watanabe ;Paul E. Brennan Dr.;Christopher D. Spilling Dr.;James S. Scott Dr.;David P. Osborn;Steven V. Ley
Angewandte Chemie International Edition 2007 Volume 46(Issue 4) pp:
Publication Date(Web):8 DEC 2006
DOI:10.1002/anie.200604053
Rapamycin synthesis all wrapped up: A new convergent synthesis of rapamycin (1) is reported that involves a macroetherification/catechol tethering strategy for construction of the macrocyclic core of this intriguing natural product. Other studies on this commercialized potent immunosuppressant delineate new cell signaling pathways of relevance to cancer chemotherapy.
Co-reporter:Gemma E. Veitch;Edith Beckmann Dr.;Brenda J. Burke Dr.;Alistair Boyer;Carles Ayats Dr.;Steven V. Ley Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 40) pp:
Publication Date(Web):30 JUL 2007
DOI:10.1002/anie.200703028
22 Years in the making: Azadirachtin (1) was synthesized for the first time by a highly convergent approach, utilizing a Claisen rearrangement and a radical cyclization as key steps. End-game strategies relied on intermediate 2, which could be obtained by synthetic methods as well as by degradation of 1. Bn=benzyl, TBS=tert-butyldimethylsilyl.
Co-reporter:Gemma E. Veitch;Edith Beckmann Dr.;Brenda J. Burke Dr.;Alistair Boyer;Sarah L. Maslen;Steven V. Ley Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 40) pp:
Publication Date(Web):30 JUL 2007
DOI:10.1002/anie.200703027
22 Years in the making: Azadirachtin (1) was synthesized for the first time by a highly convergent approach, utilizing a Claisen rearrangement and a radical cyclization as key steps. End-game strategies relied on intermediate 2, which could be obtained by synthetic methods as well as by degradation of 1. Bn=benzyl, TBS=tert-butyldimethylsilyl.
Co-reporter:Sirirat Kumarn, David M. Shaw and Steven V. Ley
Chemical Communications 2006 (Issue 30) pp:3211-3213
Publication Date(Web):19 Jun 2006
DOI:10.1039/B606338A
A sequential, organocatalysed asymmetric reaction to access chiral 1,2-oxazines from achiral ketone starting materials is reported, which proceeds in moderate to good yields and excellent enantioselectivity.
Co-reporter:Ian R. Baxendale, Jon Deeley, Charlotte M. Griffiths-Jones, Steven V. Ley, Steen Saaby and Geoffrey K. Tranmer
Chemical Communications 2006 (Issue 24) pp:2566-2568
Publication Date(Web):24 Mar 2006
DOI:10.1039/B600382F
A flow process for the multi-step synthesis of the alkaloid natural product (±)-oxomaritidine is described, mediated through the use of microfluidic pumping systems that progress material through various packed columns containing immobilized reagents, catalysts, scavengers or catch and release agents; our route involves the combination of seven separate synthetic steps linked into one continuous sequence utilizing flow chemistry.
Co-reporter:Kristian Rahbek Knudsen, Claire E. T. Mitchell and Steven V. Ley
Chemical Communications 2006 (Issue 1) pp:66-68
Publication Date(Web):28 Nov 2005
DOI:10.1039/B514636D
5-Pyrrolidin-2-yltetrazole performs as a useful organocatalyst for the asymmetric addition of malonates to a range of enones, with good to excellent enantioselectivities.
Co-reporter:Henriette M. Hansen, Deborah A. Longbottom and Steven V. Ley
Chemical Communications 2006 (Issue 46) pp:4838-4840
Publication Date(Web):03 Oct 2006
DOI:10.1039/B612436B
Using 5-(pyrrolidin-2-yl)-1H-tetrazole as an organic catalyst, the nitrocyclopropanation of 2-cyclohexen-1-one has been achieved, proceeding in high yield and with good enantioselective control.
Co-reporter:Ian R. Baxendale, Steven V. Ley, Christopher D. Smith and Geoffrey K. Tranmer
Chemical Communications 2006 (Issue 46) pp:4835-4837
Publication Date(Web):2006/10/03
DOI:10.1039/B612197G
A general flow process for the multi-step assembly of peptides has been developed and this procedure has been used to successfully construct a series of Boc, Cbz and Fmoc N-protected dipeptides in excellent yields and purities, including an extension of the method to enable the preparation of a tripeptide derivative.
Co-reporter:Claire E. T. Mitchell, Stacey E. Brenner, Jorge García-Fortanet and Steven V. Ley
Organic & Biomolecular Chemistry 2006 vol. 4(Issue 10) pp:2039-2049
Publication Date(Web):20 Apr 2006
DOI:10.1039/B601877G
5-Pyrrolidin-2-yltetrazole is a versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones. Using this catalyst, this transformation requires short reaction times, tolerates a broad substrate scope, and possibly proceeds via generation of an iminium species.
Co-reporter:Kristian Rahbek Knudsen, Antonia F. Stepan, Patrick Michel and Steven V. Ley
Organic & Biomolecular Chemistry 2006 vol. 4(Issue 8) pp:1471-1473
Publication Date(Web):13 Mar 2006
DOI:10.1039/B601888B
Diastereoselective aldol coupling reactions with butane-2,3-diacetal (BDA) protected glyceraldehyde derivatives are reported. Good selectivities of up to 20 : 1 for the homologated aldol products have been achieved in preparatively useful yields.
Co-reporter:Edward W. Tate, Darren J. Dixon and Steven V. Ley
Organic & Biomolecular Chemistry 2006 vol. 4(Issue 9) pp:1698-1706
Publication Date(Web):27 Mar 2006
DOI:10.1039/B602805E
A high-yielding enantioselective total synthesis of the bioactive styryllactone (+)-goniodiol has been realised, starting from readily available (S)-glycidol. A key step is an oxygen-to-carbon rearrangement of a silyl enol ether linked via an anomeric centre, facilitating the rapid and diastereoselective construction of this functionalised system.
Co-reporter:Giovanna Zinzalla, Lech-Gustav Milroy and Steven V. Ley
Organic & Biomolecular Chemistry 2006 vol. 4(Issue 10) pp:1977-2002
Publication Date(Web):21 Apr 2006
DOI:10.1039/B603015G
The design and synthesis of spiroketal structures and their chemical modification, leading to a collection of new small molecules for biological evaluation as orally-bioavailable lead compounds is described. Both [6,5]- and [6,6]-membered ring spiroketal units have been prepared in a stereochemically-varying fashion starting from commercially available (R)- or (S)-glycidol, in ten, eleven and twelve linear steps, in overall yields of 45, 40 and 20%, respectively. Further elaboration according to Lipinski's guidelines has given a collection of structurally-diverse, new spiroketal derivatives in high yields and with high purity.
Co-reporter:Ian R. Baxendale Dr.;Charlotte M. Griffiths-Jones Dr. ;Geoffrey K. Tranmer Dr.
Chemistry - A European Journal 2006 Volume 12(Issue 16) pp:
Publication Date(Web):4 APR 2006
DOI:10.1002/chem.200501400
This article describes the design, optimisation and development of a Suzuki cross-coupling protocol mediated by an efficient palladium-encapsulated catalyst (Pd EnCatTM) under microwave irradiation. The methodology has been used in both batch mode for classical library preparation and in continuous-flow applications furnishing multigram quantities of material. Described is a method that uses direct focused microwave heating whilst applying an external cooling source. This enables a lower than normal bulk temperature to be maintained throughout the reaction period leading to significant improvements in the overall yield and purity of the reaction products. Additional aspects of this novel heating protocol are discussed in relation to the prolonged lifetime and enhanced reactivity of the immobilised catalyst system.
Co-reporter:James A. Bull;Emily P. Balskus;Richard A. J. Horan Dr.;Martin Langner Dr. Dr.
Angewandte Chemie International Edition 2006 Volume 45(Issue 40) pp:
Publication Date(Web):20 SEP 2006
DOI:10.1002/anie.200602050
Candidate forCandida: A high-yielding and versatile synthesis of bengazole A has been developed; the first to provide access to a single stereoisomer of the natural product. Key steps include the construction of the 2,4-disubstituted oxazole under mild conditions and a diastereoselective 1,3-dipolar cycloaddition.
Co-reporter:Claire E. T. Mitchell, Stacey E. Brenner and Steven V. Ley
Chemical Communications 2005 (Issue 42) pp:5346-5348
Publication Date(Web):27 Sep 2005
DOI:10.1039/B511441A
5-Pyrrolidin-2-yltetrazole performs as an improved catalyst for the asymmetric addition of a range of nitroalkanes to cyclic and acyclic enones, with good to excellent enantioselectivity.
Co-reporter:Steen Saaby, Kristian Rahbek Knudsen, Mark Ladlow and Steven V. Ley
Chemical Communications 2005 (Issue 23) pp:2909-2911
Publication Date(Web):17 May 2005
DOI:10.1039/B504854K
Imines have been reduced to amines in high yield, and with excellent chemoselectivity, by catalytic hydrogenation in a continuous flow-reactor, utilising an electrochemically-generated hydrogen source to produce a mixed hydrogen–liquid flow stream.
Co-reporter:Connie K. Y. Lee, Andrew B. Holmes, Steven V. Ley, Ian F. McConvey, Bushra Al-Duri, Gary A. Leeke, Regina C. D. Santos and Jonathan P. K. Seville
Chemical Communications 2005 (Issue 16) pp:2175-2177
Publication Date(Web):09 Mar 2005
DOI:10.1039/B418669A
Suzuki cross-coupling reactions are effected in both conventional organic solvents, under continuous flow conditions at 70 °C, and in batch mode in supercritical carbon dioxide (scCO2), at temperatures as low as 40 °C in the presence of palladium(II) acetate microencapsulated in polyurea [PdEnCat]™ and tetra-n-butylammonium salts.
Co-reporter:Jason Siu, Ian R. Baxendale, Russell A. Lewthwaite and Steven V. Ley
Organic & Biomolecular Chemistry 2005 vol. 3(Issue 17) pp:3140-3160
Publication Date(Web):27 Jul 2005
DOI:10.1039/B503778F
In this paper we wish to report on a variety of expedient chemical transformations and purifications achieved via a generic ‘catch and release’ methodology, based on a synthetically inert bipyridyl chelating tag that can be selectively captured with a resin-bound copper(II) species. Utilising this approach we are able to derive many of the same benefits associated with both solid phase synthesis and supported reagent methods.
Co-reporter:Alexander J. A. Cobb, David M. Shaw, Deborah A. Longbottom, Johan B. Gold and Steven V. Ley
Organic & Biomolecular Chemistry 2005 vol. 3(Issue 1) pp:84-96
Publication Date(Web):29 Nov 2004
DOI:10.1039/B414742A
Tetrazole and acylsulfonamide organocatalysts derived from proline have been synthesised and applied to the asymmetric Mannich, nitro-Michael and aldol reactions to give results that are superior to the proline-catalysed counterpart.
Co-reporter:Steen Saaby, Ian R. Baxendale and Steven V. Ley
Organic & Biomolecular Chemistry 2005 vol. 3(Issue 18) pp:3365-3368
Publication Date(Web):11 Aug 2005
DOI:10.1039/B509540A
A number of oligomeric alkynes underwent [2 + 2 + 2] intramolecular trimerization to afford arenes under metal-free conditions using focussed microwave heating.
Co-reporter:Steven V. Ley, Darren J. Dixon, Richard T. Guy, Félix Rodríguez and Tom D. Sheppard
Organic & Biomolecular Chemistry 2005 vol. 3(Issue 22) pp:4095-4107
Publication Date(Web):19 Oct 2005
DOI:10.1039/B512410G
Consecutive coupling reactions of butane-2,3-diacetal protected glycolic acid derivatives with Michael acceptors and aldehydes are reported. An enantiopure sample of this building block was used to kinetically resolve a chiral Michael acceptor present as a racemic mixture of enantiomers.
Co-reporter:Dominic E. A. Brittain Dr.;Charlotte M. Griffiths-Jones Dr.;Michael R. Linder Dr.;Martin D. Smith Dr.;Catherine McCusker Dr.;Jaqueline S. Barlow Dr.;Ryo Akiyama Dr.;Kosuke Yasuda Dr. Professor Dr.
Angewandte Chemie International Edition 2005 Volume 44(Issue 18) pp:
Publication Date(Web):1 APR 2005
DOI:10.1002/anie.200500174
The structurally enticing antascomicin B (1), which exhibits potent immunosuppressant-antagonizing properties, has a complex polyketide structure. Key steps in its enantioselective total synthesis include a transannular catechol-templated Dieckmann reaction to assemble the challenging tricarbonyl functionality and a butanediacetal-directed allylation.
Co-reporter:Gillian L. Nattrass;Elena Díez;Matthew M. McLachlan;Darren J. Dixon Dr.
Angewandte Chemie International Edition 2005 Volume 44(Issue 4) pp:
Publication Date(Web):13 DEC 2004
DOI:10.1002/anie.200462264
Orthogonal and modular templating is an effective basis for the preparation of the biologically active annonaceous acetogenin 10-hydroxyasimicin (1). The versatile tartrate-derived 2,3-butanediacetal building block together with a highly diastereoselective hetero-Diels–Alder approach to the butenolide unit were usefully employed in this novel synthetic route.
Co-reporter:Matthew Ball Dr.;Matthew J. Gaunt Dr.;David F. Hook Dr.;Alan S. Jessiman;Shigeru Kawahara;Paolo Orsini;Alessra Scolaro;Adam C. Talbot;Huw R. Tanner;Shigeo Yamanoi Dr. Dr.
Angewandte Chemie International Edition 2005 Volume 44(Issue 34) pp:
Publication Date(Web):1 AUG 2005
DOI:10.1002/anie.200502008
The challenging structure and potent growth inhibition properties against a variety of human cancer cell lines make Spongistatin 1 (1) an exciting target for total synthesis. Enantioselective total synthesis has been achieved by exploiting a latent element of pseudo-symmetry (- - - - - =pseudo-C2 axis) within the ABCD bis(spiroketal) fragment (red substructure).
Co-reporter:Matthew Ball Dr.;Matthew J. Gaunt Dr.;David F. Hook Dr.;Alan S. Jessiman;Shigeru Kawahara;Paolo Orsini;Alessra Scolaro;Adam C. Talbot;Huw R. Tanner;Shigeo Yamanoi Dr. Dr.
Angewandte Chemie 2005 Volume 117(Issue 34) pp:
Publication Date(Web):1 AUG 2005
DOI:10.1002/ange.200502008
Die komplizierte Struktur und die starke wachstumshemmende Wirkung gegen viele humane Krebszelllinien haben Spongistatin 1 (1) zu einer interessanten Zielverbindung gemacht. Die hier vorgestellte enantioselektive Totalsynthese beruht auf der Pseudosymmetrie (- - - - - =Pseudo-C2-Achse) innerhalb des ABCD-Bis(spiroketal)fragments (rote Teilstruktur).
Co-reporter:Dominic E. A. Brittain Dr.;Charlotte M. Griffiths-Jones Dr.;Michael R. Linder Dr.;Martin D. Smith Dr.;Catherine McCusker Dr.;Jaqueline S. Barlow Dr.;Ryo Akiyama Dr.;Kosuke Yasuda Dr. Professor Dr.
Angewandte Chemie 2005 Volume 117(Issue 18) pp:
Publication Date(Web):4 APR 2005
DOI:10.1002/ange.200500174
Das strukturell bestechende Antascomicin B (1), das ein starker Immunsuppressiva-Antagonist ist, hat eine komplexe Polyketidstruktur. Zu den Schlüsselschritten seiner enantioselektiven Totalsynthese gehören eine transannulare Catechol-gestützte Dieckmann-Reaktion, um die anspruchsvolle Tricarbonylfunktionalität zu erhalten, und eine Butandiacetal-gesteuerte Allylierung.
Co-reporter:Gillian L. Nattrass;Elena Díez;Matthew M. McLachlan;Darren J. Dixon Dr.
Angewandte Chemie 2005 Volume 117(Issue 4) pp:
Publication Date(Web):13 DEC 2004
DOI:10.1002/ange.200462264
Orthogonale und modulare Template bilden die Grundlage für die Synthese des bioaktiven Annonaceae-Acetogenins 10-Hydroxyasimicin (1). Bei dieser neuen Syntheseroute bewährten sich die von Tartrat abgeleitete 2,3-Butandiacetal-Baueinheit und eine hoch diastereoselektive Hetero-Diels-Alder-Strategie zum Aufbau der Butenolid-Einheit.
Co-reporter:Alexander J. A. Cobb, Deborah A. Longbottom, David M. Shaw and Steven V. Ley
Chemical Communications 2004 (Issue 16) pp:1808-1809
Publication Date(Web):26 Jul 2004
DOI:10.1039/B409646K
The organocatalytic Michael addition of enamines derived from ketones to a range of nitro-olefins has been effected using the L-proline derived 5-pyrrolidin-2-yltetrazole 1.
Co-reporter:Steven V. Ley, Elena Diez, Darren J. Dixon, Richard T. Guy, Patrick Michel, Gillian L. Nattrass and Tom D. Sheppard
Organic & Biomolecular Chemistry 2004 vol. 2(Issue 24) pp:3608-3617
Publication Date(Web):17 Nov 2004
DOI:10.1039/B412788A
The preparation of butane-2,3-diacetal protected glycolic acid and related systems is described together with highly selective alkylation reactions of (R,R) and (S,S) butanediacetal protected glycolic acid. These compounds are readily deprotected to give enantiopure α-hydroxyacids, α-hydroxyesters or α-hydroxyamides by suitable choice of conditions.
Co-reporter:Steven V. Ley, Darren J. Dixon, Richard T. Guy, Maria A. Palomero, Alessandra Polara, Félix Rodríguez and Tom D. Sheppard
Organic & Biomolecular Chemistry 2004 vol. 2(Issue 24) pp:3618-3627
Publication Date(Web):17 Nov 2004
DOI:10.1039/B412790K
Highly diastereoselective coupling reactions of enolates derived from butane-2,3-diacetal protected glycolic acids 1 and 2 and their alkylated derivatives with aldehydes are reported together with their efficient acid-catalysed deprotection to yield enantiopure anti-2,3-dihydroxyesters. A procedure to provide the corresponding syn-2,3-dihydroxyesters is also described in two cases, proceeding via an acylation–reduction sequence. An usual double addition reaction of butane-2,3-diacetal protected glycolic acid to small aliphatic acid chlorides provides a synthetically useful, densely-functionalised lactone after acidic deprotection.
Co-reporter:Marianne F. Buffet, Darren J. Dixon, Steven V. Ley, Dominic J. Reynolds and R. Ian Storer
Organic & Biomolecular Chemistry 2004 vol. 2(Issue 8) pp:1145-1154
Publication Date(Web):18 Mar 2004
DOI:10.1039/B316858A
Tetrahydropyran and tetrahydrofuran containing natural products, drugs and agrochemicals often possess carbon–carbon bonds adjacent to the heteroatom. Consequently, new methods for the construction of anomeric carbon–carbon bonds are of considerable importance. We have devised a new strategy to access these systems that requires the treatment of O-glycoside alkynyl tributylstannane derivatives of furanyl and pyranyl lactols with Lewis acid to effect oxygen to carbon rearrangements. This leads to the formation of the corresponding carbon linked alkynol products that can be further manipulated to produce key structural motifs and building blocks for the assembly of complex molecules.
Co-reporter:Jason Siu, Ian R. Baxendale and Steven V. Ley
Organic & Biomolecular Chemistry 2004 vol. 2(Issue 2) pp:160-167
Publication Date(Web):16 Dec 2003
DOI:10.1039/B313012F
The development of enhanced conditions for Lewis acid catalysed Leimgruber–Batcho indole synthesis using microwave acceleration is described. This approach has permitted the preparation of a variety of heteroaromatic enamine intermediates in good yield and high purities. Subsequent catalytic hydrogenation reactions, under various conditions including the use of a solid-phase encapsulated catalyst, furnish the corresponding indole derivatives in good yields.
Co-reporter:Peter R. Hewitt, Ed Cleator and Steven V. Ley
Organic & Biomolecular Chemistry 2004 vol. 2(Issue 17) pp:2415-2417
Publication Date(Web):09 Aug 2004
DOI:10.1039/B410180D
The first total synthesis of (+)-okaramine C is described. Our previously described selenocyclisation-oxidative deselenation sequence was used to establish a 3a-hydroxy-pyrrolo[2,3-
b]indole core, which was modified by selective epimerisation to the common pyrrolo[2,3-
b]indole of the okaramines.
Co-reporter:Steven V. Ley;Alessandra Antonello;Emily P. Balskus;David T. Booth;Søren B. Christensen;Ed Cleator;Helen Gold;Klemens Högenauer;Udo Hünger;Rebecca M. Myers;Steven F. Oliver;Oliver Simic;Martin D. Smith;Helmer Søhoel;Alison J. A. Woolford
PNAS 2004 101 (33 ) pp:12073-12078
Publication Date(Web):2004-08-17
DOI:10.1073/pnas.0403300101
The thapsigargins are a family of complex guaianolides with potent and selective Ca2+-modulating properties. This article documents the evolution of a synthetic route through several iterations to a final practical
and scaleable synthetic route capable of generating both unnatural and natural products based around the guaianolide skeleton.
Co-reporter:R. Ian Storer Dr.;Toshiyasu Takemoto Dr.;Philip S. Jackson Dr.;Dearg S. Brown Dr.;Ian R. Baxendale Dr. Dr.
Chemistry - A European Journal 2004 Volume 10(Issue 10) pp:
Publication Date(Web):7 MAY 2004
DOI:10.1002/chem.200490030
Co-reporter:R. Ian Storer Dr.;Toshiyasu Takemoto Dr.;Philip S. Jackson Dr.;Dearg S. Brown Dr.;Ian R. Baxendale Dr. Dr.
Chemistry - A European Journal 2004 Volume 10(Issue 10) pp:
Publication Date(Web):26 APR 2004
DOI:10.1002/chem.200305669
The total synthesis of the cytotoxic antitumour natural product epothilone C has provided a stage for the exploitation and further development of immobilized reagent methods. A stereoselective convergent synthetic strategy was applied, incorporating polymer-supported reagents, catalysts, scavengers and catch-and-release techniques to avoid frequent aqueous work-up and chromatographic purification.
Co-reporter:Steven V. Ley;Alessandra Antonello;Emily P. Balskus;David T. Booth;Søren B. Christensen;Ed Cleator;Helen Gold;Klemens Högenauer;Udo Hünger;Rebecca M. Myers;Steven F. Oliver;Oliver Simic;Martin D. Smith;Helmer Søhoel;Alison J. A. Woolford
PNAS 2004 101 (33 ) pp:12073-12078
Publication Date(Web):2004-08-17
DOI:10.1073/pnas.0403300101
The thapsigargins are a family of complex guaianolides with potent and selective Ca2+-modulating properties. This article documents the evolution of a synthetic route through several iterations to a final practical
and scaleable synthetic route capable of generating both unnatural and natural products based around the guaianolide skeleton.
Co-reporter:Martin D. Smith, Antonia F. Stepan, Chandrashekar Ramarao, Paul E. Brennan and Steven V. Ley
Chemical Communications 2003 (Issue 21) pp:2652-2653
Publication Date(Web):30 Sep 2003
DOI:10.1039/B308465E
Palladium-containing perovskites (LaFe0.57Co0.38Pd0.05O3) have been exploited as recoverable and reuseable catalysts in Suzuki coupling reactions; residual levels of Pd after removal of the catalyst by filtration are low (2 ppm) despite evidence that the reaction is occurring via a homogeneous process.
Co-reporter:Darren J. Dixon, Christopher I. Harding, Steven V. Ley and D. Matthew G. Tilbrook
Chemical Communications 2003 (Issue 4) pp:468-469
Publication Date(Web):20 Jan 2003
DOI:10.1039/B210673F
A new chiral glycine equivalent 7 has been synthesised from glycidol using a chiral memory protocol, and its use in the synthesis of N-Z protected α-amino acids was demonstrated in a series of diasteroselective lithium enolate alkylation reactions and subsequent acid hydrolyses.
Co-reporter:Jin-Quan Yu, Hai-Chen Wu, Chandrashekar Ramarao, Jonathan B. Spencer and Steven V. Ley
Chemical Communications 2003 (Issue 6) pp:678-679
Publication Date(Web):12 Feb 2003
DOI:10.1039/B300074P
A robust and recyclable palladium catalyst [Pd0EnCat] has been prepared by ligand exchange of polyurea-encapsulated palladium(II) acetate with formic acid, resulting in deposition of Pd(0) in the support material; Pd0EnCat is shown to be a highly efficient transfer hydrogenation catalyst for chemoselective reduction of a wide range of aryl ketones to benzyl alcohols.
Co-reporter:Christopher J. Hollowood, Shigeo Yamanoi and Steven V. Ley
Organic & Biomolecular Chemistry 2003 vol. 1(Issue 10) pp:1664-1675
Publication Date(Web):24 Apr 2003
DOI:10.1039/B301676P
The total synthesis of taurospongin A by two new approaches has been achieved where π-allyltricarbonyliron lactone complexes have been used to control highly stereoselective additions of the nucleophiles to a carbonyl unit located in the side chain of these complexes.
Co-reporter:Christopher J. Hollowood and Steven V. Ley
Organic & Biomolecular Chemistry 2003 vol. 1(Issue 18) pp:3197-3207
Publication Date(Web):13 Aug 2003
DOI:10.1039/B306861G
Treatment of π-allyltricarbonyliron lactone complexes, that contain an adjacent leaving group, with lithium naphthalenide causes decomplexation to acyclic dienols in excellent yield and without any stereochemical scrambling of the allylic centre. When an endo complex is employed (E,E)-geometry prevails with good selectivity whereas (Z,E)-geometry dominates in the case of exo complexes. A mechanism consistent with the observed stereo- and regiochemistry is proposed.
Co-reporter:Christopher J. Hollowood, Steven V. Ley and Edward A. Wright
Organic & Biomolecular Chemistry 2003 vol. 1(Issue 18) pp:3208-3216
Publication Date(Web):13 Aug 2003
DOI:10.1039/B306862E
Silyl enol ethers derived from ketone functionalised π-allyltricarbonyliron lactone complexes undergo highly diastereoselective carbon–fluorine and carbon–oxygen bond formation reactions with excellent control at the α-stereogenic centre.
Co-reporter:Steven V. Ley, Ed Cleator and Peter R. Hewitt
Organic & Biomolecular Chemistry 2003 vol. 1(Issue 20) pp:3492-3494
Publication Date(Web):15 Sep 2003
DOI:10.1039/B308288A
A two-step selenocyclisation–oxidative deselenation sequence was used to establish the 3a-hydroxy-pyrrolo[2,3-b]indole core; these tricycles were used as effective precursors to 10b-hydroxy-pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4-diones.
Co-reporter:Matthew J. Gaunt, Helen F. Sneddon, Peter R. Hewitt, Paolo Orsini, David F. Hook and Steven V. Ley.
Organic & Biomolecular Chemistry 2003 vol. 1(Issue 1) pp:15-16
Publication Date(Web):03 Dec 2002
DOI:10.1039/B208982C
β-Keto 1,3-dithianes can be generated by the double conjugate addition of dithiols to propargylic ketones, esters and aldehydes in excellent yields. As masked 1,3-dicarbonyl systems these substrates can be converted to a range of functionalised oxygen-containing heterocycles that can be used in natural product synthesis.
Co-reporter:Steven V. Ley, Ed Cleator, Jürgen Harter and Christopher J. Hollowood
Organic & Biomolecular Chemistry 2003 vol. 1(Issue 19) pp:3263-3264
Publication Date(Web):29 Aug 2003
DOI:10.1039/B308793J
The synthesis of the germination self-inhibitor (−)-Gloeosporone is reported. The embedded 1,7-diol motif in the product is constructed by an ironcarbonyl tether controlled Mukaiyama aldol reaction. The key step in the synthesis is the reductive removal of the ligating iron species by treatment of an acetoxycomplex 6 with lithium naphthalenide.
Co-reporter:Ai-Lan Lee and Steven V. Ley
Organic & Biomolecular Chemistry 2003 vol. 1(Issue 22) pp:3957-3966
Publication Date(Web):08 Oct 2003
DOI:10.1039/B308761A
A general asymmetric route to both enantiomers of polysphorin has been developed. The route utilizes polymer-supported reagents, catalysts and scavengers to minimise the need for aqueous work-up and chromatography. This includes application of a method to scavenge 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and a “catch-and-release” procedure to extract the resultant diol following Sharpless asymmetric dihydroxylation. A novel enzymatic selective protection and investigations of a new asymmetric dihydroxylation using microencapsulated osmium tetroxide were also investigated during the course of this study.
Co-reporter:Emma Vickerstaffe, Brian H. Warrington, Mark Ladlow and Steven V. Ley
Organic & Biomolecular Chemistry 2003 vol. 1(Issue 14) pp:2419-2422
Publication Date(Web):20 Jun 2003
DOI:10.1039/B305713E
The first fully automated multi-step polymer assisted solution phase (PASP) synthesis is described. An array of histone deacetylase (HDAc) inhibitors was prepared by an unattended 4–5 step sequence incorporating in-line ‘catch and release’ purification.
Co-reporter:Rachel N. MacCoss, Paul E. Brennan and Steven V. Ley
Organic & Biomolecular Chemistry 2003 vol. 1(Issue 12) pp:2029-2031
Publication Date(Web):19 May 2003
DOI:10.1039/B303951J
Methods to allow the clean preparation of oligosaccharides were investigated using techniques that do not require conventional column chromatography or an aqueous work-up. The route was designed to provide rapid access to oligosaccharides and is suitable for automation and parallel library formation. The research has focused on the glycosidations of a range of glycosyl acceptors with various selenophenyl glycosyl donors using iodine as an activator in the presence of DTBMP, a hindered organic base. Hydroxyl-containing contaminants were removed by scavenging with polymer-supported tosyl chloride.
Co-reporter:Darren J. Dixon;Felix Rodríguez;Steven V. Ley;Elena Díez;Alessra Polara and
Helvetica Chimica Acta 2003 Volume 86(Issue 11) pp:3717-3729
Publication Date(Web):24 NOV 2003
DOI:10.1002/hlca.200390314
The total synthesis of phytotoxic nonenolide herbarumin II (1) has been achieved by implementation of butane diacetal (BDA)-desymmetrised glycolate building blocks. Three of the four stereogenic centres present in the key coupling fragments were generated from both enantiomeric forms of the BDA building block in highly diastereoselective alkylation and aldol reactions.
Co-reporter:Steven F. Oliver Dr.;Klemens Högenauer Dr.;Oliver Simic Dr.;Alessra Antonello;Martin D. Smith Dr.
Angewandte Chemie 2003 Volume 115(Issue 48) pp:
Publication Date(Web):10 DEC 2003
DOI:10.1002/ange.200353140
Eine vollständig substratkontrollierte Totalsynthese dreier Mitglieder der Thapsigargin-Familie (darunter Trilobolid) gelang ausgehend von (S)-Carvon. Die Synthese ist linear, effizient und liefert hohe Ausbeuten (>90 % pro Stufe). Die Divergenz in einem späten Synthesestadium erlaubt den Zugang zu einer Reihe von Naturstoffen und synthetischen Analoga.
Co-reporter:R. Ian Storer;Toshiyasu Takemoto Dr.;Philip S. Jackson Dr.
Angewandte Chemie 2003 Volume 115(Issue 22) pp:
Publication Date(Web):5 JUN 2003
DOI:10.1002/ange.200351413
Immobilisierte Reagentien und Abfangreagentien erleichtern die vielstufigen Umwandlungen und die Reinigungsschritte in der Totalsynthese von Epothilon C (1), die auch eine formale Synthese von Epothilon A einschließt.
Co-reporter:R. Ian Storer;Toshiyasu Takemoto Dr.;Philip S. Jackson Dr.
Angewandte Chemie International Edition 2003 Volume 42(Issue 22) pp:
Publication Date(Web):5 JUN 2003
DOI:10.1002/anie.200351413
A total synthesis of epothilone C (1) with concomitant formal synthesis of epothilone A is described, using immobilized reagents and scavengers to effect multistep synthetic transformations and purifications.
Co-reporter:Steven F. Oliver Dr.;Klemens Högenauer Dr.;Oliver Simic Dr.;Alessra Antonello;Martin D. Smith Dr.
Angewandte Chemie International Edition 2003 Volume 42(Issue 48) pp:
Publication Date(Web):10 DEC 2003
DOI:10.1002/anie.200353140
An entirely substrate-controlled total synthesis of three members of the thapsigargin family (e.g. trilobolide) is achieved starting from (S)-carvone. The synthesis is linear in nature but is achieved in high yield (>90 % per step). The route permits late-stage divergence, providing access to a range of natural products and structural analogues.
Co-reporter:Steven V. Ley
&
Ian R. Baxendale
Nature Reviews Drug Discovery 2002 1(8) pp:573
Publication Date(Web):
DOI:10.1038/nrd871
The increasing need to efficiently assemble small molecules as potential modulators of therapeutic targets that are emerging from genomics and proteomics is driving the development of novel technologies for small-molecule synthesis. Here, we describe some of the general applications and approaches to synthesis using one such technology — solid-supported reagents — that has been shown to significantly improve productivity in the generation of combinatorial libraries and complex target molecules.
Co-reporter:Chandrashekar Ramarao, Steven V. Ley, Stephen C. Smith, Ian M. Shirley and Nathalie DeAlmeida
Chemical Communications 2002 (Issue 10) pp:1132-1133
Publication Date(Web):23 Apr 2002
DOI:10.1039/B200674J
An interfacial polymerisation approach is adopted to encapsulate palladium(II) acetate and palladium nanoparticles in polyurea microcapsules for use in catalysis.
Co-reporter:Steven V. Ley, Chandrashekar Ramarao, Richard S. Gordon, Andrew B. Holmes, Angus J. Morrison, Ian. F. McConvey, Ian M. Shirley, Stephen C. Smith and Martin D. Smith
Chemical Communications 2002 (Issue 10) pp:1134-1135
Publication Date(Web):23 Apr 2002
DOI:10.1039/B200677B
Palladium(II) acetate microencapsulated in polyurea (MC-[Pd]) is an economical and versatile heterogeneous catalyst for a range of phosphine-free cross-coupling reactions in both conventional solvents and supercritical carbon dioxide (scCO2); the catalyst can be recovered by a simple filtration and recycled up to four times.
Co-reporter:Christopher J. Hollowood, Steven V. Ley and Shigeo Yamanoi
Chemical Communications 2002 (Issue 15) pp:1624-1625
Publication Date(Web):01 Jul 2002
DOI:10.1039/B204994P
The synthesis of taurospongin A has been achieved using, as a key step, a π-allyltricarbonyliron lactone complex to control a highly stereoselective addition of a methyl group to a carbonyl unit located in the side chain of the complex.
Co-reporter:Christopher J. Hollowood and Steven V. Ley
Chemical Communications 2002 (Issue 18) pp:2130-2131
Publication Date(Web):22 Aug 2002
DOI:10.1039/B206406P
Treatment of π-allyltricarbonyliron lactone complexes bearing an adjacent leaving group, with lithium naphthalenide causes decomplexation to acyclic dienols in excellent yield and without any scrambling of the allylic centre.
Co-reporter:Ian R. Baxendale, Ai-Lan Lee and Steven V. Ley
Organic & Biomolecular Chemistry 2002 (Issue 16) pp:1850-1857
Publication Date(Web):18 Jul 2002
DOI:10.1039/B203388G
Polymer-supported reagents have been applied to the synthesis of the natural product carpanone resulting in a clean and efficient synthesis without the requirement for conventional purification techniques. A new polymer-supported transition metal isomerisation catalyst is also reported.
Co-reporter:Kosuke Yasuda and Steven V. Ley
Organic & Biomolecular Chemistry 2002 (Issue 8) pp:1024-1025
Publication Date(Web):25 Mar 2002
DOI:10.1039/B201776H
The simultaneous use of selected immobilised oxidising reagents in a single reaction vessel provides an efficient method for the conversion of primary alcohols to the corresponding carboxylic acids.
Co-reporter:Ian R. Baxendale, Gloria Brusotti, Masato Matsuoka and Steven V. Ley
Organic & Biomolecular Chemistry 2002 (Issue 2) pp:143-154
Publication Date(Web):17 Dec 2001
DOI:10.1039/B109482N
The sequential use of solid-supported reagents and scavengers has led to an efficient synthesis of the natural products nornicotine 1, nicotine 2 and further fuctionalised derivatives. Also reported is a diastereoselective route to both enantiomers of nicotine 2.
Co-reporter:Steven V. Ley;Alain Priour
European Journal of Organic Chemistry 2002 Volume 2002(Issue 23) pp:
Publication Date(Web):8 NOV 2002
DOI:10.1002/1099-0690(200212)2002:23<3995::AID-EJOC3995>3.0.CO;2-P
The details of the total synthesis of Argyrin B, a natural product with immunosuppressive properties, are reported below. The two most unusual amino acid residues of this cyclic peptide are 4-methoxytryptophan and dehydroalanine, which were obtained by modifying known synthetic methods. The linear peptide was assembled in a most convergent fashion then cyclisation followed by generation of the sensitive dehydroalanine afforded synthetic Argyrin B (1). (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)
Co-reporter:Ian R. Baxendale ;Claudia Piutti
Angewandte Chemie 2002 Volume 114(Issue 12) pp:
Publication Date(Web):13 JUN 2002
DOI:10.1002/1521-3757(20020617)114:12<2298::AID-ANGE2298>3.0.CO;2-B
Eine reaktionsvermittelnde Sequenz aus polymeren Träger- und Abfangreagentien wurde bei der ersten Totalsynthese von (+)-Plicamin 1, einem Mitglied der Familie der Amaryllidaceae-Alkaloide, ausgehend von L-4-Hydroxyphenylglycin eingesetzt (siehe Schema).
Co-reporter:Ian R. Baxendale ;Claudia Piutti
Angewandte Chemie International Edition 2002 Volume 41(Issue 12) pp:
Publication Date(Web):12 JUN 2002
DOI:10.1002/1521-3773(20020617)41:12<2194::AID-ANIE2194>3.0.CO;2-4
A sequence of polymer-supported reagents and scavengers was used to promote the synthetic transformations in the first total synthesis of (+)-plicamine (1), a member of the amaryllidaceae alkaloid family, starting from L-4-hydroxyphenylglycine (see scheme).
Co-reporter:Deborah A. Longbottom Dr.;Angus J. Morrison Dr.;Darren J. Dixon Dr. Dr.
Angewandte Chemie International Edition 2002 Volume 41(Issue 15) pp:
Publication Date(Web):2 AUG 2002
DOI:10.1002/1521-3773(20020802)41:15<2786::AID-ANIE2786>3.0.CO;2-Z
Only through total synthesis could the absolute configuration of the 3″R,4″R ring junction of the polyenoltetramic acid polycephalin C (1) be unambiguously established. Key features of the synthesis include a double Swern oxidation, double Stille coupling, and a double Takai olefination.
Co-reporter:Patrick Michel Dr. Dr.
Angewandte Chemie International Edition 2002 Volume 41(Issue 20) pp:
Publication Date(Web):18 OCT 2002
DOI:10.1002/1521-3773(20021018)41:20<3898::AID-ANIE3898>3.0.CO;2-B
Available on a large scale in both enantiomeric forms, the butanediacetal-protected aldehyde 1 is a stable glyceraldehyde derivative. The potential of 1 as a new chiral building block is illustrated by the highly stereoselective addition of Grignard reagents (see scheme).
Co-reporter:Patrick Michel Dr. Dr.
Angewandte Chemie 2002 Volume 114(Issue 20) pp:
Publication Date(Web):18 OCT 2002
DOI:10.1002/1521-3757(20021018)114:20<4054::AID-ANGE4054>3.0.CO;2-R
In beiden enantiomeren Formen in großem Maßstab zugänglich ist der geschützte Aldehyd 1, ein stabiles Glycerinaldehyd-Derivat. Das Potenzial von 1 als neuer chiraler Synthesebaustein wurde anhand der hoch stereoselektiven Addition von Grignard-Reagentien demonstriert (siehe Schema).
Co-reporter:Darren J. Dixon Dr. Dr.;Dominic J. Reynolds Dr.
Chemistry - A European Journal 2002 Volume 8(Issue 7) pp:
Publication Date(Web):28 MAR 2002
DOI:10.1002/1521-3765(20020402)8:7<1621::AID-CHEM1621>3.0.CO;2-8
The total synthesis of the potential antitumour agent muricatetrocin C has provided an ideal stage for the exploitation and development of new chemistry. A convergent synthetic strategy has been realised incorporating three distinct pieces of methodology, these include a highly diastereoselective hetero-Diels–Alder reaction to construct the butenolide terminus, an oxygen to carbon rearrangement to install the trans-2,5-disubstituted tetrahydrofuran ring and a spatial desymmetrisation process to afford the anti-diol unit.
Co-reporter:Steven V. Ley;Ian R. Baxendale
The Chemical Record 2002 Volume 2(Issue 6) pp:
Publication Date(Web):4 DEC 2002
DOI:10.1002/tcr.10033
This article is based on a lecture presented to the Chemical Society of Japan at Wasada University on March 27, 2002, by Professor Steven V. Ley. The lecture, “Organic Synthesis in a Changing World,” was a comprehensive account of the ongoing research efforts of professor Ley's group in the development and application of solid-supported reagents and scavengers for use in organic synthesis. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 2: 377–388, 2002: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.10033
Co-reporter:Deborah A. Longbottom Dr.;Angus J. Morrison Dr.;Darren J. Dixon Dr. Dr.
Angewandte Chemie 2002 Volume 114(Issue 15) pp:
Publication Date(Web):30 JUL 2002
DOI:10.1002/1521-3757(20020802)114:15<2910::AID-ANGE2910>3.0.CO;2-3
Nur durch eine Totalsynthese konnte die absolute Konfiguration der 3″R,4″R-Ringverknüpfung der Polyenol-Tetramsäure Polycephalin C 1 unzweideutig nachgewiesen werden. Besondere Merkmale dieser Synthese sind die jeweils doppelt ausgeführte Swern-Oxidation, Stille-Kupplung und Takai-Olefinierung.
Co-reporter:Steven V. Ley, Chandrashekar Ramarao and Martin D. Smith
Chemical Communications 2001 (Issue 21) pp:2278-2279
Publication Date(Web):18 Oct 2001
DOI:10.1039/B107966M
The use of tetraalkylammonium salts or imidazolium ionic liquids in catalytic oxidations of alcohols with tetra-N-propylammonium perruthenate allows recovery and reuse of the oxidant; this concept may find application in the recovery of other homogenous catalysts.
Co-reporter:Elena Díez Dr.;Darren J. Dixon Dr. Dr.
Angewandte Chemie 2001 Volume 113(Issue 15) pp:
Publication Date(Web):3 AUG 2001
DOI:10.1002/1521-3757(20010803)113:15<2990::AID-ANGE2990>3.0.CO;2-R
Unter Nutzung eines Chiralitätsgedächtnis-Effekts wurde ein chirales Glycolsäureäquivalent, das geschützte Glycolat 2, aus chiralen 3-Halogenpropan-1,2-diolen 1 erhalten. 2 ist ein neuer und effektiv nutzbarer Synthesebaustein für die Herstellung von mono- oder dialkylierten α-Hydroxycarbonsäuren 3, einem biologisch und pharmakologisch bedeutenden Strukturmotiv.
Co-reporter:Steven V. Ley Dr.;Alessro Massi Dr.;Félix Rodríguez Dr.;David C. Horwell Dr.;Russell A. Lewthwaite Dr.;Martyn C. Pritchard Dr.;Alison M. Reid Dr.
Angewandte Chemie 2001 Volume 113(Issue 6) pp:
Publication Date(Web):14 MAR 2001
DOI:10.1002/1521-3757(20010316)113:6<1088::AID-ANGE10880>3.0.CO;2-#
Co-reporter:Darren J. Dixon Dr. Dr.;Félix Rodríguez Dr.
Angewandte Chemie 2001 Volume 113(Issue 24) pp:
Publication Date(Web):18 DEC 2001
DOI:10.1002/1521-3757(20011217)113:24<4899::AID-ANGE4899>3.0.CO;2-E
Bis zu fünf neue Stereozentren (siehe 2) können in einer Eintopfreaktion ausgehend vom Glycolsäurederivat 1 durch aufeinander folgende Drei- und Vier-Komponenten-Kupplungen aufgebaut werden. Hoch funktionalisierte α-Hydroxysäureester werden so einfach, schnell, sauber und effizient erhalten. LHMDS=Lithium-bis(trimethylsilyl)amid.
Co-reporter:Darren J. Dixon Dr. Dr.;Félix Rodríguez Dr.
Angewandte Chemie International Edition 2001 Volume 40(Issue 24) pp:
Publication Date(Web):18 DEC 2001
DOI:10.1002/1521-3773(20011217)40:24<4763::AID-ANIE4763>3.0.CO;2-D
Up to five new stereogenic centers (see 2) can be formed in one-pot consecutive three- and four-component coupling reactions starting from a butane diacetal desymmetrized glycolic acid derivative 1. Highly functionalized α-hydroxy acid derivatives are obtained in an easy, fast, clean, and efficient way. LHMDS = lithium hexamethyldisilazide.
Co-reporter:Elena Díez Dr.;Darren J. Dixon Dr. Dr.
Angewandte Chemie International Edition 2001 Volume 40(Issue 15) pp:
Publication Date(Web):2 AUG 2001
DOI:10.1002/1521-3773(20010803)40:15<2906::AID-ANIE2906>3.0.CO;2-5
According to a chiral memory protocol, a chiral glycolic acid equivalent, the butane-2,3-diacetal-desymmetrized glycolate 2, is obtained from chiral 3-halopropane-1,2-diols 1. Compound 2 is a new and effective building block for the synthesis of mono- and dialkylated α-hydroxy acids 3, which constitute a biologically and pharmacologically important structural motif.
Co-reporter:Steven V. Ley, Ian R. Baxendale, Robert N. Bream, Philip S. Jackson, Andrew G. Leach, Deborah A. Longbottom, Marcella Nesi, James S. Scott, R. Ian Storer and Stephen J. Taylor
Organic & Biomolecular Chemistry 2000 (Issue 23) pp:3815-4195
Publication Date(Web):01 Dec 2000
DOI:10.1039/B006588I
Covering: the literature until April 2000
Co-reporter:Arno Düffels, Luke G. Green, Roman Lenz, Steven V. Ley, Stephane P. Vincent, Chi-Huey Wong
Bioorganic & Medicinal Chemistry 2000 Volume 8(Issue 10) pp:2519-2525
Publication Date(Web):October 2000
DOI:10.1016/S0968-0896(00)00187-5
l-Galactosylated dimeric sialyl Lewis X (SLex) has been prepared employing a combination of chemical and enzymatic synthetic methods. GDP-l-galactose has been chemically synthesised. Enzymatic transfer of l-galactose onto the acceptor (Sia-α2,3-Gal-β1,4-GlcNAc-β1,3/6)2-Man-α1-OMe was achieved using the human α-1,3-fucosyltransferase V.
Co-reporter:Daniel K Baeschlin, Luke G Green, Michael G Hahn, Berthold Hinzen, Stuart J Ince, Steven V Ley
Tetrahedron: Asymmetry 2000 Volume 11(Issue 1) pp:173-197
Publication Date(Web):28 January 2000
DOI:10.1016/S0957-4166(99)00519-4
This paper describes the application of 1,2-diacetal protecting groups to control the reactivity tuning of glycosyl fluorides in oligosaccharide coupling reactions. The synthetic potential of this new methodology is demonstrated by the ‘one-pot’ synthesis of a linear pentasaccharide and the efficient assembly of the core oligosaccharide of the GPI anchor of yeast (Saccharomyces cerevisiae).
Co-reporter:Darren J. Dixon Dr.;Steven V. Ley Dr.;Dominic J. Reynolds
Angewandte Chemie 2000 Volume 112(Issue 20) pp:
Publication Date(Web):13 OCT 2000
DOI:10.1002/1521-3757(20001016)112:20<3768::AID-ANGE3768>3.0.CO;2-G
Co-reporter:Arno Düffels Dr.;Luke G. Green Dr. Dr.;Andrew D. Miller Dr.
Chemistry - A European Journal 2000 Volume 6(Issue 8) pp:
Publication Date(Web):13 APR 2000
DOI:10.1002/(SICI)1521-3765(20000417)6:8<1416::AID-CHEM1416>3.0.CO;2-O
The concise synthesis of five biantennary oligomannose neoglycolipids is presented. Employing a strategy based on the principles of reactivity tuning and orthogonal activation, the oligomannose moieties, isolated from the glycoprotein 63 of the parasite Leishmania mexicana amazonensis, were rapidly assembled taking advantage of common structural motifs found in these N-glycans. Deprotection of all structures was achieved in high yield by hydrogenolysis. The deprotected glycoconjugates were subsequently coupled to a cholesteroldiamine derivative using diethylsquarate as a linker. The resulting neoglycolipids will be used as additives to cationic liposome formulations in the active targeting of liposomes to macrophages.
Co-reporter:Daniel K. Baeschlin;André R. Chaperon Dr.;Luke G. Green Dr.;Michael G. Hahn Dr.;Stuart J. Ince Dr.
Chemistry - A European Journal 2000 Volume 6(Issue 1) pp:
Publication Date(Web):29 DEC 1999
DOI:10.1002/(SICI)1521-3765(20000103)6:1<172::AID-CHEM172>3.0.CO;2-5
A full account on a total synthesis of GPI anchor 1 employing butanediacetal (BDA) groups and a chiral bis(dihydropyran) is presented. The reactivity of selenium and thio glycosides was tuned by the use of BDA groups. This allowed the assembly of an appropriately protected GPI anchor precursor 2 in just six steps from the six building blocks 5-10 including only one protecting group manipulation (see Scheme 1). myo-Inositol was desymmetrised with the bis(dihydropyran) derivative 15 and appropriately protected to give inositol acceptor 21 in nine steps and 17 % overall yield (see Scheme 3). The use of common starting materials and BDA-protections give efficient access to building blocks 5, 6, 7 and 8 (see Scheme 5). A new and improved synthesis of the glucosamine donor 28 is included. In summary, a highly convergent and efficient synthesis of GPI anchor 1, which is clearly adaptable to other GPI anchors, has been reported.
Co-reporter:Dominique Depré;Arno Düffels;Luke G. Green;Roman Lenz;Chi-Huey Wong
Chemistry - A European Journal 1999 Volume 5(Issue 11) pp:
Publication Date(Web):29 OCT 1999
DOI:10.1002/(SICI)1521-3765(19991105)5:11<3326::AID-CHEM3326>3.0.CO;2-Q
The concise synthesis of nine diantennary oligosaccharides, such as 1, by chemical and chemoenzymatic protocols is presented. The compounds display Lewis X, Lewis Y, sialyl Lewis X and T-antigen epitopes supported on a 3,6-branched trimannose core. They derive from the glycans of the human glycoproteins Glycodelin-A and Glycodelin-S believed to be involved in regiospecific suppression of the female immune system.
Co-reporter:Daniel K. Baeschlin;André R. Chaperon;Virginie Charbonneau;Luke G. Green;Ulrich Lücking;Eric Walther
Angewandte Chemie International Edition 1998 Volume 37(Issue 24) pp:
Publication Date(Web):18 JAN 1999
DOI:10.1002/(SICI)1521-3773(19981231)37:24<3423::AID-ANIE3423>3.0.CO;2-I
Six building blocks, six reaction steps: The recently developed innovative methodology facilitated the convergent synthesis of the complex oligosaccharide core 1 (shown here with protecting groups) for the total synthesis of a glycosylphosphatidylinositol (GPI) anchor. The key factors are the tuning of the reactivity of the building blocks by using 1,2-diacetal protecting groups and the desymmetrization of glycerol and myo-inositol with a chiral bis(dihydropyran).
Co-reporter:Daniel K. Baeschlin;André R. Chaperon;Virginie Charbonneau;Luke G. Green;Ulrich Lücking;Eric Walther
Angewandte Chemie 1998 Volume 110(Issue 24) pp:
Publication Date(Web):12 MAR 1999
DOI:10.1002/(SICI)1521-3757(19981217)110:24<3609::AID-ANGE3609>3.0.CO;2-#
Sechs Bausteine, sechs Reaktionsschritte: Der innovative Einsatz kürzlich entwickelter Methoden ermöglichte den konvergenten Aufbau des komplexen Oligosaccharidgrundgerüsts 1 (hier mit Schutzgruppen gezeigt) für die Totalsynthese eines Glycosylphosphatidylinosit(GPI)-Ankers. Entscheidend dabei waren die Reaktivitätsabstimmung der Bausteine über 1,2-Diacetal-Schutzgruppen sowie die Desymmetrisierung von Glycerin und myo-Inosit mit einem chiralen Bis(dihydropyran).
Co-reporter:Swapna S. Mohapatra, Zoe E. Wilson, Sujit Roy, Steven V. Ley
Tetrahedron (6 April 2017) Volume 73(Issue 14) pp:1812-1819
Publication Date(Web):6 April 2017
DOI:10.1016/j.tet.2017.02.026
Co-reporter:Nuria M. Roda, Duc N. Tran, Claudio Battilocchio, Ricardo Labes, Richard J. Ingham, Joel M. Hawkins and Steven V. Ley
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 9) pp:NaN2554-2554
Publication Date(Web):2015/01/07
DOI:10.1039/C5OB00019J
We have devised a room temperature process for the cyclopropanation of electron-poor olefins using unstabilised diazo compounds, generated under continuous flow conditions. This protocol was applied to a wide range of different diazo species to generate functionalised cyclopropanes which are valuable 3D building blocks.
Co-reporter:José A. Souto, Robert A. Stockman and Steven V. Ley
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 13) pp:NaN3877-3877
Publication Date(Web):2015/02/17
DOI:10.1039/C5OB00170F
A method for the continuous preparation of alcohols by hydroboration/oxidation of olefins using flow techniques is described. The process allows the isolation of up to 120 mmol h−1 of the desired alcohol in a very rapid manner with good functional group tolerance. The flow setup can be modified to perform a continuous extraction of the desired alcohol from the biphasic mixture produced by the reaction.
Co-reporter:Mark D. Hopkin, Ian R. Baxendale and Steven V. Ley
Chemical Communications 2010 - vol. 46(Issue 14) pp:NaN2452-2452
Publication Date(Web):2010/03/05
DOI:10.1039/C001550D
A concise, flow-based synthesis of Imatinib, a compound used for the treatment of chronic myeloid leukaemia, is described whereby all steps are conducted in tubular flow coils or cartridges packed with reagents or scavengers to effect clean product formation. An in-line solvent switching procedure was developed enabling the procedure to be performed with limited manual handling of intermediates.
Co-reporter:Duc N. Tran, Claudio Battilocchio, Shing-Bong Lou, Joel M. Hawkins and Steven V. Ley
Chemical Science (2010-Present) 2015 - vol. 6(Issue 2) pp:NaN1125-1125
Publication Date(Web):2014/11/07
DOI:10.1039/C4SC03072A
The work takes advantage of an important feature of flow chemistry, whereby the generation of a transient species (or reactive intermediate) can be followed by a transfer step into another chemical environment, before the intermediate is reacted with a coupling partner. This concept is successfully applied to achieve a room temperature sp2–sp3 cross coupling of boronic acids with diazo compounds, these latter species being generated from hydrazones under flow conditions using MnO2 as the oxidant.
Co-reporter:Lucie Guetzoyan, Nikzad Nikbin, Ian R. Baxendale and Steven V. Ley
Chemical Science (2010-Present) 2013 - vol. 4(Issue 2) pp:NaN769-769
Publication Date(Web):2012/11/23
DOI:10.1039/C2SC21850J
The flow of information between chemical and biological research can present a bottleneck in pharmaceutical research. Tools that bridge these disciplines and aid information exchange have therefore clear value. Over the last few years, both synthetic chemistry and biological screening have benefited from automation, and a seamless chemistry–biology interface is now possible. We report here on the use of flow processes to perform synthesis and biological evaluation in an integrated manner. As proof of concept, a flow synthesis of a series of imidazo[1,2-a]pyridines, including zolpidem and alpidem, was developed and connected to a Frontal Affinity Chromatography screening assay to investigate their interaction with Human Serum Albumin (HSA).
Co-reporter:Julio C. Pastre, Duncan L. Browne and Steven V. Ley
Chemical Society Reviews 2013 - vol. 42(Issue 23) pp:NaN8869-8869
Publication Date(Web):2013/09/02
DOI:10.1039/C3CS60246J
The development and application of continuous flow chemistry methods for synthesis is a rapidly growing area of research. In particular, natural products provide demanding challenges to this developing technology. This review highlights successes in the area with an emphasis on new opportunities and technological advances.
Co-reporter:Mark D. Hopkin, Ian R. Baxendale and Steven V. Ley
Organic & Biomolecular Chemistry 2013 - vol. 11(Issue 11) pp:NaN1839-1839
Publication Date(Web):2012/12/05
DOI:10.1039/C2OB27002A
A flow-based route to imatinib, the API of Gleevec, was developed and the general procedure then used to generate a number of analogues which were screened for biological activity against Abl1. The flow synthesis required minimal manual intervention and was achieved despite the poor solubility of many of the reaction components.
Co-reporter:Stephen P. Andrews, Malcolm M. Tait, Matthew Ball and Steven V. Ley
Organic & Biomolecular Chemistry 2007 - vol. 5(Issue 9) pp:NaN1436-1436
Publication Date(Web):2007/03/23
DOI:10.1039/B702481A
Thapsigargin is a densely oxygenated guaianolide which displays potent sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) binding affinities. The total syntheses of designed unnatural analogues of this important natural product are described. This article constitutes the chemical synthesis behind an ongoing project. Rational modifications have been made to the lactone region of thapsigargin in order to obtain derivatives for future structure–activity relationship studies.
Co-reporter:Amanda C. Evans, Deborah A. Longbottom, Masato Matsuoka, John E. Davies, Richard Turner, Vilius Franckevičius and Steven V. Ley
Organic & Biomolecular Chemistry 2009 - vol. 7(Issue 4) pp:NaN760-760
Publication Date(Web):2009/01/06
DOI:10.1039/B813494D
A new and efficient desymmetrisation of succinic and glutaric cyclic meso-anhydrides is described, providing excellent yields and diastereoselectivities in most cases. Derivatisation of the desymmetrised products is demonstrated by their conversion into mono-protected 1,4-diols. General synthetic utility of the method is established by its application towards a key fragment in the total synthesis of the immunosuppressant antitumour natural product, rapamycin.
Co-reporter:Jan Hartwig, Jan B. Metternich, Nikzad Nikbin, Andreas Kirschning and Steven V. Ley
Organic & Biomolecular Chemistry 2014 - vol. 12(Issue 22) pp:NaN3615-3615
Publication Date(Web):2014/04/17
DOI:10.1039/C4OB00662C
Continuous flow chemistry as a process intensification tool is well known. However, its ability to enable chemists to perform reactions which are not possible in batch is less well studied or understood. Here we present an example, where a new reactivity pattern and extended reaction scope has been achieved by transferring a reaction from batch mode to flow. This new reactivity can be explained by suppressing back mixing and precise control of temperature in a flow reactor set up.
Co-reporter:Heiko Lange, Catherine F. Carter, Mark D. Hopkin, Adrian Burke, Jon G. Goode, Ian R. Baxendale and Steven V. Ley
Chemical Science (2010-Present) 2011 - vol. 2(Issue 4) pp:NaN769-769
Publication Date(Web):2011/01/28
DOI:10.1039/C0SC00603C
In order to use segmented chemical flow processing in more complex reaction sequences, a method has been developed to precisely control the addition of reagent streams during multi-step operations. Using in-line infra-red monitoring with a new LabVIEW software application, it is possible to control additional pumps to dispense further reagents in real time based upon the concentration of reaction intermediates. This enables precise mixing with perfect timing thus greatly increasing product quality and enabling segmented chemical flow processing to be used in extended reaction sequences.
Co-reporter:Philippa B. Cranwell, Matthew O'Brien, Duncan L. Browne, Peter Koos, Anastasios Polyzos, Miguel Peña-López and Steven V. Ley
Organic & Biomolecular Chemistry 2012 - vol. 10(Issue 30) pp:NaN5779-5779
Publication Date(Web):2012/03/21
DOI:10.1039/C2OB25407G
Using a simple and accessible Teflon AF-2400 based tube-in-tube reactor, a series of pyrroles were synthesised in flow using the Paal–Knorr reaction of 1,4-diketones with gaseous ammonia. An inline flow titration technique allowed measurement of the ammonia concentration and its relationship to residence time and temperature.
Co-reporter:Peter Koos, Ulrike Gross, Anastasios Polyzos, Matthew O'Brien, Ian Baxendale and Steven V. Ley
Organic & Biomolecular Chemistry 2011 - vol. 9(Issue 20) pp:NaN6908-6908
Publication Date(Web):2011/07/27
DOI:10.1039/C1OB06017A
We report on the development of a continuous flow process for the palladium catalysed methoxycarbonylation of aryl, heteroaromatic and vinyl iodides and an aryl bromide using a Teflon AF-2400 based Tube-in-Tube reactor to mediate the selective permeation of carbon monoxide into solution at elevated pressures. The low volume of pressurised gas within the reactor (5.6 mL) offers the potential for an enhanced safety profile compared to batch processes. We also present preliminary results for the use of in situFTIR to measure solution concentrations of carbon monoxide and demonstrate the use of a second reactor to effect the removal of carbon monoxide from the flow stream.
Co-reporter:Catherine F. Carter, Ian R. Baxendale, John B. J. Pavey and Steven V. Ley
Organic & Biomolecular Chemistry 2010 - vol. 8(Issue 7) pp:NaN1595-1595
Publication Date(Web):2010/02/10
DOI:10.1039/B924309G
The continuous flow synthesis of butane-2,3-diacetal protected derivatives has been achieved using commercially available flow chemistry microreactors in concert with solid supported reagents and scavengers to provide in-line purification systems. The BDA protected products are all obtained in superior yield to the corresponding batch processes.
Co-reporter:Christopher D. Smith, Ian R. Baxendale, Steve Lanners, John J. Hayward, Stephen C. Smith and Steven V. Ley
Organic & Biomolecular Chemistry 2007 - vol. 5(Issue 10) pp:NaN1561-1561
Publication Date(Web):2007/04/16
DOI:10.1039/B702995K
The cycloaddition of acetylenes with azides to give the corresponding 1,4-disubstituted 1,2,3-triazoles is reported using immobilised reagents and scavengers in pre-packed glass tubes in a modular flow reactor.
Co-reporter:Matthew O'Brien, Nicholas Taylor, Anastasios Polyzos, Ian R. Baxendale and Steven V. Ley
Chemical Science (2010-Present) 2011 - vol. 2(Issue 7) pp:NaN1257-1257
Publication Date(Web):2011/04/01
DOI:10.1039/C1SC00055A
A Tube-in-Tube reactor/injector has been developed, based on a gas-permeable Teflon AF-2400 membrane, which allows both heterogeneous and homogeneous catalytic hydrogenation reactions to be efficiently carried out at elevated pressure in flow, thereby increasing the safety profile of these reactions. Measurements of the gas permeation through the tubing and uptake into solution, using both a burette method and a novel computer-assisted ‘bubble counting’ technique, indicate that permeation/dissolution follows Henry's law and that saturation is achieved extremely rapidly. The same gas-permeable membrane has also been shown to efficiently effect removal of excess unreacted hydrogen, thus enabling further downstream reaction/processing.
Co-reporter:James W. Shearman, Rebecca M. Myers, James D. Brenton and Steven V. Ley
Organic & Biomolecular Chemistry 2011 - vol. 9(Issue 1) pp:NaN65-65
Publication Date(Web):2010/10/15
DOI:10.1039/C0OB00636J
The first total syntheses of (+)- and (−)-subereamollines A and B are reported. The enantiomeric forms of the natural products were obtained by preparative chiral HPLC separation of the corresponding racemates.
Co-reporter:Helmut Kraus, Antoine Français, Matthew O'Brien, James Frost, Alejandro Diéguez-Vázquez, Alessandra Polara, Nikla Baricordi, Richard Horan, Day-Shin Hsu, Takashi Tsunoda and Steven V. Ley
Chemical Science (2010-Present) 2013 - vol. 4(Issue 5) pp:NaN1994-1994
Publication Date(Web):2013/03/07
DOI:10.1039/C3SC50304F
An improved route to the EF fragment of the spongistatins has been developed and employed in a synthesis of spongistatin 2. The C48–C51 diene side chain, which lacks the chlorine substituent present in spongistatin 1, presented some compatibility issues during target assembly. These were overcome by implementing a late stage Stille cross coupling to construct the diene portion of the natural product.
Co-reporter:Jian-Siang Poh, Shing-Hing Lau, Iain G. Dykes, Duc N. Tran, Claudio Battilocchio and Steven V. Ley
Chemical Science (2010-Present) 2016 - vol. 7(Issue 11) pp:NaN6807-6807
Publication Date(Web):2016/07/08
DOI:10.1039/C6SC02581A
Here we report the in situ generation of transient allylic boronic species, by reacting TMSCHN2 and E-vinyl boronic acids, followed by their subsequent trapping with aldehydes as electrophiles to yield homoallylic alcohols. This metal-free reaction was initially discovered by the use of a flow chemistry approach to generate a variety of homoallylic alcohols in a straightforward fashion and then transferred to a batch protocol.
Co-reporter:Leandro de C. Alves, André L. Desiderá, Kleber T. de Oliveira, Sean Newton, Steven V. Ley and Timothy J. Brocksom
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 28) pp:NaN7642-7642
Publication Date(Web):2015/05/08
DOI:10.1039/C5OB00525F
A route to enantiopure (R)-(+)-3-methyl-6-isopropenyl-cyclohept-3-enone-1, an intermediate for terpenoids, has been developed and includes a highly chemo- and regioselective Tiffeneau–Demjanov reaction. Starting from readily available (R)-(−)-carvone, this robust sequence is available on a deca-gram scale and uses flow chemistry for the initial epoxidation reaction. The stereochemistry of the addition of two nucleophiles to the carbonyl group of (R)-(−)-carvone has been determined by X-ray diffraction studies and chemical correlation.
Co-reporter:Steffen Glöckner, Duc N. Tran, Richard J. Ingham, Sabine Fenner, Zoe E. Wilson, Claudio Battilocchio and Steven V. Ley
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 1) pp:NaN214-214
Publication Date(Web):2014/10/28
DOI:10.1039/C4OB02105C
A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from β-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide.
Co-reporter:Christopher D. Smith, Ian R. Baxendale, Geoffrey K. Tranmer, Marcus Baumann, Stephen C. Smith, Russell A. Lewthwaite and Steven V. Ley
Organic & Biomolecular Chemistry 2007 - vol. 5(Issue 10) pp:NaN1568-1568
Publication Date(Web):2007/04/16
DOI:10.1039/B703033A
The use of three orthogonally tagged phosphine reagents to assist chemical work-up via phase-switch scavenging in conjunction with a modular flow reactor is described. These techniques (acidic, basic and Click chemistry) are used to prepare various amides and tri-substituted guanidines from in situ generated iminophosphoranes.
Co-reporter:Catherine J. Smith, Francisco Javier Iglesias-Sigüenza, Ian R. Baxendale and Steven V. Ley
Organic & Biomolecular Chemistry 2007 - vol. 5(Issue 17) pp:NaN2761-2761
Publication Date(Web):2007/07/19
DOI:10.1039/B709043A
A new approach to the synthesis of 5-amino-4-cyanopyrazoles has been developed, utilising a novel flow microwave device. These products are then converted by a batch mode microwave process to structurally more complex dimeric and ‘mixed’ pyrazolopyrimidine structures.
Co-reporter:Catherine F. Carter, Ian R. Baxendale, Matthew O'Brien, John B. J. Pavey and Steven V. Ley
Organic & Biomolecular Chemistry 2009 - vol. 7(Issue 22) pp:NaN4597-4597
Publication Date(Web):2009/09/28
DOI:10.1039/B917289K
The syntheses of butane-2,3-diacetal protected tartrate derivatives are described using continuous flow processing techniques with in-line purification and I.R. analytical protocols.
Co-reporter:Andrew T. Merritt, Rebecca H. Pouwer, David J. Williams, Craig M. Williams and Steven V. Ley
Organic & Biomolecular Chemistry 2011 - vol. 9(Issue 13) pp:NaN4747-4747
Publication Date(Web):2011/05/19
DOI:10.1039/C1OB05422H
A direct synthetic approach to the spiro-γ-lactone clerodane ring system has been investigated. This work builds on that of Jung and highlights the inherent difficulties associated with the otherwise obvious Diels–Alder approach.
Co-reporter:Sirirat Kumarn, Alexander J. Oelke, David M. Shaw, Deborah A. Longbottom and Steven V. Ley
Organic & Biomolecular Chemistry 2007 - vol. 5(Issue 16) pp:NaN2689-2689
Publication Date(Web):2007/07/10
DOI:10.1039/B708646F
A sequential, organocatalysed asymmetric reaction to access chiral 1,2-oxazines and chiral pyridazines is reported, which proceeds in moderate to good yields and good to excellent enantioselectivities.
Co-reporter:Marcus Baumann, Ian R. Baxendale, Steven V. Ley, Nikzad Nikbin and Christopher D. Smith
Organic & Biomolecular Chemistry 2008 - vol. 6(Issue 9) pp:NaN1593-1593
Publication Date(Web):2008/03/12
DOI:10.1039/B801634H
The preparation and use of an azide-containing monolithic reactor is described for use in a flow chemistry device and in particular for conducting Curtius rearrangement reactions via acid chloride inputs.
Co-reporter:Marcus Baumann, Ian R. Baxendale, Steven V. Ley, Nikzad Nikbin, Christopher D. Smith and Jason P. Tierney
Organic & Biomolecular Chemistry 2008 - vol. 6(Issue 9) pp:NaN1586-1586
Publication Date(Web):2008/03/12
DOI:10.1039/B801631N
The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.
Co-reporter:Benjamin J. Deadman, Mark D. Hopkin, Ian R. Baxendale and Steven V. Ley
Organic & Biomolecular Chemistry 2013 - vol. 11(Issue 11) pp:NaN1800-1800
Publication Date(Web):2012/12/05
DOI:10.1039/C2OB27003J
Imatinib (1), nilotinib (2) and dasatinib (3) are Bcr-Abl tyrosine kinase inhibitors approved for the treatment of chronic myelogenous leukemia (CML). This review collates information from the journal and patent literature to provide a comprehensive reference source of the different synthetic methods used to prepare the aforementioned active pharmaceutical ingredients (API's).
![[4-(2-HYDROXY-2-METHYLPROPYL)PHENYL]ACETIC ACID](/data/chemimg/99000/572-59-8.png)
![[4-(2-HYDROXY-2-METHYLPROPYL)PHENYL]ACETIC ACID](/data/chemimg/99000/572-59-8_b.png)