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Contents ____________________________________________________________________
Information for Delegates Programme Speaker Abstracts Catalogue of Posters and Abstracts Sponsors Committee Exhibitors Attendee List
Information for Delegates ____________________________________________________________________
Emergency Procedures If you are infirm or hard of hearing, it is important that you notify reception immediately. If the alarm sounds, you will hear an electronic sounding alarm:
Leave the building by the nearest available exit Proceed to the assembly point in the outside courtyard Do not return to the building until authorised to do so
Security and Interruption Please note that conference badges must be worn at all times (access may be denied if not worn), and that neither the use of mobile ‘phones nor photography is permitted during the conference presentations. Smoking Smoking is not permitted in any rooms or buildings. Smokers must leave the building and smoke outside. Internet Access Wi-fi connection is available free-of-charge throughout the venue. In order to access this, please collect a card from the Reception desk or the Registration desk. Cloakroom Coat racks are located within the conference room. Evaluation Form for Completion Please be sure to complete and return your green evaluation form before you leave. Taxis Minicab Piccadilly Circus 020 7403 3333 West End Car Services 020 7734 8970 Think Smart Transport 020 7127 9127 Drinks Reception The drinks reception will be held at The Leicester Arms, 44 Glasshouse Street, Piccadilly, London W1B 5DP immediately after the event where drinks and nibbles will be served. Please wear your badges at this event, so that the bar staff can accept your drinks tickets. Drinks will be served in the upstairs private room from 6 pm to 7.30 pm, and we must vacate this area by 8 pm latest (you may, of course, move downstairs to the main pub area).
Programme Wednesday, 2nd November ____________________________________________________________________
10:00 Registration, refreshments and exhibition
Session chairman: Guy Lloyd-Jones, University of Edinburgh (UK)
10:25 Introduction and welcome
10:30 Continuous-flow organometallic catalysis using advanced fluids: towards adaptive catalytic systems for asymmetric catalysis
Walter Leitner, Institut für Technische und Makromolekulare Chemie (ITMC), University of Aachen (DE)
11:15 Rapid development of processes using automated flow reactors Richard Bourne, iPRD (Institute of Process Research and Development), University of Leeds (UK)
12:00 Lunch, exhibition and poster display
Session chairman: Paul Murray, Paul Murray Catalysis Consulting
13:15 Aerobic (alcohol) oxidation in flow Paul Alsters, DSM (NL)
14:00 Lewis base catalysis: reaction development and heterocycle synthesis Andrew Smith, University of St Andrews (UK)
14:45 Flow chemistry – blending the old with the new Ian Baxendale, Durham University (UK)
15:30 Refreshments, exhibition, and poster display
Session chairman: Andy Whiting, Durham University
16:00 Poster prize awards
16:05 Catalysis in the pharmaceutical industry : challenges and approaches Yi Hsiao (Xiao), Bristol Myers Squibb (US)
16:50 Single electron processes to enable cross-couplings Gary Molander, University of Pennsylvania (US)
Speaker kindly sponsored by Johnson Matthey
17:35 Closing remarks Andy Whiting, University of Durham (UK)
17:40 Walk to the Leicester Arms
17:50 Drinks reception at the Leicester Arms, Glasshouse Street Drinks reception kindly sponsored by BASF
20:00 Close
Walter Leitner 10.30 am ____________________________________________________________________
Continuous-Flow Organometallic Catalysis using Advanced Fluids: Towards Adaptive Catalytic Systems for Asymmetric Catalysis
Walter Leitner and Giancarlo Franciò
Institut für Technische und Makromolekulare Chemie, RWTH Aachen University Worringerweg 2, 52074 Aachen, Germany
Asymmetric catalysis using chiral transition metal complexes is a well-established technology for the synthesis of enantio-enriched products in academia and industry. The development of new chiral ligands and novel transformations continues to expand the scope of this concept in organic synthesis.[1] At the same time, there are increasing efforts to develop reaction engineering concepts for operating asymmetric catalysis in continuous-flow systems, responding to the efforts of the life science industry to implement the Green Chemistry principles. Advanced fluids such as ionic liquids (ILs) and supercritical carbon dioxide (scCO2) offer an attractive potential in this area, requiring a fundamental understanding of the systems from the molecular, through the materials, and finally to the reactor scale.[2] A key aspect in this research area is the immobilization of the chiral catalyst within a stationary phase that resides in the reactor. In order to keep the synthetic effort for catalyst preparation to a minimum, techniques relying on strong interactions of support matrices with “off-the-shelf” catalysts are most attractive in this context. The so-called “Augustine method” and “supported ionic liquid phase (SILP)” catalysts provide illustrative examples.[3] A hitherto largely neglected opportunity is to exploit these interactions as an additional control factor to enhance the performance and in particular the enantioselectivity of the molecular active species. [4,5] The present talk will discuss the scientific challenges to understand, control, and master the interaction of the organometallic catalysts with the reaction medium and immobilization matrix and provides some examples from our laboratories towards such adaptive catalytic systems. [1] For selected recent efforts from our laboratories, see: a) T. M. Konrad, P. Schmitz, W. Leitner, G.
Franciò, Chem. Eur. J. 2013, 19, 13299-13303; b) T. Hammerer, W. Leitner, G. Franciò, ChemCatChem. 2015, 7, 1583-1592; c) C. Schmitz, W. Leitner, G. Franciò, Chem. Eur. J. 2015, 21, 10696-10702; d) C. Schmitz, K. Holthusen, W. Leitner, G. Franciò, ACS Catal. 2016, 6, 1584-1589.
[2] For a review, see: G. Franciò, U. Hintermair, W. Leitner, Phil. Trans. R. Soc. A 2015, 373, 20150005 (gold open access).
[3] For example: a) Z. Zhang, G. Franciò, W. Leitner, ChemCatChem 2015, 7, 1961-1965; b) Z. Amara, M. Poliakoff, R. Duque, D. Geier, G. Franciò, C.M. Gordon, R.E. Meadows, R. Woodward, W. Leitner, Org. Proc. Dev. 2016, 20, 1321–1327.
[4] a) M. Schmitkamp, D. Chen, W. Leitner, J. Klankermayer, G. Franciò, Chem. Commun. 2007, 4012-4014; b) D. Chen, M. Schmitkamp, G. Franciò, J. Klankermayer, W. Leitner, Angew. Chem. Int. Ed. 2008, 47, 7339-7341; c) D. Chen, B Sundararaju, R. Krause, J. Klankermayer, P. H. Dixneuf, W. Leitner, ChemCatChem. 2010, 2, 55-57.
[5] P. Oczipka, D. Müller, W. Leitner, G. Franciò, Chem. Sci. 2016, 7, 678-683.
Richard Bourne 11.15 am ____________________________________________________________________
Rapid Development of Processes using automated Flow Reactors
Dr. Richard Bourne
Institute of Process Research and Development, University of Leeds Office 1.15 - School of Chemistry, University of Leeds
This talk will focus on the development of automated continuous flow systems. In particular recent research on self-optimising systems where the reactor and its process control instrumentation become an autonomous unit into which the reactants are pumped, and from which products emerge with optimized yield without requiring any intervention from the operator.
This presentation will outline the use of automated reactors with different optimisation methodologies including Design of Experiments, algorithm optimisation and kinetic profiling for the development of pharmaceutical continuous processes.
Example Feedback Optimisation of the final stage in the synthesis of EGFR kinase inhibitor
AZD9291 using an automated flow reactor.1
1. Nicholas Holmes, Geoffrey R. Akien, A. John Blacker, Robert L. Woodward, Rebecca E. Meadows and Richard A. Bourne, Reaction Chemistry and Engineering, 2016,1, 366-371
Optimal Region Located
Paul Alsters 1.15 pm ____________________________________________________________________
Aerobic (Alcohol) Oxidation in Flow
Paul Alsters, Christine Czauderna, Ruben van Summeren, Bert Dielemans, Raf Reintjens
DSM Ahead R&D-Innovative Synthesis P.O. Box 1066, 6160 BB Geleen (The Netherlands)
Catalytic aerobic oxidation is of extreme importance in the conversion of petrochemical feedstocks into higher value chemicals. Until recently, typical selectivities and reaction conditions for catalytic oxidations with molecular oxygen were usually not compatible with the molecular complexities and production facilities as encountered in fine chemicals manufacture. The past decade has generated a large variety of new catalysts for (liquid phase) aerobic oxidations. This catalyst development not only increases the application window of traditional oxidative transformations (e.g. alcohol oxidation), but also opens the door to entirely new transformations. The progress is of great industrial interest, given its power to reduce significantly (raw materials) cost, waste and number of steps. Besides these catalyst developments, also developments in reactor engineering are key to enable economic and safe industrial applications of aerobic oxidation technology. Scalable, safe, and efficient aerobic processing is enabled by continuous flow reactors, in particular zig-zag reactors for single phase conditions. 3D printing has enabled cost-efficient manufacture of such flow reactors with full freedom of design, thereby creating the ideal asset for demanding chemistry with smooth integration in existing hardware. As a result, catalytic aerobic oxidation is finally escaping from its bulk chemical stronghold and makes its way into fine chemicals/pharma manufacture. In this lecture, we present our work and interest in this area, with a focus on aerobic alcohol oxidation. One particular example is the cost-efficient synthesis of Epoxone, which opens the door to broader large-scale application of this versatile asymmetric epoxidation organocatalyst.
Andrew Smith 2.00 pm ____________________________________________________________________
Lewis Base Catalysis: Reaction Development and Heterocycle Synthesis
Prof. Andrew D. Smith
EaStCHEM, School of Chemistry, University of St Andrews, KY16 9ST [email protected]
Lewis base-mediated reactions encompass a plethora of molecular transformations. Within this area, we have developed a range of catalytic (asymmetric) processes mediated by a range of Lewis bases.1 This presentation will describe recent developments in the use of isothioureas to promote a number of selective transformations that involve the generation of either an acyl ammonium,2 ammonium enolate,3 ,-unsaturated acyl ammonium4 or ylide intermediate5 (Figure 1). The application of these methodologies to the (enantioselective) synthesis of a variety of heterocyclic products and mechanistic insights into these processes will be discussed.
N
Ar
R1
R2
O
N
N
SPh
N
SNPh
N
SNPh
Isothioureas = LB (Lewis base)
N
N
SPh
OR
N
SNPh
N
N
SPh
O
R
R
O
N
SNPh
,-unsaturated acyl ammonium
acyl ammonium ammonium enolate
ammonium ylide Figure 1: Isothioureas and intermediates in (asymmetric) Lewis base catalysis
References
1. For further information see http://chemistry.st-andrews.ac.uk/staff/ads/group/index.html 2. C. Joannesse, C. P. Johnston, C. Concellón, C. Simal, D. Philp and A. D. Smith, Angew. Chem. Int. Ed. 2009, 48, 8914-8918; P. A. Woods, L. C. Morrill, R. A. Bragg, A. M. Z. Slawin, A. D. Smith, Org. Lett. 2010, 12, 2660-2663. 3. D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin and A. D. Smith, J. Am. Chem. Soc., 2011, 133, 2714-2720; C. Simal, T. Lebl, A. M. Z. Slawin and A. D. Smith, Angew. Chem. Int Ed., 2012, 51, 3653-3657; L. C. Morrill, T. Lebl, A. M. Z. Slawin and A. D. Smith, Chem. Sci. 2012, 2, 2088-2093. D. Stark, L. C. Morrill, P-P. Yeh, A. M. Z. Slawin, T. J. C. O’Riordan and A. D. Smith, Angew. Chem. Int. Ed. 2013, 52, 11642-11646 4. E. R. T. Robinson, C. Fallan, C. Simal, A. M. Z. Slawin, A. D. Smith, Chem. Sci. 2013, 4, 2193–2200. 5. T. H. West, D. S. B. Daniels, A. M. Z. Slawin and A. D. Smith, J. Am. Chem. Soc. 2014, 136, 4476-4479.
Ian Baxendale 2.45 pm ____________________________________________________________________
Flow Chemistry – blending the old with the new
Ian R. Baxendale
University of Durham Department of Chemistry, South Road, Durham, DH1 3LE
Synthetic chemistry is the complex art, science and craft. As a discipline it has undergone many significant changes over the past few centuries as our understanding of the fundamentals of bond forming and breaking including how to exert control over these processes has been refined. Throughout this time the basic approach and apparatus available to the synthetic chemist has remained relatively constant. The presence of test tubes, round bottom flasks and beakers are historically synonymous with chemistry. This remains true today in that our approach to synthesis is a batch based practice following well defined iterative sequence of discrete reaction steps, work-ups and purifications. An alternative approach being evaluated is flow chemical processing which makes use of small dimensional reactors and packed bed columns as dynamic vessels for performing chemical transformations. This more holistic approach also attempts to integrate other aspects of the synthesis such as work-up and purification into the overall processing sequence aiming to deliver a clean product stream as one single integrated operation. Consequently the ability to further telescope and assimilate these individual transformations into more elaborate sequences enables the generation of advanced multi-step product outputs. This presentation will detail some of the achievements from our laboratory in the area of flow chemistry with emphasis being placed on the application of these techniques to synthetic organic chemistry. By way of exemplification a selection of small molecule building blocks and pharmaceutical libraries will be illustrated.
Yi Hsiao 4.05 pm ____________________________________________________________________
Catalysis in the Pharmaceutical Industry: Challenges and Approaches
Yi Hsiao
Bristol-Myers Squibb One Squibb Drive, New Brunswick, NJ 08903, US
Catalytic reactions are considered as effective, highly selective and environmentally benign approaches to complex drug candidates. However, the diversity and large number reaction parameters make it very challenging to identify suitable catalysts and develop robust processes. In fact, many reported catalytic conditions have to be considered as only local optimized for this reason. At the same time, many catalytic transformations previously deemed impossible have been found to be perfectly feasible under different conditions. In the BMS Catalysis Research group, we utilize HTP screening technology for quick hit identification; DoE and kinetic DoE for effective evaluation of reaction variables to prevent premature conclusions and local optimization; and kinetic and mechanistic studies for understanding and process development. This presentation describes the benefits and limitations of these unique approaches through the lens of several catalytic transformations utilized in recent BMS projects:
1. Asymmetric hydrogenation: the power of HTP screening 2. a-arylation: Complex reaction parameters and local optimization 3. borylation: the mechanism of catalyst activation and its impact on process robustness .
Gary Molander 4.50 pm ____________________________________________________________________
Single Electron Processes to Enable Cross-Couplings
Gary A. Molander
Department of Chemistry, University of Pennsylvania 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
In the archetypal palladium-catalyzed cross-coupling reactions, a three step catalytic cycle mechanistically based on 2-electron processes is employed: oxidative addition of a halide at Pd0, transmetalation of a nucleophile with an organopalladium(II) species, and reductive elimination, which releases the coupled product and regenerates the Pd0 catalyst. Although such methods are highly effective for Csp2-Csp2 coupling, extension to many secondary and tertiary Csp3-hybridized organometallics has proven challenging owing primarily to lower rates of transmetalation, which is rate limiting in alkylboron Suzuki protocols operating under the traditional mechanistic manifold. To date, strategies aimed at facilitating the transmetalation of Csp3 Suzuki reactions employ excess aqueous base, high temperature, or addition of stoichiometric Cu or Ag salts, thereby eliminating virtually all of the advantages of using organoboron reagents in cross-coupling. Often, the only viable alternative is to abandon the Suzuki approach and utilize more reactive organometallic coupling partners. The latter reagents lack bench stability and severely limit functional group tolerability. The limitations of the transmetalation in the more desirable Suzuki couplings are inherent to the mechanism of this process at the most fundamental level, and thus predispose Csp3-hybridized alkylboron reagents for failure. Described is a novel single electron mechanistic paradigm for cross-coupling that avoids this problem. Thus, dual catalytic cycles are established: a photoredox catalytic cycle, generating radicals from various species, and a cross-coupling catalytic cycle that funnels these radicals into a base-metal catalytic cycle that affects the cross-coupling.
R1 R2
R1
NiILL
NiIIILL
XAr NiI
LL
X
Ar-X (8)
Ar R2
R1
119
7Ni0
LL
6
3
10
SET
4
4
[PC]- (5)
[PC] (1)
*[PC] (2)
h
G
R2
R2
R1 R2
R1
R1
R2
NiIILL
R1 R2
XAr
12
4
Cross-CouplingCycle
PhotoredoxCycle
SET
Catalogue of Posters ___________________________________________________________________________________________________________
No. Title Authors Affliliation E-mail
P01 Mechanistic investigation of asymmetric hydrogenation
Yehia Amar, Alexei Lapkin
Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, CB2 3RA, Cambridge, UK
ya269@ cam.ac.uk
P02 Enhancement of cerium(IV) generation for mediated electrosynthesis of vitamin K derivatives in electrochemical flow reactors
Luis F. Arenas*, Carlos Ponce de León, Frank C. Walsh
Electrochemical Engineering Laboratory, Faculty of Engineering and the Environment, University of Southampton SO17 1BJ, UK
lfam1g13@ soton.ac.uk
P03
Phosphino decorated PEGylated polymer immobilised ionic liquid stabilised palladium and ruthenium nanoparticles: efficient catalysts for aqueous phase coupling and hydrogenation
T. Backhouse, S. Doherty, J. G. Knight
NUCAT, School of Chemistry, Bedson Building, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK
t.backhouse@ newcastle.ac.uk
P04 Cascading cycloadditions: rapid access into sp3-rich heterocycles
Matthew P. Ball and Paul W. Davies
University of Birmingham, School of Chemistry, The University of Birmingham, Birmingham, B15 2TT
mpb342@ bham.ac.uk
P05 Generating allyl metal species in situ through 1,4 metal migrations – a novel approach to nucleophilic allylation reactions
Michael Callingham, Benjamin M. Partridge, Hon Wai Lam
University of Nottingham, School of Chemistry, University Park, Nottingham, NG7 2RD, UK
michael.callingham@ nottingham.ac.uk
P06
Enantioselective nickel-catalysed anti-carbometallative cyclisations of alkynyl electrophiles enabled by reversible alkenylnickel E/Z isomerisation
Christopher Clarke, Dr Celia A. Incerti-Pradillos, Prof Hon Wai Lam
The University of Nottingham, School of Chemistry, University Park, Nottingham NG7 1RD, UK
pcxcc5@ Nottingham.ac.uk
P07 A regiodivergent catalytic Friedel-Crafts route into novel 3,3-diaryloxetane and dihydrobenzofuran motifs
Rosemary A. Crofta; Dr. James J. Mousseaub; Chulho Choib; Dr. James A. Bulla*
aImperial College London bPfizer Global Research and Development; aDept. of Chemistry, Imperial College London, South Kensington, London, SW7 2AZ, UK; bPfizer Global Research and Development, 445 Eastern Point Road, Groton, CT 06340, USA
r.croft14@ imperial.ac.uk
P08
Visible-light-mediated generation of nitrogen-centered radicals: metal-free hydroimination and iminohydroxylation cyclization reactions
Jacob Davies, Daniele Leonori* The University of Manchester, Oxford Rd, Manchester, M13 9PL, UK
jacob.davies@ postgrad.manchester.ac.uk
Catalogue of Posters ___________________________________________________________________________________________________________
No. Title Authors Affliliation E-mail
P09 Organocatalytic 1,4-addition reactions of α-CF3 enolates and the enantioselective synthesis of heterocyclic scaffolds
Robert W. Foster,† Darren S. Stead,† Nigel S. Simpkins‡
AstraZeneca: †Darwin Building, Cambridge Science Park, Cambridge, United Kingdom, CB4 0XR; ‡ School of Chemistry, University of Birmingham, Birmingham, United Kingdom, B15 2TT, UK
robert.foster1@ astrazeneca.com
P10 The transmetalation of boronic acids and their derivatives in the Suzuki-Miyaura cross-coupling reaction
Katherine Geogheghan1, Dr David Blakemore2 and Prof. Guy C. Lloyd-Jones1
1University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh, EH16 5TH; 2Pfizer, USA
k.j.geogheghan@ sms.ed.ac.uk
P11 Synthesis of lacosamide (Vimpat®) and its derivatives from commercial aziridine-(2R)-carboxylate
Hyun-Joon Ha, Hyeonsu Jeong and Nagendra Nath Yadav
Department of Chemistry, Hankuk University of Foreign Studies, Yongin, Kyunggi-Do, 17035, Korea
hjha@ hufs.ac.kr
P12 Design of smart, functional chemical reactors through ultrasonic 3D-printing
Matthew Harding, Tom Monaghan, Russell Harris, Ross Friel, Steve Christie*
Loughborough University, Department of Chemistry, Loughborough, Leicestershire, LE11 3TU, UK
m.j.harding@ lboro.ac.uk
P13 Designing particle-based quasi-homogenous catalytic systems
Thomas A. Howell a*, Olivier J. Cayre a, John Blacker b
a Institute of Particle Science and Engineering, School of Chemical and Process Engineering, University of Leeds, Leeds, LS2 9JT, UK; b Institute of Process Research and Development, School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK
chm0tah@ leeds.ac.uk
P14 Dihydrogen driven cofactor recycling for use in biocatalysed asymmetric organic synthesis
Thomas H. Lonsdale, Holly A. Reeve, Kylie A. Vincent
Department of Chemistry, University of Oxford, Inorganic Chemistry Laboratory, South Parks Rd, Oxford, UK
Thomas.lonsdale@ chem.ox.ac.uk
P15 Iterative Heck-Mizoroki/iododeboronation sequences in the synthesis of polyene natural products
Kate Madden and Andy Whiting Centre for Sustainable Chemical Processes, Chemistry Department, Durham University, UK
k.s.madden@ durham.ac.uk
P16 Expanding the substrate scope for the β-Borylation reaction: Homoallylic boronate ester derivatives
Alba Pujol Santiago,*a Elena Fernándezb and Andy Whitinga
aCentre for Sustainable Chemical Processes, Dept. of Chemistry, Durham University, South Road, Durham DH1 3LE, UK; bDept. Química Física i Inorgànica, Universitat Rovira i Virgili, 43007 Tarragona, Spain
alba.pujol-santiago@ durham.ac.uk
P17 Mechanisms of catch and release catalysis Matthew Robinson1, Andrew Campbell2 and Guy C. Lloyd-Jones1*
1University of Edinburgh; 2AstraZeneca, UK Matthew.Robinson@ ed.ac.uk
Catalogue of Posters ___________________________________________________________________________________________________________
No. Title Authors Affliliation E-mail
P18 Development of novel catalytic methods for amidation
Marco Sabatini, Lee Boulton, Tom D. Sheppard
University College London Dept. of Chemistry, 20 Gordon Street, London, WC1H 0AJ, UK
marco.sabatini.14@ ucl.ac.uk
P19 Using experimental design to optimise an iron-catalysed cross coupling reaction
James N. Sanderson†‡, Andrew P. Dominey† & Jonathan M. Percy‡
†GlaxoSmithKline / ‡University of Strathclyde; †Gunnels Wood Road, Stevenage, SG1 2NY; ‡Pure & Applied Chemistry, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, UK
james.sanderson@ strath.ac.uk
P20 Copper-catalyzed azide-alkyne cycloaddition in attaching cyanine dyes to amino acid side chain
Tamara Šmidlehner, Atanas Kurutos, Jakov Slade, Ivo Piantanida
Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
tsmidleh@ irb.hr
P21
Opportunities for catalyst studies for pharmaceutical research using soft and tender X-ray spectroscopies at Diamond Light Source
Anna Kroner, Sin-Yuen Chang, Elizabeth Shotton
Diamond Light Source Ltd, Harwell Science and Innovation Campus, Chilton, Didcot, OX11 0DE, UK
anna.kroner@ diamond.ac.uk
P01 ____________________________________________________________________
Mechanistic Investigation of Asymmetric Hydrogenation
Yehia Amar, Alexei Lapkin
Department of Chemical Engineering and Biotechnology, University of Cambridge New Museums Site, Pembroke Street, CB2 3RA, Cambridge, UK
[email protected] Delineating mechanistic insights and predicting system properties are core functions of chemical reaction studies. In this study we create an experimentally-supported theoretical model of a rhodium-catalysed homogeneous asymmetric hydrogenation, for the case of a pharmaceutically significant substrate and a series of chiral phosphine ligands. Using DFT, we predict diastereomeric excess in this reaction for various conditions, and describe the origin of enantioselection. We attempt to predict the configuration of the major product, identify transition state complexes, and identify underlying mechanistic phenomena. In addition, this framework brings about valuable knowledge about the key effects that promote high selectivity. Initial results show that single-point energy computations for intermediates across both reaction pathways can be related to diastereoselectivity, predicting the correct configuration of the product and quantitatively approximating the selectivity obtained. Among the new predictive tools that can be used to accelerate pharmaceutical process development, this method offers a path of gaining fundamental and quantitative mechanistic knowledge of complex chemical reactions. Keywords: asymmetric hydrogenation, DFT model, computational chemistry, mechanistic study
P02 ____________________________________________________________________
Enhancement of cerium(IV) generation for mediated electrosynthesis of vitamin K derivatives in electrochemical flow reactors
Luis F. Arenas*, Carlos Ponce de León, Frank C. Walsh
Electrochemical Engineering Laboratory, Faculty of Engineering and the Environment University of Southampton SO17 1BJ, UK
The generation of Ce(IV) ions in methanesulfonic acid media has found several industrial applications, including the decontamination of nuclear facilities and the synthesis of tetrahydroantraquinone for paper production [1]. In contrast to other strong oxidising agents, e.g. chromic acid, Ce(IV) ions are far less toxic and recyclable in electrochemical reactors. Another application is the mediated electrosynthesis of vitamin K (Menadione) for animal nutrition, previously performed by the Lonza Group Ltd [1,2]. In this process, the anodic oxidation of Ce(III) ions to Ce(IV) ions is followed by the chemical oxidation of a 2-methylnaphthalene (-3-) derivative:
CH3CH3
O
O2-methylnaphthalene (-3-) derivative
2-methyl-1,4-naphthalenedione (-3-) derivative
Ce(IV) Ce(III)R R
Pt anode / MSA
As in all processes involving the oxidation of Ce(III) ions, the space-time yield is highly dependent on the mass transport coefficient and the active surface area of the platinised titanium electrodes. The high current density and low mass transport at planar electrodes promote oxygen evolution, resulting in prohibitive current efficiency loses. Platinised titanium meshes have permitted a fairly efficient operation and have been implemented for more than 30 years. In view of recent advances in the manufacture of porous titanium substrates, we have proposed the use of platinised micromesh and felt for the enhanced generation of Ce(IV) oxidant. Such electrode structures allow increasing the limiting current up to 63 and 160 times in comparison a planar electrode. Furthermore, we have determined the volumetric mass transport coefficient, kmAe, a quantitative figure of merit that can be used to estimate the required electrode dimensions for an acceptable electrode potential loss and to predict the fractional conversion rate of the electroactive species in electrochemical flow reactors [3]. The values of the new electrode materials are orders of magnitude higher than those of a planar electrode and significantly higher than the commercial mesh currently used. We believe that the new, highly porous electrodes can enable efficient Ce(IV) generation for a number of specialised mediated oxidation reactions.
1. L.F. Arenas, C. Ponce de León, F. C. Walsh. Electrochemical redox processes involving soluble cerium species. Electrochimica Acta 205 (2016) 226–247.
2. D. Walker. The management of chemical process development in the pharmaceutical industry, John Wiley & Sons, 2008.
3. L.F. Arenas, C. Ponce de León, F. C. Walsh. Mass transport and active area of porous Pt/Ti electrodes for the Zn-Ce redox flow battery determined from limiting current measurements. Submitted to Electrochimica Acta
P03 ____________________________________________________________________
Phosphino decorated PEGylated polymer immobilised ionic liquid stabilised palladium and ruthenium nanoparticles: Efficient catalysts for Aqueous phase
coupling and hydrogenation
T. Backhouse, S. Doherty, J. G. Knight
NUCAT, School of Chemistry Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU
Toward the conversion of biomass derived substrates for use as platform chemicals and transportation fuels The Doherty group has recently been exploring the concept of Polymer Immobilised Ionic Liquid Phase (PIILP) catalysis, in which the ionic liquid is immobilised in the form of a cation decorated polymer.1-3 The innovation of this approach lies in the modular construction of the support as it allows heteroatom donor modified monomers, ionic liquid-like styrene-based monomers and functional cross-linkers to be combined in the same polymer; moreover, it is also possible to systematically modify each of these components to tailor the properties of the support. We have used this concept to explore whether it is possible to control the efficiency of nanoparticle based catalysts by modifying the ionic microenvironment and macromolecular architecture. Initial studies showed that diphenylphosphino-modified imidazolium-based ionic liquid stabilised Pd nanoparticles (PdNP@PPh2PIILP) are highly active catalysts for the Suzuki-Miyaura cross-coupling reaction between aryl bromides and boronic acids in a 1:1 mixture of ethanol/water and for the chemoselective hydrogenation of the C=C double bond in cinnamaldehyde. We are currently developing PEG-based ionic liquid monomers in order to explore the effect on catalyst performance of introducing additional hydrophilicity into PdNP@PPh2PIILP. To this end we have prepared a PEGylated-ionic liquid-like imidazolium monomer and the corresponding PPh2-decorated PEGylated polymer immobilised ionic liquid and are currently exploring the applications and efficacy of PdNP@PPh2PEGPIILP and RuNP@PPh2PEGPIILP as catalysts for the hydrogenation of α, β-unsaturated aldehydes, ketones and related biomass derived substrates with the aim of developing an efficient system for aqueous phase catalytic transformations; in this regards, the hydrogenation and hydrogenolysis of biomass derived compounds to platform chemicals and fuels is a key target of this project. The PdNP@PIILP systems have been characterised by a range of techniques including solid state NMR spectroscopy, SEM, TEM, XRD, XPS and BET analysis. 1 S. Doherty, J. G. Knight, M. A. Carroll, J. R. Ellison, S. J. Hobson, S. Stevens, C. Hardacre and P. Goodrich, Green Chem., 2015, 17, 1559-1571. 2 S. Doherty, J. G. Knight, J. R. Ellison, P. Goodrich, L. Hall, C. Hardacre, M. J. Muldoon, S. Park, A. Ribeiro, C. A. N. de Castro, M. J. Lourenço and P. Davey, Green Chem., 2014, 16, 1470-1479. 3 S. Doherty, J. G. Knight, J. R. Ellison, D. Weekes, R. W. Harrington, C. Hardacre and H. Manyar, Green Chemistry, 2012, 14, 925.
P04 ____________________________________________________________________
Cascading Cycloadditions: Rapid Access into sp3-Rich Heterocycles
Matthew P. Ball and Paul W. Davies
University of Birmingham School of Chemistry, The University of Birmingham, Birmingham, B15 2TT
[email protected], [email protected]
Introduction Complex fused-ring sp3-rich systems are widely found in biologically relevant compounds. Of great utility in target synthesis and hit discovery is the synthesis of complex 3-D scaffolds from readily accessible starting materials in reactions which proceed with high efficiency, in a convergent fashion. A novel method of rapidly building molecular complexity using cascading cycloadditions has been studied and developed, providing a wealth of sp3-rich heterocycles.
Discussion A cascading cycloaddition process has been explored that brings together a new gold-catalysed dipolar cycloaddition1, 2 with a classical cycloaddition to access polycyclic fused heterocycles in a single manipulation. We have studied the reactivity of both novel ylides and enynamides providing different isomeric counterparts with excellent variation of functionality. This highly regio- and diastereoselective mode of reactivity permits the formation of oxygen-bridged bicycles such as octahydropyrrolopyridines and decahydronaphthyridines. Both the suppression and the elaboration of competing pathways3 has also been studied, allowing the formation of the desired products in good to excellent yields. Subsequent bridge-opening processes have been developed providing access into different functionalised fused aliphatic heterocycles. In this manner, useful synthetic building blocks and natural product-like core structures may be assembled in just two steps from readily accessible starting materials. This poster discusses our investigations into combining orthogonal formal and classical cycloadditions for the formation of previously inaccessible bridged heterocyclic fused ring systems. This novel transformation converts simple starting materials to complex products, allowing families of sp3-rich heterocycles to be synthesized simply and efficiently, and in a modular fashion. References 1. P. W. Davies, A. Cremonesi and L. Dumitrescu, Angew. Chem. Int. Ed., 2011, 50, 8931. 2. A. D. Gillie, R. Jannapu Reddy and P. W. Davies, Adv. Synth. Catal., 2016, 358, 226 3. C. Nieto-Oberhuber, P. M. Muñoz, E. Buñuel, C. Nevado, D. J. Cárdenas, and A. M. Echavarren, Angew. Chem. Int. Ed., 2004, 43, 2402.
P05 ____________________________________________________________________
Generating Allyl Metal Species in situ through 1,4 Metal Migrations – A Novel Approach to Nucleophilic Allylation Reactions
Michael Callingham, Benjamin M. Partridge, Hon Wai Lam
University of Nottingham School of Chemistry, University Park, Nottingham, NG7 2RD
The nucleophilic allylation of carbonyls and imines is a key reaction in organic synthesis, with the products, homoallylic alcohols and amines, being high value building blocks widely used in medicinal chemistry. These processes typically rely upon the use of prefunctionalized allylmetal(loid) reagents (e.g. allyltin, allylboron, or allylsilicon compounds) and could therefore, by avoiding the necessity to prepare such reagents, benefit from the principles of C–H functionalization and result in a streamlined synthetic sequence. The catalytic in situ formation of nucleophilic allylrhodium species through the activation of allylic C-H bonds is presented. Reactivity is achieved through initial carborhodation of an enyne, followed by a 1,4-rhodium(I) migration which generates the key allylrhodium intermediate. The use of a chiral rhodium catalyst allows the allylation of a range of cyclic imines to give homoallylic amines with excellent control of stereoselectivity (>95:5 dr, up to 99% ee).
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Enantioselective nickel-catalysed anti-carbometallative cyclisations of alkynyl electrophiles enabled by reversible alkenylnickel E/Z isomerisation
Christopher Clarke, Dr Celia A. Incerti-Pradillos, Prof Hon Wai Lam
The University of Nottingham School of Chemistry, University Park, Nottingham NG7 1RD
Lig (10 mol %)cat. Ni (10 mol %)
Ar2B(OH)2 (2.0 equiv)
Me
OH
OMeO
OAr1
34-89%, 42-97% ee
Ar1
Ar2
O
R O
Ar1
O
OR
HAr1
Ar2
20-90%, 69-97% ee
or or
Nickel-catalysed addition of arylboronic acids to alkynes, followed by enantioselective cyclisation of the alkenylnickel species onto tethered ketones or enones is demonstrated. Notably, the success of these reactions is critically reliant upon the formal anti-carbonickelation of the alkyne, which is postulated to occur via the reversible E/Z isomerisation of alkenylnickel species. This novel mode of chemical reactivity has the potential to greatly expand this already very powerful field of domino reactions that previously were limited by the syn-selective nature of migratory insertions of alkynes into carbon metal bonds. (The manuscript of this work will be shortly submitted.)
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A Regiodivergent Catalytic Friedel-Crafts Route into Novel 3,3-Diaryloxetane and Dihydrobenzofuran Motifs
Rosemary A. Crofta; Dr. James J. Mousseaub; Chulho Choib; Dr. James A. Bulla* aImperial College London bPfizer Global Research and Development
aDept. of Chemistry, Imperial College London, South Kensington, London, SW7 2AZ, UK b Pfizer Global Research and Development, 445 Eastern Point Road, Groton, CT 06340, USA
[email protected], [email protected]
Benzophenone and diarylmethane cores are prevalent in biologically active species.1 However in drug discovery these motifs can present a metabolic liability due to the activated methylene or carbonyl groups. Oxetanes have been shown to be valuable motifs for modulating the metabolic susceptibility and physical properties of medicinally promising compounds, as well as replacement motifs for carbonyl and gem-dimethyl units.2 3,3-Diaryl oxetane analogs present an opportunity to block the metabolically vulnerable sites of diaryl species whilst maintaining or improving the physicochemical profile. However, there are currently no examples of 3,3-diaryl oxetanes in the literature and no methods for their preparation. This poster presents the first preparation of 3,3-diaryl oxetanes through a regiodivergent, catalytic Friedel-Crafts reaction. 3,3-Diaryl oxetanes and dihydrobenzofuran scaffolds can both be selectively prepared in one step from oxetan-3-ols with phenols. Where para-addition of the nucleophile is the primary route, 3,3-diaryl oxetanes result. Conversely, where ortho-addition is favoured, dihydrobenzofurans are formed by in situ opening of the oxetane ring by the proximal hydroxyl group. Use of electron rich phenols and variation of the preinstalled aryl group has allowed access to a number of attractive structures containing considerable complexity. The inherent reactivity of the phenol of the products provides an expedient handle for further derivatization further increasing the utility and applicability of this work.
1) For selected examples see (a) Wu, S.–B., Long, C.; Kennelly, E. J. Nat. Prod. Rep. 2014, 31, 1158–1174 (b) Chiellini, G.; Nguyen, N.–H.; Yoshihara, H. A. I.; Scanlan, T. S. Bioorg. Med. Chem. Lett. 2000, 2607–2611. (c) Jain, S. K.; Pathania, A. S.; Meena, S.; Sharma, R.; Sharma, A.; Singh, B.; Gupta, B. D.; Bhushan, S.; Bharate, S. B.; Vishwakarma, R. A.; J. Nat. Prod., 2013, 76, 1724–1730. 2) Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Carreira, E. M. Angew. Chem. Int. Ed. 2010, 49, 9052–9067.
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Visible-Light-Mediated Generation of Nitrogen-Centered Radicals: Metal-Free Hydroimination and Iminohydroxylation Cyclization Reactions
Jacob Davies, Daniele Leonori*
The University of Manchester Oxford Rd, Manchester, M13 9PL
Nitrogen-centered radicals are a powerful class of reactive intermediates that have wide application in the synthesis of N-containing molecules. However, difficulties associated with their generation have severly limited their synthetic potential. Established methods commonly rely on the homolytic cleavage of difficult to construct N-X bonds with toxic and hazardous reagents at elevated temperatures.[1] A photoredox catalysed generation of iminyl-radicals and subsequent application in novel and divergent hydroimination and iminohydroxylation cyclization reactions has been accomplished through the design of a new class of reactive O-aryl oximes (Scheme 1).[2] The low reduction potential of these bench-stable precursors allows the use of inexpensive organic dye eosin Y in replacement of iridium or ruthenium based photocatalysts. In addition, a complementary activation mode utilzing novel electron donor-acceptor complexes of the O-aryl oximes and triethylamine was realised. The ability of the aryl unit to sequentially act as a sensitizer, electron acceptor, and oxidant enabled the development of a unique Et3N and visible-light-mediated iminohydroxylation cyclization.
Scheme 1
A broad range of substrates with diverse electronic and steric properties participated well in these cyclisation reactions. Bicyclic heterocylces could be synthesised as well as products arising from di- and trisubstituted olefins generating up to three contiguous stereogenic centres. Studies currently focus on applying this method to other nitrogen-centered radicals and on developing asymmetric variants of the hydroimination and iminohydroxylation cyclizations. References: 1. S. Z. Zard Chem. Soc. Rev. 2008, 37, 1603–1618. 2. J. Davies, S. G. Booth, S. Essafi, R. A. W. Dryfe, D. Leonori Angew. Chem. Int. Ed. 2015, 54,
14017–14021
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Organocatalytic 1,4-Addition Reactions of α-CF3 Enolates and the Enantioselective Synthesis of Heterocyclic Scaffolds
Robert W. Foster,† Darren S. Stead,† Nigel S. Simpkins‡
AstraZeneca †Darwin Building, Cambridge Science Park, Cambridge, United Kingdom, CB4 0XR
‡ School of Chemistry, University of Birmingham, Birmingham, United Kingdom, B15 2TT [email protected]
The selective incorporation of fluorine into heterocyclic compounds is a valuable tool in the development of new medicines. As such, the substitution of α-CF3 enolates presents an attractive route to new fluorinated compounds. However, this approach is limited by poor enolate stability due to the ready elimination of fluoride.1 Consequently there are few reported methods for the use of α-CF3 enolates as synthetic intermediate2 and existing methods typically depend on the use of stoichiometric reagents3 and/or auxiliaries.4
base, e.g.decomposition
- LiF
unstable enolate
We have developed the first asymmetric organocatalytic method for the generation and reaction of α-CF3 enolates. The 1,4-addition of enones and racemic α-CF3 triketopiperazines (±)-1 was explored using amine catalysts, and thiourea 2 was found to give optimal yield and enantiomeric control. Crucially, no evidence for defluorination of the enolate has been observed. In addition to investigating the scope of this reaction, we have demonstrated how simple modification of the 1,4-addition product 5 can access new heterocyclic scaffolds, including bicyclicpyrazole 6 and tricyclic pyrazolopyrimidine 7.
2
2
NR3*
4
2, NR3*
NR3*
stable toHF-elimination()-1
3 5
organocatalytic (3-10 mol% 2) enantioselective (up to 97:3 er) 11 examplesup to 2.5 gram scaleaccess to complex heterocycles
ion-dipoleinteraction?
7, 81% yield
K2CO3NH2NH2
6, 100% yield
1 Y. Itoh, M. Yamanaka, K. Mikami, J. Am. Chem. Soc. 2004, 126, 13174–13175. 2 Y. Guo, X. Zhao, D. Zhang, S. –I. Murahashi, Angew. Chem. Int. Ed. 2009, 48, 2047–2049. 3 T. Shimada, M. Yoshioka, T. Konno, T. Ishihara, Org. Lett. 2006, 8, 1129–1131. 4 L. Brewitz, F. A. Arteaga, L. Yin, K. Alagiri, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2015, 137, 15929–15939.
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The Transmetalation of Boronic Acids and their Derivatives in the Suzuki-Miyaura Cross-Coupling Reaction
Katherine Geogheghan1, Dr David Blakemore2 and Prof. Guy C. Lloyd-Jones1
1 University of Edinburgh, 2 Pfizer, USA University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh, EH16 5TH
The Nobel Prize-winning Suzuki-Miyaura (SM) reaction forms a new carbon-carbon single bond via the palladium catalysed union of organoboron and organohalide compounds. It is mostly used for sp2-sp2 couplings, which is the focus of study in this work. This process proceeds through a three stage mechanism of oxidative addition, transmetalation and reductive elimination. The transmetalation of boronic acids to palladium has been widely studied and occurs through one of two possible pathways: the boronate pathway or the oxo-palladium pathway.1 However, very little is known about the transmetalation of boronic esters. Whether these species undergo direct transmetalation or prior hydrolysis to the boronic acid under SM conditions remains unknown. Initial results under fairly typical SM conditions2 show that the rate of coupling is independent of the ligation on boron, such that boronic esters 1b/1c and boronic acid 1a couple at the same absolute rate. This is thought to be a consequence of phase splitting promoted by the inorganic base and solvent composition, rendering phase transfer the turnover-limiting step. The fact that reaction rate is proportional to stirring rate supports this hypothesis. The conditions were thus adapted to maintain a monophasic system, enabling us to focus on transmetalation as the turnover-limiting step. These new conditions show there to be a significant difference in both rate and induction period when using a boronic ester 1b/1c compared to the corresponding boronic acid 1a. Further studies show that the rate of coupling of the boronic ester is independent of the rate of hydrolysis. Ester 1b hydrolyses slowly (equilibrium reached ≤ 24 h), whereas ester 1c hydrolyses quickly (equilibrium reached ≤ 5 min), but both esters give the same absolute rate of SM coupling.
Scheme 1. Development of monophasic conditions for the study transmetalation in SM reaction. References 1. Lennox, A.J.J.; Lloyd-Jones, G.C. Angew. Chem. Int. Ed. 2013, 52, 7362 – 7370 2. Butters, M.; Harvey, J.N.; Jover, J.; Lennox, A.J.J.; Lloyd-Jones, G.C.; Murray, P.M. Angew. Chem. Int. Ed. 2010, 49,
5156 – 5160
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Synthesis of Lacosamide (Vimpat®) and Its Derivatives from Commercial Aziridine-(2R)-carboxylate
Hyun-Joon Ha, Hyeonsu Jeong and Nagendra Nath Yadav
Department of Chemistry, Hankuk University of Foreign Studies Yongin, Kyunggi-Do, 17035, Korea.
An efficient and scalable synthesis of antiepileptic drug, (R)-lacosamide and its derivative was successfully achieved from commercially avaiable aziridine-(2R)-carboxylate in three simple sequential steps including regioselective aziridine ring opening, debenzylation followed by acetylation and amide formation.
Ph N
HOEt
O
HNNH
O
MeO
O2a
(R)-Lacosamide
HNNH
O
R1OR2
O
R3
The advantage of this protocol is that the starting material and reagents are commercially available and single purification by recrystallization after finishing all necessary chemical transformations yielded the final drug in >99.9% ee. We proved that this process is scalable up to multi-gram synthesis in the laboratory.
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Design of Smart, Functional Chemical Reactors through Ultrasonic 3D-Printing
Matthew Harding, Tom Monaghan, Russell Harris, Ross Friel, Steve Christie*
Loughborough University, Department of Chemistry Loughborough, Leicestershire, LE11 3TU
[email protected] Three-dimensional printing (3DP) is a manufacturing technique with the potential to transform the way chemical devices are designed and manufactured.1 The associated design freedom makes 3DP well suited for those looking to tailor devices specifically to their chemistry.2 One 3DP technology with significant potential, but which remains unexplored in this area, is that of ultrasonic additive manufacturing (UAM). This low temperature ultrasonically driven process enables similar or dissimilar metal combinations to be joined in a fully 3D design, with the unique ability to directly embed sensing elements.3 In this work, a metal flow reactor featuring an embedded catalytic section and integrated sensing elements was designed with computer aided design (CAD) and then manufactured by UAM. The device was able to perform useful synthetic reactions and provided real time feedback for reaction monitoring and optimisation. A range of 1,4-disubstitued 1,2,3-triazoles were synthesised using a continuous flow methodology4 through a copper catalysed alkyne-azide cycloaddition (CuAAC). UAM has the potential to provide highly complex, multi-material, smart chemical reactors, employing all the advantageous properties associated with 3DP. The robust nature of these fully dense metal reactors also overcomes current issues associated with the 3D printing of chemical reactionware.
1 Capel, A.J., Edmonson, S., Christie, S.D.R., Goodridge, R.D., Bibb, R.J., Thurstans, M., Lab Chip, 2013, 13, 4583. 2 Monaghan, T., Harding, M.J., Harris, R.A., Friel, R.J., Christie, S.D.R., Lab Chip, 2016, 16, 3362. 3 Monaghan, T., Capel, A.J., Christie, S.D.R., Harris, R. A., Friel, R. J., Composites: Part A, 2015, 76, 181. 4 Bogdan, A.R., Sach, N.W., Adv. Synth. Catal., 2009, 351, 849.
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Designing Particle-Based Quasi-Homogenous Catalytic Systems
Thomas A. Howell*, Olivier J. Cayre, John Blacker
Institute of Process Research and Development, School of Chemical and Process Engineering, University of Leeds, Leeds, LS2 9JT, United Kingdom,
*E-mail: [email protected]
Homogenous catalysts offer superior reactivity and control of isomerism of product molecules in comparison with heterogenous catalysts. However, homogeneous catalysts tend to be single use as they offer limited recyclability and are therefore not used for bulk material synthesis. Heterogenous catalysts are therefore preferentially used by industry despite the lower rates typically achieved on the basis that they can be recycled. The long-standing challenge that is the use of homogeneous catalysts could potentially be addressed by immobilising these species onto surfaces acting as supports to enable recycling. Currently significant effort is placed in developing appropriate supports for these types of catalysts. This work aims to develop nanoparticle supports capable of tethering homogenous catalytic species to it. In this work, we aim to provide an environment for the catalyst to act as efficiently as possible while still being chemically attached to the particle surface. This is necessary as the presence of a surface near the catalytic species can reduce its availability for the reacting species. For this purpose, we are exploring the possibility of attaching the chosen catalyst to the particle surface via polymer linkage, where the chain length can be controllably varied. As a model system, we initially choose an organometallic iridium catalyst having previously shown promise as an effective "green catalyst" capable of trans-hydrogenation reactions. The presentation will focus on the design, synthesis and characterisation of reversible addition fragmentation chain-transfer (RAFT) agent-coated silica particles. The RAFT agent enables growth of polymer-brushes. It will also look at post-functionalisation of the polymer with organometallic iridium catalyst . References Lucas, S. J., B. D. Crossley, A. J. Pettman, A. D. Vassileiou, T. E. O. Screen, A. J. Blacker and P. C. McGowan (2013). "A robust method to heterogenise and recycle group 9 catalysts." Chemical Communications 49(49): 5562-5564. Pagliaro, M. (2009). Silica-based materials for advanced chemical applications, Royal Society of Chemistry. Keywords: quasi-homogenous, heterogenous catalysis, catalytic particle, silica, polystyrene, copolymers, catalyst loading
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Dihydrogen Driven Cofactor Recycling for use in Biocatalysed Asymmetric Organic Synthesis
Thomas H. Lonsdale, Holly A. Reeve, Kylie A. Vincent
Department of Chemistry, University of Oxford, Inorganic Chemistry Laboratory, South Parks Rd, Oxford, UK
Enzymes can be used to catalyse a range of reduction reactions, often with superior selectivity than traditional, transition metal based catalysts.[1] However, it is not possible for enzymes to use dihydrogen directly to carry out these reductions and instead, enzymes typically require a biological hydride donor (the cofactors NADH or NADPH). NADH is often more expensive than the desired product, therefore a means of recycling the cofactor must be employed. At present, this involves using an additional enzyme which can regenerate NADH from NAD+ at the expense of a reductant such as glucose, however this leads to generation of stoichiometric amounts of carbon based waste. We have developed a method of recycling NADH just using H2 gas (see Figure 1, a).[2] This is effectively a single heterogeneous catalyst for selective reduction reactions. The system is completely modular and shows much better atom economy than other method of cofactor recycling currently used. Having all of the enzymes immobilised on particles also means these particles can simply be filtered off and recycled for used in subsequent reactions.
(a) (b)
Figure 1: (a) The H2-driven cofactor recycling system for selective reductions. (b) Examples of reactions which can be carried out using the H2-driven cofactor recycling system.
This work looks at extending this system for use in reductive amination reactions. Methods of direct reductive amination are aspirational for the pharmaceutical industry. Here the H2-driven cofactor recycling system is combined with an L-alanine dehydrogenase to produce chiral amino acids (see Figure 1, b).[3] Industrially, there is great interest in using more stable thermophile enzymes which operate at high temperatures and are able to withstand harsher reaction conditions. This work explores developing a high temperature cofactor recycling system, by altering the NAD+-reductase component for a variant from a thermophilic organism. This is then coupled with an alkene-reductase enzyme for high temperature cofactor recycling. [1] F. Hollmann, I. W. C. E. Arends, D. Holtmann, Green Chem. 2011, 13, 2285. [2] H. A. Reeve, L. Lauterbach, O. Lenz, K. A. Vincent, ChemCatChem 2015, 7, 3480–3487. [3] A. K. Holzer, K. Hiebler, F. G. Mutti, R. C. Simon, L. Lauterbach, O. Lenz, W. Kroutil, Org. Lett. 2015
P15 ____________________________________________________________________
Iterative Heck-Mizoroki/Iododeboronation Sequences in the Synthesis of Polyene Natural Products
Kate Madden and Andy Whiting
Centre for Sustainable Chemical Processes, Chemistry Department, Durham University [email protected]
The brominated bacterial pigments produced by the Xanthomonas genus are of interest due to their ability to absorb reactive oxygen species (ROS), thus showing promise as potential antioxidants to combat photodamage.1 Compounds 1 and 2 have been isolated and identified by mass spectrometry, but have never been fully characterised, nor the extent of their activity elucidated.2 The conjugated all-trans-octaene presents an interesting target for application of the stereoselective Heck-Mizoroki (HM)/iododeboronation (IDB) iterative cross-coupling (ICC) methodology developed in this group and used in the synthesis of other polyene natural products.3,4 In this report, we present the progress made towards the construction of these targets, along with other truncated and biologically relevant analogues, using a highly convergent approach. The ICC methodology developed within this group has proven versatile and reliable in the construction of a number of polyenyl building blocks, including key tetraenyl intermediate 3 and terminal trienyl intermediate 4. 1)(a) Jenkins, C. L.; Starr, M. P., Curr. Microbiol., 1982, 7, 323-326. (b) Rajagopal, L.; Sivakama Sundari, C.; Balasubramanian, D.; Sonti, R. V., FEBS Lett., 1997, 415, 125-128. 2) Andrewes, A. G.; Jenkins C. L.; Starr, M. P.; Shepherd, J.; Hope, H., Tetrahedron Lett., 1976, 17, 4023-4024. 3)(a) A. R. Hunt, S. K. Stewart, A. Whiting, Tetrahedron Lett., 1993, 34, 3599-3602. (b) S. K. Stewart, A. Whiting, J. Organomet. Chem., 1994, 482, 293-300. (c) S. K. Stewart, A. Whiting, Tetrahedron Lett., 1995, 36, 3929-3932. (d) A. P. Lightfoot, G. Maw, C. Thirsk, S. Twiddle, A. Whiting, Tetrahedron Lett., 2003, 44, 7645-7648. (e) S. K. Stewart, A. Whiting, Tetrahedron Lett., 1995, 36, 3925-3928. (f) A. P. Lightfoot, S. J. R. Twiddle, A. Whiting, Org. Biomol. Chem., 2005, 3, 3167-3172. 4) Madden, K. S.; Mosa, F. A.; Whiting A., Org. Biomol. Chem., 2014, 12, 7877-7899.
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Expanding the substrate scope for the β-Borylation reaction: Homoallylic boronate ester derivatives
Alba Pujol Santiago,*a Elena Fernándezb and Andy Whitinga
aCentre for Sustainable Chemical Processes, Dept. of Chemistry, Durham University South Road, Durham DH1 3LE, UK
bDept. Química Física i Inorgànica, Universitat Rovira i Virgili, 43007 Tarragona, Spain. [email protected]
Establishing new catalytic enantioselective approaches to chiral molecules is an important goal for organic chemists. Our group has been developing methodologies for the conjugate addition of boryl nucleophiles into α,β-unsaturated carbonyl compounds. An effective enantioselective, one-pot methodology for the synthesis of homoallylic boronate ester derivatives 4 was developed previously (Scheme 1).1
Scheme 1 Enantioselective synthetic pathway for the synthesis of homoallylboronates 4 from the corresponding α,β-unsaturated aldehydes 1.
Further exploitation of 4 as substrates for a second borylation reaction, led to obtaining versatile diborylated esters 5. A novel methodology had been developed which allows the control of the asymmetry induced in the new stereogenic centre created for a range of substrates [Eqn (1)] due to the presence of the two boryl units which can subsequently be transformed into other functionalities leading to building blocks for the synthesis of multi-functional, chiral compounds.
1A. Pujol, A. D. J. Calow, A. S. Batsanov and A. Whiting, Org. Biomol. Chem., 2015,13, 5122-5130
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Mechanisms of Catch and Release Catalysis
Matthew Robinson1, Andrew Campbell2 and Guy C. Lloyd-Jones1* 1University of Edinburgh; 2AstraZeneca, UK
Scalable recovery of precious metals represents a long-standing challenge across applied industrial catalysis. More recently, the field of oxidative gold catalysis has received significant attention due to the unique reactivity of gold in comparison to the other late transition metals.1 Our group reported the first gold-catalysed oxidative coupling of arylsilanes and arenes to form functionalised biaryls.2 Reactions proceed under remarkably mild conditions, and a diverse range of arylsilanes and π-rich (hetero)arenes can be used. Notably, aryl halides are well-tolerated, demonstrating orthogonality to other metal-catalysed cross-coupling reactions. Due to the relative infancy of this chemistry, a number of problems surrounding scalability remain unresolved. Weakly-ligated gold(I) complexes are notoriously unstable in solution, and rapidly decompose in the absence of an external oxidant. Catalyst recovery at the end of reaction is therefore considered to be extremely challenging. We envisaged that development of a novel ‘catch and release’ protocol, in which the catalyst is temporarily tethered to a solid support, may bypass this problem altogether; combining the advantages of modern homogeneous catalysis with robust heterogeneous separation.
A range of mechanistic studies, synthetic challenges, and potential applications will be discussed further in this poster presentation. References
1. Hopkinson, M. N.; Gee, A. D.; Gouverneur, V. Chem. Eur. J. 2011, 17, 8248. 2. Ball, L. T.; Lloyd-Jones, G. C.; Russell, C. A. Science 2012, 337, 1644.
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Development of Novel Catalytic Methods for Amidation
Marco Sabatini, Lee Boulton, Tom D. Sheppard
University College London Dept. of Chemistry 20 Gordon Street, London, WC1H 0AJ
[email protected] Chemical reactions for the formation of amide bonds are among the most commonly employed transformations in organic chemistry. Amides feature in 25% of industrially important pharmaceuticals as well as a wide selection of bioactive natural products. However, limitations to amide bond formation reactions remain, especially in regard to finding improved catalytic, waste free and chemoselective methods. These problems must be addressed in order to make this chemistry more sustainable on a process scale. Previous work in the Sheppard group has shown borate esters as a convenient reagents for direct amidation with good scope.i The poster will describe a novel catalytic method for direct amidation of carboxylic acids with amines using a borate ester. Our procedure utilises low catalyst loadings (5 - 10 mol%) using Dean-Stark apparatus for water removal. This method has been shown to be applicable to a wide selection of amides with a good reaction scope comprising of primary, secondary and aryl amines as well as a wide selection of aliphatic and aromatic carboxylic acids, in yields of up to 99%.
An aspect that makes this chemistry especially applicable to the current industrial needs is the use of a simple solid-phase work-up with commercially available resins avoiding wasteful work ups or column chromatography. 1 (a) Starkov, P.; Sheppard, T. D. Org. Biomol. Chem. 2011, 9, 1320-1323. (b) Lanigan, R. M.; Starkov, P.; Sheppard, T. D. J. Org. Chem. 2013, 78, 4512-4523. (c) Karaluka, V.; Lanigan, R. M.; Murray, P.; Badland, M.; Sheppard, T. D. Org. Biomol. Chem. 2015.
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Using Experimental Design to Optimise an Iron-Catalysed Cross Coupling Reaction
James N. Sanderson†‡, Andrew P. Dominey† & Jonathan M. Percy‡ †GlaxoSmithKline / ‡University of Strathclyde
†Gunnels Wood Road, Stevenage, SG1 2NY ‡Pure & Applied Chemistry, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL
Historically, the coupling of alkyl nucleophiles in transition-metal catalysed cross-coupling reactions has been challenging due to undesired β-hydride elimination. Iron is known to couple primary alkyl Grignard reagents with aryl chlorides in a Kumada cross-coupling reaction (Scheme 1).1-3 There are very few reports of the iron-catalysed cross-coupling of secondary alkyl Grignard reagents.3 We have used statistical design of experiments (DoE) to optimise the iron-catalysed cross-coupling between aryl chlorides and iso-propylmagnesium chloride. DoE is used widely in the pharmaceutical industry to screen, optimise and test the robustness of chemical processes. DoE can offer many advantages over the classical one-factor-at-a-time (OFAT) approach. Due to its multivariate nature it is possible to optimize several components at once, leading to a significant reduction in the overall amount of experimentation required. The statistical analysis used in an experimental design also means that it is possible to reveal interactions between parameters, a distinct benefit over OFAT studies. Following two rounds of optimisation, we arrived at conditions which allowed the successful coupling of iso-propylmagnesium chloride and electron deficient aryl chlorides. While electron rich substrates were found to be less reactive, the reaction was most effective with heteroaryl chlorides. The reaction was found to be operationally simple, and can readily be carried out on a multigram scale. The optimised reaction conditons use 1-methyl-2-pyrrolidinone (NMP) as an additive to promote the efficient and selective addition of an iso-propyl group. Our current work is focussed upon the use of DoE along with GSK’s solvent selection guide to develop a process which uses a more desirable solvent. We have also investigated the use of computational chemistry in an effort to develop a predictive model for the iron-catalysed cross-coupling reaction. 1. P. J. Rushworth, D. G. Hulcoop and D. J. Fox, J. Org. Chem., 2013, 78, 9517-9521. 2. B. D. Sherry and A. Fürstner, Acc. Chem. Res., 2008, 41, 1500-1511. 3. T. L. Mako and J. A. Byers, Inorg. Chem. Front., 2016, 3, 766-790.
Scheme 1 – Fox’s Primary Alkyl Kumada Cross-Coupling
Scheme 2 – Iron Catalysed Cross-Coupling with iso-Propylmagnesium
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DNA
Copper-catalyzed azide-alkyne cycloaddition in attaching cyanine dyes to amino acid side chain
Tamara Šmidlehner, Atanas Kurutos, Jakov Slade, Ivo Piantanida
Ruđer Bošković Institute Bijenička cesta 54, 10000 Zagreb, Croatia
Monomethine cyanine dyes are well known of high affinity to nucleic acids and proteins thus developed as molecular probes with great increase in fluorescence efficiency upon binding to macromolecules while nonfluorescent in free form [1]. Commercially available derivatives for attachment to proteins are designed for attachment to C- or N- peptide end, or for several specific amino acid side chains, but there are no available cyanine amino acids with cyanine dye at side chain, and both C- and N-end ready for peptide incorporation.
N+
Y
N N3
X
I-N+
Y
N N
X
I-
CO2MeBocHN
N N
BocHN CO2Me
1a, Y = S, X = H2a, Y = S, X = Cl3a, Y = S, X = F4a, Y = O, X = Cl
1b, Y = S, X = H2b, Y = S, X = Cl3b, Y = S, X = F4b, Y = O, X = Cl
CuI
Scheme 1. Synthesis of 1b-4b by Copper-catalyzed azide-alkyne cycloaddition from cyanine with azide moiety and amino acid with alkyne in side chain with copper wire and CuSO4(aq) as source of Cu(I) in DMF at room temperature over night. That inspired us to prepare four novel cyanine-amino acid conjugates, synthesized by Copper-catalysed azide-alkyne cycloaddition (CuAAC) method yielding 1,4-disubstituted 1,2,3-triazoles in side chain of modified amino acids (Scheme 1). Novel, intrinsically non-fluorescent compounds strongly interact with ds-DNA (calf thymus (ct)-DNA), whereby they emit strong fluorescence. Circular dichroism (CD) titrations revealed that all compounds significantly decreased the DNA band at 245 nm, pointing to strong distortion of DNA backbone. Moreover, upon binding to ct-DNA, achiral dyes became chiral, exhibiting pronounced induced CD (ICD) band in the range where only cyanine dye absorbs (450-550 nm). Strong negative ICD band points out that compounds 1b and 2b bind to DNA as monomers, while bisignate ICD bands of 3b and 4b form dimers along DNA backbone. Intriguingly, negative-positive sign of 3b ICD suggests P-configured helicity in dimer, while opposite (positive-negative) sign of 4b ICD supports M-configured helicity of dimer [2]. Presented fluorescent amino acids are suitable for further incorporations in peptides on both; amino and carboxy end, thus allowing easily tuneable fluorophore positioning along peptide. References:
1. R. R. Gupta; Heterocyclic Polymethine Dyes, Springer-Veglang Berlin Heildelberg, 2008 2. T. H. Rehm, M. Radić Stojković, S. Rehm, M. Škugor, I. Piantanida, F. Würthner, Chem. Sci.
2012, 3, 3393-3397
+DNA
P21 ____________________________________________________________________
Opportunities for Catalyst Studies for Pharmaceutical Research using Soft and Tender X-ray Spectroscopies at Diamond Light Source
Anna Kroner, Sin-Yuen Chang, Elizabeth Shotton
Diamond Light Source Ltd. Harwell Science and Innovation Campus, Chilton, Didcot, OX11 0DE, Oxfordshire
The UK’s synchrotron facility, Diamond Light Source, produces X-ray, infra-red and ultraviolet beams of exceptional brightness. The combination of brilliant light and technological platforms is extensively used by the scientific community to undertake structural investigations of a wide variety of materials on very fast timescales. The industrial user programme at Diamond is continuously growing with over 100 companies from over 12 countries now making use of beamlines and offline facilities. A suite of techniques available at Diamond include small angle X-ray scattering (SAXS), X-ray diffraction (XRD), electron microscopy, imaging, tomography, infra-red and X-ray absorption spectroscopy (XAS). With soft and tender X-ray spectroscopic techniques becoming available at Diamond, there is the opportunity to obtain exclusive information which would otherwise been impossible to obtain using conventional lab techniques. Important elements covered by X-ray energy up to 5 keV include C, N, O, P, S, Ca and first row transition metals of relevance to API, excipient, surfactant, catalyst and biological materials. The techniques are element specific, have low detection limits and may accommodate versatile sample environments (solutions, powders, crystalline solid) under in situ conditions. Accessible information include metal oxidation state, bond length, organic functional group, crystals surface termination group and depth profiling. The soft X-ray spectroscopic techniques overall expand the role of synchrotron facilities as an essential tool from following diseases progression, target identification to drug discovery, process development, improving product manufacturability and understanding the structure of a catalyst used in pharmaceutical research.
Sponsors ____________________________________________________________________
The conference is organised jointly by RSC-ACG and SCI-FCG
We would like to thank the sponsors of our meeting
Committee ____________________________________________________________________
Organising Committee Dave Alker David Alker Associates
Guy Lloyd-Jones University of Edinburgh
Paul Murray Paul Murray Catalysis Consulting
Andy Whiting Durham University
RSC-ACG Secretariat Maggi Churchouse Maggi Churchouse Events
Exhibitors ____________________________________________________________________
We are pleased to welcome our exhibitors and thank them for their kind support.