Archive (Pre-2012 Group News)

May 2012 - Communication in Org. Biomol. Chem. Published

S.A. Warren, S. Stokes, C.S. Frampton, A.J.P. White, A.C. Spivey, 'Synthesis of anti and syn Hydroxy-iso-Evoninic Acids', Org. Biomol. Chem. 2012, 4685-4688.

 The first synthesis of hydroxy-iso-evoninic acid, a pyridyl diacid found as a macrodilactone bridging ligand in bioactive Celastraceae sesquiterpenoid-based natural products, has been achieved in 9 steps and an overall yield of 26%. The synthesis utilizes a benzilic ester rearrangement (BER) and a late stage benzylic oxidation to give access to all four stereoisomers whose absolute stereochemistry was assigned following chromatographic separation and anomalous dispersion X-ray crystallography.

May 2012 - Full Paper in J. Am. Chem. Soc. Published

Evgeny Larionov, Mohan Mahesh, Alan C. Spivey, Yin Wei, Hendrik Zipse, 'Theoretical Prediction of Selectivity in Kinetic Resolution of Secondary Alcohols Catalyzed by Chiral DMAP Derivatives', J. Am. Chem. Soc. 2012, 134, 9390-9399.

 The mechanism of esterification of the secondary alcohol 1-(1-naphthyl)ethanol by isobutyric anhydride catalyzed by 4-pyrrolidinopyridine (PPY) and a series of seven single enantiomer atropisomeric 4-dialkylaminopyridines has been studied computationally at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level. Comparison of the levels of enantioselectivity predicted computationally with the results obtained experimentally allowed the method to be validated. The value of the approach is demonstrated by the successful prediction that a structural modification of an aryl group within the catalyst from phenyl to 3,5-dimethylphenyl would lead to improved levels of selectivity in this type of Kinetic Resolution (KR) reaction, as was subsequently verified following synthesis and evaluation of this catalyst. Experimentally, the selectivity of this type of KR is found to exhibit a significant deuterium isotope effect for 1-(1-naphthyl)ethanol vs. 1-duterio-1-(1-naphthyl)ethanol.

Mar 2012 - Tori Bob-Egbe Obtains her PhD

Tori Bob-Egbe completed her PhD viva on 02/03/12; external examiner Christian Bochet, University of Fribourg, Switzerland.

Tori is going to work in  in the Agriculture sector with the Greenpark Petrochemical Company based in Nigeria. Her initial task is to set up a new fertilizer plant in sub-saharan africa!

Feb 2012 - Full Paper in J. Org. Chem. Published

Daniel A. Offermann, John E. McKendrick, Jimmy J.P. Sejberg, Bingli Mo, Mary D. Holdom, Birgit A. Helm, Robin J. Leatherbarrow, Andrew J. Beavil, Brian J. Sutton, Alan C. Spivey, 'Synthesis and Incorporation into Cyclic Peptides of Tolan Amino Acids and their Hydrogenated Congeners: Construction of an Array of A-B-loop Mimetics of the Cε3 Domain of Human IgE', J. Org. Chem. 2012,77, 3197-3214 .

The disruption of the human Immunolobulin E – high affinity receptor I (IgE-FceRI) protein-protein interaction (PPI) is a validated strategy for the development of anti-asthma therapeutics. Here, we describe the synthesis of an array of conformationally constrained cyclic peptides based on an epitope of the A-B loop within the Ce3 domain of IgE. The peptides contain various tolan (i.e. 1,2-biarylethyne) amino acids and their fully and partially hydrogenated congeners as conformational constraints. Modest antagonist activity (IC₅₀ ~660 mM) is displayed by the peptide containing a 2,2’-tolan which is the one predicted by molecular modeling to best mimic the conformation of the native A-B loop epitope in IgE.

Dec 2011 - Helena Dennison Obtains her PhD and Starts Teacher Training in Bournmouth

Helena Dennison completed her PhD viva on 21/12/11; external examiner Dr Patrick Steel,University of Durham. She leaves the group to complete her Postgraduate Certificate of Education (PGCE, Bath University) and to become a Science teacher in Bournmouth, UK.

Dec 2011 - Sarah Warren Obtains her PhD and Starts Post-doc with Thorsten Bach in Munich

Sarah Warren completed her PhD viva on 20/12/11; external examiner Prof. Jim Anderson, University College London. She leaves the group to take up a postdoctoral position in the labs of Prof. Thorsten Bach at The Technical University of Munich, Germany in February 2012.

Dec 2011 - Reviews on Chiral Salen Complexes in the e-Encyclopedia of Reagents for Organic Synthesis (e-EROS) Published

Two short reviews of the use of chiral salen transition metal complexes in asymmetric synthesis published in e-EROS:

[1,1-Binaphthalen]-2-ol,3-[(1R,2R)-1,2-cyclohexanediylbis(nitrilomethylidyne)]-bis[2-phenyl-, (1R,1R)- (9CI) - Alan C. Spivey & Chih-Chung Tseng -Chiral salen ligand for enantioselective transition metal-catalyzed reactions, including Ru-, Co-, and Ir- catalyzed cyclopropanation of alkenes, Ti-catalyzed sulfoxidation and Ru-catalyzed sulfimidation of sulfides, Mn-, Ru-, and Nb- catalyzed epoxidation of alkenes, Ir- and Mn- catalyzed C–H bond functionalization, Ru oxidative kinetic resolution of sec-alcohols, and Zr- catalyzed asymmetric Baeyer–Villiger oxidations [Read review - requires subscription to e-EROS].

a nd

Cobalt, [[2,2-[(1R,2R)-1,2-cyclohexanediylbis[(nitrilo-κN)-methylidyne]]bis[4,6-bis(1,1-dimethylethyl)phenolato-κO]](2-)]-, (SP-4-2) and cobalt, [[2,2-[(1S,2S)-1,2-cyclohexanediylbis[(nitrilo-κN)-methylidyne]]bis[4,6-bis(1,1-dimethylethyl)phenolato-κO]](2-)] -, (SP-4-2) - Alan C. Spivey & Chih-Chung Tseng - Precursor to Co(III)(salen) catalysts for hydrolytic and related kinetic resolutions of terminal epoxides, asymmetric desymmetrization of meso-epoxides and oxetanes, copolymerization of epoxid es with CO< sub>2; asymmetric Diels–Alder reactions, enantioselective iodocyclizations, resolution of N-benzyl amino acids, and asymmetric radical polymerization [Read review - requires subscription to e-EROS].

Nov 2011 - Bingli Mo Obtains her PhD

Bingli Mo completed her PhD viva on 25/11/1 1; external examiner Prof. Stephen Caddick, University College London. She leaves the Spivey group and is seeking a job in the USA.

Nov 2011 - Communication in Chem. Commun. Published

Helen L. Evans, Rozanna L. Slade, Laurence Carroll, Graham Smith, Quang-De Nguyen, Lisa Iddon, Nazilla Kamaly, Henning Stöckmann, Finian J. Leeper, Eric O. Aboagye and Alan C. Spivey, 'Copper-free Click – A Promising Tool for Pre-Targeted PET Imaging', Chem. Commun. 2012,48, 991-993.

The copper-free click (CFC) reaction has been evaluated for its potential application t o in vivo pre-targeting for PET imaging. A promising biodistribution profile is demonstrated when employing [¹⁸F]2-fluoroethylazide and optimisation of the CFC reaction with a series of cyclooctynes shows that reactions proceed efficiently with tantalizing opportunities for application-specific tuning.

Oct 2011 - Andy Bayly Obtains his PhD and Starts Post-doc with Chris Abell in Cambridge

Andy Bayly completed his PhD viva on 17/10/11; external examiner Dr Andy Wilson, University of Leeds. He leaves the group to take up a postdoctoral position in the labs of Prof Chris Abell atCambridge University, Cambridge, UK.  He will be sorely missed! ...well, maybe.

Oct 2011 - Article in Synlett Published

M.J. Webber, M. Weston, D.M. Grainger, S. Lloyd, S.A. Warren, L. Powell, A. Alanine, J. Stonehouse, C.S. Frampton, A.J.P. White, A.C. Spivey, 'An Ireland–Claisen Rearrangement/Lactonisation Cascade as a Key Step in Studies Towards the Synthesis of (–)-Euonyminol', Synlett 2011, 2693-2696.

Progress towards the asymmetric total synthesis of (–)-euonyminol is described with the focus on the installation of the oxygenation pattern on the lower rim of the molecule. An Ireland-Claisen rearrangement/lactonization cascade has been developed and studies towards further elaboration have uncovered an intriguing tunable diastereoselective alpha-bromination of the resulting gamma-lactone.

Oct 2011 – Ling-Fu Nieh Joins the Group as a New PhD Student

Ling-Fu Nieh joins the group as a PhD student funded by a scholarship from Taiwan. He has 2 years of industrial experience following completion of his MSc and BSc degrees at National Taiwan University. He is working on the total synthesis of Lycorine via retro-Cope elimination.

Oct 2011 – Final Year BSc Project Students Fiona Li, George Calvert and Luca Pelazzo join the group

Fiona Li joins the group as a final year Imperial College MSci student for her research project which involves studies towards the ‘Synthesis of a novel five residue α-helix protein mimetic LRH-1 antagonist’.

George Calvert joins the group as a final year Imperial College BSc student for his research project which involves studies towards the ‘Synthesis of the core of lophirone H via a Prins cyclisation’.

Luca Pelazzo joins the group as a final year Imperial College BSc student for his research project which involves studies towards the ‘Synthesis of the core of lophirone H via a Prins cyclisation’

Sept 2011 - MRes Students Lucy Smith and Emily Kouroussis Graduate

Lucy Smith obtains a Distinction for her MRes on 'Disruption of the IgE:FceR1  protein-protein interface - towards next generation anti-asthma therapeutics' jointly supervised by Alan and Professor Robin Leatherbarrow (Imperial College Chemistry) and Dr Andrew Beavil (Kings College London, Randall Institute). She also obtained 1st prize for her presentation of her research work at the Institute of Chemical Biology MRes Conference on the 7th of Sept (Session 1).

Emily Kouroussis obtains a Merit for her MRes on 'Development of Antagonists of the Nuclear receptor LRH-1 as Potential Anti-Cancer Leads' jointly supervised by Alan and Professor Simak Ali (Oncology, Hammersmith Hospital, Imperial College London).

Aug 2011 - Erasmus Exchange Student Kerti Ausmees Rejoins the Group

Kerti Ausmees rejoins the group for a 4th year PhD 3 month exchange student from the group of Professor Tonis Kanger in the Department of Chemistry, Tallinn University of Technology, Estonia. She is continuing work on the development of atropisomeric nucleophilic organocatalysts for the acylative kinetic resolution of amines.

June 2011 - UROP Summer Project Students Zeqi Yang and Zsofia Heckenast Join the Group

Zeqi Yang joins the group as a 2nd year undergraduate student from Imperial College studying for an MSci in Chemistry. His 8 week Undergraduate Research Opportunities Scheme (UROP) placement is funded by a UROP scholarship from Imperial College. Zeqi is looking into the mechanism of aromatic substitution by cyanide anion on aryldiazonium salts.

Zsofia Heckenast joins the group as a 3rd year undergradaute student from The University of Bristol studying for an MSci in Chemistry with Research Abroad. Her 8 week Undergraduate Research Opportunities Scheme (UROP) placement is funded by a Biomedical Vacation Scholarship from the Wellcome Trust. Zsofia is looking to synthesise a sulfenic acid-containing decalin as a model for a redox active cysteine residue in a protein.

June 2011 - Article in Org. Biomol. Chem. Published

James L. Carr, Jimmy J. P. Sejberg, Fabienne Saab, Mary D. Holdom, Anna M. Davies, Andrew J. P. White, Robin J. Leatherbarrow, Andrew J. Beavil, Brian J. Sutton, Stephen D. Lindell and Alan C. Spivey, 'Synthesis of the C19 Methyl Ether of Aspercyclide A via Germyl-Stille Macrocyclisation and ELISA Evaluation of Both Enantiomers Following Optical Resolution', Org. Biomol. Chem. 2011, 9, 6814-6824.

Aspercyclide A is a biaryl ether containing 11-membered macrocyclic natural product antagonist of the human IgE-FceRI protein-protein interaction (PPI); a key interaction in the signal transduction pathway for allergic disorders such as asthma. Herein we report a novel approach to the synthesis of the C19 methyl ether of aspercyclide A, employing a Pd(0)-catalysed, fluorous-tagged alkenylgermane/arylbromide macrocyclisation (germyl-Stille reaction) as the key step, and evaluation of both enantiomers of this compound via ELISA following optical resolution by CSP-HPLC. A crystal structure for the germyl hydride used to prepare the key macrocyclisation precursor via hydrogermylation is also reported.

June 2011 - Article in Chem. Letts. Published

Chih-Chung Tseng, Mungyuen Li, Bingli Mo, Sarah A. Warren and Alan C. Spivey, 'Stereocontrolled Formation of Styrenes by Pd(0)-Catalyzed Cross-Coupling of Photoactivated (E)-Alkenylgermanes with Aryl Bromides', Chem. Letts. 2011, Special Issue Focussing on the Mizoroki-Heck & Cros-coupling Reactions, 9, 995-997.

The stereocontrolled synthesis of (E)-configured styrenes via Pd(0)-catalysed cross-couping of (E)-alkenylgermanes with aryl bromides is described. The germanes employed have bis(naphthalen-2-ylmethyl) substitution to allow photooxidative activation towards coupling and a C₈F₁₇-fluorous tag to facilitate purification by fluorous solid-phase extraction (F-SPE). The selectivities obtained suggest that a germyl-Stille rather than Heck-type mechanism predominates in the coupling step.

June 2011 - BSc Project Students Samantha Lee and Elvis Ng and MSci Student Cathy Lee Leave Group and Graduate

Samantha Lee completed her BSc research project on the development of a new series of atropisomeric chiral-DMAP catalysts for kinetic resolution of alcohols. She graduated with a 1st class honours degree. She is planning to carry out a research for an MSc in Organic Synthesis at Cambridge University under the Supervision of Professor Steven Ley.

Wang Hei Ng (Elvis Ng, 吳宏晞) completed his BSc research project ‘Towards the total synthesis of cordigol/lophirone H using a Prins reaction as a key step’. He graduated with a 1st class honours degree and Department of Chemistry Prize for Excellence in Organic Chemistry (This prize is awarded to a student (BSc or MSci) who is judged to have performed best in all aspects of Organic Chemistry throughout the degree course as judged by consideration of their coursework, exam performance and final year research project work). He is planning to carry out research for a PhD in Organic Synthesis at Hong Kong University under the supervision of Prof Pauline Chiu.

Cathy Lee completed her MSci research project on the development of a catalytic asymmetric retro-Cope elimination reaction. She graduated with a lower second class honours degree. She is planning a trip to Honk Kong over the Summer before deciding her future path.

May 2011 - Article in Coll. Czech. Chem. Comm. Published

Stellios Arseniyadis, Mohan Mahesh, Paul McDaid, Thomas Hampel, Stephen G. Davey and Alan C. Spivey 'Studies Towards the N-acylative Kinetic Resolution of NOBIN', Coll. Czech. Chem. Comm.2011, 76 (Special Issue to Celebrate 60th Birthday of Pavel Kočovský), 1239-1253.

An investigation into the N-acylation of two atropisomeric anilines, wh ich are related to NOBIN, ca t alysed by small molecule chiral pyridine-based nucleophilic catalysts is described. The first organocatalytic kinetic resolution (KR) of an atropisomeric aniline is described.

March 2011 - Aspercyclide A Synthesis Highlighted in Organic Chemistry Portal

Our recent publication: J.L. Carr, D.A. Offermann, M.D. Holdom, P. Dusart, A.J.P. White, A.J. Beavil, R.J. Leatherbarrow, S.D. Lindell, B.J. Sutton^, A.C. Spivey 'Total Synthesis of (±)-Aspercyclide A and its C19 Methyl Ether', Chem. Comm. 2010, 46, 1824-1826 is highlighted on the Organic Chemistry Portal.

Aspercyclide A (14) and its more stable methyl ether are promising lead compounds for the treatment of asthma. In the course of a synthesis of 14, Alan C. Spivey of Imperial College developed (Chem. Commun. 2010, 1824 the intramolecular Heck cyclization of 12 to 13.

Feb 2011 - Vicky Paddock Obtains her PhD and Starts Post-doc with Samir Zard in Paris

Vicky Paddock completed her PhD viva on 21/02/11; external examiner Prof Dave Knight, University of Cardiff. She leaves the group to take up a postdoctoral position in the labs of Prof Sam Zard at Ecole Polytechnique, Paris, France.

Jan 2011 - Article in Org. Biomol. Chem. Published

Helmut Haning, Carles Giró Mañas, Victoria L. Paddock, Christian G. Bochet, Andrew J. P. White, Gerald Bernardinelli, Inderjit Mann, Wolfang Oppolzer and Alan C. Spivey 'Total Synthesis of the Amaryllidaceae Alkaloid Clivonine', Org. Biomol. Chem. 2011, 9, 2809-2820.

Two syntheses of the Amaryllidaceae alkaloid clivonine are described. Both employ a previously reported 7-arylhydrindane as an intermediate but differ in the method employed for subsequent introduction of what becomes the ring-B lactone carbonyl carbon (C7). The synthesis featuring a Bischler-Napieralski reaction for this transformation constitutes the first asymmetric synthesis of natural (+)-clivonine. Crystal structures for several intermediates are also reported.

Jan 2011 - Article in J. Org. Chem. Published

Victoria L. Paddock, Robert J. Phipps, Almudena Conde Angulo, Araceli Blanco Martin, Carles Giró Mañas, Laetitia J. Martin, Andrew J. P. White and Alan C. Spivey '(±)-trans, cis-4-Hydroxy-5,6-di-O-isopropylidenecyclohex-2-ene-1-one: Synthesis and Facile Dimerization to Decahydrodibenzofurans',J. Org. Chem. 2011, 76, 1483-1486 (LINK).

An efficient synthesis of (±)-trans, cis-4-hydroxy-5,6-di-O-isopropylidenecyclohex-2-ene-1-one (3) has been developed from acetonide protected meso-1,2-dihydrocatechol derivative 1 via photooxygenation then Kornblum-DeLaMare rearrangement. The product is unstable unless its 4-hydroxy group is protected, as it undergoes facile dimerization in solution to a 1:1 mixture of diastereoisomeric decahydrodibenzofurans 8 and 9. A new synthesis of the dihydrocatechol 1 from 1,3-cyclohexadiene has also been developed.

Jan 2011 - Article in Synlett Published

Federica Pisaneschi, Jimmy J. P. Sejberg, Cecile Blain, Wang Hei Ng, Eric O. Aboagye and Alan C. Spivey '2-Substituted-2,3-dihydro-1H-quinolin-4-ones via acid catalyzed tandem Rupe rearrangement/Donnelly-Farrell ring-closure of 2-(3’-hydroxypropynyl)anilines', Synlett, 2011,  241-244.

A range of 2-substituted 2,3-dihydro-1H-quinolin-4-ones have been synthesized from anilines by a two-step process involving Sonogashira coupling with a propargyl alcohol then acid catalyzed cyclization of the resulting 2-(3’-hydroxypropynyl)anilines. The cyclization reaction appears to proceed via regioselective rearrangement of the propargyl alcohol to an alpha,beta-unsaturated ketone (Rupe rearrangement) and then 6-endo-trig ring-closure (Donnelly-Farrell cyclisation). The isolation of the alpha,beta-unsaturated ketone intermediate in one example supports this pathway.

Note after publication: We should have described this cyclisation reaction as a Meyer-Schuster rearrangement/Donnelly-Farrell ring-closure rather than a Rupe rearrangement/Donnelly-Farrell ring-closure as the propargyl alcohols employed were non-terminal. See: S. Swaminathan, K.V. Narayanan, Rupe and Meyer-Schuster Rearrangements', Chem. Rev. 1971, 71, 429-438.

Jan 2011 - BSc Research Project Students Samantha Lee and Elvis Ng Join the Group

Samantha Lee joins the group as a 3rd year BSc research project student and is working on the development of a new series of atropisomeric chiral-DMAP catalysts for kinetic resolution of alcohols.

Wang Hei Ng (Elvis Ng, 吳宏晞) joins the group as a 3rd year BSc research student and is working on the total synthesis of cordigol using a Prins reaction as a key step.

Oct 2010 - 3rd Year PhD Student Sarah Warren Starts 3 Month CASE Placement at AstraZeneca R&D, Alderley Park, Manchester

Sarah Warren is working on the asymmetric synthesis of pyridly ligands found as esterifying residues in numerous Celastraceae sesquiterpenoid natural products and is currently spending 3 months working in the labs of her AZ CASE supervisor, Dr Steve Stokes at Alderley Park.

Oct 2010 - Three New PhD Students, a 4th Year MSci Research Project Student & Two Erasmus/Exchange Students Join the Group

Melanie Mueller joins the group as a PhD student and is wor king on the development of nuclear receptor modulators. Previously, she was an undergraduate in the Freie Universitat Berlin and worked with Professor Andrew Miller in the Genetic Therapies Centre, Imperial College London.

 Lucy Smith joins the group as an MRes/PhD student jointly supervised by Professor Robin Leatherbarrow (IC, Chemistry) and is working on the development of antagonists of the IgE-FceRI protein protein interaction. Previously, she was an MSci student in Chemistry here at Imperial College London and also worked for Exscitec in collaboration with Imperial College Outreach.

Helen Evans joins the group as a PhD student jointly supervised with Professor Eric Aboagaye (IC, Oncology, Hammersmith Hospital) and is working on the development of new approaches to 18F labelling of macromolecules for Positron Emission Tomography (PET). Previously, she was an MChem student in Chemistry with a year in industry (GSK) at Reading University and carried out her 4th year research project under the direction of former group member Dr John McKendrick.

Cathy Lee joins the group as a 4th year MSci research project student and is working on the development of a catalytic asymmetric retro-Cope elimination reaction.

Amanda Teng joins the group as a 4th year undergraduate 6-month exchange student jointly supervised by Professor Robin Leatherbarrow (IC, Chemistry) and is working on the development of antagonists of the IgE-FceRI protein protein interaction. She is currently studying from a BSc degree in the Division of Chemistry and Biological Sciences at Nanyang Technological University (NTU), Singapore.

Kerti Ausmees joins the group as a 3rd year PhD 6 month exchange student from the group of Professor Tonis Kanger in the Department of Chemistry, Tallinn University of Technology, Estonia. She is working on the development of atropisomeric nucleophilic organocatalysts for the acylative kinetic resolution of amines.

Sep 2010 - Toritse Bob-Egbe wins Catalysis Science and TechnologyPoster Prize at RSC Dalton Discussions Meeting on 'Catalytic C-H and C-X Bond Activation' (Sept 13-15, 2010) at Durham University, UK

Sep 2010 - Jimmy Sejberg Returns From 4 Days of Interesting Chemistry at the ACS National Meeting (Aug 22-26, 2010) in Boston, MA, USA

Sept 2010 - Vicky Paddock presents a poster at the ESF-COST High-Level Research Conference on Natural Products Chemistry, Biology and Medicine III, Acquafredda di Maratea, Italy

Aug 2010 - Helena Dennison presents a poster at The Fourteenth Symposium on The Latest Trends in Organic Synthesis at Brock University, St Catherine's, Canada

Aug 2010 - Article in Bioorganic and Medicinal Chemistry Published

Federica Pisaneschi^,, Quang- De Nguyen, Elham Shamsaei, Matthias Glaser, Edward Robins, Maciej Kaliszczak, Graham Smith, Alan C. Spivey and Eric O. Aboagye 'Development of a New Epidermal Growth Factor Receptor Positron Emission Tomography Imaging Agent based on the 3-Cyanoquinoline Core: Synthesis and Biological Evaluation' Bioorg & Med. Chem. 2010, 18, 6634.

The Epidermal Growth Factor Receptor (EGFR/c-ErbB1/HER1) is overexpressed in many cancers including breast, ovarian, endometrial and non-small cell lung cancer. An EGFR specific imaging agent could facilitate clinical evaluation of primary tumors and/or metastases. To achieve this goal we designed and synthesized a small array of fluorine containing compounds based on a 3-cyanoquinoline core. A lead compound, 16, incorporating 2′-fluoroethyl-1,2,3-triazole was selected for evaluation as a radioligand based on its high affinity for EGFR kinase (IC₅₀ = 1.81 ± 0.18 nM), good cellular potency (IC₅₀ = 21.97 ± 9.06 nM), low lipophilicity and good metabolic stability. ‘Click’ labeling afforded [¹⁸F]16 in 37.0±3.6 % decay corrected radiochemical yield based on azide [¹⁸F]14 and 7% end of synthesis (EOS) yield from aqueous fluoride. [¹⁸F]16 was obtained with >99% radiochemical purity in a total synthesis time of 3 h. The compound showed good stability in vivo and a 4-fold higher uptake in high EGFR expressing A431 tumor xenografts compared to low EGFR expressing HCT116 tumor xenografts. Furthermore, the radiotracer could be visualized in A431 tumor bearing mice by small animal PET imaging. [¹⁸F]16 therefore constitutes a promising radiotracer for further evaluation for imaging of EGFR status.

Aug 2010 - Toritse Bob-Egbe presents a poster at Gordon Research Conference on Stereochemistry in Rhode Island, USA

Aug 2010 - Clivonine Synthesis Highlighted in Synfacts

Our recent publication: C.G. Manas, V.L. Paddock, C.G. Bochet, A.C. Spivey, A.J.P. White, I. Mann, W. Oppolzer 'Total Synthesis of the Lycorenine-type Amaryllidaceae Alkaloid (±)-Clivonine via a Biomimetic Ring-switch from a Lycorine-type Progenitor', J. Am. Chem. Soc. 2010, 132, 5176-5178 is featured in Synfacts 2010, 8, 851.

Clivonine is a lycorenine-type Amaryllidaceae alkaloid that was isolated from Clivia miniata in 1956 by Wildman. There has been one previous total synthesis reported by Irie in 1973 (J. Chem. Soc., Chem. Commun. 1973, 302). The biomimetic ring-switching pathway provides experimental evidence for Barton's proposed hypothesis concerning the rearrangement of lycorine progenitors for alkaloid biogenesis.

July 2010 - Bingli Mo Presents a Poster at ISACS1: Challenges in Organic Chemistry and Chemical Biology Conference in San Francisco, USA

July 2010 - Final Year PhD Student Vicky Paddock Awarded Prize for her Presentation at the Post Grad Symposium

Vicky Paddock was awarded joint first prize for her presenation entitled 'The Total Synthesis of Clivonine' in the Inorganic and Organic II session at Imperial's Postgradutate Symposium.

July 2010 - Aspercyclide A Synthesis Highlighted in Synfacts

Our recent publication: J.L. Carr, D.A. Offermann, M.D. Holdom, P. Dusart, A.J.P. White, A.J. Beavil, R.J. Leatherbarrow, S.D. Lindell, B.J. Sutton^, A.C. Spivey 'Total Synthesis of (±)-Aspercyclide A and its C19 Methyl Ether' Chem. Comm. 2010, 46, 1824-1826 is featured in Synfacts 2010, 7, 373.

Aspercyclide A is one of three fungal metabolites to be isolated from Aspergillus sp. found in soil extracts in 2004 and has been shown to have micromolar potency as a small molecule antagonist for blocking a protein-protein interaction that triggers an inflammatory mediator r elease. (+)-Aspercyclide C has been previously synthesiz ed using ring-closing metathesis to effect macrocyclization (A. Furstner, C. Muller Chem. Commun. 2005, 5583). Recently, (+)-a spercyclides A and B have also been synthesized using a Nozaki-Hiyama-Kishi reaction to effect macrocyclization (J. Pospisil et al. Chem. Eur. J. 2009, 15, 5956).

July 2010 - Article in Breast Cancer Research and Treatment Published

Thiruchelvam PT, Lai CF, Hua H, Thomas RS, Hurtado A, Hudson W, Bayly AR, Kyle FJ, Periyasamy M, Photiou A, Spivey AC, Ortlund EA, Whitby RJ, Carroll JS, Coombes RC, Buluwela L, Ali S 'The liver receptor homolog-1 regulates estrogen receptor expression in breas t cancer cells' Breast Cancer Res. Treat. 2011, 127, 385-396.

Estrogen receptor-alpha (ER) is expressed in the great majority of breast cancers, and the inhibition of ER action is a key part of breast cancer treatment. The inhibition of ER action is achieved using anti-estrogens, primarily tamoxifen, and with aromatase inhibitors that inhibit estrogen biosynthesis, thereby preventing ER activation. However, resistance to these therapies is common. With the aim of identifying new molecular targets for breast cancer therapy, we have identified the liver receptor homolog-1 (LRH-1) as an estrogen-regulated gene. RNA interference and over-expression studies were used to investigate the role of the LRH-1 in regulating breast cancer growth and to identify the targets of an LRH-1 action. Promoter recruitment was determined using reporter gene and chromatin immunoprecipitation (ChIP) assays. We show that LRH-1 regulates breast cancer cell growth by regulating the ER expression. Reporter gene and in vitro DNA-binding assays identified an LRH-1-binding site in the ER gene promoter, and ChIP assays have demonstrated in vivo binding at this site. We also provide evidence for new LRH-1 variants in breast cancer cells arising from the use of alternative promoters. Previous studies have shown that LRH-1 functions in estrogen biosynthesis by regulating aromatase expression. Our findings extend this by highlighting LRH-1 as a key regulator of the estrogen response in breast cancer cells through the regulation of ER expression. Hence, inhibition of LRH-1 could provide a powerful new approach for the treatment of endocrine-resistant breast cancer.

July 2010 - Former PhD Student Steven Woodhead Featured inChemistry World

Under the heading 'Transatlantic Chemist' an article in the July edition of the RSC publication Chemistry World profiles the career of Dr Steven Woodhead who was the 1st PhD student in the Spivey group from 1996-1999. After 2 x postdoctoral periods working with Bob Holton (Florida State University) and then Gerry Pattenden (Nottingham University) Steve joined Astex Therapeutics in Cambridge and has recently moved to work at the Lilly Biotechnology Centre in San Diego, California.

For the article see: http://www.rsc.org/chemistryworld/Issues/2010/July/TransatlanticChemist.asp

June 2010 - Review Chapter Updates on Organogermanium Compounds in Science of Synthesis Published

In 2002, with then PhD student Dr Chris Diaper (now at NAEJA Pharmaceutical Inc., Canada) Alan published a series of 13 short review Chapters on various classes of organogermanium compounds for Volume 5 of Science of Synthesis which covers ‘Compounds of Group 14 (Ge, Sn, Pb)’ and is edited by Dr Mark Moloney. With ex. PhD student Dr Chih-Chung Tseng (now at The Chemical Synthesis Laboratory, Biopolis, Singapore) we have now published a series of 12 updates to these Chapters.

These updates focus on the literature published in the period 2001-2009 and cover:

5.1.1 Germanium hydrides;

5.1.15 Germanium cyanides

5.1.16 Acylgermanes

5.1.18 alpha-Halo- and aplha-alkoxyvinylgermanes

5.1.19 alpha-Halo, alpha-Hydroxy, alpha-alkoxy- and alpha-aminoalkylgermanes

5.1.20 Alkynylgermanes

5.1.22 Aryl- and Heteroarylgermanes

5.1.23 Vinylgermanes

5.1.24 Propargyl- and allenylgermanes

5.1.25 Benzylgermanes

5.1.26 Allylgermanes

5.1.27 Alkylgermanes

June 2010 - 4th Year MSci Student Fleur Ferguson Awarded Prize for her Final Year Project Presentation

Fleur Ferguson was awarded joint second prize for her presentation entitled 'Computationally Aided Design and Synthesis of Agonists of the Nuclear Receptor LRH-1’ in the 'synthetic chemistry' session for the final year MSci undergraduate research project talks. She is scheduled to start a PhD in the group of Alessio Ciulli at the University of Cambridge in October.

May 2010 - James Carr, Chih-Chung (Jimy) Tseng & Laetitia Martin back for PhD Graduation

James Carr (now post-docing with Amir Hoveyda in Boston College), Chih-Chung (Jimy) Tseng (now post-docing with David Cheng in Biopolis, Singapore) and Laetitia Martin (now post-docing with Steve Ley/Novartis in Basel) were back to graduate with their PhDs in a ceremony in the Royal Albert Hall on Wed the 5th May:

April 2010 - Clivonine J. Am. Chem. Soc. Article Highlighted in Nature Chemical Biology

The group's recently published, partially biomimetic synthesis of the Amaryllidaceae alkaloid clivonine (Mar 2010, see below) is featured in the 'Research Highlights' section of Nature Chemical Biology in a commentary by Catherine Goodman entitled 'Switching up Scaffolds' http://www.nature.com/ncrembio/journal/v6/n5/full/nchembio.361.html

April 2010 - New Postdoc Jimmy Sejberg Joins the Group

Jimmy Sejberg joins the group after a PhD with Professor Mikael Begtrup at the University of Copenhagen. He is working on an MRC/EPSRC-funded project to develop small molecules that can disrupt the binding between human IgE and its high affinity receptor FceR1 (see Research).

March 2010 - New Postdoc Ola Åberg Joins the Group

Ola Åberg joins the group following a PhD with Bengt Långström at Uppsala University, Sweden. He is working on an imaging project supervised primarily by Prof Eric Aboagye, Department of Oncology, Hammersmith Hospital campus.

March 2010 - Matthew Webber Obtains his PhD and Starts Post-doc with Ben List in Mülheim

Matthew Webber completed his PhD viva on 18/03/10; external examiner Prof Tim Donohoe, University of Oxford. He leaves the group to take up a postdoctoral position in the labs of Prof Benjamin List at the Max-Plack-Institut für Kohlenforschung, Mülheim and der Ruhr, Germany.

March 2010 - Article in J. Am. Chem. Soc. Published

Carles Giro Manas, Victoria L. Paddock, Christian G. Bochet, Alan C. Spivey, Andrew J.P. White, Inderjit Mann, Wolfgang Oppolzer ‘Total Synthesis of the Lycorenine-type Amaryllidaceae Alkaloid (±)-Clivonine via a Biomimetic Ring-switch from a Lycorine-type Progenitor' J. Am. Chem. Soc. 2010, 132, 5176-5178.

A fully diastereoselective total synthesis of the lycorenine-type Amaryllidaceae alkaloid (±)-clivonine is reported via a route that employs for the first time a biomimetic ring switch from a lycorine-type progenitor, thereby corroborating experimentally the biogenetic hypothesis first expounded for these compounds by Barton in 1960.

Feb 2010 - Communication in Org. Lett. Published

A.C. Spivey, L. Laraia, A.R. Bayly, H.S. Rzepa and A.J.P.White 'Stereoselective Synthesis of cis- and trans-2,3-Disubstituted Tetrahydrofurans via Oxonium-Prins Cyclization – Access to the Cordigol Ring System' Org. Lett. 2010, 12, 900-903.

SnBr₄-promoted oxonium-Prins cyclizations to form 2,3-disubstituted tetrahydrofurans (THFs) are reported. In the absence of an internal nucleophile the carbocation intermediates are trapped by bromide to give 2,3-cis- and 2,3-trans-configured products; two variations with intramolecular trapping are also reported. One of these allows a single-step stereocontrolled synthesis of the core 2,3-cis-THF ring system of cordigol, a fungicidal polyphenol from the stem bark of Cordia goetzei. For this latter transformation, a stepwise oxonium-Prins/cation trapping pathway rather than orthoquinonemethide formation/hetero Diels-Alder cycloaddition is supported computationally.

Jan 2010 - Rimonabant work Highlighted in Synfacts

Our recent publication: Alan C. Spivey, Chih-Chung Tseng, Teyrnon C. Jones, Andrew D. Kohler and George J. Ellames 'A Method for the Parallel Solid-Phase Synthesis of Iodinated Analogues of the CB1 Receptor Inverse Agonist Rimonabant', Org. Lett. 2009, 11, 4760-4763 is featured in Synfacts 2010, 1, 115.

A method for the parallel solid-phase synthesis (SPS) of iodinated analogues of Sanofi-Aventis' type 1 cannabinoid (CB1) receptor inve rse agonist rimonabant (acomplia) has been developed. The method allows the synthesis of a range of C3 amide/hydrazide derivatives from a resin-bound C3 ester precursor. The C-Ge linkage to the hypogel-200 resin is stable to the diversification conditions but allows ipso-iododegermylative cleavage using NaI/NCS even for the products containing the oxidatively labile hydrazide moiety.

J.L. Carr, D.A. Offermann, M.D. Holdom, P. Dusart, A.J.P. White, A.J. Beavil, R.J. Leatherbarrow, S.D. Lindell, B.J. Sutton and A.C. Spivey 'Total Synthesis of (±)-Aspercyclide A and its C19 Methyl Ether'Chem. Comm. 2010, 46, 1824-1826.

The total synthesis of (±)-aspercyclide A and its C19 methyl ether derivative are described. Enzyme-linked immunosorbent assay (ELISA) studies demonstrate that both compounds display comparable antagonist activity against the IgE-FceRI protein-protein interaction

Oct 2009 - Review Chapter on Ge-Linkers in Wiley SPOS BookPublished

A.C. Spivey, C.M. Diaper, ‘Silicon and Germanium Linker Units’, in Linker Strategies in Solid-Phase Organic Synthesis Ed. P. Scott, Wiley-VCH, 2009, Chapter 16, 467-504.

Chapter 16 is a review article entitled Silicon and Germanium Linker Units.

The review provides a comprehensive overview of all silicon and germanium linkers used for Solid Phase Organic Chemistry (SPOS) complete with comparison tables for easy identification of a linker with appropriate characteristics for a particular application and 130 references. Subsections include: The preparation of silyl resins; Activation of Si-H and Si-aryl resins for substrate attachment; Silyl ether linkers; Fragmentation-based silyl linkers; Traceless/diversity silyl linkers; The preparation of germyl resins; Activation of Ge-Me and Ge-aryl resins for substrate attachment; Traceless/diversity germyl linkers.

Oct 2009 - New PhD Student Guillaume George & 4th Year MSci Project Student Fleur Ferguson Join the Group

Guillaume George starts a PhD funded by CRUK. Guillaume was a Chemistry Student at the ESPCI in Paris and also spent a year in Cambridge in the group of Prof Chris Abell prior to coming to Imperial College

Fleur Ferguson is a Chemistry MSci student at Imperial College and joins the group to carry out her final year MSci research project.

Sept 2009 - Andrew Bayly Presents a Poster at Nature Chemical Biology Conference, Cambridge, MA, USA

Andrew R. Bayly and Alan C. Spivey 'Towards New a-Helix Mimetics for Nuclear Receptor-Cofactor Binding Interactions'

Oct 2009 - Communication in Org. Lett. Published

Alan C. Spivey, Chih-Chung Tseng, Teyrnon C. Jones, Andrew D. Kohler and George J. Ellames 'A Method for the Parallel Solid-Phase Synthesis of Iodinated Analogues of the CB1 Receptor Inverse Agonist Rimonabant', Org. Lett. 2009, 11, 4760-4763.

A method for the parallel solid-phase synthesis (SPS) of iodinated analogues of Sanofi-Aventis' type 1 cannabinoid (CB1) receptor inverse agonist rimonabant (acomplia) has been developed. The method allows the synthesis of a range of C3 amide/hydrazide derivatives from a resin-bound C3 ester precursor. The C-Ge linkage to the hypogel-200 resin is stable to the diversification conditions but allows ipso-iododegermylative cleavage using NaI/NCS even for the products containing the oxidatively labile hydrazide moiety.

Sept 2009 - Review Article in Topics in Current Chemistry Published

A.C. Spivey and S. Arseniyadis in Asymmetric Organocatalysis, Ed. B. List, Top. Curr. Chem. 2010,291, 233-280.

A review article entitled Amine, Alcohol & Phosphine Catalysts for Acyl Transfer Reactions

An overview of the area of organocatalytic asymmetric acyl transfer processes is presented includingO- and N-acylation. The material has been ordered according to the structural class of catalyst employed rather than reaction type with the intention to draw mechanistic parallels between the manner in which the various reactions are accelerated by the catalysts and the concepts employed to control transfer of chiral information from the catalyst to the substrates.

Aug 2009 - News & Views Article in Na ture Chemistry Published

M.J. Webber and A.C. Spivey, 'Molecular Modelling: Supporting Saytzeff', Nature Chemistry - News & Views 2009, 1, 435-436.

Highlighting a recent report from Hiberty et al. who used a computational technique to derive the physical origin of Saytzeff's Rule.