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Professor T.J. Donohoe

Organic Chemistry

timothy.donohoe@chem.ox.ac.uk

Telephone: 44 (0) 1865 275 649

Research Group Web Pages

Tim co-manages OxSynC, which helps to connect Oxford Synthetic Chemistry experts with researchers in other fields

Group News

December 2013 A recent paper by Chris and Anne on first and second generation synthesis routes to the anti-tumour compound Streptonigrin, was selected by J. Org. Chem as a Featured Article.

November 2013 A new paper by Louis, Darren and Di on ketone methylation using methanol was selected by Angewandte Chemie as a Hot Paper. Images from the paper were also selected for the Angewandte cover.

October 2013 Congratulations to Kate Melikhova (2nd year DPhil), who has recently been awarded one of the Lilly Prizes for Excellence in Organic Chemistry Research for her first year work.

July 2013 Congratulations to Johannes Walker (part II student), who has recently been awarded a Departmental prize for the quality of his part II thesis.

July 2013 Congratulations to Kate Melikhova (1st year DPhil), who has recently been awarded a scholarship by the SCI.

April 2013 A postdoc position, funded by EPSRC, is available in the group, to start on or soon after 01/06/2013. Please see: http://www.chem.ox.ac.uk/jobs.asp

March 2013 Jobs! many congratulations to Rob Pullin who has recently been offered a job as a medicinal chemist at Vertex, and to Ben Pilgrim who will take up a Herchel Smith Postdoctoral Research Fellowship at the University of Cambridge in conjunction with a Fellowship at Corpus Christi College; also to Chris Jones who was recently awarded an independent Ramsay Memorial Fellowship to be held at Queen Mary, University of London.

December 2012 Radek Lipinski's paper on the synthesis of the ABC ring system of pectenotoxin-4 is designated as a Hot Paper in Angewandte Chemie.

November 2012 Congratulations to Matthew Tatton (3rd year DPhil) who was recently awarded a Syngenta sponsored Scientific Scholarship.

August 2012 Tim has won the 2012 AstraZeneca, GlaxoSmithKline, Pfizer & Syngenta Prize for Process Chemistry Research. The award will be presented at the forthcoming 30th SCI Process Development Symposium held in Cambridge between 5th-7th December. Tim will receive a trophy and a cheque for £16000 to support further research.

February 2012 Congratulations to Christian Winter and Robert Pullin, who along with David Daniels (Ed Andersen group) were winners of the SCI's 1st National Retrosynthesis Competition. Ten teams, from both academia and industry, were selected for the final, which was held on 29th February at the SCI, London. Their presentation of the retro- and forward synthesis of Alsmaphophorazine E, was judged overall winner of the competition

October 2011 Well done to Ben Pilgrim, a third year DPhil student who was awarded a poster prize at the Organic Chemistry Poster Symposium held in the CRL. Ben’s poster was entitled the ‘Palladium-Catalyzed Synthesis of Isoquinolines’.

September 2011 Congratulations to Ben Pilgrim, a third year DPhil student who has been awarded a poster prize at the 26^th Postgraduate Symposium of the RSC Heterocyclic and Synthesis Group. The symposium was held at the AstraZeneca site at Alderley Edge on 22^nd September. Ben’s poster was entitled the ‘Palladium-Catalyzed Synthesis of Isoquinolines’.

September 2011 Congratulations to Chris Jones who has recently completed the synthesis of streptonigrin in 14 linear steps and 11% overall yield. This work was recently accepted for publication in J. Am. Chem. Soc

July 2011 Congratulations to Alice Gatland who has been awarded one of the Departmental Thesis Prizes for her Part II thesis entitled A novel hydride shift approach to the synthesis of spiroketals.

May 2011 Tim has been awarded the 2011 Synthetic Organic Chemistry Award by the Royal Society of Chemistry. The prize is given for the development of new methods or strategies employed in the construction of organic molecules. The prize will be presented at a symposium held later in the year.

May 2011 A paper on work done by Ben Pilgrim and Leigh Aldous (in collaboration with Richard Compton) was chosen as a 'hot article' by the New Journal of Chemistry.

April 2011 Well done to Paul Winship who has recently completed the synthesis of (-)-neodysiherbane A: Paul's route takes just 7 steps and the overall yield is 24%. The work has recently been accepted for publication in Angewandte Chemie.

October 2010 Congratulations to D.Phil student Darren Poole for winning a GlaxoSmithKline Award in Organic Chemistry Part II. These prizes are awarded to the two highest ranked Oxford graduates who continue into postgraduate research in Organic Chemistry at Oxford.

September 2010 Congratulations to D. Phil student Mike Tucker who has been awarded one of the Lilly Prizes for Excellence in Organic Chemistry Research for his first year work.

July 2010 Congratulations to Part II students Nick Race and Constanze Neumann who have both won prizes for their final year Part II theses. Nick won the Brian Bannister prize and Constanze won a runners-up prize.

February 2010 Science, PNAS and Nature Chemistry journals highlight Donohoe group work on metathesis.
Science, PNAS and Nature Chemistry journals have both highlighted work recently published by the Donohoe group on the construction of aromatic compounds using cross metathesis (T. J. Donohoe, J. F. Bower, PNAS, 2010, 107, 3373). This work features a first in class method of making valuable organic compounds in a particularly concise manner and application to the synthesis of complex pharmaceutical and natural product targets is anticipated.

More news can be found here.

Research

Our research interests are in synthetic organic chemistry, and the contribution that this science can make to the fields of medicine and natural products. We concentrate on developing new methodologies for synthetic organic chemistry and asymmetric synthesis and then employing our chemistry to make biologically important natural products.

Our work is directly relevant to the pharmaceutical industry and the research group is supported by multi-national companies including Merck, AstraZeneca, GlaxoSmithKline, Lily, Novartis, Roche, Aventis and Pfizer. The facilities available for research in our labs in the CRL are second to none.

The research group consists of four part II’s, twelve DPhil students and four postdoctoral assistants. We meet two/three times per week to discuss advances in the laboratory and hold problem sessions to highlight recent developments in the literature.

We are an active and vibrant research group with a positive dynamic and friendly atmosphere. Excellent support is given to new part II’s and DPhil students in the form of mentorship by a senior group members. Our research interests are wide ranging, encompassing osmium-mediated processes, Birch reduction of pyrroles and pyridinium salts, carbohydrate chemistry and ring closing metathesis as a strategy for the formation of aromatic heterocycles. With each new method that we develop, we are also keen to show that it is useful in total synthesis. In this regard, the group has built up significant expertise in the synthesis of natural products; some of our current targets are shown below.

Oxidation: One research theme is the controlled oxidation of alkenes with catalytic osmium reagents. Our work on the tethered aminohydroxylation of allylic carbamates has encompassed an understanding of the mechanism and introduced a new set of N-O based re-oxidants into the aminohydroxylation regimen (the result is a much more powerful and high yielding aminohydroxylation procedure). This methodology allowed us to prepare the aminocyclitol (-)-hygromycin in a particularly efficient manner. Our work culminated in a completion of the synthesis of the natural product in only 17 linear steps (and 10% overall yield) by using a Mitsunobu glycosylation that allowed the formation of the difficult glycoside linkage with good stereoselectivity.

Our investigations into the osmium mediated formation of THFs and pyrrolidines from diols and aminoalcohols, revealed the advantages of utilising the Os(IV)-(VI) couple, avoiding the presence of Os(VIII). We also uncovered an OMs displacement/ hydride shift sequence, followed by intramolecular trapping of the oxonium ion to form a trans-THF (supported by deuterium labelling). The combination of double oxidative cyclisation and a hydride shift was used in the synthesis of the natural products (+)-cis-sylvaticin and (+)-sylvaticin.

Partial Reduction We have a longstanding interest in developing the partial reduction of aromatic heterocycles using single electron reducing agents such as LiDBB. Our work has been able to reduce pyrroles, pyridines and furans in a selective and high yielding manner, and the heterocycles that are prepared via this chemistry have lots of potential for natural (and medicinal) product synthesis. In fact, each of these aromatic ring systems has been used as the starting point in the synthesis of complex and biologically active natural products.

By studying the mechanism using cyclic voltammetry (with R. G. Compton) we have been able to understand the processes that take place and design new arenes for partial reduction, thus allowing greater scope for synthetic work.

Selected Publications

Publications (>160 publications; those so far since 2011 are shown below; full list available here).

1) Osmium-free direct syn-dihydroxylation of alkenes, Carole J. R. Bataille and Timothy J. Donohoe, Chem. Soc. Rev. 2011, 40, 114-128.

2) Recent Developments in Methodology for the Direct Oxyamination of Olefins, Timothy J. Donohoe, Aida Flores, Cedric K.A. Callens, Adam J. Lacy, Akshat H. Rathi, Chem. Eur. J., 2011, 17, 58-76.

3) Heteroaromatic Synthesis via Olefin Cross-Metathesis: Entry to Polysubstituted Pyridines, Timothy J. Donohoe, José Basutto, Akshat H. Rathi and John F. Bower, Organic Letters, 2011, 13, 1036-1039.

4) Palladium nanoparticle-modified carbon nanotubes for electrochemical hydrogenolysis in ionic liquids, Yao Meng, Leigh Aldous, Ben S. Pilgrim, Timothy J. Donohoe and Richard G. Compton, New Journal of Chemistry, 2011, 35, 1369-1375.

5) Exerting Control over the Acyloin Reaction, Timothy J. Donohoe, Ali Jahanshahi, Michael J. Tucker, Farrah L. Bhatti, IshmaelA. Roslan, Mikhail Kabeshov and Gail Wrigley, Chemical Communications, 2011, 47, 5849-5851.

6) Dehydrogenation of Cyclic-Thioethers Bound to a [Rh(diphosphine)]+ Fragment, Romeao Dallanegra, Ben S. Pilgrim, Adrian B. Chaplin, Timothy J. Donohoe and Andrew S. Weller, Dalton Transactions, 2011, 40, 6626-6628.

7) A short and efficient synthesis of neodysiherbaine A using catalytic oxidative cyclisation, Timothy J. Donohoe, Paul Winship, Matthew R. Tatton and Peter Szeto, Angewandte Chemie, Int. Ed. 2011, 50, 7604-7606.

8) Intramolecular Hydride Addition to Pyridinium Salts: New Routes to Enantiopure Dihydropyridones, Timothy J. Donohoe, Matthew J. Connolly, Akshat H. Rathi and Lesley Walton, Organic Letters, 2011, 13, 2074-2077.

9) The Influence of Exocyclic Stereochemistry on the Tethered Aminohydroxylation Reaction, Timothy J. Donohoe, Adam R. Lacy, Akshat H. Rathi, and Daryl S. Walter, Chemistry: An Aisian Journal, 2011, 6, 3214-3222.

10) Surface plasmon resonance imaging of glycoarrays identifies novel and unnatural carbohydrate-based ligands for potential ricin sensor development, Margherita Fais, Rositsa Karamanska, Sarah Allman, Shirley A. Fairhurst, Paolo Innocenti, Antony J. Fairbanks, Timothy J. Donohoe, Benjamin G. Davis, David A. Russell and Robert A. Field, Chemical Science, 2011, 2, 1952.

11) Tethered aminohydroxylation, Timothy J. Donohoe and Stefanie Mesch, Asymmetric Synthesis – The Essentials II. Edited by Mathias Christmann and Stefan Brase, WILEY-VCH, 2011, in the press.

12) Synthesis of 2,4,6-Trisubstituted Pyridines via an Olefin Cross-Metathesis/Heck-Cyclisation-Elimination Sequence, Timothy J. Donohoe, John F. Bower, David B. Baker,José A. Basutto, Louis K. M. Chan and Peter Gallagher, Chemical Communications, 2011, 47, 10611.

13) Amino acid based reoxidants for aminohydroxylation: application to the construction of amino acid-aminoalcohol conjugates, Timothy J. Donohoe, Cedric K. A. Callens, Aida Flores, Stefanie Mesch, Darren L. Poole and Ishmael A. Roslan, Angewandte Chemie Int Ed., 2011, 50, 10957.

14) Total Synthesis of (±)-Streptonigrin: De-novo Construction of a Pentasubstituted Pyridine using Ring Closing Metathesis, Timothy J. Donohoe, Christopher Jones and Luiz Claudio Barbosa, J. Am. Chem. Soc., 2011, 133, 16418.

15) Improvements in the Tethered Aminohydroxylation Reaction and its Application to Total Synthesis, Timothy J. Donohoe, Cedric K. A. Callens, Adam R. Lacy, Christian Winter, European Journal of Organic Chemistry, 2012, 643-650 (plus cover picture for this issue).

16) Direct Preparation of thiazoles, imidazoles, imidazopyridines and thiazolidines from alkenes, Timothy J. Donohoe, Mikhail Kabeshov, Akshat Rathi and Ian E. D. Smith, Org. Biomol. Chem., 2012, 10, 1093-1101.

17) Olefin Cross-Metathesis for the Synthesis of Heteroaromatic Compounds, Timothy J. Donohoe, John F. Bower and Louis K. M. Chan, Organic and Biomolecular Chemistry, 2012, 10, 1322-1328. Designated as a Hot Article.

18) Hydrogen-Bonding-Mediated Directed Osmium Dihydroxylation, Timothy J. Donohoe,* Carole J. R. Bataille, Paolo Innocenti, Organic Reactions 2012, 76, 1-47. ISBN:978-0-470-63843-9.

19) A green approach to Fenton chemistry: Hydroxylation of salicylic acid in aqueous medium using electrogeneration of Fenton's Reagent. J. Panchompoo, L. Aldous, R. G.Compton, M. Kabeshov, B. Pilgrim, T. J. Donohoe, New. J. Chem. 2012, 36, 1265.

20) Synthesis of substituted isoquinolines utilizing palladium-catalyzed α-arylation of ketones, T. J. Donohoe, B. S. Pilgrim, G. R. Jones, J. A. Bassuto, Proc Natl Acad Sci USA, 2012, 109, 11605-11608.

21) Natural Product Synthesis as a Challenging Test of Newly Developed Methodology, T. J. Donohoe, R. Pullin, Chemical Commun. 2012, 48, 11924-11938.

22) Asymmetric Synthesis of the Fully Elaborated Pyrrolidone Core of Oxazolomycin A, T. J. Donohoe, T. J. C. O'Riordan, M. Peifer, C. R. Jones, T. J. Miles, Organic Lett. 2012, 14, 5460-5463.

23) Partial and complete reduction of pyrroles, furans, thiophenes and their benzo-analogues and of aromatic heterocycles containing more than one heteroatom, Timothy J. Donohoe,* Christopher Jones and Christian Winter, Comprehensive Organic Synthesis II , Ed. G. Molander and P. Knochel, Elsevier, 2013, in the press.

24) Oxidative cyclisation for the synthesis of complex THF-containing natural products, Timothy, J. Donohoe, R. D. C. Pullin, Radoslaw M. Lipinski, Pure & Applied Chem. 2013, 85, 1175-1184.

25) Interplay of cascade oxidative cyclisation and hydride shifts in the synthesis of the ABC spiroketal ring system of pectenotoxin-4, T. J. Donohoe, R. M. Lipinski, Angewandte Chemie, 2013, 52, 2491-2494. Designated as a HOT paper.

26) Osmium-Catalyzed Oxidative Cyclization of Dienes and their Derivatives, Timothy J. Donohoe* and Ben Pilgrim, Journal of Organic Chemistry, 2013, 78, 2149-2167. Work from this paper featured in the cover picture for JOC.

27) Vinyl Weinreb Amides: A Versatile Alternative to Vinyl Ketone Substrates for Heck Arylation, David Baker, Peter Gallagher and Timothy J. Donohoe,* Tetrahedron, 2013, 69, 3690-3697.

28) Lithium-4,4'-Di-tert-butylbiphenylide, Christopher R. Jones and Timothy J. Donohoe, Encyclopedia of Reagents for Organic Synthesis, 2013, in the press.

29) Tethered Aminohydroxylation: Synthesis of the β Amino Acid of Microsclerodermins A and B, Robert Pullin, Akshat Rathi, Ekaterina Melikhova, Christian Winter, Amber Thompson and Timothy J. Donohoe, Organic Letters, 2013, 15, 5492-5495.

30) Modular isoquinoline synthesis using catalytic enolate arylation and in-situ functionalization, Ben Pilgrim, Alice Gatland, Charlie McTernan, Panayiotis Procopiou, Timothy Donohoe, Organic Letters, 2013, 15, 6190-6193.

31) Total Synthesis of the Antitumor Antibiotic (+/-)-Streptonigrin: First and Second Generation Routes for de-novo Pyridine Formation using Ring Closing Metathesis, Timothy Donohoe, Christopher Jones, Anne Kornahrens, Luiz Barbosa, Louise Walport, Matthew Tatton, Michael O'Hagan, Akshat Rathi, David Baker, J. Org. Chem. 2013, 78, 12338-12350. Selected as a Featured Article.

32) Rhodium-Catalyzed Ketone Methylation Using Methanol Under Mild Conditions: Formation of Alpha-Branched Products, Louis K. M. Chan, Darren L. Poole, Di Shen, Mark P. Healy and Timothy J. Donohoe, Angewandte Chemie Int. Ed., 2014, 53, 761-765. Designated as a HOT paper.