Research in this group is concentrated in the 'core science' area of organic synthesis, primarily in three interrelated themes: the discovery of new reactions, the invention of new stereocontrolled processes, especially for asymmetric synthesis, and the application of new chemical ideas to natural product synthesis. We are, in general, interested in discovering new reactions and reagents, and in applying our chemistry to problems in synthesis. The major areas are outlined below.
Natural Product Synthesis
The design of efficient and elegant pathways for the synthesis of complex natural products remains a fascinating and testing area for research in organic chemistry. Some of our current targets are shown below.
Asymmetric Synthesis
The search for new and ever more selective reactions, especially for asymmetric synthesis, is one of the most important and challenging topics for research today. We are interested in developing new methods for the enantioselective control of organic reactions. This research falls into three main areas:
- Atom-transfer catalysts and reagents for oxidation, epoxidation and aziridination
- The development of novel ligand systems for metal-mediated transformations
- New asymmetric systems for chiral recognition
Atom-Transfer Catalysts and Reagents: Sulfoxidation
We are interested in developing new methods for the enantioselective control of organic reactions, and a particularly important development was the discovery of a new and highly enantioselective catalytic system for asymmetric oxidation, for example of sulfides (illustrated left) and alkenes. This system, which uses hydrogen peroxide as the oxidant and an optically pure sulfonylimine as chiral mediator, is remarkably simple to carry out, requires no preparation and isolation of sensitive reagent, no close monitoring, and provides remarkably clean reactions in an inexpensive and environmentally friendly process.
Synth. Commun., 2003, 1943-1949
J. Org. Chem., 2000, 65, 6756-6760
Tetrahedron, 2000, 56, 9683-9695
Phosphorus, Sulfur and Silicon, 1999, 153, 247-258
Tetrahedron, 1998,54, 14581-14596
Org. Chem., 1997, 62, 6093-6094
We have applied some of the key ideas of this process to the challenging area of catalytic asymmetric epoxidation of alkenes. Our approach employs imminium ion salts as catalysts in the presence of either OxoneTM or tetraphenylphosphonium mono-peroxysulfate (TPPP) as the stoichiometric oxidant. Investigations using asymmetric tetrahydroisoquinolinium salts have provided promise the simple and mild procedure described with unprecidented ees of up to 97%. This has resulted in the enantiopure synthesis of the anti-hypertensive agent Levcromakalim.
Tetrahedron, 2006, 62, 6607-6613
Synthesis, 2005, 3405-3411
Tetrahedron Asymmetry, 2005, 16, 3488-3491
Org. Lett., 2005, 7, 375-377
J. Org. Chem., 2004, 69,3595-3597
Org. Lett., 2004, 6, 1543-1546
Synlett, 2002, 580-582
J. Org. Chem., 2001, 66, 6926-6931
J. Chem. Soc.-Perkin Trans. 1, 2000, 3325-3334
Atom-Transfer Catalysts and Reagents: Nitrogen-Transfer
Also with potential application in the area of atom-transfer processes, we have recently reported the first stable enantiomerically pure N-H oxiziridines. We are actively investigating their application as chiral electrophilic nitrogen-transfer agents. This approach offers an interesting alternative to the traditional chiral auxiliary chemistry.
J. Org. Chem., 2002, 67,7787-7796
J. Org. Chem., 2000, 65, 4204-4207
Ligand Systems for Metal-Mediated Transformations: Allylic Substitution
Synlett, 2000, 379-381
We have recently described the first enantioselective syntheses of a number of enantiomerically pure calix[4]resoricinarene derivatives. Our route enables ready access to multigram quantities of the diastereoisomerically pure tetrakis(benzoxazines) (below) in a short route starting from resorcinol and dodecanal. Subsequent transformation provides C4n symmetric calix[4]resorcinarene derivatives as single enantiomers. The residual phenol and secondary amine groups allow for further functionalistaion and the possibility of accessing a wide range of axially chiral calix[4]resorcinarene derivatives. We are actively preparing materials of this type and investigating their application in the areas of chiral recognition and asymmetric catalysis.
Eur. J. Org. Chem., 2006, 5135-5151
Eur. J. Org. Chem., 2006, 5117-5134
Tetrahedron, 2005, 61, 5876-5888
Eur. J. Org. Chem., 2004, 5126-5134
Synlett, 2004, 2606-2608
Tetrahedron Lett., 2003, 44, 2965-2970
Synlett, 2003, 997-1001
Synlett, 2003, 1002-1006
Synlett, 2001, 412-414
J. Am. Chem. Soc., 1999, 121, 6751-6752
Chiral Recognition Agents: Calix[4]resorcinarene Derivatives
The bowl-shape of these molecules is evident from this x-ray structure representation of a tetrakis(benzoxazine).
1.'An ytterbium-catalysed intramolecular aldehyde-ene reaction approach to guaianolide and pseudoguaianolide diterpenoids: Synthesis of the guaiane skeleton',
P C B Page, G Gambera, C M Hayman, M Edgar, Synlett, 2006, 3411-3414
2.'The preparation and absolute configurations of enantiomerically pure C4 symmetric tetra-alkoxyresorcin[4]arenes obtained from camphorsulfonate derivatives',
B R Buckley, P C B Page, Y Chan, H Heaney, M Klaes, M J McIldowie, V McKee, J Mattay, M Mocerino, E Moreno, B W Skelton, A H White, Eur. J. Org. Chem., 2006, 5135-5151
3.'Mannich and o-Alkylation Reactions of Tetraalkoxyresorcin[4]arenes. The Use of Some Products in Ligand Assisted reactions',
B R Buckley, J Y Boxhall, P C B Page, Y Chan, M R J Elsegood, H Heaney, K E Holmes, M J McIldowie, V McKee, M J McGrath, M Mocerino, A M Poulton, E P Sampler, B W Skelton, A H White, Eur. J. Org. Chem., 2006, 5117-5134
4.'Non-aqueous iminium salt mediated catalytic asymmetric epoxidation',
P C B Page, B R Buckley, D Barros, A J Blacker, H Heaney, B A Marples, Symposium in Print 'Recent advances in oxidation chemistry', Tetrahedron, 2006, 62, 6607-6613
5.'New chiral iminium salt catalysts for asymmetric epoxidation,'
P C B Page, B R Buckley, G A Rassias, A J Blacker, Eur. J. Org. Chem., 2006, 803-813
6.'Highly Efficient Catalysts for Epoxidation Mediated by Iminium Salts',
P C B Page, B R Buckley, L F Appleby, P A Alsters, Synthesis, 2005, 3405-3411
7.'Organocatalysis of asymmetric epoxidation mediated by iminium salts: Comments on the mechanism',
P C B Page, D Barros, B R Buckley, A J Blacker, B A Marples, Tetrahedron Asymmetry, 2005, 16, 3488-3491
8.'A New Paradigm in N-Heterocyclic Carbenoid Ligands',
P C B Page, B R Buckley, S D R Christie, M Edgar, A M Poulton, M R J Elsegood, V McKee, J. Organomet. Chem., 2005, 690, 6210-6216
9.'The highly diastereoselective synthesis of oxazolidines derived from ketones and ephedrine and pseudoephedrine',
B R Buckley, P C B Page, M Edgar, M R J Elsegood, C M Hayman, H Heaney, G A Rassias, S A Talib, J Liddle, S A Readshaw, Synlett, 2005, 971
10.'Asymmetric epoxidation of cis-alkenes mediated by iminium salts; highly enantioselective synthesis of levcromakalim',
P C B Page, H Heaney, B R Buckley, B A Marples, A J Blacker, Org. Lett., 2005, 7, 375-377
11.'The efficient synthesis of alkoxyesters from hydroxy carboxylic acids using dimsyllithium in dimethylsulfoxide followed by alkylation with an alkyl halide',
P C B Page, Y Chan, H Heaney, M J McGrath, E Moreno, Synlett, 2004, 2606-2608
12.'Organocatalysis of asymmetric epoxidation mediated by iminium salts under non-aqueous conditions',
P C B Page, D Barros, B R Buckley, A Ardakani, B A Marples, J. Org. Chem., 2004, 69, 3595-3597
13.'Iminium salt catalysts for asymmetric epoxidation: The first high enantioselectivities',
P C B Page, B R Buckley and A J Blacker, Org. Lett., 2004, 6, 1543-1546
14.'Heterogeneous enantioselective catalysed carbonyl- and imino- ene reactions using copper bis(oxazoline) zeolite Y',
N A Caplan, F E Hancock, P C B Page, G J Hutchings, Angew. Chem. Int. Ed., 2004, 43, 1685-1688
15.'Observation of the enhancement in enantioselectivity with conversion for the aziridination of styrene using copper bis(oxazoline) complexes',
J Gullick, S Taylor, D Ryan, P McMorn, M Coogan, D Bethell, P C B Page, F E Hancock, F King, G J Hutchings, Chem. Commun., 2003, 2808-2809
16.'Synthesis of an isomer of the oxaspirobicyclic tetronic acid unit of the CCK-B receptor antagonist tetronothiodin',
P C B Page, H Vahedi, K J Batchelor, S J Hindley, M Edgar, P Beswick, Synlett, 2003, 1022-1024
17.'A short and versatile route to a key intermediate for lactacystin synthesis',
P C B Page, A S Hamzah, D C Leach, S M Allin, D M Andrews, G A Rassias, Org. Lett., 2003, 5, 353-355
18.'The first stable enantiomerically pure chiral N-H oxaziridines: Synthesis and reactivity',
P C B Page, V L Murrell, C Limousin, D D P Laffan, Donald Bethell, Alexandra M Z Slawin, and Timothy A D Smith, J. Org. Chem., 2000, 67, 4204-4207
19.'An IMDA approach to tigliane and daphnane diterpenoids: Generation of rings A, B and C incorporating C-18',
P C B Page, C M Hayman, H L McFarland, D J Willock, N M Galea, Synlett, 2002, 583-587
20.'The first enantioselective syntheses of axially chiral enantiomerically pure calix[4]resorcinarene derivatives',
P C B Page, H Heaney, E P Sampler, J. Am. Chem. Soc., 1999, 121, 6751-6752
