Collaborative Projects

Over the years, we have enjoyed fruitful collaborations on a number of multidisciplinary projects. Some of these are highlighted below:

Macrocyclon: Structure-Activity-Relationship

 

Collaborators: Helen Hailes (University College London), Alison Hill (University of Exeter)

 

Synthesised by Cornforth in 1951, Macrocyclon was found to exhibit greater anti-tuberculosis activity than Streptomycin. More recently, biological studies showed that Macrocyclon exhibits a novel mechanism of action that is different from drugs currently used against tuberculosis. This has re-ignited substantial interest in the molecule as an exciting therapeutic candidate for the treatment of MDR-TB.

The active ingredient of Macrocyclon is not known, as it contains a mixture of  para-octyl-calix[8]arenes, flanked by highly substituted alkyl groups on the upper rim, and variable polyethylene glycol chains on the lower rim (figure 1). The objective of this project is to synthesise a series of Macrocyclon analogues, with systematic variations in the p-substituent (R), the terminal group (R’) and the chain length (n), such that the biological effect of each of these components can be delineated by SAR studies.

Publications:

 

1. "Multigram synthesis of well-defined extended bifunctional polyethylene glycol chains", F. A. Loiseau, A. M. Hill and K. K. Hii, J. Org. Chem., 2004, 69, 639-647.

DOI: 10.1021/jo035042v

 

2. "Preparation of Macrocyclon Analogues: Calix[8]arenes with Extended Polyethylene Glycol Chains", F. A. Loiseau, A. M. Hill and K. K. Hii, Tetrahedron, 2007, 63, 9947-9959.

DOI: 10.1016/j.tet.2007.07.057

Figure 1. Macrocyclon derivatives.

"In situ Investigation of the Oxidative Addition in Homogeneous Pd Catalysts by Synchronised Time Resolved UV-Vis/XAFS", G. Guilera, M. A. Newton, C. Polli, M. Guinó and K. K. Hii, Chem. Commun., 2006, 4306-4309.

DOI:10.1039/b606772g

Abstract: Simultaneous structuro-kinetic information obtained via time-resolved stopped-flow/UV-Vis spectroscopy/dispersive EXAFS (EDE) experiments (figure 1) elucidated a two-step process for the addition of iodobenzene to [(Ph3P)2Pd(dba)] (Scheme 1).

Figure 1. Real time variation of UV-vis spectral bands (432 and 491 nm) and the corresponding XANES feature as 10 eq. of PhI are added to the toluene solution of [(PPh3)2Pd(dba)] (40 mM).

Scheme 1. Relative timescales of oxidative addition and subsequent cis-trans isomerisation reactions.

Coupling fast X-ray and spectroscopic techniques for mechanistic investigations

 

Collaborators: Gemma Guilera and Mark Newton (European Synchrotron Research Facilities, ESRF, Grenoble, France)

Development of Scaleable Atom-Economical Redox Reactions

 

Collaborators: Dr. Klaus Hellgardt and Prof. Geoff Kelsall (Department of Chemical Engineering, Imperial College London)

 

The project initiated in 2009 with funding from the EPSRC and the Pharmacat Consortium (AstraZeneca, GlaxoSmithKline and Pfizer). The aim is to develop green processes for the oxidation and reduction of organic molecules, utilising a combination of electrochemistry, flow and catalytic technology.

 

 

Molecular modelling of catalyst transition states

Collaborator: Prof. Henry S. Rzepa (Imperial College London)

Unusual Regiodivergence in Metal-Catalysed Intramolecular Cyclisation of g-Allenols, J.  L. Arbour, H. S. Rzepa, A. J. P. White and K. K. Hii, Chem. Commun., 2009, 7125-7127.

DOI: 10.1039/b913295c

Abstract: Different O-heterocycles can be obtained from a common g-allenol precursor by using Ag, Zn or Sn catalysts; the results were rationalised by molecular modelling.

Catalysis in flow: the practical and selective aerobic oxidation of alcohols to aldehydes and ketones, N. Zotova, K. Hellgardt, G. H. Kelsall, A. S. Jessiman and K. K. Hii, Green Chem., 2010, 12, 2157-2163.

DOI: 10.1039/C0GC00493F

Abstract: A safe, practical and selective process for the aerobic oxidation of alcohols to aldehydes and ketones has been developed using an Ru catalyst in a continuous flow reactor. Benzylic and allylic alcohols are oxidised selectively to their corresponding aldehydes and ketones, including substrates containing N- and S-heteroatoms. The rate of turnover is compatible with that previously reported using batch or microchannel reactors under optimised conditions. A preliminary kinetic model is derived that is supported by experimental observations. Last but not least, tandem oxidation–olefination may be achieved without the need to isolate the alcohol intermediate or to switch solvent.

Catalysis in flow: Au-catalysed alkylation of amines by alcohols, NN. Zotova, F. J. Roberts, G. H. Kelsall, A. S. Jessiman, K. Hellgardt, and K. K. Hii, Green Chem., 2012, 14, 226.

DOI: 10.1039/c1gc16118k

Abstract: By using a greater reaction space afforded by a flow reactor, commercially available Au/TiO2 can be used for highly selective direct alkylation of amines by alcohols, without the need for an inert atmosphere or base. A brief survey of substrates includes the alkylation of aromatic, aliphatic and chiral amines by a number of primary and secondary alcohols, in high yield and selectivity. The synthesis of Piribedil, a drug used in the treatment of Parkinson’s disease, can be achieved in a single synthetic operation without the need for column chromatography. Mechanistic aspects of the reaction were revealed through modelling of reaction profiles, and the origin of selectivity is attributed to the accessibility of high temperature. The presence of water was found to be crucial for catalyst activity.

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