Page 20 - PERIODIC Magazine Issue 6

Co
A Chemical llaboration

Biopharmaceutical leader UCB has teamed up with the Department of
Chemistry to create the Late Stage Functionalisation (LSF) project, a new
synthetic programme designed to produce industrially-relevant compounds
with real world applications.

Four academics from Organic Chemistry - Professors
Christopher Schofield, Darren Dixon, Martin Smith and
Michael Willis - as well as a group of four post-doctoral
researchers, are the Oxford team in the industrial
collaboration between the Department and Anglo-Belgian
biopharmaceutical company UCB.
Whereas many projects involve the synthesis of
compounds in the hope that pharmaceutical companies Through this sulfonation method a number of drugs have
would be interested in producing them on a larger scale, been functionalised, including Linezolid, an antibiotic
this project differs in that UCB communicate with the used to treat bacterial pneumonia, and Promethazine, an
department directly on the problems that they want antihistamine with a variety of medical uses.
solved. All of these projects involve the functionalisation
of compounds at a late or final stage of syntheses; the “The LSF approach allows us to append different groups
synthetic methodologies are developed by the department to complex molecules,” explains Professor Michael Willis.
and used on prototype scaffolds typically seen in “The introduction of polar groups at the end of a long
medicinal chemistry programmes, then utilised by UCB to synthetic route means that there are far fewer protection
functionalise complex drug molecules containing similar steps, which is highly desirable.”
functional groups.
Part of the success of the project is down to the technology
Synthetic organic chemistry in recent years has focussed that the scientists working on the LSF project have at
on the addition of non-polar functional groups, such as their disposal. The Art Robbins ‘Scorpion’ is a high-tech
alkanes, to compounds. The LSF project, however, is piece of equipment that can be used to perform high-
based on the introduction of polar functionalities, such throughput chemistry; 96 different reactions can be carried
as cyanides (RCN), sulfonyls (SO R), alcohols (ROH) and out at the same time, allowing the rapid optimisation of
2
azides (RN ), where R is usually an aromatic, drug-like reaction conditions. This is linked to a UPLC (ultra-high
3
group. Thus far, the group have successfully synthesised a performance liquid chromatography) system, which
range of cyanides of 6-ring N-containing heteroaromatics, produces data relating to the chemical reactions rapidly,
as well as sulfonylated anilines, using the LSF method. ready for the scientists to analyse. The use of automated
chemistry removes labour intensive processes and means
An example of this research in action is the sulfonation that optimal reaction conditions can be discovered faster.
of anilines using light-mediated catalysis. The amine
substrate is oxidised to its radical form and reacted with a The LSF team plan to continue the polar functionalisation
sulfonyl radical, generated through the oxidation of sodium of drug molecules, however there is also a lot of scope for
methanesulfinate (MeSO Na), forming the sulfonated future projects using similar techniques. “Adapting our
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product. Both oxidation reactions occur through the methodology for use in Chemical Biology is something
use of iridium catalysis; this is through the reduction of that we’re interested in at the moment” explained Bryony
an Ir species to an Ir species. The iridium catalyst is Elbert, a post-doctoral researcher working on the project.
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IV
regenerated using visible light and a sacrificial molecule of “For example, we could use the chemistry to make
K S O . probes to try to figure out what’s happening in biological
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reactions.”
The product of this reaction is not a drug target itself,
however the synthetic methodology developed by The LSF model is an exciting project that shows a lot of
the Department can subsequently be used by UCB to promise; although still in its early stages, it has already
sulfonate lead compounds; the science is developed reminded the scientific community how important it is to
by the department and employed in house by UCB. consider new ways of tackling challenging syntheses.

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Periodic The Magazine of the Department of Chemistry