Mechanistic and kinetic study on the anomerisation reaction and application in pharmaceutical research
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2024-01-08Author
Holland, Trish
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Abstract
It is becoming increasingly apparent that carbohydrate-based pharmaceutically
active compounds (PACs) play a key role in pharmaceutical advancement. Many
new carbohydrate-based PACs have recently been developed with a plethora of
functions ranging from antiviral and anticancer effects to drug delivery systems.
With this increased interest in carbohydrate-based pharmaceutical research,
gaps in the knowledge of carbohydrate chemistry have become apparent, with
many challenges still being faced by carbohydrate chemists, including the
stereoselective synthesis of anomers. The synthesis of glycosidic links is an
essential aspect in the development of carbohydrate-based PACs. A possible
route to the selective synthesis of carbohydrate anomers is the anomerisation
reaction that is generally preformed using a Lewis acid catalyst. The aim of this
thesis was to synthesise the new galacturonic acid derivative 2,3,4-tri-O-acetyl β-D-galactopyranosiduronic acid, methyl ester using the Koenigs-Knorr
glycosylation reaction and investigate the kinetics of the anomerisation of this
compound. The rate constant for this compound was calculated to be 5x10-5 at
RT. This result led to an interest in the varying kinetic rate constants of different
uronic acid derivatives. Therefore, further study of the kinetics of the
anomerisation reaction of previously synthesised compounds was undertaken,
specifically the change in rate constants of the reaction when varying the
temperature, uronic acid derivative and catalyst concentration was investigated.
The three uronic acid derivatives investigated were 2,3,4-Tri-O-acetyl-β-D galactopyranosiduronic acid, methyl ester ,Butyl 2-O-(4-phenylbenzoyl)-3,4-di O-benzoyl-α-D-glucopyranosiduronic acid methyl ester,
Butyl 2-O-(4-bromolbenzoyl)-3,4-di-O-benzoyl-α-D-glucopyranosiduronic acid
methyl ester and Butyl 2-O-(4-methylbenzoyl)-3,4-di-O-benzoyl-α-D glucopyranosiduronic acid, methyl ester
By varying the temperature at which the anomerisation reaction takes place, the
activation energy could be calculated from a set of experimentally determined
rate constants and were found to be 17.71, 60.43 and 30.94 KJ/Mol respectively.
This showed that EDG groups on the C2 substituent tended to increase the
activation energy of the anomerisation reaction for compounds (5) and (6).
Compound (7) activation energy was Due to probable experimental error, the
rate constant calculated for compound (7) at 45°C was disregarded. Therefore
the activation energy calculated may not be as accurate and more investigation
is needed to evaluate trends in the effect of EDG and EWG groups on activation
energy.
Catalyst concentration studies were carried out and it was found that increasing
the concertation above a 1:1 ratio had little to no effect on the reaction rate,
indicating that the rate determining step of this reaction only requires one SnCl4
molecule.