Aspartame (Molecule of the Month for November 2001)
Aspartame is an artificial sweetener. Although it has roughly the same number of calories per gram as table sugar (sucrose), it is around 200 times sweeter. It is also known by the brand names, Nutrasweet, Equal, Spoonful and Equal Measure.
It was discovered by accident by James Schlatter, a chemist of G D Searle Co. in 1965, when he was testing an anti-ulcer drug. Its use in carbonated drinks was finally approved in 1983, following a decade-long battle against the objections of Dr. John Olney (a neuroscience researcher), James Turner (a consumer attorney) and investigations into the research practices of G D Searle.
Two of the components of aspartame (phenylalanine and aspartic acid) are chiral, which means that they have two isomers that are non-superimposable mirror images. This means that the final aspartame molecule will have two stereogenic centers. If the incorrect enantiomers are used, the aspartame molecule will not have the correct shape to fit the binding site of the ‘sweetness’ receptors on the tongue.
In the synthesis of aspartame, the starting materials are a racemic mixture (equal quantities of both enantiomers) of phenylalanine, and aspartic acid. Only the L enantiomer of phenylalanine is used: this is separated from the racemate by reacting it with acetic anhydride and sodium hydroxide. If the product of this reaction is then treated with the enzyme porcine kidney acylase and an organic extraction with H+ carried out, the L enantiomer is found in the aqueous layer and the D enantiomer remains in the organic layer.
Treatment of L-phenylalanine with methanol and hydrochloric acid esterifies the –CO2H group, and this ester is then reacted with aspartic acid to give the final product. It is important that the amine group on aspartic acid is protected with carbobenzyloxy groups and the acid group nearest the amine protected with benzyl groups, to prevent the L-phenylalanine reacting with these and giving unwanted byproducts. The acid group that is required to react is activated with Castro’s reagent. Castro’s reagent is displaced as L-phenylalanine is added, but the protective groups must be removed after the reaction. Carbobenzyloxy is removed by a reaction with hydrogen and platinum (IV) oxide with methanol and chloroform; benzyl is removed by reaction with hydrogen/palladium/carbon plus methanol and chloroform, completing the aspartame synthesis.
Aspartame is hydrolysed in the body to three chemicals, aspartic acid (40%), phenylalanine (50%) and methanol (10%). Aspartic acid is an amino acid. Much research has been carried out to determine its behaviour in the body when it is taken in its free form, i.e. unbound to proteins. It is claimed that when it is ingested the blood plasma levels of aspartate and glutamate rise significantly. Both aspartate and glutamate act as neurotransmitters in the brain, carrying information from neuron to neuron. When there is an excess of neurotransmitter, certain neurons are killed by allowing too much calcium into the cells. This influx causes excessive numbers of free radicals to build up which kill the cells. The neural cell damage that is caused by excessive aspartate and glutamate is the reason they are referred to as ‘excitotoxins’: they ‘excite’ or stimulate the neural cells to death.
Phenylalanine is another amino acid and is found normally in the brain. It is advised that people with the genetic disorder, phenylketonuria (PKU) do not consume aspartame as they are unable to metabolize the phenylalanine that is produced on its hydrolysis. A high level of phenyalanine in the brain is extremely harmful and sometimes fatal.
Methanol is highly toxic; it is gradually released in the small intestine when the methyl group of the aspartame encounters the enzyme chymotrypsin. It has been pointed out that some fruit juices and alcoholic beverages contain small amounts of methanol. It is important to remember, however, that methanol never appears alone. In every case, ethanol is present, usually in much higher amounts; ethanol reduces the effects of methanol toxicity in humans.
Formal Chemical Name (IUPAC)
L-aspartyl-L-phenylalanine methyl ester
Update by Karl Harrison
(Molecule of the Month for November 2001 )