Honors Cup Synthetic Proposal
Section: 250-1
Group Members: Jenni Westerhuis, Andrew Krause, Bill Geisert
Title: Synthesis of L-aspartic acid N-thiocarboxyanhydride (an aspartame precursor)
Introduction: (what makes your target interesting?)
Possessing about 180 times the sweetness of sucrose (sugar), aspartame is used as an artificial
sweetener. Marketed as NutraSweet® and Equal®, most all of us have used aspartame in our
diet at one point or another. It is used in many commercially produced foods and beverages.
Aspartame is essentially composed of two amino acids, namely aspartic acid and phenylalanine.
Because of it’s potency in comparison with sugar and it’s amino acid composition, it has two
very important nutritional applications. It’s caloric content (4 calories per gram) is lower than
that of sugar which, along with it’s increased potency, helps in weight management. Also, it can
be used to introduce sweet tasting foods in a carbohydrate limited diabetic diet. Another
important property is that, because of it’s chemical structure, it is metabolized into it’s
constituents: aspartic acid, phenylalanine and methanol, all substances found naturally in the
human body.
L-aspartic acid N-thiocarboxyanhydride (our target molecule) is the final intermediate in one
reported syntheses of aspartame. The synthesis of aspartame (and also our target) should be of
special interest to introductory organic chemistry students as it employs some very important
synthetic chemistry principles. The aspartame molecule that is used as a sweetener is chiral,
containing two stereocenters. This chiralty must be maintained in order that the product has it’s
intended sweet taste. Our target molecule contains one of these stereocenters, thus we must
preserve it’s chiralty in our synthesis. The other important principle is that of functional group
protection. L-aspartic acid has two reactive carboxyl groups. In order to produce the correct
product in a reaction with phenylalanine, one of the carboxyl groups must be protected and made
non-reactive. Several methods have been developed to do this and the synthesis of our target
molecule is one such method. As you can see in the reaction scheme below, one carboxyl group
is protected by the formation of a ring structure which is, in the last step of aspartame synthesis
(not included here), non-reactive with phenylalanine. In the last step of aspartame synthesis, our
target is reacted with phenylalanine and the ring opened yielding the intended product.
Overall synthetic reaction scheme
I
O
S
S
S
O
HO
(S)
2-iodopropane
2
K
potassium ethyl xanthogenate
OH
S
O
Aliquat 336
3
1
NH2
O
isopropyl ethyl xanthate
L-aspartic acid
5
4
NaOH
CH3OH
O
O
O
HN
S
PBr3
HO
(S)
phosphorus tribromide
7
O
OH
O
HN
(S)
HO
O
L-aspartic acid N-thiocarboxyanhydride
8
ethyl acetate
S
N-(Ethoxythiocarbonyl)-L-aspartic acid
6
Step 1
Synthetic transformation 1:
I
S
S
iodomethane
O
S
2
K
potassium ethyl xanthogenate
1
O
S
methyl ethyl xanthate
Aliquat 336
3
4
Experimental 1
Under reflux and in an ice bath, potassium ethyl xanthate (27.0 mmol, 4.32 g), 2-iodopropane
(27.0 mmol, 4.59 mL) and Aliquat® 336 (2.7 mmol, 1.23 mL) are combined in 30 mL water.
The mixture (yellow in color) is stirred vigorously at 70 °C until a yellow oil comes to the
surface and the aqueous solution becomes completely colorless (approximately 5-10 minutes).
The reaction mixture is allowed to cool to room temperature. 50-70 mL of petroleum ether
added and the organic layer is separated, dried with MgSO4 and filtered over a small layer of
silica gel. The solvent is then removed by rotary evaporation, leaving a residue. This residue is
then purified by recrystallization in acetone/methanol to yield isopropyl ethyl xanthate. The
product can be characterized by IR showing strong absorption bands at 1045 cm-1 and 1218 cm-1.
Though not reported in the paper from which this synthesis was taken, No NMR data have been
reported for this product yet we predict 1H-NMR peaks in the following integrations: 3H
(triplet), 2H (quartet), 1H (septet), 6H (doublet).
The reaction conditions above are not expressed in the reference from which this specific
synthesis was taken. They have been presented here due to the exothermic nature of this reaction
in reference to a similar synthesis that made use of similar conditions. All quantities here have
been scaled to 54% of the referenced synthesis. No specific drying agent was specified in the
referenced synthesis and thus a typical drying agent, MgSO4, is used here.
Expected yield:
50-60 % 1.36-1.63 g
Safety, disposal and green issues 1:
2-iodopropane – Highly flammable. Keep away from sources of ignition.
Potassium ethyl xanthogenate – Harmful if swallowed. Irritating to eyes, respiratory system
and skin. In case of contact with eyes, rinse immediately with plenty of water and seek medical
advice. Wear suitable protective clothing.
Aliquat 336 – Harmful if swallowed. Irritating to the skin. Risk of serious damage to eyes. Very
toxic to aquatic organisms. In case of contact with eyes, rinse immediately with plenty of water
and seek medical advice. Wear eye/face protection. This material and/or its container must be
disposed of as hazardous waste. Avoid release to the environment. Refer to special instructions
safety data sheet.
Step 2
Synthetic transformation 2: (Chemdraw picture of second transformation)
O
HO
(S)
OH
O
S
HO
O
(S)
HN
O
OH
O
S
isopropyl ethyl xanthate
4
O
NH2
L-aspartic acid
5
NaOH
CH3OH
S
N-(Ethoxythiocarbonyl)-L-aspartic acid
6
Experimental 2: L-aspartic acid (10.1 mmol, 1.34 g) is suspended in 2 mL of water in an ice
bath, and 50% aqueous sodium hydroxide solution (0.02 mmol) is added dropwise. Isopropyl
ethyl xanthate (10.8 mmol, 1.78 g) in 2 mL of methanol is added in one portion. This mixture is
heated at 45 º C for 2 hours, cooled to room temperature, and washed with two 5 mL portions of
CH2Cl2. The CH2Cl2 layers are discarded and 12 M HCl is added to the aqueous layer in an ice
bath. The solution is saturated with solid sodium chloride and extracted with two 15 mL
portions of ethyl acetate. These organic extracts are dried with MgSO4 and the solvent is
removed by rotary evaporation to give a white crystalline solid, N-(Ethoxycarbonyl)-L-aspartic
acid; mp 133 ˚C;
1
H NMR δ 1.23 (t. 3 H, J = 7 Hz), 2.67 (d, 2 H, J = 6 Hz), 4.37 (q, 2 H, J = 7 Hz), 4.93 (dt, 1 H, J
= 6 Hz, 8 Hz), 9.26 (d, 1 H, J = 8 Hz); IR (KBr) 1739, 1724, 1515 cm-1.
Quantities of reactants scaled to use 10.8 mmol of product from step 1. The literature suggests
use of methyl ethyl xanthate instead of isopropyl ethyl xanthate. Because of specific dangers
associated with reagents involved in producing methyl ethyl xanthate, we have substituted a
similar intermediate here which we predict, based on the chemistry involved in the reaction, will
have a very similar reactivity. The replaced substituent is lost during this step and will have no
effect on the structure of our target molecule.
Expected yield: 50-60 % 0.82-0.98 g
Safety, disposal and green issues 2:
L-aspartic acid- Toxic if ingested. Do not inhale dust. Wear safety glasses.
Methyl ethyl xanthate- Harmful if swallowed. Irritating to eyes, respiratory system and skin.
In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.
Wear suitable protective clothing.
Methylene Chloride- Harmful if absorbed through skin. Causes irritation. Fatal if swallowed.
Avoid contact with eyes, skin and clothing. Wear gloves and eye protection.
Ethyl acetate- Keep away from heat and ignition sources. Harmful if swallowed. Avoid
breathing vapors. Use with adequate ventilation. Avoid contact with eyes, skin, and clothes.
Wash thoroughly after handling. Keep container closed.
Step 3
Synthetic transformation 3: (Chemdraw picture of third transformation)
O
O
HO
(S)
O
OH
HN
O
PBr3
phosphorus tribromide
7
O
HN
S
(S)
HO
O
S
N-(Ethoxythiocarbonyl)-L-aspartic acid
6
ethyl acetate
L-aspartic acid N-thiocarboxyanhydride
8
Experimental 3
N-(Ethoxythiocarbonyl)-L-aspartic acid (5mmol, 1.11g) is dissolved in ethyl acetate (6.02 mL)
in a round bottom flask. This solution is placed in an ice bath and chilled to 0 °C. PBr3 (3.9
mmol, 1.06 g) is added in one portion. The apparatus is removed from the ice bath and allowed
to spontaneously rise to 35-40 °C. This solution is stirred for 10 minutes during which a
granular white precipitate is formed. The reaction mixture is then cooled to 0-5 °C and the
precipitate, namely (S)-aspartic acid N-thiocarboxyanhydride (mp – 200-205 °C; IR 3225, 1739,
1724, 1653, 1399 cm-1; 1H NMR δ 2.83 (2H, d) 4.70 (1H, t) 9.23 (2H, bs) in DMSO-d6) , is
collected by filtration. The product is washed with approx. 10 mL of ether and dried with
MgSO4.
The literature sites quantities in molar equivalents and these have been followed here. No
specific drying agent was stated in the references, so again MgSO4 has been used here. Specific
quantities of filtration eluent were not suggested in the literature, so an appropriate amount based
on scale of this reaction has been suggested.
Expected yield: 57-67% .5 - .587g
Safety, disposal and green issues 3:
Phosphorus tribromide- Reacts violently with water. Causes Burns. Irritating to the respiratory
system. In case of contact with eyes, rinse immediately with plenty of water and seek medical
advice. In case of accident or if you feel unwell, seek medical advice immediately (show label
where possible).
Overall budget:
Chemical
L-aspartic acid
Aliquat 336
Iodomethane
Phosphorus
Tribromide
Potassium Ethyl
Xanthogenate
(Potassium Ethyl
Xanthate)
Supplier
Aldrich
Aldrich
Aldrich
Aldrich
Cost
$0.12 /g
$0.15 /mL
$0.15 /mL
$2.68 /g
Amt. Needed
1.34 g
1.23 mL
4.59 mL
1.06 g
Total
$0.16
$0.18
$0.69
$2.84
Aldrich
$0.35 /g
4.32 g
$1.51
Total costs per synthesis: $5.38
References (include at least two different sources for your experimentals):
ChemCases (http://science.kennesaw.edu/~mhermes/nutra/)
Vinick, F; Jung, S. Tetrahedron Lett. 1982, 23, 1315-1318.
Vinick, F; Jung, S. J. Org. Chem. 1982, 47, 2199-2201.
Lindeberg, G. J. Chem. Ed. 1987, 64, 1062-1064.
Barany, G.; Schroll, A. L.; Mott, A. W.; Halsrud, D.A. J. Org. Chem. 1983, 48, 4750-4761.
Degani, I.; Fochi, R.; Synthesis 1978, 1978, 365-368.
Nutrition fact sheet: straight answers about aspartame. Journal of the American Dietetic
Association 2003, 103, 801-802.