Honors Cup Synthetic Proposal

Transcription

1 Honors Cup ynthetic Proposal ection: Group Members: Jenni Westerhuis, Andrew Krause, Bill Geisert Title: ynthesis 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 Nutraweet 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. ur 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. everal 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.

2 verall synthetic reaction scheme I K potassium ethyl xanthogenate 1 2-iodopropane 2 Aliquat H NH 2 isopropyl ethyl xanthate L-aspartic acid 4 5 NaH CH 3 H () H HN H () L-aspartic acid N-thiocarboxyanhydride 8 PBr 3 phosphorus tribromide 7 ethyl acetate H () H HN N-(Ethoxythiocarbonyl)-L-aspartic acid 6

3 tep 1 ynthetic transformation 1: K potassium ethyl xanthogenate 1 I iodomethane 2 Aliquat methyl ethyl xanthate 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 ml of petroleum ether added and the organic layer is separated, dried with Mg 4 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 1 H-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, Mg 4, is used here. Expected yield: % g afety, 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.

4 tep 2 ynthetic transformation 2: (Chemdraw picture of second transformation) H () H H () H HN NH 2 isopropyl ethyl xanthate L-aspartic acid 4 5 NaH CH 3 H 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 CH 2 Cl 2. The CH 2 Cl 2 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 Mg 4 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: % g afety, 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.

5 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. tep 3 ynthetic transformation 3: (Chemdraw picture of third transformation) H () H PBr 3 HN HN phosphorus tribromide 7 H () 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. PBr 3 (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 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 ()-aspartic acid N-thiocarboxyanhydride (mp C; IR 3225, 1739, 1724, 1653, 1399 cm -1 ; 1 H NMR δ 2.83 (2H, d) 4.70 (1H, t) 9.23 (2H, bs) in DM-d 6 ), is collected by filtration. The product is washed with approx. 10 ml of ether and dried with Mg 4. The literature sites quantities in molar equivalents and these have been followed here. No specific drying agent was stated in the references, so again Mg 4 has been used here. pecific 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% g afety, 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).

6 verall budget: Chemical upplier Cost Amt. Needed Total L-aspartic acid Aldrich $0.12 /g 1.34 g $0.16 Aliquat 336 Aldrich $0.15 /ml 1.23 ml $0.18 Iodomethane Aldrich $0.15 /ml 4.59 ml $0.69 Phosphorus Aldrich $2.68 /g 1.06 g $2.84 Tribromide Potassium Ethyl Xanthogenate (Potassium Ethyl Xanthate) 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 ( Vinick, F; Jung,. Tetrahedron Lett. 1982, 23, Vinick, F; Jung,. J. rg. Chem. 1982, 47, Lindeberg, G. J. Chem. Ed. 1987, 64, Barany, G.; chroll, A. L.; Mott, A. W.; Halsrud, D.A. J. rg. Chem. 1983, 48, Degani, I.; Fochi, R.; ynthesis 1978, 1978, Nutrition fact sheet: straight answers about aspartame. Journal of the American Dietetic Association 2003, 103,