Checked by Pradeep B. Madan, George P. Yiannikouros, and David L. Coffen.
1. Procedure
D.
(R)-3-Amino-3-(p-methoxyphenyl)propionic acid.
2 A
125-mL Erlenmeyer flask containing a magnetic stirring bar is charged with
20 mL of tetrahydrofuran,
20 mL of 95% ethanol, and heterocycle
4 (2.39 g, 9.2 mmol). The mixture is stirred and cooled to −35°C to −45°C with an
acetone-dry ice bath. About
0.6 mL of aqueous 9 N hydrochloric acid is added dropwise until a pH of approximately 7 is obtained as determined by pH paper. A solution of
sodium borohydride, prepared by dissolving
0.5 g of sodium borohydride (13.0 mmol) in approximately 1.5 mL of water (minimum amount) containing 1 drop of
30% aqueous sodium hydroxide solution, is added dropwise alternately with
9 N hydrochloric acid to the stirred solution of
4 such that a pH of 6–8 is maintained. During the addition, the bath temperature should be maintained between −35°C and −45°C. After the addition of
sodium borohydride solution is complete, the reaction mixture is stirred at −35°C for 1 hr. During this time, the reaction mixture is maintained at a pH of 7 by occasional addition of
9 N hydrochloric acid (about 0.4 mL additional is required). The reaction mixture is then stored at −20°C overnight. After warming to room temperature, the reaction mixture is transferred to a
separatory funnel and the pH is raised to 9 by addition of aqueous
40% sodium hydroxide (1.5 mL). After dilution with 30 mL of water, the mixture is extracted three times with
20-mL portions of ether, and the combined
ether extracts are washed with
10 mL of saturated sodium chloride. After the organic layer is dried over
potassium carbonate, the solution is concentrated under reduced pressure giving
2.01 g (
85%) of the
acyl aminal as a slightly yellow solid that is used without further purification (Note
14).
An 0.80-g (3.0 mmol) portion of the crude aminal above is dissolved in
8 mL of 4.5 N hydrochloric acid solution and heated to 100°C in a boiling water bath for 2.5 hr. The clear liquid reaction mixture is transferred to an
evaporating dish and left to evaporate in a fume
hood. The residue is dissolved in
2 mL of 2 N hydrochloric acid solution and the pH of the solution is adjusted to 7 by slow addition of
30% aqueous sodium hydroxide with swirling, at which time the whole mixture solidifies. The solid mixture is kept at −20°C overnight, followed by addition of 10 mL of water and stirring with a
glass rod. The solids are collected by suction affording
0.38–0.41 g (
63–69%) of the
β-amino acid of

85% purity as a slightly yellow crystalline solid, mp
235°C (dec);
[α]D −4° (1 N
HCl,
c 1.86) (Note
15).
2. Notes
2. An extra 8.0 g may precipitate by saturation of the filtrate with
sodium chloride and storing the solution in a
refrigerator overnight. This material is of significantly inferior chemical and diastereomeric purity. The initial precipitate, however, is usually 92% optically pure as compared to the material obtained by recrystallization from 1:4 ethanol/water, and exhibits constant rotation upon further recrystallization. The rotation for twice recrystallized
1 is
[α]D −115° (CH
3OH,
c 2.05). However, this purification procedure (recrystallization) is not necessary, since heterocycle
3 is easily crystallized to ≥99% ee as the final isolation step. Spectral characteristics for pure
1 are:
1H NMR (400 MHz, D
2O/K
2CO
3, 10 mg/mL) δ: 1.16 (s, 9 H), 2.87–2.96 (m, 2 H), 3.83 (s, 3 H), 4.58 (m, 1 H), 5.33 (s, 1 H); IR (KBr) cm
−1: 3283, 2966, 1719, 1631, 1314, 1220, 1090, 779.
3. The flask possesses three vertical side necks of equal height. The middle neck and one side neck were fitted with 1-hole septa pierced by 1-cm diameter cylindrical graphite electrodes (Sargent Welch). The electrodes were inserted 7 cm into the solution, supplying a working electrode surface of 23 cm
2, and were 5 cm apart. A thermometer was inserted through the third neck with room to vent gases. A power supply (Southwest Technical Products Corp.) is attached to the electrodes with alligator clips. These conditions provide 34–37 V at 0.60 A.
4.
Methanol was purchased from Fisher Scientific Company and used without further purification.
5.
Triethylamine was purchased from the Aldrich Chemical Company, Inc., distilled, and stored over KOH pellets.
6. This represents the time necessary to pass 2.5 F/mol for the quantity stated at 0.60 A.
7. Methoxylated product
2 consists of diastereomers in a 3:1 ratio, the main proton resonances [
1H NMR (400 MHz, CDCl
3)] being δ: 0.95 and 1.02 (s, 9 H), 2.6–2.9 (m, 2 H), 3.35 and 3.39 (s, 3 H), 3.77 (s, 3 H), 5.17–5.29 (m, 1 H), 8.07–8.1 (s (br), 1 H).
8.
Dowex 50W-X8 cation exchange resin, 200–400 mesh, in the hydrogen form was purchased from J. T. Baker Chemical Company. It was placed in a
sintered-glass funnel and washed with three bed-volumes each of
10% hydrochloric acid, water,
methanol, and
acetone, and then dried under vacuum. The checkers recommend Soxhlet extraction of the resin for complete recovery of product
3.
9. Product
3 has the following spectral properties:
1H NMR (400 MHz, CDCl
3) δ: 0.95 (s, 9 H), 3.83 (s, 3 H), 5.15–5.45 (m, 2 H), 7.2–7.5 (m, 1 H), 8.0–8.5 (m, 1 H);
13C NMR (100 MHz, CDCl
3)δ: 25.5, 40.7, 54.0, 72.0, 104.8, 137.5, 153.3, 164.6; IR (thin film) cm
−1: 3201, 2966, 1731, 1666, 1443, 1331, 1249. The submitters report an optical rotation for
3 of
[α]D +434° (EtOAc,
c 1.70). Enantiomeric purity of
3 has been established by acylation of
3 with
(s)-O-methylmandelic acid chloride followed by
1H NMR analysis. Integration of the GC traces reveals that the resulting diastereomeric purity is equivalent to the enantiomeric purity of the mandelate (99%).
10. All glassware was
oven dried at 120°C prior to use.
Diethylamine was distilled from
calcium hydride.
Palladium(II) acetate, Pd(OAc)2 (53 mg, 0.24), (cancer suspect agent), without added triarylphosphine, gave
4 at a slightly lower yield as compared to Pd(PPh
3)
4.
11. During the course of the reaction, the solution is black. When the reaction is complete, the solution is clear brown with some black precipitate.
12. Some decomposition of the product, which appeared to be the major side reaction in this procedure, may occur in this step. The submitters found that decomposition is significant when the temperature is ≥20°C, and the desired material is left in contact with the basic solution for extended periods of time. This procedure is the most efficient for larger amounts of material. For smaller amounts, base can be added to the aqueous layer in a separatory funnel and the resulting solution can be extracted with
methylene chloride. In many cases the submitters have obtained material directly from this extraction that was suitable for further transformations.
13. The compound appears to be capable of isolation by sublimation, but this has not been checked. The submitters report obtaining
4 having mp
123–125°C and
[α]D −47° (CHCl
3,
c 3.3). The reasons for the discrepancy in rotation have not been determined. The spectral properties of pure
4 are as follows:
1H NMR (400 MHz, CDCl
3) δ: 1.27 (s, 9 H), 2.35 (dd, 1 H, J = 16.5, 12.0), 2.72 (dd, 1 H, J = 16.5, 5.7), 3.80 (s, 1 H), 4.71 (dd, 1 H, J = 12.0, 5.7), 6.89 (d, 2 H, J = 9), 7.3 (d, J = 9), 8.66 (s (br), 1 H);
13C NMR (100 MHz, CDCl
3) δ: 27.7, 37.6, 55.4, 56.7, 114.0, 127.5, 134.8, 158.8, 160.2, 171.7; IR (KBr) cm
−1: 3237, 3000, 1702, 1662, 1508 1254, 1135, 920, 832.
14. The properties of pure saturated heterocycle are as follows: mp
136–138°C,
[α]D +27.67° (CH
2Cl
2,
c 1.2);
1H NMR (400 MHz, CDCl
3) δ: 0.99 (s, 9 H), 2.33–2.72 (m, 2 H), 3.82 (s, 3 H), 3.97–4.04 (m, 1 H), 4.12 (s, 1 H), 6.03 (s (br), 1 H), 6.9 (d, 2 H, J = 10), 7.3 (d, 2 H, J = 10);
13C NMR (100 MHz, CDCl
3) δ: 24.9, 34.5, 39.8, 55.0, 55.4, 76.0, 114.1, 127.4, 134.2, 159.2, 171.6; IR (KBr) cm
−1: 3190, 2954, 1655, 1514, 1472, 1243, 1173.
15. Further purification including removal of the slight yellow color could be effected by recrystallization from boiling water. Physical properties of the purified amino acid product are as follows: mp
239°C (dec),
[α]D −4.35° (1 N HCl,
c 1.86);
1H NMR (400 MHz, D
2O) δ: 3.02–3.25 (m, 2 H), 3.83 (s, 3 H), 4.90 (m, 1 H), 7.03 (d, 2 H, J = 10), 7.45 (d, 2 H, J = 10);
13C NMR (100 MHz, D
2O) δ: 38.7, 52.1, 56.6, 115.9, 128.7, 129.8, 160.8, 174.5; IR (KBr) cm
−1: 2960, 2364, 2150, 1615, 1518, 1404, 1250, 1184.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The key element in this technology is heterocycle
3. Although
asparagine has been cyclized with
acetone,
53 cyclocondensation with aldehydes has not been described in detail, except for
tetrahydropyrimidinone formation using
formaldehyde.
54 Electrochemical oxidative decarboxylation, on the other hand, is a well-known procedure
55 with broad applicability.
56 Our initial synthesis of
3 was accomplished with
lead(IV) acetate;
57,58 the two-step method described here is cleaner and the cost and hazards of using and disposing of lead are precluded. Furthermore, the acid catalyst is easily recyclable. The two enantiomers of
3 are easily prepared from the corresponding enantiomers of
asparagine which are readily available and inexpensive. The intermediate
3 and analogues are highly crystalline, stable, and possess large specific rotations which allows determination of the enantiomeric purity.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
amine
β-AMINO ACIDS
1(2H)-Pyrimidinecarboxylic acid, 2-(1,1-dimethylethyl)-3,4-dihydro-4-oxo-, methyl ester, (R)- or (S)-
β-amino acid
L-Asparagine monohydate
β-amino acid (R)-β-tyrosine
ethanol (64-17-5)
potassium carbonate (584-08-7)
hydrochloric acid,
HCl (7647-01-0)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether (60-29-7)
sodium hydroxide (1310-73-2)
formaldehyde (630-08-0)
sodium bicarbonate (144-55-8)
sodium chloride (7647-14-5)
nitrogen (7727-37-9)
acetone (67-64-1)
carbon (7782-42-5)
potassium hydroxide (1310-58-3)
diethylamine (109-89-7)
methylene chloride (75-09-2)
amino (15194-15-7)
magnesium sulfate (7487-88-9)
Tetrahydrofuran (109-99-9)
methyl chloroformate (79-22-1)
dimethylformamide (68-12-2)
asparagine (70-47-3)
triethylamine (121-44-8)
calcium hydride (7789-78-8)
sodium borohydride (16940-66-2)
argon (7440-37-1)
pivalaldehyde (630-19-3)
palladium(II) acetate (3375-31-3)
tetrakis(triphenylphosphine)palladium(0) (14221-01-3)
lead(IV) acetate (546-67-8)
2-tert-Butyl-1-carbomethoxy-2,3-dihydro-4(1H)-pyrimidinone (131791-81-6)
(R)-3-Amino-3-(p-methoxyphenyl)propionic acid (131690-57-8)
(S,S)-2-tert-Butyl-1-carbomethoxy-6-carboxy-2,3,5,6-tetrahydro-4(1H)-pyrimidinone (138723-45-2)
L-asparagine monohydrate (5794-13-8)
(S)-2-tert-Butyl-1-carbomethoxy-2,3-dihydro-4(1H)-pyrimidinone (131791-75-8)
(R)-2-tert-Butyl-6-(4-methoxyphenyl)-5,6-dihydro-4(1H)-pyrimidinone (131791-77-0)
4-iodoanisole (696-62-8)
(S)-O-methylmandelic acid chloride
tetrahydropyrimidinone (1852-17-1)
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