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DOI:10.15227/orgsyn.070.0029

Organic Syntheses, Coll. Vol. 9, p.63 (1998); Vol. 70, p.29 (1992).

N-(BENZYLOXYCARBONYL)-L-VINYLGLYCINE METHYL
ESTER[3-Butenoic acid, 2-[[(phenylmethoxy)carbonyl]amino]-, methyl ester, (S)-]Submitted by Michael Carrasco, Robert J. Jones, Scott Kamel, H. Rapoport1, and Thien Truong.
Checked by Antje Grützmann and Ekkehard Winterfeldt.

1. Procedure
A. N-(Benzyloxycarbonyl)-L-methionine methyl ester (2). A 3-L, three-necked, Morton flask
equipped with an efficient mechanical stirrer, thermometer, and a dropping funnel is charged with Lmethionine methyl ester hydrochloride (117.6 g, 0.56 mol) (Note 1), potassium bicarbonate (282.3 g,2.82 mol, 500 mol %), water (750 mL), and ether (750 mL), and the solution is cooled to 0°C. Benzylchloroformate (105 g, 88.6 mL, 0.62 mol, 110 mol %, Aldrich Chemical Company, Inc.) is added
dropwise over 1 hr, the cooling bath is removed, and the solution is stirred for 5 hr. Glycine (8.5 g, 0.11mol, 20 mol %, Aldrich Chemical Company, Inc.) is added (to scavenge excess chloroformate) and thesolution is stirred for an additional 18 hr. The organic layer is separated, and the aqueous layer isextracted with ether (2 × 200 mL). The combined organic layers are washed with 0.01 M hydrochloricacid (2 × 500 mL), water (2 × 500 mL), and saturated brine (500 mL), and then dried (Na2SO4), filtered,and evaporated on a rotary evaporator. The resulting oil is further dried in a Kugelrohr oven (50°C, 0.1mm, 12 hr) to leave product 2 as a clear oil that solidifies upon cooling: 165–166 g (98–99%), mp 42–43°C.
B. Methyl L-2-(benzyloxycarbonylamino)-4-(methylsulfinyl)butanoate (3). A 5-L, three-necked,
Morton flask equipped with an efficient mechanical stirrer, thermometer, and dropping funnel ischarged with 2 (166.0 g, 0.56 mol) and methanol (1.5 L), and the solution is cooled to 0°C. A solutionof sodium periodate (NaIO4) (131.4 g, 0.61 mol, 110 mol %) in water (2 L) is added dropwise over aperiod of 1.5 hr. The cooling bath is removed and the mixture is stirred for 18 hr. The product isvacuum-filtered through Celite and divided into two portions. Each portion is extracted with chloroform(6 × 200 mL), washed with water (300 mL) and brine (300 mL), dried (Na2SO4), filtered, andevaporated by rotary evaporation (bath temperature <30°C). The resulting oils are combined and further
dried in a Kugelrohr oven (30°C, 0.1 mm, 12 hr), yielding the product as a waxy solid: 173.2 g, 99%.
C. N-(Benzyloxycarbonyl)-L-vinylglycine methyl ester (4). Sulfoxide 3 (35.0 g, 0.11 mol) and Pyrex
helices (35 g) are placed in a 1-L, round-bottomed flask, thoroughly mixed by shaking, and distilledfrom a preheated rocking Kugelrohr apparatus (195–200°C, 0.1–0.3 mm, 1 hr) into a chilled receiving

flask cooled in powdered dry ice to afford a yellow oil (Note 2) and (Note 3). Low pressure
chromatography (LPC) of the crude oil gives the N-protected vinylglycine methyl ester 4 (17.4 g, 62%)of 95% purity (Note 4) and (Note 5). Medium pressure liquid chromatography (MPLC) of the crude oilprovides pure 4 in 60% yield from 3 (Note 6). L-Vinylglycine hydrochloride can be obtained from 4 inalmost quantitative yield by refluxing in 6 N hydrochloric acid for 1 hr.2

2. Notes
1. L-Methionine methyl ester hydrochloride is commercially available (Aldrich Chemical Company,Inc.); however, it is prepared easily as follows: A 3-L, three-necked, Morton flask is equipped with anefficient mechanical stirrer. The flask is charged with L-methionine (100.0 g, 0.67 mol) and methanol(0.7 L), the solution is cooled to 0°C, and hydrogen chloride gas is bubbled through the mixture for 15min (in about 2 min the solution becomes homogeneous). The cooling bath is removed, the solution isstirred for 18 hr, and the solvent is evaporated. Further drying under reduced pressure gives Lmethionine methyl ester hydrochloride as a white solid (132.5 g, 99%), that is suitable for mostpurposes. It can be recrystallized by dissolving in hot methanol (500 mL) and precipitating with ether (1L) to give the pure hydrochloride: 117.6 g, 88%, mp 152–153°C.
2. Caution: Stench. The entire reaction apparatus—Kugelrohr oven, vacuum pump, and subsequentchromatography—should be kept in an efficient fume hood.
3. TLC of the distillate shows 4 (2/1, hexanes/ethyl acetate; visualization by staining with 5% ethanolicmolybdophosphoric acid and charring) as the major product (Rf 0.37) along with minor amounts of the(E)- and (Z)-α,β-unsaturated isomer (Rf 0.40 and 0.30).
4. LPC conditions are as follows: 9-cm diameter column; 800 mL of 230–400 mesh EM Science silica
gel; 4/1, hexanes/ethyl acetate (1.8 L) to 2/1, hexanes/ethyl acetate.
5. The 1H NMR spectrum of 4 is as follows: (CDCl3) δ: 3.77 (s, 3 H, CO2CH3), 4.94 (m, 1 H, α-H), 5.13(s, 2 H, CH2PH), 5.28 (dd, 1 H, J = 1.2, 10.3, Hcis), 5.36 (dd, 1 H, J = 1.4, 17.1, Htrans), 5.47 (bd, 1 H,NH), 5.91 (m, 1 H, Hvinyl), 7.35 (s, 5 H, ArH).
6. MPLC conditions are as follows: 40 cm × 6-cm column; 230–400 mesh EM Science silica gel; flowrate 18 mL/min; model 153 Altex UV Detector; retention time ca. 100 min; 4/1, hexanes/ethyl acetate.
The distillate was chromatographed in 2.5-g batches. The checkers experienced significant losses in thisstep, which may be highly sensitive to the type of silica and the apparatus used. In any case the material
obtained after the first chromatography will be acceptable for most purposes.

Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory";
National Academy Press; Washington, DC, 1995.

3. Discussion
Vinylglycine is a natural amino acid found in mushrooms.3 It is an inhibitor of pyridoxal-linked
aspartate aminotransferase,4 5 and has also been postulated as an intermediate in the enzymaticconversion of homoserine to threonine6 and α-ketobutyrate.7 Protected vinylglycine is also a versatile
asymmetric starting material for synthesis.8 Variants have been prepared in racemic,9,10,11,12,13,14 opticallyactive,15 optically pure,2,16,17,18 and isotopically labeled form.5,19,20,21 This procedure is derived from ourearlier publication2 and contains improvements in procedure and scale-up.

References and Notes
1.
2.
3.
4.
5.
6.

Department of Chemistry, University of California, Berkeley, CA 94720.
Afzali-Ardakani, A.; Rapoport, H. J. Org. Chem. 1980, 45, 4817.
Dardenne, G.; Casimir, J.; Marlier, M.; Larsen, P. O. Phytochemistry 1974, 13, 1897.
Rando, R. R.; Relyea, N.; Cheng, L. J. Biol. Chem. 1976, 251, 3306;
Rando, R. R. Biochemistry 1974, 13, 3859.
Flavin, M.; Slaughter, C. J. Biol. Chem. 1960, 235, 1112.

Posner, B. I.; Flavin, M. J. Biol. Chem. 1972, 247, 6402.
Shaw, K. J.; Luly, J. R.; Rapoport, H. J. Org. Chem. 1985, 50, 4515.
Friis, P.; Helboe, P.; Larsen, P. O. Acta Chem. Scand., Ser. B 1974, 28, 317.
Baldwin, J. E.; Haber, S. B.; Hoskins, C.; Kruse, L. I. J. Org. Chem. 1977, 42, 1239.
Hudrlik, P. F.; Kulkarni, A. K. J. Am. Chem. Soc. 1981, 103, 6251.
Vyas, D. M.; Chiang, Y.; Doyle, T. W. J. Org. Chem. 1984, 49, 2037.
Greenlee, W. J. J. Org. Chem. 1984, 49, 2632.
Fitzner, J. N.; Pratt, D. V.; Hopkins, P. B. Tetrahedron Lett. 1985, 26, 1959.
Schöllkopf, U.; Nozulak, J.; Groth, U. Tetrahedron 1984, 40, 1409.
Hanessian, S.; Sahoo, S. P. Tetrahedron Lett. 1984, 25, 1425.
Barton, D. H. R.; Crich, D.; Hervé, Y.; Potier, P.; Thierry, J. Tetrahedron 1985, 41, 4347.
Pellicciari, R.; Natalini, B.; Marinozzi, M. Synth. Commun. 1988, 18, 1715.
Chang, M. N. T.; Walsh, C. T. J. Am. Chem. Soc. 1981, 103, 4921.
Sawada, S.; Nakayama, T.; Esaki, N.; Tanaka, H.; Soda, K.; Hill, R. K. J. Org. Chem. 1986, 51,3384.
21. Rosegay, A.; Taub, D. Synth. Commun. 1989, 19, 1137.

7.
8.
9.
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14.
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16.
17.
18.
19.
20.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)silicahexanesbrinehydrogen chloride,hydrochloric acid (7647-01-0)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether (60-29-7)
chloroform (67-66-3)
Glycine (513-29-1)
L-Methionine (63-68-3)
benzyl chloroformate (501-53-1)
threonine (72-19-5)
potassium bicarbonate (298-14-6)
Sodium periodate (7790-28-5)

Molybdophosphoric acid (51429-74-4)
N-(Benzyloxycarbonyl)-L-vinylglycine methyl ester
3-Butenoic acid, 2-[[(phenylmethoxy)carbonyl]amino]-, methyl ester, (S)- (75266-40-9)
N-(Benzyloxycarbonyl)-L-methionine methyl ester (56762-93-7)
L-methionine methyl ester hydrochloride (2491-18-1)
Methyl L-2-(benzyloxycarbonylamino)-4-(methylsulfinyl)butanoate
L-Vinylglycine hydrochloride
Vinylglycine
homoserine (672-15-1)
α-ketobutyrate
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