Org. Synth. 1992, 70, 29
DOI: 10.15227/orgsyn.070.0029
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. Rapoport
1, 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 L-methionine 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. Benzyl chloroformate (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, 0.11 mol, 20 mol %, Aldrich Chemical Company, Inc.) is added (to scavenge excess chloroformate) and the solution is stirred for an additional 18 hr. The organic layer is separated, and the aqueous layer is extracted with ether (2 × 200 mL). The combined organic layers are washed with 0.01 M hydrochloric acid (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, 0.1 mm, 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 is charged with
2 (166.0 g, 0.56 mol) and
methanol (1.5 L), and the solution is cooled to 0°C. A solution of
sodium periodate (NaIO4) (131.4 g, 0.61 mol, 110 mol %) in water (2 L) is added dropwise over a period of 1.5 hr. The cooling bath is removed and the mixture is stirred for 18 hr. The product is vacuum-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 (Na
2SO
4), filtered, and evaporated 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 distilled from 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 oil provides pure
4 in
60% yield from
3 (Note 6).
L-Vinylglycine hydrochloride can be obtained from
4 in almost 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 an efficient 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 15 min (in about 2 min the solution becomes homogeneous). The cooling bath is removed, the solution is stirred for 18 hr, and the solvent is evaporated. Further drying under reduced pressure gives
L-methionine methyl ester hydrochloride as a white solid (
132.5 g,
99%), that is suitable for most purposes. It can be recrystallized by dissolving in hot
methanol (500 mL) and precipitating with
ether (1 L) 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 subsequent chromatography—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% ethanolic molybdophosphoric acid and charring) as the major product (R
f 0.37) along with minor amounts of the (E)- and (Z)-α,β-unsaturated isomer (R
f 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: (CDCl
3) δ: 3.77 (s, 3 H, CO
2CH
3), 4.94 (m, 1 H, α-H), 5.13 (s, 2 H, CH
2PH), 5.28 (dd, 1 H, J = 1.2, 10.3, H
cis), 5.36 (dd, 1 H, J = 1.4, 17.1, H
trans), 5.47 (bd, 1 H, NH), 5.91 (m, 1 H, H
vinyl), 7.35 (s, 5 H, ArH).
6.
MPLC conditions are as follows:
40 cm × 6-cm column; 230–400 mesh EM Science silica gel; flow rate 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 this step, 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.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
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 enzymatic conversion 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 optically active,
15 optically pure,
2,16,17,18 and isotopically labeled form.
5,19,20,21 This procedure is derived from our earlier publication
2 and contains improvements in procedure and scale-up.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
silica
hexanes
brine
hydrogen 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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