Submitted by O. P. Goel, U. Krolls, M. Stier, and S. Kesten
1..
Checked by Susumu Ohira and James D. White.
1. Procedure
A.
Boc-L-leucine N-methyl-O-methylcarboxamide. A
1-L, three-necked, round-bottomed flask is equipped with a mechanical stirrer, an electronic digital thermometer, and a graduated addition funnel. The flask is charged with
39.1 g (0.4 mol) of N,O-dimethylhydroxylamine hydrochloride (Note
1) and
236 mL of methylene chloride (Note
2). The suspension is stirred and cooled to 2°C with an
ice–water bath.
N-Methylpiperidine. (Note 3), 48.8 mL (0.41 mol), is placed in the addition funnel and added dropwise while the temperature is maintained at 2° ± 2°C. A clear colorless solution results which is kept cold and used in the following reaction.
A
5-L, three-necked, round-bottomed flask is equipped with a mechanical stirrer, a thermometer, and an addition funnel with drying tube. The flask is charged with
100 g (0.4 mol) of Boc-L-leucine hydrate (Note
4),
458 mL of tetrahydrofuran (Note
2), and
1.8 L of methylene chloride. A clear solution results on stirring, which is cooled to −20° ± 2°C by immersing the flask in a
dry ice–2-propanol bath.
N-Methylpiperidine, 48.8 mL (0.41 mol), is placed in the addition funnel and added rapidly to the mixture, while the temperature is allowed to rise to −12° ± 2°C.
Methyl chloroformate (Note 5), 31 mL (0.4 mol), is then placed in the addition funnel and added rapidly to the mixture with good stirring, while the temperature is kept at −12° ± 2°C. Two minutes later the solution of
N,O-dimethylhydroxylamine, prepared as described earlier, is added. The
cooling bath is removed and the clear solution allowed to warm to room temperature over 4 hr (Note
6). The solution is again cooled to 5°C and extracted with two
500-mL portions of aqueous 0.2 N hydrochloric acid and two
500-mL portions of aqueous 0.5 N sodium hydroxide (Note
7). The solution is washed with
500 mL of saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and concentrated on a
rotary evaporator at a bath temperature of 30–35°C. The residue is further evacuated on an oil pump to constant weight. The residual colorless syrup weighs
100–102 g (
91–93%),
[α]D23 −24 to −25° (
1.5% in methanol) (Note
8).
B.
N-tert-Butoxycarbonyl-L-leucinal: Boc-L-leucinal. A
5-L, four-necked, round-bottomed flask is equipped with an efficient mechanical stirrer, a thermometer, a pressure-equalizing addition funnel, and an air-cooled condenser fitted with an argon blanket adapter. The flask is charged under an argon blanket with
17.7 g (95% pure, 0.44 mol) of lithium aluminum hydride (Note
9), and
1.5 L of anhydrous ethyl ether (Note
10). The gray suspension is stirred at room temperature for 1 hr or until most of the solid is finely dispersed. The flask is immersed in a
dry ice–2-propanol bath and the suspension cooled to −45°C. A solution of the
Boc-L-leucine N-methyl-O-methycarboxamide, obtained in Part A, in
300 mL of anhydrous ethyl ether is placed in the addition funnel and added to the
lithium aluminum hydride suspension in a steady stream (Note
11) while the reaction temperature is maintained −35° ± 3°C. The cooling bath is removed and the mixture is stirred and allowed to warm to +5°C. The mixture is once again cooled to −35°C and a solution of
96.4 g (0.71 mol) of potassium bisulfate (Note
12) in 265 mL of deionized water is placed in the addition funnel. This is added cautiously at first and then rapidly, while the temperature is allowed to rise to −2° ± 3°C. The cooling bath is removed and the mixture stirred for 1 hr. The reaction mixture is filtered through a 2-in. pad of Celite (Note
13). The filter cake is washed with two
500-mL portions of ethyl ether. The combined
ether layers are washed in sequence with three
350-mL portions of cold (5°C) 1 N hydrochloric acid, two
350-mL portions of saturated aqueous sodium bicarbonate solution, and
350 mL of saturated sodium chloride solution. The organic solution is dried over
magnesium sulfate and evaporated on a rotary evaporator (bath at 30°C). The residual, slightly cloudy syrup weighs
69–70 g (
87–88%),
[α]23 −49 to −51° (
1.65% in methanol) (Note
14). The product is stored in a freezer (−17°C) prior to use. It solidifies readily at 5°C (Note
15).
2. Notes
3.
N-Methylpiperidine was obtained from the Aldrich Chemical Company, Inc., and used as received.
4. Bachem Inc. was the source of
Boc-L-leucine hydrate. It was not necessary to prepare anhydrous
Boc-L-leucine. The yield and quality of the product were unaffected by the presence of water during the reaction.
6. The reaction mixture may be stirred overnight for convenience.
7. The organic solution should be kept at 5–15°C during extractions.
8. The crude product is
96–99% pure by HPLC and is satisfactory for use in the next reaction. HPLC was carried out on a Varian 5500 instrument using a
250-cm × 4.6-mm-i.d. Alltech C-18 column with 60 : 40
methanol : 0.5
M NH
4H
2PO
4 (pH 3) as the mobile phase,
UV detector at 210 nm. Thin-layer chromatography on silica gel plates (EM) and development with
hexane : EtOAc (3 : 1) indicates that the major product spot is at
Rf = 0.32. Starting
Boc-L-leucine, if present, appears at
Rf = 0.16; detector:
ninhydrin and gradual warming on a
hot plate. The physical properties are as follows: IR (liquid film) cm
−1: 2960(s), 1714(s), 1665(s);
1H NMR (200 MHz, CDCl
3) δ: 0.92 [2d appear as t, 6 H,
J = 6.8, CH(CH
3)
2], 1.40, [s, 9 H, C(CH
3)
3], 1.38–1.44 (m, 2 H, C
3-H), 1.59–1.76 (m, 1 H, C
4-H), 3.17, and 3.14 (s and a rotamer singlet, 3 H, N-CH
3), 3.76 and 3.67 (s, and a rotamer singlet, 3 H, O-CH
3), 4.7 (m, 1 H, C
2-H), 5.06 (m, 1 H, N-H).
10.
Ethyl ether was obtained from the Fisher Scientific Co.
11. The
lithium aluminum hydride suspension should be cooled to −45°C prior to addition of the amide. Higher initial temperatures (−30°C and above) lead to an impurity as shown by TLC.
13. A gel-like precipitate is formed from the inorganic by-products. A thick Celite pad helps to prevent clogging of the filter funnel.
14. Consistently higher optical rotations than reported were obtained.
2 NMR and capillary gas-chromatographic analyses indicated chemical purity of
98–99%.
Varian 6000, RSL-310, 15-m, fused silica column, 0.25 mm i.d., film thickness 0.25 μm, at 60°C for 4 min and then 60–220°C at 10°C/min, H
2 as carrier gas at 10 psi. TLC under the conditions described in Note 8 shows the major spot at
Rf = 0.53. The spectral properties are as follows: IR (liquid film) cm
−1: 2961(s), 1736(s), 1698(b);
1H NMR (200 MHz, CDCl
3) δ: 0.96 (d, 6 H,
J = 6.4, CH (CH
3)
2), 1.45 (s, 9 H, C(CH
3)
3), 1.48–1.81 (m, 3 H, C
3-H, C
4-H): 4.24 (m, 1 H, C
2-H); 4.92 (broad singlet, 1 H, N-H); 9.59 (s, 1 H, C
1-H).
15.
Boc-L-leucinal racemizes if stored at room temperature. Although it solidified in the cold it became liquid at room temperature. It is very soluble in
pentane at room temperature, but crystallizes from
pentane at −30°C. It is reported
2 to melt at
63–66°C.
3. Discussion
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved