Checked by Eugene Ho and David L. Coffen.
1. Procedure
B.
tert-Butyl [1-(tert-butoxycarbonyl)-3-oxo-4-pentenyl]carbamate. The crude bromination product from the previous step is taken up in
240 mL of dry tetrahydrofuran (THF) (Note
7) and transferred to a
1000-mL flask equipped with a stirrer, thermometer, dropping funnel, and argon inlet. The solution is cooled to −78°C and a solution of
42 g (0.20 mol) of dichlorodiethoxytitanium [TiCl2 (OEt)2] in
80 mL of dry THF (Note
8) is added at such a rate that the internal temperature does not exceed −72°C. When the addition is complete, the reaction mixture is stirred at −78°C for 10 min and then
24 g (0.170 mol) of 2-trimethylsiloxybutadiene (Note
9) in
100 mL of THF is added dropwise, causing only a slight increase in temperature (−72°C). The reaction mixture is allowed to warm to room temperature overnight and poured into
700 mL of ice-cooled, saturated sodium bicarbonate solution. After filtration through Celite, the aqueous phase is extracted with three
200-mL portions of ether. The combined organic layers are washed twice with water, dried over
magnesium sulfate (MgSO4), filtered, and concentrated. The remaining dark oil (29 g) is subjected to
flash chromatography (20-cm column diameter, ether/hexane 1:3);
8.44–8.73 g (
33–36%) (Note
10) of the product is obtained as a slightly yellowish oil (Note
11).
2. Notes
2.
N-Bromosuccinimide was purchased from Fluka Chemical Corporation, recrystallized from water, and dried well in a
vacuum desiccator.
4. The rotatory evaporator was washed with
ethanol and ether. Bromination on a smaller scale can be carried out in a
three-necked, round-bottomed flask with a thermometer, argon inlet, and stirring bar. External cooling with a water bath to keep the internal temperature between 15° and 20°C is important. The use of more concentrated solutions should be avoided, since dimerization instead of bromination becomes the dominant reaction.
5. The water bath was coated with
aluminum foil in order to increase the efficiency of the irradiation.
6. TLC (
ethyl acetate/
hexane 1:3;
vanillin/concd. H
2SO
4/heat) reveals complete consumption of the starting material and only small amounts of impurities. The crude product is stable for several weeks at −20°C under
argon.
2
8.
Tetraethyl orthotitanate, 22.9 g (0.100 mol), (Fluka Chemical Corporation, bulb-to-bulb-distilled at
110–115°C/0.1 mm) is dissolved in
80 mL of dry THF.
Titanium chloride (TiCl4) (Fluka Chemical Corporation), 19.0 g (0.100 mol, distilled at
136°C/atmospheric pressure) was added dropwise while cooling with an
acetone/dry ice bath to keep the temperature below 0°C. Alternatively, TiCl
4 may be added to a solution of Ti(OEt)
4 (obtained from Aldrich Chemical Company, Inc.) in
hexane at 0°C; the solvent is evaporated and replaced by THF.
3
10. In an experiment on one tenth the scale, the yield was
57%.
4
11. The physical properties are as follows:
1H-NMR (CDCl
3) δ: 1.44 (s, 18 H), 3.08 (dd, 1 H, J = 4 and 18), 3.28 (dd, 1 H, J = 4 and 18), 4.45 (m, 1 H), 5.48 (d, 1 H, J = 8, N-H), 5.91 (dd, 1 H, J = 2 and 10), 6.25 (dd, 1 H, J = 2 and 18), 6.34 (dd, 1 H, J = 10 and 18); IR (CHCl
3) cm
−1: 3430, 3000, 2980, 2930, 1740, 1720, 1710, 1630, 1500.
12. When the filter cake contains
hydrogen chloride, it is very hygroscopic. It should therefore be covered immediately with dry
ether after the ethereal
hydrogen chloride solution has been aspirated.
13. The physical properties are as follows:
1H NMR (MeOD) δ: 3.05 (dt, 2 H, J = 2 and 6), 3.20 (dd, 1 H, J = 7 and 20), 3.29 (dd, 1 H, J = 4 and 20), 3.79 (t, 2 H, J = 6), 4.30 (dd, 1 H, J = 4 and 7); IR (nujol) cm
−1: 3300–2300 broad, 3060, 2960, 2920, 2860, 1740, 1725, 1600, 1570.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Elimination of HBr leads to an acylimino acetate that should be able to undergo an aza-Diels–Alder reaction with dienes to give pipecolic acid derivatives not readily accessible by other methods. Indeed,
1, in the presence of TiCl
2(OEt)
2, reacts with Danishefsky's diene between −78°C and room temperature to give the cyclic compound
2 in 72% yield. In a thermal reaction of
2-trimethylsiloxybutadiene with another electrophilic
glycine equivalent, Jung and co-workers
6 isolated a cyclic product of type
3. Under the reaction conditions described here, the reaction product is not
3 but the enone
4, which by itself is an interesting bifunctional intermediate. However, upon deprotection the anticipated ring closure takes place in a very clean fashion. Pure
4-ketopipecolic acid hydrochloride crystallizes out of the ethereal
hydrogen chloride solution in quantitative yield, which illustrates the advantage of the use of
1 in amino acid synthesis, i.e., the ease of deprotection, often a critical step.
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