Checked by Takashi Ooi and Hisashi Yamamoto.
1. Procedure
B.
3-(S)-[(tert-Butyldiphenylsilyl)oxy]-2-butanone. An
oven-dried, 1-L, three-necked, round-bottomed flask is charged with
20.0 g (56.2 mmol) of ethyl 2-(S)-[(tert-butyldiphenylsilyl)oxy]propanoate and the flask is fitted with a
mechanical stirrer, a
100-mL addition funnel, and a
rubber septum. A
low temperature thermometer (Note
3) is inserted through the rubber septum and
250 mL of dry tetrahydrofuran (Note
1) is injected with a syringe. The mechanically stirred solution is cooled to −105°C (Note
4) and maintained until the temperature has stabilized. The addition funnel is charged with
52 mL of a 1.4 M ether solution of halide-free methyllithium (73 mmol) and this solution is added dropwise with mechanical stirring over 35–40 min. The internal temperature is never allowed to rise above −100°C (Note
5). When addition is complete,
20 mL (158 mmol) of trimethylsilyl chloride (Note
6) is injected and the resulting clear solution is warmed to room temperature over 20 min with the aid of a water bath. At this time
200 mL of 1 N hydrochloric acid is added and vigorous stirring is continued for 1 hr (Note
7). The mixture is poured slowly into a
2-L Erlenmeyer flask containing
30 g of solid sodium bicarbonate and then concentrated to remove
tetrahydrofuran under reduced pressure using a rotary evaporator. The resulting aqueous suspension is transferred to a 1-L separatory funnel and extracted with
400 mL of ethyl acetate. The organic layer is washed with two 400-mL portions of water, dried over anhydrous
sodium sulfate, filtered, and concentrated using a rotary evaporator to give
18.2 g (
99%) of
3-(S)-[(tert-butyldiphenylsilyl)oxy]-2-butanone as a clear colorless oil (Note
8) and (Note
9).
2. Notes
1.
(S)-Ethyl lactate, [α]14D −10° (neat) and other chemicals employed in this procedure were obtained from Aldrich Chemical Company, Inc. Anhydrous
tetrahydrofuran was prepared by distillation under
argon from
sodium benzophenone ketyl.
2. Gas chromatographic analysis using a 25-m 10% SP 2100 silicone column showed that this sample was >95% pure and contained one major unidentified impurity. Material of this purity is acceptable for use in the second step. A sample showing no detectable impurities by GLC analysis can be obtained by flash chromatography on silica gel
(5:95 ethyl acetate-hexane). This sample has the following spectral characteristics:
[α]D −45.1° (MeOH,
c 1.0);
1H NMR (500 MHz, CDCl
3) δ: 1.09 (s, 9 H, t-Bu), 1.14 (t, 3 H, J = 7.1, OCH
2CH
3), 1.37 (d, 3 H, J = 6.7, CH
3), 3.99–4.04 (m, 2 H, OCH
2CH
3), 4.27 ( q, 1 H, J = 6.7, CH), 7.36–7.41 (m, 6 H, Ph), 7.65–7.69 (m, 4 H, Ph);
13C NMR (125 MHz, CDCl
3) δ: 14.0, 19.2, 21.2, 26.8, 60.5, 68.9, 127.6, 129.7, 133.1, 133.5, 135.7, 135.8, 173.6; IR (film) cm
−1: 2980, 2933, 2859, 1753, 1735, 1429, 1198, 1139, 1112, 1081, 823, 739, 702, 690, 611. Anal. Calcd for C
21H
28O
3Si: C, 70.74; H, 7.92. Found: C, 70.94; H, 7.89.
3. An OMEGA 450 ATT (Type T)
thermocouple thermometer was used.
4. A minimum amount of liquid
nitrogen contained in a
1-L Dewar bowl was used to cool the solution to −105°C.
5. It is crucial that the internal temperature of the reaction mixture never exceed −100°C during the addition of the
methyllithium solution. If the temperature begins to rise, the dropwise addition of the reagent should be slowed. Periodic addition of a small amount of liquid
nitrogen to the cooling bath may also be necessary.
7. Hydrolysis of the reaction mixture may be accomplished by addition of 200 mL of water instead of
200 mL of 1 N hydrochloric acid. In the former case complete hydrolysis requires 5 hr and in the latter hydrolysis is complete within 1 hr.
8. Gas chromatographic analysis using a 25-m 10% SP 2100 silicone column showed that this sample was >95% pure and contained one major unidentified impurity. A sample of 100% purity may be obtained by flash chromatography on silica gel (1:9
ethyl acetate-hexane). This sample has the following spectral characteristics:
[α]D −3.1° (MeOH,
c 1.0);
1H NMR (300 MHz, CDCl
3): δ: 1.10 (s, 9 H, t-Bu), 1.19 (d, 3 H, J = 6.8, CH
3), 2.16 (s, 3 H, COCH
3), 4.17 (q, 1 H, J = 6.8, CH), 7.36–7.40 (m, 6 H, Ph), 7.60–7.66 (m, 4 H, Ph);
13C NMR (75 MHz, CDCl
3) δ: 19.2, 20.6, 24.9, 26.9, 75.7, 127.6, 127.8, 129.9, 135.7, 211.7; IR (film) cm
−1: 2961, 2933, 2859, 1719, 1428, 1114, 823, 741, 703, 691; MS (Cl) m/z 327.1760 (327.1780 calcd for C
20H
26O
2Si, MH). Anal. Calcd for C
20H
26O
2Si: C, 73.57; H, 8.03. Found: C, 73.52; H, 8.07.
9. The enantiomeric excess of the product is >96%. This was determined by treating a sample of the ketone sequentially with
methyllithium and
tetrabutylammonium fluoride (THF, −78°C). The resulting diol was converted to its Mosher diester
2 3 [2.5 eq of
(+)-α-methoxytrifluoromethylphenylacetic acid, 3 eq of
dicyclohexylcarbodiimide, and 0.2 eq of
4-(dimethylamino)pyridine, CH
2Cl
2] and the crude esterification reaction mixture was analyzed using 500 MHz
1H NMR. None of the minor diastereomer was observed; doping experiments established that 2% of the minor diastereomer would have been detected [diagnostic signals: d 5.03 (q, J = 6.2, major diastereomer); δ 5.17 (q, J = 6.1, minor diasteromer)].
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The sequence detailed here provides
3-(S)-((tert-butyldiphenylsilyl)oxy)-2-butanone in high purity and on a preparative scale from inexpensive
(S)-ethyl lactate. This optically active ketone should be a useful intermediate for the preparation of a variety of enantiomerically pure materials. It has been used in our laboratory for an asymmetric synthesis of
(+)-muscarine4 and in the preparation of various other optically active tetrahydrofurans.
5 Mitsunobu inversion of
(S)-ethyl lactate followed by protection to provide
2-(R)-((tert-butyldiphenylsilyl)oxy)propanoate6 affords, by this method, ready access to the enantiomer of the title compound.
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