As shown in Scheme 1, (4S)-4-benzyloxazolidinone (2) was reacted with crotonoyl chloride to give
compound 3 in 85.8% yield in the presence of NaH. Then 4 was obtained via asymmetric Michael addition of ethylmagnesium
bromide to 3 in 98% diasteromeric excess and 87.3% yield, which was analyzed by HPLC and purified by flash column
chromatography. Nondestructive removal of the auxiliary group of 4 gave (S)-3-methylpentan-1-ol (5) in 83.2% yield. The
(
8
S)-5 was smoothly converted to tosylate in the presence of pyridine, and then converted to the corresponding bromide 6 in
1.6% yield by treating with lithium bromide. The bromide 6 was prepared as a Grignard reagent and then reacted with
propionyl morpholine to get (S)-6-methyl-3-octanone (1) in 84.5% yield, and the overall yield of (S)-1 was 43.0%. In these
reactions, the stereocenter of the compounds was not touched, and the spectral data of (S)-1 were in accord with the literature,
as well as the specific rotation value [3].
EXPERIMENTAL
All organic solvents were dried by standard methods. TLCs were performed on precoated plates of silica gel HF254
(
0.5 mm, Yantai, China). Flash column chromatography was performed on silica gel H (Yantai, China). Melting points were
measured on a WRS-1A digital melting point apparatus and uncorrected. Optical rotations were determined with a Perkin–
1
Elmer Model 241 MC polarimeter. IR spectra were recorded on an IR spectrum One (PE) spectrometer, and H NMR
1
3
(
600 MHz) and C NMR (150 MHz) spectra were recorded on a Varian Unity INOVA600 spectrometer in CDCl using TMS
3
as internal standard. The diastereoisomeric purity was determined by means of HPLC (Dionex, Ultimate3000 pump) using
solid-phase extraction in reversed phase mode (C8 phase) (70:30 water–methanol, 1 mL/min, 254 nm).
(
S)-3-((E)-But-2-enoyl)-4-benzyloxazolidinone (3). NaH (0.35 g, 31.04 mmol) was added portionwise to a solution
of (S)-4-benzyloxazolidinone 2 (5.0 g, 28.22 mmol) in dry THF (70 mL) and the mixture was stirred for 30 min at room
temperature. Crotonyl chloride (1.7 mL, 33.86 mmol) was added dropwise to the mixture and the solution was allowed to
stand for 5 h. The reaction mixture was quenched with H O (50 mL) and then THF was removed under reduced pressure. The
2
aqueous layer was extracted with CH Cl (50 mL ꢀ 3) and the organic layers were combined, washed with dilute HCl, aqueous
2
2
saturated NaHCO , and brine, dried over anhydrous MgSO , and concentrated. Purification of the crude product by flash
3
4
2
0
column chromatography (n-hexane–EtOAc, 8:1, v/v) gave a white solid 3 (5.9 g, 85.8%). [ꢁ] +75.3ꢂC (c 2.0, CHCl ), lit.
11] [ꢁ]D +77.9ꢂC (c 2.0, CHCl ). Mp 84.8–85.1ꢂC, lit. [11] 85.0–86.0ꢂC. IR (NaCl, cm ): 1769, 1677, 1630. H NMR
CDCl , ꢃ, ppm, J/Hz): 1.99 (3H, t, J = 0.6, J = 5.4, CH ), 2.80 (1H, dd, J = 9.6, J = 13.2, PhCH ), 3.33 (1H, dd, J = 3.0,
J = 13.2, PhCH ), 4.19 (2H, m, OCH ), 4.7 (1H, m, CH), 7.22–7.35 (m, 7H, Ar-H, CH=CH). C NMR (CDCl , ꢃ): 18.55,
D
3
2
0
–1
1
[
(
3
3
1
2
3
1
2
2
1
1
3
2
2
2
3
3
7.78, 55.21, 66.03, 121.73, 127.24, 128.88 (2C), 129.41 (2C), 135.30, 147.01, 153.39, 164.89.
(
S)-3-((S)-3-Methylpentanoyl)-4-benzyloxazolidinone (4). Bromoethane (3.43 mL, 40.78 mmol) was added dropwise
under argon to a suspension of magnesium turnings (1.04 g, 42.8 mmol) in dry THF (20 mL). The mixture was stirred for 1 h
under reflux. The resulting dark solution was cooled to 0ꢂC and transferred via a cannula to a solution of 3 (5.0 g, 20.39 mmol)
in THF (30 mL) at –78ꢂC, and the mixture was stirred at –78ꢂ for 3 h. The reaction was quenched by saturated aqueous NH Cl
4
(
20 mL). After evaporation of the solvent, the aqueous layer was extracted with ethyl acetate, and the organic layer was
washed with saturated aqueous NH Cl and brine, dried over anhydrous MgSO , filtered, and concentrated. Purification of the
4
4
2
0
crude product by flash column chromatography (n-hexane–EtOAc, 16:1, v/v) gave a colorless oil 4 (5.2 g, 87.3%). [ꢁ]
21.25ꢂC (c 2.0, EtOAc). IR (NaCl, cm ): 1784, 1698. H NMR (CDCl , ꢃ, ppm, J/Hz): 0.84–0.90 (6H, m, 2CH ), 0.90–0.96
D
–
1
1
+
3
3
(
2H, m, CH ), 1.24 (1H, m, CH), 1.40 (1H, t, J = 1.2, J = 6.0, COCH ), 1.98 (1H, t, J = 1.8, J = 4.2, COCH ), 2.95 (1H, dd,
2 1 2 2 1 2 2
J = 5.4, J = 10.8, PhCH ), 3.25 (1H, dd, J = 9.0, J = 10.2, PhCH ), 4.11 (2H, m, OCH ), 4.63 (1H, m, NCH), 7.17 (2H, d,
1
2
2
1
2
2
2
1
3
J = 7.2, Ph), 7.19 (1H, d, J = 7.8, Ph), 7.28 (2H, t, J = 7.8, J = 6.6, Ph). C NMR (CDCl , ꢃ): 11.21, 19.13, 29.29, 30.98,
1
2
3
3
7.76, 41.98, 54.97, 65.89, 127.02, 128.65 (2C), 129.16 (2C), 135.17, 153.14, 172.53.
(
S)-3-Methylpentan-1-ol (5). A solution of NaBH (0.61 g, 30.3 mmol) in ethanol (10 mL) was added dropwise to a
4
solution of 4 (3.0 g, 10.9 mmol) in THF (20 mL) at 0ꢂC. The ice bath was removed and the mixture was stirred at room
temperature for 2 h. The mixture was then recooled to 0ꢂC, and dilute HCl was added carefully to quench the excess hydride
reagent. After evaporation of the solvent, the aqueous layer was extracted with Et O, and the organic layer was washed with
2
brine, dried over anhydrous MgSO , filtered, and concentrated. Purification of the crude product by flash column chromatography
4
2
0
20
(
n-hexane–EtOAc, 6:1, v/v) gave 5 as a colorless oil (0.93 g, 83.2 %). [ꢁ] + 8.58ꢂC (neat), lit. [12] [ꢁ]D +8.77ꢂC (neat).
IR (NaCl, cm ): 3300. H NMR (CDCl , ꢃ, ppm, J/Hz): 0.84–0.95 (6H, m, 2CH ), 1.13–1.25 (2H, m, 2CH ), 1.36 (1H, m,
CH), 2.34 (1H, s, OH), 2.92 (1H, m, OCH ), 3.40 (1H, m, OCH ). C NMR (CDCl , ꢃ): 11.42, 20.58, 30.43, 31.24, 39.52, 60.15.
D
–
1
1
3
3
2
13
2
2
3
8
4