X. Chen et al. / Tetrahedron: Asymmetry 13 (2002) 43–46
45
spectrometer. 1H NMR spectra were recorded on a
Bruker ARX 400 NMR spectrometer. Chemical shifts
are indicated in l units (ppm) relative to TMS. Elemen-
tal analysis was carried out on Elementar Vario El.
Optical rotations were measured on a Perkin–Elmer
241 MC polarimeter. HPLC was performed on
HP1100. THF was distilled under nitrogen from
sodium. HMDS was dried with calcium hydroxide.
The compound 5 obtained above was dissolved in dry
toluene (10 mL) and reacted with Lawesson’s reagent
(2.1 g, 5.2 mmol) at 100°C for 5 h. The mixture was
concentrated under vacuum, purified by silica gel
column chromatography with methylene dichloride/
petroleum ether (1:1) and recrystallized from ethanol to
give 6 (2.96 g, 69% from 4) as a light yellow solid: mp
46–47°C; [h]2D0=+142.8 (c=1.31, chloroform); IR
(KBr): 2925, 2852, 1743, 1645, 1476, 1423, 1191 cm−1;
1
2.1. Synthesis of trans-4-cyclohexyl-N-benzyl-
L
-pyro-
FABMS: m/z 408 (M+1, 10); H NMR (CD3OD): l
glutamic acid 4
1.15–1.52 (10H, m, CH2), 1.67–1.73 (2H, m, CH2),
2.11–2.15 (1H, m, CH), 3.01 (1H, m, CH), 4.17–4.25
(2H, m, NCH2Ph), 5.13 (2H, s, OCH2Ph), 5.86–5.93
(1H, d, J=14.8 Hz, CH), 7.14–7.43 (10H, m, ArH).
Anal. calcd for C25H29O2SN: C, 73.67; H, 7.17; N, 3.43;
S, 7.86. Found: C, 73.53; H, 7.16; N, 3.54; S, 7.79%.
To a solution of hexamethyldisilazane (HMDS, 28 mL,
134 mmol) in dry THF (40 mL) was added n-butyl-
lithium (69 mL, 134 mmol) dropwise under nitrogen at
−10°C. After stirring the mixture for 30 min, N-benzyl-
L
-pyroglutamic acid 2 (14.2 g, 65 mmol) in THF (45
mL) was added and the stirring was continued for 1 h.
3-Bromocyclohexene (6.8 mL, 65 mmol) in THF (10
mL) was added and the mixture was stirred at −10°C
for 2 h then stirred for a further 2 h at room tempera-
ture. The reaction mixture was quenched by addition of
2N aqueous HCl (100 mL) and extracted with ethyl
acetate (3×50 mL). The combined organic layers were
washed with brine, dried over Na2SO4 and then concen-
trated. The crude product was purified by flash chro-
matography (silica gel, ethyl acetate/petroleum
ether=1:1) to give viscous oil 3 (19 g).
2.3. Synthesis of the trans-4-cyclohexyl-L-proline 1
To a solution of 6 (2.96 g, 7.25 mmol) in 95% ethanol
(60 mL) was added Raney-Ni (6 g). After heating under
reflux for 1.5 h, the reaction mixture was cooled and
filtered through Celite. The filtrate was concentrated
under reduced pressure to obtain 7 and 8 (total 2.2 g),
which was used in the next step without further
separation.
The obtained intermediates 7 and 8 (2.2 g), 10% Pd/C
(0.22 g), anhyd. methanol (45 mL) and glacial acetic
acid (5 mL) were added to a high-pressure reactor. This
mixture was hydrogenated under 20 atm hydrogen pres-
sure at 50°C for 2 h. The catalyst was removed by
filtration and the solvent was removed under reduced
pressure to obtain a white solid, which was recrystal-
lized from methanol–ethyl acetate to afford pure 1 (0.5
g, 35% from 6): mp 230°C; [h]2D0=−33.8 (c=0.42,
CH3COOH), ee%=93%; IR (KBr): 3422, 3111, 2926,
2849, 1623, 1448, 1384, 1288 cm−1; FABMS: m/z 198
The product 3 (19 g) was dissolved in ethyl acetate (120
mL) and hydrogenated in the presence of 10% Pd/C
(1.9 g) at room temperature under 1 atm hydrogen
pressure for 2 h. The mixture was filtered and the
filtrate was concentrated in vacuo. The residue was
recrystallized from ethyl acetate to afford 4 as a white
solid (10.2 g, 52% from 2): mp 167–168°C; [h]2D0=+77.9
(c=1, CHCl3); IR (KBr): 3452, 2913, 2848, 1733, 1652,
1
1441 cm−1; H NMR (CD3OD): l 1.20–2.32 (10H, m,
CH2), 1.71–1.75 (1H, d, J=8 Hz, CH), 2.05–2.11 (2H,
q, J=10.7 Hz, CH2), 2.65–2.67 (1H, m, CH), 3.86–4.18
(2H, m, PhCH2), 5.17–5.25 (1H, d, J=15.2 Hz, CH),
7.17–7.37 (5H, m, ArH), 9.8–10.3 (1H, s, COOH).
FABMS: m/z 302 (M+1, 100), 219 (M−C6H11, 18);
anal. calcd for C18H23NO3: C, 71.76; H, 7.67; N, 4.65.
Found: C, 71.61; H, 7.62; N, 4.54%.
1
(M+1, 100), 152 (M−COOH); H NMR (CD3OD): l
1.00–1.07 (2H, m, CH2), 1.23–1.28 (4H, m, CH2), 1.68–
1.78 (6H, m, CH2), 1.92–1.95 (2H, m, CH2), 2.28–2.48
(1H, m, CH), 2.86 (1H, t, J=10.9 Hz, CH), 3.55–3.58
(1H, m, CH), 4.02–4.05 (1H, t, NH). Anal. calcd for
C11H19O2N–0.5H2O: C, 64.05; H, 9.77; N, 6.79. Found:
C, 63.98; H, 9.74; N, 6.65%.
The determination of the diastereomeric ratio of 4 was
completed by HPLC (ZORBAX Extend-C18 column,
elution with acetonitrile:water=75:25, 1 mL/min, 220
nm).
Acknowledgements
2.2. Synthesis of the benzyl trans-4-cyclohexyl-5-thio-
N-benzyl-L-pyroglutamate 6
This work was supported by the National Natural
Science Foundation of China (Grant No. 20172001,
29872023).
To a solution of 4 (3.13 g, 10.4 mmol) in dry THF (45
mL) was added triethylamine (1.59 mL, 11.4 mmol) and
benzyl bromide (1.31 mL, 10.86 mmol). After heating
under reflux for 6 h, the mixture was cooled, filtered
and then concentrated. The residue was extracted with
chloroform (3×40 mL), washed successively with satu-
rated aqueous sodium bicarbonate (30 mL) and brine
(2×50 mL), dried over Na2SO4 and concentrated under
reduced pressure to give 5 as a light yellow oil (4.1 g).
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