1228
T. Ema et al. / Tetrahedron: Asymmetry 13 (2002) 1223–1229
C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C,
69.77; H, 6.47; N, 14.68%.
+30.6 (c 1.08, CH2Cl2) for (S)-1b with 85% e.e.; 1H
NMR (200 MHz, CDCl3): l 1.23 (d, J=6.2 Hz, 3H),
2.65–2.90 (m, 2H), 3.83 (s, 3H), 4.00–4.12 (m, 1H),
6.86–6.95 (m, 2H), 7.13–7.27 (m, 2H); HPLC: Chiral-
pak AD, hexane/i-PrOH=9:1, flow rate 0.5 mL/min,
detection 254 nm, (S) 14 min, (R) 16 min. (R)-2b: 18%
4.3. General procedure for determination of absolute
configurations
1
The typical experimental procedures for the rapid
method and the double-confirmation method are as
follows. The latter is recommended to raise reliability,
but the former is much more time- and cost-effective.
yield; 94% e.e.; [h]2D5=−20 (c 0.50, CHCl3); H NMR
(200 MHz, CDCl3): l 1.21 (d, J=6.4 Hz, 3H), 1.96 (s,
3H), 2.85 (d, J=7.0 Hz, 2H), 3.82 (s, 3H), 5.16 (sext.,
J=6.4 Hz, 1H), 6.82–6.90 (m, 2H), 7.09–7.27 (m, 2H);
13C NMR (50 MHz, CDCl3): l 19.7, 21.3, 36.6, 55.2,
70.5, 110.2, 120.2, 126.0, 127.8, 131.1, 157.7, 170.6; IR
(neat): 1736, 1244 cm−1.
4.3.1. Rapid method (step 1). A heterogeneous solution
of lipase PS (270 mg), alcohol (0.82 mmol), and vinyl
ester (1.64 mmol) in dry i-Pr2O (5 mL) was stirred at
450 rpm in a test tube with a rubber septum in a
thermostat at 30°C. The progress of the reaction was
monitored by TLC, and the reaction was stopped by
filtration at an appropriate conversion (typically 30–
50%). After the solvent was removed under reduced
pressure, alcohol and ester were separated by silica gel
column chromatography. The ester was converted to
the corresponding alcohol, and the enantiomeric
excesses were then determined by chiral HPLC or chiral
GC. The E value was calculated according to the
literature.13 The absolute configurations were deter-
mined by the transition-state model.
4.3.5. Kinetic resolution of 1-(3,5-dibenzyloxy-
phenyl)ethanol, 1c. Reaction time 8 h. (S)-1c: 54% yield;
68% e.e.; [h]2D6=−12.4 (c 1.00, CHCl3); HPLC: Chiral-
pak AD, hexane/i-PrOH=9:1, flow rate 0.5 mL/min,
detection 280 nm, (R) 51 min, (S) 58 min. (R)-2c: 40%
yield; >98% e.e.; [h]2D8=+73.9 (c 1.01, CHCl3); 1H NMR
(200 MHz, CDCl3): l 1.50 (d, J=6.5 Hz, 3H), 2.06 (s,
3H), 5.03 (s, 4H), 5.80 (q, J=6.5 Hz, 1H), 6.55 (t,
J=2.2 Hz, 1H), 6.60 (d, J=2.2 Hz, 2H), 7.35–7.41 (m,
10H); 13C NMR (50 MHz, CDCl3): l 21.3, 22.2, 70.1,
72.1, 101.1, 105.3, 127.6, 128.0, 128.6, 136.7, 144.2,
160.0, 170.3; IR (neat): 1736, 1597, 1240 cm−1.
4.3.2. Double-confirmation method (step 2). Subse-
quently, the optically active alcohol obtained in the
lipase-catalyzed kinetic resolution was converted to the
MTPA derivative as follows. A solution of the alcohol
(0.05 mmol), (S)-MTPA-Cl (0.15 mmol, acyl chloride
of (R)-MTPA), 4-(dimethylamino)pyridine (0.03
mmol), and dry pyridine (1.2 mmol) in dry toluene (0.5
mL) was stirred at room temperature overnight. The
reaction was stopped by adding water (1 mL). The
product was extracted with EtOAc (5×1 mL), washed
with 10% HCl (0.5 mL), and then washed with satu-
rated aqueous NaHCO3 (0.5 mL). The mixture was
dried over Na2SO4, and the solvent was removed under
reduced pressure. The product was purified by silica gel
4.3.6. Kinetic resolution of 1-(4-benzyloxy-2-methoxy-3-
methylphenyl)ethanol, 1d. Reaction time 7 days. (S)-1d:
69% yield; 43% e.e.; [h]2D2=−11.1 (c 1.00, CHCl3);
HPLC: Chiralpak AD, hexane/i-PrOH=9:1, flow rate
0.5 mL/min, detection 254 nm, (S) 22 min, (R) 24 min.
(R)-2d: 30% yield; 90% e.e.; [h]2D2=+56.7 (c 1.00,
CHCl3); 1H NMR (500 MHz, CDCl3): l 1.50 (d, J=6.5
Hz, 3H), 2.06 (s, 3H), 2.22 (s, 3H), 3.79 (s, 3H), 5.07 (s,
2H), 6.17 (q, J=6.5 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H),
7.17 (d, J=8.5 Hz, 1H), 7.33–7.44 (m, 5H); 13C NMR
(50 MHz, CDCl3): l 9.4, 21.4, 21.9, 61.0, 67.6, 70.1,
107.6, 120.1, 123.9, 127.1, 127.5, 127.8, 128.5, 137.3,
156.3, 157.6, 170.3; IR (neat): 1736, 1600, 1240 cm−1.
1
column chromatography. 500 MHz H NMR spectrum
4.3.7. Kinetic resolution of 1-(4-(imidazol-1-yl)-
phenyl)ethanol, 1e. Despite the poor solubility of 1e in
i-Pr2O, the reaction proceeded. Reaction time 2 days.
(S)-1e: 51% yield; >98% e.e.; [h]1D7=−33 (c 0.48,
MeOH); HPLC: Chiralcel OJ, hexane/i-PrOH=7:1
(0.1% diethylamine), flow rate 0.7 mL/min, detection
254 nm, (S) 50 min, (R) 58 min. (R)-2e: 47% yield;
was measured, and the doublet signals of the methyl
group of the alkoxy moiety were used for absolute
configuration determination according to the
literature.2
4.3.3. Kinetic resolution of 1-(pentafluorophenyl)ethanol,
1a. Reaction time 3 days. (S)-1a: 45% yield; 64% e.e.;
[h]D18=−4.2 (c 0.45, n-pentane), lit.14 [h]2D8=−7.1 (c 1.0,
1
>98% e.e.; [h]1D4=+108 (c 0.66, CHCl3); H NMR (500
MHz, CDCl3): l 1.56 (d, J=6.5 Hz, 3H), 2.09 (s, 3H),
5.90 (q, J=6.5 Hz, 1H), 7.22 (t, J=1.0 Hz, 1H), 7.28 (t,
J=1.5 Hz, 1H), 7.37–7.48 (m, 4H), 7.89 (t, J=1.0 Hz,
1H); 13C NMR (50 MHz, CDCl3): l 21.2, 22.2, 71.5,
118.3, 121.6, 127.6, 130.0, 135.4, 136.7, 141.3, 170.2; IR
(neat): 1732, 1525, 1244 cm−1.
1
n-pentane) for (S)-1a with >94% e.e.; H NMR (200
MHz, CDCl3): l 1.65 (d, J=6.8 Hz, 3H), 5.26 (q,
J=6.8 Hz, 1H); GC: CP-cyclodextrin, Inj. 250°C, Col.
100°C, Det. 220°C, (R) 15 min, (S) 18 min. (R)-2a: 29%
yield; >99% e.e.; [h]D16=+43 (c 0.82, n-pentane); 1H
NMR (200 MHz, CDCl3): l 1.65 (d, J=6.8 Hz, 3H),
2.07 (s, 3H), 6.09 (q, J=6.8 Hz, 1H); 13C NMR (50
MHz, CDCl3): l 19.6, 20.8, 63.3, 170.1; IR (neat): 1747,
1521, 1236 cm−1.
Acknowledgements
4.3.4. Kinetic resolution of 1-(2-methoxyphenyl)-2-
propanol, 1b. Reaction time 25 h. (S)-1b: 55% yield;
63% e.e.; [h]2D1=+23.6 (c 1.00, CH2Cl2), lit.15 [h]2D5=
We are grateful to the SC-NMR Laboratory of
Okayama University for the measurement of NMR
spectra.