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T. Kitayama et al. / Tetrahedron: Asymmetry 24 (2013) 621–627
4.5.2. (S)-4-(40-Aacetyloxyphenyl)-2-butanol (S)-5
in 67 and 33% yield, and 46% and 99% ee, respectively. Enantiome-
rically pure (S)-2 was obtained after same treatment with the
above method under other conditions of lipase-catalyzed transe-
sterification using Meito QLM or CAL-B as shown in Table 3.
½
a 2D4
ꢁ
¼ þ15:8 (c 0.632, EtOH) 99% ee, ½a D24
¼ þ14:4 (c 1.32,
ꢁ
EtOH) 79% ee.12 1H NMR (CDCl3): d 1.23 (d, 3H, J = 6.2 Hz, CH3 at
C1), 1.73–1.79 (m, 2H, CH2 at C3), 2.29 (s, 3H, CH3 at COCH3),
2.63–2.79 (m, 2H, CH2 at C4), 3.84 (m, 1H, CH at C2), 6.99 (ddd,
2H, J = 8.5, 4.4, and 0.1 Hz, H at C30 and C50), 7.20 (ddd, 2H,
J = 8.5, 4.4, and 0.1 Hz, H at C20 and C60).
4.8. Hydrolysis of (R)-9
Compound (R)-9 in MeOH (1 mL) was added to K2CO3 (188 mg,
1.36 mmol) and stirred at room temperature for 2 h. Next, H2O
(10 mL) was added to the reaction mixture. The aqueous solution
was extracted with ethyl acetate (3 ꢀ 10 mL). The combined or-
ganic extracts were washed with brine (3 ꢀ 30 mL), dried over
Na2SO4, and concentrated on a rotary evaporator to obtain a color-
less oil. Chromatography on silica gel, eluting with a 4:1 mixture of
hexane and ethyl acetate, afforded (R)-2 in 90% yield.
4.5.3. (R)-4-(40-Hydroxyphenyl)-2-butyl acetate (R)-6
½
a 2D4
ꢁ
¼ þ2:3 (c 0.963, EtOH) 98% ee, ½a D24
¼ þ2:1 (c 1.42, EtOH)
ꢁ
98% ee.12 1H NMR (CDCl3): d 1.24 (d, 3H, J = 6.3 Hz, CH3 at C1),
1.71–1.94 (m, 2H, CH2 at C3), 2.03 (s, 3H, OCOCH3 at C2), 2.50–
2.64 (m, 2H, CH2 at C4), 4.91 (m, 1H, CH at C2), 6.75 (ddd, 2H,
J = 8.5, 4.6, and 0.2 Hz, H at C30 and C50), 7.03 (ddd, J = 8.5, 4.6,
and 0.2 Hz, 2H, H at C20 and C60).
4.5.4. (R)-4-(40-Acetyloxyphenyl)-2-butyl acetate (R)-7
4.9. Acetylation of (S)-2
½
a 2D4
ꢁ
¼ þ8:6 (c 0.244, EtOH) 99% ee), ½a D24
¼ þ6:1 (c 1.64, EtOH)
ꢁ
98% ee.12 1H NMR (CDCl3): d 1.24 (d, 3H, J = 6.3 Hz, CH3 at C1),
1.74–1.96 (m, 2H, CH2 at C3), 2.02 (s, 3H, OCOCH3 at C2), 2.28 (s,
3H, OCOCH3 at Ar), 2.56–2.70 (m, 2H, CH2 at C4), 4.93 (m, 1H, CH
at C2), 6.99 (ddd, 2H, J = 8.5, 4.5, and 0.1 Hz, H at C30 and C50),
7.17 (ddd, 2H, J = 8.5, 4.5, and 0.1 Hz, H at C20 and C60).
A mixture of (S)-2 (71 mg, 0.36 mmol), 1 and 5 equiv of acetic
anhydride, and several drops of pyridine was stirred at room tem-
perature for 20 min and 60 min. The progress of the acetylation
was monitored by TLC. After consumption of the substrate, H2O
(10 mL) was added to the reaction mixture. The aqueous solution
was extracted with ethyl acetate (3 ꢀ 10 mL). The combined or-
ganic extracts were washed with a saturated NaHCO3 solution
(3 ꢀ 30 mL) and brine (3 ꢀ 30 mL), dried over Na2SO4, and concen-
trated on a rotary evaporator to obtain a colorless oil. Chromatog-
raphy on silica gel, eluting with a 4:1 mixture of hexane and ethyl
acetate, afforded (S)-8 and (S)-10 in 83% and 99% yield,
respectively.
4.6. General procedure of lipase-catalyzed transesterification of
zingerol 2
After exhaustive drying of THF, substrate, and lipase under
0.1 mmHg conditions, substrate 2 (50 mg, 0.26 mmol), vinyl ace-
tate (33.5 mg, 0.39 mmol), and the lipase (dry MeitoQLM, 25 mg)
in i-Pr2O (0.75 mL) with molecular sieves 4 Å were stirred for
approximately 30 min at 35 °C. The reaction mixture was filtered
and the filtrate was concentrated. Chromatography on silica gel,
eluting with a 4:1 mixture of hexane and ethyl acetate, afforded
(S)-zingerol ((S)-2) and (R)-4-(40-hydroxy-30-methoxyphenyl)-2-
butyl acetate (R)-9 in 68 and 32% yield, respectively. (S)-4-(40-Acet-
yloxy-30-methoxyphenyl)-2-butanol (S)-8 and (R)-4-(40-acetyloxy-
30-methoxyphenyl)-2-butyl acetate (R)-10 were obtained under
other conditions of lipase-catalyzed transesterification, as shown
in Table 3, and purified by silica gel column chromatography using
a 4:1 mixture of hexane and ethyl acetate as an eluent.
The reaction was followed by GC using a column of InertCap5
(detector and injection temperature, 220 °C; column temperature,
170 °C; carrier gas, He; linear velocity: 30 cm/s, FID detector). Un-
der these conditions, the retention times of 2, 8, 9 and 10 were 8.8,
15.4, 12.9, and 22.9 min, respectively. The enantiomeric excess of 9
and 10 were determined directly and those of 2 and 8 were deter-
mined after synthesizing the corresponding acetates by GC using a
column of CP-CD (detector and injection temperature, 200 °C; col-
umn temperature, 160 °C; carrier gas He; linear velocity: 30 cm/s,
FID detector). Under these conditions, the retention times of (R
and S)-2, (R and S)-8, (R)-9, (S)-9, (R)-10, and (S)-10 were 33, 68,
40, 39, 80, and 78 min, respectively.
4.10. Acetylation of (R)-2
A mixture of (R)-2 (71 mg, 0.36 mmol), 1 equiv of acetic anhy-
dride, and several drops of pyridine was stirred at room tempera-
ture for 20 min. The progress of the acetylation was monitored by
TLC. After consumption of the substrate, H2O (10 mL) was added to
the reaction mixture. The aqueous solution was extracted with
ethyl acetate (3 ꢀ 10 mL). The combined organic extracts were
washed with saturated NaHCO3 solution (3 ꢀ 30 mL) and brine
(3 ꢀ 30 mL), dried over Na2SO4, and concentrated on a rotary evap-
orator to obtain a colorless oil. Chromatography on silica gel, elut-
ing with a 4:1 mixture of hexane and ethyl acetate, afforded (R)-8
in 82% yield.
4.11. Acetylation of (R)-9
A mixture of (R)-9 (107 mg, 0.45 mmol), 1.5 equiv. of acetic
anhydride, and several drops of pyridine was stirred at room tem-
perature for 1 h. The progress of the acetylation was monitored by
TLC. After consumption of the substrate, H2O (10 mL) was added to
the reaction mixture. The aqueous solution was extracted with
ethyl acetate (3 ꢀ 10 mL). The combined organic extracts were
washed with saturated NaHCO3 solution (3 ꢀ 30 mL) and brine
(3 ꢀ 30 mL), dried over Na2SO4, and concentrated on a rotary evap-
orator to obtain a colorless oil. Chromatography on silica gel, elut-
ing with a 4:1 mixture of hexane and ethyl acetate, afforded (R)-10
in 96% yield.
4.7. General procedure for the lipase-catalyzed
transesterification of zingerol 2 on a gram scale
After exhaustive drying of THF, substrate, and lipase under
0.1 mmHg conditions, substrate 2 (5.00 g, 26.0 mmol), vinyl ace-
tate (3.35 g, 39.0 mmol), and the lipase (dry MeitoQLM, 2.50 g) in
i-Pr2O (75.0 mL) with molecular sieves 4 Å were stirred for approx-
imately 30 min at 35 °C. The reaction was followed by GC using a
column of InertCap5 and the ee was determined by GC using a col-
umn of CP-CD. The reaction mixture was filtered and the filtrate
was concentrated. Chromatography on silica gel, eluting with a
4:1 mixture of hexane and ethyl acetate, afforded (S)-2 and (R)-9
4.12. Hydrolysis of (S)-10
A powder of Na2CO3 (97.9 mg, 0.90 mmol) was added to (S)-
10 (87.1 mg, 0.30 mmol) in MeOH and the mixture was stirred
at room temperature for 4 h. After consumption of the substrate,
H2O (10 mL) was added to the reaction mixture. The aqueous
solution was extracted with ethyl acetate (3 ꢀ 10 mL). The