W. P. Juma et al. / Tetrahedron: Asymmetry 28 (2017) 1169–1174
1173
1
28.3, 126.3, 122.5, 116.1, 72.6, 34.4, 31.1, 20.8. HRMS m/z calcd for
ken. The dichloromethane layer was separated and dried over Na
SO and subjected to flash column chromatography on silica gel
using ethyl acetate/ hexane as eluent.
2
-
+
C
14
H15NO
2
Na [M+Na ]: 252.1000, found: 252.0985. Chiral HPLC:
m amylose-2 (250 Â 4.6 mm); mobile phase, Hexane: IPA
96:4); flow rate = 1 mL/min, t = 9.45 min, t = 13.08 min.
4
Lux 5
l
(
R
R
4
.5.1. Preparation (S±-ꢀ(S±-2-cyano-1-phenylallyl]3,3,3-trifluoro-
2-methoxy-2-phenylpropanoate 6a
S)-[(S)-2-Cyano-1-phenylallyl]3,3,3-trifluoro-2-methoxy-2-
4
4
.4. Enzymatic hydrolysis reactions of 5a–c
.4.1. General procedure for enzymatic hydrolysis screening
(
phenylpropanoate 6a (230 mg, 80%) was isolated as a colourless
À1
reactions
The substrate (7 mg) was added to pH 7.00 phosphate buffer
1 mL) containing enzyme (7 mg). The reaction mixture was put
oil. R
2230, 1753, 1453, 1167; H NMR (300 MHz, CDCl
(m, 9H), 7.24–7.20 (m, 1H), 6.49 (s, 1H), 6.13 (d, J = 1.2 Hz, 1H),
f
= 0.64 (30% ethyl acetate/hexane); IR (neat, cm ) 2952,
1
3
) d 7.46–7.30
(
1
3
on an orbital shaker at the specified temperature and monitored
using TLC and chiral HPLC.
5.98 (d, J = 1.5 Hz, 1H), 3.60–3.57 (m, 3H); C NMR (100 MHz,
CDCl ) d 165.2, 134.1, 133.2, 131.5, 129.8, 129.6, 129.0, 128.5,
27.2 (br s), 127.1, 123.1 (q, JC-F = 289 Hz), 122.2, 116.0, 84.7 (q,
C-F = 28 Hz), 76.3, 55.9. HRMS m/z calcd for C20 NO Na [M
3
1
4
5
4
.4.2. Enzymatic hydrolysis of (± ±-2-cyano-1-phenylallyl acetate
J
H
16
F
3
3
+
a
+Na ]: 398.0980, found: 398.0985.
.4.2.1. Isolation of (+±-4a.
Compound 5a (1.00 g) was added
to a mixture containing Amano lipase from P. fluorescens (534730)
1.00 g) in phosphate buffer (50 mL) at pH 7.00. The resulting mix-
4.5.2. Preparation of (S±-ꢀ(S,E±-4-cyano-1-phenylpenta-1,4-dien-
3-yl] 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate 6b
(
ture was stirred for 44 h at 30 °C and the product was extracted
using ethyl acetate. Purification by column chromatography (10%
ethyl acetate/hexane) afforded as colourless oils (+)-4a [180 mg,
(S)-[(S,E)-4-Cyano-1-phenylpenta-1,4-dien-3-yl]
oro-2-methoxy-2-phenylpropanoate 6b was isolated as a colour-
3,3,3-triflu-
less oil (80 mg, 82%). R
(neat, cm ) 2951, 2224, 1753, 1452, 1167; H NMR (CDCl
f
= 0.75 (40% ethyl acetate/hexane); IR
À1
1
4
6%, ee = 94%; [
a
]
D
= +68.4 (c 0.5, MeOH)] and scalemic (À)-5a
3
,
(
404 mg, ee = 53%).
500 MHz) d 7.53–7.49 (m, 2H), 7.44–7.29 (m, 8H), 6.74 (d,
J = 15.7 Hz, 1H), 6.16 (br s, 1H), 6.15–6.13 (m, 2H), 6.07 (dd,
1
3
4
.4.2.2. Isolation of (˱-5a.
Compound 5a (1.50 g) was
3
J = 15.8, 7.4 Hz, 1H), 3.62–3.61 (m, 3H); C NMR (126 MHz, CDCl )
reacted under the conditions described in 4.4.2.1 for 14 d, after
which column chromatography (10% ethyl acetate/hexane)
d 165.3, 137.2, 134.9, 133.3, 131.7, 129.8, 129.1, 128.8, 128.5, 127.3
(br s), 127.0, 123.2 (q, JC-F = 289 Hz), 121.3, 120.70, 116.0, 84.8 (q,
afforded (À)-5a [544 mg, 73%, ee = 99%;
[
a]
D
= À27.8 (c 0.5,
18 3 3
JC-F = 28 Hz), 75.3, 55.9. HRMS m/z calcd for C22H F NO Na [M
+Na ]: 424.1136, found: 424.1135.
+
MeOH)] and (+)-4a (655 mg, ee = 84%).
4
1
4
.4.3. Enzymatic hydrolysis of (± ±-(E±-4-cyano-1-phenylpenta-
4.5.3. Preparation of (S±-ꢀ(S±-2-cyano-5-phenylpent-1-en-3-yl]
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate 6c
(S)-[(S)-2-Cyano-5-phenylpent-1-en-3-yl]3,3,3-trifluoro-2-
methoxy-2-phenylpropanoate 6c was isolated as a colourless oil
,4-dien-3-yl acetate 5b
.4.3.1. Isolation of (+±-4b.
Compound 5b (0.60 g) was added
to a mixture containing Amano AK lipase (lot 0351202) (0.60 g) in
phosphate buffer (50 mL) at pH 7.00. The resulting mixture was
stirred for 24 h at 25 °C and the product was extracted using ethyl
acetate. Purification by column chromatography (20% ethyl acet-
ate/hexane) afforded as colourless oils (+)-4b [100 mg, 42%,
(56 mg, 82%). R
cm ) 3030, 2229, 1752, 1453, 1167; H NMR (300 MHz, CDCl
f
= 0.59 (20% ethyl acetate /hexane); IR (neat,
À1
1
3
) d
7.58–7.48 (m, 2H), 7.46–7.38 (m, 3H), 7.32–7.18 (m, 3H), 7.08–
7.02 (m, 2H), 6.14 (s, 1H), 6.07 (d, J = 1 Hz, 1H), 5.43 (dd, J = 8.4,
5.2 Hz, 1H), 3.60–3.54 (m, 3H), 2.60–2.47 (m, 2H), 2.30–2.15 (m,
ee = 97%;
[a
]
D
= +50.4 (c 0.5, MeOH)] and scalemic (À)-5b
1
3
(
336 mg, ee = 33%).
1H), 2.11–1.97 (m, 1H); C NMR (126 MHz, CDCl
39.6, 134.6, 131.7, 129.9, 128.7, 128.6, 128.3, 127.2 (br s), 126.5,
123.2 (q, JC-F = 290 Hz), 121.5, 115.7, 84.6 (q, JC-F = 28 Hz), 74.9,
3
) d 165.9,
1
4
.4.3.2. Isolation of (˱-5b.
Compound 5b (1.17 g) was
+
reacted under the conditions descried in 4.4.3.1, except the
enzyme used was LipozymeÒ CALB L (Novozymes). After 14 days,
column chromatography (20% ethyl acetate/hexane) afforded as
20 3 3
55.7, 34.3, 30.6. HRMS m/z calcd for C22H F NO Na [M+Na ]:
426.1293, found: 426.1285.
colourless oils (À)-5b [330 mg, 69%, ee = 92%; [
a
]
D
= À58.8 (c 0.5,
4.5.4. Preparation of (R±-ꢀ(S±-2-cyano-1-phenylallyl] 3,3,3-tri-
fluoro-2-methoxy-2-phenylpropanoate 7a
MeOH)] and (+)-4b (465 mg, ee = 81%).
(
R)-[(S)-2-Cyano-1-phenylallyl]3,3,3-trifluoro-2-methoxy-2-
4
.4.4. Enzymatic hydrolysis of (± ±-2-cyano-5-phenyl-pent-1-
phenylpropanoate 7a was isolated as a colourless oil (133 mg,
À1
ene-yl acetate 5c
82%). R
2230, 1753, 1452, 1167; H NMR (300 MHz, CDCl
(m, 10H), 6.56–6.52 (m, 1H), 6.06 (d, J = 1.0 Hz, 1H), 5.93 (d,
f
= 0.64 (30% ethyl acetate/hexane); IR (neat, cm ) 2951,
1
Compound 5c (0.72 g) was added to a mixture containing Lipo-
3
) d 7.45–7.30
Ò
zyme CALB L (Novozymes) (0.72 g) in phosphate buffer (50 mL) at
1
3
pH 7.00. The resulting mixture was stirred for 64 h at 35 °C and the
product was extracted using ethyl acetate. Purification by column
chromatography (20% ethyl acetate/hexane) afforded as colourless
3
J = 1.4 Hz, 1H), 3.47 (s, 3H); C NMR (75 MHz, CDCl ) d 165.2,
134.3, 132.1, 131.7, 129.8, 129.1, 128.5, 127.4, 127.3 (br s), 123.2
(q, JC-F = 289 Hz), 122.0, 115.7, 84.7 (q, JC-F = 28 Hz), 75.9, 55.6.
+
oils (+)-4c [130 mg, 44%, ee = 95%; [
a
]
D
= +31.6 (c 0.5, MeOH)] and
HRMS m/z calcd for C20
H
16
F
3
NO
3
Na [M+Na ]: 398.0980, found:
scalemic (À)-5c (440 mg, ee = 25%).
398.0969.
4
.5. General method for the preparation of Mosher derivatives
4.5.5. Preparation of (R±-ꢀ(S,E±-4-cyano-1-phenylpenta-1,4-dien-
-yl] 3,3,3-trifluoro-2-methoxy-2-phenylpropan-oate 7b
(R)-[(S,E)-4-Cyano-1-phenylpenta-1,4-dien-3-yl] 3,3,3-triflu-
oro-2-methoxy-2-phenylpropan-oate 7b was isolated as a colour-
3
(
+)- or (À)-Alcohol (1 equiv), and either (R)-MTPA or (S)-MTPA
(
3.2 equiv), DCC (2 equiv) and DMAP (0.39 equiv) were added to
a 25 mL round bottom flask containing dichloromethane (3 mL).
The mixture was stirred at room temperature for 30 min. Water
was added to the reaction mixture in a separation funnel and sha-
less oil (58 mg, 84%). R
(neat, cm ) 2950, 2219, 1752, 1452, 1167; H NMR (500 MHz,
CDCl ) d 7.54–7.50 (m, 2H), 7.45–7.30 (m, 8H), 6.85 (d,
3
f
= 0.75 (40% ethyl acetate/hexane); IR
À1
1