4
D. W. Kim et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
3
7.39 (dd, JH–F = 8.8, 4J = 3.0, 1H), 7.25 (ddd, 3J = 9.1, JH–F = 7.7,
4.2.7. General procedure for the synthesis of 1a–e
4J = 3.0, 1H), 6.97 (dd, 3J = 9.1, JH–F = 4.6, 1H), 4.69 (dd, J = 6.0,
A solution of triphenylphosphine (1.5 equiv) and diethyl azodi-
carboxylate (1.5 equiv) in THF at 0 °C was stirred for 15 min and
then added dropwise to a solution of 5a–e (1.0 equiv) in THF at
0 °C. The reaction mixture was stirred for 1 h at 0 °C and the vola-
tiles removed by evaporation. The crude product was purified
using column chromatography (n-hexane/ethyl acetate = 3:1) to
afford the product 1a–e as slightly yellow solids.
4
4.0, 1H), 3.85 (s, 3H), 3.55 (dd, J = 17.6, 4.0, 1H), 3.44 (dd, J = 17.6,
6.0, 1H), 1.60 (br s, 1H); 13C NMR: d 202.1 (d, JC–F = 2.7), 173.9,
4
4
1
2
158.8 (d, JC–F = 1.4), 154.9 (d, JC–F = 237.8), 124.7 (d, JC–F = 23.5),
3
3
2
120.1 (d, JC–F = 7.3), 118.7 (d, JC–F = 6.2), 114.8 (d, JC–F = 23.2),
66.6, 52.9, 41.9; [
a]
D
20 = +13.8 (c 2.0, CHCl3); ee >99%, Chiralpak IA
column,
n-hexane/ethanol = 60:40,
flow
rate = 1.0 mL/min,
tR = 8.95 (S) and 11.11 min (R); HRMS calcd for C11H12FO5+
[M+H]+, 243.0663. Found 243.0658.
4.2.8. Methyl (R)-6-fluoro-4-oxochroman-2-carboxylate 1a
Compound 1a (270 mg) was obtained according to Section 4.2.7
from 5a (500 mg, 2.06 mmol). Yield 60%. 1H NMR: d 7.53 (dd, 3JH–F
=
4.2.3. Methyl (S)-4-(5-chloro-2-hydroxyphenyl)-2-hydroxy-4-
oxo-butanoate 5b
3
8.1, 4J = 3.1, 1H), 7.25 (ddd, 3J = 9.1, JH–F = 7.7, 4J = 3.1, 1H), 7.10
4
(dd, 3J = 9.1, JH–F = 4.2, 1H), 5.09 (dd, J = 8.4, 5.6, 1H), 3.82 (s, 3H),
Compound 5b (334 mg) was obtained according to Section 4.2.1
from 4b (400 mg, 1.47 mmol). Yield 88%. 1H NMR: d 11.8 (s, 1H),
7.69 (d, J = 2.4, 1H), 7.43 (dd, J = 8.8, 2.4, 1H), 6.96 (d, J = 8.8, 1H),
4.67 (dd, J = 6.0, 4.0, 1H), 3.83 (s, 3H), 3.56 (dd, J = 17.6, 4.0, 1H),
3.46 (dd, J = 17.6, 6.0, 1H), 1.61 (br s, 1H); 13C NMR: d 202.1,
174.0, 161.0, 136.8, 129.1, 123.8, 120.3, 119.8, 66.5, 52.9, 41.9;
4
3.08–3.05 (m, 2H); 13C NMR: d 188.8 (d, JC–F = 1.9), 168.9, 157.6
1
4
2
(d, JC–F = 241.7), 156.3 (d, JC–F = 1.8), 124.0 (d, JC–F = 24.5), 121.4
3
3
2
(d, JC–F = 6.5), 119.9 (d, JC–F = 7.4), 112.1 (d, JC–F = 23.4), 75.3,
52.9, 39.2; [
column,
a]
20 = ꢁ38.3 (c 0.85, CHCl3); ee >99%, Chiralcel ODH
D
n-hexane/ethanol = 98:2,
flow
rate = 0.8 mL/min,
20 = +16.8 (c 1.0, CHCl3); ee >99%, Chiralpak IA column, n-hex-
ane/ethanol = 60:40, flow rate = 1.0 mL/min, tR = 7.88 (S) and
9.66 min (R). HRMS calcd for
tR = 24.98 (R) and 25.13 min (S). HRMS calcd for C11H10FO4+
[a]
D
[M+H]+, 225.0558. Found 225.0571.
C
11H12ClO+5 [M+H]+, 259.0369.
Found 259.0386.
4.2.9. Methyl (R)-6-chloro-4-oxochroman-2-carboxylate 1b
Compound 1b (295 mg) was obtained according to Section 4.2.7
from 5b (400 mg, 1.55 mmol). Yield 80%. 1H NMR: d 7.98 (d, J = 2.4,
1H), 7.59 (dd, J = 8.8, 2.4, 1H), 7.02 (d, J = 8.8, 1H), 5.10 (dd, J = 8.4,
5.6, 1H), 3.82 (s, 3H), 3.08–3.05 (m, 2H); 13C NMR: d 188.6, 169.0,
158.7, 136.5, 128.0, 126.5, 121.8, 120.1, 75.1, 53.2, 39.4;
4.2.4. Methyl (S)-4-(5-bromo-2-hydroxyphenyl)-2-hydroxy-4-
oxo-butanoate 5c
Compound 5c (298 mg) was obtained according to Section 4.2.1
from 4c (400 mg, 1.26 mmol). Yield 77%. 1H NMR: d 11.82 (s, 1H),
7.83 (d, J = 2.4, 1H), 7.56 (dd, J = 8.8, 2.4, 1H), 6.91 (d, J = 8.8, 1H),
4.67 (dd, J = 6.0, 4.0, 1H), 3.83 (s, 3H), 3.55 (dd, J = 17.6, 4.0, 1H),
3.45 (dd, J = 17.6, 6.0, 1H), 1.57 (br s, 1H); 13C NMR: d 202.0,
173.9, 161.4, 139.5, 132.1, 120.4, 110.7, 66.5, 52.9, 41.9;
[a]
20 = ꢁ50.2 (c 1.5, CHCl3); ee >99%, Chiralcel ODH column, n-hex-
D
ane/ethanol = 98:2, flow rate = 0.8 mL/min, tR = 25.13 (R) and
26.56 min (S). HRMS calcd for C11H10ClO+4 [M+H]+, 241.0262.
Found 241.0254.
[a]
20 = +15.4 (c 1.0, CHCl3); ee >99%, Chiralpak IA column, n-hex-
D
ane/ethanol = 60:40, flow rate = 1.0 mL/min, tR = 7.73 (S) and
9.13 min (R). HRMS calcd for C11H12BrO+5 [M+H],+ 302.9863. Found
302.9874.
4.2.10. Methyl (R)-6-bromo-4-oxochroman-2-carboxylate 1c
Compound 1c (155 mg) was obtained according to Section 4.2.7
from 5c (300 mg, 0.99 mmol). Yield 55%. 1H NMR: d 7.98 (d, J = 2.4,
1H), 7.59 (dd, J = 8.8, 2.4, 1H), 7.02 (d, J = 8.8, 1H), 5.10 (dd, J = 8.4,
5.6, 1H), 3.82 (s, 3H), 3.06–3.05 (m, 2H); 13C NMR: d 188.4, 169.0,
159.2, 139.3, 129.6, 122.3, 120.4, 115.2, 75.4, 53.2, 39.4;
4.2.5. Methyl (S)-4-(2-hydroxy-4-methoxyphenyl)-2-hydroxy-4-
oxo-butanoate 5d
Compound 5d (360 mg) was obtained according to Section 4.2.1
from 4d (700 mg, 2.61 mmol). Yield 55%. 1H NMR: d 12.38 (s, 1H),
7.63 (d, J = 8.8, 1H), 6.45 (dd, J = 8.8, 2.4, 1H), 6.42 (d, J = 2.4, 1H),
4.66 (dd, J = 6.0, 4.0, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.51 (dd,
J = 17.6, 4.0, 1H), 3.42 (dd, J = 17.6, 6.0, 1H); 13C NMR: d 200.9,
174.2, 166.5, 165.4, 131.6, 113.4, 108.0, 100.9, 67.0, 55.6, 52.8,
[a]
20 = ꢁ47.8 (c 1.5, CHCl3); ee >99%, Chiralcel ODH column,
D
n-hexane/ethanol = 98:2, flow rate = 0.8 mL/min, tR = 26.37 (S)
and 27.73 min (R). HRMS calcd for C11H10BrO+4 [M+H]+, 284.9757.
Found 284.9711.
20 = +26.5 (c 0.3, CHCl3); ee >99%, Chiralpak IA column,
4.2.11. Methyl (R)-7-methoxy-4-oxochroman-2-carboxylate 1d
Compound 1d (175 mg) was obtained according to Section 4.2.7
from 5d (250 mg, 0.98 mmol). Yield 74%. 1H NMR: d 7.84 (d, J = 8.8,
1H), 6.61 (dd, J = 8.8, 2.4, 1H), 6.56 (d, J = 2.4, 1H), 5.08 (dd, J = 8.4,
5.6, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.01–2.99 (dd, J = 5.6, 2.4, 2H);
13C NMR: d 188.1, 169.2, 166.4, 162.1, 128.7, 114.7, 110.8, 101.0,
41.4; [a]
D
n-hexane/ethanol = 60:40, flow rate = 1.0 mL/min, tR = 9.59 (S)
and 15.04 min (R). HRMS calcd for C12H15O+6 [M+H]+, 255.0863.
Found 255.0863.
4.2.6. Methyl (S)-4-(2-hydroxy-5-methoxyphenyl)-2-hydroxy-4-
oxo-butanoate 5e
75.4, 55.7, 52.9, 39.1; [a]
20 = +12.5 (c 2.2, CHCl3); ee >99%,
D
Chiralcel ODH column, n-hexane/2-propanol = 90:10, flow
rate = 0.8 mL/min, tR = 23.63 (S) and 28.20 min (R). HRMS calcd
for C12H13O+5 [M+H]+, 237.0758. Found 237.0756.
Compound 5e (145 mg) was obtained according to Section 4.2.1
from 4e (300 mg, 1.19 mmol). Yield 51%. 1H NMR: d 11.52 (s, 1H),
7.15 (d, J = 2.4, 1H), 7.13 (d, J = 8.8, 1H), 6.94 (dd, J = 8.8, 2.4, 1H),
4.64 (dd, J = 6.0, 4.0, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.57 (dd,
J = 17.6, 4.0, 1H), 3.47 (dd, J = 17.6, 6.0, 1H); 13C NMR: 202.6,
174.3, 157.2, 152.1, 125.1, 119.8, 118.9, 112.5, 66.9, 56.2, 53.1,
4.2.12. Methyl (R)-6-methoxy-4-oxochroman-2-carboxylate 1e
Compound 1e (78 mg) was obtained according to Section 4.2.7
from 5e (150 mg, 0.59 mmol). Yield 56%. 1H NMR: d 7.30 (d,
J = 2.4, 1H), 7.12 (dd, J = 8.8, 2.4, 1H), 7.02 (d, J = 8.8, 1H), 5.05 (t,
J = 7.0, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.05–3.03 (d, J = 7.6, 2H);
13C NMR: d 189.6, 169.2, 154.7, 154.6, 125.5, 120.7, 119.4, 107.4,
42.1; [a]
20 = +8.8 (c 0.14, CHCl3); ee >98%, Chiralpak IA column,
D
n-hexane/ethanol = 60:40, flow rate = 1.0 mL/min, tR = 8.11 (R)
and 11.40 min (S). HRMS calcd for C12H15O+6 [M+H]+, 255.0863.
Found 255.0854. (S)-4-(2,5-dihydroxyphenyl)-2-hydroxy-4-oxo-
butyric acid methyl ester was also isolated as a side product.
Yield 18%. 1H NMR: d 7.07 (d, J = 2.4, 1H), 6.97 (dd, J = 8.8, 2.4,
1H), 6.77 (d, J = 8.8, 1H), 4.60 (dd, J = 6.0, 4.0, 1H), 3.75 (s, 3H),
3.36 (dd, J = 17.6, 4.0, 1H), 3.45 (dd, J = 17.6, 6.0, 1H).
75.3, 55.8, 52.9, 39.5; [
a
]
20 = ꢁ67.3 (c 0.1, CHCl3); ee >99%,
D
Chiralcel ODH column, n-hexane/2-propanol = 90:10, flow
rate = 0.8 mL/min, tR = 15.83 (S) and 18.64 min (R). HRMS calcd
for C12H13O+5 [M+H]+, 237.0758. Found 237.0745.