Y. H. Kim et al. / Tetrahedron: Asymmetry 13 (2002) 2501–2508
2507
4.15. ( )-cis-2-Bromomethyl-2-(2,4-dichlorophenyl)-1,3-
dioxolane-4-carboxylic acid methyl ester
4.18. Enzymatic esterification of ( )-cis-2-bromomethyl-
2-(2,4-dichlorophenyl)-1,3-dioxolane-4-carboxylic acid
(optimized conditions)
( )-cis-2-Bromomethyl-2-(2,4-dichlorophenyl)-1,3-dioxo-
lane-4-carboxylic acid (100 mg, 0.292 mmol) in toluene
(10 ml) was stirred at rt. MeOH (59.1 ml, 1.46 mmol, 5
equiv.) and p-toluenesulfonic acid (6 mg, 0.03 mmol,
0.1 equiv.) was added to a solution. The mixture was
heated to reflux temperature for 1 h. The mixture was
quenched by water. The product was extracted with
ether, the organic layer was washed with satd NaHCO3
and brine. The extract was dried with anhydrous
MgSO4 and evaporated in vacuo. The residue was
purified by column chromatography (n-hexane:ethyl
acetate=10:1) (yield=96%). 1H NMR (300 MHz,
CDCl3) l 3.79 (s, 3H), 4.04 (m, 3H), 4.35 (dd, J=8.7
Hz, J=3.9 Hz, 1H), 4.63 (dd, J=7.2 Hz, J=3.6 Hz
1H), 7.23 (dd, J=8.1 Hz, J=2.1 Hz, 1H), 7.39 (d,
J=2.1 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H).
( ) - cis - 2 - Bromomethyl - 2 - (2,4 - dichlorophenyl) - 1,3-
dioxolane-4-carboxylic acid (10 g, 28.1 mmol) was dis-
solved in 1,2-dichloroethane (500 ml) and MeOH (4.6
,
ml, 112.4 mmol, 4 equiv.), and molecular sieves 4 A (10
g) was added to the solution. CAL-B (10 g, 1 mass
equiv.) was added to the solution and then each mix-
ture was stirred at 60°C. The mixture was filtered and
the filtrate was concentrated to a small volume in
vacuo. The residue was treated with satd NaHCO3 and
the resulting aqueous layer was washed with ether. The
organic layer was washed with brine. The extract was
dried with anhydrous MgSO4 and evaporated in vacuo.
The water layer was made acidic with concentrated
HCl, the product was extracted with ethyl acetate. The
extract was washed with brine, dried with anhydrous
MgSO4, evaporated in vacuo to leave an oily residue
and recrystallized with ethyl acetate/n-hexane to afford
a white crystalline solid of (2R,4R)-cis-2-bromomethyl-
2-(2,4-dichlorophenyl)-1,3-dioxolane-4-carboxylic acid.
4.16. ( )-cis-2-Bromomethyl-2-(2,4-dichlorophenyl)-1,3-
dioxolane-4-carboxylic acid ethyl ester
Unreacted (2R,4R)-carboxylic acid: 1H NMR (300
MHz, CDCl3) l 4.26 (m, 3H), 4.43 (dd, J=8.9 Hz,
J=4.6 Hz, 1H), 4.67 (dd, J=6.2 Hz, J=3.9 Hz 1H),
7.17 (dd, J=8.6 Hz, J=2.0 Hz, 1H), 7.33 (d, J=2.2
Hz, 1H), 7.53 (d, J=8.5 Hz, 1H) 13C NMR (75 MHz,
CDCl3) l 34.547 68.509 74.061 109.741 127.048 130.021
131.446 132.886 133.486 136.091 174.699; IR (KBr)
2894, 1712, 1586, 1268, 1042 cm−1; GC/MSD retention
time (min) 12.52, m/z 50, 59, 67, 75, 89, 99, 109, 123,
136, 145, 159, 173, 189, 197, 205, 215, 223, 240, 253,
275 (100), 311; [h]D26=+28 (c 1, MeOH, ee=98%).
( ) - cis - 2 - Bromomethyl - 2 - (2,4 - dichlorophenyl) - 1,3-
dioxolane-4-carboxylic acid (200 mg, 0.56 mmol) in
toluene (10 ml) was stirred at rt. EtOH (160 ml, 2.8
mmol, 5 equiv.) and p-toluenesulfonic acid (13 mg, 0.06
mmol, 0.1 equiv.) was added to a solution. The mixture
was heated to reflux temperature for 1 h. The mixture
was quenched with water. The product was extracted
with ether, the organic layer was washed with satd
NaHCO3, brine. The extract was dried with anhydrous
MgSO4 and evaporated in vacuo. The residue (244 mg)
was purified by column chromatography (n-hex-
ane:ethyl acetate=10:1) (yield=97%). 1H NMR (300
MHz, CDCl3) l 1.29 (t, J=7.16 Hz, 3H), 4.02 (m, 4H),
4.31 (m, 4H), 4.63 (dd, J=7.3 Hz, J=3.9 Hz 1H), 7.26
(dd, J=8.4 Hz, J=2.1 Hz, 1H), 7.42 (d, J=2.1 Hz,
1H), 7.56 (d, J=8.6 Hz, 1H).
1
(2S,4S)-Ester product: H NMR (300 MHz, CDCl3) l
3.79 (s, 3H), 4.04 (m, 3H), 4.35 (dd, J=8.7 Hz, J=3.9
Hz, 1H), 4.63 (dd, J=7.2 Hz, J=3.6 Hz 1H), 7.23 (dd,
J=8.1 Hz, J=2.1 Hz, 1H), 7.39 (d, J=2.1 Hz, 1H),
7.53 (d, J=8.4 Hz, 1H).
4.17. ( )-cis-2-(Bromomethyl)-2-(2,4-dichlorophenyl)-
1,3-dioxalane-4-methanol, 1
Acknowledgements
( ) - cis - 2 - Bromomethyl - 2 - (2,4 - dichlorophenyl) - 1,3-
dioxolane-4-carboxylic acid 2 (325 mg, 1 mmol) in
tetrahydrofuran (3 ml) was stirred at rt. Borane–
dimethylsulfide complex in THF solution (2.0 M, 1.5
ml, 1.5 mmol, 1.5 equiv.) was added to a solution at
0°C. The mixture was stirred at 0°C to rt for 2 h. The
excess hydride was carefully destroyed with water. The
product was extracted with ethyl acetate, the organic
layer was washed with satd NaHCO3, brine. The
extract was dried with anhydrous MgSO4 and evapo-
rated in vacuo. The residue was purified by column
chromatography (n-hexane: ethyl acetate=4:1) (yield=
Financial support from the Ministry of Science and
Technology is gratefully acknowledged. We also thank
Novo-Disk Korea for their gifts of CAL-B.
References
1. Williams, K.; Lee, E. Drugs 1985, 30, 333–354.
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1
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