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A. Gümüßs, C. Tanyeli / Tetrahedron: Asymmetry 23 (2012) 1405–1409
tion Products, Inc., P1500-SN-4000-UV2000 instrument using a
Chiralcel OD-H analytical column (250 ꢂ 4.60 mm). Flash column
chromatography was performed on silica gel (60-mesh, Merck).
The reactions were monitored by thin layer chromatography using
Merck 0.2 mm silica gel 60 F254 analytical aluminium plates. Melt-
ing points were obtained on a Thomas Hoover capillary melting
point apparatus and are uncorrected. CRL (Candida rugosa lipase)
and PPL (lipase, type II, from porcine pancreas) were purchased
from Aldrich. Novazyme 435 was donated by Novo Nordisk AS,
Bagsverd, Denmark.
by concentration of the filtrate under vacuum. The crude product
was purified by flash column chromatography using EtOAc/hexane
(1:2) as eluent to afford (+)-515 and (ꢁ)-8.
4.3.1. ((1S,2R,4R)-1,4-Dichloro-7,7-dimethoxy-5,6-dioxobicyclo-
[2.2.1]heptan-2-yl)methyl acetate (+)-5
This was obtained as a yellow liquid. (0.17 g, 98%). ½a D20
¼ þ24:6
ꢃ
(c 3.7, MeOH). 1H NMR: d 4.17 (dd, 1H, CH2O, J = 12.0 and 1.7 Hz),
3.98 (dd, 1H, CH2O, J = 12.1 and 3.1 Hz), 3.67 (s, 3H, OCH3), 3.50 (s,
3H, OCH3), 2.96–2.92 (m, 1H, CH), 2.68 (t, 1H, exo CH2, J = 12.6 Hz),
2.10 (dd, 1H, endo CH2, J = 13.1 and 4.8 Hz), 1.84 (s, 3H, CH3). 13C
NMR: d 187.5, 186.3, 168.6, 101.4, 77.5, 73.7, 58.7, 51.7, 50.6,
4.2. General procedure for the enzymatic resolution of alcohols
42.0, 32.8, 18.9. IR (KBr): 2900, 1785, 1720, 1440, 1200 cmꢁ1
.
To a stirred solution of rac-1 or rac-3 (500 mg) in vinyl acetate
(5 mL), enzyme (as shown in Table 1) was added in one portion and
the reaction mixture stirred at 25 °C (TLC monitoring). The reaction
mixture was filtered and vinyl acetate was evaporated under re-
duced pressure. The products were purified by flash column chro-
matography (EtOAc/hexane, 1:4).
4.3.2. ((1S,2R,4R)-1,4,7,7-Tetrachloro-5,6-dioxobicyclo[2.2.1]-
heptan-2-yl)methyl acetate (ꢁ)-8
This was obtained as a yellow liquid. (0.16 g, 90%). ½a D20
¼ ꢁ46:0
ꢃ
(c 1.0, MeOH). 1H NMR: d 4.31 (dd, 1H, CH2O, J = 12.3 and 1.8 Hz),
4.12 (dd, 1H, CH2O, J = 12.5 and 3.5 Hz), 3.14–3.09 (m, 1H, CH), 2.84
(t, 1H, exo CH2, J = 12.7 Hz), 2.36 (dd, 1H, endo CH2O, J = 13.6 and
4.9 Hz), 1.93 (s, 3H, COCH3); 13C NMR: d 185.2, 184.3, 169.3, 92.9,
82.5, 78.9, 59.2, 44.1, 34.4, 19.8. IR (KBr): 2880, 1780, 1715,
4.2.1. ((1S,2S,4R)-1,4,5,6-Tetrachloro-7,7-dimethoxybicyclo[2.2.1]-
hept-5-en-2-yl) methanol (ꢁ)-1
This was obtained as
¼ ꢁ15:1 (c 1.8, MeOH).
a
white solid; Mp: 83.5–84 °C;
1443, 1206 cmꢁ1
.
HRMS, Calcd [M+H]+, 331.9177, Measured
½
a 2D0
ꢃ
[M+H]+ 331.9173.
4.2.2. ((1R,2R,4S)-1,4,5,6-Tetrachloro-7,7-dimethoxybicyclo[2.2.1]-
hept-5-en-2-yl)methyl acetate (+)-2
4.4. Cerium catalyzed oxidation of (1R,2R,4S)-(+)-2
This was obtained as a colorless oil; (0.22 g, 39% yield);
To a stirred solution of dihaloalkene (1R,2R,4S)-(+)-2 (0.18 g,
0.50 mmol) in acetonitrile (6 mL) at 0 °C was added a solution of
CeCl3ꢀ7H2O (0.05 mmol) and NaIO4 (0.16 g, 0.75 mmol) in water
(1 mL). The mixture was stirred and monitored by TLC. The crude
product was purified by flash column chromatography to afford
½
a 2D0
ꢃ
¼ þ11:4 (c 1.8, MeOH) for 94% ee.12 The enantiomeric purity
of the product was determined by HPLC analysis (Daicel Chiralcel
OD-H, hexane/i-PrOH 99:1, flow rate = 0.3 mL minꢁ1, k = 230 nm,
tR = 19.8 min (minor), tR = 21.3 min (major) in comparison with
the racemic sample. 1H NMR: d 4.13 (dd, 1H, CH2O, J = 11.6 and
5.3 Hz), 3.86 (dd, 1H, CH2O, J = 11.6 and 7.2 Hz), 3.61 (s, 3H,
OCH3), 3.55 (s, 3H, OCH3), 2.99–2.92 (m, 1H, CH), 2.50 (dd, 1H,
exo CH2, J = 11.7 and 9.2 Hz), 2.04 (s, 3H, CH3), 1.67 (dd, 1H, endo
CH2, J = 11.9 and 4.1 Hz). 13C NMR: d 170.6, 130.2, 128.3, 111.9,
77.0, 74.3, 62.6, 52.7, 51.6, 45.8, 39.1, 20.7.
a
-diketone (+)-515 (0.15 g, 90%).
4.5. Oxidative cleavage of a-diketones (1S,2R,4R)-(+)-5 and
(1S,2R,4R)-(ꢁ)-8
To a stirred solution of a-diketone (+)-5 (0.13 g, 0.40 mmol) or
acetate (ꢁ)-8 (0.8 g, 2.4 mmol) in methanol (3 ml) was added
30% H2O2 (0.30 mL) followed by the slow addition of 6 M NaOH
solution (0.15 mL). The mixture was stirred at room temperature
for 1 h and then, 5% HCl (10 mL) was added. The reaction mixture
was extracted with ethyl acetate (3 ꢂ 10) mL. The combined organ-
ic layer was washed with water (3 ꢂ 10 mL) and brine (2 ꢂ 10 mL),
and dried over MgSO4. The solvent was evaporated and the crude
carboxylic acids 6, 9, and 10 were obtained without any further
isolation.
4.2.3. ((1R,2S,4S)-1,4,5,6,7,7-Hexachlorobicyclo[2.2.1]hept-5-en-
2-yl)methanol (+)-3
This was obtained as
½ ꢃ ¼ þ35:1 (c 1.5, MeOH).
a white solid; Mp: 166–167 °C;
a 2D0
4.2.4. ((1S,2R,4R)-1,4,5,6,7,7-Hexachlorobicyclo[2.2.1]hept-5-en-
2-yl)methyl acetate (ꢁ)-4
This was obtained as a colorless oil; (0.25 g, 40% yield);
½
a 2D0
ꢃ
¼ ꢁ1:5 (c 1.53, MeOH) for 97% ee.11c The enantiomeric purity
of the product was determined by HPLC analysis (Daicel Chiralcel
OD-H, hexane/i-PrOH 98:2, flow rate = 1.0 mL minꢁ1, k = 254 nm,
tR = 6.3 min (minor), tR = 6.8 min (major) in comparison with the
racemic sample. 1H NMR: d 1.86 (dd, 1H, endo CH2, J = 4.2 and
12.6 Hz), 1.99 (s, 3H, CH3), 2.60 (dd, 1H, exo CH2, J = 8.9 and
12.6 Hz), 3.00–3.13 (m, 1H, CH), 3.92 (dd, 1H, CH2O, J = 6.7 and
11.7 Hz), 4.08 (dd, 1H, CH2O, J = 5.8 and 11.7 Hz). 13C NMR: d
21.1, 38.6, 46.4, 62.7, 79.0, 81.3, 102.9, 130.5, 132.3, 170.8.
4.6. Esterification of carboxylic acids 6, 9 and 10
At first, KOH (0.56 g, 10.0 mmol) was dissolved in water
(1.2 mL) and cooled in an ice-bath. Then cold diethyl ether
(10 mL) was added. When the temperature was 0 °C, N-methyl-
N-nitrosourea was slowly added. After the gas evolution was com-
plete, the ether phase was separated and dried over KOH, then fil-
tered and cooled to 0 °C. Next, carboxylic acid 6 or the mixture of 9
and 10 (0.40 mmol) in ether were added dropwise. After the tem-
perature reached 20 °C, the ether was evaporated. The crude prod-
uct was purified by flash column chromatography (EtOAc/hexane
1:3) to afford (+)-715 or (ꢁ)-11 and (ꢁ)-12.
4.3. Ruthenium catalyzed oxidation of (1R,2R,4S)-(+)-2 and
(1S,2R,4R)-(ꢁ)-4
To a stirred solution of dihaloalkene (1R,2R,4S)-(+)-2 (0.20 g,
0.55 mmol) or (1S,2R,4R) (-)-4 (1.0 g, 2.7 mmol) in acetonitrile
(6 mL) at 0 °C was added a solution of RuCl3ꢀ3H2O (0.038 mmol
or 0.19 mmol) and NaIO4 (0.82 mmol or 4.02 mmol) in water
(1 mL). The mixture was stirred and monitored by TLC. The result-
ing suspension was filtered through a thin pad of silica gel followed
4.6.1. (3aR,5S,6aR)-Methyl 5,6a-dichloro-6,6-dimethoxy-1-oxo-
hexahydro-1H-cyclopenta[c]furan-5-carboxylate (+)-7
This was obtained as a colorless solid. (0.11 g, 90%). ½a D20
¼ þ7:2
ꢃ
(c 0.6, MeOH). Mp: 118–120 °C. 1H NMR: d 4.61 (t, 1H, CH2O,
J = 9.0 Hz), 4.14 (dd, 1H, CH2O, J = 9.3 and 3.6 Hz), 3.86 (s, 3H,