Access to the Enantiomers of Dorzolamide Intermediates
ralcel OD column (250ϫ46 mm ID), those of rac-cis-3 by GC with
89%, ee 98%, de 98%). [α]2D5 = +213.4 (c = 1.0, CHCl3); m.p. 99–
a Supelco Beta DexTM 120 capillary column (30 mϫ0.25 mmϫ 100 °C.
0.25 µm), and those of rac-cis-4 by GC with a Varian capillary
Preparation of (4R,6R)- and (4S,6S)-6-Methyl-5,6-dihydro-4H-
column (25 mϫ0.25 mm) of WCOT fused silica with CP-Chirasil-
DEX CB as the stationary phase. When succinic or glutaric anhy-
dride was used as the acyl donor the half acid in the sample
(200 µL) was derivatized before analysis with a solution (20 µL)
of 2 (trimethylsilyl)diazomethane in hexane in the presence of
methanol (20 µL) and analysis was performed by HPLC equipped
with a Daicel Chiracel OD-H column (250ϫ46 mm ID). The
HPLC method was also used to monitor the epimerization reac-
tions of rac-cis-3 because it affords base-line separation of all four
diastereomers of compound 3. An HPLC analytical method was
also developed for rac-cis-4 to confirm the absolute configuration
of the enantiomers by comparing the order of peaks and the config-
uration assigned in an existing patent.[16] The determination of E
was based on the equation given below by using linear regression
{E as the slope of the line ln[(1 – c)(1 – eeS)] vs. ln[(1 – c)(1 +
eeS)]}.[19]
thieno[2,3-b]thiopyran-4-ols: Compound (4S,6R)-3 (ee 98%, de
98%) or (4R,6S)-3 (ee 99%, de 99%) (0.50 g, 2.69 mmol) was dis-
solved in TBME (2.70 mL) and 1 H2SO4 (2.70 mL) was added.
The biphasic system was vigorously shaken at room temperature
for 24 h for epimerization before the organic phase was separated
and washed with brine and dried with Na2SO4. Evaporation
yielded (4R,6R)-3 (ee 98%, de 58%) or (4S,6S)-3 (ee 99%, de 51%),
respectively. The progress of the epimerization was followed by
HPLC analysis (Chiralcel OD-H column, 1% isopropyl alcohol in
hexane, 0.7 mLmin–1 flow, 238 nm).
Compound (4S,6S)-3 (ee 99%, de 51%) (0.07 g, 0.41 mmol) was
dissolved in TBME (4 mL) and lipase PS-D (0.10 g) and vinyl but-
anoate (0.09 g, 0.10 mL, 0.81 mmol) were added for diastereomeric
purification. After 1 h, purification as before yielded (4S,6S)-3 as
a white-pink solid (0.04 g, 0.23 mmol, 57%, ee 99%, de 96%).
[α]2D5 = –222.5 (c = 1.1, CHCl3); m.p. 81–82 °C). 1H NMR (CDCl3,
500 MHz): δ = 1.42 (d, J = 6.5 Hz, 3 H, 6-CH3), 1.80–1.86 (m, 1
H, 5-H), 2.29 (dt, J = 14.5, J = 2.5 Hz, 1 H, 5-H), 3.53–3.60 (m, 1
H, 6-H), 4.85 (t, J = 3.0 Hz, 1 H, 4-H), 6.99 (d, J = 5.5 Hz, 1
H, 3-H), 7.05 (d, J = 5.5 Hz, 1 H, 2-H) ppm. 13C NMR (CDCl3,
126 MHz): δ = 20.33 (6-CH3), 33.20 (C-6), 40.32 (C-5), 63.64 (C-
4), 121.64 (C-3), 127.88 (C-2), 133.14 (C-8), 133.47 (C-9) ppm.
HRMS: calcd. for C8H10S2O [M]+ 186.01731; found 186.01720.
MS: m/z (%) = 186 (88), 169 (7), 153 (28), 144 (100), 116 (9), 110
(28), 84 (7).
E = ln[(1 – c)(1 – eeS)]/ln[(1 – c)(1 + eeS)] with c = eeS/(eeS + eeP)
Preparation of (4S,6R)- and (4R,6S)-6-Methyl-5,6-dihydro-4H-
thieno[2,3-b]thiopyran-4-ols: Compound rac-cis-3 (5.00 g, 26.84
mmol, m.p. 96–97 °C, de 91%) was dissolved in TBME (264 mL)
and lipase PS-D (6.50 g) and vinyl butanoate (3.67 g, 4.08 mL,
32.21 mmol) were added. The reaction was stopped at 48% conver-
sion after 1 h by filtering off the enzyme and evaporating the sol-
vent. Purification by column chromatography [silica, ethyl acetate/
hexane (3:7)] yielded first the ester (4R,6S)-6 as a light-yellow oil
(3.02 g, 11.77 mmol, yield 91%, ee 95%, de 78%). [α]2D5 = –80.0 (c
= 1.0, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 0.97 (t, J =
7.5 Hz, 3 H, COCH2CH2CH3), 1.43 (d, J = 6.5 Hz, 3 H, 6-CH3),
1.69 (sext, J = 7.5 Hz, 2 H, OCOCH2CH2CH3), 1.97–2.04 (m, 1
H, 5-H), 2.34 (t, J = 7.5 Hz, 2 H, OCOCH2CH2CH3), 2.51 (ddd,
J = 13.5, J = 6.0, J = 2.0 Hz, 1 H, 5-H), 3.57–3.61 (m, 1 H, 6-H),
6.03 (dd, J = 8.5, J = 6.0 Hz, 1 H, 4-H), 6.86 (d, J = 5.5 Hz, 1
H, 3-H), 7.04 (d, J = 5.5 Hz, 1 H, 2-H) ppm. 13C NMR (CDCl3,
Compound (4R,6R)-3 (ee 99%, de 58%; 0.25 g, 1.34 mmol) was
dissolved in TBME (13 mL) and lipase PS-D (0.33 g) and vinyl
butanoate (0.30 g, 0.34 mL, 2.68 mmol) were added. The normal
work-up after 21 h yielded first (4R,6R)-6 as a light-yellow liquid
(0.25 g, 0.98 mmol, ee 96%, de 70%). For deprotection, (4R,6R)-6
(0.15 g, 0.58 mmol) was dissolved in TBME (6 mL) and n-butanol
(0.08 g, 0.11 mL, 1.17 mmol) and lipase PS-D (0.44 g) were added.
The reaction was shaken at 47 °C for 3 d. The reaction was stopped
by filtering off the enzyme and then the solvent was evaporated.
Purification as before yielded (4R,6R)-3 as a white solid (0.05 g,
0.28 mmol, 48%, ee 97%, de 93%). [α]2D5 = +229.7 (c = 1.0, CHCl3);
m.p. 80–81 °C.
126 MHz):
δ
=
13.69 (OCOCH2CH2CH3), 18.54 (OC-
OCH2CH2CH3), 20.81 (6-CH3), 36.50 (OCOCH2CH2CH3), 37.20
(C-6), 37.56 (C-5), 67.76 (C-4), 121.55 (C-3), 126.86 (C-2), 130.65
(C-8), 132.44 (C-9), 173.42 (OCOCH2CH2CH3) ppm. HRMS:
calcd. for C12H16S2O2 [M]+ 256.05917; found 256.05950. MS: m/z
(%) = 256 (91), 186 (7), 169 (100), 153 (87), 143 (8), 136 (13), 71
(27).
Preparation of (4S,6R)- and (4R,6S)-4-Hydroxy-6-methyl-5,6-di-
hydro-4H-thieno[2,3-b]thiopyran 7,7-Dioxide: rac-cis-4 (2.00 g,
9.16 mmol, m.p. 123–125 °C, de 97%) was dissolved in the mixture
toluene/acetone (9:1; 90 mL) and lipase PS-D (0.91 g) and vinyl
acetate (1.58 g, 1.69 mL, 18.32 mmol) were added. The reaction
was stopped at 50% conversion after 3 h by filtering off the enzyme
and then evaporating the solvent. Purification by column
chromatography [silica, ethyl acetate/hexane (1:1)] yielded first the
ester (4R,6S)-(8) as a white solid (0.97 g, 3.72 mmol, 87%, ee 97%,
de 99%). [α]2D5 = –18.5 (c = 1.0, CHCl3); m.p. 111–113 °C. 1H NMR
(CDCl3, 500 MHz): δ = 1.53 (d, J = 7.0 Hz, 3 H, 6-CH3), 2.15 (s,
3 H, OCOCH3), 2.64 (dddd, J = 14.5, J = 5.5, J = 2.5 Hz, 1 H, 5-
H), 2.62–2.63 (m, 1 H, 5-H), 3.48–3.55 (m, J = 2.5 Hz, 1 H, 6-H),
6.03 (dd, J = 9.0, J = 6.0 Hz, 1 H, 4-H), 6.95 (d, J = 5.0 Hz, 1
H, 3-H), 7.58 (d, J = 5.0 Hz, 1 H, 2-H) ppm. 13C NMR (CDCl3,
126 MHz): δ = 11.47 (6-CH3), 21.02 (OCOCH3), 35.18 (C-5), 55.84
(C-6), 66.45 (C-4), 126.32 (C-3), 130.89 (C-2), 136.75 (C-8), 141.73
(C-9), 170.27 (OCOCH3) ppm. HRMS: calcd. for C8H10S2O4 [M]+
260.01770; found 260.01740. MS: m/z (%) = 260 (18), 217 (47), 174
(28), 154 (32), 135 (26), 111 (22), 91 (12), 69 (10).
For deprotection, (4R,6S)-6 (1.00 g, 3.91 mmol, ee 95%) was dis-
solved in TBME (39 mL) and n-butanol (0.58 g, 0.71 mL,
7.80 mmol) and lipase PS-D (1.95 g) were added. The reaction was
shaken at 47 °C for 30.5 h until 92% conversion was reached. The
enzyme was filtered off and the solvent evaporated. Purification as
above yielded (4R,6S)-3 as a white solid (0.61 g, 3.30 mmol, 84%,
ee 99%, de 99%). [α]2D5 = –214.4 (c = 1.0, CHCl3); m.p. 98–99 °C.
1H NMR (CDCl3, 500 MHz): δ = 1.41 (d, J = 7.0 Hz, 3 H, 6-CH3),
1.89 (ddd, J = 21.0, J = 10.0, J = 2.0 Hz, 1 H, 5-H), 2.44 (ddd, J
= 13.0, J = 5.5, J = 2.0 Hz, 1 H, 5-H), 3.53–3.60 (m, 1 H, 6-H),
4.86 (dd, J = 10.0, J = 6.0 Hz, 1 H, 4-H), 7.04 (d, J = 5.0 Hz, 1
H, 3-H), 7.08 (d, J = 5.0 Hz, 1 H, 2-H) ppm. 13C NMR (CDCl3,
126 MHz): δ = 20.84 (6-CH3), 37.68 (C-6), 42.43 (C-5), 67.09 (C-
4), 121.55 (C-3), 126.63 (C-2), 131.08 (C-8), 135.16 (C-9). HRMS:
calcd. for C8H10S2O [M]+ 186.01731; found 186.01720. MS: m/z
(%) = 186 (88), 169 (7), 153 (28), 144 (100), 116 (9), 110 (28), 84
(7).
The unreacted alcohol (4S,6R)-3 from the resolution mixture was For deprotection, (4R,6S)-8 (0.5 g, 1.92 mmol, ee 97%) was dis-
eluted after (4R,6S)-6 as a white-grey solid (2.33 g, 12.50 mmol, solved in the mixture toluene/acetone (9:1; 19 mL) and n-butanol
Eur. J. Org. Chem. 2009, 5594–5600
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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