2422 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Friesen et al.
146.7, 150.7, 165.0. FAB HRMS (C25H27N2O4F2, M + H+) calcd,
SO4, filtered, and concentrated. The crude material was
resubjected to the same reaction conditions. After workup, the
residue was subjected to flash chromatography (silica gel,
EtOH/CH2Cl2, 3:97 to 1:9) to provide (+)-2e (70 mg, 50%) as a
white foam. [R]25D +10.9° (c 1, CHCl3). 1H NMR (500 MHz): δ
0.68 (m, 2H), 0.82 (m, 2H), 1.47 (s, 6H), 3.26 (m, 2H), 3.93 (m,
1H), 4.41 (t, 1H), 4.68 (br s, 1H), 6.30 (d, 1H), 6.76 (t, 1H),
6.99 (dd, 1H), 7.09 (d, 1H), 7.17 (d, 1H), 7.41 (dd, 1H), 7.48 (d,
1H), 7.60 (d, 1H), 7.83 (dd, 1H), 8.519 (d, 1H), 11.50 (br s, 1H).
13C NMR (125 MHz, CDCl3): δ 6.2, 30.5, 37.5, 49.4, 51.5, 71.7,
114.5, 115.9 (t), 117.7, 118.6, 120.0, 120.1, 122.6, 133.2, 136.2,
136.6, 138.5, 140.7, 143.1, 146.8, 150.5, 164.4, 164.7. FAB
HRMS (C25H27N2O4F2, M + H+) calcd, 457.193 89; found,
457.193 81.
2-{1-Meth yl-1-[(2-tr im eth ylsilyleth oxy)m eth oxy]eth yl}-
th ia zole (17a ). To a solution of thiazole (2.88 g, 33.8 mmol)
in ether (50 mL) at -78 °C was added n-BuLi (21.1 mL of a
1.6 M solution in hexane, 33.8 mmol) dropwise. After the
mixture was stirred at this temperature for 20 min, acetone
(2.73 mL, 37.2 mmol) was added. After 30 min, the mixture
was partitioned between 25% NH4OAc and ethyl acetate. The
aqueous phase was extracted with ethyl acetate. The combined
organics were washed with brine, dried over MgSO4, filtered,
and concentrated. The crude alcohol (3.42 g, 23.9 mmol) was
dissolved in CH2Cl2 (25 mL) and diisopropylethylamine (10.4
mL, 59.7 mmol) and cooled to 0 °C. 2-(Trimethylsilyl)ethoxym-
ethyl chloride (4.65 mL, 26.3 mmol) was added. The mixture
was stirred at room temperature for 20 h and at reflux for 2
h. A 25% NH4OAc solution was added, and the mixture was
extracted with CH2Cl2. The organics were washed brine, dried
over MgSO4, filtered, and concentrated. The residual material
was subjected to flash chromatography (silica gel, hexane/ethyl
acetate, 9:1) to provide 17a (3.28 g, 36%) as a yellow liquid.
1H NMR (500 MHz): δ 0.01 (s, 9H), 0.87 (t, 2H), 1.65 (s, 6H),
3.67 (t, 2H), 4.79 (s, 2H), 7.51 (d, 1H), 7.69 (d, 1H).
457.193 89; found, 457.193 81.
(+)-2c: [R]25 +8.7° (c 1, CHCl3). 13C NMR (125 MHz): δ
D
6.1, 6.2, 30.49, 30.53, 40.1, 49.1, 51.6, 71.7, 114.2, 115.8 (t),
118.7, 120.0, 122.7, 126.5, 136.1, 138.6, 138.8, 140.2, 146.7,
150.7, 165.0. FAB HRMS (C25H27N2O4F2, M + H+) calcd,
457.193 89; found, 457.193 81.
(()-3-{2-[(3-Cyclopr opyloxy-4-diflu or om eth oxy)ph en yl]-
2-{-5-[2-(1-h yd r oxy-1-m et h yl)et h yl]p yr id yl}et h yl}p yr i-
d in e N-Oxid e ((()-2d ). To a solution of ethyl 3-pyridylacetate
N-oxide (5.09 g, 28.1 mmol) in THF (100 mL) and HMPA (5
mL, 28.7 mmol) at 0 °C was added KHMDS (60 mL of a 0.5 M
solution in toluene, 30 mmol) dropwise. After being stirred at
room temperature for 90 min, the mixture was recooled to 0
°C and a solution of (()-14 (3.44 g, 6.69 mmol) in THF (30
mL) was added dropwise. The mixture was stirred at 60 °C
for 6 h and then poured into saturated NH4Cl and diluted with
ethyl acetate. The layers were separated, and the aqueous
phase was extracted with ethyl acetate. The combined organics
were washed with brine, dried over MgSO4, filtered, and
concentrated. The residue was subjected to flash chromatog-
raphy (silica gel, CH2Cl2/EtOH, 99:1 to 95:5) to provide 4.44 g
of partially purified ester as a yellow oil. This material was
dissolved in a mixture of THF/MeOH/water (3:1:1, 60 mL). A
1.7 N LiOH (12 mL, 20.4 mmol) solution was added, and the
mixture was heated at 60 °C for 10.5 h and at room temper-
ature for 15 h. A 2 N HCl (12 mL) solution was slowly added.
The volatiles were removed on the rotovap, and the residue
was partitioned between water and ethyl acetate. The aqueous
phase was extracted three times with ethyl acetate. The
combined organics were washed with brine, dried over Na2-
SO4, filtered, and concentrated to provide 3.52 g of crude acid
(()-22. Crude (()-22 was dissolved in DMSO (20 mL) and
heated at 130 °C for 4 h. The mixture was poured into water
(200 mL) and extracted with CH2Cl2, and the organics were
washed with brine, dried over Na2SO4, filtered, and concen-
trated. The residue was subjected to flash chromatography
(silica gel, EtOH/ethyl acetate, 1:4 to 1:1) to provide (()-2d
(1.22 g, 39% from (()-14) as a white foam. 1H NMR (500
MHz): δ 0.68 (m, 2H), 0.80 (m, 2H), 1.44 (s, 6H), 3.48 (m, 2H),
3.90 (m, 1H), 4.55 (t, 1H), 4.62 (s, 1H), 6.72 (t, 1H), 7.00 (d,
1H), 7.07 (d, 1H), 7.14 (d, 1H), 7.20 (t, 1H), 7.49 (s, 1H), 7.59
(d, 1H), 7.85 (d, 1H), 7.90 (d, 1H), 8.05 (s, 1H), 8.51 (s, 1H).
(()-[(3-Cyclobu tyloxy-4-d iflu r om eth oxy)p h en yl]{2-[1-
m eth yl-1-(2-tr im eth ylsilyleth oxy)m eth oxy]eth ylth ia zol-
5-yl}m eth a n ol ((()-18a ). To a solution of 17a (1.72 g, 6.31
mmol) in ether (20 mL) at -78 °C was added n-BuLi (3.94
mL of a 1.6 M solution in hexane, 6.31 mmol) dropwise. After
the mixture was stirred at this temperature for 30 min, a
solution of 5b (1.53 g, 6.31 mmol) in ether (4 mL) was added
dropwise. After 45 min, 25% NH4OAc and ethyl acetate were
added. The layers were separated, and the aqueous phase was
extracted with ethyl acetate. The combined organics were
washed successively with 25% NH4OAc buffer and brine, dried
over MgSO4, filtered, and concentrated. The residual material
was subjected to flash chromatography (silica gel, hexane/ethyl
acetate, 65:35) to provide (()-18a (2.34 g, 72%) as a pale-yellow
Sep a r a tion of En a n tiom er s of (()-2d . A solution of (()-
2d (1.22 g) in EtOH/hexane (15 mL, 2:3) was injected (3 ×
400 g) onto a CHIRALPAK AD preparative (5 cm × 50 cm)
HPLC column (eluting with hexane/EtOH, 3:2, at 60 mL/min
with UV detection at 270 nm). The enantiomers were sepa-
rated with the faster eluting enantiomer having a retention
time of ∼7.5 min (enantiomer 1) and the slower eluting
enantiomer having a retention time of ∼12.5 min (enantiomer
2). The eluants were concentrated to provide (+)-2d (enanti-
omer 1, 463 mg, >99% ee) as a white foam and (-)-2d
(enantiomer 2, 485 mg, >99% ee) as a white foam.
1
oil. H NMR (500 MHz): δ 0.01 (s, 9H), 0.87 (dd, 2H), 1.59 (s,
3H), 1.60 (s, 3H), 1.71 (m, 1H), 1.82 (m, 1H), 2.13 (m, 2H),
2.45 (m, 2H), 3.65 (dd, 2H), 4.75 (m, 1H), 4.76 (s, 2H), 5.35 (d,
1H), 6.09 (d, 1H), 6.87 (t, 1H), 7.04 (dd, 1H), 7.12 (m, 2H), 7.47
(s, 1H).
(+)-2d : [R]25 +24.56° (c 1, CHCl3). 13C NMR (125 MHz): δ
(()-4-{2-[(3-Cyclobu tyloxy-4-d iflu r om eth oxy)p h en yl]-
2-[5-(2-(1-m et h yl-1-[(2-t r im et h ylsilylet h oxy)m et h oxy]-
eth yl)th ia zolyl)]eth yl}p yr id in e ((()-20a ). Following the
procedures described for the preparation of (()-15 but substi-
tuting the alcohol (()-18a (2.31 g, 4.48 mmol) for (()-13, (()-
20a (2.26 g, 86%) was obtained as a pale-yellow gum. 1H NMR
(500 MHz): δ 0.00 (s, 9H), 0.87 (dd, 2H), 1.58 (s, 3H), 1.59 (s,
3H), 1.69 (m, 1H), 1.81 (m, 1H), 2.04 (m, 1H), 2.12 (m, 1H),
2.35-2.48 (m, 2H), 3.39 (dd, 1H), 3.46 (dd, 1H), 3.63 (dd, 2H),
4.70-4.75 (m, 2H), 4.74 (s, 2H), 6.82 (t, 1H), 6.92 (m, 2H), 7.06
(d, 1H), 7.15 (d, 2H), 7.48 (s, 1H), 8.37 (d, 2H).
Sep a r a tion of En a n tiom er s of (()-20a . A solution of (()-
20a (2.26 g) in 2-propanol/hexane (28 mL, 1:3.7) was injected
(5 × 460 mg) onto a CHIRALPAK AD preparative (5 cm × 50
cm) HPLC column (eluting with hexane/2-propanol, 96:4, at
75 mL/min with UV detection at 280 nm). The enantiomers
were separated with the faster eluting enantiomer having a
retention time of ∼42 min (enantiomer 1) and the slower
eluting enantiomer having a retention time of ∼52 min
(enantiomer 2). The eluants were concentrated to provide the
D
6.54, 6.59, 31.1, 38.3, 49.5, 52.3, 72.8, 115.6, 117.7 (t), 119.3,
121.4, 122.8, 126.1, 126.5, 136.6, 137.6, 137.8, 139.5, 140.1,
142.6, 148.3, 151.3, 166.8. FAB HRMS (C25H27N2O4F2, M +
H+) calcd, 457.193 89; found, 457.193 81.
(-)-2d : [R]25 -26.53° (c 1, CHCl3). 13C NMR (125 MHz): δ
D
6.54, 6.59, 31.1, 38.3, 49.5, 52.3, 72.8, 115.6, 117.7 (t), 119.3,
121.4, 122.8, 126.0, 126.5, 136.6, 137.6, 137.8, 139.5, 140.1,
142.6, 148.3, 151.3, 166.8. FAB HRMS (C25H27N2O4F2, M +
H+) calcd, 457.193 89; found, 457.193 81.
(+)-5-{2-[(3-Cyclopr opyloxy-4-diflu or om eth oxy)ph en yl]-
2-{-5-[2-(1-h yd r oxy-1-m eth yl)eth yl]p yr id yl}eth yl}p yr id -
2-on e ((+)-2e). To a solution of (+)-2d (enantiomer 1, 142 mg,
0.31 mmol) and Et3N (216 µL, 1.55 mmol) in THF (3 mL) at 0
°C was added TFAA (110 µL, 0.78 mmol). The mixture was
stirred at room temperature for 3 h, 2 N NaOH and MeOH
were added, and the mixture was stirred at room temperature
for 15 h. The mixture was partitioned between 25% NH4OAc
and ethyl acetate. The aqueous phase was extracted with ethyl
acetate. The organics were washed with brine, dried over Na2-