Tan et al.
residue was dissolved in EtOAc (250 mL) and washed with
saturated aqueous NaHCO3 (170 mL). The aqueous layer was
back-extracted with EtOAc (2 × 60 mL). The combined organic
solutions were washed with brine (60 mL) and dried over
Na2SO4. Evaporation of solvent gave 5.76 g of crude ester,
which was subjected to bulb-to-bulb distillation (1.6 Torr) to
afford 4.87 g of ester 7 as a yellow oil.
An analytically pure sample was obtained by flash silica gel
column chromatography (hexanes/MTBE) to give 9 as a
1
colorless solid: mp 28-30 °C; H NMR (400 MHz, CDCl3) δ
5.00 (dd, J ) 48.2, 3.5 Hz, 1 H), 4.45 (m, 1 H), 3.85 (s, 3 H),
3.51 (m, 1 H), 3.42 (m, 1 H), 2.64-2.52 (dm, J ) 34.5 Hz, 1
H), 2.14 (m, 1 H), 1.91 (m, 1 H), 0.88 (s, 9 H), 0.054 (s, 3 H),
and 0.051 (s, 3 H); 13C NMR (101 MHz, CDCl3) δ 168.8 (d, J )
24.1 Hz), 88.3 (d, J ) 186.1 Hz), 75.4 (d, J ) 1.6 Hz), 58.3,
57.2 (d, J ) 7.2 Hz), 52.8 (d, J ) 19.3 Hz), 52.7, 38.3, 25.9,
18.0, -4.5, and -4.7; 19F NMR (377 MHz, CDCl3) δ -199.9
(dd, J ) 48.2, 34.5 Hz); LRMS m/z 305 (M + 1), 121 (base
peak); [R]2D5 -27 (c 1.0, CHCl3). Anal. Calcd for C14H25FO4Si:
C, 55.23; H, 8.28; F, 6.24. Found: C, 55.27; H, 8.63; F, 6.31.
An analytically pure sample was obtained by further flash
silica gel column chromatography to give 7 as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 5.84 (m, 1 H), 5.55 (m, 1 H),
4.95 (dd, J ) 48.8, 5.5 Hz, 1 H), 4.49 (dt, J ) 7.2, 4.6 Hz, 1 H),
3.82 (s, 3 H), 3.11 (dm, J ) 24.4 Hz, 1 H), 2.75 (m, 1 H), 2.51
(s, 1 H), and 2.33 (m, 1 H); 13C NMR (101 MHz, CDCl3) δ 170.0
(d, J ) 24.1 Hz), 132.3, 126.1 (d, J ) 5.0 Hz), 89.5 (d, J )
188.0 Hz), 73.9 (d, J ) 4.0 Hz), 57.1 (d, J ) 20.1 Hz), 52.6,
and 41.8; 19F NMR (377 MHz, CDCl3) δ -196.5; IR (film) 3409,
Methyl (1R,2R,4S,5S,6R)-2-{[tert-Butyl(dimethyl)silyl]-
oxy}-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-6-carboxyl-
ate (10). To a solution of epoxide TBS-ether 9 (assay wt 1.60
kg, 5.24 mol) in THF (16.1 L) was added a solution of Et3Al
(1.0 M in hexanes, 6.81 L, 6.81 mol), while maintaining the
batch temperature at -60 °C over 1 h, and the resulting
solution was stirred at -60 °C for 20 min. A solution of
LHMDS (1.0 M solution in hexanes, 7.86 L, 7.86 mol) was
added to the reaction mixture over 1 h while maintaining the
batch temperature below -60 °C, and the reaction was aged
at -60 °C. The progress of the reaction was monitored by GC.
After complete consumption of the epoxide (6 h), an aqueous
solution of citric acid (3 M, 10.5 L) was added over 1 h while
maintaining the batch temperature below -50 °C. After MTBE
(12.4 L) was added, the resulting suspension was allowed to
gradually warm to 15 °C with stirring. Two liquid phases were
produced after addition of H2O (4.93 L). The organic layer was
separated and washed twice with saturated aqueous NaHCO3
(11.1 L then 5.6 L). GC assay of the organic solution indicated
1.54 kg (96%) of 10. Concentration of the organic layer afforded
crude alcohol as a yellow oil, which was used for the next
reaction without further purification.
An analytically pure sample was obtained by flash silica gel
column chromatography to give 10 as a colorless glass: 1H
NMR (400 MHz, CDCl3) δ 4.47 (d, J ) 4.4 Hz, 1 H), 4.34 (m,
1 H), 3.83 (s, 3 H), 2.44 (d, J ) 6.8 Hz, 1 H), 2.37 (d, J ) 11.2
Hz, 1 H), 2.25 (d, J ) 6.8 Hz, 1 H), 2.07 (m, 1 H), 1.84 (m, 1
H), 0.91 (s, 9 H), 0.131 (s, 3 H), and 0.128 (s, 3 H); 13C NMR
(101 MHz, CDCl3) δ 169.2 (d, J ) 26.5 Hz), 79.7 (d, J ) 244.3
Hz), 74.1, 74.0, 52.9, 44.6 (d, J ) 10.4 Hz), 37.9 (d, J ) 12.0
Hz), 37.6 (d, J ) 11.2 Hz), 25.8, 18.0, -4.8, and -4.9; 19F NMR
(377 MHz, CDCl3) δ -217.1 (m); LRMS m/z 305 (M + 1), 304
(M), 303 (M - 1), 75 (base peak); [R]2D5 +8.6 (c 1.9, CHCl3).
Anal. Calcd for C14H25FO4Si: C, 55.23; H, 8.28, F, 6.24.
Found: C, 55.44; H, 8.46; F, 6.39.
Methyl (1R,2R,5S,6S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-
6-fluoro-4-oxobicyclo[3.1.0]hexane-6-carboxylate (16). To
a solution of bicyclic mono-TBS-diol 10 (2.08 kg, 6.83 mol) in
acetonitrile (8.0 L) at -5 °C was added acetic acid (0.70 L)
and water (2.5 L), followed by RuCl3 hydrate (14.20 g). To the
mixture was added aqueous sodium hypochlorite solution
(∼13%; 7.0 L) over 2 h, keeping the temperature around 0 °C.
The resulting mixture was stirred at 0 °C for another 1 h until
all bicyclic mono-TBS-diol 10 disappeared, monitoring by TLC
and NMR. The excess aqueous sodium hypochlorite was
decomposed by the addition of 2-propanol (0.70 L) and aging
at 0 °C for 15 min. The two layers were separated, and the
organic solution was used for the next reaction without further
treatment.
An analytically pure sample was obtained by flash silica gel
column chromatography (MTBE/hexane) to give 16 as a
colorless crystalline solid: mp 70-71 °C; 1H NMR (400 MHz,
CDCl3) δ 4.66 (d, J ) 5.4 Hz, 1 H), 3.86 (s, 3 H), 2.73 (m, 2 H),
2.54 (dt, J ) 19.1, 5.7 Hz, 1 H), 2.22 (dd, J ) 19.1, 3.8 Hz, 1
H), 0.91 (s, 9 H), 0.13 (s, 3 H), and 0.11 (s, 3 H); 13C NMR (101
MHz, CDCl3) δ 206.2, 167.1 (d, J ) 26.1 Hz), 78.9 (d, J ) 246.4
Hz), 67.6 (d, J ) 2.8 Hz), 53.4, 47.5 (d, J ) 3.9 Hz), 42.0 (d,
J ) 11.4 Hz), 39.6 (d, J ) 13.3 Hz), 25.7, 18.0, -4.76, and
3059, 1744, 1439, 1288, 1209, 1153, 1099, 1048, 951, 733 cm-1
;
[R]2D5 -123.5 (c 1.02, CHCl3). HRMS calcd for C8H11FO3 (M +
H+) 175.0770, found 175.0773.
Methyl (2S)-Fluoro[(1R,2S,3R,5S)-3-hydroxy-6-oxabi-
cyclo[3.1.0]hex-2-yl]acetate (8). To a solution of olefin 7
(1.92 kg, 11.0 mol) in toluene (4.83 L) was added vanadyl
acetylacetonate (VO(acac)2, 58.3 g, 0.22 mol) at 0 °C. After a
solution of TBHP (5.7 M in decane, 38.6 mL) was added to
the solution at 0 °C, the resulting suspension was allowed to
warm to 14 °C. An additional solution of TBHP (5.7 M in
decane, 4.36 L) was slowly added to the reaction mixture over
50 min while maintaining the batch temperature between 14
and 28 °C. The resulting suspension was stirred for another 2
h, and then heated at 40 °C for 8 h. Excess TBHP was
quenched with aqueous Na2S2O3 solution (2.95 kg of Na2S2O3
and 4.71 kg of H2O), which was slowly added at 0 °C. The
resulting mixture was stirred at 20 °C for 1.5 h. The disap-
pearance of peroxides was confirmed by test paper. The
aqueous layer was separated and extracted with EtOAc (2 ×
9.42 L). The combined organic solutions were washed with
brine (6.33 L). The brine layer was back-extracted with EtOAc
(4 × 3.42 L). GC assay of the combined organic solutions
indicated 1.90 kg (91%) of product 8. The combined organic
solutions were concentrated, and the resulting residue was
purified by silica gel chromatography in a filter pot (first eluted
with hexanes/EtOAc (4/1) then pure EtOAc).
Analytically pure sample was prepared by flash silica gel
column chromatography (hexanes/MTBE) followed by recrys-
tallization (EtOAc) to give 8 as a pale yellow solid: mp 31-33
°C; 1H NMR (400 MHz, CDCl3) δ 5.01 (dd, J ) 48.3, 3.9 Hz, 1
H), 4.13 (br s, 1 H), 3.86 (s, 3 H), 3.71 (m, 1 H), 3.59 (m, 1 H),
2.77 (dd, J ) 32.8, 3.9 Hz, 1 H), 2.30 (br s, 1 H), and 2.11 (m,
2 H); 13C NMR (101 MHz, CDCl3) δ 168.4 (d, J ) 24.1 Hz),
88.1 (d, J ) 186.1 Hz), 73.2 (d, J ) 1.6 Hz), 58.4, 57.1 (d, J )
5.6 Hz), 52.8, 51.6 (d, J ) 19.3 Hz), and 37.7 (d, J ) 1.6 Hz);
19F NMR (377 MHz, CDCl3) δ -200.8 (dd, J ) 48.3, 32.8 Hz);
LRMS m/z 191 (M + 1), 189 (M - 1), 172 ([M - H2O]+), 59
([COOCH3]+, base peak); [R]25 -56 (c 1.0, CHCl3). Anal. Calcd
D
for C8H11FO4: C, 50.53; H, 5.83; F, 9.99. Found: C, 50.36; H,
5.92; F, 10.05.
Methyl (2S)-((1R,2R,3R,5S)-3-{[tert-Butyl(dimethyl)si-
lyl]oxy}-6-oxabicyclo[3.1.0]hex-2-yl)(fluoro)acetate (9).
To a solution of epoxy alcohol 8 (1.60 kg, 8.40 mol) and DMF
(3.40 L) was added imidazole (1.26 kg, 18.5 mol) at 10 °C.
TBSCl (1.52 kg, 10.1 mol) was added to the reaction mixture
while maintaining the batch temperature below 8 °C. The
resulting solution was stirred at 5 °C for 10 min, then allowed
to warm to 20 °C over 30 min and stirred for 2 h at the same
temperature. The consumption of the starting alcohol was
monitored by GC, and the reaction mixture was diluted with
cold toluene (17.0 L, 5 °C). The resulting mixture was washed
with H2O (5.67 L), saturated aqueous NaHCO3 (5.67 L), H2O
(2 × 5.67 L), and brine (5.67 L). HPLC assay of the organic
solution indicated 2.38 kg (93%) of 9. Concentration of the
solution gave 9 as a yellow liquid, which was used for the next
step without further purification.
8032 J. Org. Chem., Vol. 70, No. 20, 2005