13
(1R,2S,4S,5R,6S)-6-(tert-Butyldimethylsilyloxy)-3-fluoro-2,5-
dimethylbicyclo-[2.2.2]octan-2-yl 2-diazoacetate (49).
(2R)-5-Acetyl-9-[(tert-butyldimethylsilyl)oxy]-2,8-
ACCEPTED MANUSCRIPT
dimethyl-3-oxatricyclo[5.2.2.02,6]undecan- 4-one (43).
A flame-dried round-bottom flask was charged with ketone
(1R,4S,5R,6S)-6-(tert-Butyldimethylsilyloxy)-3-fluoro-5-
A flame dried round-bottom flask was charged with diazo-
acetate 41 (100.0 mg, 0.25 mmol) under an argon atmosphere.
Anhydrous CH2Cl2 (9.0 mL, 0.03M) was added. The reaction
mixture was vigorously stirred at room temperature while adding
Rh2(oct)4 (1.0 mg, 0.5 mol%) in one portion. After 20 minutes,
TLC analysis showed no starting material. The reaction was
concentrated under reduced pressure and the residue was purified
by flash column chromatography using 5% EtOAc in hexanes as
an eluent. The product was obtained as a white solid (28.9 mg,
methylbicyclo[2.2.2]octan-2-one (0.30 g, 1.05 mmol) under an
argon atmosphere. Anhydrous THF (12.0 mL) was added, and
the flask was cooled to -78 °C in a dry ice/acetone bath. 1.6M
MeLi solution (1.30 mL, 2.10 mmol) was then added. The
reaction mixture was warmed to room temperature and stirred for
2 hours before saturated NH4Cl solution was added. The mixture
was extracted with Et2O (3x), and the organic phases were
combined and washed with brine, dried over anhydrous MgSO4,
filtered through short silica gel plug and concentrated to yield
1
31% yield). H NMR (400 MHz, CDCl3) δ 11.54 (s, 1H, major),
3.65 (d, J = 4.0 Hz, 1H, minor), 3.34 (dd, J = 5.2 Hz and 2.3 Hz,
1H, minor), 3.31 (dd, J = 5.2 Hz and 2.3 Hz, 1H, major), 2.70 (t,
J = 3.4 Hz, 1H, minor), 2.60 (d, J = 2.3 Hz, 1H, major), 2.45 (s,
3H, minor), 1.92 (s, 3H, major), 1.84 (q, J = 2.9 Hz, 1H, minor),
1.83-1.80 (m, 1H, major), 1.71-1.51 (m, major/minor), 1.44-1.35
(m, major/minor), 1.39 (s, 3H, minor), 1.38 (s, 3H, major), 1.34-
1.21 (m, major/minor), 1.02 (d, J = 6.9 Hz, 3H, minor), 0.96 (d, J
= 6.9 Hz, 3H, major), 0.89 (s, 9H, minor), 0.88 (s, 9H, major),
0.04 (s, 3H, minor), 0.03 (s, 3H, major), 0.02 (s, 3H, minor), 0.00
(s, 3H, major). 13C NMR (100.25 MHz, CDCl3) δ 200.8, 175.6,
171.3, 168.4, 99.7, 85.9, 85.4, 78.3, 77.9, 59.9, 48.0, 44.6, 41.7,
41.6, 37.1, 36.8, 36.4, 36.0, 29.5, 27.7, 27.3, 25.8, 25.8, 21.9,
21.7, 19.0, 18.8, 18.7, 18.6, 18.0, -4.3, -4.3, -4.6, -4.7. HRMS-CI
m/z: [M+H]+, calculated for C20H32O5Si, 381.2097; found
381.2098. Rf: 0.68 in 20% EtOAc/hexanes.
crude
product.
Crude
(1R,2S,4S,5R,6S)-6-(tert-
Butyldimethylsilyloxy)-3-fluoro-2,5-dimethylbicyclo-
[2.2.2]octan-2-ol was subjected to the next step without any
1
further purification. H NMR (500 MHz, CDCl3) δ 4.86 (s, 1H),
4.22 (dd, J = 51.0 Hz and 3.4 Hz, 1H), 3.46 (t, J = 3.4 Hz, 1H),
2.18-2.11 (m, 1H), 1.85-1.79 (m, 1H), 1.66-1.62 (m, 1H), 1.61-
1.48 (m, 2H), 1.26 (s, 3H), 1.28-1.13 (m, 2H), 1.04 (d, J = 6.9
Hz, 3H), 0.89 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H). 13C NMR
(125.76 MHz, CDCl3) δ 96.0, 94.4, 79.8, 70.7, 70.6, 43.0, 37.7,
37.5, 33.4, 28.6, 25.8, 20.2, 18.0, 17.9, 15.9, 15.8, -4.5, -4.6. 19F
NMR (470.62 MHz, CDCl3) δ -197.21 (d, J = 50.9 Hz, 1F). m/z:
[M+Na]+, calculated for C16H31FO2Si, 325.1970; found 325.1976.
Rf: 0.51 in 20% EtOAc/hexanes.
A flame-dried round-bottom flask was charged with the
tertiary alcohol (1.05 mmol) from the previous reaction and
dioxinone 40 (0.22 mL, 1.58 mmol) under an argon atmosphere.
Xylene (0.21 mL, 5.0M) was added, and the flask was placed in a
preheated (100 °C) oil bath. After 30 minutes the reaction
mixture was allowed to cool to room temperature. Afterwards,
the crude reaction mixture was purified by column
chromatography on silica gel using 5% EtOAc in hexanes as an
(2R)-9-[(tert-Butyldimethylsilyl)oxy]-2,8-dimethyl-3-
oxatricyclo [5.2.2.02,6]undecan-4-one (45).
A flame dried round-bottom flask was charged with diazo-
acetate 42 (163.0 mg, 0.46 mmol) under an argon atmosphere.
Anhydrous CH2Cl2 (15.4 mL, 0.03M) was added. The reaction
mixture was vigorously stirred at room temperature while adding
Rh2(oct)4 (1.8 mg, 0.5 mol%) in one portion. After 20 minutes,
TLC analysis showed no starting material. The reaction was
concentrated under reduced pressure and the residue was purified
by flash column chromatography using 10% EtOAc in hexanes
as an eluent. The product was obtained as a white solid (36.0 mg,
eluent.
6-[(tert-Butyldimethylsilyl)oxy]-3-fluoro-2,5-
dimethylbicyclo[2.2.2]octan-2-yl-3-oxobutanoate was obtained
as a white solid (349 mg, 86%) that was directly used in the next
reaction. Rf: 0.51 in 20% EtOAc/hexanes.
1
A flame-dried round-bottom flask was charged with the β-
ketoester (1.00 g, 2.59 mmol) under an argon atmosphere.
Anhydrous MeCN (26.0 mL, 0.1M) was added and the flask was
cooled to 0 °C in an ice/water bath. NEt3 (0.54 mL, 3.88 mmol)
followed by pABSA (0.68 g, 2.85 mmol) were then added. After
10 minutes the reaction mixture was allowed to warm to room
temperature and stir for 1 hour (monitored by TLC). After 1 hour
LiOH (1.09 g, 25.9 mmol) and water (3.5 mL, 0.7M) were added
to the above solution. The reaction mixture was heated at 55 °C
for 24 hours (monitored by TLC). After completion, the reaction
mixture was cooled to room temperature before adding saturated
NH4Cl solution. The product was extracted with Et2O (3x). The
organic phases were combined and washed with brine, dried over
anhydrous MgSO4, filtered and concentrated to yield crude
product. The crude product was purified by column
chromatography on silica gel using 5% EtOAc in hexanes as an
eluent. The product 49 was obtained as a yellow oil (0.82 g,
86%). 1H NMR (400 MHz, CDCl3) δ 4.61 (bs, 1H), 4.16 (dd, J =
49.0 Hz and 1.8 Hz, 1H), 3.35-3.29 (m, 1H), 2.56-2.50 (m, 1H),
2.17-2.08 (m, 1H), 1.72 (s, 3H), 1.70-1.53 (m, 2H), 1.43-1.34 (m,
2H), 1.30-1.20 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H),
0.04 (s, 3H), 0.04 (s, 3H). 13C NMR (100.52 MHz, CDCl3) δ
~165, 97.5, 95.6, 80.1, 80.0, 78.8, 47.7, 41.3, 38.7, 38.5, 33.3,
26.2, 25.7, 24.3, 21.6, 18.5, 17.3, 17.1, -4.8. Rf: 0.31 in 5%
EtOAc/hexanes. FTIR (neat, cm-1): 2955, 2928, 2104, 1695,
1369, 1241.
24% yield). H NMR (500 MHz, CDCl3) δ 3.32 (dd, J = 5.7 Hz
and 2.3 Hz, 1H), 2.79 (dd, J = 18.9 Hz and 10.9 Hz, 1H), 2.39
(dd, J = 18.9 Hz and 2.9 Hz, 1H), 2.10 (dt, J = 10.9 Hz and 2.9
Hz, 1H), 1.84-1.81 (m, 1H), 1.70-1.51 (m, 3H), 1.47-1.36 (m,
2H), 1.40 (s, 3H), 1.28-1.19 (m, 1H), 1.02 (d, J = 6.9 Hz, 3H),
0.89 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H). 13C NMR (125.76 MHz,
CDCl3) δ 176.7, 86.4, 78.0, 43.6, 42.0, 37.3, 35.3, 32.9, 27.5,
25.8, 22.0, 19.3, 18.5, 18.0, -4.6. m/z: [M+H]+, calculated for
C18H32O3Si, 325.2199; found 325.2206. Rf: 0.23 in 20%
EtOAc/hexanes.
(5R)-9-[(tert-Butyldimethylsilyl)oxy]-5,8-dimethyl-4-
oxatricyclo [5.2.2.01,5]undecan-3-one (44).
From the above reaction, product 44 was obtained as a white
1
solid (12.5 mg, 8% yield). H NMR (400 MHz, CDCl3) δ 3.29-
2.25 (m, 1H), 2.26 (dd, J = 109.4 Hz and 16.9 Hz, 2H), 2.04 (d, J
= 13.3 Hz, 1H), 1.90 (dd, J = 13.3 Hz and 5.0 Hz, 1H), 1.83-1.69
(m, 2H), 1.68-1.50 (m, 4H), 1.40 (s, 3H), 1.34- 1.21 (m, 1H),
1.03 (d, J = 7.3 Hz, 3H), 0.87 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H).
13C NMR (100.52 MHz, CDCl3) δ 176.6, 84.7, 82.6, 44.4, 44.3,
39.3, 37.6, 32.1, 27.9, 25.9, 23.8, 19.4, 19.0, 17.8, -4.0, -4.8. Rf:
0.31 in 20% EtOAc/hexanes.
(5R)-9-[(tert-Butyldimethylsilyl)oxy]-5,8-dimethyl(6,6-D2)-4-
oxatricyclo [5.2.2.01,5]undecan-3-one (52).