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J. Li et al. / Bioorg. Med. Chem. 20 (2012) 4356–4363
for 1 h, then cooled to 0 °C. Ice-cold water (3 mL) was added and
the reaction mixture was stirred for 20 min at room temperature.
The reaction mixture was filtered through a pad of Celite and
rinsed with ether (4 ꢁ 10 mL). The filtrate is washed with water
(2 ꢁ 5 mL), then brine (20 mL). The product was re-extracted with
from the combined aqueous layers with ether (4 ꢁ 10 mL). The or-
ganic phases were combined and dried over MgSO4, and the sol-
vent was removed under reduced pressure (max. 30 °C), to yield
the brominated cycloaddition product as a dark brown oil (1.7 g).
This product was directly used in the next step.
white solid (0.047 g, 62%). FTIR (neat, cmꢀ1
) m 3059, 3031, 2985,
2960, 2924, 2877, 1729, 1492, 1465; 1H NMR (500 MHz, CDCl3) d
7.35 (m, 2H), 7.27 (m, 3H), 5.05 (t, J = 4.9 Hz, 1H), 4.27 (s, 1H),
2.09 (dt, J = 15.2, 4.6 Hz, 2H), 1.76 (m, 4H), 1.59 (dd, J = 15.4,
1.0 Hz, 2H); 13C NMR (125.7 MHz, CDCl3) d 170.7, 134.0, 129.2,
128,6, 127.2, 73.1, 67.8, 42.3, 35.8, 28.3; ESI-HRMS m/z calcd for
C
15H18O3: 269.1148 [M+Na+], found 269.1150.
5.1.6. 8-Methyl-8-azabicyclo[3.2.1]octan-3-yl benzoate (5)
Tropine (0.13 g, 0.92 mmol), benzoic acid (0.13 g, 1.06 mmol), 1-
The brominated cycloaddition product (1.5 g) was dissolved in
MeOH (1.5 mL), and 10% of this solution was added to a suspension
ofzinc-coppercouple(1.2 g)andNH4Cl(1.26 g, 2.35 mmol)inMeOH
(5 mL) at ꢀ78 °C. After stirring for 15 min, the mixture was warmed
to 0 °C and the remaining cycloaddition product was added drop-
wise, followed by stirring for 1.5 h at room temperature. The reac-
tion mixture was cooled to 0 °C and then filtered. The residue was
rinsed with ether (4 ꢁ 10 mL). The combined organic phases were
washed with brine (20 mL), and the aqueous phase was extracted
with CHCl3 (5 ꢁ 20 mL). The combined organic phases were dried
over MgSO4, concentrated in vacuo, filtered through a pad of
K2CO3, and washed with CHCl3 (3 ꢁ 20 mL). The filtrate was concen-
trated under reduced pressure yielding a brown oil. The crude prod-
uct was purified by flash column chromatography on silica gel
(hexane/ether, 10:1) to give final bicyclic ketone (3a) as a pale solid
ethyl-3-(3-dimethylaminopropyl)
carbodiimide
hydrochloride
(0.194 g, 0.101 mmol), and 4-dimethylaminopyridine (0.092 mmol,
0.011 g) were dissolved in DCM (15 mL). The reaction mixture was stir-
red for 48 h at room temperature. The reaction solution was washed
with NaHCO3 (2 ꢁ 10 mL), H2O (2 ꢁ 10 mL), brine (10 mL), dried over
Na2SO4, and concentrated in vacuo. Purification via silica gel flash col-
umn chromatography (DCM/MeOH/NH4OH, 50:5:1) affords product 5
as a light yellow solid (0.14 g, 64%). FTIR (neat, cmꢀ1
)
m
2931, 1714,
1
1601, 1450; H NMR (500 MHz, CDCl3) d 8.02 (m, 2H), 7.55 (m, 1H),
7.45 (m, 2H), 5.26 (t, J = 5.4 Hz, 1H), 3.26 (s, 2H), 2.32 (s, 3H), 2.24 (dt,
J = 14.4, 4.0 Hz, 2H), 2.10 (m, 4H), 1.84 (d, J = 14.6 Hz 2H); 13C NMR
(125.7 MHz, CDCl3) d 165.9, 132.8, 130.9, 129.4, 128.4, 68.1, 59.9,
40.5, 36.7, 25.8; ESI-HRMS m/z calcd for C15H19NO2: 246.1489
[M+H+], found 246.1489.
(0.18 g, 43% over two steps). FTIR (neat, cmꢀ1
)
m
2962, 2916, 1714,
5.1.7. 8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-(dimethy
lamino)phenyl)acetate (6)
1246, 1043; 1H NMR (500 MHz, CDCl3) d 6.27 (s, 2H), 5.06 (d,
J = 5.1 Hz, 2H), 2.76 (dd, J = 17.0, 5.2 Hz, 2H), 2.34 (dd, J = 16.3,
0.6 Hz, 2H); 13C NMR (125.7 MHz, CDCl3) d 205.3, 133.3, 77.2, 46.7;
EI-HRMS m/z calcd for C7H8O2: 124.05243 [M+], found: 124.05256.
Tropine (0.30 g, 2.12 mmol), 4-(dimethylamino)phenylacetic
acid (0.31 g, 1.70 mmol), 1-ethyl-3-(3-dimethylaminopropyl) car-
bodiimide hydrochloride (0.49 g, 2.54 mmol) and 4-dimethylami-
nopyridine (0.21 mmol, 0.026 g) were dissolved in DCM (12 mL)
and stirred for 20 h at room temperature. The reaction mixture
was washed with NaHCO3 (2 ꢁ 15 mL), H2O (2 ꢁ 15 mL), brine
(20 mL), dried over Na2SO4, and concentrated in vacuo. The product
was purified by silica gel flash column (DCM/MeOH/NH4OH,
5.1.4. 8-Oxabicyclo[3.2.1]octan-3-ol (3b)
8-Oxabicyclo[3.2.1]oct-6-en-3-one 3a (0.12 g, 0.97 mmol) was
dissolved in anhydrous EtOH (10 mL), followed by addition of
10% Pd/C (12 mg). The mixture was stirred under under an atmo-
sphere of hydrogen for 8 h at the room temperature. The reaction
mixture was filtered through Celite and the solvent was removed
under reduced pressure to generate crude product as a pale oil.
The oil was diluted in THF (5 mL) and cooled to ꢀ78 °C, followed
4:1:0.1) to yield 6 as a yellow oil (0.37 g, 71%). FTIR (neat, cmꢀ1
2933, 2873, 2848, 1726, 1567; 1H NMR (500 MHz, CDCl3) d
)
m
7.19 (m, 2H), 6.66 (m, 2H), 4.97 (t, J = 5.4, 1H), 3.50 (s, 2H), 3.05
(s, 2H), 2.94 (s, 6H), 2.26 (s, 3H), 2.09 (dt, J = 14.7, 4.8 Hz, 2H),
1.92 (m, 2H), 1.78 (m, 2H), 1.66 (d, J = 14.4 Hz); 13C NMR
(125.7 MHz, CDCl3) d 171.4, 149.8, 129.9, 122.0, 112.9, 67.6, 59.8,
41.3, 40.8, 40.4, 36.5, 25.5; ESI-HRMS m/z calcd for C18H26N2O2:
303.2067 [M+H+], found 303.2067.
by addition of L-Selectride (0.16 mL, 0.75 mmol) dropwise. After
stirring for 1 h at ꢀ78 °C, the reaction mixture was stirred in an
ice-water bath for 2 h. The reaction was quenched by adding EtOH
(5 mL). The mixture was concentrated under reduced pressure and
re-dissolved in DCM (20 mL). The organic layer was washed with
water (1 ꢁ 10 mL) and brine (10 mL). The combined aqueous
phases were re-extracted with DCM (3 ꢁ 15 mL). Combined organ-
ic phases were dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy on silica gel (hexane/EtOAc, 7:1) to yield the final product
5.1.8. 6,7-Dehydrohyoscyamine (7)
Scopolamine (0.1 g, 0.33 mmol) and zinc-copper couple (3 g) in
anhydrous EtOH were heated to reflux for 8 h. The reaction mix-
ture was filtered through a pad of Celite and concentrated under
reduced pressure. Purification was via silica gel flash chromatogra-
phy (DCM/MeOH/NH4OH, 20:1:0.05) to afford 7 a white solid
3b as a pale white solid (70 mg, 56%). FTIR (neat, cmꢀ1
) m 3420,
2946, 2921, 1243; 1H NMR (500 MHz, CDCl3) d 4.38 (s, 2H), 4.34
(t, J = 4.8 Hz, 1H), 2.26 (m, 2H), 2.14 (ddd, J = 14.9, 9.1, 14.9, Hz,
2H), 1.95 (m, 2H), 1.66 (dd, J = 14.9, 1.3 Hz); 13C NMR
(125.7 MHz, CDCl3) d 73.5, 64.6, 39.0, 28.8; EI-HRMS m/z calcd
for C7H12O2: 128.08372 [M+], found: 128.08379.
(0.08 g, 80%). FTIR (neat, cmꢀ1
) m 3063.3, 2936.2, 2855.3, 1724.3,
1493.7; 1H NMR (500 MHz, CDCl3) d 7.30 (m, 5H), 5.80 (dd,
J = 5.6, 1.9 Hz, 1H), 5.42 (dd, J = 5.5, 1.9 Hz, 1H), 5.01 (t,
J = 6.1 Hz), 4.12 (dd, J = 11.3, 8.8 Hz, 1H), 3.80 (dd, J = 11.3, 5.2 Hz,
1H), 3.72 (dd, J = 8.8, 5.2 Hz, 1H), 3.34 (m, 1H), 3.24 (m, 1H), 2.20
(m, 4H), 2.14 (ddd, J = 15.0, 6.0, 3.6 Hz, 1H), 1.68 (d, 14.9 Hz, 1H),
1.52 (d, 14.9 Hz, 1H); 13C NMR (125.7 MHz, CDCl3) d 171.9, 135.9,
131.6, 131.6, 128.7, 128.3, 127.6, 67.9, 65.4, 65.3, 64.2, 54.3, 41.5,
33.7, 33.5; ESI-HRMS m/z calcd for C17H21NO3: 288.1594 [M+H+],
5.1.5. 8-Oxabicyclo[3.2.1]octan-3-yl 2-phenylacetate (3)
8-Oxabicyclo[3.2.1]octan-3-ol 3b (0.04 g, 0.31 mmol), phenyl
acetic acid (0.048 g, 0.04 mmol), 1-ethyl-3-(3-dimethylaminopro-
pyl) carbodiimide hydrochloride (0.066 g, 0.34 mmol), and 4-
dimethylaminopyridine (10 mol %, 0.004 g) were dissolved in
DCM (5 mL). The reaction mixture was stirred for 36 h at room
temperature. The reaction solution was washed with NaHCO3
(2 ꢁ 10 mL), H2O (2 ꢁ 10 mL), brine (10 mL), dried over Na2SO4,
and concentrated in vacuo. Purification via silica gel flash column
chromatography (hexane/ether, 4:1) generated product 3 as a
found 288.1594. ½a D24
ꢀ9.7° (c = 0.50, CHCl3)
ꢃ
Acknowledgments
We gratefully acknowledge Dr. Randy Whittal and Mr. Bela Reiz
(University of Alberta) for assistance with mass spectrometric
analysis. This work was supported by the Natural Sciences and