Full Paper
(258 mg, 94 %) as a yellow oil. Rf = 0.21 (EtOAc/cyclohexane, 1:2).
1H NMR, COSY (400 MHz, CDCl3, 323 K): δ = 6.51 (dd, J = 6.2, 2.5 Hz,
0.5 H, 7-H, dia 1), 6.30 (dd, J = 6.1, 2.4 Hz, 0.5 H, 6-H, dia 2), 6.25
(dd, J = 6.1, 2.5 Hz, 0.5 H, 6-H, dia 1), 6.22 (dd, J = 6.0, 2.5 Hz, 0.5
H, 7-H, dia 2), 5.24–5.16 (br. s, 0.5 H, 1-H, dia 2), 5.00–4.95 (br. s, 0.5
H, 1-H, dia 1), 4.95–4.90 (br. s, 0.5 H, 5-H, dia 2), 4.89–4.82 (br. s, 0.5
H, 5-H, dia 1), 3.78 (s, 1.5 H, OCH3), 3.76 (s, 1.5 H, OCH3, dia 2), 3.72
(s, 1.5 H, OCH3), 3.71 (s, 1.5 H, OCH3, dia 1), 3.70–3.66 (m, 0.5 H, 2-
H, dia 1), 3.26 (s, 0.5 H, 2-H, dia 2), 3.00 (dd, J = 16.2, 4.4 Hz, 0.5 H,
4-Ha, dia 2), 2.76–2.62 (m, 0.5 H, 4-Ha, dia 1), 2.40 (dt, J = 16.1,
1.3 Hz, 0.5 H, 4-Hb), 2.39 (dd, J = 15.8, 1.6 Hz, 0.5 H, 4-Hb) ppm. 13C
NMR, HSQC, HMBC (100 MHz, CDCl3, 323 K): δ = 200.8 (C-3, dia 2),
199.6 (C-3, dia 1), 168.4 (CO, dia 1), 168.2 (CO, dia 2), 153.2 (NCO),
153.1 (NCO), 136.3 (C-6, dia 2), 134.3 (C-6, dia 1), 133.5 (C-7, dia 1),
132.7 (C-7, dia 2), 62.4 (C-2, dia 1), 60.3 (C-2, dia 2), 59.5 (C-1, dia 2),
58.3 (C-1, dia 1), 57.1 (C-5, dia 2), 56.6 (C-5, dia 1), 53.0 (OCH3), 52.8
(OCH3), 52.6 (OCH3, dia 1), 52.3 (OCH3, dia 2), 44.8 (C-4), 44.3 (C-
16.0 Hz, 2 H, 2-Hb, 4-Hb), 1.50 [s, 9 H, C(CH3)3] ppm. Spectroscopic
data are in accordance with the literature.[36]
Methyl 3-Oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate (13b):
A solution of ꢀ-keto ester 7b (51 mg, 0.213 mmol, 1 equiv.), LiCl
(23 mg, 0.532 mmol, 2.5 equiv.) and H2O (2 drops) in DMSO (1.7 mL)
was heated at 130 °C for 7 h. After cooling, water (3 mL) was added
and the product was extracted with EtOAc (5 × 4 mL). The com-
bined organic layers were washed with brine, dried with MgSO4,
filtered and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography (EtOAc/cyclohexane, 2:3)
to afford the N-Moc-6,7-dehydrotropinone 13b (16 mg, 41 %) as a
white solid. Rf = 0.39 (EtOAc/cyclohexane, 1:1), m.p. 68–70 °C. 1H
NMR (400 MHz, CDCl3): δ = 6.29–6.17 (br. s, 2 H, 6-H, 7-H), 4.89–4.78
(br. d, 2 H, 1-H, 5-H), 3.77 (s, 3 H, OCH3), 2.84–2.59 (m, 2 H, 2-Ha, 4-
Ha), 2.39 (d, J = 15.9 Hz, 2 H, 2-Hb, 4-Hb) ppm. Spectroscopic data
are in accordance with the literature.[37]
4) ppm. IR (film): ν = 1738, 1701, 1450 cm–1. HRMS (ESI) m/z
Methyl 3-Hydroxy-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate
(15): L-Selectride® (1 M in THF, 0.19 mL, 0.188 mmol, 1.1 equiv.) was
added dropwise to a solution of 13b in THF (1.7 mL) at –78 °C. The
solution was then stirred at room temp. for 50 min. After cooling
˜
262.0688 ([M + Na]+, calcd. for C11H13NO5Na 262.0691).
8-Methyl 2-Benzyl 3-Oxo-8-azabicyclo[3.2.1]oct-6-ene-2,8-di-
carboxylate (7c): TBAF (1
M in THF, 0.94 mL, 0.936 mmol, 1.5 equiv.)
to 0 °C, 1
M NaOH (0.58 mL) and 35 % aqueous H2O2 (0.58 mL) were
was added to a solution of silyl enol ether 12c (268 mg, 0.624 mmol,
1 equiv.) in THF (1.1 mL) at 0 °C. The solution was stirred at room
temp. for 1 h. Sat. aq. NH4Cl (2 mL) was then added and the product
was extracted with EtOAc (3 × 3 mL). The combined organic layers
were dried with MgSO4, filtered and concentrated under reduced
pressure. The crude product was purified by flash chromatography
(EtOAc/cyclohexane, 1:3 to 1:2) to afford the desired keto ester 7c
(159 mg, 81 %) as a yellow oil. Rf = 0.29 (EtOAc/cyclohexane, 1:2).
1H NMR, COSY (400 MHz, CDCl3, 323 K): δ = 7.40–7.28 (m, 5 H, Ph),
6.48 (dd, J = 6.2, 2.5 Hz, 0.5 H, 7-H, dia 1), 6.30 (dd, J = 6.1, 2.4 Hz,
0.5 H, 6-H, dia 2), 6.24 (dd, J = 6.1, 2.5 Hz, 0.5 H, 6-H, dia 1), 6.20
(dd, J = 6.1, 2.5 Hz, 0.5 H, 7-H, dia 2), 5.27–5.25 (br. s, 0.5 H, 1-H, dia
2), 5.23 (d, J = 12.3 Hz, 0.5 H, CH2Ph, dia 1), 5.17 (d, J = 12.3 Hz, 0.5
H, CH2Ph, dia 1), 5.13 (s, 1 H, CH2Ph, dia 2), 5.02–4.97 (br. s, 0.5 H,
1-H, dia 1) 4.97–4.91 (br. s, 0.5 H, 5-H, dia 2), 4.89–4.82 (br. s, 0.5 H,
5-H, dia 1), 3.78–3.74 (m, 0.5 H, 2-H, dia 1), 3.76 (s, 1.5 H, CO2CH3),
3.64 (s, 1.5 H, CO2CH3), 3.31 (s, 1 H, 0.5 H, 2-H, dia 2), 2.98 (dd, J =
16.1, 4.4 Hz, 0.5 H, 4-Ha, dia 2), 2.76–2.61 (m, 0.5 H, 4-Ha, dia 1), 2.41
(d, J = 16.2 Hz, 0.5 H, 4-Hb, dia 2), 2.39 (dd, J = 15.9, 1.6 Hz, 0.5 H,
4-Hb, dia 1) ppm. 13C NMR, HSQC, HMBC (100 MHz, CDCl3, 323 K):
δ = 200.7 (C-3, dia 2), 199.5 (C-3, dia 1), 167.8 (CO2Bn, dia 2), 167.6
(CO2Bn, dia 1), 153.2 (NCO2CH3), 153.0 (NCO2CH3), 136.4 (C-6, dia 2),
135.6 (Cq-Ar, dia 1), 135.3 (Cq-Ar, dia 2), 134.2 (C-6, dia 1), 133.5 (C-
7, dia 1), 132.7 (C-7, dia 2), 128.73 (CH-Ar), 128.68 (CH-Ar), 128.53
(CH-Ar), 128.44 (0.5 CH-Ar), 128.35 (0.5 CH-Ar), 128.30 (CH-Ar), 67.6
(CH2Ph, dia 2), 67.2 (CH2Ph, dia 1), 62.5 (C-2, dia 1), 60.4 (C-2, dia 2),
59.5 (C-1, dia 2), 58.3 (C-1, dia 1), 57.0 (C-5, dia 1), 56.6 (C-5, dia 2),
52.9 (OCH3), 52.7 (OCH3), 44.9 (C-4, dia 2), 44.3 (C-4, dia 1) ppm. IR
added. The solution was stirred at room temp. for 15 min and 1
M
HCl (0.58 mL) was added. The product was extracted with CH2Cl2
(3 × 2 mL). The combined organic layers were dried with MgSO4,
filtered and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography (EtOAc/cyclohexane, 2:1
to 4:1) to afford the alcohol 15 (24 mg, 75 %) as a pale yellow oil.
Rf = 0.19 (EtOAc/cyclohexane, 4:1). 1H NMR (400 MHz, CDCl3): δ =
6.48–6.34 (br. s, 2 H, 6-H, 7-H), 4.70–4.52 (br. d, J = 21.8 Hz, 2 H, 1-
H, 5-H), 3.94 (tt, J = 5.9, 1.0 Hz, 1 H, 3-H), 3.72 (s, 3 H, OCH3), 2.35–
2.11 (m, 2 H, 2-Ha, 4-Ha), 2.09–1.94 (br. s, 1 H, OH), 1.79 (dd, J =
15.1, 1.3 Hz, 2 H, 2-Hb, 4-Hb) ppm. Spectroscopic data are in accord-
ance with the literature.[38]
6-Hydroxytropinone
(1.20 mL, 9.89 mmol, 1 equiv.) was added to 3
The solution was stirred at room temp. for 15 h. The solution was
then neutralized using 6 aq. NaOH (≈ 8 mL) and stirred for 30 min.
(16):
2,5-Dihydro-2,5-dimethoxyfuran
N
aq. HCl (18 mL).
M
This solution was added to a solution of NaOAc·3H2O (5.65 g,
41.6 mmol, 4.2 equiv.), MeNH2·HCl (735 mg, 10.9 mmol, 1.1 equiv.)
and 3-oxoglutaric acid (1.59 g, 10.9 mmol, 1.1 equiv.) in H2O
(69 mL). The solution was stirred at room temp. for 5 d. K2CO3
(7.4 g) and NaCl (7.4 g) were added and the solution was stirred at
room temp. for 45 min. The product was extracted with CHCl3 (12 ×
50 mL). The combined organic layers were dried with MgSO4, fil-
tered and concentrated under reduced pressure. The crude product
was purified by flash chromatography (MeOH/CH2Cl2, 1:99 to 3:97
+ 10 % Et3N) to afford hydroxytropinone 15 (450 mg, 30 %) as a
brown solid. An analytical sample of 16 was purified by recrystalliza-
tion in iPrOH to obtain the spectroscopic data. Rf = 0.36 (MeOH/
CH2Cl2, 5:95 + 10 % Et3N), m.p. 120–121 °C. 1H NMR (400 MHz,
CDCl3): δ = 4.07 (d, J = 5.5 Hz, 1 H, 6-H), 3.63–3.56 (m, 1 H, 1-H or
5-H), 3.38 (d, J = 5.2 Hz, 1 H, 1-H or 5-H), 2.74–2.61 (m, 2 H, 2-Ha, 4-
Ha), 2.66 (s, 3 H, CH3), 2.24–2.13 (m, 2 H, 2-Hb or 4-Hb, OH), 2.13–
1.94 (m, 3 H, 2-Hb or 4-Hb, 7-H) ppm. Spectroscopic data are in
accordance with the literature.[39]
(film): ν = 1737, 1703, 1450 cm–1. HRMS (ESI) m/z 338.1004 ([M +
˜
Na]+, calcd. for C17H17NO5Na 338.1004).
tert-Butyl
3-Oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate
(13a): A solution of ꢀ-keto ester 7a (28 mg, 99.2 μmol, 1 equiv.),
LiCl (11 mg, 0.248 mmol, 2.5 equiv.) and H2O (2 drops) in DMSO
(0.82 mL) was heated at 130 °C for 1 h. After cooling, water (2 mL)
was added and the product was extracted with EtOAc (3 × 2 mL).
The combined organic layers were washed with brine, dried with
MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography (EtOAc/cyclo-
hexane, 1:5) to afford the N-Boc-6,7-dehydrotropinone 13a (8 mg,
34 %) as an orange solid. Rf = 0.35 (EtOAc/cyclohexane, 1:3). 1H
NMR (400 MHz, CDCl3): δ = 6.26–6.16 (m, 2 H, 6-H, 7-H), 4.88–4.69
(br. d, 2 H, 1-H, 5-H), 2.87–2.56 (m, 2 H, 2-Ha, 4-Ha), 2.36 (d, J =
8-Methyl-8-azaspiro[bicyclo[3.2.1]octane-3,2′-[1,3]dioxolan]-6-
ol (20): pTsOH·H2O (244 mg, 1.28 mmol, 1.1 equiv.) was added to
a solution of hydroxytropinone 16 (181 mg, 1.17 mmol, 1 equiv.)
and ethylene glycol (0.65 mL, 11.7 mmol, 10 equiv.) in benzene
(5.5 mL). The solution was refluxed with a Dean–Stark trap for 3 h.
After cooling, Na2CO3 (366 mg) and brine (11 mL) were added. The
product was extracted with CHCl3 (6 × 10 mL). The combined or-
Eur. J. Org. Chem. 2016, 1156–1164
1161
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim