The Journal of Organic Chemistry
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Compound 14. To a solution of NH3 at −78 °C were slowly
added Na (345 mg, 15 mmol, 10 equiv) and compound 24 (580 mg,
1.5 mmol, 1 equiv) in THF (15 mL). The reaction mixture was stirred
at −78 °C for 0.5 h. The reaction was quenched with the addition of
MeOH. After NH3 was evaporated at room temperature, the crude
product was purified by flash silica gel chromatography (DCM/MeOH
HRMS (EI) calcd for C21H26N2O2 [M]+ 338.1994, found 338.2000;
[α]D = −14.8° (c = 0.8 M, CHCl3).
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Compound 27. A 25 mL flask was charged with compound 26 (54
mg), pyridine (3 mL), and acetic anhydride (3 mL). The mixture was
stirred at room temperature for 3 h and concentrated. The residue was
dissolved in 15 mL of DCM, washed with saturated NH4OH/brine
(1/1), dried over Na2SO4, and concentrated. The crude product was
purified by flash silica gel chromatography (DCM/MeOH 40/1) to
give pure compound 27 (57 mg, 95% yield) as a white solid: 1H NMR
(CDCl3, 300 MHz) δ 1.12 (m, 1H), 1.19−1.31 (m, 1H), 1.32−1.46
(m, 2H), 1.56−1.65 (m, 3H), 1.68−1.74 (m, 1H), 1.82−2.07 (m, 3H),
2.19 (s, 3H), 2.21−2.30 (m, 1H), 2.52 (m, 1H), 2.56−2.69 (m, 1H),
3.64 (s, 1H), 3.88 (s, 3H), 4.16 (m, 1H), 4.85 (d, J = 16.8 Hz, 1H),
5.00 (d, J = 9.9 Hz, 1H), 5.60 (m, 1H), 6.86 (t, J = 7.8 Hz, 2H), 7.12
(t, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 18.9, 22.9, 23.1,
34.6, 34.9, 40.6, 41.7, 45.3, 48.2, 55.5, 63.7, 67.9, 112.3, 114.9, 118.6,
126.6, 129.4, 132.5, 139.5, 149.7, 170.7, 171.9; HRMS (EI) calcd for
1
20/1) to give compound 14 (400 mg, 90% yield): H NMR (CDCl3,
300 MHz) δ 1.38 (m, 1H), 1.45−1.60 (m, 3H), 1.76 (m, 1H), 1.82−
1.98 (m, 2H), 2.18 (m, 1H), 2.32 (m, 1H), 2.63−2.79 (m, 3H), 2.98
(m, 1H), 3.70 (s, 1H), 3.90 (s, 3H), 4.88−5.07 (m, 2H), 5.85 (m, 1H),
6.57 (d, J = 7.5 Hz, 1H), 6.97 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 7.8 Hz,
1H), 8.23 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 19.9, 22.8, 25.1,
34.7, 35.0, 41.9, 46.1, 55.3, 56.4, 101.6, 110.8, 112.6, 117.3, 119.7,
126.3, 128.8, 133.6, 134.9, 145.7; HRMS (EI) calcd for C19H24N2O
[M]+ 296.1889, found 296.1886; [α]D20 = +20.3° (c = 0.7 M, CHCl3).
Compound 25. To a solution of compound 14 (200 mg, 0.67
mmol, 1 equiv) in DCM (15 mL) was added Et3N (108 mg, 1.0 mmol,
1.5 equiv). To the resulting solution was added 2-chloroacetyl chloride
(76 mg, 0.67 mmol, 1 equiv) at 0 °C. The reaction mixture was stirred
at room temperature for 2 h. The mixture was quenched with addition
of H2O (10 mL) and extracted with DCM. The solvent was removed
by evaporation to dryness. The crude product was purified by flash
silica gel chromatography (ethyl acetate/petroleum ether 1/3) to give
compound 25 (190 mg, 75% yield) as a yellow oil: 1H NMR (CDCl3,
300 MHz) δ 1.28−1.47 (m, 2H), 1.54−1.99 (m, 4.4H), 2.04−2.27 (m,
1H), 2.31−2.50 (m, 1H), 2.56−2.80 (m, 2.3H), 2.90 (m, 0.7H), 3.61
(m, 0.6H), 3.92 (s, 3H), 4.29 (dd, J = 11.7 Hz, J = 12 Hz, 1.3H), 4.40
(m, 0.6H), 4.54 (m, 0.3H), 4.76 (s, 0.3H), 5.13 (m, 2H), 5.74 (s,
0.6H), 5.85 (m, 1H), 6.60 (t, J = 6.3 Hz, J = 6.3 Hz, 1H), 6.79−7.00
(m, 2H), 8.31 (s, 0.6H), 8.48 (s, 0.3H); 13C NMR (CDCl3, 75 MHz)
δ 19.5, 20.2, 21.6, 24.6, 25.4, 32.1, 36.7, 37.2, 37.7, 40.4, 40.7, 41.7,
41.9, 42.2, 53.1, 55.3, 59.0, 101.8, 101.9, 107.4, 108.1, 111.1, 111.4,
118.3, 118.7, 120.1, 120.7, 126.4, 127.1, 127.4, 133.5, 134.0, 134.4,
134.5, 145.6, 145.7, 166.1; HRMS (EI) calcd for C21H25ClN2O2 [M]+
20
C23H28N2O3 [M]+ 380.2100, found 380.2098; [α]D = +33.9° (c =
0.85 M, CHCl3).
Compound 28. To a solution of compound 27 (40 mg, 0.1 mmol,
1 equiv) in THF/H2O (8 mL, 1/1) were added K2OsO4·2H2O (1.94
mg, 0.005 mmol, 0.05 equiv) and NMO (58.6 mg, 0.5 mmol, 5 equiv).
The reaction mixture was stirred at room temperature for 4 h. Then
NaIO4 (107 mg, 0.5 mmol, 5 equiv) was added, and the resulting
mixture was stirred for 2 h. Saturated aqueous Na2S2O3 (8 mL) was
added, and the resulting solution was stirred for 0.5 h. The reaction
mixture was extracted with DCM. The organic phase was dried over
Na2SO4 and concentrated. The residue was purified by flash silica gel
chromatography (DCM/MeOH 40/1) to give pure compound 28 (34
1
mg, 85% yield) as a white solid: H NMR (CDCl3, 300 MHz) δ 1.27
(m, 1H), 1.43 (m, 1H), 1.56−1.87 (m, 5H), 1.93 (m, 1H), 2.00−2.094
(m, 2H), 2.16−2.22 (m, 4H), 2.22−2.28 (m, 1H), 2.52 (m, 1H),
2.59−2.72 (m, 1H), 3.88 (s, 3H), 3.90 (s, 1H), 4.17 (m, 1H), 6.81 (d,
J = 7.5 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 9.66
(t, J = 2.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 18.8, 23.0, 24.3,
34.7, 35.1, 40.5, 45.0, 48.1, 49.9, 55.5, 62.3, 67.5, 112.5, 114.6, 126.7,
129.4, 138.8, 149.8, 170.9, 171.9, 200.9; HRMS (EI) calcd for
C22H26N2O4 [M]+ 382.1893, found 382.1890; [α]D20 = +24° (c = 0.88
M, CHCl3).
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372.1605, found 372.1604; [α]D = −88.9° (c = 0.82 M, CHCl3).
Compound 15. To a solution of compound 25 (155 mg, 0.42
mmol, 1 equiv) in acetone (10 mL) was added NaI (623 mg, 4.2
mmol, 10 equiv). The reaction mixture was stirred under reflux for 2 h.
EtOAc (10 mL) was added, and the resulting solution was washed
with H2O. The solvent was removed by evaporation to dryness. The
crude product was dissolved in THF (10 mL), and AgOTf (213 mg,
0.83 mmol, 2 equiv) was added. The resulting mixture was stirred at
room temperature for 0.5 h. EtOAc (10 mL) was added. The solution
was washed with saturated aqueous NaHCO3 and purified by flash
silica gel chromatography (DCM/MeOH 40/1) to give pure
(+)-10-Oxocylindrocarpidine 7. To a solution of compound 28
(34 mg, 0.09 mmol, 1 equiv) in MeOH (5 mL) at 0 °C was added a
solution of KOH (12.6 mg, 0.23 mmol, 2.6 equiv) in MeOH (3 mL),
followed by a solution of I2 (30 mg, 0.12 mmol, 1.3 equiv) in MeOH
(3 mL). The reaction mixture was stirred for 2 h and then quenched
with saturated aqueous Na2S2O3 (3 mL). The resulting mixture was
extracted with DCM (3 × 6 mL), dried over Na2SO4, and
concentrated. The residue was purified by flash silica gel
chromatography (DCM/MeOH 40/1) to give (+)-10-oxocylindro-
1
compound 15 (77 mg, 55% yield): H NMR (CDCl3, 300 MHz) δ
1.37−1.62 (m, 5H), 1.65−1.82 (m, 2H), 2.16 (m, 1H), 2.48 (m, 1H),
2.65−2.79 (m, 2H), 2.84−2.09 (m, 2H), 3.61 (m, 1H), 3.93 (s, 3H),
4.28 (m, 1H), 4.80 (m, 1H), 4.94 (m, 1H), 5.55 (m, 1H), 6.88 (m,
2H), 7.15 (t, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 20.2,
24.1, 24.2, 34.3, 37.2, 38.7, 40.7, 41.1, 54.3, 55.9, 69.2, 111.2, 113.1,
1
carpidine 7 (23.8 mg, 65% yield) as a canary yellow oil: H NMR
(CDCl3, 400 MHz) δ 1.28−1.33 (m, 1H), 1.41−1.49 (m, 1H), 1.50−
1.61 (m, 2H), 1.67−1.74 (m, 2H), 1.86−1.95 (m, 1H), 1.98−2.12 (m,
3H), 2.20 (s, 3H), 2.22−2.29 (m, 1H), 2.54 (d, J = 16.8 Hz, 1H), 2.65
(m, 1H), 3.61 (s, 3H), 3.89 (s, 3H), 4.04 (s, 1H), 4.15−4.21 (m, 1H),
4.47 (br s, 1H), 6.85−6.94 (m, 2H), 7.13 (t, J = 7.9 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 18.8, 23.1, 24.5, 34.3, 34.6, 40.5, 41.6,
45.1, 48.2, 51.4, 55.5, 61.9, 67.6, 112.4, 114.9, 126.6, 129.5, 139.0,
149.8, 171.5, 172.0; HRMS (EI) calcd for C23H28N2O5 [M]+
119.1, 127.6, 132.0, 142.3, 147.3, 151.2, 170.3, 185.0; HRMS (EI)
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calcd for C21H24N2O2 [M]+ 336.1838, found 336.1844; [α]D
=
−36.8° (c = 0.62 M, CHCl3).
Compound 26. To a stirred solution of compound 15 (60 mg,
0.18 mmol, 1 equiv) in MeOH (8 mL) was added NaBH4 (33.7 mg,
0.9 mmol, 5 equiv) at −78 °C. After 5 min, the resulting mixture was
warmed to 0 °C. After the mixture was stirred for 100 min, NaBH4
(6.7 mg, 0.18 mmol, 1 equiv) was added. After the mixture was stirred
for 1 h, the reaction was quenched with saturated aqueous NaHCO3
and the resulting mixture was extracted with DCM. The organic phase
was dried over Na2SO4 and purified by flash silica gel chromatography
(DCM/MeOH 50/1) to give pure compound 26 (54 mg, 88% yield):
1H NMR (CDCl3, 300 MHz) δ 1.07 (m, 1H), 1.22−1.49 (m, 3H),
1.52−1.72 (m, 6H), 2.02−2.19 (m, 2H), 2.59 (m, 1H), 2.78 (m, 1H),
3.43 (m, 1H), 3.64 (s, 1H), 3.82 (s, 3H), 4.16 (m, 1H), 4.87 (m, 1H),
4.99 (m, 1H), 5.63 (m, 1H), 6.63−6.83 (m, 3H); 13C NMR (CDCl3,
75 MHz) δ 19.0, 23.0, 26.0, 34.7, 35.0, 40.5, 41.5, 45.3, 49.3, 55.3, 63.7,
64.6, 110.0, 114.8, 118.4, 120.0, 132.0, 132.9, 138.4, 146.0, 173.1;
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412.1998, found 412.1994; [α]D = +21.4° (c = 0.8 M, CHCl3).
Compound 29. To a solution of compound 15 (500 mg, 1.49
mmol, 1 equiv) in Et2O (20 mL) was added LiAlH4 (226 mg, 5.95
mmol, 4 equiv). The reaction mixture was stirred at room temperature
for 0.5 h, at reflux for 4 h, and at room temperature for 16 h. H2O (60
μL), KOH (60 μL, 15% aqueous), and H2O (180 μL) were added in
sequence. The resulting slurry was filtered and rinsed with Et2O. The
solvent was removed by evaporation to dryness and then purified by
flash silica gel chromatography (DCM/MeOH 40/1) to give pure
1
compound 29 (265 mg, 55% yield): H NMR (CDCl3, 300 MHz) δ
1.02 (d, J = 13.5 Hz, 1H), 1.21 (m, 1H), 1.35−1.54 (m, 4H), 1.54−
1.84 (m, 4H), 1.90−2.04 (m, 2H), 2.15−2.40 (m, 4H), 3.08 (m, 2H),
3.58 (m, 1H), 3.82 (s, 3H), 4.81 (m, 1H), 4.92 (m, 1H), 5.66 (m, 1H),
2478
dx.doi.org/10.1021/jo402741g | J. Org. Chem. 2014, 79, 2473−2480