Synthesis of Antitumor Nuphar Alkaloids
of TFA was added via syringe the mixture was warmed to room
temperature. After the reaction mixture was stirred for 2 h the
solvent was concentrated, EtOAc/hexane (1:1, 2 mL) was added,
and the solution was passed through a short silica gel pad, eluting
with 30% EtOAc/hexane to remove the p-toluenesulfinyl products.
Elution with methanol gave the crude ammonium triflate salt, which
was concentrated and placed in a 25-mL, one-necked, round-
bottomed flask equipped with a magnetic stirring bar and argon
balloon. Dichloromethane (5 mL) was added followed by 0.007 g
(0.065 mmol) of benzaldehyde via syringe, then 0.2 g of anhydrous
MgSO4 was added. The reaction mixture was stirred at room
temperature for 3 h, concentrated, and washed with saturated
NaHCO3 (5 mL). The solution was extracted with EtOAc (3 × 5
mL), dried (Na2SO4), and concentrated to give 0.018 g (76%) of
brown oil of the crude imine 11: 1H NMR (CDCl3) δ 8.39 (s, 1H),
7.80 (s, 1H), 7.52 (m, 4H), 7.38 (m, 2H), 6.38 (s, 1H), 4.80 (m,
1H), 3.14 (m, 1H), 2.80 (dd, J ) 7.2, 6.0 Hz, 1H), 2.42 (q, J ) 7.2
Hz, 2H), 1.02 (t, J ) 7.2 Hz, 3H). In a 25-mL one-necked, round-
bottomed flask equipped with a magnetic stirring bar and argon
balloon was placed 0.017 g (0.065 mmol) of the crude imine 11 in
anhydrous benzene (5 mL). To the solution was added 0.09 g (0.39
mmol) of p-toluenesulfonic acid monohydrate and the reaction
mixture was heated in an oil bath at 60 °C for 3 h. At this time the
solvent was concentrated, and the residue was washed with saturated
NaHCO3 (2 × 5 mL) and extracted with EtOAc (3 × 5 mL). The
combined organic phases were dried (Na2SO4) and concentrated.
Column chromatography (20% EtOAc/hexane, 1% Et3N) afforded
0.012 g (67%) of a colorless oil: [R]23D -87.3 (c 0.1, CHCl3); IR
-76.5 (c 0.1, CHCl3); IR (neat) 3127, 3054, 2921, 1610 cm-1; 1H
NMR (CDCl3) δ 7.20 (s, 1H), 7.14 (s, 1H), 6.78 (dd, J ) 8.4, 6.6
Hz, 1H), 6.28 (s, 1H), 5.80 (d, J ) 10.4 Hz, 1H), 4.13 (q, J ) 7.8
Hz, 2H), 3.78 (td, J ) 7.4, 2.3 Hz, 1H), 3.12 (td, J ) 7.4, 2.3 Hz,
1H), 2.38 (d, J ) 7.8 Hz, 2H), 2.18 (m, 1H), 1.44 (br s, 1H), 1.09
(t, J ) 7.6 Hz, 3H), 0.80 (d, J ) 7.2 Hz, 3H); 13C NMR (CDCl3)
209.1, 166.3, 147.6, 145.3, 142.5, 140.4, 124.5, 109.7, 64.6, 61.0,
52.2, 50.3, 31.2, 14.5, 10.5; HRMS calcd for C15H19NO4 (M + H)
277.1314, found 277.1314.
(2S,3S,6S)-(-)-1-Aza-2-((E)-ethyl-4-oxo-butenoxy)-3-methyl-
6-(3-furyl)-1′,3′-dithiospiro[5,4]decane (15). In a 25-mL, single-
necked, round-bottom flask equipped with a magnetic stirring bar,
rubber septum, and argon balloon was placed 0.02 g (0.72 mmol)
of (-)-14b in CH2Cl2 (10 mL) and the solution was cooled to 0
°C. To the solution was added 0.037 mL (4 mmol) of ethanedithiol
and 0.056 mL (4 mmol) of boron trifluoride via syringe. The
reaction was warmed to room temperature, stirred for 2 h, and
quenched by addition of 2 N NaOH (10 mL). The solution was
extracted with CH2Cl2 (2 × 5 mL), and the combined organic phases
were dried (Na2SO4) and concentrated. Chromatography gave 0.024
g (93%) of a yellow oil: [R]23 -76.5 (c 0.1, CHCl3); IR (neat)
D
2921, 2729, 1345 cm-1; 1H NMR (CDCl3) δ 7.36 (d, J ) 7.4 Hz,
1H), 7.21 (s, 1H), 6.82 (dd, J ) 8.4, 6.6 Hz, 1H), 6.40 (s, 1H),
5.86 (d, J ) 10.2 Hz, 1H), 4.18 (q, J ) 7.8 Hz, 2H), 3.98 (dd, J )
6.6, 2.1 Hz, 1H), 3.23 (m, 6H), 2.38 (d, J ) 8.4, 2.2 Hz, 1H), 2.21
(m, 1H), 1.58 (br s, 1H), 1.21 (t, J ) 7.6 Hz, 3H), 1.08 (d, J ) 7.2
Hz, 3H); 13C NMR (CDCl3) 167.5, 146.7, 142.3, 139.3, 124.8,
122.7, 109.5, 68.4, 63.5, 60.9, 51.6, 43.7, 40.2, 39.7, 30.5, 12.4,
12.2; HRMS calcd for C17H23NO3S2 (M + H) 353.1119, found
353.1121.
1
(neat) 2324, 1690, 1098 cm-1; H NMR (CDCl3) δ 7.29 (m, 7H),
6.39 (s, 1H), 4.03 (dd, J ) 7.0, 5.2 Hz, 1H), 3.52 (d, J ) 7.2 Hz,
1H), 2.55 (m, 2H), 2.60 (m, 1H), 1.70 (br s, 1H), 0.98 (d, J ) 7.2
Hz, 3H); 13C NMR (CDCl3) δ 210.3, 144.9, 142.7, 139.8, 129.4,
128.3, 128.1, 127.4, 109.0, 69.3, 52.5, 51.8, 50.0, 11.1; HRMS calcd
for C16H17NO2Li (M + Li) 262.1420, found 262.1425.
(2S,3R,6S)-(-)-2-(2-Ethoxycarbonylethyl)-6-(3-furyl)-3-meth-
ylpiperidine (16). In a 25-mL, single-necked, round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and argon
balloon was placed 0.3 g of Raney 2800 Nickel (Aldrich). The
Raney nickel was washed with absolute EtOH (2 × 10 mL) and
0.05 g (0.14 mmol) of (-)-15 in absolute EtOH (10 mL) was added.
The reaction mixture was refluxed for 2 h and cooled to room
temperature, then the catalyst was removed by filtration. The filtrate
was washed with EtOH and the combined washings were concen-
trated and purified by preparative TLC (CH2Cl2/EtOAc, 1:1) to
afford 0.029 g (78%) of a colorless oil: [R]23D -38.7 (c 1.6, CH2-
(2S,3S,6S)-(-)-2-((E)-Ethyl-4-oxo-butenoxy)-3-methyl-6-(3-fu-
ryl)-4-piperidone (14b). In a 25-mL, single-necked, round-bottom
flask equipped with a magnetic stirring bar, rubber septum, and
argon balloon was placed 0.05 g (0.163 mmol) of (-)-9 in
anhydrous methanol (10 mL). The solution was cooled to 0 °C,
and 0.07 mL of TFA (0.978 mmol) was added via syringe. After
the reaction mixture was stirred for 2 h the solvent was concentrated,
EtOAc/hexane (1:1, 2 mL) was added, and the solution was passed
through a short silica gel pad eluting with 30% EtOAc/hexane to
remove the p-toluenesulfinyl products. Elution with methanol gave
the crude ammonium triflate salt, which was concentrated and
placed in a 25-mL one-necked, round-bottomed flask equipped with
a magnetic stirring bar and argon balloon. Dichloromethane (5 mL)
was added at room temperature followed by addition via syringe
of 0.02 g (0.163 mmol) of (E)-ethyl-4-oxo-2-butenoate followed
by 0.2 g of anhydrous MgSO4. The reaction mixture was stirred at
room temperature for 2 h, concentrated, and washed with saturated
NaHCO3 (5 mL). The solution was extracted with EtOAc (3 × 5
mL), dried (Na2SO4), and concentrated to give 0.031 g (86%) of
Cl2) [lit.18b [R]23 -39.3 (c 1.8, CH2Cl2)]; IR (neat) 2921, 2729,
D
1345 cm-1; 1H NMR (CDCl3) δ 7.35 (d, J ) 7.2 Hz, 1H), 7.20 (s,
1H), 6.39 (s, 1H), 4.13 (q, J ) 7.4 Hz, 2H), 3.58 (dd, J ) 11.2, 2.2
Hz, 1H), 2.43 (dd, J ) 8.8, 6.7 Hz, 1H), 2.42 (t, J ) 7.7 Hz, 1H),
2.26 (td, J ) 8.4, 3.0 Hz, 1H), 1.97 (m, 1H), 1.77 (m, 2H), 1.62
(m, 4H), 1.44 (br s, 1H), 1.25 (t, J ) 7.3 Hz, 3H), 0.90 (d, J ) 6.0
Hz, 3H). Spectral properties were identical with those of (-)-16
previously reported.18b
(2S,3S,6S)-(-)-6-(3-Furyl)-3-methyl-2-[(E)-1-propenyl]-4-pi-
peridone (14a). In a 25-mL, single-necked, round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and argon
balloon was placed 0.04 g (0.137 mmol) of (-)-9 in anhydrous
methanol (10 mL). The solution was cooled to 0 °C, and TFA (0.06
mL, 0.824 mmol) was added via syringe. After the reaction mixture
was stirred for 2 h the solvent was concentrated, EtOAc/hexane
(1:1, 2 mL) was added, and the solution was passed through a short
silica gel pad eluting with 30% EtOAc/hexane to remove the
p-toluenesulfinyl products. Elution with methanol gave the crude
ammonium triflate salt, which was concentrated and placed in a
25-mL, one-necked, round-bottomed flask equipped with a magnetic
stirring bar and argon balloon. Dichloromethane (5 mL) was added
at room temperature followed by addition via syringe of 0.013 g
(0.136 mmol) of 4-methyl-3-penten-1-al and 0.2 g of anhydrous
MgSO4. The reaction mixture was stirred at room temperature for
1.5 h, concentrated, and washed with saturated NaHCO3 (5 mL).
The solution was extracted with EtOAc (3 × 5 mL), dried (Na2-
1
brown oil of crude 13b; H NMR (CDCl3) δ 8.25 (d, J ) 7.8 Hz,
1H), 7.40 (t, J ) 2.8 Hz, 1H), 7.31 (s, 1H), 6.36 (m, 1H), 6.29 (s,
1H), 4.84 (dd, J ) 7.2, 6.0 Hz, 1H), 4.22 (q, J ) 7.4 Hz, 2H), 3.39
(m, 1H), 3.15 (dd, J ) 8.2, 6.4 Hz, 1H), 2.90 (dd, J ) 8.2, 4.6 Hz,
1H), 2.38 (dq, J ) 7.6, 4.2 Hz, 2H), 1.30 (t, J ) 7.8 Hz, 3H), 1.01
(t, J ) 7.6 Hz, 3H).
In a 25-mL, one-necked, round-bottomed flask equipped with a
magnetic stirring bar and argon balloon was placed 0.031 g (0.011
mmol) of the crude imine 13b in anhydrous benzene (5 mL)
followed by the addition of 0.015 g (0.066 mmol) of p-toluene-
sulfonic acid monohydrate. After heating the mixture at 60 °C in
an oil bath for 4 h, the solvent was concentrated and the residue
was washed with saturated NaHCO3 (2 × 5 mL) and extracted with
EtOAc (3 × 5 mL). The combined organic phases were dried (Na2-
SO4) and concentrated. Column chromatography (20% EtOAc/
1
SO4), and concentrated to give 0.026 g (90%) of a brown oil; H
hexane, 1% Et3N) afforded 0.023 g (74%) of a colorless oil: [R]23
NMR (CDCl3) δ 7.88 (d, J ) 7.8 Hz, 1H), 7.32 (s, 1H), 7.25 (d,
D
J. Org. Chem, Vol. 71, No. 11, 2006 4225