5980 J . Org. Chem., Vol. 62, No. 17, 1997
Wu and Bai
208, 180, 164, 132, 117 (100), 91. Anal. Calcd for C12H15NO4:
C, 60.76; H, 6.33; N, 5.91. Found: C, 60.81; H, 6.41; N, 5.86.
Eth yl 3-Oxo-4-(2-Cya n oeth yl)cycloh ex-4-en e-1-ca r box-
yla te (5). To a stirred suspension of diketo ester 4 (2.45 g,
10.3 mmol) in ether (100 mL) was added CH2N2 in ether
portionwise until the solid was dissolved. Ether was distilled
off, and the residue was dissolved in methanol (100 mL).
CeCl3‚7H2O (3.90 g, 10.46 mmol) was added, and the mixture
was cooled to 0 °C with an ice-bath. To this solution was added
NaBH4 (0.85 g, 22.9 mmol) carefully in small portions, followed
by stirring at 0 °C for 30 min, and the mixture was allowed to
stand at rt for 2.5 h. Water (30 mL) was added, and the
stirring was continued for an additional 2 h. After removal
of methanol, 6 N HCl (10 mL) was added, and the mixture
was stirred for 20 min and then extracted with EtOAc (3 ×
50 mL). The organic layers were combined, washed with brine
and water, and dried. The solvent was removed, and the
residue was chromatographed on silica gel (EtOAc:petroleum
ether ) 1:8) to give 1.65 g of 5 as an oil (73%): IR (KBr) 2982,
J ) 4.1 Hz, 12.1 Hz), 2.30-2.40 (m, 3H), 2.28 (dd, 1H, J ) 7.4
Hz, 12.0 Hz), 2.18 (m, 1H), 2.08 (m,1H), 1.96 (m, 1H), 1.80
(dd, 1H, J ) 3.6 Hz, 12.3 Hz), 1.72 (s, 1H), 1.65 (m, 2H), 1.60
(d, 1H, J ) 15.4 Hz), 1.40-1.50 (m, 1H), 1.16-1.23 (m, 2H);
13C NMR (CD3OD) δ 173.0, 137.0, 105.2, 68.0, 63.2, 43.8, 43.2,
39.2, 38.0, 36.0, 24.3, 32.1, 31.0, 25.4, 24.2, 21.3; MS m/z 276
(M+), 255, 217, 203 (100), 189, 175, 134, 91. Anal. Calcd for
C16H24N2O2: C, 69.56; H, 8.69; N, 10.14. Found: C, 69.46; H,
8.73; N, 10.02.
Method B: A mixture of ketal amine 7 (0.65 g, 2.8 mmol),
3,4-dihydro-6-methylpyridone 9 (0.6 g, 5.6mmol), and 70%
aqueous perchloric acid (0.6 g) in dioxane (5 mL) was heated
under reflux for 22 h and cooled. Workup as mentioned above
gave 0.70 g (89%) of 10.
16-Hydr oxy-N-(ben zyloxycar bon yl)-2,3-dih ydr olycodin -
1-on e (11). To a stirred mixture of amine 10 (0.20 g, 0.72
mmol), saturated aqueous Na2CO3 (5 mL), and EtOAc (10 mL)
was slowly added ClCOOCH2Ph (1 mL) at 0 °C. After the
addition was complete, the reaction mixture was allowed to
warm to rt and stirred overnight. The organic layer was
separated, and the aqueous layer was extracted with EtOAc.
The organic layers were combined, washed with brine and
water, and dried. The solvent was removed in vacuo, and the
residue was chromatographed on silica gel (EtOAc) to give 0.21
g of 11 as a white solid (71%): mp 102-103.5 °C. IR (KBr)
2247, 1732, 1676 cm-1
;
1H NMR δ 6.90 (t, 1H, J ) 4.0 Hz),
4.15 (q, 2H, J ) 7.0 Hz), 3.05 (m, 1H), 2.65 (m, 4H), 2.50 (m,
4H), 1.25 (t, 3H, J ) 7.0 Hz); MS m/z 221 (M+), 179, 160, 148
(100), 121, 107.
Eth yl 4-(2-Cya n oeth yl)-3-(eth ylen ed ioxy)cycloh ex-4-
en e-1-ca r boxyla te (6). A solution of ketone 5 (2.0 g, 3.05
mmol), ethylene glycol (2 mL, 35.5 mmol), and TsOH (20 mg)
in benzene (100 mL) was heated at reflux under a Dean-Stark
trap for 8 h to remove water. The reaction mixture was cooled
and diluted with EtOAc (100 mL), washed with 5% sodium
carbonate (30 mL), and dried. The solvent was removed, and
the residue was chromatographed on silica gel (EtOAc:petro-
leum ether ) 1:8) to give 2.2 g of 6 as a colorless oil (92%): IR
(KBr) 2980, 2245, 1728, 1678, 1440 cm-1; 1H NMR δ 5.80 (m,
1H), 4.20 (q, 2H, J ) 7.0 Hz), 3.95-4.05 (m, 4H), 3.05 (m,1H),
2.70 (m, 2H), 2.52 (m, 2H), 2.30 (m, 4H), 1.00 (t, 3H, J ) 7.0
Hz); MS m/z 265 (M+) , 220, 205 (100), 208 , 148 , 121. Anal.
Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C,
63.16; H, 7.26; N, 5.25.
1
3500, 2980,1720, 1666 cm-1; H NMR δ 7.80 (s, 1H), 7.45 (m,
5H), 5.05 (m, 2H), 4.22 (d, 1H, J ) 17 Hz), 4.10 (dd, 1H, J )
7.4Hz, 11 Hz), 3.84 (dd, 1H, J ) 5.5 Hz, 10.6 Hz), 3.50 (dd,
1H, J ) 5.5 Hz, 10.6 Hz), 2.85 (d, 1H, J ) 11.2 Hz), 2.56 (m,
2H), 2.50 (m, 2H), 2.40 (dt, 1H, J ) 8.2 Hz, 12 Hz), 2.05-2.10
(m, 2H), 2.00 (m, 1H), 1.90 (t, 1H, J ) 7.5 Hz), 1.70 (t, 2H, J
) 10.4), 1.64 (m, 1H), 1.60 (1H, d, J ) 12.6 Hz), 1.62 (m, 2H),
1.50 (m, 2H), 1.30 (m, 2H); MS m/z 410 (M+), 391, 319, 203
(100), 177, 152, 91. Anal. Calcd for C24H30N2O4: C, 70.24; H,
7.32; N, 3.41. Found: C, 70.16; H, 7.38; N, 3.32.
16-(Mesyloxy)-N-(ben zyloxyca r bon yl)-2,3-d ih yd r olyco-
d in -1-on e (12). To a solution of alcohol 11 (0.25 g, 0.61 mmol)
in CH2Cl2 (5 mL) was added Et3N (0.5 mL) slowly at 0 °C,
and the reaction mixture was stirred at this temperature for
20 min. A solution of mesyl chloride (0.28 mL, 1.74 mmol) in
CH2Cl2 (1 mL) was added, and the stirring was continued for
an additional 20 min. The reaction mixture was diluted with
ether (10 mL), washed with brine and water, and dried. After
removal of the solvent in vacuo, the residue was chromato-
graphed on silica gel (EtOAc:petroleum ether ) 1:1) to give
0.26 g of 12 as white solid (87%): mp 103-104 °C. IR (KBr)
1-(3-Am in opr opyl)-4-(h ydr oxym eth yl)-6-(eth ylen ediox-
y)cycloh ex-1-en e (7). To a stirred suspension of LiAlH4 (2.28
g, 60 mmol) in ether (100 mL) was added cyano ester 6 (1.60
g, 6.0 mmol) in 20 mL of ether slowly at 0 °C. After the
addition was complete, the reaction mixture was stirred for
an additional 2 h at 0 °C and quenched by successive addition
of water (2.28 mL), 15% solution of NaOH (2.28 g), and water
(6.9 mL). The precipitate was filtered off, and the solid was
extracted with ether several times. The organic layers were
combined and dried, and the ether was evaporated. Chroma-
tography of the residue on silica gel (CHCl3:MeOH ) 6:1) gave
0.87 g of 7 as a light yellow solid (64%): mp 86-87.5 °C. IR
1
2980,1700, 1668 cm-1; H NMR δ 7.80 (s, 1H) 7.33 (m, 5H),
5.04 (s, 2H), 4.22 (d, 1H, J ) 13.5 Hz), 4.04 (m, 2H), 2.97 (s,
3H), 2.94 (dd, 1H, J ) 3.4 Hz, 12.5 Hz), 2.52 (m, 1H), 2.46 (t,
2H, J ) 8.3 Hz), 2.26 (m, 1H), 2.06 (m, 1H), 2.02 (m, 2H), 1.96
(m, 1H), 1.76 (d, 1H, J ) 13.3 Hz), 1.70 (m, 2H), 1.67 (m, 1H),
1.60 (m, 1H), 1.60 (d, 1H J ) 12.3 Hz), 1.56 (dd, 1H, J ) 5.6
Hz, 11.6 Hz), 1.52 (m, 1H), 1.35 (dt, 1H, J ) 4.0 Hz, 13.0 Hz);
13C NMR δ 172.0, 156.4, 137.2, 132.5, 128-129 (5C), 110.5,
76.3, 67.5, 63.0, 45.5, 44.3, 38.8, 37.6, 37.2, 33.2, 32.6, 31.0,
29.6, 27.8, 25.5, 21.0; MS m/z 488 (M+, 100), 409, 337, 257,
201, 149, 91. Anal. Calcd for C25H32N2O6S: C, 61.47; H, 6.56;
N, 5.74. Found: C, 61.32; H, 6.60; N, 5.71.
1
(KBr) 3350, 2940, 1570 cm-1; H NMR δ 5.45 (s, 1H), 3.60-
3.80 (m, 4H), 3.15 (s, 2H, J ) 3.1 Hz), 2.45 (t, 2H, J ) 6.3 Hz),
1.86 (d, 1H, J ) 11.3 Hz), 1.68 (m, 2H), 1.58 (d, 2H, J ) 12
Hz), 1.46 (d, 1H, J ) 11.2 Hz), 1.35 (m, 2H), 1.04 (t, 1H, J )
12Hz); MS m/z 227 (M+) , 208, 203, 154 , 112 (100), 84. Anal.
Calcd for C12H21NO3: C, 63.44; H, 9.25; N, 6.17. Found: C,
63.28; H, 9.31; N, 6.14.
16-Hydr oxy-N-d em eth yl-2,3-d ih yd r olycodin -1-on e (10).
Method A: To a stirred solution of ketal 7 (1.78 g, 7.84 mmol)
in THF (20 mL) was added a 17% aqueous solution (5 mL) of
perchloric acid, and the resulting mixture was stirred at rt
for 4 h. THF was evaporated under reduced pressure, and
the residue was neutralized with ammonia solution at 0 °C
and then extracted with CH2Cl2. The organic layers were
combined, washed with water, and dried. After removal of the
solvent, the residue was added to a mixture of 9 (1.74 g, 15.6
mmol) and 70% perchloric acid (1.7 g, 15 mmol) in dioxane
(20 mL), heated at reflux for 20 h, and cooled. The reaction
mixture was concentrated and treated with saturated Na2CO3
solution (10 mL), extracted with CH2Cl2, washed with water,
and dried. Removal of the solvent in vacuo followed by
chromatography of the residue on silica gel (CHCl3:MeOH )
10:1) gave 1.04 g of 10 as a white solid (48%): mp 138.5-140
16-(Mesyloxy)-N-(ben zyloxycar bon yl)lycodin -1-on e (13).
To a stirred solution of 12 (0.14 g, 0.3 mmol) in CH2Cl2 (6 mL)
was slowly added SO2Cl2 (0.031 mL 0.31 mmol) at 5 °C , and
the stirring was continued for 10 min. After the solvent was
distilled off, the residue was heated at 120 °C under N2 for 20
min and then cooled to 0 °C. The oil thus obtained was treated
with 5% aqueous ammonia solution, and the mixture was
extracted with CH2Cl2. The organic phase was washed with
brine and water, and dried. After removal of the solvent in
vacuo, the residue was chromatographed on silica gel (EtOAc:
petroleum ether ) 3:1) to give 0.12 g of 13 as white solid
(81%): mp 119-120 °C. IR (KBr) ν 3432, 2920, 1700, 1660,
1
1606 cm-1; H NMR δ 7.46 (m, 5H), 7.18 (d, 1H, J ) 9.5 Hz),
6.52 (d, 1H, J ) 9.5 Hz), 5.10 (d, 1H, J ) 12.3 Hz), 5.04 (d,
1H, J ) 12.4 Hz), 4.24 (d, 1H, J ) 13.5 Hz), 4.10 (dd, 1H, J )
4.6 Hz, 10.6 Hz), 4.04 (dd, 1H, J ) 4.6 Hz, 10.6 Hz), 3.02 (d,
1H, J ) 13.9 Hz), 2.96 (s, 3H), 2.46 (m, 3H), 2.10 (d, 1H, J )
12.6 Hz), 2.08 (m, 1H), 1.60-1.30 (m, 3H), 1.58 (m, 3H), 1.40
1
°C. IR (KBr) 3500, 3100,2697, 1633 cm-1; H NMR (CD3OD)
δ 3.28 (dd, 1H, J ) 5.3 Hz, 11.2 Hz), 3.22 (dd, 1H, J ) 5.3 Hz,
11.2 Hz),3.06 (d, 1H, J ) 11.8 Hz), 3.04 (m, 1H), 2.78 (dt, 1H,