Doi et al.
1H, J ) 16.4 Hz), 2.70 (d, 1H, J ) 16.4 Hz), 2.46-2.63 (m, 5H),
2.26 (d, 1H, J ) 16.9 Hz), 1.90-1.95 (m, 1H), 1.78-1.82 (m,
1H); 13C NMR (67.8 MHz, CDCl3) δ 159.0, 150.7, 137.0, 136.2,
135.3, 134.5, 134.4, 131.4, 131.3, 130.7, 129.1, 128.7, 128.6, 118.2,
113.8, 110.7, 93.0, 79.7, 69.9, 55.3, 51.9, 51.8, 45.3, 44.2, 38.5,
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by chromatography on silica gel (30%
ethyl acetate in hexane) to give 3-(4-methoxybenzyloxy)-6-
(hydroxymethyl)spiro[4.4]nonan-2-one (13) (1.67 g, 5.50 mmol,
92%, diastereomer mixture). Major isomer: 1H NMR (400 MHz,
CDCl3) δ 7.30-7.27 (m, 2H), 6.88 (d, J ) 8.7 Hz, 2H), 4.78 (d,
J ) 11.1 Hz, 2H), 4.61 (d, J ) 11.6 Hz, 2H), 3.91 (dd, J ) 9.2,
8.7 Hz, 1H), 3.80 (s, 3H), 3.68 (dd, J ) 10.6, 6.8 Hz, 1H), 3.59
(dd, J ) 10.6, 6.3 Hz, 1H), 2.43 (d, J ) 17.8 Hz, 1H), 2.18-1.87
(m, 5H), 1.69-1.57 (m, 4H), 1.37-1.32 (m, 1H); 13C NMR (67.8
MHz, CDCl3) δ 216.2, 159.4, 129.7, 129.6, 113.8, 78.9, 72.0, 63.7,
55.3, 49.5, 44.1, 43.5, 41.5, 40.5, 27.7, 22.0; IR (neat) 3463, 2951,
1744, 1612, 1586, 1513, 1466, 1399, 1302, 1248, 1174, 1034, 822,
754, 518 cm-1; HRMS (ESI-TOF) calcd for [C18H24O4 + Na]+
327.1567, found 327.1564.
3-(4-Methoxybenzyloxy)-6-methylenespiro[4.4]nonan-2-one (14).
To a solution of 3-(4-methoxybenzyloxy)-6-(hydroxymethyl)spiro-
[4.4]nonan-2-one (13) (175 mg, 0.569 mmol), trimethylamine
hydrochloride (5 mg, 0.0569 mmol), and triethylamine (0.16 mL,
1.14 mmol) in dichloromethane (3 mL) was added p-toluenesulfonyl
chloride (163 mg, 0.853 mmol) at 0 °C. After being stirred at the
same temperature for 30 min, the reaction mixture was quenched
with 1 M HCl. The aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
chromatography on silica gel (15% ethyl acetate in hexane) to give
3-(4-methoxybenzyloxy)-6-(p-toluenesulfonyloxymethyl)spiro[4.4]-
nonan-2-one (247 mg, 0.539 mmol, 95%, diastereomer mixture).
Major isomer: 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J ) 7.7
Hz, 2H), 7.36-7.26 (m, 4H), 6.87 (d, J ) 8.7 Hz, 2H), 4.75 (d,
J ) 11.6 Hz, 1H), 4.58 (d, J ) 11.6 Hz, 1H), 4.01-3.80 (m, 6H),
2.44 (s, 3H), 2.23-1.24 (m, 11H); 13C NMR (100 MHz, CDCl3) δ
215.0, 159.4, 145.0, 132.7, 130.0, 129.6, 127.9, 113.9, 78.6, 72.0,
70.7, 55.3, 46.1, 44.0, 43.3, 41.3, 39.7, 27.6, 21.8, 21.6; IR (neat)
2957, 1749, 1613, 1598, 1515, 1464, 1361, 1249, 1176, 1097, 955,
817, 667, 555 cm-1; HRMS (ESI-TOF) calcd for [C25H30O6S +
Na]+ 481.1655, found 481.1656.
37.1; IR (neat) 1613, 1514, 1448, 1328, 1310, 1144, 1078 cm-1
;
HRMS (ESI-TOF) calcd for [C32H34O6S2 + Na]+ 601.1694, found
601.1689.
3-Methylene-8,8-di(phenylsulfonyl)-6-vinylspiro[4.4]nonan-2-
one (12). To a solution of 7-(4-methoxybenzyloxy)-8-methylene-
3,3-di(phenylsulfonyl)-1-vinylspiro[4.4]nonane (10) (685 mg, 1.18
mmol) in dichloromethane (3.8 mL) and water (0.2 mL) was added
DDQ (537 mg, 2.37 mmol) at 0 °C. After being stirred at room
temperature, the reaction mixture was diluted with diethyl ether
and quenched with saturated aqueous NaHSO3 solution and
saturated aqueous NaHCO3 solution. The aqueous layer was
extracted with diethyl ether. The combined organic layers were
washed with saturated aqueous NaHCO3 solution and brine, dried
over MgSO4, and concentrated in vacuo. The crude 3-methylene-
8,8-di(phenylsulfonyl)-6-vinylspiro[4.4]nonan-2-ol (399 mg, 0.869
mmol) was used in the next reaction without further purification.
To a solution of 2-hydroxy-3-methylene-8,8-di(phenylsulfonyl)-
6-vinylspiro[4.4]nonane (399 mg, 0.869 mmol) and NMO (204 mg,
1.74 mmol) in dichloromethane (5 mL) was added TPAP (15 mg,
0.0435 mmol). After being stirred at room temperature, the reaction
mixture was directly subjected to silica gel chromatography (25%
ethyl acetate in hexane) to give 3-methylene-8,8-di(phenylsulfonyl)-
6-vinylspiro[4.4]nonan-2-one (12) (196 mg, 0.429 mmol, 36%, two
steps): 1H NMR (400 MHz, CDCl3) δ 8.02-8.09 (m, 4H), 7.73-
7.76 (m, 2H), 7.60-7.65 (m, 4H), 5.99 (s, 1H), 5.53-5.62 (m,
1H), 5.34 (s, 1H), 5.02-5.12 (m, 2H), 2.53-2.82 (m, 7H), 2.39
(s, 2H); 13C NMR (100 MHz, CDCl3) δ 203.9 (C), 144.3 (C,), 136.7
(C, Ph), 135.9 (C, Ph), 135.0 (CH, Ph), 134.9 (CH, Ph), 134.2 (CH),
131.6 (CH, Ph), 131.4 (CH, Ph), 129.0 (CH, Ph), 128.9 (CH, Ph),
119.8 (CH2), 118.2 (CH2), 92.4 (C), 52.0 (CH), 49.8 (CH2), 48.1
(C), 43.0 (CH2), 37.3 (CH2), 37.0 (CH2); IR (solid) 1727, 1638,
1447, 1309, 1143, 1075, 920, 731, 689, 552, 511, 483, 466 cm-1
.
3-(4-Methoxybenzyloxy)-6-(hydroxymethyl)spiro[4.4]nonan-
2-one (13). Into dry methanol (100 mL) was added activated
magnesium turnings (washed with 0.1 M HCl, water, methanol,
and diethyl ether and heated at 100 °C) (1.25 g, 51.6 mmol). The
mixture was stirred at 50 °C. When gas evolution started, a solution
of 7-(4-methoxybenzyloxy)-8-methylene-3,3-di(phenylsulfonyl)-1-
vinylspiro[4.4]nonane (10) (1.20 g, 2.06 mmol) in THF (5 mL)
was added at the same temperature. After being stirred for 3 h, the
reaction mixture was quenched with 3 M HCl at 0 °C. The aqueous
layer was extracted with diethyl ether. The combined organic layers
were washed with saturated aqueous NaHCO3 solution and brine,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by chromatography on silica gel (5% ethyl acetate in
hexane) to give 2-(4-methoxybenzyloxy)-3-methylene-6-vinylspiro-
[4.4]nonane (489 mg, 1.63 mmol, 79%, diastereomer mixture).
Ozone was bubbled into a solution of 2-(4-methoxybenzyloxy)-
3-methylene-6-vinylspiro[4.4]nonane (230 mg, 0.770 mmol) in
dichloromethane (2 mL) and methanol (2 mL) at -78 °C. The
solution was purged by bubbling nitrogen to remove excess ozone,
and the ozonide was reduced by addition of dimethyl sulfide (225
µL, 3.08 mmol) at the same temperature. The reaction mixture was
allowed to gradually warm to room temperature and diluted with
diethyl ether. The organic layer was washed with 1 M HCl and
brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by chromatography on silica gel (20% ethyl acetate
in hexane) to give 3-(4-methoxybenzyloxy)-6-formylspiro[4.4]-
nonan-2-one (177 mg, 0.586 mmol, 76%, diastereomer mixture).
To a solution of 3-(4-methoxybenzyloxy)-6-formylspiro[4.4]-
nonan-2-one (1.80 g, 5.95 mmol) in THF (25 mL) was added LiAl-
(Ot-Bu)3H (0.5 M in diglyme, 13.1 mL, 6.55 mmol) at -78 °C.
The reaction mixture was quenched with a 10% aqueous solution
of potassium sodium tartrate at -78 °C. The aqueous layer was
To a solution of diphenyl diselenide (27 mg, 0.0876 mmol) in
THF (1 mL) and methanol (1 mL) was added sodium borohydride
(6.6 mg, 0.175 mmol) at 0 °C. The reaction mixture was allowed
to warm to room temperature and stirred for 30 min. A solution of
3-(4-methoxybenzyloxy)-6-(p-toluenesulfonyloxymethyl)spiro[4.4]-
nonan-2-one (57.4 mg, 0.125 mmol) in THF (1 mL) was added
and stirred at reflux. The reaction mixture was diluted with ethyl
acetate and washed with water and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by chromatography
on silica gel (20% ethyl acetate in hexane) to give 3-(4-methoxy-
benzyloxy)-6-(phenylselenylmethyl)spiro[4.4]nonan-2-one (47 mg,
0.106 mmol, 85%, diastereomer mixture).
To a solution of 3-(4-methoxybenzyloxy)-6-(phenylselenylmethyl)-
spiro[4.4]nonan-2-one (390 mg, 0.879 mmol) in THF (5 mL) was
added hydrogen peroxide (107 µL, 1.06 mmol) at 0 °C. The reaction
mixture was allowed to warm to room temperature and stirred for
1 h. The reaction mixture was concentrated in vacuo. The residue
was purified by chromatography on silica gel (20% ethyl acetate
in hexane) to give 3-(4-methoxybenzyloxy)-6-methylenespiro[4.4]-
nonan-2-one (14) (190 mg, 0.663 mmol, 75%, diastereomer
1
mixture): H NMR (270 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 6.91-
6.84 (m, 2H), 4.99-4.77 (m, 3H), 4.66-4.55 (m, 1H), 4.08-3.94
(m, 1H), 3.80 (s, 3H), 2.49-2.18 (m, 4H), 2.04-1.56 (m, 6H); IR
(neat) 3070, 2956, 1748, 1651, 1613, 1586, 1515, 1465, 1398, 1302,
1248, 1174, 1112, 1036, 881, 821 cm-1
.
3-Hydroxy-6-methylenespiro[4.4]non-3-en-2-one (15). To a
solution of 3-(4-methoxybenzyloxy)-6-methylenespiro[4.4]nonan-
2-one (14) (215 mg, 0.751 mmol) in dichloromethane (3.3 mL)
and water (0.18 mL) was added DDQ (256 mg, 1.13 mmol) at
0 °C. After being stirred at room temperature, the reaction mixture
was diluted with diethyl ether and quenched with a saturated
3670 J. Org. Chem., Vol. 72, No. 10, 2007