4516 J . Org. Chem., Vol. 66, No. 13, 2001
Molander et al.
was stirred for 1 h at room temperature and then added over
2 h to a solution of R,R′-dibromo-o-xylene in 70 mL of
anhydrous DMF. The reaction mixture was stirred for an
additional 48 h and then cooled to 0 °C before being hydrolyzed
with 200 mL of ice. The organic materials were extracted with
Et2O, and the organic phase was washed with brine and dried
over MgSO4. Flash chromatography (50% EtOAc/petroleum
ether) yielded 2.3 g (19%) of the title compound and 1.3 g (11%)
of 3-(2-bromomethylbenzyloxy)-2-methylcyclohex-2-enone as
colorless crystals. 2-(2-Br om om eth yl)ben zyl-2-m eth ylcy-
2H), 2.33-2.25 (m, 1H), 2.22-2.17 (m, 2H), 2.08-1.95 (m, 2H),
1.76-1.70 (m, 1H), 1.23 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
209.8, 85.9, 52.8, 39.6, 38.9, 37.1, 35.7, 27.0, 19.9, 19.3; IR (film)
ν
max 1712, 1350, 1174 cm-1; HRMS (CI+) calc for (MH)+ C10H18
-
ClO4S 269.0614, found 269.0627.
Gen er a l P r oced u r e for th e Sequ en ced Rea ction s Us-
in g Sa m a r iu m (II) Iod id e. Samarium metal (420 mg, 2.8
mmol) was added under a flow of N2 to an oven-dried flask.
20 mL of THF were added, the suspension was cooled between
-10 °C and 0 °C, and CH2I2 (699 mg, 2.6 mmol) was added.
The mixture was stirred at room temperature for 2 h, and NiI2
(2% mol) was added. After stirring 5 min, the deep-blue
solution was cooled to the requisite temperature, and the
substrate (1 mmol) in 10 mL of THF was added over 5 min.
The reaction was irradiated or not with visible light (250 W
krypton lamp) while keeping the temperature at the previously
mentioned level. After the starting material was consumed
(TLC or GC analysis), the reaction mixture was warmed to
room temperature and stirred for 1 h. The resultant solution
was quenched with a saturated aqueous solution of Rochelle’s
salt and extracted several times with Et2O. The organic
extracts were washed with brine and dried over MgSO4. The
products were purified by flash chromatography unless stated
otherwise.
3R-Hydr oxy-6R-m eth ylh exah ydr open talen -1-on e (2b).16b
Prepared from 1b (279 mg, 1 mmol) according to the general
procedure described above (under irradiation, -30 °C for 3 h)
to afford, after flash chromatography (50% EtOAc/petroleum
ether), 2b (144 mg, 94%) as a colorless gel:1H NMR (CDCl3,
500 MHz) δ 2.51-2.42 (m, 1H), 2.34-2.24 (m, 1H), 2.13-2.04
(m, 1H), 1.98-1.72 (m, 5H), 1.63-1.42 (m, 3H), 1.10 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 222.0, 87.4, 58.6, 40.1, 36.2, 35.9,
32.8, 22.2, 16.3; IR (film) νmax 3452, 1731 cm-1; HRMS (CI+)
calc for (MH)+ C9H15O2 155.1072, found 155.1073.
(Z)-10-Meth yl-5,7,8,11-tetr a h yd r oben zocyclon on en -6-
on e (21). 17 (60 mg, 0.2 mmol) was added to a solution of
NaOMe (11 mg, 0.2 mmol) in 3 mL of MeOH and heated to
reflux for 1 h. The MeOH was evaporated, and 3 mL of water
were added. The aqueous phase was extracted with EtOAc,
and the combined organic phases were washed with brine and
dried over MgSO4. After evaporation of the solvent, the
resulting solid was recrystallized (Et2O/petroleum ether) to
yield 21 (34 mg, 88%) as colorless crystals: mp 118-120 °C;
1H NMR (CDCl3, 500 MHz) δ 7.19-7.11 (m, 4H), 5.23 (t, J )
8.5 Hz, 1H), 3.76 (s, 2H), 3.39 (s, 2H), 2.76-2.67 (m, 2H), 2.62-
2.55 (m, 2H), 1.57 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 210.0,
138.2, 136.5, 134.0, 132.5, 130.8, 127.0, 126.9, 122.6, 45.8, 44.0,
37.0, 24.1, 22.9; IR (film) νmax 2959, 1704, 1470 cm-1; HRMS
(CI+) calcd for (M)+ C14H16O 200.120115, found 200.120287.
1
clop en ta n e-1,3-d ion e: mp 86-88 °C; H NMR (CDCl3, 500
MHz) δ 7.35-7.30 (m, 1H), 7.25-7.19 (m, 2H), 7.10-7.05 (m,
1H), 4.68 (s, 0.6H), 4.60 (s, 1.4H), 3.19 (m, 2H), 2.69-2.57 (m,
2H), 2.23-2.14 (m, 2H), 1.28 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 217.3, 136.5, 136.3, 135.0, 131.1, 130.9, 130.4, 130.2,
129.92, 128.88, 127.9, 127.8, 58.1, 28.0, 44.2, 37.7, 37.5, 35.7,
31.9, 21.0, 20.8; IR (film) νmax 2969, 1762, 1722, 1449 cm-1
;
HRMS (CI+) calc for (MH)+ C14H16BrO2 295.0333, found
295.0329. 3-(2-Br om om eth yl)ben zyloxy-2-m eth ylcycloh ex-
1
2-en on e: mp 94 °C; H NMR (CDCl3, 500 MHz) δ 7.41-7.32
(m, 4H), 5.37 (s, 2H), 4.66 (s, 2H), 2.71-2.67 (m, 2H), 2.46-
2.40 (m, 2H), 1.65 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 205.2,
183.1, 135.3, 134.5, 130.6, 129.3, 129.2, 128.7, 117.1, 68.4, 43.6,
33.5, 25.2, 6.1; IR (film) νmax 2920, 1632, 1339 cm-1; HRMS
(CI+) calcd for (MH)+ C14H16BrO2 295.0333, found 295.0344.
Gen er a l P r oced u r e for th e F in k elstein Rea ction . 2-(3-
Iod op r op yl)-2-m eth ylcycloh exa n e-1,3-d ion e (1d ). To the
chloride precursor (4 g, 20 mmol) in 150 mL of acetone was
added 30 g (0.2 mol) of NaI. The solution was heated at reflux
for 12 h and cooled to room temperature, and 200 mL of water
was added. The aqueous phase was extracted with Et2O, and
the combined organic phases were washed with 10% aqueous
Na2S2O3 and brine and dried over MgSO4. Purification by flash
chromatography (50% EtOAc/petroleum ether) afforded 5.2 g
(88%) of 1d as a yellow oil:1H NMR (CDCl3, 500 MHz) δ 3.07
(dd, J ) 1.3, 6.7 Hz, 2H), 2.65-2.51 (m, 4H), 1.98-1.82 (m,
4H), 1.62-1.57 (m, 2H), 1.21 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 209.7, 64.9, 37.8, 37.1, 28.6, 20.2, 17.6, 5.8; IR (film)
νmax 1725, 1693, 1456 cm-1; HRMS (CI+) calcd for (MH)+
C10H15CIO2 295.0195, found 295.0187.
Gen er a l P r oced u r e for Red u ction a n d Mesyla tion of
t h e 1,3-Dion es. Met h a n esu lfon ic Acid , (Z)-(2R*,3R*)-2-
(2-Ch lor oeth yl)-2-m eth yl-3-oxocycloh exyl Ester (14a ). To
the dione 1a in 30 mL of THF at room temperature was added
dropwise 2.5 mL of a 0.5 M solution of aqueous NaBH4. The
solution was stirred for 1 h at room temperature, 60 mL of
water were added, and the pH was adjusted to 2 with a 0.5 M
aqueous HCl solution. The aqueous phase was extracted with
Et2O, and the combined organic phases were washed with
brine and dried over MgSO4. The crude mixture (60/40 cis/
trans) was purified by flash chromatography (30% EtOAc/
petroleum ether) to yield 756 mg (79%) of the alcohol as a
colorless liquid. To 1.65 g (8.7 mmol) of the alcohol in 140 mL
of CH2Cl2 and 1.8 g (18 mmol) of Et3N at -78 °C were added
1.5 g (13 mmol) of MsCl. The solution was stirred for 2 h at
the same temperature and hydrolyzed with 150 mL of brine.
The aqueous phase was extracted with Et2O, and the combined
organic phases were washed with brine and dried over MgSO4.
Purification by flash chromatography (30% EtOAc/petroleum
ether) and recrystallization (Et2O/EtOAc/petroleum ether)
yielded 1.70 g (73%) of 14a as colorless crystals: mp 84-86
°C; 1H NMR (CDCl3, 500 MHz) δ 4.71 (t, J ) 4.8 Hz, 1H), 3.55-
3.47 (m, 1H), 3.44-3.38 (m, 1H), 3.02 (s, 3H), 2.49-2.38 (m,
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (GM 35249) and Merck
& Co. for their generous support. We also thank Dr.
Patrick J . Caroll for performing the X-ray crystal
structure determinations.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details, 1H and 13C NMR spectra for all compounds, and X-ray
structural data for 5a and 5b. This material is available free
J O001513R