160 J . Org. Chem., Vol. 64, No. 1, 1999
Zheng et al.
2.35 (s, 3H), 2.23 (s, 3H), 1.46 (s, 6H). MS m/z 261 (M + 1).
Anal. Calcd for C16H20O3: C, 73.80; H, 7.75. Found: C, 73.58;
H, 7.79.
Meth od B. Compound 12 (8.26 g, 31.65 mmol) was heated
at 200 °C under N2 for 7 h to give 8.26 g (100%) of the
rearranged product 8.
Exp er im en ta l Section
1H NMR spectra were recorded at 300 MHz. IR spectra were
recorded on a FTIR spectrophotometer with KBr pellets. Mass
spectra were obtained at the Mass Spectrometry Laboratory
for Biotechnology at North Carolina State University. HPLC
analyses were carried out using a dual pump system with a
UV-vis detector (detection wavelength: 220 nm, solvent:
acetonitrile and water). The column was a C18 reversed phase
analytical column from YMC (4.6 × 250 mm, ODS-A, S-5 µm
120A). Unless stated otherwise commercial reagents were from
Aldrich and used without further purification. The amino-
methyl resin (0.8 meq/g, 1% cross linking, 100-200 mesh) and
protected amino acids were from Bachem Inc. Acetonitrile and
THF were HPLC grade from Fisher Scientific Inc. TFA was
peptide synthesis grade. The standard tripeptide, tetrapeptide,
and pentapeptide were prepared using standard solution phase
peptide synthesis procedures.1
6-Hyd r oxy-4,4,5,8-tetr a m eth ylh yd r ocou m a r in (6). 2,5-
Dimethylbenzoquinone (5, 10 g, 73.5 mmol) was dissolved in
300 mL of ether, which was mixed with an aqueous solution
of sodium hydrosulfite (178 g in 150 mL of water, 85% pure,
870 mmol). The mixture was shaken until the ether layer
became near colorless. The ether layer was separated. The
aqueous layer was extracted with ethyl ether (3 × 200 mL).
The combined ether layers were washed with brine (2 × 150
mL) and dried over MgSO4. Filtration and solvent evaporation
gave 10.03 g (72.6 mmol) of the dihydroquinone as a white
solid.
The dihydroquinone was mixed with 3,3-dimethylacrylic
acid (8.00 g, 80 mmol) and methanesulfonic acid (111 mL). The
mixture was stirred at 85 °C under nitrogen atmosphere for 3
h and then cooled to room temperature. To the mixture was
added 300 g of ice with stirring. The gray-white precipitate
was extracted with ethyl acetate (4 × 100 mL). The combined
organic layers were washed with saturated sodium bicarbonate
solution (2 × 100 mL) and water (3 × 100 mL) and dried over
MgSO4. After filtration and evaporation, a residue was ob-
tained, which was recrystallized in ethyl acetate and hexanes
(1:1, v/v) to give 13.02 g (81%) of the desired product. 1H NMR
(CDCl3) δ: 6.57 (s, 1H), 4.85 (s, 1H), 2.56 (s, 2H), 2.33 (s, 3H),
2.22 (s, 3H), 1.46 (s, 6H). MS m/z 220 (M+). Anal. Calcd for
7-Allyl-6-(m eth oxym eth oxy)-4,4,5,8-tetr a m eth ylh yd r o-
cou m a r in (9). Compound 8 (8.26 g, 31.65 mmol) and DIPEA
(57.2 mL, 317.7 mmol) were dissolved in 160 mL of methylene
chloride. The mixture was cooled in an ice-water bath and
stirred under N2. Methoxymethyl chloride (12.2 mL, 159 mmol)
was added dropwise. After the addition, the mixture was
stirred at room temperature under N2 overnight. The mixture
was diluted with 140 mL of methylene chloride and washed
with 10% HCl solution (2 × 50 mL) and water (3 × 50 mL)
and dried over MgSO4. Filtration and solvent evaporation gave
a yellow residue, which was purified on a silica gel column
(hexanes and ethyl acetate, 3/1, v/v) to give 8.61 g (87%) of a
solid product. 1H NMR (CDCl3) δ: 5.96 (m, 1H), 5.07-4.95 (m,
2H), 4.90 (s, 2H), 3.63 (s, 3H), 3.47 (d, J ) 5.7 Hz, 2H), 2.58
(s, 2H), 2.40 (s, 3H), 2.22 (s, 3H), 1.47 (s, 6H). MS m/z 305 (M
+ 1). Anal. Calcd for C18H24O4: C, 71.03; H, 7.95. Found: C,
70.98; H, 7.87.
7-(3-H yd r oxy-1-p r op yl)-6-(m et h oxym et h oxy)-4,4,5,8-
tetr a m eth ylh yd r ocou m a r in (10). Compound 9 (4.09 g,
13.46 mmol) was dissolved in 7 mL of freshly distilled THF.
Argon was passed through the mixture for 20 min. The
solution was cooled in an ice-water bath. BH3-THF solution
(1.0 M, 5.05 mL, 5.05 mmol) was added dropwise with stirring.
After the addition, the mixture was stirred at 0 °C for 2 h.
Water (about 1 mL) was added dropwise to destroy the
excessive borane hydride until hydrogen evolution ceased.
NaOH solution (2 N, 3.4 mL) and 30% H2O2 solution (1.7 mL,
16.2 mmol) were added. The mixture was stirred for 30 min
and neutralized with 5% HCl solution. The organic compounds
were extracted with EtOAc (3 × 50 mL), washed with water
(3 × 30 mL), and dried over MgSO4. The solvents were
removed in a vacuum. The residue was purified on a silica gel
column (EtOAc/hexanes ) 1/3, v/v) to give 3.19 g (70%) of the
product. 1H NMR (CDCl3) δ: 4.91 (s, 2H), 3.63 (s, 3H), 3.60 (t,
J ) 6.0 Hz, 2H), 2.81 (t, J ) 7.4 Hz, 2H), 2.56 (s, 2H), 2.38 (s,
3H), 2.24 (s, 3H), 1.77 (m, 2H), 1.45 (s, 6H). MS m/z 323 (M +
1). Anal. Calcd for C18H26O5: C, 67.06; H, 8.13. Found: C,
66.98; H, 8.09.
C
13H16O3: C, 70.89; H, 7.32. Found: C, 70.73; H, 7.41.
3-(3′,6′-Dioxo-2′,5′-d im et h ylcycloh exa -1′,4′-d ien e)-3,3-
d im eth ylp r op ion ic Acid (7). To a solution of lactone 6 (300
mg, 1.364 mmol) in a mixture of acetonitrile (9 mL), acetone
(1 mL), and water (9 mL) was added NBS (243 mg, 1.364
mmol) in portions with stirring at room temperature. After
being stirred at room temperature for 30 min, the reaction
solution turned yellow. Then the organic solvents were evapo-
rated under reduced pressure, and the remaining solution was
extracted with ether (1 × 30 mL). The ethereal solution was
then extracted with sat. NaHCO3 (3 × 10 mL), and the
combined aqueous phase was washed with ether (3 × 10 mL).
After acidification of the aqueous solution with concd HCl to
pH 2-3, the aqueous solution was extracted with ether (2 ×
20 mL). After drying over MgSO4, ether was evaporated to give
6-Hyd r oxy-7-(3-p r op ion ic a cid )-4,4,5,8-tetr a m eth ylh y-
d r ocou m a r in (11). Compound 10 (2.11 g, 6.55 mmol) was
dissolved in 50 mL of methylene chloride. PCC (2.127 g, 9.89
mmol) was added in portions with stirring at room tempera-
ture. The total reaction time was 3.5 h. The reaction mixture
was filtered through a short silica gel column. The silica gel
was washed with a solution of ethyl acetate and hexane (1:1,
v/v). The filtrates were evaporated to give the aldehyde (1.97
g) which was dissolved in 8 mL of acetone and 2 mL of water,
and then KMnO4 (1.00 g) was added. The mixture was stirred
for 1 h and then acidified with 5% HCl solution. The white
precipitates were extracted with ethyl acetate (3 × 30 mL),
washed with water (3 × 15 mL), and dried over MgSO4.
Filtration and solvent evaporation gave 1.27 g (58%) of the
1
a yellow oily product (197 mg, 61%). H NMR (CDCl3) δ 6.44
1
(s, 1H), 3.01 (s, 2H), 2.13 (s, 3H), 1.97 (s, 3H), 1.45 (s, 6H).
7-Allyl-6-h ydr oxy-4,4,5,8-tetr am eth ylh ydr ocou m ar in (8).
Meth od A. To a solution of quinone 7 (393 mg, 1.66 mmol) in
anhydrous methylene chloride (4 mL) was added BF3‚OEt2
(610 mL, 4.98 mmol) at -78 °C with constant stirring under
N2. A solution of allyltributyltin (1.275 g, 3.30 mmol) in
anhydrous methylene chloride (5 mL) was slowly added from
a syringe, and then the reaction was warmed to room tem-
perature. After stirring at room temperature for 1 h, the
reaction mixture was quenched with 10 mL of 10% KF aqueous
solution and stirred for 2 h. Then the white solid was filtered
off, and the organic phase was separated and washed with sat.
NaHCO3 solution and water. After drying over MgSO4, the
solvent was evaporated to give a residue, which was purified
on a silica gel column (CH2Cl2 as a eluent) to give 407 mg (88%)
of a solid product. 1H NMR (CDCl3) δ: 6.01-5.88 (m, 1H), 5.12
(m, 2H), 4.80 (bs, 1 H), 3.44 (d, J ) 5.7 Hz, 2H), 2.56 (s, 2H),
product. H NMR (CD3OD) δ: 4.91 (s, 2H), 3.58 (s, 3H), 3.02
(t, J ) 8.6 Hz, 2H), 2.59 (s, 2H), 2.46 (t, J ) 8.6 Hz, 2H), 2.38
(s, 3H), 2.23 (s, 3H), 1.43 (s, 6H). MS m/z 337 (M + 1). Anal.
Calcd for C18H24O6: C, 64.27; H, 7.19. Found: C, 64.17; H,
7.14.
6-(Allyloxy)-4,4,5,8-tetr am eth ylh ydr ocou m ar in (12). The
lactone 6 (7.08 g, 32.17 mmol) and allyl bromide (7.79 g, 64.35
mmol) were dissolved in 50 mL of acetone. K2CO3 (8.88 g, 64.35
mmol) and NaI (0.2 g) were added into the solution. The
mixture was stirred at 60 °C for 80 h and then evaporated.
The residue was partitioned between water and methylene
chloride. The organic layer was separated. The aqueous layer
was further extracted with methylene chloride (4 × 50 mL),
and the combined CH2Cl2 layers were washed with water (3
× 50 mL) and dried over MgSO4. Solvent evaporation gave
8.26 g (99%) of a white solid (12). 1H NMR (CDCl3) δ: 6.63 (s,
1H), 6.13-6.01 (m, 1H), 5.46-5.26 (m, 2H), 4.50 (d, J ) 5.1