S.P. Chavan et al. / Tetrahedron 68 (2012) 8509e8514
8513
(m, 2H), 3.85 (s, 3H), 5.48e5.65 (m,1H), 6.85e6.90 (d, J¼8.6 Hz,1H),
(3 mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to afford a residue, which was purified by
silica gel column chromatography using ethyl acetate/hexane
(1.5:8.5) as eluent to furnish the tetralone 3 (40 mg, 95% based on
the recovery 54 mg of acid 4) as a white solid with melting point
203e205 ꢁC.
7.18e7.24 (m, 2H). 13C NMR (50 MHz, CDCl3þCCl4):
d 9.99, 10.05,
16.15, 37.11, 37.54, 55.25, 65.74, 66.61, 68.71, 69.33, 78.69, 79.36,
110.01, 120.41, 120.68, 122.89, 122.99, 127.11, 127.28, 130.08, 158.93,
160.23, 160.28, 175.09, 175.33. MS (EI): m/z 293 [MþH]þ, 315
[MþNa]þ. Anal. Calcd for C16H20O5: C, 65.74; H, 6.90. Found: C,
65.84; H, 6.86.
Compound 3: Rf (15% EtOAc/hexane) 0.7; IR (Nujol) 2923, 2853,
Compound 10: white solid, melting point 90e116 ꢁC (mixture of
diastereomers); Rf (80% EtOAc/hexane) 0.8; IR (CHCl3) 3444, 2978,
1774, 1610, 1504 cmꢂ1; 1H NMR (200 MHz, CDCl3þCCl4, mixture of
1745, 1702, 1636, 1602, 1508 cmꢂ1 1H NMR (200 MHz, CDCl3):
;
d
2.21 (d, J¼2 Hz, 3H), 2.36 (s, 3H), 2.62 (dd, J¼16, 12 Hz, 1H), 3.51
(dd, J¼16, 6 Hz, 1H), 3.95 (s, 3H), 5.17e5.31 (m, 1H), 7.53 (s, 1H), 7.56
(s, 1H). 13C NMR (50 MHz, CDCl3):
9.82, 16.94, 45.24, 55.80, 76.76,
two diastereomers):
d
1.18 and 1.21 (d, J¼7.2 Hz, 1H), 1.90e2.30 (m,
d
2H), 2.24 (s, 3H), 2.83e2.95 (q, 1H), 3.58e3.70 (m, 2H), 3.84 and
3.85 (s, 3H), 4.34e4.41 (m, 1H), 5.08e5.17 (m, 1H), 6.82 and 6.86 (d,
J¼8 Hz, 1H), 7.17e7.25 (m, 2H). 13C NMR (50 MHz, CDCl3, mixture of
107.67, 120.86, 125.25, 129.23, 131.88, 135.35, 152.65, 159.83, 174.17,
192.61. MS (ESI): m/z 259 [MþH]þ, 281 [MþNa]þ. Anal. Calcd for
C15H14O4: C, 69.76; H, 5.46. Found: C, 69.44; H, 5.39.
two diastereomers):
d 7.40, 7.65, 16.19, 32.45, 32.59, 47.57, 48.56,
55.12, 64.04, 65.00, 79.56, 80.10, 86.58, 87.49, 90.82, 91.79, 109.60,
109.76, 123.56, 123.58, 126.67, 126.84, 127.01, 127.15, 128.74, 131.09,
157.16, 157.32, 177.08, 177.39. MS (EI): 315 [MþNa]þ. Anal. Calcd for
C16H20O5: C, 65.74; H, 6.90. Found: C, 65.59; H, 6.95.
4.1.7. 5-Hydroxy-7-methoxy-1,5,8-trimethyl-4,5-dihydronaphtho
[2,1-b]furan-2(3aH)-one (13). To a dry round bottom flask under
argon was added tetralone 3 (100 mg, 1.4 mmol) in dry THF (2 mL).
The solution was cooled to ꢂ78 ꢁC and MeMgBr (1.4 M, Aldrich
make) (0.43 mL, 0.6 mmol) was added dropwise. The reaction was
stirred at same temperature for 1 h, then slowly allowed to come
room temperature and further stirred at room temperature for 5 h.
The reaction was quenched with saturated NH4Cl and extracted
with ethyl acetate (3ꢃ3 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered and, concentrated under
reduced pressure. The crude product was purified by flash column
chromatography (20% EtOAc/hexane) to provide the product 13
(103 mg, 97% yield) as a white semisolid compound. Rf (50% EtOAc/
hexane) 0.5; IR (Nujol) 3529, 2925, 2855, 1739, 1646, 1613 cmꢂ1; 1H
4.1.5. 2-(3-(4-Methoxy-3-methylphenyl)-4-methyl-5-oxo-2,5-
dihydrofuran-2-yl)acetic acid (4). To a magnetically stirred solution
of lactone 9 (270 mg, 0.92 mmol) in acetone/water (3:1), NaIO4
(556 mg, 2.6 mmol) was added portion wise and stirred for 15 min
at room temperature. The solid residue was separated by filtration.
The filtrate was extracted with DCM (3ꢃ5 mL). The combined or-
ganic layer was washed with brine (7 mL) and dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
crude aldehyde was used in the next reaction without further
purification.
NMR (200 MHz, CDCl3þCCl4):
d
1.63 (s, 3H), 1.85 (t, J¼11.4 Hz, 1H),
A solution of NaClO2 (230 mg, 2.5 mmol) in water (2 mL) was
added dropwise to a stirred mixture of crude aldehyde (210 mg,
0.81 mmol) in acetonitrile (5 mL) and NaH2PO4 (324 mg,
2.13 mmol) in water (2 mL) and 2.13 mL of 35% H2O2, keeping the
temperature at 10 ꢁC with water cooling. Oxygen evolved from the
solution and the reaction was monitored by TLC until the end of the
reaction (about 4 h). A small amount (100 mg) of Na2SO3 was added
to destroy the unreacted HOCl and H2O2. After acidification with
10% aqueous HCl (3 mL), it was extracted with ethyl acetate
(3ꢃ5 mL). The combined organic layer was washed with brine
(3 mL) and dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue was done on
a silica gel column using ethyl acetate/hexane (5:5) as eluent to
furnish the acid 4 (200 mg, 78%) as a white solid, melting point
135e137 ꢁC. Rf (80% EtOAc/hexane) 0.6 (long tail); IR (CHCl3) 3456,
2.12 (d, J¼2 Hz, 3H), 2.26 (s, 3H), 2.81 (dd, J¼11, 4 Hz, 1H), 3.93 (s,
3H), 4.88e4.97 (m, 1H), 7.19 (s, 1H), 7.39 (s, 1H). 13C NMR (50 MHz,
CDCl3þCCl4):
d 9.84, 16.16, 29.68, 31.65, 46.32, 55.48, 71.57, 77.11,
96.11, 107.66, 116.92, 118.74, 127.26, 129.00, 145.15, 155.74, 160.09,
175.21. MS (ESI): m/z 275 [MþH]þ, 297 [MþNa]þ. Anal. Calcd for
C16H18O4: C, 70.06; H, 6.61. Found: C, 70.26; H, 6.69.
4.1.8. (3aS,5R)-7-Methoxy-1,5,8-trimethyl-4,5-dihydronaphtho[2,1-
b]furan-2(3aH)-one [heritonin, 2]. To a magnetically stirred solution
of hydroxy compound 13 (30 mg, 0.11 mmol) in DCM (3 mL) at
ꢂ78 ꢁC was added BF3$OEt2 (0.07 mL, 0.55 mmol) and Et3SiH
(0.1 mL, 0.66 mmol) dropwise. The reaction was allowed to warm
up to room temperature over 30 min and stirred at room temper-
ature for 3 h and quenched by adding saturated NaHCO3 solution
(3 mL) and extracted with DCM (3ꢃ5 mL). The organic layer was
washed with brine (5 mL), dried over anhydrous Na2SO4 and fil-
tered. Evaporation of the solvent and purification of the residue on
a silica gel (5% EtOAc/hexane) to provide the product heritonin 2
(27 mg, 96% yield) as a white solid, melting point 115e117 ꢁC (lit.
115e116 ꢁC). IR (Nujol) 2926, 2854, 1747, 1659, 1611 cmꢂ1; 1H NMR
3020, 2950, 1747, 1651, 1606, 1507 cmꢂ1 1H NMR (200 MHz,
;
CDCl3þCCl4):
d
2.07 (d, J¼1.5 Hz, 3H), 2.27 (s, 3H), 2.41 (dd, J¼9.6,
18 Hz,1H), 2.83 (dd, J¼2.5,17 Hz,1H), 3.90 (s, 3H), 5.75 (m,1H), 6.93
(d, J¼8.4 Hz, 1H), 7.17 (d, J¼2 Hz, 1H), 7.23 (dd, J¼8, 2 Hz, 1H). 13C
NMR (50 MHz, CDCl3þC2D6SO):
d 10.05, 16.20, 38.68, 55.33, 77.75,
110.20, 121.33, 122.44, 127.02, 127.26, 129.79, 158.18, 158.96, 171.36,
174.13. MS (EI): m/z 277 [MþH]þ, 299 [MþNa]þ. Anal. Calcd for
C15H16O5: C, 65.21; H, 5.84. Found: C, 65.31; H, 5.89.
(CDCl3, 200 MHz):
d
1.46 (d, J¼7 Hz, 3H), 1.36e1.64 (m, 1H), 2.14 (d,
J¼1.6 Hz, 3H), 2.25 (s, 3H), 2.58e2.69 (m, 1H), 3.04e3.22 (m, 1H),
3.89 (s, 3H), 4.85e4.94 (m, 1H), 6.84 (s, 1H), 7.41 (s, 1H). 13C NMR
(CDCl3, 50 MHz):
d 9.88, 15.98, 21.70, 31.95, 38.62, 55.32, 78.14,
4.1.6. 7-Methoxy-1,8-dimethyl-3a,4-dihydronaphtho[2,1-b]furan-
2,5-dione (3). To a magnetically stirred solution of acid 4 (110 mg,
0.4 mmol) in DCM (3 mL), was added dropwise excess oxalyl
chloride (1.0 mL) and stirred overnight at room temperature. Ex-
cess oxalyl chloride and solvent was distilled out at 120 ꢁC (oil bath
temperature). The crude acid chloride was used in the next reaction
without further purification.
To the stirred solution of crude acid chloride (100 mg) in DCM
(3 mL) under reflux was added catalytic amount (0.02 mL) of tri-
fluoromethanesulphonic acid. The reaction mixture was heated to
reflux for 3 h and it was diluted with water and extracted with DCM
(3ꢃ3 mL). Combined organic layers were then washed with brine
108.32, 115.86, 120.65, 125.70, 129.57, 142.21, 156.71, 159.53, 175.63.
MS (ESI): m/z 259 [MþH]þ, 281 [MþNa]þ.
4.1.9. (3aS,5R)-7-Hydroxy-1,5,8-trimethyl-4,5-dihydronaphtho[2,1-
b]furan-2(3aH)-one4 [heritol, 1]. Ethanethiol (1 mL) was added to
a
magnetically stirred solution of methyl ether 2 (20 mg,
0.078 mmol) and anhydrous aluminum chloride (50 mg,
0.375 mmol) in DCM (1 mL) at room temperature. The reaction
mixture was allowed to stir for 12 h. Water was added to the re-
action mixture and the separated solid was extracted with DCM
(3ꢃ5 mL). The combined organic layer was dried over anhydrous
Na2SO4, filtered, and evaporated under reduced pressure to furnish