Mallinger et al.
tert-butoxide (4.4 mL, 4.4 mmol, 1 M in THF) in THF (10 mL),
tetronic acid 3p was obtained as a white solid (0.38 g, 70%): mp
245 °C; TLC Rf 0.20 (95:5 CH2Cl2/MeOH); IR (KBr pellet) νmax
thioglycolate. The preparation of other heterocycles by a similar
one-pot method is underway. Finally, we described the straight-
forward three-step syntheses of three natural vulpinic acids
13a-c from readily available tetronic acid 3d. This is the first
total synthesis of recently isolated methyl 3′,5′-dichloro-4,4′-
di-O-methylatromentate 13c. It should be noted that the synthesis
of compounds 13a and 13c (obtained in 70 and 48% yield,
respectively, from ester 3d) certainly represents one of the most
efficient routes to unsymmetrical vulpinic acids. This result was
obtained because of the one-step 3-aryltetronic acid preparation
and also the avoidance of any protection/deprotection step in
the course of the synthetic sequence.
832, 1247, 1275, 1389, 1516, 1612, 1644, 1686, 2635, 2941 cm-1
;
1H NMR (400 MHz, acetone-d6) δ 1.26-1.37 (m, 1H), 1.60-1.80
(m, 7H), 2.00-2.08 (m, 2H), 3.80 (s, 3H), 6.93 (d, 2H, J ) 9.1
Hz), 7.39 (d, 2H, J ) 9.1 Hz), 10.46 (bs, 1H, OH); 13C NMR (100
MHz, acetone-d6) δ 22.8 (2C), 25.1, 33.5 (2C), 55.5, 81.6, 99.8,
114.3 (2C), 123.7, 129.8 (2C), 159.5, 171.6, 177.6; MS (ESI-TOF)
m/z 275 [M + H]+; HRMS (ESI-TOF) calcd for C16H18NaO4 [M
+ Na]+ 297.1103, found 297.1112.
Dimethyl 2,2′-(Naphthalene-1,7-diyl)diacetate (7). To lithium
acetate (0.93 g, 14 mmol, 4 equiv) and tetrakistriphenylphosphine
palladium (0.61 g, 0.53 mmol, 0.15 equiv) were successively added
a solution of ditriflate 5 (1.5 g, 3.5 mmol, 1 equiv) in degassed
THF (22 mL) and ketene silyl acetal 6 (2.0 g, 11 mmol, 3 equiv),
which was previously prepared from methyl acetate21 and contained
about 20% methyl (trimethylsilyl)acetate. The reaction mixture was
refluxed for 3 h. After it had cooled to rt, water was added, and
then the layers were separated. The aqueous layer was extracted
with ethyl acetate. The combined organic layers were dried over
MgSO4, filtered, and concentrated under vacuum. The residue was
purified by column chromatography (silica gel, 9:1 to 8:2 pentane/
EtOAc) to give diester 7 as a colorless oil (3.2 g, 83%): TLC Rf
0.40 (8:2 pentane/EtOAc); IR (NaCl, film) νmax 831, 1013, 1164,
Experimental Section
General Procedure A for the Synthesis of Tetronic Acids
(in THF). To a solution of ester 1 (1 equiv) and hydroxyester 2
(1.2 equiv) in anhydrous THF was added a 1 M solution of
potassium tert-butoxide (2.2 equiv) in THF. The suspension
obtained was then refluxed under argon overnight. After cooling
to rt, the reaction mixture was poured into cooled 1 N HCl. The
aqueous layer was extracted with ethyl acetate, and the combined
organic layers were then washed with water and dried over Na2SO4.
After filtration and concentration under vacuum, the residue was
purified by column chromatography (silica gel, 200:1 and then 95:5
containing 0.2% acetic acid CH2Cl2/methanol) to give the corre-
sponding tetronic acid 3.
General Procedure B for the Synthesis of Tetronic Acids
(in DMF). To a solution of ester 1 (1 equiv) and hydroxyester 2
(1.2 equiv) in DMF was added a 1 M solution of potassium tert-
butoxide (2.2 equiv) in THF. The solution was stirred under argon
at rt overnight. The reaction mixture was then poured into cooled
1 N HCl. The aqueous layer was extracted with ethyl acetate, and
the combined organic layers were then washed several times with
water and dried over Na2SO4. After filtration and concentration
under vacuum, the residue was purified by column chromatography
(silica gel, 200:1 and then 95:5 containing 0.2% acetic acid CH2Cl2/
methanol) to give the corresponding tetronic acid 3.
1
1206, 1264, 1435, 1510, 2953, 3055 cm-1; H NMR (400 MHz,
acetone-d6) δ 3.69 (s, 3H), 3.72 (s, 3H), 3.83 (s, 2H), 4.07 (s, 2H),
7.40-7.43 (m, 2H), 7.45 (dd, 1H, J ) 8.3, 1.6 Hz), 7.75-7.80 (m,
1H), 7.84 (d, 1H, J ) 8.3 Hz), 7.87 (bs, 1H); 13C NMR (100 MHz,
acetone-d6) δ 39.0, 41.8, 52.2 (2C), 124.1, 125.6, 127.4, 127.9,
128.4, 129.2, 130.4, 132.1, 132.2, 132.9, 172.0, 172.1; MS (ESI-
TOF) m/z 295 [M + Na]+; HRMS (ESI-TOF) calcd for C16H16NaO4
[M + Na]+ 295.0946, found 295.0945.
3,3′-(Naphthalene-1,7-diyl)bis(4-hydroxyfuran-2(5H)-one) (8).
To a solution of dimethyl 2,2′-(naphthalene-1,7-diyl)diacetate 7
(0.10 g, 0.37 mmol, 1 equiv) and anhydrous methyl glycolate (0.062
mL, 0.81 mmol, 2.2 equiv) in anhydrous THF (2 mL) was added
a 1 M solution of potassium tert-butoxide (1.6 mL, 1.6 mmol, 4.4
equiv) in THF. The suspension obtained was then refluxed under
argon overnight. After cooling to rt, the reaction mixture was poured
into cooled 1 N HCl (5 mL). The aqueous layer was extracted with
ethyl acetate, and the combined organic layers were then washed
with brine and dried over Na2SO4. After filtration and concentration
under vacuum, the residue was purified by precipitation in acetone
to give the corresponding bis(tetronic acid) 8 (84 mg, 70%): mp
>280 °C dec; IR (KBr pellet) νmax 837, 1024, 1043, 1161, 1315,
4-Hydroxy-3-phenylfuran-2(5H)-one (3a). According to general
procedure A, from methyl phenylacetate (0.29 mL, 2.0 mmol),
methyl glycolate (0.19 mL, 2.4 mmol), and potassium tert-butoxide
(4.4 mL, 4.4 mmol, 1 M in THF) in THF (10 mL), tetronic acid 3a
was obtained as a beige solid (0.34 g, 97%): mp 253 °C (lit.14 254
°C); TLC Rf 0.10 (9:1 CH2Cl2/MeOH); IR (KBr pellet) νmax 680,
782, 1019, 1061, 1163, 1316, 1351, 1397, 1433, 1462, 1499, 1599,
1
1
1695, 2621, 2935 cm-1; H NMR (400 MHz, acetone-d6) δ 4.79
1346, 1421, 1569, 1617, 1663, 1703, 2620, 2932 cm-1; H NMR
(s, 2H), 7.22-7.27 (m, 1H), 7.35-7.40 (m, 2H), 7.98-8.15 (m,
2H); 13C NMR (100 MHz, acetone-d6) δ 66.7, 100.2, 127.5, 127.8
(2C), 128.8 (2C), 131.5, 173.3, 173.9; MS (ESI-TOF) m/z 177 [M
+ H]+, 199 [M + Na]+.
(400 MHz, DMSO-d6) δ 4.80 (s, 2H), 4.90 (s, 2H), 7.37 (d, 1H, J
) 7.2 Hz), 7.50 (dd, 1H, J ) 8.0, 7.2 Hz), 7.87 (d, 1H, J ) 8.0
Hz), 7.93 (d, 1H, J ) 8.8 Hz), 8.11 (dd, 1H, J ) 8.8, 1.5 Hz), 8.39
(bs, 1H); 13C NMR (100 MHz, DMSO-d6) δ 66.2, 66.9, 97.4, 99.1,
123.0, 124.6, 125.1, 127.5, 127.6, 127.7, 128.3, 128.5, 131.4, 131.8,
173.0, 173.4, 175.1, 175.7; MS (ESI-TOF) m/z 347 [M + Na]+,
671 [2M + Na]+; HRMS (ESI-TOF, negative-ion mode) calcd for
C18H11NaO6 [M - H]- 323.0556, found 323.0565.
1,3-Dichloro-5-iodo-2-methoxybenzene (15). To a solution of
2,6-dichlorophenol (10 g, 61 mmol, 1 equiv) in THF (110 mL)
was added N-iodosuccinimide (20 g, 92 mmol, 1.5 equiv). The
resulting mixture was stirred for 2 h, and then a 10% aqueous
solution of Na2S2O3 and Et2O were added. The aqueous layer was
extracted with Et2O. The combined organic layers were then washed
with brine, dried over MgSO4, filtered, and concentrated under
vacuum. The resulting white solid was dissolved in DMF (110 mL),
and then K2CO3 (39 g, 282 mmol, 4.6 equiv) and methyl iodide
(8.0 mL, 129 mmol, 2.1 equiv) were added. After 48 h, water was
added, and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with 1% HCl and brine, dried
over MgSO4, filtered, and concentrated under vacuum. The residue
obtained was purified by column chromatography using a combi-
4-Hydroxy-3-(4-methoxyphenyl)-5-methylfuran-2(5H)-one (3l).
According to general procedure A, from methyl 4-methoxypheny-
lacetate (0.32 mL, 2.0 mmol), (-)-methyl L-lactate (0.23 mL, 2.4
mmol), and potassium tert-butoxide (4.4 mL, 4.4 mmol, 1 M in
THF) in THF (10 mL), tetronic acid 3l was obtained as a yellow
solid (0.43 g, 97%): mp 202 °C; TLC Rf 0.20 (9:1 CH2Cl2/MeOH);
IR (KBr pellet) νmax 830, 999, 1082, 1171, 1249, 1390, 1516, 1611,
1
1695, 2658, 2932 cm-1; H NMR (400 MHz, acetone-d6) δ 1.53
(d, 3H, J ) 6.6 Hz), 3.80 (s, 3H), 4.94 (q, 1H, J ) 6.6 Hz), 6.94
(d, 2H, J ) 9.1 Hz), 7.89 (d, 2H, J ) 9.1 Hz); 13C NMR (100
MHz, acetone-d6) δ 18.5, 55.4, 73.7, 100.1, 114.2 (2C), 123.7, 129.4
(2C), 159.5, 172.4, 175.3; MS (ESI-TOF) m/z 221 [M + H]+, 243
[M + Na]+. Anal. Calcd for C12H12O4: C, 65.45; H, 5.49. Found:
C, 65.28; H, 5.45.
4-Hydroxy-3-(4-methoxyphenyl)-1-oxaspiro[4.5]dec-3-en-2-
one (3p). According to general procedure A, from methyl 4-meth-
oxyphenylacetate (0.32 mL, 2.0 mmol), anhydrous methyl 1-hy-
droxycyclohexanecarboxylate 2f (0.35 mg, 2.2 mmol), and potassium
1128 J. Org. Chem. Vol. 74, No. 3, 2009