Synthesis of puraquinonic acid ethyl ester and deliquinone via a common intermediate

Article abstract of DOI:10.1021/jo020029g

Both compounds were prepared via a common intermediate. The key features included the direct synthesis of the indan skeleton and the radical addition to a quinone.

Full text of DOI:10.1021/jo020029g

Syn th esis of P u r a qu in on ic Acid Eth yl Ester
a n d Deliqu in on e via a Com m on
In ter m ed ia te
George A. Kraus* and Prabir K. Choudhury
Department of Chemistry, Iowa State University,
Ames, Iowa 50011
F IGURE 1.
SCHEME 1
gakraus@iastate.edu
Received J anuary 15, 2002
Abstr a ct: Both compounds were prepared via a common
intermediate. The key features included the direct synthesis
of the indan skeleton and the radical addition to a quinone.
SCHEME 2
Natural products bearing the indan subunit are in-
creasing in number and many exhibit interesting biologi-
1
cal activity. In some cases such as illudin A (1), the six-
2
membered ring subunit bears a spiro cyclopropane. In
other cases such as puraquinonic acid (2, R ) H) and
3
deliquinone (3), there is a quinone (Figure 1). Fomajorin
(
4) is a metabolite of basidiomycete Heterobasidion
4
annosum. Puraquinonic acid induces differentiation of
HL-60 cells. Puraquinonic acid has been synthesized by
Clive and co-workers using a clever variant of the
5
Nazarov cyclization. Although illudin A has not been
synthesized, other members of this family have been
6
prepared. We recently communicated the synthesis of
7
racemic deliquinone. We report herein a full account of
The reaction of 5 (X ) H) with m-chloroperbenzoic acid
proceeded in modest yield and was not reproducible.
We next focused on a synthesis of indan ester 5 (X )
OMe). This was achieved by the reaction of 2,3-dimethyl-
anisole with 2 equiv of N-bromosuccinimide in carbon
tetrachloride. The resulting dibromide 7 reacted with
Meldrum’s acid and sodium hydride in DMSO to provide
this work plus a synthesis of the ethyl ester of puraquinon-
ic acid.
Our strategy for the synthesis of 2 and 3 centered on
the preparation of indan ester 5 (X ) H), a readily
8
available compound. We initially planned to construct
quinone 6 from the ester 5 (X ) H) by oxidation (Scheme
). m-Chloroperbenzoic acid, methylrhenium trioxide,
9
10
12
1
the indan dilactone 8. The use of DMSO as the solvent
1
1
and palladium acetate have been reported to convert
,2-disubstituted aromatic rings directly into benzoquin-
ones. Unfortunately, attempted oxidation of 5 (X ) H)
to quinone 6 using either methylrhenium trioxide or
palladium acetate returned recovered starting material.
was critical, since solvents such as ethanol afforded 2:1
adducts as significant byproducts. The reaction of 8 with
ethanol and pyridine produced 5 (X ) OMe) in 87%
isolated yield. This compound was generated by ester
formation followed by decarboxylation. The resulting
ester was methylated using lithium diisopropylamide
(LDA) and methyl iodide in THF at -78 °C to generate
ester 9 in quantitative yield (Scheme 2).
Introduction of the two-carbon side chain was the next
objective. It was achieved by demethylation of the aryl
methyl ether using 2-phenylethylthiol and aluminum
trichloride.13 With reagents such as boron trichloride or
iodotrimethylsilane, cleavage of the ester was competitive
with demethylation. Alkylation of the phenol produced
the ether 10. Claisen rearrangement at 200 °C in DMF
cleanly provided phenol 11 in 77% yield from 9 (Scheme
1
(
1) Other terpenes containing the indan subunit: Takupovic, J .;
J eske, F.; Morgenstern, T.; Tsichritzis, F.; Marco, J . A.; Berendsohn,
W. Phytochemistry 1998, 47, 1583. Bruce, I.; Cooke, N. G.; Diorazio,
L. J .; Hall, R. G.; Irving, E. Tetrahedron Lett. 1999, 40, 4279. Ranu,
B. C.; Sarkar, M.; Chakraborti, P. C.; Ghatak, U. R. J . Chem. Soc.,
Perkin Trans. 1 1982, 865.
2) For a general synthetic approach, see: Padwa, A.; Curtis, E. A.;
Sandanayaka, V. P. J . Org. Chem. 1997, 62, 1317.
3) Clericuzio, M.; Han, F.; Pan, F.; Pang, Z.; Sterner, O. Acta Chem.
Scand. 1998, 52, 1333. Becker, U.; Erkel. G.; Anke, T.; Sterner, O.
Nat. Prod. Lett. 1997, 9, 229. Degos, L. Leukemia Res. 1990, 14, 717.
4) Sonnenbichler, J .; Dietrich, J .; Schaefer, W.; Zetl, I. Biol. Chem.
Hoppe-Seyler 1993, 374, 1047.
(
(
(
(
(
(
(
(
5) Hisaindee, S.; Clive, D. L. J . Tetrahedron Lett. 2001, 42, 2253.
6) Aungst, R. A.; Chan, C.; Funk, R. L. Org. Lett. 2001, 3, 2611.
7) Kraus, G. A.; Choudhury, P. K. Tetrahedron Lett. 2001, 42, 6649.
8) Neudeck, H. K. Monatsh. Chem. 1989, 120, 623.
3
).
Phenol 11 was viewed as a key intermediate for both
the synthesis of deliquinone and the synthesis of
9) Asakawa, Y.; Matsuda, R.; Tori, M.; Sono, M. J . Org. Chem. 1998,
5
3, 5453.
(
(
10) J acob, J .; Espenson, J . H. Inorg. Chim. Acta 1998, 270, 55.
11) Yamaguchi, S.; Inoue, M.; Enomoto, S. Bull. Chem. Soc. J pn.
(12) Ridvan, L.; Zavada, J . Tetrahedron 1997, 53, 14793.
(13) Node, N.; Nishide, K.; Fuji, K.; Fujita, E. J . Org. Chem. 1980,
45, 4275.
1
986, 59, 2881.
1
0.1021/jo020029g CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/12/2002
J . Org. Chem. 2002, 67, 5857-5859
5857

SCHEME 3
tion, and the solvent was evaporated. The residue was recrystal-
lized from diethyl ether-pentane to give compound 7 as white
crystals in 87% (25.5 g) yield.
Sodium hydride (60% in mineral oil, 4.6 g, 2.2 equiv) was
washed with dry pentane and suspended in DMSO (75 mL).
Meldrum’s acid (15.8 g, 110 mmol) in DMSO (30 mL) was added
to the stirred slurry (after homogenization; 10 min, stirring at
room temperature) followed by 2,3-bis(bromomethyl)anisole (14.7
g, 50 mmol) in DMSO (30 mL). The reaction mixture was stirred
at 50 °C for 3 h, poured into 0.04 M aqueous HCl (500 mL, 0
°
C), and extracted with ethyl acetate (3 × 150 mL). The
combined extracts were washed with water, dried over Na SO ,
2
4
and evaporated. The residue was recrystallized from diethyl
ether to furnish compound 8 as white crystals in 80% (11 g) yield.
SCHEME 4
Compound 8: 1H NMR (CDCl
3
, 300 MHz) δ 1.77 (s, 3H), 1.79
(
s, 3H), 3.63 (s, 2H), 3.72 (s, 2H), 3.79 (s, 3H), 6.71 (d, J ) 8.0
13
Hz, 1H), 6.80 (d, J ) 7.5 Hz, 1H), 7.20 (t, J ) 7.8 Hz, 1 H);
C
3
NMR (CDCl , 75 MHz) δ 28.8, 28.9, 43.3, 45.5, 52.2, 55.1, 105.1,
1
08.6, 116.0, 126.4, 129.4, 141.1, 155.6, 170.5; HRMS calcd for
276.0997, found 276.1002.
Eth yl 4-Meth oxy-2-m eth ylin d a n -2-ca r boxyla te 9. Com-
15 16 5
C H O
pound 8 (3.0 g, 10.87 mmol) was dissolved in dry ethanol (1.5
mL)-pyridine (15 mL) containing copper powder (0.125 g, 2
mmol) and boiled under argon for 4 h. After removal of pyridine,
the residue was diluted with ether and filtered through Celite
pad. Solvent was removed, and the residual green liquid was
purified by SGC by using 1:9 ethyl acetate/hexane to afford the
ester as a colorless oil in 86% yield (2.05 g).
The ester (1 equiv, 1.9 g, 8.63 mmol) in dry THF (10 mL) was
added to LDA (1.1 equiv) solution at -78 °C and stirred for 1 h
at the same temperature. Methyl iodide (5 equiv) was added to
the reaction mixture at -78 °C and warmed to room tempera-
ture. The reaction mixture was quenched with saturated am-
monium chloride solution, extracted with ether (3 × 100 mL),
puraquinonic acid. Ozonolysis followed by reductive
workup of the ozonolysis product with excess lithium
aluminum hydride afforded a triol. This triol could be
4
dried over MgSO , and evaporated. The residue was purified by
SGC by using 0.5:9.5 ethyl acetate/hexane to obtain ester 9 as
2
converted to quinone 12 using salcomine (Co(SALEN) )
a colorless oil in 96% yield (1.95 g).
and oxygen.14 Reaction of quinone 12 with ammonium
persulfate, acetic acid, and a catalytic amount of silver
nitrate at 70 °C produced quinone 3 in 68% yield. This
reaction proceeds by way of a radical intermediate.
Ammonium persulfate oxidizes the silver(I) salt to a
silver(II) salt, which decarboxylates to give the methyl
radical.15 The use of organometallic reagents such cup-
rates or organozinc reagents failed to introduce the
methyl group.
Compound 9: 1H NMR (CDCl
3
, 300 MHz) δ 1.30 (t, J ) 5.4
Hz, 3H), 1.40 (s, 3H), 2.84 (d, J ) 11.7 Hz, 1H), 2.88 (d, J )
12.03 Hz, 1H), 3.43 (d, J ) 12.3 Hz, 1H), 3.54 (d, J ) 11.9 Hz,
1
1
H), 3.84 (s, 3H), 4.21 (q, J ) 5.3 Hz, 2H), 6.70 (d, J ) 6.0 Hz,
13
H), 6.84 (d, J ) 5.6 Hz, 1H), 7.17 (t, J ) 5.8 Hz, 1H); C NMR
, 75 MHz) δ 14.4, 25.6, 40.9, 44.4, 49.3, 55.2, 60.8, 108.1,
(CDCl
3
1
2
17.1, 128.1, 128.9, 143.3, 156.2, 177.7; HRMS calcd for C14
34.1255, found 234.1259.
18 3
H O
E t h yl 2-Met h yl-4-(2-p r op en yloxy)in d a n -2-ca r b oxyla t e
10. To a mixture of phenethylthiol (1.75 mL, 3 equiv) and
dichloromethane (10 mL) was added aluminum chloride (1.75
g, 3 equiv) at 0 °C. The resulting solution was warmed to room
temperature, and ester 9 (1.023 g, 4.37 mmol) in dichlo-
romethane (10 mL) was added with stirring. After being stirred
for 8 h, the reaction mixture was poured into ice-water, acidified
with dilute HCl, extracted with dichloromethane, and dried over
MgSO . After removal of solvent, the residue was purified by
4
SGC by using 1:9 ethyl acetate/hexane to obtain the phenol as
a colorless oil in 93% yield (0.895 g).
To a stirred suspension of sodium hydride (8.36 mmol, 1.1
equiv, 60% dispersion in mineral oil, which had been washed
with pentane) in anhydrous DMF (10 mL) at 0 °C was added a
solution of the phenol (1.67 g, 7.60 mmol) in DMF (10 mL), and
the resulting solution was stirred at room temperature for 0.5
h. The solution was again cooled to 0 °C, allyl bromide (2 equiv,
Similarly, the product from the ozonolysis of 11 was
reduced with sodium borohydride to afford ester 13 in
7
0% yield. This compound reacted with ammonium
persulfate, silver nitrate, and acetic acid to provide the
ethyl ester of puraquinonic acid in 72% yield (Scheme
4
).
In summary, the synthesis of deliquinone and the
synthesis of the ethyl ester of puraquinonic acid were
achieved by a direct and flexible route. The direct
assemblage of the indan unit and the persulfate-mediated
quinone alkylation are key features of this route.
Exp er im en ta l Section
1
.3 mL) was added, and stirring was continued to reach room
P r ep a r a tion of Dila cton e 8. 2,3-Dimethylanisole (13.8 g,
00 mmol) and N-bromosuccinimide (37.38 g, 210 mmol) were
dissolved in dry carbon tetrachloride (1000 mL), and the mixture
was refluxed under argon for 3 h while being exposed to a 275
W high-intensity sunlamp. The solution was cooled to room
temperature, the suspended succinimide was removed by filtra-
temperature (1 h). The reaction mixture was then poured into
saturated brine (25 mL) and extracted with ether (4 × 75 mL).
The organic phases were combined, washed with saturated brine
(50 mL), and dried (MgSO ). Evaporation of the solvent yielded
4
a red oil that was purified by SGC by using 1:19 ethyl acetate/
1
hexane to obtain compound 10 as a colorless oil in 96% yield
(
1.88 g).
Compound 10: 1H NMR (CDCl
, 300 MHz) δ 1.31 (t, J ) 7.1
3
(14) Bloomer, J . L.; Stagliano, K. W. Tetrahedron Lett. 1993, 34,
Hz, 3H), 1.41 (s, 3H), 2.85 (d, J ) 16.0 Hz, 1H), 2.93 (d, J )
16.5 Hz, 1H), 3.51 (d, J ) 16.5 Hz, 1H), 3.55 (d, J ) 16.1 Hz,
1H), 4.21 (q, J ) 7.1 Hz, 2H), 4.56 (d, J ) 5.0 Hz, 2H), 5.28-
7
1
57.
(15) J acobsen, N.; Torssell, K. J ustus Liebigs Ann. Chem. 1972, 763,
35.
5
858 J . Org. Chem., Vol. 67, No. 16, 2002

5
.48 (m, 2H), 6.03-6.15 (m, 1H), 6.7 (d, J ) 8.1 Hz, 1H), 6.85
was continued at the same temperature for 1 h. The ethanol
was removed under reduced pressure at room temperature, and
the residue was acidified with cold dilute hydrochloric acid,
1
3
(
3
d, J ) 7.4 Hz, 1H), 7.15 (t, J ) 7.8 Hz, 1H); C NMR (CDCl ,
7
5 MHz) δ 14.2, 25.4, 40.9, 44.3, 49.2, 60.6, 68.5, 109.3, 117.0,
17.1, 127.9, 129.1, 133.5, 143.3, 155.2, 177.5; HRMS calcd for
260.1412, found 260.1416.
E t h yl 4-H yd r oxy-2-m et h yl-5-(2-p r op en yl)in d a n -2-ca r -
boxyla te 11. Compound 10 (1 g, 3.84 mmol) in anhydrous DMF
8 mL) was heated in sealed tube at 200 °C for 7 h. After removal
1
C
extracted with ethyl acetate (3 × 25 mL), and dried over Na
2
-
16
H
20
O
3
SO . After removal of solvent, the crude product was purified
4
by SGC by using 1:3 ethyl acetate/hexane to afford the diol ester
in 72% yield (0.19 g).
(
To a stirred solution of diol ester (0.08 g, 0.3 mmol) in
acetonitrile (5 mL) was added salcomine hydrate (0.4 equiv).
Oxygen was bubbled through the solution for 5 min, and then
the solution was stirred for an additional 24 h in the oxygen
atmosphere. Acetonitrile was removed under reduced pressure,
and the residue was purified by SGC by using 3:1 ethyl acetate/
hexane to yield compound 13 as a yellow viscous liquid in 98%
yield.
of DMF under reduced pressure, the residue was purified by
SGC by using 1:9 ethyl acetate/hexane to yield the compound
1
1 as a colorless oil in 82% yield along with starting compound
in 8%.
Compound 11: 1H NMR (CDCl
3
, 300 MHz) δ 1.27 (t, J ) 5.3
Hz, 3H), 1.4 (s, 3H), 2.78 (d, J ) 11.8 Hz, 1H), 2.82 (d, J ) 11.9
Hz, 1H), 3.37-3.49 (m, 4H), 4.18 (q, J ) 5.3 Hz, 2H), 4.9 (s,
1
1
2
1
H), 5.15-5.21 (m, 2H), 5.97-6.07 (m, 1H), 6.74 (d, J ) 5.6 Hz,
Compound 13: 1H NMR (CDCl
Hz, 3H), 1.39 (s, 3H), 1.68 (t, J ) 4 Hz, 1H), 2.68-2.75 (m, 4H),
3
, 300 MHz) δ 1.27 (t, J ) 5.3
H), 6.93 (d, J ) 5.6 Hz, 1H); 13C NMR (CDCl
5.7, 35.4, 40.3, 44.3, 49.9, 60.9, 116.6, 117.1, 122.9, 127.5, 129.3,
37.0, 142.2, 150.9, 177.7; HRMS calcd for C16 260.1412,
, 75 MHz) δ 14.4,
3
3
2
4
1
.35 (m, 2H), 3.83 (dd, J ) 8.5, 4.4 Hz, 2H), 4.18 (q, J ) 5.4 Hz,
H
20
O
3
13
H), 6.59 (s, 1H); C NMR (CDCl
2.2, 42.5, 47.3, 61.3, 61.5, 134.6, 146.1, 146.3, 146.6, 176.5,
86.0, 186.3; HRMS calcd for C15 278.1154, found 278.1157.
P r ep a r a tion of Com p ou n d s 2 a n d 3. A mixture of quinone
13, 0.055 g, 0.2 mmol or 12, 0.024 g, 0.1 mmol), acetic acid (1.5
3
, 75 MHz) δ 14.4, 26.2, 32.7,
found 260.1416.
,7-Dih ydr o-4,7-dioxo-2-m eth yl-5-(2-h ydr oxyeth yl)in dan -
-m eth a n ol 12. Ozone was bubbled through a solution of
compound 11 (0.26 g, 1 mmol) in dichloromethane (8 mL) at -78
C for 7 min. Argon was passed through the ozonide solution at
4
18 5
H O
2
(
°
equiv), silver nitrate (0.2 equiv), and ammonium persulfate (1.2
equiv) in 1 mL of 1:1 acetonitrile/water was heated at 65-70 °C
for 3-4 h. The solution was diluted with methylene chloride.
The organic layer was washed with water, dried over sodium
sulfate, and concentrated in vacuo. The crude residue was
purified by preparative thin-layer chromatography using 1:1 and
room temperature for 5 min, dichloromethane was removed
under reduced pressure at room temperature, immediately the
ozonide in anhydrous THF (5 mL) was added dropwise to lithium
aluminum hydride (3 equiv) in THF (2 mL) at 0 °C, and stirring
was continued for 0.5 h at 0 °C. The reaction mixture was then
decomposed by addition of a few drops of water followed by 10%
sulfuric acid. The reaction mixture was then extracted with ethyl
3
:1 ethyl acetate/hexane to furnish the compounds 2 and 3 as
viscous brown liquid in 64% and 68% yield, respectively, along
with the starting compounds 13 and 12 in 13% and 15% yield.
acetate (3 × 25 mL) and dried (Na
2 4
SO ). Solvent was removed
under reduced pressure, and the residue was purified by SGC
by using 1:1 ethyl acetate/hexane to furnish the triol as a viscous
oil in 63% yield (0.14 g).
Compound 2 (R ) Et): 1H NMR (CDCl
3
, 300 MHz) δ 1.26 (t,
J ) 7.1 Hz, 3H), 1.37 (s, 3H), 1.78 (br s, 1H), 2.07 (s, 3H), 2.67-
2
2
1
1
2
.80 (m, 4H), 3.34 (d, J ) 16.3 Hz, 2H), 3.77 (br t, J ) 5.8 Hz,
To a stirred solution of the triol (0.044 g, 0.2 mmol) in
acetonitrile (5 mL) was added salcomine hydrate (0.4 equiv).
Oxygen was bubbled through the solution for 5 min, and then
the solution was stirred for an additional 24 h in the oxygen
atmosphere. Acetonitrile was removed under reduced pressure,
and the residue was purified by SGC by using 3:1 ethyl acetate/
hexane to yield the compound 12 as a yellow viscous liquid in
13
H), 4.17 (q, J ) 7.1 Hz, 2H); C NMR (CDCl
3
, 100 MHz) δ
2.4, 14.4, 26.2, 30.1, 42.5, 42.6, 47.2, 61.4, 61.7, 141.5, 142.9,
45.6, 146.0, 176.6, 186.0, 186.5; HRMS calcd for C16
92.1310, found 292.1312.
20 5
H O
Compound 3: 1H NMR (CDCl
, 300 MHz) δ 1.17 (s, 3H), 2.07
s, 3H), 2.49 (d, J ) 16.1 Hz, 1H), 2.54 (d, J ) 17.7 Hz, 1H),
3
(
2
2
4
.77-2.86 (m, 4H), 3.50 (br s, 2H), 3.76 (dd, J ) 11.4, 5.7 Hz,
H); 13C NMR (CDCl
, 75 MHz) δ 12.4, 25.1, 30.1, 40.7, 40.8,
3.0, 61.7, 70.2, 141.5, 142.8, 146.8, 147.2,186.5, 187.0; HRMS
250.1205, found 250.1208.
9
8% yield.
Compound 12: 1H NMR (CDCl
, 300 MHz) δ 1.17 (s, 3H), 1.65
3
3
(
)
3
br s, 1H), 1.72 (br s, 1H), 2.48 (d, J ) 19.0 Hz, 1H), 2.54 (d, J
calcd for C14
18 4
H O
19.5 Hz, 1H), 2.68 (t, J ) 6.1 Hz, 2H), 2.81-2.88 (m, 2H),
.51 (br s, 2H), 3.82 (dd, J ) 10.6, 5.5 Hz, 2H), 6.57 (s, 1H); 13
C
NMR (CDCl
1
2
3
, 75 MHz) δ 25.1, 32.7, 40.5, 40.7, 43.1, 61.3, 70.1,
Ack n ow led gm en t. We thank Iowa State University
for partial support of this research.
34.6, 146.6, 147.3, 147.4, 186.5, 186.8; HRMS calcd for C13
H
16
O
4
36.10486, found 236.1050.
Eth yl 4,7-Dih yd r o-4,7-d ioxo-2-m eth yl-5-(2-h d r oxyeth yl)-
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
obtained compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
in d a n -2-ca r boxyla te 13. Ozone was bubbled through a solution
of compound 11 (0.26 g, 1 mmol) in absolute ethanol (6 mL) at
-
78 °C for 5-7 min. The ozonide solution was then added
dropwise to sodium borohydride in ethanol at 0 °C, and stirring
J O020029G
J . Org. Chem, Vol. 67, No. 16, 2002 5859