A synthesis of a thysanone analog

Article abstract of DOI:10.1016/S0040-4020(02)00823-2

Hemiacetal 10 was prepared in 13 steps from dimethoxybenzaldehyde. Key steps included the salcomine oxidation of a phenol and a selective deprotection using boron trichloride.

Full text of DOI:10.1016/S0040-4020(02)00823-2

Tetrahedron 58 (2002) 7391–7395
A synthesis of a thysanone analog
*
George A. Kraus and Herbert Ogutu
Department of Chemistry, Iowa State University, 2759 Gilman Hall, Ames, IA 50011, USA
Received 17 June 2002; accepted 11 July 2002
Abstract—Hemiacetal 10 was prepared in 13 steps from dimethoxybenzaldehyde. Key steps included the salcomine oxidation of a phenol
and a selective deprotection using boron trichloride. q 2002 Elsevier Science Ltd. All rights reserved.
In the process of screening microbial extracts for lead
compounds that would be developed into chemotherapeutic
agents for eventual control/cure of the common cold, Singh
and co-workers isolated thysanone (1), a novel naphtho-
quinone. Thysanone is an effective inhibitor (IC50
13 mg/mL) of human rhinovirus 3C-protease (Scheme 1).1
anion of 3 (NaH, THF, 08C) reacted with 2,4-dimethoxy-
benzaldehyde to provide the bis-ester adduct in 75% yield.
The tert-butyl ester was then selectively cleaved with 90%
aqueous trifluoroacetic acid to afford acid 4 in almost
quantitative yield. Acid 4, potassium acetate, and acetic
anhydride were heated for 3 h to produce 5a in 75% yield.5
Diester 5a was treated with acetyl chloride in methanol at
08C to yield naphthol 5b in almost quantitative yield
(Scheme 2).
With 5b in hand, we studied the oxidation of naphthol 5b to
naphthoquinone 2. After several unsuccessful attempts
(potassium dinitrodisulfonate (complex mixture),6 phenyl
iodo-di-trifluoroacetate (mixture of three products),7 salco-
mine (no reaction),8 and ceric ammonium nitrate (no
reaction)9) we had to rethink our approach. The O-alkyl-
ation of naphthol 5b was accomplished using allyl bromide
and potassium carbonate. The reaction gave ether 5c in 90%
yield. Compound 5c in DMF was purged with argon and
heated in a sealed tube to 2108C. After several experiments,
conditions were established wherein naphthol 6a was
produced in 75% yield. One of the side products of this
reaction was a dihydronaphthofuran.10 This by-product was
likely produced via trace amounts of acid. This by-product
could be minimized by washing the tube with base before
conducting the Claisen rearrangement.
Scheme 1.
The positive strand RNA genome of human rhinoviruses
(HRVs) is translated directly into a viral polyprotein
(200 kD) precursor which undergoes a series of proteolytic
cleavages to generate viral gene products. Processing of the
polyprotein is dependent upon two virally encoded
proteases (‘3C-protease’ and ‘2A-protease’) which have
no known cellular homologues. They represent attractive
targets for the development of antiviral agents. Thysanone
inhibits HRV-3C protease, thus curtailing viral replication.
To date, there has been one total synthesis of thysanone and
a few syntheses of analogs.2 The strategy used by Gill and
co-workers in their total synthesis is quite different from our
approach. As part of a program for the synthesis of tethered
mixed mechanism antivirals (TMMA), we intend to connect
thysanone with hypericin, a natural product with a broad
range of antiviral activity.3 To effect this connection, we
have developed a synthesis of a thysanone analog with a
hydroxymethyl group instead of a methyl group.
Phenol 6a was readily silylated (tert-butyldimethylsilyl
chloride, imidazole, CH2Cl2) to produce 6b. Unfortunately,
treatment of 6b with DIBAL resulted in recovered starting
material. LAH reduction of 6b afforded alcohol 7 in 95%
yield. PCC oxidation of 7 proceeded in 90% yield to give
aldehyde 8.11 The dihydroxylation of 8 using a catalytic
amount of osmium tetroxide with NMO as the oxidant
directly afforded a lactol in 75% yield. The lactol was
dissolved in methanol containing a catalytic amount of
concentrated sulfuric acid. Instead of replacing the hydroxyl
group at C-1 with a methoxyl group, a cyclic acetal was
formed. Additionally, the TBS ether was cleaved to give
naphthol 9. Potassium dinitrodisulfonate, ceric ammonium
Our synthetic route began with known phosphonate 3.4 The
Keywords: thysanone analog; hemiacetal; chemotherapeutic agents.
*
Corresponding author. Tel.: þ1-515-294-7794; fax: þ1-515-294-0105;
e-mail: gakraus@iastate.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00823-2

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G. A. Kraus, H. Ogutu / Tetrahedron 58 (2002) 7391–7395
Scheme 2.
nitrate, and phenyl iodo-di-trifluoroacetate did not oxidize
naphthol 9. However, when naphthol 9 was treated with a
catalytic amount of salcomine in the presence of oxygen, a
naphthoquinone was formed in 60% yield. Selective
demethylation at C-9 peri to the carbonyl C-10 was
achieved with 1.1 equiv. of boron trichloride, at 08C in
methylene chloride.12 In addition to the demethylation, the
acetal also opened, resulting in hemiacetal 10 (Scheme 3).
1. Experimental
1.1. Data for compounds
1.1.1. 2-(2,4-Dimethoxy-benzylidene)-succinic acid
1-ethyl ester (4). To a suspension of 1.46 g (36.5 mmol)
sodium hydride (60% dispersion, hexane washed) in 50 mL
of dry THF was added phosphonate 3 (12.2 g, 36 mmol)
dropwise. The reaction mixture was stirred for 2 h at 08C
under argon. A solution of 2,4-dimethoxybenzaldehyde
(5.82 g, 35.0 mmol) in 30 mL THF was prepared in a
250 mL flask. The anion solution was added dropwise with
stirring to the aldehyde solution at 08C under argon. The
cooling bath was removed and the reaction mixture was
stirred and allowed to warm to rt overnight. After 18 h,
water (20 mL) was added and the solvent was removed in
vacuo. The residue was partitioned between water and
methylene chloride. The organic phase was collected, dried
over sodium sulfate, filtered and evaporated to dryness in
vacuo. The product was purified by flash column chroma-
tography using hexanes and ethyl acetate (30:1). The pure
The stereochemistry of 10 was assigned in analogy to that of
thysanone, which exists as a single stereoisomer with the
hydroxyl group in the axial orientation. The synthesis by
Gill and co-workers2 generated the hemiacetal unit by
hydrolysis of a benzylic bromide. This hydrolysis afforded a
single isomer whose NMR spectrum was identical to that of
natural thysanone.
Hemiacetal 10 was prepared in 13 steps from dimethoxy-
benzaldehyde. This compound will be useful for structure–
activity studies as well as for the synthesis of tethered
antiviral agents.
Scheme 3.

G. A. Kraus, H. Ogutu / Tetrahedron 58 (2002) 7391–7395
7393
product was obtained in 75% yield as a viscous oil. 1H NMR
(300 MHz, CDCl3) d 1.33 (t, J¼7.2 Hz, 3H), 1.46 (s, 9H),
3.40 (s, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 4.25 (q, J¼7.2 Hz,
2H), 6.46 (d, J¼2.4 Hz, 1H), 6.50 (dd, J1¼8.4 Hz, J2¼
2.4 Hz, 1H), 7.26 (d, J¼8.4 Hz, 1H), 7.91 (s, 1H). 13C NMR
(300 MHz, CDCl3) d 14.4, 28.2, 35.5, 55.5, 55.6, 60.9,
80.9, 98.5, 104.4, 117.2, 125.2, 130.6, 137.2, 159.1, 161.9,
167.9, 170.9. MS (m/z) 350 (Mþ), 294, 249, 166, 148, 89,
61, 43. HRMS calcd for C19H26O6 350.1729, found
350.1735.
1.1.4. 4-Allyloxy-6,8-dimethoxy-naphthalene-2-carb-
oxylic acid ethyl ester (5c). To a stirred solution of
3.71 g (13.4 mmol) of 5b in 50 mL of acetone was added
3.73 g (27 mmol) of potassium carbonate and 3.3 g
(27 mmol) of allyl bromide. The resulting mixture was
heated under reflux and the reaction was monitored by TLC.
After 18 h, the reaction mixture was cooled, and then
suction filtered through a pad of Celite. The filtrate was
concentrated in vacuo, and the product was purified by flash
column chromatography using hexanes and ethyl acetate
1
(15:1), to give 5c, a pale yellow solid, in 90% yield. H
The tert-butyl ester (5.2 g, 14.86 mmol) was dissolved in
20 mL of trifluoroacetic acid/water (9/1) at rt. The mixture
was stirred, and the progress of the reaction monitored by
TLC. When the reaction was complete, the solvent was
removed under reduced pressure to give crude compound 4.
The crude product was partitioned between 10% aqueous
sodium hydrogen carbonate (100 mL) and ethyl acetate
(50 mL). The aqueous phase was separated, acidified with
concentrated hydrochloric acid to pH 2, and extracted with
ethyl acetate (3£30 mL). The organic extract was dried and
evaporated under reduced pressure to give pure 4, a white
solid, in almost quantitative yield. 1H NMR (300 MHz,
CDCl3) d 1.35 (t, J¼7.2 Hz, 3H), 3.52 (s, 2H), 3.83 (s, 3H),
3.84 (s, 3H), 4.34 (q, J¼7.2 Hz, 2H), 6.47 (d, J¼2.4 Hz,
1H), 6.55 (dd, J1¼8.4 Hz, J2¼2.4 Hz, 1H), 7.31 (d, J¼
8.4 Hz, 1H), 7.99 (s, 1H). 13C NMR (300 MHz, CDCl3) d
14.3, 34.3, 55.7, 55.8, 62.0, 98.8, 104.9, 116.6, 123.3, 130.9,
139.6, 159.2, 164.5, 168.9, 178.3. MS (m/z ) 294 (Mþ), 294,
249, 166, 148, 89, 61, 43. HRMS calcd for C15H18O6
294.2998, found 294.2986.
NMR (300 MHz, CDCl3) d 1.44 (t, J¼7.2 Hz, 3H), 3.95 (s,
3H), 3.99 (s, 3H), 4.42 (q, J¼7.2 Hz, 2H), 4.78 (d, J1¼
4.8 Hz, 2H), 5.35 (dd, J1¼10.1 Hz, J2¼1.5 Hz, 1H), 5.52
(dd, J1¼17.1 Hz, J2¼1.5 Hz, 1H), 6.13–6.26 (m, 1H), 6.55
(d, J¼2.1 Hz, 1H), 7.17 (d, J¼2.1 Hz, 1H), 7.43 (d, J¼
1.5 Hz, 1H), 8.52 (s, 1H). 13C NMR (300 MHz, CDCl3) d
14.7, 52.3, 55.6, 55.8, 69.3, 92.9, 98.7, 105.7, 117.3, 118.4,
121.8, 124.3, 130.1, 133.4, 153.3, 157.7, 160.3, 167.8. MS
(m/z) 316 (Mþ), 271, 243, 227, 199, 139, 128. HRMS calcd
for C18H20O5 316.1311, found 316.1314.
1.1.5. 3-Allyl-4-hydroxy-6,8-dimethoxy-naphthalene-2-
carboxylic acid ethyl ester (6a). A flame-dried pressure
tube, cooled under a stream of argon, was charged with
1.58 g (5 mmol) of ether 5c and dissolved in 5 mL of
dimethylformamide. The solution was degassed with argon
for 10 min. The pressure tube was sealed and placed in an
oil bath. The temperature of the oil bath was raised to 2108C,
and the solution stirred at this temperature for 6 h. The tube
was cooled to rt and the solvent removed under reduced
pressure. The resulting crude product was purified by flash
column chromatography using hexanes and ethyl acetate
(10:1) to afford naphthol 6a in 78% yield as the major
1.1.2. 4-Acetoxy-6,8-dimethoxy-naphthalene-2-carboxylic
acid ethyl ester (5a). The acid 4 (4.2 g, 14.3 mmol) and
anhydrous potassium acetate (1.54 g, 15.7 mmol) were
dissolved in acetic anhydride (50 mL). The solution was
heated at reflux for 2 h. The solvent was removed in
vacuo, and the product was purified by recrystallization
from ethanol to give a pale yellow crystalline solid in 75%
yield. 1H NMR (300 MHz, CDCl3) d 1.42 (t, J¼7.2 Hz, 3H),
2.46 (s, 3H), 3.92 (s, 3H), 3.99 (s, 3H), 4.44 (q, J¼7.2 Hz,
2H), 6.54 (d, J¼2.1 Hz, 1H), 6.67 (d, J¼2.1 Hz, 1H), 7.81
(d, J¼1.5 Hz, 1H), 8.80 (s, 1H). 13C NMR (300 MHz,
CDCl3) d 14.7, 21.3, 55.6, 56.0, 61.3, 91.8, 98.8, 119.4,
122.5, 123.5, 124.6, 131.4, 145.6, 158.2, 161.2, 166.5,
169.5.
1
product. H NMR (300 MHz, CDCl3) d 1.42 (t, J¼7.2 Hz,
3H), 3.88 (d, J¼1.8 Hz, 2 H), 3.92 (s, 3H), 3.99 (s, 3H), 4.43
(q, J¼7.2 Hz, 2H), 5.19 (dd, J1¼4.2 Hz, J2¼1.5 Hz, 1H),
5.24 (dd, J1¼17.1 Hz, J2¼1.5 Hz, 1H), 6.07–6.20 (m, 1H),
6.50 (d, J¼2.1 Hz, 1H), 7.05 (d, J¼2.1 Hz, 1H), 8.37 (s,
1H). 13C NMR (300 MHz, CDCl3) d 14.6, 32.0, 55.6, 55.8,
61.1, 92.2, 98.4, 116.4, 118.7, 119.0, 120.5, 125.8, 128.5,
136.6, 149.9, 157.4, 160.2, 168.3. MS (m/z) 316 (Mþ), 269,
255, 243, 227, 211, 199, 139, 128. HRMS calcd for
C18H20O5 316.1311, found 316.1314.
1.1.6. 3-Allyl-4-(tert-butyldimethyl-silyloxy)-6,8-di-
methoxy-naphthalene-2-carboxylic acid ethyl ester
(6b). Naphthol 6a (377 mg, 1.2 mmol) was dissolved in
methylene chloride (20 mL) and treated with tert-butyl
dimethylsilyl chloride (270 mg, 1.8 mmol), imidazole
(123 mg, 1.8 mmol), and dimethylaminopyridine (20 mg).
The mixture was stirred for 18 h at rt after which the solvent
was removed in vacuo. The residue was purified by flash
column chromatography (hexane–ethyl acetate 25:1) to
give silyl ether 6b in 92% yield. 1H NMR (300 MHz,
CDCl3) d 0.21 (s, 6H), 1.13 (s, 9H), 1.44 (t, J¼7.2 Hz, 3H),
3.88 (d, J¼6.6 Hz, 2H), 3.92 (s, 3H), 3.96 (s, 3H), 4.37 (q,
J¼7.2 Hz, 2H), 4.89 (dd, J1¼5.1 Hz, J2¼1.5 Hz, 1H), 4.97
(dd, J1¼15.1 Hz, J2¼1.5 Hz, 1H), 5.86–5.97 (m, 1H), 6.50
(d, J¼2.1 Hz, 1H), 7.05 (d, J¼2.1 Hz, 1H), 8.40 (s, 1H). 13C
NMR (300 MHz, CDCl3) d 22.7, 14.6, 19.0, 26.0, 30.0,
32.2, 55.6, 55.8, 61.0, 94.3, 98.0, 115.0, 119.7, 120.6, 126.2,
127.1, 131.7, 137.7, 148.4, 157.5, 159.7, 168.7. MS (m/z)
MS (m/z ) 294 (Mþ), 294, 249, 166, 148, 89, 61, 43. HRMS
calcd for C17H18O6 318.1103, found 318.1112.
1.1.3. 4-Hydroxy-6,8-dimethoxy-naphthalene-2-carb-
oxylic acid ethyl ester (5b). To a solution of 1.84 g
(5.79 mmol) of 5a in 10 mL of methanol was added 94.2 mg
(1.2 mmol) of acetyl chloride at 08C. The mixture was
stirred at 08C and allowed to warm to rt. After 12 h, the
solvent was removed in vacuo, and the product was purified
by recrystallization from ethanol to give a grayish-white
1
solid in 95% yield. H NMR (300 MHz, CDCl3) d 1.46 (t,
J¼7.2 Hz, 3H), 3.96 (s, 3H), 3.99 (s, 3H), 4.46 (q, J¼
7.2 Hz, 2H), 6.55 (d, J¼2.1 Hz, 1H), 7.15 (d, J¼2.1 Hz,
1H), 7.56 (d, J¼1.5 Hz, 1H), 8.50 (s, 1H). 13C NMR
(CDCl3) 14.6, 55.8, 55.9, 61.3, 92.6, 98.9, 109.4, 118.2,
122.3, 124.7, 129.0, 150.8, 157.8, 160.3, 167.6.

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G. A. Kraus, H. Ogutu / Tetrahedron 58 (2002) 7391–7395
316 (Mþ), 269, 255, 243, 227, 211, 199, 139, 128. HRMS
monitored by tlc analysis. After 42 h of stirring at rt, tlc
analysis indicated the complete disappearance of 8 and the
appearance of a new, more polar spot. A 1:1 (w/w) mixture
of sodium hydrosulfite and sodium sulfite (700 mg) was
then added to the reaction mixture and stirring continued for
30 min. The mixture was then filtered through a short pad of
Celite on a 150 mL sintered-glass funnel. The Celite pad
was washed with three 15 mL portions of acetone. The
filtrate, combined with the acetone wash, was dried over
sodium sulfate. The solvent was removed under reduced
pressure, and the product was purified by flash column
chromatography using hexanes and ethyl acetate (1:1) to
afford a hemiacetal in 72% yield. 1H NMR (300 MHz,
CDCl3) d 0.23 (s, 3H), 0.26 (s, 3H), 1.11 (s, 9H), 2.79
(br d, J¼17.1 Hz, 1H), 3.32 (br dd, J1¼17.1 Hz, J2¼
1.5 Hz, 1H), 3.69 (br dd, J1¼7.2 Hz, J2¼1.8 Hz, 1H), 3.89
(s, 3H), 3.94 (s, 3H), 4.00 (td, J1¼6.3 Hz, J2¼1.8 Hz,
1H), 4.94–4.98 (m, 1H), 6.12 (s, 1H), 6.45 (d, J¼2.4 Hz,
1H), 6.89 (d, J¼ 2.4 Hz, 1H), 7.62 (s, 1H), 13C NMR
(300 MHz, CDCl3) d 23.4, 23.1, 19.0, 26.3, 31.8, 55.5,
55.8, 68.2, 72.4, 93.6, 97.7, 101.2, 112.3, 117.7, 121.6,
129.7, 132.0, 148.6, 158.1. MS (m/z ) 420 (Mþ), 402, 345,
315, 273, 228. HRMS calcd for C22H32O6Si 420.1968,
found 420.1973.
calcd for C24H34O5Si 430.6093, found 430.6085.
1.1.7. [3-Allyl-4-(tert-butyldimethylsilyloxy)-6,8-di-
methoxynaphthalen-2-yl]-methanol (7). A solution of 6b
(570 mg, 1.32 mmol) dissolved in 20 mL of THF was added
dropwise to a stirred suspension of lithium aluminum
hydride (150 mg, 3.96 mmol) and 20 mL THF at 58C under
argon. The reaction was stirred under these conditions for
1.5 h and then quenched with the sequential dropwise
addition of the following: water (0.15 mL), 15% sodium
hydroxide solution (0.15 mL), and water (0.45 mL). This
mixture was stirred for 6 h at rt and then suction filtered
through a short pad of Celite and silica gel. The filtering pad
was washed with three 5 mL portions of ethyl acetate. The
filtrate was combined with the ethyl acetate wash, dried over
anhydrous sodium sulfate, and concentrated under reduced
pressure to give a crude mixture of 7. The residue was
purified by flash column chromatography using hexanes and
1
ethyl acetate (10:1), to afford 7 in 95% yield. H NMR
(300 MHz, CDCl3) d 0.23 (s, 6H), 1.11 (s, 9H), 3.68 (br d,
J¼5.7 Hz, 2H), 3.91 (s, 3H), 3.95 (s, 3H), 4.78 (s, 2H), 4.90
(br dd, J1¼17.1 Hz, J2¼1.8 Hz, 1H), 5.00 (br dd, J1¼
10.2 Hz, J2¼1.8 Hz, 1H), 5.90–6.03 (m, 1H), 6.47 (d,
J¼2.1 Hz, 1H), 6.95 (d, J¼2.1 Hz, 1H), 7.85 (s, 1H). 13C
NMR (300 MHz, CDCl3) d 22.6, 19.0, 26.3, 30.9, 55.5,
55.7, 64.4, 94.2, 97.5, 115.2, 115.6, 121.5, 125.1, 129.2,
135.5, 137.3, 148.3, 156.7, 157.8. MS (m/z) 388 (Mþ), 370,
312. HRMS calcd for C22H32O4Si 388.2070, found
388.2076.
To a solution of hemiacetal (340 mg, 0.81 mmol) in 20 mL
of methanol was added 2 drops of 6 M sulfuric acid. The
mixture was heated at reflux for 1 h, after which the solvent
removed under reduced pressure. The residue was directly
subjected to flash column chromatography (hexane–ethyl
acetate 1:1), affording 9 in 75% yield as a pale yellow solid.
1H NMR (300 MHz, CDCl3) d 2.79 (br d, J¼16.5 Hz, 1H),
3.31 (br dd, J1¼16.2 Hz, J2¼5.1 Hz, 1H), 3.73 (br dd,
J1¼7.5 Hz, J2¼1.5 Hz, 1H), 3.92 (s, 3H), 3.96 (s, 3H), 4.03
(td, J1¼7.5 Hz, J2¼1.5 Hz, 1H), 4.98–5.02 (m, 1H), 6.18 (s,
1H), 6.48 (d, J¼2.1 Hz, 1H), 6.89 (d, J¼2.1 Hz, 1H), 7.57
(s, 1H). 13C NMR (300 MHz, CDCl3) d 25.5, 54.9, 55.3,
65.6, 68.6, 76.5, 92.0, 97.4, 108.5, 116.6, 121.2, 125.2,
131.0, 148.9, 156.6, 157.7. MS (m/z ) 288 (Mþ), 258, 230,
215, 187. HRMS calcd for C16H16O5 288.0998, found
288.1002.
1.1.8. 3-Allyl-4-(tert-butyldimethylsilyloxy)-6,8-di-
methoxynaphthalene-2-carbaldehyde (8). To a solution
of 7 (0.53 g, 1.36 mmol) in methylene chloride (20 mL) was
added a finely ground portions of a mixture of pyridinium
chlorochromate (0.52 g, 2.72 mmol) and Celite (1.18 g)
over a period of 30 min at rt. The reaction mixture was
stirred for 18 h at rt, after which it was diluted with
methylene chloride and filtered through a short pad of
Celite. The Celite pad was washed with two 10 mL portions
of methylene chloride which were combined with the
filtrate, dried over sodium sulfate, and evaporated under
reduced pressure. The residue was purified by flash column
chromatography (hexane–ethyl acetate 10:1) giving 8 in
90% yield. 1H NMR (300 MHz, CDCl3) d 0.23 (s, 6H), 1.12
(s, 9H), 3.96 (br d, J¼5.7 Hz, 2H), 3.91 (s, 3H), 3.98 (s, 3H),
4.90 (br dd, J1¼17.1 Hz, J2¼1.8 Hz, 1H), 4.97 (br dd,
J1¼10.2 Hz, J2¼1.8 Hz, 1H), 5.90–6.03 (m, 1H), 6.49 (d,
J¼2.1 Hz, 1H), 6.98 (d, J¼2.1 Hz, 1H), 7.85 (s, 1H), 10.16
(s, 1H). 13C NMR (300 MHz, CDCl3) d 23.6, 14.4, 22.9,
26.3, 29.3, 30.3, 55.7, 55.9, 94.8, 98.2, 115.5, 125.3, 125.9,
129.2, 130.7, 137.5, 148.5, 158.1, 160.9, 193.1. MS (m/z)
386 (Mþ), 369, 329, 301, 296, 260. HRMS calcd for
C22H30O4Si 386.1913, found 386.1919.
1.1.10. 1,9-Dihydroxy-3-hydroxymethyl-7-methoxy-3,4-
dihydro-1H-benzo[g]isochromene-5,10-dione (10). To a
solution of 9 (124 mg, 0.43 mmol) in 25 mL acetonitrile
was added bis(salicylidene)ethylenediiminocobalt(II) (salco-
mine) (5 mg, 0.15 mmol). Oxygen was bubbled into the
solution for 2 h and the mixture was stirred at rt for 18 h.
The reaction mixture was diluted with 10 mL acetonitrile
and filtered through a short pad of Celite. The solvent was
removed in vacuo and the crude product was purified by
flash column chromatography (ethyl acetate–hexane 2:1) to
give a quinone, a crystalline yellow solid, in 60% yield. 1H
NMR (300 MHz, CDCl3) d 2.45 (br d, J¼19.5 Hz, 1H), 3.05
(br ddd, J1¼19.5 Hz, J2¼4.5 Hz, J3¼2.4 Hz 1H), 3.67 (br
dd, J1¼7.8 Hz, J2¼1.8 Hz, 1H), 3.92 (s, 3H), 3.96 (s, 3H),
4.02 (td, J1¼6.0 Hz, J2¼2.4 Hz, 1H), 4.89–4.92 (m, 1H),
6.39 (s, 1H), 6.73 (d, J¼2.4 Hz, 1H), 7.23 (d, J¼2.4 Hz,
1H). 13C NMR (300 MHz, CDCl3) d 26.2, 29.6, 56.4, 56.7,
69.1, 71.5, 93.2, 103.6, 104.6, 136.0, 136.6, 143.0, 162.3,
164.9, 180.7, 185.3. MS (m/z ) 302 (Mþ), 303, 284, 271,
255, 227. HRMS calcd for C16H14O6 302.0790, found
302.0795.
1.1.9. 8,10-Dimethoxy-1,3,4,5-tetrahydro-1,4-epoxy-2-
naphthoxepin-6-ol (9). To a magnetically stirred solution
of 8 (364 mg, 0.94 mmol) and N-methylmorpholine N-oxide
(165 mg, 1.41 mmol) in 25 mL of 10% water in acetone
(v/v) was added a solution of osmium tetroxide (4.7 mL,
0.094 mmol) in tert-butyl alcohol (0.02 M, 1.0 g of osmium
tetroxide in 196 mL of tert-butyl alcohol containing 0.5%
tert-butyl hydroperoxide). The reaction progress was

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7395
2. (a) Donner, C. D.; Gill, M. J. Chem. Soc., Perkin Trans. 1
2002, 938–948. (b) Gill, M.; Donner, C. D. Tetrahedron Lett.
1999, 40, 3921. (c) Brimble, M. A.; Elliott, R. J. R.
Tetrahedron 2002, 58, 183–189. (d) Singh, S. B.; Graham,
P. L.; Reamer, R. A.; Cordingley, M. G. Bioorg. Med. Chem.
Lett. 2001, 11, 3143–3146.
To a solution of quinone (24 mg, 0.079 mmol) in dry
methylene chloride (10 mL) under argon, 1 M boron
trichloride solution in methylene chloride (0.095 mL,
0.095 mmol) was added at 08C. The reaction mixture was
stirred at 08C for 1 h and at rt for 2 h. After the reaction was
complete, the reaction mixture was diluted with methylene
chloride, washed with brine, dried over sodium sulfate, and
concentrated under reduced pressure. The residue was
purified by flash column chromatography (eluting with 2:1
ethyl acetate/hexane) to give 10, an orange solid, in 58%
yield. 1H NMR (300 MHz, d6-acetone) d 2.38 (br dd,
J1¼19.5 Hz, J2¼10.2 Hz, 1H), 2.70 (br dd, J1¼19.5 Hz,
J2¼3.6 Hz, 1H), 3.72 (t, J¼5.1 Hz, 2H), 3.98 (s, 3H), 4.26–
4.34 (m, 1H), 6.00 (s, 1H), 6.76 (d, J¼2.4 Hz, 1H), 7.11 (d,
J¼2.4 Hz, 1H).
3. Wills, N. J.; Park, J.; Wen, J.; Kesavan, S.; Kraus, G. A.;
Petrich, J. W.; Carpenter, S. Wen. Photochem. Photobiol.
2001, 74, 216–220.
4. Owton, W. M.; Gallagher, P. T.; Juan-Montesinos, A. Synth.
Commun. 1993, 23, 2119.
5. Boger, D. L.; Turnbull, P. J. Org. Chem. 1998, 63, 8004.
6. Achari, B.; Bandyopadhyay, S.; Basu, K.; Pakrashi, S. C.
Tetrahedron 1985, 41, 107.
7. Tamura, Y.; Yakura, T.; Tohma, H.; Kikuchi, K.; Kita, Y.
Synthesis 1989, 127.
13C NMR (300 MHz, CDCl3) d 24.4, 56.0, 59.9, 64.6, 66.4,
85.9, 106.0, 107.5, 136.6, 145.8, 156.8, 159.2, 164.6, 175.9,
185.2. MS (m/z) 302 (Mþ), 303, 284, 271, 255, 227. HRMS
calcd for C15H14O7 306.0740, found 306.0744.
8. (a) Bloomer, J. L.; Stagliano, K. W. Tetrahedron Lett. 1993,
34, 757. (b) Corey, E. J.; Martinez, E. J. Org. Lett. 1999, 1, 75.
9. Hewson, A. T.; Sharpe, D. A.; Wadsworth, A. H. Synth.
Commun. 1989, 19, 2095.
10. The structure assigned to the by-product was
Acknowledgments
We thank the National Institutes of Health and the Roy
J. Carver Charitable Trust for support of this work.
References
11. Zhu, J.; Beugelmans, R.; Bourdet, S.; Chastanet, J.; Roussi, G.
J. Org Chem. 1995, 60, 6389.
1. Singh, S. B.; Cordingley, M. G.; Ball, R. G.; Smith, J. L.;
Dombrowski, A. W.; Goetz, M. A. Tetrahedron Lett. 1991, 32,
5279.
12. Demuynck, M.; DeClerq, P.; Vandewelle, M. J. Org. Chem.
1979, 44, 4863.