Xanthone natural products via N -heterocyclic carbene catalysis: Total synthesis of atroviridin

Article abstract of DOI:10.1021/jo200303c

The total synthesis of atroviridin has been accomplished by a linear route involving the N-heterocyclic carbene (NHC)-catalyzed aroylation of the fluorobenzene derivative, Claisen cyclization of the O-propargylated benzophenones, and intramolecular 1,4-addition of the quinone intermediates. The result provides a viable route to xanthone natural products.

Full text of DOI:10.1021/jo200303c

ARTICLE
pubs.acs.org/joc
Xanthone Natural Products via N-Heterocyclic Carbene Catalysis:
Total Synthesis of Atroviridin
Yumiko Suzuki,* Yoshinori Fukuta, Shinya Ota, Masayo Kamiya, and Masayuki Sato
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
S Supporting Information
b
ABSTRACT: The total synthesis of atroviridin has been
accomplished by a linear route involving the N-heterocyclic
carbene (NHC)-catalyzed aroylation of the fluorobenzene
derivative, Claisen cyclization of the O-propargylated benzo-
phenones, and intramolecular 1,4-addition of the quinone
intermediates. The result provides a viable route to xanthone
natural products.
Scheme 1. Nucleophilic Aroylation Catalyzed by NHC
’ INTRODUCTION
N-Heterocyclic carbenes (NHCs) are widely employed both
as ligands for transition-metal systems1,2 and as small-molecule
organic catalysts for chemical synthesis.1,3 We have focused our
research interests on the use of NHCs as organocatalysts4 and
developed a method to catalyze the nucleophilic aroylation of
fluorobenzenes by NHC (Scheme 1).5 In this reaction, the fluoro
substituents are replaced by aroyl groups originating from
aldehydes to afford benzophenones. It is thought that the
“Breslow intermediate,” which is also produced during benzoin
condensation, is a part of the reaction pathway (Scheme 2). In
the course of developing a synthetic route to heterocyclic
compounds through NHC catalysis,6 we envisioned the potential
use of this catalysis in the total synthesis of atroviridin (1), which
is a xanthone natural product (Figure 1).
Scheme 2. Plausible Mechanism for Aroylation
Atroviridin (1) is a polyphenolic xanthone isolated from the
stem bark of Garcinia atroviridis (Guttiferae), a lofty tree
indigenous to Thailand.7 A decoction of the leaves and root of
this tree is used as a folk medicine for earache. A number of
xanthone and xanthonoid natural products isolated from tropical
trees of the genus Garcinia have been reported to possess
bioactivities.8 The first total synthesis of 1 was reported by the
Theodorakis’ group.9
With the aim of developing an alternative synthetic route to
xanthone natural products, we set out to investigate a total
synthesis of 1 (Scheme 3). We sought to construct a xanthone
nucleus at the last stage of synthesis through intramolecular con-
jugate addition of the quinone intermediate 2, a procedure that
mirrors a presumed biosynthetic pathway.9 We believed the quinone
2to be accessible from benzophenone/chromene 3by oxidation. We
expected 3to be formed from the benzophenone 4via substitution of
the fluoro and nitro groups by O-nucleophiles, propargylation of the
hydroxyl group, and subsequent Claisen cyclization. We planned to
prepare 4 from 2,4,5-trifluoronitrobenzene (5) and 2-fluoro-6-
methoxybenzaldehyde (6) by NHC catalysis.
’ RESULTS AND DISCUSSION
The synthesis of benzophenone/chromene 15 via benzophe-
none 4 is summarized in Scheme 4. The reaction of 5 with 6 in
Received: February 22, 2011
Published: April 06, 2011
r
2011 American Chemical Society
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DMF at room temperature for 2 h, in the presence of NHC
derived from 1,3-dimethylimidazolium iodide (7) (10 mol %),
produced 4 in 76% yield. After removal of the methyl group, the
fluorine group at the 4 position (atroviridin numbering) of 8 was
regioselectively substituted by a methoxy group, and the 7-hy-
droxy group was protected with the benzyl group in the reaction
with K2CO3 and benzyl bromide in methanol at room tempera-
ture to afford the intermediate 9. Conversion of the nitro group
to the hydroxyl group10 took place by the reaction of 9 with the
anion of benzaldoxime in DMSO at room temperature. The
resulting compound 10 was O-propargylated with 3-chloro-3-
methylbutyne11 using DBU and catalytic CuCl2 in CH2Cl2,
followed by Claisen cyclization12 in toluene heated at reflux to
produce the chromene 12 in good yield. The remaining fluoro
groups of 12 were replaced by methoxy groups in the reaction
with sodium methoxide in DMF at 80 °C to afford the inter-
mediate 13. The deprotection of benzyl ether was accomplished
quantitatively by Pd/C-catalyzed hydrogenation in the presence
of 1,4-cyclohexadiene,13 leaving the C(30)ꢀC(40) double bond
intact. The acetylation of 14 using Ac2O in pyridine provided 15.
The attempted oxidation of 15 using CAN failed to give the
quinone 16 (Scheme 5). The tosylate 18 was then prepared from
14 using NaH and p-TsCl in THF, and the removal of methyl
groups of 15 and 18 was examined prior to the oxidation to
quinone. However, all attempts including treatment with BBr3,
MgBr2, or AlBr3 were unsuccessful. These results, which are
shown in Scheme 5, prompted us to abandon the use of methyl
ethers for protecting 1-, 4-, and 10a-hydroxy groups.
Figure 1. Structure for atroviridin.
Scheme 3. Retrosynthetic Analysis of Atroviridin (1)
Atroviridin (1) was synthesized as summarized in Scheme 6.
The fluorine group at the 4 position of 4 was regioselectively
substituted by an allyloxy group in the reaction with K2CO3/allyl
alcohol at room temperature to afford the intermediate 20 in 81%
yield. Conversion of the nitro group to the hydroxyl group took
place by the reaction of 20 with the anion of benzaldoxime in
DMSO at room temperature for 3 h (73% yield). The resulting
compound 21 was O-propargylated with 3-chloro-3-methylbu-
tyne using DBU and catalytic CuCl2 in CH2Cl2 (22, 70% yield,
100% conversion) followed by Claisen cyclization in toluene
heated at reflux to produce the chromene 23 quantitatively. The
remaining fluoro groups of 23 were replaced by allyloxy groups in
the reaction with the alkoxide of allyl alcohol in DMF at 60 °C for
3.5 h to afford the intermediate 24 in 87% yield. The removal of
allyl groups using dimedone and Pd(PPh3)4 in THF quantita-
tively afforded the trihydroxy intermediate 25. Our aim was to
obtain the quinone 26; therefore, we subjected 25 to oxidation
using MnO2 in CH2Cl2 at room temperature for 2 h to afford
tetracyclic the triketone 27 (86% yield), which was produced
by the spontaneous intramolecular conjugate addition of 26.
We had expected the annulation of 26 to produce an aromatized
Scheme 4. Synthesis of Benzophenone/Chromene Intermediate 15
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dihydroxy product 28 (enol tautomer of 27), owing to its
stability. However, we found that the keto tautomer is kinetically
stable14 enough to be isolated in pure form by recrystallization.
Removal of the methyl group from 27 using BBr3 in CH2Cl2
between ꢀ78 °C and ꢀ60 °C for 2 h afforded 1 in 58% yield.
Given that the last step of the synthesis in Scheme 6—the
removal of the methyl group—showed low reproducibility
because of difficulties both in preventing undesired products
and in purifying 1, we planned to use an alternative protecting
group for the 7-hydroxy group. Thus, the benzyl ether 29 was
prepared from 8 and then subjected to the conversion of the nitro
group to the hydroxyl group, followed by O-propargylation and
Claisen cyclization to produce the benzophenone/chromene 30
(Scheme 7). The substitutions of the remaining fluoro groups to
allyloxy groups needed to be performed carefully at 30 °C to
avoid the co-occurring Claisen rearrangement of the 10a-allyloxy
group of 31. After removal of the allyl groups, oxidation with
MnO2 afforded the trihydroxy intermediate 32 in good yield.
Deprotection of the benzyl ether using BBr3 and the aromatiza-
tion to xanthone promoted by n-Bu4NI in toluene heated to
reflux provided 1.
In summary, we have completed the total synthesis of
atroviridin (1) in 9 and 11 steps. In comparison with Theodor-
akis’ synthesis (14 steps), the numbers of synthetic steps were
reduced. The key features of this synthesis are the use of NHC-
catalyzed aroylation to prepare a benzophenone intermediate,
regio- and chemoselective nucleophilic aromatic substitutions by
O-nucleophiles, Claisen cyclization, and intramolecular 1,4-addi-
tion. This result provides a viable route to xanthone natural
products. Further synthetic studies on this class of xanthonoids
are underway.
Scheme 5. Attempted Syntheses of Quinone Intermediates
16 and 19
’ EXPERIMENTAL SECTION
50-Methoxy-4-nitro-2, 20,5-trifluorobenzophenone (4)4.
Under an atmosphere of argon, 60% sodium hydride in oil (812 mg,
20.3 mmol) was added to a mixture of 1,3-dimethylimidazolium iodide 7
(302 mg, 1.35 mmol), 2,4,5-trifluoronitrobenzene (5) (1.54 mL, 13.5
mmol), and 2-fluoro-5-methoxybenzaldehyde (6) (1.60 mL, 20.3
mmol) in dehydrated DMF (30 mL). The mixture was stirred at 0 °C
for 10 min and then at room temperature for 1 h. After the reaction, the
mixture was poured into iceꢀwater and then neutralized with dilute
hydrochloric acid. The product was extracted with ethyl acetate and then
washed with water and brine. After the product was dried over Na2SO4,
the organic layer was concentrated, and the residue was purified by silica
gel column chromatography (hexaneꢀethyl acetate) to give 4 (3.19 g,
Scheme 6. Synthesis of 1
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Scheme 7. Alternative Synthesis of 1
76%) as yellow prisms (recrystallized from hexaneꢀdichloromethane):
mp 98ꢀ99 °C; 1H NMR (500 MHz, CDCl3) δ 3.86 (3H, s), 7.06 (2H, t,
J = 9.5 Hz), 7.15ꢀ7.18 (1H, m), 7.29 (1H, dd, J = 5.5, 3.0 Hz), 7.58 (1H,
dd, J = 9.5, 5.5 Hz), 7.86 (1H, dd, J = 9.0, 5.5 Hz); 13C NMR (CDCl3)
δ 56.0, 113.4, 114.1 (dd, JFC = 29.4, 3.0 Hz), 117.5 (d, JFC = 24.0 Hz),
153.0 (d, JFC = 250.7 Hz), 155.1, 156.1 (d, JFC = 249.5 Hz), 186.6; IR
(CHCl3) 1527 (NO2), 1666 (CO) cmꢀ1; HRMS (FAB) m/z calcd for
C21H16F2NO5 (M þ 1)þ 400.0997, found 400.1011.
50-Benzyloxy-2,20-difluoro-4-hydroxy-5-methoxybenzo-
phenone (10). Under an atmosphere of argon, benzaldoxime
(533 mg, 4.4 mmol) and 60% sodium hydride in oil (220 mg,
5.5 mmol) were added to a solution of 9 (880 mg, 2.2 mmol) in
dehydrated DMSO (22 mL). The mixture was stirred at room tempera-
ture for 2 h and acidified with 10% hydrochloric acid with ice-cooling.
The product was extracted with ethyl acetate, washed with water and
brine, and then dried over MgSO4. The organic layer was concentrated,
and the residue was purified by silica gel column chromatography
(hexaneꢀethyl acetate) to give 10 (627 mg, 77%) as yellow prisms
119.9 (dd, JFC = 25.2, 2.4 Hz), 122.7 (d, JFC = 8.4 Hz), 125.2 (d, JFC
=
13.1 Hz), 134.2 (dd, JFC = 16.8, 8.4 Hz), 138.7 (dd, JFC = 16.2, 8.4 Hz),
151.5 (dd, JFC = 263.9, 3.6 Hz), 154.9 (dd, JFC = 258.0, 2.4 Hz), 156.0,
156.2 (d, JFC = 249.5 Hz), 186.2; IR (CHCl3) 1537 (NO2), 1668
(CdO) cmꢀ1; HRMS (FAB) m/z calcd for C14H9F3NO 4 (M þ 1)þ
312.0484, found 312.0504.
50-Hydroxy-4-nitro-2, 20, 5-trifluorobenzophenone (8).
Hydrobromic acid (9 mL) and a few drops of benzalkonium chloride
were added to a solution of 4 (3.2 g, 10.3 mmol) in acetic acid (20 mL).
The mixture was stirred at reflux for 36 h and then neutralized with 10%
NaOH. The product was extracted with ethyl acetate and then washed
with water and brine. After the product was dried over MgSO4, the
organic layer was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexaneꢀethyl acetate) to
1
(recrystallized from hexaneꢀdichloromethane): mp 119ꢀ122 °C; H
NMR (500 MHz, CDCl3) δ 3.95 (3H, s), 5.06 (2H, s), 6.18 (1H, s), 6.65
(1H, d, J = 11.0 Hz), 7.02 (1H, t, J = 9.0 Hz), 7.09ꢀ7.07 (1H, m), 7.19
(1H, dd, J = 5.5, 3.0 Hz), 7.30 (1H, d, J = 6.0 Hz), 7.43ꢀ7.34 (5H, m);
13C NMR (126 MHz, CDCl3) δ 56.4, 70.7, 102.9 (d, JFC = 27.6 Hz),
111.2 (d, JFC = 3.6 Hz), 115.0, 116.7 (d, JFC = 25.2 Hz), 118.0 (d, JFC
=
1
12.0 Hz), 120.1 (d, JFC = 8.4 Hz), 127.6, 128.1, 128.6, 136.3, 148.2, 151.5
(d, JFC = 13.2 Hz), 154.7, 154.9 (d, JFC = 245.9 Hz), 157.7 (d, JFC = 250.7
Hz), 188.3; IR (CHCl3) 1647 (CO), 3369 (OH) cmꢀ1; HRMS (FAB)
m/z calcd for C21H17F2O4 (M þ 1)þ 371.1095, found 371.1097.
5-Benzyloxy-2,20-difluoro-4-(1,1-dimethylpropargyloxy)-
50-methoxybenzophenone (11). Under an atmosphere of argon,
copper(II) chloride (0.10 mg, 0.0007 mmol) and 3-chloro-3-methyl-1-
butyne (120 μL, 1.04 mmol) were added to a solution of 10 (964 mg,
2.6 mmol) in distilled dichloromethane (25 mL). The mixture was
cooled to 0 °C, and DBU (504 μL, 3.4 mmol) was added. The mixture
was stirred at room temperature for 3 h, and the solvent was evaporated.
The product was extracted with ethyl acetate, washed with water and
brine, and then dried over MgSO4. The organic layer was concentrated,
and the residue was purified by silica gel column chromatography
(hexaneꢀethyl acetate) to give 11 (983 mg, 87%) as a slightly yellow
give 23 (3.02 g, 99%) as a yellow oil: H NMR (500 MHz, CDCl3)
δ 6.03(1H, s), 7.03 (1H, t, J = 9.5 Hz), 7.14ꢀ7.11 (1H, m), 7.27 (1H, dd,
J = 5.5, 3.5 Hz), 7.57 (1H, dd J = 10.0, 5.5 Hz), 7.86 (1H, dd, J = 8.5, 5.5
Hz); 13C NMR (126 MHz, CDCl3) δ 114.3 (dd, JFC = 32.0, 2.4 Hz),
116.0, 117.7 (d, JFC = 25.2 Hz), 119.9 (dd, JFC = 24.0, 2.4 Hz), 123.4 (d,
JFC = 8.5 Hz), 125.2 (d, JFC = 13.2 Hz), 133.9 (dd, JFC = 16.0, 7.8 Hz),
138.7 (dd, JFC = 18.0, 8.4 Hz), 151.6 (dd, JFC = 264.1, 3.6 Hz), 152.5 (d,
JFC = 2.4 Hz), 154.9 (d, JFC = 235.5 Hz), 156.0 (d, JFC = 247.1 Hz), 186.6;
IR (CHCl3) 1533 (NO2), 1664 (CO), 3442 (OH) cmꢀ1; HRMS (FAB)
m/z calcd for C13H7F3NO4 (M þ 1)þ 298.0327, found 298.0297.
50-Benzyloxy-2,20-difluoro-5-methoxy-4-nitrobenzophe-
none (9). Under an atmosphere of argon, benzyl bromide (3.3 g,
19.3 mmol) and potassium carbonate (3.55 g, 25.7 mmol) were added to
a solution of 4 (3.82 g, 12.9 mmol) in methanol (70 mL). The mixture
was stirred at room temperature for 2 days and then at 60 °C for 3 days.
After the reaction was complete, methanol was evaporated off, and the
residue was extracted with ethyl acetate and then washed with water and
brine. After being dried over MgSO4, the organic layer was concentrated,
and the residue was recrystallized from dichloromethane and hexane to
afford 9. The filtrate was concentrated and purified by silica gel column
chromatography (hexaneꢀethyl acetate) to give 9 as yellow prisms
(recrystallized from hexaneꢀdichloromethane): yield 4.06 g (79%); mp
80ꢀ80.5 °C; 1H NMR (500 MHz, CDCl3) δ 3.99 (3H, s), 5.10 (2H, s),
7.06 (1H, t, J = 9.5 Hz), 7.20ꢀ7.19 (1H, m), 7.40ꢀ7.36 (7H, m),7.61
(1H, d, J = 9.0 Hz); 13C NMR (126 MHz, CDCl3) δ 57.2, 70.9, 113.8 (d,
JFC = 28.8 Hz), 115.0 (d, JFC = 10.8 Hz), 117.5 (d, JFC = 24.0 Hz), 122.7
(d, JFC = 8.4 Hz), 126.2 (d, JFC = 12.0 Hz), 127.7, 128.4, 128.8, 132.2
(d, JFC = 15.6 Hz), 136.3, 141.1 (d, JFC = 8.4 Hz), 149.3 (d, JFC = 2.4 Hz),
1
oil: H NMR (500 MHz, CDCl3) δ 1.75 (6H, s), 2.66 (1H, s), 3.86
(3H, s), 5.07 (2H, s), 7.03 (1H, t, J = 9.5 Hz), 7.10ꢀ7.09 (1H, m),
7.44ꢀ7.21 (8H, m); 13C NMR (126 MHz, CDCl3) δ 14.1, 22.6, 29.3,
56.4, 70.7, 74.0, 75.3, 84.6, 107.6 (d, JFC = 27.6 Hz), 112.1 (d, JFC = 3.6
Hz), 115.0, 116.8 (d, JFC = 24.0 Hz), 119.6 (d, JFC = 13.2 Hz), 120.2 (d,
JFC = 8.4 Hz), 127.6, 128.1, 128.6, 128.8, 136.3, 148.0, 150.3 (d, JFC
=
10.8 Hz), 155.0 (d, JFC = 248.3 Hz), 156.0 (d, JFC = 250.0 Hz), 188.5; IR
(CHCl3) 1654 (CO), 3264 (alkyne) cmꢀ1; HRMS (FAB) m/z calcd for
C26H23F2O4 (M þ 1)þ 437.1564, found 437.1566.
6-(5-Benzyloxy-2-fluorobenzoyl)-2,2-dimethyl-5-fluoro-
8-methoxychromene (12). Under an atmosphere of argon, a
solution of 11 (265 mg, 0.6 mmol) in dehydrated toluene (15 mL)
was refluxed for 22 h. After the solution was cooled, the solvent was
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evaporated. The residue was purified by silica gel column chromatog-
raphy (hexaneꢀethyl acetate) to give 12 (242 mg, 91%) as a colorless
amorphous powder: 1H NMR (500 MHz, CDCl3) δ 1.53 (6H, s), 3.89
(3H, s), 5.07 (2H, s), 5.69 (1H, d, J = 10.0), 6.48 (1H, d, J = 10.0), 7.04
(1H, t, J = 9.0 Hz), 7.08ꢀ7.07 (1H, m), 7.21ꢀ7.18 (2H, m), 7.44ꢀ7.34
(5H, m); 13C NMR (126 MHz, CDCl3) δ 28.1, 30.9, 56.5, 70.7, 78.2,
110.2 (d, JFC = 20.4 Hz), 112.1 (d, JFC = 2.4 Hz), 114.7 (d, JFC = 6.0 Hz)
5,8-Dimethoxy-2,2-dimethyl-6-(2-methoxy-5-tosyloxy-
benzoyl)chromene (18). Under an atmosphere of argon, TsCl
(95 mg, 0.50 mmol) was added to a solution of 14 (169 mg, 0.46
mmol) in dehydrated THF (7 mL). The mixture was stirred at room
temperature for 20 min, and then 60% NaH in oil (22 mg, 0.55 mmol)
was added. After being stirred for another 30 min, the mixture was
poured into water, and the product was extracted with ethyl acetate. The
organic layer was washed with water, dried over MgSO4, and concen-
trated. The residue was purified by silica gel column chromatography
(hexaneꢀethyl acetate) to give 18 (242 mg, 100%) as colorless prisms
115.0, 116.7 (d, JFC = 24.0 Hz), 117.7 (d, JFC = 13.2 Hz), 119.9 (d, JFC
=
7.2 Hz), 127.6, 128.2, 128.6, 130.7, 136.3, 144.8, 147.6 (d, JFC = 7.2 Hz),
151.8 (d, JFC = 253.1 Hz), 154.7, 154.8 (d, JFC = 245.9 Hz), 188.3, 207.1;
IR (CHCl3) 1637 (CO) cmꢀ1; HRMS (FAB) m/z calcd for
C26H23F2O4 (M þ 1)þ 437.1564, found 437.1549.
1
(recrystallized from hexaneꢀdichloromethane): mp 146ꢀ147 °C; H
NMR (500 MHz, CDCl3) δ 1.51 (6H, s), 2.43 (3H, s), 3.32 (3H, s), 3.69
(3H, s), 3.86 (3H, s), 5.68 (1H, d, J = 10.0 Hz), 6.50 (1H, d, J = 10.0 Hz),
6.83 (1H, d, J = 9.0 Hz), 6.98 (1H, d, J = 3.0 Hz), 7.09 (1H, s), 7.11 (1H,
dd, J = 9.0, 3.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.71 (2H, d, J = 8.0 Hz); 13C
NMR (126 MHz, CDCl3) δ 21.7, 27.9, 56.1, 56.4, 63.1, 76.9, 111.9,
113.0, 115.3, 116.7, 122.9, 123.6, 125.4, 128.5, 129.8, 130.4, 131.9, 132.1,
142.4, 144.8, 145.5, 147.3, 151.1, 156.3, 192.2; IR (CHCl3) 1636
(CdO) cmꢀ1; HRMS (FAB) m/z calcd for C28H29O8S(M þ 1)þ
525.1583, found 525.1569.
5-Allyloxy-2,20-difluoro-50-methoxy-4-nitrobenzophe-
none (20). Under an atmosphere of argon, potassium carbonate (553
mg, 4 mmol) was added to a solution of 4 (622 mg, 2 mmol) in allyl
alcohol (15 mL). The mixture was stirred at room temperature over-
night. After the reaction, the allyl alcohol was evaporated off, and the
residue was extracted with ethyl acetate, washed with water and brine,
and dried over MgSO4. The organic layer was concentrated, and the
residue was purified by silica gel column chromatography (hexaneꢀ
ethyl acetate) to give 20 (568 g, 81%) as yellow prisms (recrystallized
from hexane-dichloromethane): mp 80ꢀ80.5 °C; 1H NMR (500 MHz,
CDCl3) δ 3.86 (3H, s), 4.72 (2H, dt, J = 5.0, 1.5 Hz), 5.36 (1H, dd, J =
11.0, 1.0 Hz), 5.49 (1H, dd, J = 17.5, 1.5 Hz), 5.99ꢀ6.07 (1H, m), 7.05
(1H, t, J = 9.5 Hz), 7.12ꢀ7.15 (1H, m), 7.25 (1H, dd, J = 5.5, 3.5 Hz),
7.34 (1H, d, J = 5.5 Hz), 7.62 (1H, d, J = 8.5 Hz); 13C NMR (CDCl3)
δ 56.0, 70.8, 113.5 (d, JFC = 2.4 Hz), 113.6 (d, JFC = 24.0 Hz), 116.3 (d,
JFC = 2.4 Hz), 117.3 (d, JFC = 24.0 Hz), 119.0, 121.9 (d, JFC = 8.4 Hz),
126.1 (d, JFC = 13.2 Hz), 131.1, 132.1 (dd, JFC = 14.4, 2.4 Hz), 141.4 (d,
JFC = 7.2 Hz), 148.1 (d, JFC = 3.6 Hz), 153.1 (dd, JFC = 252.5, 2.4 Hz),
155.9, 155.9 (dd, JFC = 251.5, 2.4 Hz), 187.5; IR (CHCl3) 1528 (NO2),
1668 (CdO) cmꢀ1; HRMS (FAB) m/z calcd for C17H14F2NO5
(M þ 1)þ 350.0840, found 350.0839.
6-(5-Benzyloxy-2-methoxybenzoyl)-5,8-dimethoxy-2,2-
dimethylchromene (13). Under an atmosphere of argon, 1 M
sodium methoxide in methanol (2.58 mL, 2.58 mmol) was added to a
solution of 12 (225 mg, 0.516 mmol) in dehydrated DMF (12 mL). The
mixture was stirred at 80 °C for 25 h, poured into iceꢀwater, and then
neutralized with hydrochloric acid. The product was extracted with ethyl
acetate, washed with water and brine, and then dried over MgSO4. The
organic layer was concentrated, and the residue was purified by silica gel
column chromatography (hexaneꢀethyl acetate) to give 13 (212 mg,
89%) as colorless prisms (recrystallized from hexaneꢀacetone): mp
124ꢀ126 °C; 1H NMR (500 MHz, CDCl3) δ 1.52 (6H, s), 3.42 (3H, s),
3.66 (3H, s), 3.83 (3H, s), 5.04 (2H, s), 5.66 (1H, d, J = 10.0), 6.54 (1H,
d, J = 10.0), 6.87 (1H, d, J = 8.5 Hz), 7.09ꢀ7.03 (3H, m), 7.42ꢀ7.30
(5H, m); 13C NMR (126 MHz, CDCl3) δ 28.0, 56.6, 63.3, 70.8, 77.2,
113.0, 113.3, 115.5, 115.8, 117.1, 118.7, 124.6, 127.7, 128.1, 128.6, 130.4,
131.5, 137.0, 144.7, 146.8, 150.9, 152.3, 152.5, 194.1, 207.2; IR (CHCl3)
1635 (CO) cmꢀ1; HRMS (FAB) m/z calcd for C28H28O6 (M þ 1)þ
461.1964, found 461.1953.
6-(5-Hydroxy-2-methoxybenzoyl)-5,8-dimethoxy-2,2-di-
methylchromene (14). Under an atmosphere of argon, 1,4-cyclo-
hexadiene (85 μL, 0.9 mmol) and Pd/C (41 mg) were added to a
solution of 13 (41 mg, 0.09 mmol) in methanol (2 mL). The mixture was
stirred for 1.5 h and then filtered through Celite. The filtrate was
concentrated, and the residue was purified by silica gel column chro-
matography (hexaneꢀethyl acetate) to give 14 (35.2 mg, quant) as
colorless prisms (recrystallized from hexaneꢀacetone): mp 131ꢀ
133 °C; 1H NMR (500 MHz, CDCl3) δ 1.50 (6H, s, CH3), 3.49 (3H,
s, OCH3), 3.66 (3H, s, OCH3), 3.83 (3H, s, OCH3), 4.85 (1H, s), 5.66
(1H, d, J = 10.0 Hz), 6.55 (1H, d, J = 10.0 Hz), 6.83 (1H, d, J = 9.0 Hz),
6.93ꢀ6.92 (2H, m), 7.07 (1H, s); 13C NMR (126 MHz, CDCl3) δ 27.8,
56.2, 56.3, 63.2, 77.4, 113.0, 113.4, 115.3, 116.3, 116.7, 119.0, 124.1
130.3 130.7, 144.3, 146.7, 149.7, 150.7, 151.6, 194.8; IR (CHCl3)
1637 (CO), 3437 (OH) cmꢀ1; HRMS (FAB) m/z calcd for
C21H23O6 (M þ 1)þ 371.1495, found 371.1489.
5-Allyloxy-2,20-difluoro-4-hydroxy-50-methoxybenzophe-
none (21). Under an atmosphere of argon, benzaldoxime (250 μL,
3.3 mmol) and 60% sodium hydride in oil (164 mg, 4.1 mmol) were
added to a solution of 20 (572 mg, 1.6 mmol) in dehydrated DMSO
(15 mL). The mixture was stirred at room temperature for 3 h and
acidified with 10% hydrochloric acid with ice-cooling. The product was
extracted with ethyl acetate, washed with water and brine, and dried over
MgSO4. The organic layer was concentrated, and the residue was
purified by silica gel column chromatography (hexaneꢀethyl acetate)
to give 21 (381 mg, 73%) as yellow prisms (recrystallized from hexaneꢀ
dichloromethane): mp 66ꢀ67 °C; 1H NMR (500 MHz, CDCl3) δ 3.83
(3H, s), 4.66 (2H, d, J = 5.5 Hz), 5.36 (1H, dd, J = 10.5, 1.0 Hz), 5.43
(1H, dd, J = 17.0, 1.0 Hz), 6.02ꢀ6.10 (1H, m), 6.32 (1H, s), 6.67 (1H, d,
J = 11.5 Hz), 7.02 (2H, dd, J = 6.5, 1.5 Hz), 7.09 (1H, d, J = 5.5 Hz), 7.31
6-(5-Acetoxy-2-methoxybenzoyl)-5,8-dimethoxy-2,2-di-
methylchromene (15). Under an atmosphere of argon, pyridine
(2 μL) was added to a solution of 14 (38.7 mg, 0.104 mmol) in acetic
anhydride (3 mL). The mixture was stirred at reflux for 5 h, poured into
2% hydrochloric acid, and then extracted with diethyl ether. The organic
layer was washed with 2% sodium hydroxide and brine. After being dried
over Na2SO4, the organic layer was concentrated, and the residue was
purified by silica gel column chromatography (hexaneꢀethyl acetate) to
give 15 (42 mg, 98%) as a colorless powder (recrystallized from
1
(1H, d, J = 7.0 Hz); 13C NMR (CDCl3) δ: 55.9, 70.3, 102.5 (dd, JFC
28.8, 2.4 Hz), 113.8 (d, JFC = 2.4 Hz), 116.9 (d, JFC = 24.0 Hz), 117.3
(dd, JFC = 21.6, 3.6 Hz), 119.2, 120.0 (d, JFC = 8.4 Hz), 127.9 (d, JFC
15.6 Hz), 131.3, 147.5 (d, JFC = 2.4 Hz), 149.5 (d, JFC = 2.4 Hz), 151.5
(d, JFC = 10.8 Hz), 155.0 (dd, JFC = 245.9, 2.4 Hz), 155.7, 158.2 (dd, JFC
=
hexaneꢀacetone): mp 121ꢀ123 °C; H NMR (500 MHz, CDCl3)
δ 1.50 (6H, s), 2.27 (3H, s), 3.44 (3H, s), 3.72 (3H, s), 3.85 (3H, s), 5.66
(1H, d, J = 10.0), 6.54 (1H, d, J = 10.0), 6.92 (1H, dd, J = 7.0, 2.5 Hz),
7.11 (1H, s), 7.16ꢀ7.15 (2H, m); 13C NMR (126 MHz, CDCl3) δ 21.1,
26.8, 28.0, 56.3, 56.5, 63.4, 112.1, 113.2, 115.5, 117.0, 122.6, 124.1, 124.7,
130.4, 131.6, 143.7, 144.8, 147.0, 151.1, 155.6, 193.0; IR (CHCl3) 1647
(CO), 1761 (CO) cmꢀ1; HRMS (FAB) m/z calcd for C23H25O7
(M þ 1)þ 413.1600, found 413.1600.
=
=
254.9, 2.4 Hz), 187.5; IR (CHCl3): 1647 (CdO), 3370 (OH) cmꢀ1
;
HRMS (FAB) m/z calcd for C17H15F2O4 (M þ 1)þ 321.0938, found
321.0936.
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ARTICLE
5-Allyloxy-2,20-difluoro-4-(1,1-dimethylpropargyloxy)-50-
methoxybenzophenone (22). Under an atmosphere of argon,
copper(II) chloride (0.10 mg, 0.0007 mmol) and 3-chloro-3-methyl-1-
butyne (120 μL, 1.04 mmol) were added to a solution of 21 (303 mg,
0.95 mmol) in distilled dichloromethane (10 mL). The mixture was
cooled to 0 °C, and DBU (184 μL, 1.23 mmol) was added. The mixture
was refluxed overnight and evaporated. The product was extracted with
ethyl acetate, washed with water and brine, and dried over MgSO4. The
organic layer was concentrated, and the residue was purified by silica gel
column chromatography (hexaneꢀethyl acetate) to give 22 (226 mg,
70%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 1.74 (6H, s), 2.65
(1H, s), 3.83 (3H, s), 4.56 (2H, dt, J = 5.5, 1.5 Hz), 5.28 (1H, dq, J = 10.0,
1.5 Hz), 5.42 (1H, dq, J = 17.5, 1.5 Hz), 6.01ꢀ6.08 (1H, m), 7.01ꢀ7.03
(2H, m), 7.10ꢀ7.12 (1H, m), 7.28 (1H, d, J = 3.5 Hz), 7.30 (1H, d, J =
2.5 Hz); 13C NMR (CDCl3) δ 29.3, 55.9, 70.4, 74.2, 75.1, 84.7, 108.2 (d,
JFC = 27.6 Hz), 113.8 (d, JFC = 2.4 Hz), 115.0 (d, JFC = 3.6 Hz), 116.7 (d,
JFC = 24.0 Hz), 117.7, 119.5 (d, JFC = 8.4 Hz), 119.9 (d, JFC = 13.2 Hz),
ethyl acetate, washed with water and brine, and dried over MgSO4. The
organic layer was concentrated, and the residue was purified by silica gel
column chromatography (hexaneꢀethyl acetate) to give 25 (163 mg,
quant) as yellow prisms (recrystallized from hexaneꢀdichloro-
1
methane): mp 202ꢀ204 °C; H NMR (500 MHz, CDCl3) δ 1.53
(6H, s), 3.78 (3H, s), 5.12 (1H, s), 5.65 (1H, d, J = 9.5 Hz), 6.77 (1H, d,
J = 9.5 Hz), 7.00 (1H, d, J = 9.5 Hz), 7.07ꢀ7.10 (2H, m), 7.16 (1H, s),
9.65 (1H, s), 11.54 (1H, s); 13C NMR (CDCl3) δ 28.5, 56.0, 79.3, 109.8,
111.9, 115.7, 116.1, 117.2, 119.1, 120.3, 122.1, 128.4, 136.9, 147.0, 151.6,
154.0, 154.5, 201.2; IR (CHCl3) 1643 (CdO), 3420 (OH) cmꢀ1
;
HRMS (FAB) m/z calcd for C19H19O6 (M þ 1)þ 343.1182, found
343.1193.
2,2-Dimethyl-8-methoxypyrano[2,3-b]xanthene-5,6,12-
(2H,5aH,12aH)-trione (27). Manganese dioxide (967 mg, 11.2
mmol) was added to a solution of 25 (385 mg, 1.12 mmol) in distilled
dichloromethane (25 mL). The mixture was stirred at room temperature
for 3.5 h and filtrated through Celite. The filtrate was concentrated, and
the residue was purified by silica gel column chromatography (hexaneꢀ
ethyl acetate) to give 27 (330 mg, 86%) as yellow prisms (recrystallized
from hexaneꢀdichloromethane): mp 172ꢀ174 °C; H NMR (500 MHz,
CDCl3) δ 1.56 (3H, s), 1.61 (3H, s), 3.07 (1H, d, J = 16.5 Hz), 3.28 (1H,
d, J = 16.5 Hz), 3.78 (3H, s), 5.71 (1H, d, J = 10.0 Hz), 6.45 (1H, d, J =
10.0 Hz), 6.98 (1H, d, J = 3.0 Hz), 7.20 (1H, d, J = 9.0 Hz), 7.33 (1H, dd,
J = 9.0, 3.0 Hz); 13C NMR (CDCl3) δ 27.5, 28.1, 43.3, 55.9, 81.1,
92.4, 104.5, 114.4, 115.2, 117.7, 119.3, 129.2, 131.3, 155.6, 156.6, 167.6,
128.5 (d, JFC = 16.8 Hz), 132.9, 147.1 (d, JFC = 2.4 Hz), 151.0 (d, JFC
=
10.8 Hz), 155.0 (d, JFC = 244.7 Hz), 155.6, 156.3 (d, JFC = 253.0 Hz),
188.6; IR (CHCl3) 1653 (CdO) cmꢀ1; HRMS (FAB) m/z calcd for
C22H21F2O 4 (M þ 1)þ 387.1408, found 387.1433.
8-Allyloxy-5-fluoro-6-(2-fluoro-5-methoxybenzoyl)-2,2-
dimethylchromene (23). Under an atmosphere of argon, a solution
of 22 (187 mg, 0.48 mmol) in dehydrated toluene (35 mL) was refluxed
overnight. After cooling, the solvent was evaporated. The residue was
purified by silica gel column chromatography (hexaneꢀethyl acetate) to
give 23 (187 mg, quant) as a yellow oil: 1H NMR (500 MHz, CDCl3)
δ 1.52 (6H, s), 3.82 (3H, s), 4.61 (2H, dt, J = 5.5, 1.5 Hz), 5.28 (1H, dq,
J = 11.0, 1.5 Hz), 5.39 (1H, dq, J = 17.5, 1.5 Hz), 5.69 (1H, d, J = 10.0
Hz), 6.01ꢀ6.09 (1H, m), 6.49 (1H, d, J = 10.0 Hz), 7.01ꢀ7.02 (2H, m),
7.07ꢀ7.09 (1H, m), 7.21 (1H, d, J = 6.5 Hz); 13C NMR (CDCl3) δ 28.2,
55.9, 70.8, 78.1, 110.4 (d, JFC = 19.2 Hz), 113.8 (d, JFC = 2.4 Hz), 114.8
(d, JFC = 6.0 Hz), 115.6 (d, JFC = 2.4 Hz), 116.7 (d, JFC = 24.0 Hz), 117.8
183.5, 186.5, 194.8; IR (CHCl3) 1711, 1674, 1632 (CdO) cmꢀ1
;
HRMS (FAB) m/z calcd for C19H17O6 (M þ 1)þ 341.1025, found
341.1032.
5-Allyloxy-50-benzyloxy-2,20-difluoro-4-nitrobenzophe-
none (29). Under an atmosphere of argon, benzyl bromide (2.08 mL,
17.5 mmol) and potassium carbonate (3.22 g, 23.3 mmol) were added to
a solution of 8 (3.29 g, 11.6 mmol) in allyl alcohol (50 mL). The mixture
was stirred at room temperature for 24 h and then at 50 °C for 84 h. After
the reaction, allyl alcohol was evaporated off, and the residue was
extracted with ethyl acetate, washed with water and brine, and then
dried over MgSO4. The organic layer was concentrated, and the residue
was concentrated and purified by silica gel column chromatography
(hexaneꢀethyl acetate) to give 29 (2.42 g, 49%) as yellow needles
(dd, JFC = 9.7, 4.8 Hz), 118.0, 119.2 (d, JFC = 8.4 Hz), 128.9 (d, JFC
15.6 Hz), 130.8 (d, JFC = 2.4 Hz), 143.5 (d, JFC = 2.4 Hz), 148.5 (d, JFC
=
=
7.2 Hz), 153.0 (d, JFC = 255.6 Hz), 154.7 (d, JFC = 244.6, 2.4 Hz), 155.5,
188.4; IR (CHCl3) 1647 (CdO) cmꢀ1; HRMS (FAB) m/z calcd for
C22H21F2O4 (M þ 1)þ 387.1408, found 387.1427.
1
6-(2-Allyloxy-5-methoxybenzoyl)-5,8-diallyloxy-2,2-di-
methylchromene (24). Under an atmosphere of argon, 60% sodium
hydride in oil (25 mg, 0.63 mmol) was added to a solution of 23
(45.8 mg, 0.12 mmol) and allyl alcohol (44 μL, 0.63 mmol) in
dehydrated DMF (2 mL). The mixture was stirred at 60 °C for 3.5 h,
poured into iceꢀwater, and then neutralized with hydrochloric acid. The
product was extracted with ethyl acetate, washed with water and brine,
and dried over MgSO4. The organic layer was concentrated, and the
residue was purified by silica gel column chromatography (hexaneꢀ
(recrystallized from hexaneꢀacetone): mp 133.5ꢀ137 °C; H NMR
(500 MHz, CDCl3) δ 4.71 (2H, d, J = 5.0 Hz), 5.09 (2H, s), 5.36 (1H, d,
J = 11.5 Hz), 5.49 (1H, d, J = 17.0 Hz), 5.99ꢀ5.99 (1H, m), 7.06 (1H, t,
J = 9.5 Hz), 7.17ꢀ7.18 (1H, m), 7.31ꢀ7.31 (7H, m), 7.61 (1H, d, J = 8.5
Hz); 13C NMR (126 MHz, CDCl3) δ 70.84, 113.66 (d, JFC = 28.8 Hz),
114.93, 116.36 (d, JFC = 2.4 Hz), 117.41 (d, JFC = 24.0 Hz), 118.98,
122.66 (d, JFC = 8.4 Hz), 126.12 (d, JFC = 13.2 Hz), 127.54, 128.30,
128.70, 131.14, 132.00 (d, JFC = 14.4 Hz), 136.08 141.46 (d, JFC = 8.4
Hz), 148.12 (d, JFC = 2.4 Hz), 153.11 (d, JFC = 249.5 Hz), 155.03, 156.02
1
ethyl acetate) to give 24 (48.0 mg, 87%) as a yellow oil: H NMR
(d, JFC = 248.3 Hz), 187.51; IR (ATR) 1526 (NO2), 1654 (CO) cmꢀ1
;
(500 MHz, CDCl3) δ 1.46 (6H, s), 3.79 (3H, s), 4.12 (2H, dt, J = 5.5, 1.5
Hz), 4.36 (2H, dt, J = 5.5, 1.5 Hz), 4.57 (2H, dt, J = 5.5, 1.5 Hz),
5.00ꢀ5.10 (4H, m), 5.23 (1H, dq, J = 10.5, 1.5 Hz), 5.34 (1H, dq, J =
17.5, 1.5 Hz), 5.65 (1H, d, J = 10.0 Hz), 5.60ꢀ5.73 (2H, m), 5.99ꢀ6.07
(1H, m), 6.54 (1H, d, J = 10.0 Hz), 6.84 (1H, d, J = 9.0 Hz), 6.96 (1H, dd,
J = 9.0, 3.5 Hz), 7.06 (1H, d, J = 3.5 Hz), 7.10 (1H, s); 13C NMR
(CDCl3) δ 27.8, 55.8, 70.0, 70.7, 76.8, 114.3, 114.4, 115.9, 116.5, 116.9,
117.2, 117.4, 117.6, 118.0, 125.1, 130.3, 131.3, 132.8, 133.1, 133.5, 143.4,
HRMS (FAB) m/z calcd for C23H18F2NO5 (M þ 1)þ 426.1153, found
426.1185.
5-Allyloxy-50-benzyloxy-2,20-difluoro-4-hydroxybenzo-
phenone (33). Under an atmosphere of argon, benzaldoxime
(254 mg, 2.1 mmol) and 60% sodium hydride in oil (84 mg, 2.1 mmol)
were added to a solution of 29 (425 mg, 1.0 mmol) in dehydrated
DMSO (10 mL). The mixture was stirred at 20 °C for 7 h and then
acidified with 10% hydrochloric acid with ice-cooling. The product was
extracted with ethyl acetate, washed with water and brine, and then dried
over MgSO4. The organic layer was concentrated, and the residue was
purified by silica gel column chromatography (hexaneꢀethyl acetate) to
give 33 (281 mg, 71%) as a yellow oil: H NMR (500 MHz, CDCl3)
δ 4.65 (2H, d, J = 5.7 Hz), 5.06 (2H, s), 5.36 (1H, d, J = 10.2 Hz), 5.43
(1H, d, J = 17.0 Hz), 6.03ꢀ6.08 (1H, m), 6.27 (1H, s), 6.66 (1H, d, J =
10.8 Hz), 7.02 (1H, t, J = 9.4 Hz), 7.07ꢀ7.10 (1H, m), 7.18ꢀ7.19 (1H,
m), 7.29ꢀ7.43 (6H, m); 13C NMR (126 MHz, CDCl3) δ 70.45, 70.74,
147.3, 149.4, 151.5, 153.5, 193.8; IR (CHCl3) 1647 (CdO) cmꢀ1
;
HRMS (FAB) m/z calcd for C28H30O6 Mþ 462.2042, found 462.2042.
5,8-Dihydroxy-6-(2-hydroxy-5-methoxybenzoyl)-2,2-di-
methylchromene (25). Under an atmosphere of argon, dimedone
(387 mg, 2.76 mmol) was added to a solution of 24 (213 mg, 0.46 mmol)
and tetrakis(triphenylphosphine)palladium (266 mg, 0.23 mmol) in
distilled THF (15 mL). The mixture was refluxed for 2.5 h. After the
reaction, the solvent was evaporated. The product was extracted with
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The Journal of Organic Chemistry
ARTICLE
103.11 (d, JFC = 27.6 Hz), 112.95 (d, JFC = 3.6 Hz), 115.05 (d, JFC = 2.4
Hz), 116.76 (d, JFC = 24.0 Hz), 118.06 (d, JFC = 12.0 Hz), 119.20, 120.15
(d, JFC = 8.4 Hz), 127.58, 128.17, 128.63, 128.85 (d, JFC = 15.6 Hz),
132.07, 136.38, 142.16 (d, JFC = 2.4 Hz), 151.87 (d, JFC = 13.2 Hz),
154.73, 154.96 (d, JFC = 248.3 Hz), 157.76 (d, JFC = 251.9 Hz); IR
(ATR) 1649 (CO), 3360 (OH) cmꢀ1; HRMS (FAB) m/z calcd for
C23H19F2O4 (M þ 1)þ 397.1251, found 397.1242.
70.8, 114.3, 115.8, 115.9, 116.6, 117.0, 117.3, 117.4, 117.6, 119.0, 125.2,
127.5, 127.9, 128.5, 130.3, 131.5, 132.9, 133.2, 133.6, 137.0, 143.5, 147.4,
149.5, 151.8, 152.7, 193.7; IR (ATR) 1645 (CO), 1633 cmꢀ1; HRMS
(FAB) m/z calcd for C34H34O6 (M þ 1)þ 538.2355, found 538.2332.
6-(5-Benzyloxy-2-hydroxybenzoyl)-5,8-dihydroxy-2,2-di-
methylchromene (35). Under an atmosphere of argon, dimedone
(480 mg, 3.42 mmol) was added to a solution of 31 (307 mg, 0.57 mmol)
and tetrakis(triphenylphosphine)palladium (330 mg, 0.29 mmol) in
dehydrated THF (15 mL). The mixture was refluxed for 4 h. After the
reaction, the solvent was evaporated. The product was extracted with
ethyl acetate, washed with water and brine, and then dried over MgSO4.
The organic layer was concentrated, and the residue was purified by silica
gel column chromatography (hexaneꢀethyl acetate) to give 35 (204 mg,
86%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 1.53 (6H, s), 5.02
(2H, s), 5.06 (1H, s), 5.64 (1H, d, J = 10.0 Hz), 6.77 (1H, d, J = 10.0 Hz),
6.99 (1H, d, J = 9.0 Hz), 7.11 (1H, s), 7.13ꢀ7.17 (2H, m), 7.32 (1H, t,
J = 7.0 Hz), 7.37ꢀ7.43 (4H, m), 9.70 (1H, s), 11.52 (1H, s); 13C NMR
(126 MHz, CDCl3) δ 28.4, 71.0, 79.2, 109.8, 111.9, 116.1, 117.1,
117.1, 119.1, 120.4, 123.2, 127.6, 128.1, 128.4, 128.6, 136.7, 136.9,
147.1, 150.7, 154.0, 154.8, 200.1; IR (ATR) 1639 (CO), 3458
(OH) cmꢀ1; HRMS (FAB) m/z calcd for C25H23O6 (M þ 1)þ
419.1495, found 419.1507.
8-Benzyloxy-2,2-dimethylpyrano[2,3-b]xanthene-5,6,12-
(2H,5aH,12aH)-trione (32). Manganese dioxide (382 mg, 4.4 mmol)
was added to a solution of 35 (184 mg, 0.44 mmol) in dehydrated
dichloromethane (15 mL). The mixture was stirred at room temperature
for 12 h and filtrated through Celite. The filtrate was concentrated, and
the residue was purified by silica gel column chromatography (hexaneꢀ
ethyl acetate) to give 32 (183 mg, quant) as an orange amorphous solid:
1H NMR (500 MHz, CDCl3) δ 1.54 (6H, s), 3.06 (1H, d, J = 16.5 Hz),
3.27 (1H, d, J = 16.5 Hz), 5.02 (2H, s), 5.70 (1H, d, J = 10.0 Hz), 6.45
(1H, d, J = 10.0 Hz), 7.04 (1H, d, J = 2.5 Hz), 7.21 (1H, d, J = 9.0 Hz),
7.33ꢀ7.41 (6H, m); 13C NMR (126 MHz, CDCl3) δ 27.7, 28.4, 43.5,
70.8, 81.4, 92.5, 106.3, 114.7, 115.4, 117.9, 119.6, 127.5, 128.3, 128.7,
129.9, 131.5, 136.0, 154.9, 156.8, 167.9, 183.7, 186.6, 194.9; IR (ATR)
1716 (CO), 1705 (CO), 1676 (CO) cmꢀ1; HRMS (FAB) m/z calcd for
C25H21O6 (M þ 1)þ 417.1338, found 417.1333.
5-Allyloxy-50-benzyloxy-2,20-difluoro-4-(1,1-dimethylpro-
pargyloxy)benzophenone (34). Under an atmosphere of argon,
copper(II) chloride (0.20 mg, 0.0015 mmol) and 3-chloro-3-methyl-1-
butyne (279 μL, 2.43 mmol) were added to a solution of 33 (876 mg,
2.21 mmol) in distilled dichloromethane (25 mL). The mixture was
cooled to 0 °C, and DBU (430 μL, 2.87 mmol) was added. The mixture
was stirred at room temperature overnight, and the solvent was
evaporated. The product was extracted with ethyl acetate, washed with
water and brine, and then dried over MgSO4. The organic layer was
concentrated, and the residue was purified by silica gel column chro-
matography (hexaneꢀethyl acetate) to give 34 (678 mg, 66%) as a
yellow oil: 1H NMR (500 MHz, CDCl3) δ 1.74 (6H, s), 2.65 (1H, s),
4.55 (2H, d, J = 5.0 Hz), 5.06 (2H, s), 5.28 (1H, dd, J = 11.0, 1.0 Hz),
5.42 (1H, dd, J = 17.5, 1.0 Hz), 6.02ꢀ6.07 (1H, m), 7.02 (1H, t, J = 9.0
Hz), 7.07ꢀ7.11 (1H, m), 7.20ꢀ7.21 (1H, m), 7.28ꢀ7.29 (2H, m),
7.34ꢀ7.41 (7H, m); 13C NMR (126 MHz, CDCl3) δ 29.34, 70.40,
70.75, 74.17, 75.09, 84.74, 108.24 (d, JFC = 27.6 Hz), 115.03 (d, JFC = 3.6
Hz), 115.09 (d, JFC = 2.4 Hz), 116.82 (d, JFC = 24.0 Hz), 117.69, 119.91 (d,
JFC = 12.0 Hz), 120.29 (d, JFC = 8.4 Hz), 127.59, 128.17, 128.59 (d, JFC
=
12.0 Hz), 128.64, 132.93, 136.36, 147.15, 151.00 (d, JFC = 10.8 Hz), 154.73
(d, JFC = 2.4 Hz), 155.07 (d, JFC = 247.1 Hz), 156.24 (d, JFC = 252.3 Hz),
188.49; IR (ATR) 1654 (CO), 3292 (alkyne) cmꢀ1; HRMS (FAB) m/z
calcd for C28H25F2O4 (M þ 1)þ 463.1721, found 463.1738.
6-(5-Benzyloxy-2-fluorobenzoyl)-2,2-dimethyl-5-fluoro-
8-allyloxychromene (30). Under an atmosphere of argon, a solution
of 34 (678 mg, 1.47 mmol) in dehydreated toluene (15 mL) was refluxed
for 24 h. After the solution was cooled, the solvent was evaporated. The
residue was purified by silica gel column chromatography (hexaneꢀ
ethyl acetate) to give 30 (678 mg, 100%) as a yellow oil: 1H NMR (500
MHz, CDCl3) δ 1.52 (6H, s), 4.60 (2H, d, J = 5.1 Hz), 5.06 (2H, s), 5.28
(1H, d, J = 11.5 Hz), 5.39 (1H, dd, J = 17.0, 1.0 Hz), 5.69 (1H, d, J = 10.0
Hz), 6.00ꢀ6.10 (1H, m), 6.49 (1H, d, J = 10.0 Hz), 7.02 (1H, t, J = 9.0
Atroviridin (1) from 27. Under an atmosphere of argon, tribro-
moborate (24 μL, 0.25 mmol) was added to a solution of 27 (17.0 mg,
0.05 mmol) in dehydrated dichloromethane (3 mL) at ꢀ78 °C. The
mixture was stirred at ꢀ78 °C for 10 min and then at ꢀ60 °C for 2 h. The
reaction was stopped by addition of methanol. The product was
extracted with ethyl acetate, washed with water and brine, and dried
over MgSO4. The organic layer was concentrated, and the residue was
purified by silica gel column chromatography (hexaneꢀethyl acetate) to
give 1 (9.4 mg, 58%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6)
δ 1.46 (6H, s), 5.78 (1H, d, J = 10.3 Hz), 6.63 (1H, d, J = 10.3 Hz), 7.31
(1H, dd, J = 9.2, 2.9 Hz), 7.41 (1H, d, J = 2.9 Hz), 7.52 (1H, d, J = 9.2 Hz),
8.77 (1H, br s), 10.03 (1H, br s), 12.71 (1H, s); 1H NMR (acetone-d6) δ
1.49 (6H, s), 5.77 (2H, d, J = 9.7 Hz), 6.72 (2H, d, J = 9.7 Hz), 7.38 (2H,
dd, J = 9.2, 2.9 Hz), 7.50 (2H, d, J = 9.2 Hz), 7.58 (2H, d, J = 2.9 Hz), 7.90
(1H, s), 8.98 (1H, s), 12.80 (1H, s); 13C NMR (126 MHz, DMSO-d6) δ
28.3, 78.5, 102.8, 104.1, 108.5, 115.5, 119.7, 120.7, 125.3, 126.0, 129.2,
145.7, 149.0, 149.3, 149.7, 154.6, 181.0; 13C NMR (126 MHz, acetone-
d6) δ 27.7, 78.6, 102.8, 104.0, 108.8, 115.5, 119.0, 120.8, 124.9, 128.4,
144.8, 148.0, 149.7, 149.9, 154.3, 181.3; HRMS (FAB) m/z calcd for
C18H15O6 (M þ 1)þ 327.0869, found 327.0862.
Hz), 7.06ꢀ7.10 (1H, m), 7.16ꢀ7.22 (2H, m), 7.32ꢀ7.43 (5H, m); 13
NMR (126 MHz, CDCl3) δ 28.15, 70.74, 70.76, 78.12, 110.43 (d, JFC
C
=
20.4 Hz), 114.75, 114.79, 115.03 (d, JFC = 2.4 Hz), 115.62 (d, JFC = 3.6
Hz), 116.76 (d, JFC = 24.0 Hz), 117.78 (d, JFC = 12.0 Hz), 118.01, 119.95
(d, JFC = 8.4 Hz), 127.58, 128.17, 128.63, 128.94 (d, JFC = 15.6 Hz),
130.78 (d, JFC = 2.4 Hz), 133.12, 136.37, 143.51, 148.53 (d, JFC = 7.2
Hz), 152.97 (d, JFC = 255.5 Hz), 154.71 (d, JFC = 247.1 Hz), 188.26; IR
(ATR) 1639 (CO) cmꢀ1; HRMS (FAB) m/z calcd for C28H25F2O4
(M þ 1)þ 463.1721, found 463.1739.
6-(2-Allyloxy-5-benzyloxybenzoyl)-5,8-diallyloxy-2,2-di-
methylchromene (31). Under an atmosphere of argon, 60% NaH in
oil (200 mg, 5.0 mmol) was added to a solution of 30 (462 mg,
1.0 mmol) and allyl alcohol (340 μL, 5.0 mmol) in dehydrated DMF
(20 mL). The mixture was stirred at 30 °C for 2 h, poured into
iceꢀwater, and then neutralized with hydrochloric acid. The product
was extracted with ethyl acetate, washed with water and brine, and then
dried over MgSO4. The organic layer was concentrated, and the residue
was purified by silica gel column chromatography (hexaneꢀethyl
1
acetate) to give 31 (281 mg, 53%) as a slightly yellow oil: H NMR
Atroviridin (1) from 32. Under an atmosphere of argon, 1 M
tribromoborate in dichloromethane (0.5 mL) was added to a solution of
32 (30 mg, 0.072 mmol) in dehydrated dichloromethane (30 mL) at
ꢀ78 °C. The mixture was stirred at ꢀ78 °C for 10 min, and then the
temperature was allowed to rise to ꢀ17 °C in 3.5 h. The reaction was
stopped by adding methanol at ꢀ78 °C. The product was extracted with
chloroform, washed with water and brine, and then dried over MgSO4.
(500 MHz, CDCl3) δ 1.48 (6H, s), 4.07 (2H, d, J = 5.5 Hz), 4.36 (2H, d,
J = 4.5 Hz), 4.57 (2H, d, J = 5.0 Hz), 5.01ꢀ5.08 (6H, m), 5.23 (1H, dd,
J = 11.0, 1.0 Hz), 5.34 (1H, dd, J = 17.0, 1.0 Hz), 5.57ꢀ5.73 (3H, m),
6.00ꢀ6.05 (1H, m), 6.53 (1H, d, J = 10.0 Hz), 6.83 (1H, d, J = 9.0 Hz),
7.02 (1H, dd, J = 9.0, 3.0 Hz), 7.10 (1H, s), 7.14 (1H, d, J = 3.0 Hz),
7.22ꢀ7.50 (5H, m); 13C NMR (126 MHz, CDCl3) δ 27.8, 70.0, 70.7,
3966
dx.doi.org/10.1021/jo200303c |J. Org. Chem. 2011, 76, 3960–3967

The Journal of Organic Chemistry
ARTICLE
The organic layer was concentrated, and the residue was purified by silica
gel column chromatography (hexane/ethyl acetate/dichloromethane)
to give the crude debenzylated product. A mixture of the product and
tetrabutylammonium iodide (30 mg) in toluene was refluxed for 3 h and
concentrated. The residue was purified by silica gel column chromatog-
raphy (hexane/ethyl acetate/dichloromethane) to give 1 (13 mg, 55%)
as a yellow solid.
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1972, 1382–1387. (b) Brown, P. E.; Lewis, R. A.; Waring, M. A. J. Chem.
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(c) K€undig, E. P.; García, A. E.; Lomverget, T.; Bernardinelli, G. Angew.
Chem., Int. Ed. 2006, 45, 98–101.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
compound characterization data for the synthesis of 8ꢀ15, 17,
18, and 29ꢀ35 and copies of 1H and 13C NMR spectra of 1, 4, 8,
20ꢀ25, 27, and 29ꢀ35. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: suzuyumi@u-shizuoka-ken.ac.jp.
’ REFERENCES
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dx.doi.org/10.1021/jo200303c |J. Org. Chem. 2011, 76, 3960–3967