Synthesis of espicufolin based on 6-endo ring closure of o-alkynoylnaphthols

Article abstract of DOI:10.1039/b007859j

Regioselective halogenation of 3-acetoxymethyl-7-chloro-5,8-dimethoxy-1-naphthol 5 was achieved by DBH or I₂/N-methylmorpholine to give the corresponding 2-halogeno-1-naphthols 8 and 11, which were converted to 1-methoxymethoxy-3-(alk-2-ynoyloxymethyl)-2-halogenonaphthalenes 17 and 18 in good yields. An intramolecular acyl-transfer reaction of the 2-halogenonaphthalenes triggered by halogen-lithium exchange with BuLl at -78 °C gave 1-methoxymethoxy-2-alkynoyl-3-(hydroxymethyl)naphthalenes 21 in high yields. After protection of the hydroxymethyl group as a benzoate, formation of a γ-pyrone ring was easily achieved by deprotection of the methoxymethyl group followed by spontaneous 6-endo ring closure under mildly acidic conditions. The pyrone derivative having a 1-methylpropyl group was successfully converted to espicufolin 1.

Full text of DOI:10.1039/b007859j

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Synthesis of espicufolin based on 6-endo ring closure of
o-alkynoylnaphthols†
Hidemitsu Uno,*a Katsuji Sakamoto,a Erina Honda,a Kaori Fukuhara,a Noboru Ono,b
Junya Tanakac and Masahiro Sakanakac
1
a Advanced Instrumentation Center for Chemical Analysis, Ehime University, Bunkyo-cho 2-5,
Matsuyama 790-8577, Japan
b Department of Chemistry, Faculty of Science, Ehime University, Bunkyo-cho 2-5,
Matsuyama 790-8577, Japan
c Department of Physiology and Anatomy, Ehime University School of Medicine, Shigenobu,
Ehime 791-0295, Japan. E-mail: uno@dpc.ehime-u.ac.jp; Fax: ϩ81-89-927-9670
Received (in Cambridge, UK) 27th September 2000, Accepted 27th November 2000
First published as an Advance Article on the web 10th January 2001
Regioselective halogenation of 3-acetoxymethyl-7-chloro-5,8-dimethoxy-1-naphthol 5 was achieved by DBH or
I2/N-methylmorpholine to give the corresponding 2-halogeno-1-naphthols 8 and 11, which were converted to
1-methoxymethoxy-3-(alk-2-ynoyloxymethyl)-2-halogenonaphthalenes 17 and 18 in good yields. An intramolecular
acyl-transfer reaction of the 2-halogenonaphthalenes triggered by halogen–lithium exchange with BuLi at Ϫ78 ЊC
gave 1-methoxymethoxy-2-alkynoyl-3-(hydroxymethyl)naphthalenes 21 in high yields. After protection of the
hydroxymethyl group as a benzoate, formation of a γ-pyrone ring was easily achieved by deprotection of the
methoxymethyl group followed by spontaneous 6-endo ring closure under mildly acidic conditions. The pyrone
derivative having a 1-methylpropyl group was successfully converted to espicufolin 1.
Introduction
Neuronal cell-protecting substances in the event of ischemia
have attracted increasing attention from scientists in many
fields. Many kinds of such compounds have been reported.1 In
the event of ischemia, L-glutamic acid existing as an excitatory
neurotransmitter in the brain is believed to play the important
role of increasing the level of oxidants such as superoxide anion
and oxygen radicals in the neuronal cells, which then cause
neuronal cell death.2 In 1996, Seto et al. found a novel neuronal
cell-protecting substance, espicufolin 1, in the culture broth of
Streptomyces sp. cu39 in the course of their screening for
suppressors of glutamate toxicity using neuronal hybridoma
N18-RE-105 cells.3 However, the mechanism of action of
Scheme 1 Biosynthesis of pyranoanthraquinone families.
espicufolin was suggested not to relate to antioxidative activity
following an investigation of buthionine sulfoximine toxicity.3
analogues. We have devised a novel approach to naphtho-
During the course of our project exploring efficient neuronal-
cell-protecting substances, we were interested in the mechanism
of action and in vivo activity of espicufolin 1.
[1,2-b]pyrantriones based on an intramolecular alkynoyl
transfer followed by 6-endo closure under acidic conditions,7
and succeeded in preparing (S)-espicufolin.8 In this paper, we
describe the detailed study for the preparation of espicufolin.
The in vitro study of espicufolin using rat neuronal cells of
17-day embryos is also described.
Espicufolin 1 has a 1,8-dihydroxyanthraquinone skeleton
fused with a γ-pyrone ring and one unknown stereogenic center
at the 14-position, and is considered as a new member of the
pyranoanthraquinone family. Some of these family members
were reported to show important properties such as antitumor
and antibiotic activities.4 These pyranoanthraquinone families
are thought to be biosynthesized from a nonaketide having an
appropriate starting unit (Scheme 1).5 In the biosynthesis of
espicufolin and premithramycinone,6 2-methylbutanoyl and
acetyl groups are used as the starting unit, and the ending acetyl
group is modified to hydroxymethyl and methoxycarbonyl
groups, respectively. We have planned to synthesize espicufolin
1 via the route in which the two parts can be easily modified for
syntheses of other family members in addition to espicufolin
Results and discussion
Retro-synthesis
Our retrosynthetic pathway is shown in Scheme 2. Since the
regioselective Diels–Alder reaction of chloronaphthoquinone
with 1-methoxycyclohexa-1,3-diene has been established as one
of the most reliable methods for construction of anthraquin-
ones bearing hydroxy groups,9 we focused our attention on
the preparation of pyranonaphthoquinone 2. This pyrano-
naphthoquinone 2 could be prepared by the intramolecular
cyclization of o-alkynoylnaphthalene 3; a similar and successful
method using such a reaction was reported for the preparation
of the kapurimycin A3 analogue.10 The o-alkynoylnaphthalene
3 would be prepared from the known naphthol 4.11
† Experimental details for 13, 15, 17a, 18c, 18d, 18e, 21c, 21d, 21e, 25c,
25d, 25e, 26c, 26e, 27e, 28 and 29 are available as supplementary data.
For direct electronic access see http://www.rsc.org/suppdata/p1/b0/
b007859j/
DOI: 10.1039/b07859j
J. Chem. Soc., Perkin Trans. 1, 2001, 229–238
This journal is © The Royal Society of Chemistry 2001
229

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Scheme 2 Retro-synthesis of espicufolin.
Halogenation of naphthols
As attempts to introduce an acetyl group at the 2-position of 4
by the Friedel–Crafts reaction and the Fries rearrangement
both failed, we thought to introduce the acyl groups by the
reaction of a lithio derivative from 4 with acylating reagents.
Since the starting 4 has a chlorine atom, the directed ortho-
lithiation method12 of alkyllithiums utilizing the neighbour-
ing hydroxy group as a methoxymethoxy group cannnot be
applied. We decided to generate the lithio compound by
the halogen–lithium exchange reaction. Thus, we examined the
regioselective halogenation of the naphthols 4 and 5, the latter
of which can be quantitatively obtained by selective acetylation
with Ac2O in the presence of a catalytic amount of HClO4
(Scheme 3).
Scheme 3 Reagents and conditions: i) Ac2O, HClO4, rt; ii) NBS or
DBH; iii) I2, NMM, rt.
was remarkably improved to 77%. Slight electronic and steric
changes from 5 to 4 hampered the iodination. The iodination of
4 under similar conditions resulted in considerable formation
of dimers such as 10 (32%) in addition to 9 (43%). 2,2Ј-Dimer
10 was isolated in 24% yield by recrystallization of the dimeric
mixture.
Treatment of the naphthol 4 with 1.2 equiv. of N-bromo-
succiniodide (NBS) in CH2Cl2 gave a regioisomeric mixture of
2-bromonaphthol 6 and 4-bromonaphthol 7 in respective yields
of 24% and 14% (run 1). The regiochemistry of 6 and 7 was
unambiguously determined by differential nuclear Overhauser
effect (NOE) experiments. Regioselective bromination giving
the 2-bromonaphthols 6 (92%) and 8 (98%) was achieved using
NBS in dimethylformamide (DMF).13 This preference for the
2-bromo derivatives over 4-bromo derivatives was quite differ-
ent from the result obtained in the bromination of 1-hydroxy-
9,10-anthraquinones, where the bromination preferentially
occurred at the 4-position.14 This difference could be due to
the steric effect of the peripheral methoxy substituent in the
naphthols 4 and 5. When 1.0 or 1.2 equiv. (0.5 or 0.6 mol per
the naphthol) of 1,3-dibromo-5,5-dimethylhydantoin (DBH)
was used as the brominating reagent,15 the target bromide 6 was
obtained in good yields (88–90%) irrespective of the solvent
(DMF or CH2Cl2). This high regioselectivity of DBH would be
attributed to the bulkiness of DBH compared to NBS. The
advantage of using DBH should be emphasized because both
the bromine atoms were available for this bromination. Reac-
tion of 5 with I2 and N-methylmorpholine (NMM) gave mainly
dimeric compounds such as 12 in 66% yield in addition to
2-iodonaphthol 11 (31%).16 No formation of a 4-iodo derivative
was observed. One of the dimers was isolated in 36% yield by
recrystallization and the structure was determined as the 2,2Ј-
Intramolecular acyl-transfer reaction
As debromination and deacetylation of 8 to 4 were observed
upon treatment of 8 with n-BuLi, the 2-bromo- and 2-
iodonaphthols 8 and 11 were first converted into methoxy-
methyl ethers 13 and 14, in 96% and 89% yield, respectively
(Scheme 4). The acetyl group of 13 and 14 was then hydrolyzed
to give alcohols 15 and 16 in respective yields of 92% and 93%.
Then, intermolecular acylation of the alcohol 15 at the
2-position was attempted. When the alcohol 15 was treated with
2 equiv. of n-BuLi at Ϫ78 ЊC followed by methyl 4-methylpent-
2-ynoate, none of the acylated compound was formed and the
simply debrominated compound 20 was obtained in quanti-
tative yield. This fact may indicate that the bromine–lithium
exchange is followed by rapid quenching of the carbanion by
the intramolecular hydroxy group or that the carbanion at the
2-position is severely hindered by the adjacent substituents.
Therefore, we decided to utilize the 3-hydroxymethyl group as
an acyl group carrier. The 3-hydroxymethyl group of 15 and 16
was acylated with a variety of alkynoic acids17 to give alkynoyl
esters 17a and 18a–18e in good yields (60–94%).18
An intramolecular acyl-transfer reaction was examined by
generation of an anion at the 2-position of the naphthalenes
under various conditions. First, a halogen–lithium exchange
reaction of 13 and 14 was carried out [reaction (1)]. The reac-
tion of 13 with an equal equivalent of n-BuLi at Ϫ78 ЊC gave
almost the same amount of the aimed for product 19 (33%) and
a simply deacylated alcohol 15 (28%). From the NMR analysis,
the 2-acetyl compound 19 was proved to exist as a ca. 1:7
1
dimer 12 by H NMR analysis. Structures of other dimeric
compounds in the mother liquor were assumed to be 2,4Ј- and
1
4,4Ј-dimers and their partially iodinated compounds by H
NMR analysis, though the precise assignment could not be
done. In order to suppress the formation of dimers, the reaction
was carried out at a lower concentration. When the reaction
was conducted at a 0.05 M concentration, yield of the iodide 11
230
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(2)
Scheme 4 Reagents and conditions: i) MOMCl, Et3N, CH2Cl2,
rt; ii) NaOH, THF–MeOH, rt; iii) alk-2-ynoic acid, BOPCl, Et3N,
CH2Cl2, rt.
2,3-dienoyloxy compound 22 would be generated by proton
abstraction from the acidic butynoyl moiety followed by pro-
tonation to the α-position upon quenching. As an allenic sp
carbon is more susceptible toward nucleophilic attack than is
an acetylenic sp carbon, mainly due to stability of the resulting
intermediates (allylic vs. vinylic), the oxepin formation giving 23
would proceed via the acetylene–allene tautomerization of 21c
followed by an intramolecular ring closure.
(1)
Intramolecular cyclization of o-alkynoylnaphthols
At first, we attempted to remove the methoxymethyl group of
2-alkynoylnaphthalenes 21 under acidic conditions prior to the
intramolecular cyclization. Treatment of the 2-alkynoyl com-
pound 21a with HCl in aq. tetrahydrofuran (THF)–PriOH,
however, gave undesired oxepine derivative 24 as the main
product in 62% yield. Formation of 24 was the formal 7-endo-
digonal ring closure which was reported as a favourable
process.19 Thus, the 3-hydroxymethyl group of 21a–21e was
protected as the benzoate esters 25a–25e (Scheme 5).
mixture of keto and hemiacetal forms in CDCl3 at ambient
temperature. When 2.1 equivalents of tert-BuLi were employed
instead of n-BuLi, the yield of 2-acetyl compound 19 was
greatly improved to 75%, and compound 20 was formed as a
by-product in 8% yield. In the reaction of the iodo derivative 14
with n-BuLi at Ϫ78 ЊC, the aimed for product 19 was formed as
a sole product in 88% yield.
The compound 25a was refluxed in a THF–PriOH–HCl
(3 M) solution under argon to give the target pyrone 26a in 85%
Next, the alkynoyl-transfer reaction was examined [reaction
(2)]. The reaction of 17a with tert-BuLi at Ϫ78 ЊC was ham-
pered by the nucleophilic attack to give a considerable amount
of 20 (52%) as well as 21a (40%), probably due to the sterically
less hindered nature of the alkynoyl ester moiety. The side reac-
tion giving 20 could not be suppressed by reduction of the
reaction temperature to Ϫ100 ЊC, and a mixture of 20 (41%)
and 21a (59%) was obtained. On the other hand, highly reactive
iodo compound 18a underwent smooth alkynoyl-transfer
reaction even on treatment with n-BuLi at Ϫ78 ЊC to give the
desired compound 21a in 80% yield as well as a small amount
of 20 (5%). Transformation of other alkynoyloxy derivatives
(S)-18b, (R)-18b, 18c, 18d and 18e was also achieved in respect-
ive yields of 95, 95, 65, 73 and 95%. In the case of 3-(but-
2-ynoyloxymethyl)naphthalene 18c with n-BuLi, the yield of
21c was slightly low (65%). From NMR and IR analyses of
the by-products, buta-2,3-dienoyloxy and oxepin derivatives 22
and 23 were formed in respective yields of 3 and 4%. The buta-
Scheme 5 Reagents and conditions: i) 21a, HCl, aq. THF–PriOH,
reflux; ii) BzCl, pyridine, rt; iii) 25a–25e, HCl, aq. THF–PriOH, reflux.
J. Chem. Soc., Perkin Trans. 1, 2001, 229–238
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yield. When the reaction was carried out under air, however, an
intractable mixture was obtained. In this mixture, considerable
amounts of dimeric compounds were identified by H NMR
Preparation of espicufolin
The obtained naphtho[1,2-b]pyran-4-one 26b was transformed
into espicufolin 1. First, deprotection of the benzoyl group was
tested by using 26a as a substrate [reaction (3)]. When 26a was
1
and MS analyses, though the structures could not be assigned.
In the cases of aliphatic alkynoyl derivatives (S)-25b, (R)-25b
and 25c, yields of the pyrones (S)-26b, (R)-26b and 26c were
good (77, 77 and 65%, respectively). On the other hand, a simi-
lar reaction of aralkynoyl compound 25d gave a mixture of
pyrone 26d (41%) and furanone 27d (41%). A similar result
was obtained in the reaction of 25e; a mixture of 26e (48%)
and 27e (46%) was formed. In order to suppress the undesired
5-membered-ring formation, we examined the cyclization of
enaminones derived from addition of diethylamine to the triple
bond.20 The aralkynoyl compounds 25d and 25e were treated
with diethylamine and then the crude enaminones were refluxed
under acidic conditions to afford only pyrones 26d and 26e in
excellent yields (87 and 92%, respectively).
(3)
Mechanistic considerations of the cyclization
Possible reaction pathways to the observed products are illus-
trated in Scheme 6.7 Since the oxidative dimerization was
treated with NaOH in aq. THF–MeOH at room temperature
for 1 h, the target compound 28 and γ-lactone 29 were obtained
in 33 and 37% yield, respectively. The by-product 29 would
be derived from the hydrolysis of the γ-pyrone ring of 28 to a
β-diketo derivative, which would decompose by the intra-
molecular nucleophilic attack of the adjacent hydroxymethyl
group. In fact, shortening the reaction time increased the yield
of 28 to 70% and lowering the reaction temperature to 0 ЊC
brought about almost quantitative formation of 28. As oxid-
ation of 28 with cerium() ammonium nitrate (CAN), how-
ever, gave a complex mixture probably due to the highly
electron-rich nature of the substrate, we decided to deprotect
the benzoyl group at the final step.
Conversion of the γ-pyrone-fused naphthalene derivative
(S)-26b to the target γ-pyrone-fused anthraquinone was
achieved by the reported protocol.11 Oxidation of (S)-26b with
CAN gave naphthoquinone (S)-30 in 75% yield (Scheme 7).
One-pot conversion11 of naphthoquinone 30 to the anthra-
quinone resulted in intractable mixture formation, from which
the target anthraquinone 32 was obtained in an only trace
amount. As hydrogen chloride developed during the aromatiz-
ation would destroy the γ-pyrone moiety at the elevated
temperature employed, we employed the two-step method.
The Diels–Alder reaction of (S)-30 with 1-methoxycyclohexa-
1,3-diene followed by elimination of hydrogen chloride with
pyridine gave (S)-31 as a mixture of diastereomers (≈1:1)
in 69% yield. The target anthraquinone (S)-32 was obtained
in 74% yield by heating neat (S)-31 at 150 ЊC. Cleavage of
the methyl ether (to afford 33) followed by saponification of the
benzoyl group at 0 ЊC provided (S)-espicufolin [(S)-1] in 50%
yield. Similarly, (R)-espicufolin [(R)-1] was also prepared. The
analytical data of the synthesized (R)-espicufolin were identical
with the reported data for natural espicufolin in all respects
including the [α]D-value [(R)-1: ϩ8.5 (CHCl3, c 0.02); (S)-1:
Ϫ11.3 (CHCl3, c 0.02); natural espicufolin: ϩ9.4 (CHCl3, c
0.02)]. Therefore, the unknown chiral center of C-14 of natural
espicufolin was determined to be R.
Scheme 6 Proposed reaction pathways.
observed in the presence of oxygen and the furanone formation
was observed only in the reactions of the aralkynoyl derivatives
25d and 25e, we have suspected the participation of a radical
intermediate such as C which then leads to the undesired
furanones 27 in the 5-exo-digonal fashion.21 It is very difficult to
confirm the participation of the naphthoxyl radical intermedi-
ate, because naphthoxyl radicals are far more stable than
phenoxyl radicals and are readily formed under various condi-
tions.22 Indeed, even in the presence of tocopherol as a radical
scavenger or azoisobutyronitrile (AIBN) as a radical pro-
moter, the ratio of 26:27 was unchanged. In spite of all of
our efforts, participation of the radical intermediate could
not be confirmed. Although formation of the furanones 27 is
not clear at this moment, the main reaction pathways leading
to 26 are as follows. Under acidic conditions, protonation
of the ynone carbonyl would occur to give an allenyl cationic
intermediate A. The intermediate would be attacked at the
β-position either by an intramolecular hydroxy group (6-endo-
digonal mode; route a)23 or by water or PriOH (route b, via
B) followed by 6-exo-trigonal or 6-endo-trigonal ring closure21
to give 26.
in vitro Examination of espicufolin
To examine if espicufolin can promote neuronal survival, an
in vitro study was conducted with the use of rat cerebrocortical
neurons. Rat cerebrocortical neurons were separated from
brains of 17-day embryos.24 The neurons were seeded on poly-
L-lysine-coated 24-well plates at a density of ≈500 000 cells
cmϪ2 and cultured for 16 h in Dulbecco’s modified Eagle’s
medium (DMEM, Sigma) with 10% fetal calf serum. There-
after the medium was replaced with a serum-free DMEM
232
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had no protective activity but weak cytotoxicity against rat
embryonic neuronal cells.
Experimental
Mps were measured on a Yanagimoto micromelting apparatus
and are uncorrected. Unless otherwise specified, NMR spectra
were obtained with a JEOL GSX-270 or EX-400 spectrometer
at ambient temperature by using CDCl3 as solvent, and tetra-
methylsilane as internal standard for 1H and 13C. Mass spectra
were measured with a Hitachi M80B spectrometer under the EI
(electron impact, 20 eV) ionizing conditions. [α]D-Values were
measured with a JASCO DIP-1000 polarimeter and are given
in units of 10Ϫ1 deg cm2 gϪ1. THF was distilled from sodium
benzophenone ketyl, and dichloromethane was distilled from
CaH2 prior to use. DMF was distilled under reduced pressure
and then stored over molecular sieves (MS) 4 Å. Pyridine was
distilled from CaH2 and stored over MS 4 Å.
3-Acetoxymethyl-7-chloro-5,8-dimethoxy-1-naphthol 5
To a stirred suspension of 4 (7.550 g, 28.1 mmol) and acetic
anhydride (3.17 ml, 33.7 mmol) in dry CH2Cl2 (100 ml) was
added one drop of conc. perchloric acid at room temperature.
The suspension became a clear solution. After the mixture
had been stirred for 2 h, aq. NaHCO3 (50 ml) was added.
The organic phase was separated and the aqueous phase
was extracted with CH2Cl2 (2 × 30 ml). The combined organic
phase was washed with brine (50 ml), dried over Na2SO4, fil-
tered through a short column of silica gel, and concentrated to
give 8.67 g (99%) of 5. Recrystallization from CH2Cl2–hexane
gave 7.826 g (90%) of 5 as colorless needles (Found: C, 57.80;
H, 4.84. C15H15ClO5 requires C, 57.98; H, 4.87%), mp 100–
102 ЊC; Rf (30% EtOAc–hexane) 0.3; δH 2.13 (3H, s), 3.96
(3H, s), 4.03 (3H, s), 5.18 (2H, s), 6.72 (1H, s, H6), 6.96 (1H, d,
J 1.2, H2), 7.68 (1H, d, J 1.2, H4) and 9.44 (1H, s, OH);
δC 21.0, 55.9, 62.3, 66.2, 106.2 (C-6), 111.9 (C-2 or -4), 112.8
(C-4 or C-2), 117.7, 121.7, 126.8, 135.3, 144.8 (C-8), 152.7 (C-1
Scheme 7 Reagents and conditions: i) CAN, MeCN; ii) 1-methoxy-
cyclohexa-1,3-diene, CH2Cl2, pyridine; iii) 150 ЊC; iv) BBr3, CH2Cl2; v)
NaOH, THF–MeOH, 0 ЊC.
containing calf serum albumin, insulin, transferrin, sodium
selenite and 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic
acid (HEPES) (pH 7.3). After the neurons were cultured for 4
or 5 days, they were exposed to glutamate (300 µM) or sodium
nitroprusside (SNP; 300 µM) to induce neuronal death. 12 h
before neurons were exposed to the cytotoxic agents, 100 fg
mlϪ1, 10 pg mlϪ1, 1 ng mlϪ1, 100 ng mlϪ1 and 10 µg mlϪ1 of
( )- and (S)-espicufolins were added into the culture medium.
By incubation of the neurons with 300 µM L-glutamic acid
for 4 or 8 h, 30 and 45% of the neurons degenerated in the
absence of espicufolin, respectively. The viability was estimated
by the use of a redox indicator Alarmar Blue as described.25
Espicufolin did not significantly improve the viability of the
neurons which were exposed to glutamate. On the contrary, all
neurons degenerated when they were incubated with 10 µg mlϪ1
of ( )- and (S)-espicufolin. SNP, a nitric oxide donor, is known
to induce apoptotic neuronal death.25 Espicufolins at any
concentration did not rescue the neurons from SNP-induced
apoptotic neuronal death. Taken together, we concluded that
espicufolin is not able to promote survival of rat neurons
against the toxicity of -glutamic acid and nitric oxide.
or -5), 153.5 (C-5 or C-1) and 170.8 (C᎐O); m/z (rel. intensity)
᎐
312 [Mϩ(37Cl), 34], 310 [Mϩ(35Cl), 100], 297 (22), 295 (64), 255
(18) and 253 (53); νmax (KBr)/cmϪ1 3379, 1738, 1367, 1253 and
1055.
Halogenation of naphthols 4 and 5
NBS Method in CH2Cl2. To a stirred solution of 4 (269 mg,
1 mmol) in CH2Cl2 (10 ml) was added NBS (214 mg, 1.2 mmol)
at room temperature. After 2 h, the reaction was quenched by
addition of 5 ml of 1 M NaHSO3. The organic phase was
separated and the aqueous phase was extracted with CH2Cl2
(2 × 10 ml). The combined organic phase was washed with
brine, dried over Na2SO4, filtered through a short column of
silica gel, and concentrated. The residue was chromatographed
on silica gel (20–50% EtOAc–hexane).
NBS Method in DMF. To a stirred solution of a naphthol
(24 mmol) in 48 ml of dry DMF was transferred a solution
of NBS (3.560 g, 20 mmol) in dry DMF (20 ϩ 10 ml) by a
cannula. The mixture was stirred overnight and then water
(300 ml) was added. The precipitates were filtered off, washed
with water (3 × 50 ml), and dried to give the crude bromo-
naphthol. Recrystallization from CH2Cl2–hexane gave the pure
material.
Conclusions
We developed an efficient preparation of naphtho[1,2-b]pyran-
4-ones with a combination of alkynoyl transfer and intra-
molecular cyclization. The target naphtho[1,2-b]pyran-4-ones
with various kinds of substituents were prepared from the
corresponding 2-alkynoyl-1-naphthols by proper choice of the
reaction conditions. Espicufolin was prepared by this route.
This methodology would be applicable for the preparation of
other members of the pyranoanthraquinone family such as
indomycinones,4 premithramycinones6 and AH-1763 IIa.26
Regretfully, our in vitro study showed (S)- and ( )-espicufolin
DBH Method. The reaction was carried in the same manner
as above except for the use of DBH.
Iodination. To a stirred solution of a naphthol (9 mmol) and
I2 (18 mmol) in dry CH2Cl2 was added NMM (aq. 1.19 ml, 10.8
mmol) at room temperature. After 3 h, a mixture of aq.
NaHSO3 (1 M; 20 ml) and water (50 ml) was added. The mix-
ture was extracted with CHCl3 (3 × 50 ml). The organic extract
was washed with brine, dried over Na2SO4, and concentrated.
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The residue was recrystallized from CH2Cl2–hexane and/or
chromatographed on silica gel (20–50% EtOAc–hexane).
2-Bromo-7-chloro-3-hydroxymethyl-5,8-dimethoxy-1-naphthol
6. Colorless needles (Found: C, 44.85; H, 3.47. C13H12BrClO4
requires C, 44.92; H, 3.48%), mp 184–186 ЊC; Rf (30% EtOAc–
hexane) 0.35; δH 2.17 (1H, br, OH), 3.96 (3H, s), 4.04 (3H, s),
4.86 (2H, br), 6.73 (1H, s, H6), 7.80 (1H, s, H4) and 10.20 (1H, s,
OH); δC 56.0, 62.6, 65.6 (ArCH2O), 106.5 (C-6), 107.2, 112.6
(C-4), 117.6, 122.3, 125.2, 138.7, 143.9 (C-8), 149.5 and 152.7
(C-1 and -5); m/z (rel. intensity) 350 [Mϩ(37Cl81Br), 20], 348
[Mϩ(35Cl81Br ϩ 37Cl79Br), 76], 346 [Mϩ(35Cl79Br), 59], 335 (24),
333 (100) and 331 (77); νmax (KBr)/cmϪ1 3241, 1600, 1490, 1388,
1345 and 1050.
4-Bromo-7-chloro-3-hydroxymethyl-5,8-dimethoxy-1-naphthol
7. δH 2.04 (1H, br, OH), 3.91 (3H, s), 3.99 (3H, s), 4.83 (2H,
br), 6.82 (1H, s, H6), 7.15 (1H, s, H2) and 9.82 (1H, s, OH). This
compound could not be isolated.
3-Acetoxymethyl-2-bromo-7-chloro-5,8-dimethoxy-1-naphthol
8. Colorless crystals (Found: C, 45.89; H, 3.59. C15H14BrClO5
requires C, 46.24; H, 3.62%), mp 183–185 ЊC; Rf (30% EtOAc–
hexane) 0.65; δH 2.17 (3H, s), 3.96 (3H, s), 4.04 (3H, s), 5.30
(2H, s, CH2O), 6.73 (1H, s, H6), 7.74 (1H, s, H4) and 10.23 (1H,
s, OH); δC 20.9, 56.0, 62.5, 66.3 (ArCH2O), 106.5 (C-6), 107.8,
114.1 (C-4), 117.8, 122.7, 124.8, 133.9, 143.8 (C-8), 149.7 (C-1
117.7, 118.3, 122.0, 126.4, 134.9, 144.9, 149.9, 152.8 and 170.5;
m/z (rel. intensity) 620 [Mϩ(37Cl35Cl), 25], 618 [Mϩ(35Cl2), 36],
500 (71), 498 (100), 485 (29) and 483 (40); νmax (KBr)/cmϪ1 3296,
1734, 1344, 1246, 1234 and 1047.
3,3Ј-Bis(acetoxymethyl)-7,7Ј-dichloro-1,1Ј-dihydroxy-5,5Ј,
8,8Ј-tetramethoxy-2,4Ј-binaphthyl. Rf (30% EtOAc–hexane)
0.25; δH 1.98 (3H, s), 2.18 (3H, s), 3.97 (3H, s), 4.00 (3H, s), 4.01
(3H, s), 4.05 (3H, s), 5.03 (1H, d, J 13.2, CH2O), 5.04 (1H, d,
J 13.2, CH2O), 5.27 (2H, s, CH2O), 6.76 (2H, s, H6 and H6Ј),
7.75 (1H, s, H2Ј), 7.88 (1H, s, H4), 9.76 (1H, s, OH) and 10.58
(1H, s, OH).
3-Acetoxymethyl-7-chloro-2-iodo-5,8-dimethoxy-1-(methoxy-
methoxy)naphthalene 14. The naphthol 11 (5.796 g, 13.27
mmol) and NaH (60% dispersion; 0.53 g, 13.3 mmol) were
placed in a flask and dry DMF (55 ml) was added under Ar.
The mixture was cooled in an ice-bath and then MOMCl (1.21
ml, 15.9 mmol) was added by a syringe. After the mixture had
been stirred for 6 h, water (500 ml) was added. The precipitates
were filtered, washed with water (100 ml), and dried. The
precipitates were dissolved in warm CHCl3 (100 ml) and the
solution was filtered through a column of MgSO4 and silica gel,
which was washed with CHCl3 (3 × 50 ml). Concentration of
the filtrate gave 6.26 g (98%) of 14 as an amber-white solid.
Recrystallization from CH2Cl2–diethyl ether–hexane gave 5.623
g (88%) of 14 as colorless crystals (Found: C, 42.48; H, 3.77.
C17H18ClIO6 requires C, 42.29; H, 3.68%), mp 155–157 ЊC;
Rf (20% EtOAc–hexane) 0.45; δH 2.19 (3H, s), 3.76 (3H, s),
3.82 (3H, s), 3.97 (3H, s), 5.13 (2H, s, OCH2O), 5.29 (2H, s,
ArCH2O), 6.84 (1H, s, H6) and 8.06 (1H, s, H4); δC 20.9, 55.9,
56.0, 59.1, 70.7 (ArCH2O), 97.8 (C-2), 101.7 (OCH2O), 107.1
(C-6), 119.5 (C-4), 122.8, 126.4, 126.9, 135.7, 143.4, 151.6, 152.1
or -5), 152.6 (C-5 or C-1) and 170.5 (C᎐O); m/z (rel. intensity)
᎐
392 [Mϩ(37Cl81Br), 26], 390 [Mϩ(35Cl81Br ϩ 37Cl79Br), 100], 388
[Mϩ(37Cl79Br), 77], 375 (28), 373 (22), 331 (12), 267 (35), 251
(98) and 223 (53); νmax (KBr)/cmϪ1 3211, 1736, 1367, 1348, 1250,
1240 and 1045.
7-Chloro-3-hydroxymethyl-2-iodo-5,8-dimethoxy-1-naphthol
9. Colorless crystals (Found: C, 39.60; H, 3.25. C13H12ClIO4
requires C, 39.57; H, 3.07%), mp 162–163 ЊC; Rf (40% EtOAc–
hexane) 0.6; δH 2.14 (1H, t, J 6.4, OH), 3.97 (3H, s), 4.05 (3H,
s), 4.82 (2H, d, J 6.4, ArCH2O), 6.78 (1H, s, H6), 7.82 (1H, s,
H4) and 10.53 (1H, s, OH); δC 56.0, 62.6, 69.7 (ArCH2O), 84.3
(C-2), 106.8 (C-6), 112.7, 116.8, 122.0, 126.2, 141.0, 143.8, 152.0
and 152.7; m/z (rel. intensity) 396 [Mϩ(37Cl), 34], 394 [Mϩ(35Cl),
100], 381 (31), 379 (92) and 219 (10); νmax (KBr)/cmϪ1 3293,
1598, 1481, 1386, 1374, 1343, 1047 and 953.
7,7Ј-Dichloro-1,1Ј-dihydroxy-3,3Ј-bis(hydroxymethyl)-5,5Ј,
8,8Ј-tetramethoxy-2,2Ј-binaphthyl 10. Colorless crystals
(Found: C, 52.32; H, 4.47. C26H24Cl2O8ؒCH2Cl2 requires C,
52.28; H, 4.47%), mp 257–259 ЊC; Rf (40% EtOAc–hexane) 0.2;
δH 2.78 (2H, br, OH), 3.99 (6H, s), 4.00 (6H, s), 4.48 (2H, d,
J 13.2, CH2O), 4.50 (2H, d, J 13.2, CH2O), 6.75 (2H, s, H6 and
H6Ј), 7.96 (2H, s, H4 and H4Ј) and 9.81 (2H, s, OH); δC 56.0,
62.5, 64.2 (ArCH2O), 106.2 (C-6), 114.1 (C-4), 117.5, 119.0,
121.9, 126.6, 139.5, 144.7, 149.7 and 152.9; m/z (rel. intensity)
536 [Mϩ(37Cl35Cl), 38], 534 [Mϩ(35Cl35Cl), 60], 516 (20), 500
(70), 498 (100), 485 (46), 483 (62), 468 (23) and 453 (33); νmax
(KBr)/cmϪ1 3392, 3226, 1599, 1488, 1339 and 1051.
and 170.5 (C᎐O); m/z (rel. intensity) 480 (Mϩ, 33), 436 (13), 376
᎐
(53), 293 (100) and 266 (21); νmax (KBr)/cmϪ1 1743, 1583, 1321,
1228 and 1049.
7-Chloro-3-hydroxymethyl-2-iodo-5,8-dimethoxy-1-(methoxy-
methoxy)naphthalene 16. The acetate 14 (2.20 g, 4.58 mmol) was
dissolved in freshly distilled THF (100 ml) and MeOH (35 ml).
To the stirred solution was added aq. NaOH (1.0 M; 15 ml) at
room temperature. After 1 h, brine (100 ml) was added. The
suspension was extracted with EtOAc (3 × 50 ml). The organic
phase was washed with brine (50 ml), dried over MgSO4, and
concentrated to give a crude product. Chromatography on silica
gel (20–30% EtOAc–hexane) gave 2.08 g of 16 as colorless crys-
tals (Found: C, 41.04; H, 3.66. C15H16ClIO5 requires C, 41.07;
H, 3.68%), mp 134–135 ЊC; Rf (40% EtOAc–hexane) 0.55;
δH 2.75 (1H, t, J 7.4, OH), 3.77 (3H, s), 3.79 (3H, s), 3.91 (3H,
s), 4.75 (2H, d, J 7.4, CH2OH), 5.15 (2H, s, OCH2O), 6.74 (1H,
s, H6) and 7.95 (1H, s, H4); δC 55.9, 59.0, 61.7, 69.9 (ArCH2O),
96.6 (C-2), 101.8 (OCH2O), 106.7 (C-6), 117.4 (C-4), 122.2
(C-8a), 125.3 (C-7 or -4a), 127.1 (C-4a or -8), 140.2 (C-3), 143.2
(C-8), 151.2 (C-1) and 151.8 (C-5); m/z (rel. intensity) 438 (Mϩ,
77), 375 (66), 311 (17), 279 (43) and 251 (100); νmax (KBr)/cmϪ1
3434, 1585, 1477, 1455, 1411, 1330, 1311, 1247, 1211 and 1187.
3-Acetoxymethyl-7-chloro-2-iodo-5,8-dimethoxy-1-naphthol
11. Colorless crystals (Found: C, 41.10; H, 3.23. C15H14ClIO5
requires C, 41.26; H, 3.23%), mp 164–166 ЊC; Rf (30% EtOAc–
hexane) 0.5; δH 2.18 (3H, s), 3.97 (3H, s), 4.05 (3H, s), 5.27 (2H,
s, ArCH2O), 6.76 (1H, s, H6), 7.75 (1H, s, H4) and 10.6 (1H, s,
OH); δC 20.9, 55.9, 62.5, 70.3 (ArCH2O), 84.7 (C-2), 106.6
(C-6), 106.6 (C-4), 113.9, 122.3, 125.6, 136.2, 143.4 (C-8), 152.1
General procedure for condensation of 3-(hydroxymethyl)-
naphthalenes 15 and 16 with alkynoic acid
To a solution of a 3-(hydroxymethyl)naphthalene (1.5 mmol),
alkynoic acid (1.8 mmol) and Et3N (0.50 ml, 3.6 mmol) in
dry CH2Cl2 (2 ml) was added N,N-bis(2-oxooxazolidin-3-yl)-
phosphorodiamidic chloride (BOPCl) (458 mg, 1.8 mmol) at
room temperature under argon. After 20 h, the reaction
mixture was quenched by addition of saturated aq. NaHCO3
(10 ml). The organic phase was separated and the aqueous
phase was extracted with CHCl3 (3 × 20 ml). The combined
organic phases were washed with brine (50 ml), dried over
MgSO4, and concentrated to give a crude product, which was
purified by recrystallization or column chromatography on
silica gel.
(C-1 or -5), 152.4 (C-5 or C-1) and 170.4 (C᎐O); m/z (rel. inten-
᎐
sity) 436 (Mϩ, 100), 310 (59), 252 (97) and 223 (10); νmax (KBr)/
cmϪ1 3286, 1737, 1369, 1346, 1242 and 1047.
3,3Ј-Bis(acetoxymethyl)-7,7Ј-dichloro-1,1Ј-dihydroxy-5,5Ј,
8,8Ј-tetramethoxy-2,2Ј-binaphthyl 12. Colorless crystals, mp
225–226 ЊC (Found: C, 57.40; H, 4.56. C30H28Cl2O10ؒ¹H2O
¯
²
requires C, 57.34; H, 4.65%); Rf (30% EtOAc–hexane) 0.3;
δH 1.99 (6H, s), 3.99 (6H, s), 4.02 (6H, s), 5.05 (2H, d, J 13.2,
CH2O), 5.08 (2H, d, J 13.2, CH2O), 6.77 (2H, s, H6 and H6Ј),
7.91 (2H, s, H4 and H4Ј) and 9.78 (2H, s, OH); δC 20.8, 56.0,
62.5, 64.9 (ArCH2O), 106.4 (C-6 and -6Ј), 113.0 (C-4 and -4Ј),
234
J. Chem. Soc., Perkin Trans. 1, 2001, 229–238

View Article Online
7-Chloro-2-iodo-5,8-dimethoxy-1-methoxymethoxy-3-
(1H, d, J 1.0, H5); δC 55.8 (ArCH2O), 56.5 (MeO), 61.5 (MeO),
[(4-methylpent-2-ynoyloxy)methyl]naphthalene 18a. 87% Yield;
colorless crystals (Found: C, 47.08; H, 4.15. C21H22ClIO6
requires C, 47.34; H, 4.16%), mp 161–163 ЊC; Rf (30% EtOAc–
hexane) 0.7; δH 1.24 (6H, d, J 6.8), 2.71 (1H, sept, J 6.8), 3.76
(3H, s), 3.81 (3H, s), 3.97 (3H, s), 5.12 (2H, s, OCH2O), 5.38
(2H, s, ArCH2O), 6.84 (1H, s, H6) and 8.09 (1H, s, H4); δC 20.6
65.1 (MeO), 96.3 (OCH2O), 106.5 (C-3), 112.6, 114.0, 121.1,
124.5, 127.5, 138.8, 145.1 (C-1), 151.7 and 152.9; m/z (rel. inten-
sity) 314 [Mϩ(37Cl), 36], 312 [Mϩ(35Cl), 100], 282 (12), 267 (23),
250 (22), 249 (16) and 237 (12); νmax (KBr)/cmϪ1 3487, 1591,
1342, 1263, 1145, 1055 and 970.
(CHMe2), 21.7 (CHMe2), 56.1, 59.1, 61.8, 71.9 (ArCH2O), 72.0
7-Chloro-3-hydroxymethyl-5,8-dimethoxy-1-(methoxy-
methoxy)-2-(4-methylpent-2-ynoyl)naphthalene 21a. Pale yellow
crystals (Found: C, 61.77; H, 5.78. C21H23ClO6 requires C,
61.99; H, 5.70%), mp 128–130 ЊC; Rf (30% EtOAc–hexane)
0.35; 21a exists as a 5:1 mixture of keto and hemiketal forms.
Keto form: δH 1.18 (6H, d, J 6.8), 2.73 (1H, sept, J 6.8), 3.27
(1H, br, OH), 3.54 (3H, s), 3.78 (3H, s), 3.84 (3H, s), 4.66 (2H, s,
CH2OH), 5.06 (2H, s, OCH2O), 6.70 (1H, s, H6) and 7.90 (1H, s,
H4); δC 20.9 (CHMe2), 21.6 (CHMe2), 55.7, 57.9, 61.5, 62.8
(ArCH2O), 82.0 (C-2Ј), 101.8 (OCH2O), 101.9 (C-3Ј), 107.4,
118.1, 122.0, 125.5, 127.7, 133.3, 136.1, 144.4, 150.8, 151.7 and
181.6 (C-1Ј).
Hemiketal form: δH 1.13 (3H, d, J 6.8), 1.15 (3H, d, J 6.8),
2.60 (1H, sept, J 6.8), 3.68 (3H, s), 3.80 (3H, s), 3.87 (3H, s),
5.02 (1H, d, J 6.7, OCH2O), 5.13 (1H, d, J 13.2, ArCH2O), 5.19
(1H, d, J 6.7, OCH2O), 5.24 (1H, d, J 13.2, ArCH2O), 5.42 (1H,
br, OH), 6.71 (1H, s, H6) and 7.77 (1H, s, H4); δC (typical
signals) 71.0 (CH2O), 78.5, 90.3, 98.4 (hemiketal C), 102.0
(OCH2O), 123.0, 124.7, 129.0, 133.3, 134.8, 137.6, 144.7, 146.8
150.8 and 151.0; m/z (rel. intensity) 408 [Mϩ(37Cl), 8], 406
[Mϩ(35Cl), 23], 346 (100), 331 (81), 329 (64), 308 (45), 276 (53)
and 265 (85); νmax (KBr)/cmϪ1 3508, 3332, 2214, 1655, 1635,
1587, 1333, 1215 and 1047.
i
᎐
᎐
(COC᎐), 95.1 (᎐CPr ), 97.9 (C-2), 101.8 (OCH O), 107.2 (C-6),
᎐
᎐
2
120.2 (C-4), 123.0, 126.3, 127.0, 134.8, 143.4, 151.7, 152.2 and
153.5; m/z (rel. intensity) 534 [Mϩ(37Cl), 8], 532 [Mϩ(35Cl), 10],
376 (81), 293 (33), 129 (100) and 112 (45); νmax (KBr)/cmϪ1 2235,
1714, 1587, 1251 and 1165.
(S)-7-Chloro-2-iodo-5,8-dimethoxy-1-methoxymethoxy-3-
[(4-methylhex-2-ynoyloxy)methyl]naphthalene (S)-18b. 90%
Yield; colorless crystals (Found: C, 48.65; H, 4.46. C22H24ClIO6
requires C, 48.33; H, 4.42%), mp 144–146 ЊC; [α]D27 Ϫ5.06 (c 1.00,
CHCl3); Rf (30% EtOAc–hexane) 0.7; δH 1.03 (3H, t, J 7.3), 1.23
(3H, d, J 6.8), 1.57 (2H, m), 2.53 (1H, m), 3.76 (3H, s), 3.82
(3H, s), 3.97 (3H, s), 5.13 (2H, s, OCH2O), 5.38 (2H, s,
ArCH2O), 6.84 (1H, s, H6) and 7.26 (1H, s, H4); δC 11.6
(CH2CH3), 19.4 (CHCH3), 27.6 (CH2CH3), 28.9 (CHCH3),
s
᎐
᎐
56.1, 59.1, 61.8, 71.8 (ArCH O), 73.1 (COC᎐), 94.3 (᎐CBu ),
᎐
᎐
2
97.8 (C-2), 101.8 (OCH2O), 107.2 (C-6), 120.1 (C-4), 123.0,
126.3, 127.0, 134.9, 143.4, 151.7, 152.5 and 153.5; m/z (rel.
intensity) 548 [Mϩ(37Cl), 1], 546 [Mϩ(35Cl), 3], 376 (100), 293
(31), 249 (12) and 109 (3); νmax (KBr)/cmϪ1 1714, 1585, 1332,
1321, 1247 and 1054.
(R)-18b: 90% yield; [α]D27 ϩ14.5 (c 1.07, CHCl3).
(S)-7-Chloro-3-hydroxymethyl-5,8-dimethoxy-1-(methoxy-
methoxy)-2-(4-methylhex-2-ynoyl)naphthalene (S)-21b. Pale yel-
low crystals (Found: C, 62.40; H, 5.83. C22H25ClO6 requires C,
62.78; H, 5.99%), mp 92–93 ЊC; [α]D31 ϩ11.6 (c 0.65, CHCl3); Rf
(30% EtOAc–hexane) 0.45; 21b exists as a 6:1 mixture of keto
and hemiketal forms. Keto form: δH 1.03 (3H, t, J 7.3, H6Ј), 1.24
(3H, d, J 7.3, 4Ј-Me), 1.56 (2H, m, H5Ј), 2.63 (1H, m, H4Ј), 3.04
(1H, br t, J 6.4, OH), 3.58 (3H, s), 3.84 (3H, s), 3.95 (3H, s), 4.71
(2H, d, J 6.4, ArCH2O), 5.10 (2H, s, OCH2O), 6.83 (1H, s, H6)
and 8.04 (1H, s, H4); δC 11.5 (C-6Ј), 19.4 (4Ј-Me), 28.1 (C-5Ј),
29.0 (C-4Ј), 56.0, 58.1, 61.6, 63.6 (CH2OH), 83.3 (C-2Ј), 101.3
(C-3Ј), 102.2 (OCH2O), 107.8, 119.0, 122.3, 125.9, 128.0, 133.9,
136.2, 144.7, 151.4, 152.0 and 181.8 (C-1Ј).
General procedure for nucleophilic acyl-transfer reaction
To a stirred solution of an ester 13, 14, 17 or 18 (1 mmol) in
THF (20 ml) was slowly added a solution of BuLi (1.2 mmol) at
the indicated temperature in the text under argon. After 1 h,
water (20 ml) was added and then the mixture was warmed to
room temperature. The mixture was extracted with EtOAc
(3 × 20 ml). The extract was washed with brine (50 ml), dried
over MgSO4, and concentrated. The residue was purified by
silica gel column chromatography (20–50% EtOAc–hexane) to
give 2-acylnaphthalene 19 or 21, which was recrystallized from
CH2Cl2–diethyl ether–hexane if necessary.
2-Acetyl-7-chloro-3-hydroxymethyl-5,8-dimethoxy-1-
(methoxymethoxy)naphthalene 19. Colorless crystals (Found: C,
57.17; H, 5.35. C17H19ClO6 requires C, 57.55; H, 5.40%), mp
125–128 ЊC; Rf (20% EtOAc–hexane) 0.3; 19 exists as a 1:7
mixture of keto and hemiketal forms. Keto form: δH 2.74 (3H, s,
Ac), 2.90 (1H, t, J 5.9, OH), 3.46 (3H, s), 3.85 (3H, s), 3.96 (3H,
s), 4.63 (2H, d, J 5.9, CH2OH), 5.07 (2H, s, OCH2O), 6.84 (1H, s,
H6) and 8.04 (1H, s, H4); δC (typical signals) 32.9, 55.9, 58.1,
61.7, 63.9 (ArCH2O), 102.3 (OCH2O), 107.5 (C-6), 119.6 and
206.0 (Ac).
Hemiketal form: δH 2.01 (3H, s, Me), 3.54 (3H, s), 3.85 (3H,
s), 3.96 (3H, s), 4.66 (1H, s, OH), 5.03 (1H, d, J 5.9, OCH2O),
5.10 (1H, d, J 13.2, CH2OH), 5.22 (1H, d, J 5.9, OCH2O), 5.30
(1H, d, J 13.2, CH2OH), 6.81 (1H, s, H6) and 7.90 (1H, s, H4);
δC 27.3, 56.0, 57.5, 61.5, 70.5 (ArCH2O), 101.5 (OCH2O), 106.5,
106.5 (C-1 and C-6), 111.4 (C-4), 122.6, 124.8, 129.1, 135.6,
138.8, 144.7 (C-8), 146.7 (C-1) and 152.1 (C-5); m/z (rel. inten-
sity) 356 [Mϩ(37Cl), 38], 354 [Mϩ(35Cl), 100], 250 (55) and 249
(53); νmax (KBr)/cmϪ1 3444, 1643, 1599, 1508, 1344 and 1052.
Hemiketal form (1:1 diastereomeric mixture): δH 1.02 (3H
both, t, J 7.3, H5Ј), 1.18 (3H of one diastereomer, d, J 7.3,
4Ј-Me), 1.19 (3H of another diastereomer, d, J 7.3, 4Ј-Me), 1.53
(2H, m, H4Ј), 2.49 (1H, m, H3Ј), 3.71 (3H of one diastereomer,
s), 3.72 (3H of another diastereomer, s), 3.85 (3H both, s),
3.96 (3H both, s), 5.0–5.4 (5H, m, CH2O, OH and OCH2OMe),
6.81 (1H both, br s, H6) and 7.89 (1H both, br s, H4); δC 14.0
(C-6Ј), 15.2 (C-6Ј), 20.2 (4Ј-Me), 20.2 (4Ј-Me), 27.5 (C-5Ј),
27.5 (C-5Ј), 29.5 (C-4Ј), 29.6 (C-4Ј), 57.9, 61.5, 65.8, 71.2
(C-3), 71.2 (C-3), 79.8 (C-1Ј), 89.3, 98.5, 101.4, 101.4, 102.2,
106.6, 111.3, 123.0, 124.8, 129.2, 135.1, 137.8, 137.8, 144.9 and
147.0; m/z (rel. intensity) 420 (Mϩ, 27), 360 (100), 343 (75), 330
(60), 294 (72), 265 (97) and 248 (58); νmax (KBr)/cmϪ1 3456,
2200, 1650, 1334 and 1068.
(R)-21b: [α]D27 Ϫ10.7 (c 0.65, CHCl3).
6-(Buta-2,3-dienoyloxymethyl)-2-chloro-1,4-dimethoxy-8-
(methoxymethoxy)naphthalene 22. White solid, Rf (30%
EtOAc–hexane) 0.55; δH 3.60 (3H, s, MeO), 3.87 (3H, s, MeO),
3.96 (3H, s, MeO), 5.25 (2H, m, ᎐CH ), 5.28 (2H, s), 5.31 (2H,
᎐
2
2-Chloro-6-hydroxymethyl-1,4-dimethoxy-8-(methoxy-
s), 5.71 (1H, t, J 6.4, COCH᎐), 6.81 (1H, s, H3), 7.19 (1H, s, H7)
᎐
methoxy)naphthalene 20. Colorless needles (Found: C, 57.37; H,
5.39. C15H17ClO5 requires C, 57.61; H, 5.48%), mp 108–109 ЊC;
Rf (20% EtOAc–hexane) 0.25; δH 2.32 (1H, br, OH), 3.59 (3H,
s), 3.86 (3H, s), 3.92 (3H, s), 4.76 (2H, br, ArCH2OH), 5.29 (2H,
s, OCH2O), 6.76 (1H, s, H3), 7.16 (1H, d, J 1.0, H7) and 7.82
and 7.92 (1H, s, H5); δC 55.9 (MeO), 56.5 (MeO), 61.6 (MeO),
66.6 (ArCH O), 79.4 (᎐CH ), 87.8 (COCH᎐), 96.5 (OCH O),
᎐
᎐
2
2
2
106.7, 113.5, 116.0, 121.6, 125.1, 127.4, 133.5, 145.2, 151.8,
153.0, 165.7 (C᎐O) and 216.1 (᎐C᎐); m/z (rel. intensity) 380
᎐
᎐ ᎐
[Mϩ(37Cl), 33], 378 [Mϩ(35Cl), 100], 316 (15), 301 (18), 250 (76)
J. Chem. Soc., Perkin Trans. 1, 2001, 229–238
235

View Article Online
and 249 (49); νmax (KBr)/cmϪ1 1968, 1938, 1720, 1590, 1342,
and then quenched with saturated aq. NaHCO3 (≈30 ml). The
1159 and 1053.
reaction mixture was extracted with CHCl3 (3 × 20 ml). The
combined extract was washed with brine (50 ml), dried over
MgSO4, and concentrated. The residue was purified by silica gel
or activated alumina column chromatography.
8-Chloro-7,10-dimethoxy-6-(methoxymethoxy)-3-methyl-
naphtho[2,3-c]oxepin-5(1H)-one 23. Pale yellow crystals (Found:
C, 60.14; H, 5.09. C19H19ClO6 requires C, 60.24; H, 5.06%), mp
175–177 ЊC; Rf (30% EtOAc–hexane) 0.4; δH 2.00 (3H, s, 3-Me),
3.53 (3H, s, MeO), 3.86 (3H, s, MeO), 3.98 (3H, s, MeO), 5.07
(2H, s, OCH2O), 5.22 (2H, s, H1), 5.54 (1H, s, H4), 6.88 (1H, s,
H9) and 7.99 (1H, s, H11); δC 22.2 (3-Me), 56.1 (MeO), 57.7
(MeO), 61.9 (MeO), 74.9 (C-1), 102.2 (OCH2O), 107.9, 108.4,
118.9, 124.0, 126.7, 127.8, 130.5, 135.3, 145.5, 150.2, 152.0,
168.5 (C-3) and 190.5 (C-5); m/z (rel. intensity) 380 [Mϩ(37Cl),
42], 378 [Mϩ(35Cl), 100], 316 (17), 301 (19), 251 (37), 250 (88)
and 249 (59); νmax (KBr)/cmϪ1 1652, 1616, 1592, 1456, 1331,
1155 and 1045.
Prior treatment with Et2NH. To a stirred solution of an
alkynone 25 (1 mmol) in a mixture of THF (10 ml) and propan-
2-ol (5 ml) was added diethylamine (0.2 ml, 2 mmol) at room
temperature under argon. After the consumption of 25 was
checked by TLC (ca. 24 h), aq. HCl (3 M, 2 ml) was added and
the mixture was refluxed for 16 h. The mixture was cooled to
room temperature and then quenched with saturated aq.
NaHCO3 (≈30 ml). The mixture was extracted with CHCl3
(3 × 20 ml). The combined extract was washed with brine (50
ml), dried over MgSO4, and concentrated. The residue was
purified by silica gel column chromatography.
General procedure for benzoylation of alcohols 21a–e
8-Chloro-6-hydroxy-7,10-dimethoxy-3-(1-methylethyl)-
naphtho[2,3-c]oxepin-5(1H)-one 24. Pale yellow crystals
(Found: C, 62.52; H, 5.32. C19H19ClO5 requires C, 62.90; H,
5.28%), mp 207–209 ЊC; Rf (30% EtOAc–hexane) 0.25; δH 1.20
(6H, d, J 6.8), 2.93 (1H, sept, J 6.8), 3.96 (3H, s), 4.09 (3H, s),
5.58 (2H, s, H1), 6.57 (1H, s, H4), 6.77 (1H, s, H9), 7.61 (1H, s,
H11) and 10.62 (1H, s); δC 19.1, 41.0, 56.1, 62.6, 75.6 (C-1), 99.6
(C-4), 105.2, 107.6, 116.8, 117.5, 121.8, 128.6, 140.0, 145.8,
151.4, 152.3, 164.9 (C-3) and 203.5 (C-5); m/z (rel. intensity) 364
[Mϩ(37Cl), 12], 362 [Mϩ(35Cl), 32], 321 (36), 319 (100), 304 (16),
294 (20) and 289 (16); νmax (KBr)/cmϪ1 1599, 1507, 1358, 1209
and 1029.
To a stirred solution of an alcohol 21a–e (1 mmol) in dry pyri-
dine (5 ml) was slowly added freshly distilled benzoyl chloride
(1.1 mmol) at 0 ЊC under argon. After 3 h, water (20 ml) was
added and the mixture was warmed to room temperature. The
mixture was extracted with CHCl3 (3 × 20 ml). The combined
extract was washed successively with cool aq. HCl (3 M; 3 × 20
ml), saturated aq. NaHCO3 (50 ml) and brine (50 ml), dried
over MgSO4, and concentrated. The residue was purified by
silica gel column chromatography to give the corresponding
benzoyl ester 25a–e, which was recrystallized from CH2Cl2–
diethyl ether–hexane if necessary.
3-Benzoyloxymethyl-7-chloro-5,8-dimethoxy-1-(methoxy-
methoxy)-2-(4-methylpent-2-ynoyl)naphthalene 25a. 69% Yield;
yellow crystals (Found: C, 65.68; H, 5.42. C28H27ClO7 requires
C, 65.82; H, 5.33%), mp 135–137 ЊC; Rf (30% EtOAc–hexane)
0.55; δH 1.16 (6H, d, J 6.8), 2.68 (1H, sept, J 6.8), 3.59 (3H, s),
3.86 (3H, s), 3.95 (3H, s), 5.11 (2H, s, OCH2O), 5.60 (2H, s,
CH2OBz), 6.87 (1H, s, H6), 7.41 (2H, m, Bz), 7.53 (1H, m, Bz),
8.07 (2H, m, Bz) and 8.15 (1H, s, H4); δC 20.9 (CHMe2), 21.6
(CHMe2), 56.0 (MeO), 57.9 (MeO), 61.7 (MeO), 64.7 (CH2Bz),
81.9 (C-2Ј), 101.2 (C-3Ј), 102.1 (OCH2O), 107.8, 120.1, 123.0,
126.4, 127.4, 128.2, 128.2, 129.8, 130.5, 132.9, 133.9, 144.7,
150.5, 152.0, 166.0 and 180.3 (C-1Ј); m/z (rel. intensity) 510
[Mϩ(35Cl), 3], 450 (10), 405 (5), 373 (13), 344 (21) and 105 (100);
νmax (KBr)/cmϪ1 2203, 1714, 1663, 1335, 1267, 1036, 917 and 714.
5-Benzoyloxymethyl-9-chloro-7,10-dimethoxy-2-(1-methyl-
ethyl)naphtho[1,2-b]pyran-4-one 26a. Pale yellow crystals
(Found: C, 65.58; H, 4.42. C24H19ClO6 requires C, 65.68; H,
4.36%), mp 169–171 ЊC; Rf (30% EtOAc–hexane) 0.45; δH 2.53
(3H, s), 3.95 (3H, s), 3.97 (3H, s), 6.15 (2H, CH2OBz), 6.34 (1H,
s, H3), 7.01 (1H, s, H8), 7.47 (2H, m, Bz), 7.57 (1H, m, Bz), 8.17
(2H, m, Bz) and 8.27 (1H, s, H6); δC 20.0, 56.2, 61.3, 65.8
(CH2OBz), 109.8 (C-3), 112.9 (C-11), 117.4 (C-6), 119.2
(C-10a), 119.9 (C-4b), 127.0 (C-9), 127.1 (C-6a), 128.3, 129.8,
130.5, 132.9, 133.0, 145.4, 151.6, 154.5, 164.3, 166.2 (C᎐O) and
᎐
179.1 (C᎐O); m/z (rel. intensity) 440 [Mϩ(37Cl), 1], 438
᎐
[Mϩ(35Cl), 3], 335 (35), 333 (100), 305 (8), 303 (23) and 105 (5);
νmax (KBr)/cmϪ1 1718, 1654, 1619, 1335, 1273 and 1068.
(S)-5-Benzoyloxymethyl-9-chloro-7,10-dimethoxy-2-(1-
(S)-3-Benzoyloxymethyl-7-chloro-5,8-dimethoxy-1-(methoxy-
methoxy)-2-(4-methylhex-2-ynoyl)naphthalene (S)-25b. 87%
Yield; yellow crystals (Found: C, 66.20; H, 5.54. C29H29ClO7
requires C, 66.35; H, 5.57%), mp 97–99 ЊC; [α]D31 ϩ10.7 (c 0.98,
CHCl3); Rf (30% EtOAc–hexane) 0.6; δH 0.95 (3H, t, J 7.3, H6Ј),
1.14 (3H, d, J 6.8, 4Ј-Me), 1.47 (2H, m, H5Ј), 2.50 (1H, m, H4Ј),
3.58 (3H, s, MeO), 3.85 (3H, s, MeO), 3.97 (3H, s, MeO), 5.10
(2H, s, OCH2OMe), 5.59 (2H, s, CH2OBz), 6.87 (1H, s, H6),
7.41 (2H, m, Bz), 7.54 (1H, m, Bz), 8.06 (2H, m, Bz) and 8.16
(1H, s, H4); δC 11.5 (C-6Ј), 19.3 (4Ј-Me), 28.0 (C-5Ј), 29.0 (C-4Ј),
56.0 (MeO), 58.0 (MeO), 61.7 (MeO), 64.7 (CH2OBz), 83.1
(C-2Ј), 100.5 (C-3Ј), 102.2 (OCH2OMe), 107.8, 120.2, 123.0,
126.4, 127.5, 128.2, 129.9, 130.6, 133.0, 133.9, 134.1, 144.8,
150.7, 152.1, 166.1 (COPh) and 180.4 (C-1Ј); m/z (rel. intensity)
526 [Mϩ(37Cl), 1], 524 [Mϩ(35Cl), 3], 464 (10), 419 (5), 387 (8),
343 (10) and 105 (100); νmax (KBr)/cmϪ1 2204, 1716, 1648 and
1590.
methylpropyl)naphtho[1,2-b]pyran-4-one (S)-26b. Pale yellow
crystals (Found: C, 67.29; H, 5.21. C27H25ClO6 requires C,
67.43; H, 5.24%), mp 141–142 ЊC; [α]D29 Ϫ2.64 (c 1.00, CHCl3); Rf
(30% EtOAc–hexane) 0.5; δH 1.01 (3H, t, J 7.3, H3Ј), 1.40 (3H,
d, J 6.8, 1Ј-Me), 1.74 (1H, m, H2Ј), 1.94 (1H, m, H2Ј), 2.76 (1H,
m, H1Ј), 3.91 (3H, s), 3.93 (3H, s), 6.12 (2H, CH2OBz), 6.32 (1H,
s, H3), 6.95 (1H, s, H8), 7.45 (2H, m, Bz), 7.56 (1H, m, Bz), 8.15
(2H, m, Bz) and 8.21 (1H, s, H6); δC 11.5 (C-3Ј), 17.5 (1Ј-Me),
27.2 (C-2Ј), 39.9 (C-1Ј), 56.0, 61.4, 65.6 (CH2OBz), 109.6 (C-3),
110.8 (C-11), 116.9 (C-5), 119.0, 119.9, 126.7, 126.9, 128.2,
129.6, 130.3, 132.7, 132.8, 145.5, 151.3, 154.5, 166.0, 171.8
(C᎐O) and 179.2 (C᎐O); m/z (rel. intensity) 482 [Mϩ(37Cl), 1],
᎐
᎐
480 [Mϩ(35Cl), 3], 377 (36), 375 (100) and 345 (11); νmax (KBr)/
cmϪ1 1716, 1651, 1626, 1489, 1336, 1273 and 710.
(R)-26b: [α]D28 ϩ1.98 (c 1.02, CHCl3).
5-Benzoyloxymethyl-9-chloro-7,10-dimethoxy-2-phenyl-
naphtho[1,2-b]pyran-4-one 26d. Pale yellow crystals (Found: C,
68.58; H, 4.33. C29H21ClO6ؒ¹H2O requires C, 68.31; H,
(R)-25b: [α]D28 Ϫ9.72 (c 0.99, CHCl3).
¯
²
General procedure for intramolecular reaction of alkynones
25a–e
4.35%), mp 236–240 ЊC; Rf (33% EtOAc–hexane) 0.4; δH 3.85
(3H, s), 3.96 (3H, s), 6.18 (2H, s, ArCH2O), 6.95 (1H, s, H3),
7.03 (1H, s, H8), 7.47 (2H, m), 7.57 (4H, m), 8.17 (4H, m) and
8.31 (1H, s, H6); δC 56.3, 61.7, 65.8 (CH2OBz), 109.7 (C-3),
110.0 (C-11), 117.8 (C-5), 119.3, 120.5, 126.5, 127.1, 127.4,
A solution of an alkynone 25a–e (1 mmol) in a mixture of THF
(10 ml), propan-2-ol (5 ml) and aq. HCl (3 M; 3 ml) was
refluxed for 24 h. The mixture was cooled to room temperature
236
J. Chem. Soc., Perkin Trans. 1, 2001, 229–238

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128.4, 129.2, 129.8, 130.5, 131.5, 131.7, 132.9, 133.1, 145.8,
151.7, 154.4, 162.8, 166.3 (COPh) and 179.3 (C-4); m/z (rel.
intensity) 502 [Mϩ(37Cl), 1], 500 [Mϩ(35Cl), 3], 397 (36), 395
(100), 367 (10) and 365 (26); νmax (KBr)/cmϪ1 1716, 1641, 1622,
1390, 1279 and 713.
m, H9 or H10), 6.60 (1H, d, J 7.6, H10 or H9), 7.51 (2H, m),
7.62 (1H, m) and 8.19 (3H, m, H6 and ArH); δC (most signals
of the diastereomers appeared as pairs in identical positions;
numerals in brackets are signals due to the other isomer) 11.6
[11.7] (C-3Ј), 17.8 (1Ј-Me), 25.4 (C-2Ј), 27.3 [27.3], 31.4, 33.5,
40.4 [40.4], 55.6 (OMe), 65.3 (CH2OBz), 85.6 (C-11), 110.7,
118.4, 120.1, 125.0, 128.5, 129.8, 131.5, 133.3, 134.5, 135.2,
135.2, 144.9, 148.5, 151.0, 155.2, 166.0 (CO), 173.4 [173.5]
(C-2), 179.0 (C-10), 179.5 (C-4), 179.5 (C-7) and 180.1 (C-12);
m/z 524 (Mϩ, 0.07), 496 (2.3), 391 (100), 362 (4) and 105 (12);
νmax (KBr)/cmϪ1 2869, 1724, 1664, 1652, 1587, 1560 and 1465.
(R)-31: 54% yield; [α]D25 ϩ22.2 (c 1.0, CHCl3).
4-Benzoyloxymethyl-2-benzylidene-8-chloro-6,9-dimethoxy-
naphtho[1,2-b]furan-3(2H)-one 27d. Yellow crystals (Found: C,
68.07; H, 4.24. C29H21ClO6ؒ¹H2O requires C, 68.31; H,
¯
²
4.35%), mp 232–233 ЊC; Rf (33% EtOAc–hexane) 0.6; δH 3.98
(3H, s), 4.06 (3H, s), 5.90 (2H, s, ArCH2O), 6.98 (1H, s, H7 or
᎐CHPh), 6.99 (1H, s, ᎐CHPh or H7), 7.4–7.6 (6H, m), 8.03 (1H,
᎐
᎐
s, H5) and 8.11 (4H, m); δC 56.2, 62.4, 62.6 (CH2OBz), 110.6,
114.0, 116.9, 117.0, 117.0, 125.9, 128.4, 129.0, 129.6, 129.8,
130.1, 130.3, 130.9, 131.7, 132.2, 133.0, 145.2, 146.8, 152.3,
164.4 (C-2), 166.2 (COPh) and 183.8 (C-3); m/z (rel. intensity)
502 [Mϩ(37Cl), 7], 500 [Mϩ(35Cl), 17], 397 (36), 395 (100), 367
(8), 365 (21) and 105 (29); νmax (KBr)/cmϪ1 1718, 1693, 1647,
1618, 1581, 1522, 1277 and 714.
(S)-5-Benzoyloxymethyl-11-methoxy-2-(1-methylpropyl)-
anthra[1,2-b]pyran-4,7,12-trione (S)-32
The Diels–Alder adduct (S)-31 (10 mg, 0.019 mmol) was heated
to 150 ЊC on a melting-point apparatus. After 30 min, the residue
was recrystallized from MeOH to give 7 mg (74%) of (S)-32 as
yellow crystals (Found: Mϩ, 496.1516. C30H24O7 requires M,
496.1522), mp 277–279 ЊC; [α]D20 Ϫ25.3 (c 0.50, CHCl3); Rf (30%
EtOAc–hexane) 0.1; δH (espicufolin numbering) 1.00 (3H, d,
J 7.6, H16), 1.44 (3H, d, J 7.0, H17), 1.79 (1H, m, H15), 1.98 (1H,
m, H15), 2.80 (1H, m, H14), 4.06 (3H, s, OMe), 6.17 (2H, s, H13),
6.33 (1H, s, H3) , 7.37 (1H, d, J 7.0, H10), 7.53 (2H, m), 7.62 (1H,
m), 7.67 (1H, dd, J 7.0 and 7.6, H8), 7.78 (1H, d, J 7.6, H9), 8.22
(2H, m) and 8.47 (1H, s, H6); δC 11.6 (C-16), 17.9 (C-17), 27.3
(C-15), 40.2 (C-14), 56.2 (OMe), 65.4 (C-13), 110.6 (C-3), 118.3
(C-11a), 118.6 (C-8), 118.7 (C-6), 119.3 (C-12a), 123.3 (C-4a),
123.6 (C-10), 125.3, 129.8, 129.9, 131.5, 133.3 (C-7a), 134.5
(C-6a), 144.6 (C-9), 155.3 (C-5), 155.7 (C-12b), 159.7 (C-11),
166.1 (COPh), 173.8 (C-2), 179.0 (C-4), 180.3 (C-7) and 182.8
(C-12); m/z 496 (Mϩ, 1.5), 391 (100), 359 (6) and 105 (13);
νmax (KBr)/cmϪ1 1716, 1680, 1645, 1585, 1558, 1463, 1444, 1419,
1392, 1369 and 1344.
(S)-5-Benzoyloxymethyl-9-chloro-2-(1-methylpropyl)naphtho-
[1,2-b]pyran-4,7,10-trione (S)-30
The naphthol (S)-26b (84 mg, 0.17 mmol) was dissolved in
acetonitrile (15 mL) and then aq. cerium() ammonium nitrate
(CAN) (0.25 g, 0.46 mmol in 1.4 mL) was added. During the
addition, the starting yellow colour turned dark brown and
then reddish orange. After 30 min, the mixture was poured into
a 100 ml separating funnel and CH2Cl2 (20 ml) and water (20
ml) were added. The organic phase was separated and the
aqueous phase was extracted with CH2Cl2 (3 × 20 ml). The
combined organic phase was washed with brine (50 ml), dried
over MgSO4, filtered through a short silica-gel column which
was washed with diethyl ether (50 ml) and concentrated in the
dark by a rotary evaporator. Recrystallization from CH2Cl2–
diethyl ether–hexane gave 58 mg (75%) of the title compound
(S)-30 as orange crystals (Found: C, 66.48; H, 4.30. C25H19ClO6
requires C, 66.60; H, 4.25%), mp 196–198 ЊC; [α]D31 Ϫ7.84 (c 1.0,
CHCl3); Rf (30% EtOAc–hexane) 0.6; δH 0.98 (3H, t, J 7.5, H3Ј),
1.43 (3H, d, J 6.7, 1Ј-Me), 1.80 (1H, m, H2Ј), 1.96 (1H, m, H2Ј),
2.74 (1H, m, H1Ј), 6.16 (2H, s, CH2O), 6.31 (1H, s, H3), 7.26
(1H, s, H8), 7.53 (2H, m), 7.64 (1H, m), 8.19 (2H, m) and 8.25
(1H, s, H6); δC 11.7 (C-3Ј), 17.9 (1Ј-Me), 27.3 (C-2Ј), 40.5 (C-1Ј),
65.3 (CH2OBz), 111.1 (C-3), 118.9 (C-6), 125.1 (C-4a or -10a),
128.6, 129.6, 133.4, 134.0, 134.6, 147.9, 155.8, 166.0 (CO), 173.6
(C-2), 174.9 (C-4), 178.7 (C-10), 181.5 (C-7), and one carbon
(C-4a or -10a) could not be found; m/z 450 (Mϩ, 2), 345 (100),
249 (12) and 105 (68); νmax (KBr)/cmϪ1 1716, 1680, 651, 1267,
883 and 711.
(R)-32: 83% yield; [α]D24 ϩ27.0 (c 0.30, CHCl3).
(S)-5-Benzoyloxymethyl-11-hydroxy-2-(1-methylpropyl)anthra-
[1,2-b]pyran-4,7,12-trione (S)-33
To a solution of compound (S)-32 (11 mg, 0.022 mmol) in dry
CH2Cl2 (5 ml) was added dropwise 1.0 M BBr3 in CH2Cl2 (0.05
ml, 0.05 mmol) at Ϫ78 ЊC. After 30 min, the reaction mixture
was quenched with saturated aq. NaHCO3 (10 ml) and then
warmed to room temperature. The organic phase was separated
and the aqueous phase was extracted with CH2Cl2 (10 ml × 2).
The combined organic phases were washed successively with
saturated aq. NaHCO3 (20 ml) and brine (20 ml), dried over
MgSO4, filtered and concentrated. The residue was recrystal-
lized from CH2Cl2–diethyl ether–hexane to give 8 mg (75%) of
(S)-33 as yellow crystals (Found: Mϩ, 482.1357. C29H22O7
requires M, 482.1366), mp 227–229 ЊC; [α]D20 Ϫ19.7 (c 0.30,
CHCl3); Rf (30% EtOAc–hexane) 0.5; δH 1.00 (3H, d, J 7.3,
H16), 1.45 (3H, d, J 6.7, H17), 1.80 (1H, m, H15), 1.99 (1H, m,
H15), 2.76 (1H, m, H14), 6.19 (2H, s, H13), 6.33 (1H, s, H3), 7.37
(1H, dd, J 8.2 and 1.2, H10), 7.52 (2H, m), 7.63 (1H, m), 7.70
(1H, dd, J 8.2 and 7.6, H8), 7.85 (1H, d, J 7.6 and 1.2, H9), 8.22
(2H, m), 8.47 (1H, s, H6) and 12.84 (1H, s, OH); δC 11.7 (C-16),
17.9 (C-17), 27.4 (C-15), 40.5 (C-14), 65.4 (C-13), 111.1 (C-3),
116.8 (C-11a), 119.4 (C-8), 119.5 (C-6), 120.8 (C-12a), 125.3
(C-4a), 125.4 (C-10), 128.6, 129.8, 129.9, 132.2, 133.4 (C-7a),
136.5 (C-6a), 136.6 (C-9), 147.0 (C-5), 156.4 (C-12b), 162.6
(C-11), 166.0 (COPh), 173.6 (C-2), 178.9 (C-4), 181.6 (C-7), 187
(C-12); m/z 482 (Mϩ, 1.2), 440 (31), 362 (100), 281 (33) and 122
(83); νmax (KBr)/cmϪ1 3438, 1718, 1654, 1637, 1587, 1461, 1267
and 1220.
(R)-30: 77% yield; [α]D28 ϩ7.22 (c 1.0, CHCl3).
(S)-5-Benzoyloxymethyl-11-methoxy-2-(1-methylpropyl)-8,11-
dihydro-8,11-ethanoanthra[1,2-b]pyran-4,7,12-trione (S)-31
The quinone 30 (45 mg, 0.1 mmol) and 1-methoxycyclohexa-
1,3-diene (0.018 ml, 0.15 mmol) in CH2Cl2 (1 ml) were stirred at
room temperature for 24 h. The reaction mixture was concen-
trated to give a dark brown oil, which was dissolved in pyridine
(0.2 ml). After 24 h, 5% aq. HCl (10 ml) was added and the
mixture was extracted with CHCl3 (20 ml × 3). The combined
extract was washed successively with 5% aq. HCl (20 ml × 3),
saturated aq. NaHCO3 (30 ml), and brine (30 ml), dried over
MgSO4, filtered and concentrated. The residue was purified by
silica gel chromatography followed by recrystallization from
CH2Cl2–diethyl ether–hexane to give 36 mg (69%) of a
diastereomeric mixture of (S)-31 as yellow crystals, mp 150 ЊC
(decomp.); [α]D23 Ϫ20.3 (c 0.93, CHCl3); Rf 0.45 (30% EtOAc–
hexane); δH 0.97 (3H, m, H3Ј), 1.40 (3H, d, J 7.0, 1Ј-Me), 1.75
(1H, m, H2Ј), 1.83 (1H, m, H2Ј), 1.90 (2H, m, CH2CH2), 2.00
(2H, m, CH2CH2), 2.72 (1H, m, H1Ј), 3.67 (3H, s, OMe), 4.41
(1H, m, H8), 6.13 (2H, m, CH2O), 6.25 (1H, s, H3), 6.41 (1H,
(R)-33: 52% yield; [α]D23 ϩ23.3 (c 0.30, CHCl3).
(S)-Espicufolin (S)-1
The benzoate (S)-33 (13 mg, 0.027 mmol) in dry THF (5 mL)
was dissolved in MeOH (0.43 ml) and 1 M NaOH (0.11 ml) at
J. Chem. Soc., Perkin Trans. 1, 2001, 229–238
237

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Quinones: Recent Advances, Blackie Academic & Professional,
London, 4th edn., 1997.
0 ЊC. The mixture was stirred for 40 min at 0 ЊC. The reaction
was quenched with saturated aq. NH4Cl (10 ml) and the mix-
ture was concentrated by a rotary evaporator. The residual
syrup was extracted with EtOAc and the extract was washed
successively with saturated aq. NaHCO3 (20 ml) and brine (20
ml), dried over MgSO4, filtered, and concentrated by a rotary
evaporator to give a crude product, which was recrystallized
from CH2Cl2–diethyl ether–hexane to give 7 mg (69%) of (S)-1
as yellow crystals (Found: Mϩ, 378.1104. C22H18O6 requires M,
378.1103), mp 185–187 ЊC; [α]D23 Ϫ11.28 (c 0.02, CHCl3); Rf (30%
EtOAc–hexane) 0.25; δH (DMSO-d6) 0.93 (3H, d, J 7.3, H16),
1.38 (3H, d, J 6.8, H17), 1.75 (1H, m, H15), 1.92 (1H, m, H15),
2.78 (1H, m, H14), 5.16 (2H, d, J 4.8, H13), 5.56 (1H, t, J 4.8,
13-OH), 6.34 (1H, s, H3), 7.38 (1H, d, J 8.3, H10), 7.68 (1H, d,
J 7.3, H8), 7.77 (1H, dd, J 8.3 and 7.3, H9), 8.51 (1H, s, H6)
and 12.65 (1H, s, -11–OH); δC (DMSO-d6) 11.17 (C-16), 17.30
(C-17), 26.56 (C-15), 39.19 (C-14), 62.07 (C-13), 110.3 (C-3),
116.6 (C-11a), 118.5 (C-8), 118.7 (C-6), 119.6 (C-12a), 123.9
(C-4a), 124.4 (C-10), 132.0 (C-7a), 135.9 (C-6a), 136.4 (C-9),
153.1 (C-5), 155.5 (C-12b), 161.2 (C-11), 172.4 (C-2), 178.1
(C-4), 181.4 (C-7), and 186.8 (C-12); νmax (KBr)/cmϪ1 3473,
1676, 1647, 1583, 1460, 1272 and 1220; m/z 378 (Mϩ, 11), 267
(21), 320 (9), 349 (18) and 378 (100).
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(R)-1: 63% yield, mp 186–187 ЊC (lit.,3 184–186 ЊC); [α]D25
ϩ8.50 (c 0.02, CHCl3) {natural espicufolin: [α]D23 ϩ9.44 (c 0.02,
CHCl3)}.
( )-1, mp 189–192 ЊC.
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Acknowledgements
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We thank Professor Haruo Seto for the gift of natural (R)-
espicufolin. This work was partly supported by a Grant-in-Aid
for Scientific Research (No. 12640521) from the Ministry of
Education, Science, Sports and Culture.
22 K. Mukai, K. Okabe and H. Hosose, J. Org. Chem., 1989, 54,
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