An efficient method for the one-pot construction of the 1H-naphtho[2,3-c]pyran-5,10-dione system

Article abstract of DOI:10.1039/b106933k

2-(1-Hydroxyalkyl)-1,4-naphthoquinones are found to react with pyrrolidino enamines in toluene to give 1H-naphtho[2,3-c]pyran-5,10-diones in good yields via a tandem conjugate addition-cyclization sequence, followed by an elimination of pyrrolidine. 2-Hydroxymethyl-1,4-naphthoquinone and morpholino enamines undergo a similar sequence, without loss of morpholine, to yield 3-morpholino-3,4-dihydro-1H-naphtho[2,3-c]pyran-5,10-diones. The 3-morpholino group of these products can be replaced with a hydro, a hydroxy, or a methoxy group. Imines also react with 2-(1-hydroxyalkyl)-1,4-naphthoquinones to give the corresponding 1H-naphtho[2,3-c]pyran-5,10-diones, including a natural product (pentalongin). The utility of these reactions is demonstrated in the synthesis of pyranonaphthoquinone antibiotics, viz. (±)-eleutherin and (±)-isoeleutherin.

Full text of DOI:10.1039/b106933k

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An efficient method for the one-pot construction of the
H-naphtho[2,3-c]pyran-5,10-dione system
1
Kazuhiro Kobayashi,* Masaharu Uchida, Tomokazu Uneda, Keiichi Yoneda, Miyuki Tanmatsu,
Osamu Morikawa and Hisatoshi Konishi
1
Department of Materials Science, Faculty of Engineering, Tottori University, Koyama-minami,
Tottori 680-8552, Japan
Received (in Cambridge, UK) 31st July 2001, Accepted 27th September 2001
First published as an Advance Article on the web 29th October 2001
2
1
-(1-Hydroxyalkyl)-1,4-naphthoquinones are found to react with pyrrolidino enamines in toluene to give
H-naphtho[2,3-c]pyran-5,10-diones in good yields via a tandem conjugate addition–cyclization sequence, followed
by an elimination of pyrrolidine. 2-Hydroxymethyl-1,4-naphthoquinone and morpholino enamines undergo a similar
sequence, without loss of morpholine, to yield 3-morpholino-3,4-dihydro-1H-naphtho[2,3-c]pyran-5,10-diones. The
3
-morpholino group of these products can be replaced with a hydro, a hydroxy, or a methoxy group. Imines also react
with 2-(1-hydroxyalkyl)-1,4-naphthoquinones to give the corresponding 1H-naphtho[2,3-c]pyran-5,10-diones,
including a natural product (pentalongin). The utility of these reactions is demonstrated in the synthesis of
pyranonaphthoquinone antibiotics, viz. (±)-eleutherin and (±)-isoeleutherin.
Compounds based on the 1H-naphtho[2,3-c]pyran-5,10-dione
skeleton have aroused considerable interest amongst synthetic
chemists, because some members of this family have been found
in Nature and shown to possess a variety of biological prop-
1
erties. A number of interesting methods have been reported
2
for the preparation of this class of compounds. Most of
them, however, are based on multi-step conversions, although
2b
Aldersley et al. have prepared 3-phenyl-1H-naphtho[2,3-c]-
pyran-5,10-dione in one step using the conjugate additions of
phenacylpyridinium ylide to 2-(aryloxymethyl)-1,4-naphtho-
2q
quinones and most recently De Kimpe and co-workers have
reported on its application to the first total synthesis of
isagarin. We found that 2-(1-hydroxyalkyl)-1,4-naphthoquin-
3
ones reacted with enamines or imines to give 1H-naphtho-
[2,3-c]pyran-5,10-dione derivatives in one pot, via a tandem
conjugate addition–cyclization sequence. The method was suc-
cessfully applied to very rapid access to biologically active
4
5
natural products, such as pentalongin, eleutherin, and iso-
5
eleutherin. In this paper, details of this new general construc-
tion of the 1H-naphtho[2,3-c]pyran-5,10-dione system are
6
reported.
Results and discussion
We began by investigating the reactions of 2-(1-hydroxyalkyl)-
1
,4-naphthoquinones 1 and 2 with enamines 3–6, in expectation
of the formation of 1H-naphtho[2,3-c]pyran-5,10-dione deriv-
atives 7–12 through addition of enamines to quinones in the
1
,4-addition manner at the 3-position, followed by intramol-
ecular cyclization of the resulting zwitterion intermediates. As
expected, when the reactions were carried out in toluene at
room temperature under argon, and followed by usual aqueous
work-up and subsequent purification by preparative TLC
Scheme 1
formation of complicated mixtures of products, presumably
arising from the further addition of this enamine to the initially
formed intermediate. The reaction of 2-(1-hydroxy-1-methyl-
ethyl)-1,4-naphthoquinone with 1-pyrrolidinocyclohexene in
toluene was very sluggish, and the starting quinone was
recovered almost quantitatively. This may be attributed to the
steric interactions during the reaction. Heating of the reaction
mixture at reflux temperature resulted in the formation of an
intractable mixture of products.
(
PLC) on silica gel, the expected products 7–12 were obtained
as shown in Scheme 1. The products were, in general, dark red
solids. The results are summarized in Table 1, which indicates
that the yields were generally good. The reaction proved to be
applicable to a stable enamine, 3-pyrrolidino-1,2-dihydro-
naphthalene 5, though the yield of the expected product 9
was moderate (entry 3). It should be noted that the use of
1
-pyrrolidinopropene, derived from propanal, resulted in the
DOI: 10.1039/b106933k
J. Chem. Soc., Perkin Trans. 1, 2001, 2977–2982
This journal is © The Royal Society of Chemistry 2001
2977

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Table 1 Preparation of 1H-naphtho[2,3-c]pyran-5,10-diones 7–12
from 2-(1-hydroxyalky1)-1,4-naphthoquinones 1 or 2 and pyrrolidine
enamines 3–6
a
Entry
Quinone
Enamine
Product (yield/%)
1
2
3
4
5
6
1
1
1
1
2
2
3
4
5
7 (81)
8 (83)
9 (48)
b
6
10 (81)
11 (73)
12 (62)
Scheme 3
3
4
δ 2.7–2.8 due to the 12b-H on irradiation of the signal at δ 3.6–
3.65 due to the 4a-H. The cis stereochemical outcome of this
reduction is a result of the attack by a hydride on the inter-
mediate oxonium ion from the least hindered face. Treatment of
a
b
Yields of purified products (PLC on SiO ). A mixture of stereo-
isomers was used.
2
1
6 with toluene-p-sulfonic acid in benzene resulted in elimin-
We next investigated the reactions of 2-hydroxymethyl-1,4-
naphthoquinone 1 with morpholino enamines 13 and 14 in
place of pyrrolidine enamines. It was found that the reactions
gave 3-morpholino-3,4-dihydro-1H-naphthopyran-5,10-diones
ation of morpholine to give 10 in high yield (Scheme 4). The
1
5 and 16, respectively, in fair yields, as a single diastereomer
in each case, as outlined in Scheme 2. These products were
Scheme 4
3
-morpholino group of 16 could be replaced cleanly by a
methoxy group on treatment with toluene-p-sulfonic acid in
methanol to produce 18 in good yield. The 3-hydroxy deriv-
ative 19 was obtained in moderate yield on treatment with
titanium() tetrachloride and quenching of the resulting salts
with water (Scheme 5). Each of the compounds 18 and 19 was
Scheme 2
sufficiently stable to be purified by PLC on silica gel. The
formation of these 3-morpholino derivatives may be ascribed
to the lower basicity of morpholine compared with that of
pyrrolidine. The stereochemistry of 15 was tentatively deter-
1
mined by comparing its H NMR spectrum with that of
1
7, whose stereochemistry was unambiguously determined as
described below. The cis-configuration of 3-Et and 4-Me in 16
was evident by H NMR NOE experiments. Thus, irradiation
Scheme 5
1
of the signal at δ 1.15 due to 4-Me resulted in enhancements of
the signals at δ 1.72 due to one of the methylene protons of 3-Et
produced as a single diastereomer, and their stereochemistry
was determined by comparing their H NMR spectra with that
1
(
12%) and at δ 0.98 due to the methyl protons of 3-Et (8.7%),
of 16, whose stereochemistry was unambiguously determined
while any enhancement of the signals due to the morpholine
protons was not observed.
as described above.
Subsequently, envisaging that imines would tautomerize to
their enamine forms in the reaction mixtures and should
undergo a similar reaction sequence with the (hydroxyalkyl)-
naphthoquinones 1, 2 and 20 to lead to the formation of the
desired naphthopyrandiones, we investigated the reactions of 1,
2 and 20 with imines 21–23. It was found that the sequence
proceeded smoothly and gave somewhat complicated mixtures
compared with those from using enamines, from which the
corresponding 1H-naphtho[2,3-c]pyran-5,10-dione derivatives
In order to demonstrate the synthetic usefulness of these
morpholinonaphthopyrandiones 15 and 16, transformations
into some related derivatives were then studied. Compound 15
was treated with triethylsilane in TFA at room temperature to
provide the corresponding dihydro derivative 17 in fair yield as
a single diastereomer (Scheme 3). The stereochemistry of this
product was also confirmed by NOE experiments between the
two conjunctive protons; an 8.4% enhancement of the signal at
2
978
J. Chem. Soc., Perkin Trans. 1, 2001, 2977–2982

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Table 2 Preparation of 1H-naphtho[2,3-c]pyran-5,10-diones 24–28
from 2-(1-hydroxyalkyl)-1,4-naphthoquinones 1, 2, or 20 and imines
Table 3 Preparation of (±)-eleutherin 33 and its derivatives 32 and 34
a
2
1–23
Entry
27 or 28
Reaction temp.
Product(s) (yield/%)
a
Entry
Quinone
Imine
Product (yield/%)
1
2
3
4
27
28
28
28
rt
rt
32 (98)
b
b
b
33 (8) 34 (42)
b
c
b
1
2
3
4
5
1
1
21
24 (44)
Ϫ20 ЊC to rt
Ϫ20 ЊC
33 (7) 34 (56)
22
25 (60)
26 (39)
27 (53)
28 (55)
33 (66)
b
1
23
22
22
a
b
Yields of purified products (PLC on SiO ). Separable by PLC on
2
2
20
SiO2.
a
b
Yields of purified products (PLC on SiO ). A mixture of stereo-
2
c
isomers was used. Pentalongin (ref. 4).
Scheme 7
Scheme 6
2
4–28 were isolated in moderate to fair yields (Scheme 6). The
results are summarized in Table 2. Compound 24 is an anti-
4
biotic (pentalongin) isolated from Pentas longiflora. Although
the yields were somewhat lower than those using enamines, the
use of imines may offer an advantage, because these imines
are generally easier to prepare than are the corresponding
enamines.
The reactions forming naphthopyrandione derivatives 7–12,
5, 16 and 24–28 are thought to proceed via the conjugate
1
addition of enamines or imines at the 3-position of the (hydroxy-
alkyl)naphthoquinones 1, 2 and 20 to form the iminium inter-
mediates 29, which is followed by intramolecular cyclization to
give the dihydroquinone intermediates 30. These intermediates
are then oxidized upon exposure to air to give the amino-
naphthopyrandione products 31 (15 and 16). In the case of
using pyrrolidine enamines or imines the elimination of an
amine occurs during work-up and/or purification procedures to
give 7–12 and 24–28 (Scheme 7).
Scheme 8
Having established a simple and efficient route to 1H-
naphtho[2,3-c]pyran-5,10-dione derivatives, we next turned our
attention to application of the present method to the synthesis
of useful natural products and planned the conversion of the
naphthopyrandione 28 into (±)-eleutherin 33 and (±)-isoeleuth-
erin 34. Eleutherin and isoeleutherin are antibiotics, found in
Scheme 8 and Table 3. First, as the model reaction, compound
27 was treated with triethylsilane in TFA at room temperature.
The reduction took place within minutes to afford cis-1,3-
dimethyl-3,4-dihydro-1H-naphtho[2,3-c]pyran-5,10-dione 32
[(±)-demethoxyeleutherin] exclusively in excellent yield (entry
1). Compound 28 was then subjected to reduction under the
same conditions. Unfortunately, however, the reaction is less
5a
Eleutherin bulbosa. The conversion was accomplished by
reduction using triethylsilane in TFA, and is summarized in
J. Chem. Soc., Perkin Trans. 1, 2001, 2977–2982
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9
reliable, affording a ca. 1 : 5 mixture of the desired product 33
along with its diastereoisomer, (±)-isoeleutherin 34, in moder-
ate combined yield (entry 2), while these products were easily
separated from each other by PLC on silica gel. Although the
low stereoselectivity in this reaction was disappointing, we
reached the conclusion that the formation of 34 is a result of
isomerization of the initially formed desired product 33 under
hexane–EtOAc gave (1,4-dimethoxynaphthalen-2-yl)methanol
Ϫ1
(1.5 g, 99%) as a white solid; mp 74–76 ЊC; νmax/cm 3400 and
1628; δH (60 MHz) 2.40 (1H, br s), 3.89 (3H, s), 3.95 (3H, s),
4.87 (2H, br s), 6.75 (1H, s), 7.25–7.55 (2H, m) and 7.85–8.3
(2H, m).
This alcohol (1.4 g, 6.5 mmol) was dissolved in MeCN
(56 cm ) and a solution of CAN (7.2 g, 13 mmol) in water
3
7
3
the reaction conditions, and reasoned that carrying out the
(6.5 cm ) was added at 0 ЊC. After the mixture had been stirred
reaction at lower temperature should suppress the isomeriz-
ation and allow us to obtain the desired product 33 exclusively
in satisfactory yield. As expected, the reaction at Ϫ20 ЊC pro-
ceeded more cleanly than that at room temperature and resulted
in the formation of 33 as the sole diastereoisomer in fair yield
for 3 min at the same temperature, usual work-up followed
by recrystallization from CCl gave 1 (1.2 g, 99%) as yellow
4
11
needles; mp 117–118 ЊC (lit., 111–112 ЊC).
12
2-(1-Hydroxyethyl)-1,4-naphthoquinone
2
(
(
entry 4). We later found that the yield of 34 was improved
56%, 33 : 34 = 1 : 8) when compound 28 was treated with
To a stirred solution of (1,4-dimethoxynaphthalen-2-yl)-
magnesium bromide, generated from the reaction of 2-bromo-
triethylsilane in TFA at Ϫ20 ЊC and then the mixture was
allowed to warm gradually to room temperature (entry 3). IR
and H NMR data as well as melting points for 32, 33, and 34
are consistent with literature values. Thus, these natural prod-
ucts were obtained in two steps from 20, which was synthesized
almost quantitatively in two steps (NaBH reduction followed
by oxidation with CAN) from known 1-(1-hydroxy-4,8-
dimethoxynaphthalen-2-yl)ethanone as reported by Uno. So
this sequence constitutes a very concise total synthesis of these
natural products.
5f
1
,4-dimethoxynaphthalene (1.3 g, 5.0 mmol) with magnesium
3
turnings (0.13 g, 5.2 mmol) in THF (18 cm ) at reflux temper-
ature for 1 h, was added dropwise acetaldehyde (1.4 g, 32 mmol)
at 0 ЊC. After 1 h the mixture was worked up as usual. Purifi-
cation of the residue by column chromatography on SiO2
gave 1-(1,4-dimethoxynaphthalen-2-yl)ethanol (1.0 g, 89%) as
a yellow solid; mp 99–101 ЊC (lit., 101–102 ЊC).
1
5
4
12
12
5f
This compound (0.83 g, 3.6 mmol) was oxidized with CAN
(
2.8 g, 5.2 mmol) as described for the preparation of 1 to
give 2 (0.42 g, 58%) as a yellow solid; mp 92–94 ЊC (from
In summary, the studies recorded herein demonstrate that
H-naphtho[2,3-c]pyran-5,10-dione and 1H-3,4-dihydronaph-
12
hexane–Et O) (lit., 88–89 ЊC).
2
1
tho[2,3-c]pyran-5,10-dione derivatives can be prepared from
readily available starting materials. The method has advan-
tages, particularly with regard to ease of operation and appli-
cability to the concise total synthesis of important natural
products.
2
-(1-Hydroxyethyl)-8-methoxy-1,4-naphthoquinone 20
5f
1
-(1-Hydroxy-4,8-dimethoxynaphthalen-2-yl)ethanone (0.55
g, 2.3 mmol) was treated with NaBH (0.26 g, 6.8 mmol) in
THF (25 cm ), as described for the reduction of 1,4-
dimethoxynaphthalene-2-carbaldehyde, to give 2-(1-hydroxy-
ethyl)-4,8-dimethoxy-1-naphthol (0.52 g, 96%) as a yellow
viscous oil: R 0.31 (2 : 1 EtOAc–hexane) (Found: C, 68.0; H,
4
3
Experimental
f
Ϫ1
6
.6. C H O requires C, 67.75; H, 6.5%); νmax/cm 3404, 1634
All mps were recorded with a Laboratory Devices MEL-TEMP
II melting-point apparatus and are uncorrected. IR spectra
were determined using KBr disks (unless stated otherwise)
14 16 4
and 1611; δ (60 MHz) 1.58 (3H, d, J 6.3), 2.77 (1H, d, J 4.6),
H
3
.95 (3H, s), 4.06 (3H, s), 5.31 (1H, quint, J 5.8), 6.84 (1H,
1
d, J 7.6), 6.90 (1H, s), 7.30 (1H, dd, J 8.4 and 7.6), 7.83 (1H, d,
J 8.4) and 9.30 (1H, s).
with a Perkin-Elmer 1600 Series FT IR spectrometer. H NMR
spectra were determined in CDCl3 using SiMe4 as internal
reference with a JEOL JNM-GX270 FT NMR spectro-
meter operating at 270 MHz or a JEOL JNX-PMX 60 NMR
spectrometer operating at 60 MHz. J-Values are given in
Hz. Low-resolution mass spectra were recorded on a JEOL
AUTOMASS 20 spectrometer (Center for Joint Research and
Development, this University). Column chromatography was
carried out on Merck Kieselgel 60 F254. TLC was carried out on
Merck Kieselgel 60 PF254. All of the solvents used were dried
over appropriate drying agents and distilled under argon prior
to use.
This compound (0.33 g, 1.3 mmol) was oxidized with CAN
(
1.4 g, 2.6 mmol), as described for the preparation of 1, to give
2
0 (0.28 g, 92%) as a yellow solid; mp 98–104 ЊC (from CCl4)
(
Found: C, 67.05; H, 5.2. C H O requires H, 67.25; H, 5.2%);
13 12 4
Ϫ1
νmax/cm 3510, 3400, 3172, 1662, 1648 and 1626; δ (60 MHz)
H
1
.50 (3H, d, J 6.5), 2.58 (1H, d, J 3.6), 4.11 (3H, s), 4.98 (1H,
m), 6.90 (1H, d, J 1.1), 7.30 (1H, dd, J 7.6 and 1.8), 7.68 (1H, t,
J 7.6) and 7.73 (1H, dd, J 7.6 and 1.8).
1
7
,2,3,5-Tetrahydrocyclopenta[b]naphtho[2,3-d]pyran-6,11-dione
. Typical procedure for the reactions of 2-(1-hydroxyalkyl)-1,4-
naphthoquinones with enamines or imines
Starting materials
To a stirred solution of 2-hydroxymethyl-1,4-naphthoquinone 1
1
1
3
2
-Pyrrolidinocyclopentene 3, 1-pyrrolidinocyclohexene 4, and
3
(
86 mg, 0.46 mmol) in toluene (5 cm ) under argon was added
-morpholinocyclohexene 13 were commercially available.
8
1-pyrrolidinocyclopentene 3 (0.12 g, 0.91 mmol), and stirring
-Pyrrolidino-1,2-dihydronaphthalene 5, 3-pyrrolidinopent-
8
8
was continued overnight at room temperature. The resulting
-ene 6, 3-morpholinopent-2-ene 14, N-ethylidenecyclo-
3
9
10
reaction mixture was diluted with Et
successively with water, aq. NH
layer was dried over anhydrous Na SO and concentrated under
O (20 cm ) and washed
2
hexylamine 21, N-isopropylideneisopropylamine 22, and
N-(1-phenylethylidene)cyclohexylamine 23, were prepared
following the appropriate procedures reported previously.
10
Cl, and then brine. The organic
4
2
4
reduced pressure. The residue was subjected to PLC on SiO2
1 : 5 AcOEt–hexane) to give 7 (0.12 g, 81%) as dark red
(
2
-Hydroxymethyl-1,4-naphthoquinone 1
needles; mp 117–119 ЊC (from hexane) (Found: C, 76.2; H, 4.85.
Ϫ1
This compound was initially prepared according to the route
C H O requires C, 76.2; H, 4.8%); νmax/cm 1668 and 1644;
16
12
3
11
developed by Antonini et al. Unfortunately, however, we were
unable to obtain this compound both in pure form and in good
yield. The following route was therefore attempted. To a stirred
δH (270 MHz) 2.04 (2H, quint, J 7.4), 2.50 (2H, t, J 7.4), 2.96
(2H, t, J 7.4), 5.28 (2H, s), 7.65–7.75 (2H, m) and 8.05–8.1 (2H,
ϩ
m); m/z 252 (M , 100%).
5f
solution of 1,4-dimethoxynaphthalene-2-carbaldehyde (1.5 g,
3
7
2
.1 mmol) in THF (20 cm ) was added NaBH4 (0.83 g,
1 mmol) and stirring was continued for 70 min at room
2,3,4,6-Tetrahydro-1H-benzo[b]naphtho[2,3-d]pyran-7,12-
dione 8. Dark red needles; mp 105–107 ЊC (from hexane)
(Found: C, 76.8; H, 5.1. C H O requires C, 76.7; H, 5.3%);
temperature. Usual work-up followed by recrystallization from
17
14
3
2
980 J. Chem. Soc., Perkin Trans. 1, 2001, 2977–2982

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Ϫ1
νmax/cm 1670 and 1644; δ (270 MHz) 1.7–1.75 (4H, m), 2.15–
1,3-Dimethyl-1H-naphtho[2,3-c]pyran-5,10-dione 27. Red
H
2
.2 (2H, m), 2.75–2.8 (2H, m), 5.00 (2H, s), 7.65–7.75 (2H, m)
needles; mp 81–83 ЊC (from hexane) (Found: C, 75.25; H, 5.0.
ϩ
Ϫ1
and 8.0–8.1 (2H, m); m/z 266 (M , 50%) and 210 (100).
C H O requires C, 75.0; H, 5.05%); νmax/cm 1670, 1654 and
15
12
3
1
622; δ (270 MHz) 1.41 (3H, d, J 6.5), 2.02 (3H, s), 5.70 (1H,
H
5
,6-Dihydro-8H-dinaphtho[2,1-b;2,3-d]pyran-9,14-dione 9. A
q, J 6.5), 5.89 (1H, s), 7.6–7.75 (2H, m) and 8.0–8.1 (2H, m);
m/z 240 (M , 46%) and 225 (100).
ϩ
dark red oil; R 0.40 (1 : 5 AcOEt–hexane) (Found: C, 80.25; H,
.5. C H O requires C, 80.25; H, 4.5%); νmax/cm (neat)
21 14 3
f
Ϫ1
4
1
678, 1669 and 1645; δ (270 MHz) 1.7–2.57 (2H, t, J 7.3), 2.93
9-Methoxy-1,3-dimethyl-1H-naphtho[2,3-c]pyran-5,10-dione
28. Red needles; mp 133–137 ЊC (from hexane) (Found:
H
(
2H, t, J 7.3), 5.07 (2H, s), 7.1–7.25 (4H, m), 7.7–7.75 (2H, m)
ϩ
Ϫ1
and 8.0–8.15 (2H, m); m/z 314 (M , 100%).
C, 71.05; H, 5.1. C H O requires C, 71.1; H, 5.2%); νmax/cm
16
14
4
1
653 and 1626; δH (270 MHz) 1.39 (3H, d, J 6.3), 2.00 (3H, d,
J 1.1), 3.99 (3H, s), 5.66 (1H, q, J 6.3), 5.82 (1H, q, J 1.1), 7.23
1H, dd, J 8.4 and 1.1), 7.61 (1H, dd, J 8.4 and 7.9) and 7.75
3
-Ethyl-4-methyl-1H-naphtho[2,3-c]pyran-5,10-dione 10. A
dark-red solid; mp 91–92 ЊC (from hexane) (Found: C, 75.5; H,
(
Ϫ1
5
.6. C H O requires C, 75.55; H, 5.55%); νmax/cm 1665 and
ϩ
16
14
3
(1H, dd, J 7.9 and 1.1); m/z 270 (M , 58%) and 255 (100).
1
645; δ (270 MHz) 1.17 (3H, t, J 7.4), 2.18 (3H, s), 2.39 (2H, q,
H
J 7.4), 4.94 (2H, s), 7.65–7.75 (2H, m) and 8.0–8.1 (2H, m);
m/z 254 (M , 79%) and 225 (100).
cis-2,3,4,4a,6,12b-Hexahydro-1H-benzo[b]naphtho[2,3-d]pyran-
ϩ
7
,12-dione 17
To a stirred dark-red solution of compound 15 (0.13 g,
5
-Methyl-1,2,3,5-tetrahydrocyclopenta[b]naphtho[2,3-d]-
3
0
.38 mmol) in TFA (0.94 cm ) at room temperature was added
pyran-6,11-dione 11. Dark-red needles; mp 149–151 ЊC (from
hexane) (Found: C, 76.5; H, 5.25. C H O requires C, 76.7; H,
.3%); νmax/cm 1667 and 1645; δH (270 MHz) 1.44 (3H, d,
J 6.8), 1.95–2.1 (2H, m), 2.4–2.55 (2H, m), 2.95–3.05 (2H, m),
.83 (1H, q, J 6.8), 7.65–7.75 (2H, m) and 8.0–8.1 (2H, m);
dropwise Et SiH (0.11 g, 0.95 mmol); the solution turned
3
17
14
3
Ϫ1
brown immediately. After stirring of the mixture for 30 min,
TFA was removed under reduced pressure. The residue was sub-
5
jected to PLC on SiO to give 17 (61 mg, 60%) as a yellow solid;
5
2
ϩ
mp 82–83 ЊC (from hexane) (Found: C, 76.15; H, 6.05. C H O
m/z 266 (M , 100%).
17 16
3
Ϫ1
requires C, 76.1; H, 6.0%); νmax/cm 1660 and 1631; δH
(270 MHz) 1.35–2.1 (8H, m), 2.7–2.8 (1H, m), 3.6–3.65 (1H,
m), 4.60 (1H, dd, J 18.9 and 2.6), 4.88 (1H, d, J 18.9), 7.65–7.75
6
-Methyl-2,3,4,6-tetrahydro-1H-benzo[b]naphtho[2,3-d]-
pyran-7,12-dione 12. A red oil; R 0.26 (1 : 10 AcOEt–hexane)
Found: C, 77.1; H, 5.7. C H O requires C, 77.1; H, 5.75%);
νmax/cm (neat) 1670 and 1646; δH (270 MHz) 1.35 (3H, d,
J 6.9), 1.5–1.65 (2H, m), 1.85–1.95 (2H, m), 2.2–2.35 (2H, m),
f
ϩ
(
(2H, m) and 8.0–8.15 (2H, m); m/z 268 (M , 100%).
18
16
3
Ϫ1
Conversion of the 3-morpholino-3,4-dihydro-1H-naphtho-
2
7
.55–2.65 (1H, m), 2.8–2.95 (1H, m), 5.63 (1H, q, J 6.9),
.6–7.75 (2H, m) and 8.0–8.1 (2H, m); m/z 280 (M , 100%).
pyrandione 16 into the naphthopyrandione 10
ϩ
A solution of compound 16 (67 mg, 0.20 mmol) and p-TsOH
3
(
35 mg, 0.20 mmol) in benzene (6 cm ) was stirred overnight at
(
4aR*,12bR*)-4a-Morpholino-2,3,4,4a,6,12b-hexahydro-1H-
room temperature. The mixture was washed successively with
aq. NaHCO and then brine, and dried over anhydrous Na SO .
benzo[b]naphtho[2,3-d]pyran-7,12-dione 15. Orange needles;
mp 175–179 ЊC (from hexane–Et O) (Found: C, 71.1; H, 6.55;
N, 3.95. C H NO requires C, 71.35; H, 6.55; N, 3.95%);
3
2
4
2
Evaporation of the solution gave a residue, which was purified
by PLC on SiO to afford compound 10 (46 mg, 90%).
21
23
4
Ϫ1
2
νmax/cm 1659 and 1639; δH (270 MHz) 1.25–2.0 (8H, m),
.3–2.5 (2H, m), 2.55–2.7 (2H, m), 3.0–3.15 (1H, m), 3.45–3.6
4H, m), 4.55 (1H, dd, J 19.6 and 1.8), 4.62 (1H, d, J 19.6),
2
(
(
3R*, 4R*)-3-Ethyl-3-methoxy-4-methyl-3,4-dihydro-1H-
ϩ
naphtho[2,3-c]pyran-5,10-dione 18
7
2
.65–7.8 (2H, m) and 8.05–8.15 (2H, m); m/z 353 (M , 23%),
82 (33) and 267 (100).
To a stirred solution of compound 16 (67 mg, 0.20 mmol) in
MeOH (6 cm ) containing HC(OMe) (23 mg, 0.22 mmol) was
added p-TsOH (35 mg, 0.20 mmol). The mixture was stirred
at room temperature for 11 h, and then was neutralized by
3
3
(
3R*,4R*)-3-Ethyl-4-methyl-3-morpholino-3,4-dihydro-1H-
naphtho[2,3-c]pyran-5,10-dione 16. Orange needles; mp 157–
59 ЊC (from hexane–Et O) (Found: C, 70.6; H, 6.85; N, 4.15.
1
2
addition of NaHCO . After filtration, the filtrate was evapor-
3
Ϫ1
C H NO requires C, 70.35; H, 6.8; N, 4.1%); νmax/cm 1660
2
0
23
4
ated to give a residue, which was purified by PLC on SiO to
2
and 1639; δ (270 MHz) 0.98 (3H, t, J 7.4), 1.15 (3H, d, J 6.9),
H
afford title compound 18 (47 mg, 84%) as a yellow solid; mp 84–
1
2
3
.72 (1H, dq, J 14.3 and 7.4), 1.98 (1H, dq, J 14.3 and 7.4),
.5–2.6 (2H, m), 2.8–2.9 (2H, m), 3.08 (1H, qd, J 6.9 and 1.6),
.35–3.55 (4H, m), 4.50 (1H, dd, J 19.4 and 1.6), 4.54 (1H, d,
8
9 ЊC (from hexane–Et O) (Found: C, 71.5; H, 6.25. C H O
2 17 18 4
Ϫ1
requires C, 71.3; H, 6.35%); νmax/cm 1661 and 1644; δH (270
MHz) 0.96 (3H, t, J 7.6), 1.12 (3H, d, J 6.9), 1.70 (1H, dq, J 14.8
and 7.6), 1.91 (1H, dq, J 14.8 and 7.6), 3.04 (1H, qd, J 6.7 and
J 19.4), 7.7–7.75 (2H, m) and 8.05–8.15 (2H, m); m/z 341
ϩ
(
M , 28%), 255 (68) and 199 (100).
2
.2), 3.23 (3H, s), 4.43 (1H, dd, J 19.7 and 2.2), 4.72 (1H,
d, J 19.7), 7.65–7.75 (2H, m) and 8.0–8.15 (2H, m); m/z 286
4
1
H-Naphtho[2,3-c]pyran-5,10-dione (pentalongin) 24. A red
ϩ
(
M , 15%), 284 (48), 254 (58) and 198 (100).
4a
solid; mp 160–162 ЊC (decomp.) (from hexane) (lit., 160–
Ϫ1
1
6
8
61 ЊC); νmax/cm 1670 and 1652; δH (270 MHz) 5.16 (2H, s),
.11 (1H, d, J 5.6), 6.97 (1H, d, J 5.6), 7.65–7.75 (2H, m) and
.05–8.15 (2H, m).
(3R*,4R*)-3-Ethyl-3-hydroxy-4-methyl-1H-2,3-dihydro-
naphtho[2,3-c]pyran-5,10-dione 19
To a stirred solution of compound 16 (36 mg, 0.11 mmol) in
3
3
-Methyl-1H-naphtho[2,3-c]pyran-5,10-dione 25. Dark red
crystals; mp 136–137 ЊC (from hexane) (Found: C, 74.05; H,
.25. C H O requires C, 74.35; H, 4.45%); νmax/cm 1672,
657sh and 1626; δ (270 MHz) 2.04 (3H, s), 5.17 (2H, s), 5.95
DME (0.5 cm ) at Ϫ20 ЊC was added TiCl
4
(30 mg, 0.16 mmol).
The reaction mixture was stirred for 30 min at the same tem-
Ϫ1
3
4
1
(
(
perature, after which water (10 cm ) was added to the mixture.
14
10
3
3
The resulting mixture was extracted with Et O twice (10 cm
H
2
1H, s), 7.65–7.75 (2H, m) and 8.0–8.1 (2H, m); m/z 226
each). The combined extracts were dried over anhydrous
Na SO and concentrated under reduced pressure. The residue
ϩ
M , 100%).
2
4
was purified by PLC on SiO to give compound 19 (16 mg, 58%)
2
2
b,13
3
-Phenyl-1H-naphtho[2,3-c]pyran-5,10-dione
26. Red
as a yellow solid; mp 152–154 ЊC (from hexane–Et O) (Found:
2
1
3
Ϫ1
prisms; mp 185–189 ЊC (from hexane–CH Cl ) (lit., 188–
C, 70.4; H, 5.8. C H O requires C, 70.6; H, 5.9%); νmax/cm
2
2
16 16
4
1
91 ЊC).
3404, 1663 and 1643 sh; δ (270 MHz) 1.07 (3H, t, J 7.3), 1.15
H
J. Chem. Soc., Perkin Trans. 1, 2001, 2977–2982
2981

View Article Online
(
3H, d, J 7.3), 1.71 (1H, dq, J 14.2 and 7.3), 1.90 (1H, dq, J 14.2
(g) M. A. Brimble and S. J. Phythian, Tetrahedron Lett., 1993, 34,
5
813; (h) G. A. Kraus, J. Li, M. S. Gordon and J. H. Jensen, J. Am.
and 7.3), 2.18 (1H, br s), 3.50 (1H, q, J 7.3), 4.68 (1H, dd, J 19.4
Chem. Soc., 1993, 115, 5859; (i) M. A. Brimble and S. M. Lynds,
J. Chem. Soc., Perkin Trans. 1, 1994, 493; (j) V. I. Hugo, Synth.
Commun., 1994, 24, 2563; (k) G. Attardo, T. Breining, M.
Courchesne, J. L. Kraus, S. Lamothe, J. F. Lavallee, E. Lebeau, D.
Nguyen and R. Reji PCT Int. Pat., 11382, 1994, Chem. Abstr., 1996,
124, 30252e; (l ) G. Attardo, W. Wang, T. Breining, T. Li, Y. St.-Denis
and J. L. Kraus, PCT Int. Pat., 12588, 1995, Chem. Abstr., 1995, 123,
285186p; (m) M. A. Brimble, S. J. Phythian and H. Prabaharan,
J. Chem. Soc., Perkin Trans. 1, 1995, 2855; (n) M. A. Brimble, L. J.
Duncalf and S. J. Phythian, Tetrahedron Lett., 1995, 36, 9209; (o)
M. A. Brimble, L. J. Duncalf and S. J. Phythian, J. Chem. Soc.,
Perkin Trans. 1, 1997, 1399; (p) M. A. Brimble, L. J. Duncalf and D.
Neville, J. Chem. Soc., Perkin Trans. 1, 1998, 4165; (q) B. Kesteleyn,
L. Van Puyvelde and N. De Kimpe, J. Org. Chem., 1999, 64, 438;
and 1.9), 4.76 (1H, dd, J 19.4 and 1.1), 7.65–7.75 (2H, m) and
ϩ
8
.0–8.15 (2H, m); m/z 254 [(M Ϫ H O) , 100%].
2
cis-1,3-Dimethyl-3,4-dihydro-1H-naphtho[2,3-c]pyran-5,10-dione
(±)-demethoxyeleutherin] 32
[
To a stirred solution of compound 27 (28 mg, 0.12 mol) in TFA
3
(
0.3 cm ) at room temperature was added Et SiH (0.34 g, 0.29
3
mmol). After removal of TFA under reduced pressure the
residual solid was recrystallized from hexane to give compound
3
2 (28 mg, 98%) as yellow needles; mp 141–144 ЊC (from
5f
hexane) (lit., 143.5–145 ЊC).
(
r) P. Contant, M. Haess, J. Riegel, M. Scalone and H. Visnick,
cis-9-Methoxy-1,3-dimethyl-3,4-dihydro-1H-naphtho[2,3-c]-
pyran-5,10-dione [(±)-eleutherin] 33
Synthesis, 1999, 821; (s) B. Kesteleyn, N. De Kimpe and L. Van
Puyvelde, J. Org. Chem., 1999, 64, 1173; (t) B. Kesteleyn, N. De
Kimpe and L. Van Puyvelde, Synthesis, 1999, 1881; (u) C. D.
Donner and M. Gill, Tetrahedron Lett., 1999, 40, 3921; (v) M. A.
Brimble, M. R. Nairn and J. S. O. Park, J. Chem. Soc., Perkin Trans.
A solution of compound 28 (34 mg, 0.13 mmol) in TFA
3
(
0.30 cm ) was treated with Et SiH (0.36 g, 0.31 mmol) at
3
1
, 2000, 697. For earlier reports, see pertinent references. cited in
Ϫ20 ЊC and the solvent was removed under reduced pressure.
these papers. See also: Y. Naruta and K. Maruyama, J. Synth. Org.
Chem. Jpn., 1984, 42, 415; Y. Naruta and K. Maruyama, in The
Chemistry of Quinonoid Compounds, ed. S.Patai and Z. Rappoport,
Wiley, New York, 1988, vol. 2, p. 241; R. H. Thomson, in The Total
Synthesis of Natural Products, ed. J. ApSimon, Wiley, New York,
1992, vol. 8, p. 311.
The residue was purified by PLC on SiO to give title compound
2
3
3 (23 mg, 66%) as yellow needles; mp 157–158 ЊC (from
5a 5f
hexane) (lit., mp 155–156 ЊC; lit., 158–160 ЊC).
trans-9-Methoxy-1,3-dimethyl-3,4-dihydro-1H-naphtho[2,3-c]-
pyran-5,10-dione [(±)-isoeleutherin] 34
3
For previous syntheses of heterocycle-fused quinones based on
reactions of quinones with enamines, see H. Kakisawa and Y.
Inouye, Tetrahedron Lett., 1969, 1929; H. Kakisawa and M. Tateishi,
Bull. Chem. Soc. Jpn., 1970, 43, 824; M. Tateishi, T. Kusumi
and H. Kakisawa, Tetrahedron, 1971, 27, 237; W. S. Murphy and
P. J. O’Sullivan, Tetrahedron Lett., 1992, 33, 531; K. Kobayashi,
K. Tanaka, T. Uneda, K. Maeda, O. Morikawa and H. Konishi,
Synthesis, 1998, 1243.
4 Isolation (a) L. Hari, L. F. De Buyck and H. L. De Pooter,
Phytochemistry, 1991, 30, 1726. Spectral assignments (b) N. De
Kimpe, L. Van Puyvelde, J. Schripsema, C. Erkelens and R.
Verpoorte, Magn. Reson. Chem., 1993, 31, 329. Synthesis (c) T.
Naito, Y. Makita, S. Yazaki and C. Kaneko, Chem. Pharm. Bull.,
A solution of compound 28 (31 mg, 0.11 mmol) in TFA (0.29
3
cm ) was treated with Et SiH (0.33 g, 0.28 mmol) at Ϫ20 ЊC and
3
the mixture was allowed to warm to room temperature. After
removal of TFA the residue was purified by PLC on SiO to
give the title compound 34 (17 mg, 56%) as yellow needles along
2
with 33 (2 mg, 7%). Compound 34: mp 153–155 ЊC (from
5a
5a
5f
hexane) (lit., 154–155 ЊC; lit., 149–151 ЊC).
References
1
986, 34, 1505; (d ) T. Hayashi, F. T. Smith and K. H. Lee, J. Med.
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2
For recent studies on the synthesis of compounds having this
skeleton, see (a) G. A. Kraus, J. Shi and D. Reynolds, J. Org. Chem.,
1
990, 55, 1105; (b) M. F. Aldersley, S. H. Chishti, F. M. Dean, M. E.
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(
(
c) U. P. Dhokte and A. S. Rao, Synth. Commun., 1991, 21, 1263;
d ) C. B. de Koning, R. G. F. Giles and I. R. Green, J. Chem. Soc.,
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2
982
J. Chem. Soc., Perkin Trans. 1, 2001, 2977–2982