Synthesis of diospyrin, a potential agent against leishmaniasis and related parasitic protozoan diseases

Article abstract of DOI:10.1002/1099-0690(200004)2000:7<1313::AID-EJOC1313>3.0.CO;2-I

The first synthesis of diospyrin [2,6'-bis(5-hydroxy-7-methyl-1,4- naphthoquinone), 1] was achieved by employing Suzuki coupling between 5 and 14 as the key reaction to connect the two 7-methyljuglone units.

Full text of DOI:10.1002/1099-0690(200004)2000:7<1313::AID-EJOC1313>3.0.CO;2-I

FULL PAPER
Synthesis of Diospyrin, a Potential Agent Against Leishmaniasis and Related
Parasitic Protozoan Diseases
Masao Yoshida[a] and Kenji Mori*[a]
Keywords: Leishmaniasis / Natural products / Phytochemistry / Quinones / Suzuki coupling
The first synthesis of diospyrin [2,6Ј-bis(5-hydroxy-7-methyl-
1,4-naphthoquinone), 1] was achieved by employing Suzuki
coupling between 5 and 14 as the key reaction to connect
the two 7-methyljuglone units.
Introduction
cei brucei, the causative agents of the protozoan diseases
leishmaniasis and trypanosomiasis.[11] Because we are
working on the synthesis of the sex pheromone of the
sandfly Lutzomyia longipalpis, the vector of Leishmania
parasites, we have become interested in synthesizing diospy-
rin (1), which directly attacks the parasites themselves.[12]
Another good reason to attempt the synthesis of 1 was to
prove unambiguously the correctness of the structure 1. The
structural elucidation of diospyrin depended on its 1H
NMR analysis,[3,4,13] and there is no reported synthesis of
1 to date.
Diospyrin was first isolated in 1961 by Kapil and Dhar
as an orange-red constituent of Diospyros montana Roxb.
(Ebenaceae), a small or medium-sized tree found through-
out India.[1] Its structure was proposed by Ganguly and
Govindachari in 1966 as a dimer of 7-methyljuglone linked
between C-2 and C-3Ј.[2] Subsequent studies by Sidhu and
Pardhasaradhi led to the correct structure of diospyrin as
Scheme 1 shows the retrosynthetic analysis of diospyrin.
The two naphthoquinone moieties should be synthesized
separately, and then they must be coupled by using either
the Stille reaction via organotin intermediates[14] or Suzuki
coupling via organoboronic acid intermediates.[15] Recent
endeavors in the synthesis of michellamine A and related
compounds[16–19] were very instructive to us in designing
our own synthesis.
Our synthesis of diospyrin (1) is summarized in
Scheme 2. The first stage of the synthesis was to prepare
the naphthalene building blocks 6 and 13. A Diels–Alder
reaction between the known 1-methoxy-3-methyl-1-trime-
thylsilyloxy-1,3-butadiene (2)[20] and 2,5-dibromo-1,4-
benzoquinone (3) afforded 4. This was methylated with
methyl iodide and silver oxide to give 5, whose reduction
with tin(II) chloride[21] was followed by further methylation
of the resulting naphthalenediol to furnish 6. For the syn-
thesis of 13, another Diels–Alder reaction was executed.
For that purpose, 2-bromo-1-methoxy-3-methyl-1-trime-
thylsilyloxy-1,3-butadiene (8) was prepared from the known
methyl 2-bromosenecioate (7).[22] A Diels–Alder reaction
between 8 and 1,4-benzoquinone (9) proceeded in dichloro-
methane, and the resulting mixture was treated with dilute
hydrochloric acid to remove the partly remaining trimethyl-
silyl group, giving a mixture of 10 and 11. This was fully
methylated with methyl iodide and silver oxide to afford
pure 11. Reduction of 11 with tin(II) chloride furnished 12,
which was then methylated to give 13. We first attempted
the conversion of 6 or 13 to the corresponding tributyltin
derivatives by their lithiation followed by stannylation.
These attempts, however, were unsuccessful, and the use of
the Stille reaction for the coupling of the two naphthalene
units was abandoned.
Scheme 1. Structure and retrosynthetic analysis of diospyrin
depicted in 1 (Scheme 1) with a linkage between C-2 and
C-6Ј.[3,4] Isolation of diospyrin and its derivatives from D.
montana was also reported by Musgrave and co-workers.[5]
Waterman and co-workers then examined a number of Di-
ospyros species in Africa, and isolated 1 from many of
them.[6,7] Other African plants of the Euclea species are also
known to produce 1.[8,9] Diospyrin (1) is optically inact-
ive,[5] and thus there is no restricted rotation around the
connecting bond between C-2 and C-6Ј.
In 1995 Hazra et al. reported the in vitro antiplasmoidal
effects of diospyrin (1), suggesting it to be a useful model
for the development of antimalarial drugs.[10] Then, in 1996
they reported in vitro activity of diosyrin and its derivatives
against Leishmania donovani, Trypanosoma cruzi and T. bru-
[a]
Department of Chemistry, Faculty of Science, Science
University of Tokyo,
Kagurazaka 1–3, Shinjuku-ku, Tokyo 162–8601, Japan
Fax: (internat.) ϩ 81-3/3235-2214
Eur. J. Org. Chem. 2000, 1313Ϫ1317
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0407Ϫ1313 $ 17.50ϩ.50/0
1313

M. Yoshida, K. Mori
FULL PAPER
phosphate). Fortunately, coupling between the bromo-1,4-
naphthoquinone 5 and 14 was successful under the stand-
ard conditions employing tetrakis(triphenylphosphane)pal-
ladium(0) as the catalyst in the presence of sodium carbon-
ate to give the coupling product 15 as orange-red needles
in 53% yield.
Oxidative demethylation of 15 with ceric ammonium ni-
trate[21,25] furnished diospyrin dimethyl ether (16) as yellow
needles melting at 256–258 °C (ref.[3] m.p. 256 °C). Further
demethylation of 16 to 1 was problematic, and the attempts
with boron tribromide, 47% hydrobromic acid, lithium
chloride in DMF, trimethylsilyl iodide, and potassium thio-
phenolate in diethylene glycol were all unsuccessful. The
only fruitful method to achieve the demethylation was to
treat 16 with aluminum chloride in dichloromethane at
room temperature.[26] The resultant diospyrin (1), m.p. 256–
258 °C (ref.[1] m.p. 258 °C) is identical with the authentic
sample provided by Dr. Hazra in every respect including its
1
IR, H NMR, and 13C NMR spectra.. The overall yield of
diospyrin (1) was 19% based on 2 (5 steps) or 9% based on
7 (9 steps).
In conclusion, the first and unambiguous synthesis of di-
ospyrin was achieved and its structure was firmly estab-
lished as 1. It should be added that the leishmanicidal activ-
ity of synthetic diaryl(heteroaryl)ethanes was reported
very recently.[27]
Experimental Section
General: Boiling points: Uncorrected values. – Melting points: Yan-
aco MP-S3, Uncorrected values. – MS: Hitachi M-80B. – IR: Jasco
A-102. – UV/Vis: Shimadzu MPS-2000. – 1H NMR: Jeol JNM-EX
90A (90 MHz), Jeol JNM–LA 500 (500 MHz) (TMS at δ ϭ 0.00,
CHCl3 at δ ϭ 7.26 as internal standard). – 13C NMR: Jeol JNM–
LA 400 (100 MHz) (TMS at δ ϭ 0.00, CDCl3 at δ ϭ 77.0 as an
internal standard), Jeol JNM–LA 500 (125 MHz) (TMS at δ ϭ
0.00, CDCl3 at δ ϭ 77.0 as an internal standard).
2-Bromo-5-hydroxy-7-methyl-1,4-naphthoquinone (4): The known 1-
methoxy-3-methyl-1-trimethylsilyloxy-1,3-butadiene (2) was pre-
pared from senecioic acid.[20] To a solution of 2,5-dibromo-1,4-
benzoquinone (3, 12.8 g, 48.1 mmol) in 80 mL of dry THF at 0 °C
under argon was added a solution of 2 (9.87 g, 53.0 mmol) in
45 mL of dry THF dropwise from a syringe pump over 1 h. The
resulting solution was stirred at room temperature for 5 h and then
concentrated under reduced pressure. The residue was chromato-
graphed on silica gel and then recrystallized from hexane/ethyl
acetate to afford 5.62 g (44%) of 4 as orange red needles, m.p.
132.0–133.5 °C. – IR (KBr): ν˜max ϭ 3060 cm–1 (w, C–H), 1670 (m,
CϭO), 1630 (s, CϭO), 1580 (m, Ar), 1560 (m, Ar). – 1H NMR
(90 MHz, CDCl3): δ ϭ 2.44 (br s, 3 H, 7-Me), 7.11 (br s, 1 H, 8-
H), 7.45 (s, 1 H, 3-H), 7.54 (br s, 1 H, 6-H), 11.71 (s, 1 H, 5-OH). –
13C NMR (100 MHz, CDCl3): δ ϭ 22.2, 112.6, 122.4, 124.8, 130.4,
140.4, 140.5, 148.5, 161.9, 177.5, 186.9. – C11H7BrO3 (267.1): calcd.
C 49.47, H 2.64; found C 49.66, H 2.66.
Scheme 2. Synthesis of diospyrin (1); reagents: (a) THF, room
temp. (44%); (b) MeI, Ag2O, reflux (quant. for 5; 55% for 11 based
on 8); (c) SnCl2, conc. HCl, EtOH (97%); (d) MeI, NaH, DMF
(93% for 6; 92% for 13); (e) LDA, TMSCl, THF (65%); (f) i)
CH2Cl2, room temp.; ii) 1  HCl, MeOH; (g) nBuLi, THF,
B(OMe)3, –78 °C ഠ room temp. (66%); (h) Pd(PPh3)4, Na2CO3 aq.,
EtOH, toluene, reflux (53%); (i) Ce(NH4)2(NO3)6, MeCN, H2O
(quant.); (j) AlCl3, CH2Cl2 (82%).
The obvious alternative approach was to employ Suzuki
coupling,[15,23] whose application in the synthesis of phy-
toalexin was recently reported by us.[24] The desired boronic
acid 14 was prepared by lithiation of 13 and subsequent
reaction with trimethyl borate. By washing out the accom-
panying impurities with hot hexane, 14 could be obtained
in 66% yield. The coupling of 14 with 6 in the presence of
tetrakis(triphenylphosphane)palladium(0), however, failed
under the conditions using four different bases (sodium car-
2-Bromo-5-methoxy-7-methyl-1,4-naphthoquinone (5): A mixture of
4 (4.00 g, 15.0 mmol), powdered Ag2O (5.22 g, 22.5 mmol), and
methyl iodide (80 mL) was stirred and heated under reflux for 1 h.
The mixture was then filtered through Celite and the filter cake
bonate, barium hydroxide, cesium carbonate and potassium was washed with chloroform. The filtrate and the washings were
1314 Eur. J. Org. Chem. 2000, 1313Ϫ1317

Synthesis of Diospyrin, a Potential Agent Against Leishmaniasis
FULL PAPER
combined and evaporated to afford 4.25 g (quant.) of 5 as a yellow
solid. The crude product was used in the next reaction without
further purification. An analytical sample of 5 was obtained by
recrystallization from hexane/chloroform as yellow needles, m.p.
168.5–170.0 °C. – IR (KBr): ν˜max ϭ 3100 cm–1 (w, C–H), 3020 (w,
C–H), 3000 (w, C–H), 2950 (w, C–H), 2850 (w, C–H), 1665 (s, Cϭ
O), 1640 (s, CϭO), 1600 (s, Ar). – 1H NMR (90 MHz, CDCl3):
δ ϭ 2.48 (br s, 3 H, 7-Me), 3.99 (s, 3 H, 5-OMe), 7.12 (br s, 1 H,
8-H), 7.36 (s, 1 H, 3-H), 7.63 (br s, 1 H, 6-H). – 13C NMR
(100 MHz, CDCl3): δ ϭ 22.3, 56.5, 117.0, 118.8, 121.5, 132.8,
136.6, 142.4, 146.7, 160.1, 178.5, 181.3. – C12H9BrO3 (281.11):
calcd. C 51.27, H 3.23; found C 51.29, H 3.24.
1 H, 4cis-H), 5.18 (br s, 1 H, 4trans-H). This oil was employed
immediately for the next step.
6-Bromo-5-hydroxy-7-methyl-1,4-naphthoquinone (10): To a solu-
tion of 8 (13.2 g, 47.4 mmol) in 300 mL of dry dichloromethane at
room temperature under argon was added 1,4-benzoquinone (9,
10.2 g, 94.8 mmol). The resulting solution was stirred at room tem-
perature for 12 h, concentrated under reduced pressure, and the
residue was dissolved in 300 mL of methanol. After addition of 1
 HCl (4 mL), the solution was stirred for 1 h at 0 °C, and again
concentrated under reduced pressure. The residue was dissolved in
chloroform and ethyl acetate, dried with MgSO4 and concentrated
under reduced pressure. The residue was chromatographed on silica
gel (500 g, hexane/ethyl acetate 30:1) to afford 7.06 g (56%) of a
mixture of 10 and 11 as an orange/red solid. The crude product
was used in the next reaction without further purification. – 1H
NMR (90 MHz, CDCl3): δ ϭ 2.56 (s, 3 H, 7-Me), 6.95 (s, 2 H, 2-
H, 3-H), 7.52 (s, 1 H, 8-H), 12.64 (s, 1 H, 5-OH).
2-Bromo-1,5,8-trimethoxy-3-methylnaphthalene (6): To a stirred sus-
pension of 5 (2.00 g, 7.11 mmol) in ethanol (80 mL) at 50 °C was
added a solution of tin(II) chloride (4.72 g, 24.9 mmol) in concen-
trated HCl (5.0 mL). After 30 min at the same temperature, it was
then poured into cold water (300 mL). The precipitated product
was collected by filtration and washed with water. The resulting
crude product (1.94 g, 97%), isolated as a white solid, was used in
6-Bromo-5-methoxy-7-methyl-1,4-naphthoquinone (11): A mixture
of 10 and 11 (7.06 g), powdered Ag2O (9.18 g, 39.6 mmol), and
methyl iodide (120 mL) was stirred and heated under reflux for 1 h.
The mixture was then filtered through Celite and the filter cake
was washed with chloroform. The filtrate and the washings were
combined and evaporated to afford 7.29 g (55% from 8) of 11 as a
yellow solid. The crude product was used in the next reaction with-
out further purification. An analytical sample of 11 was obtained
by recrystallization from hexane/chloroform as a yellow solid, m.p.
152.0–153.5 °C. – IR (KBr): ν˜max ϭ 3050 cm–1 (w, C–H), 3000 (w,
C–H), 2950 (w, C–H), 2860 (w, C–H), 1665 (s, CϭO), 1610 (m,
the next reaction without further purification. – IR (KBr): ν˜max
ϭ
3360 cm–1 (br s, OH), 3020 (w, C–H), 2970 (w, C–H), 2950 (w, C–
H), 2840 (w, C–H), 1625 (m, Ar), 1605 (s, Ar). – 1H NMR
(90 MHz, CDCl3): δ ϭ 2.49 (s, 3 H, 7-Me), 4.04 (s, 3 H, 5-OMe),
5.45 (s, 1 H, 1-OH or 4-OH), 6.67 (br s, 1 H, 8-H), 6.85 (s, 1 H, 3-
H), 7.59 (br s, 1 H, 6-H), 8.90 (s, 1 H, 4-OH or 1-OH).
To a stirred suspension of sodium hydride (60% dispersion in min-
eral oil, 297 mg, 7.41 mmol) in DMF (30 mL) at room temperature
under argon was added a solution of the reduction product
(700 mg, 2.47 mmol) in DMF (10 mL). The mixture was stirred at
room temperature for 45 min. After cooling to 0 °C, methyl iodide
(0.46 mL, 7.41 mmol) was added and the resulting mixture was
stirred at room temperature for 6 h. It was then diluted with chloro-
form. The chloroform solution was washed with water and brine,
dried with MgSO4, and concentrated under reduced pressure. The
residue was chromatographed on silica gel (40 g, hexane/ethyl acet-
ate 10:1) to afford 718 mg (93%) of 6 as a colorless solid. An analyt-
ical sample of 6 was obtained by recrystallization from hexane as
colorless needles, m.p. 95.0–96.0 °C. – IR (KBr): ν˜max ϭ 3000
cm–1 (w, C–H), 2950 (w, C–H), 2930 (w, C–H), 2840 (w, C–H),
1620 (m, Ar), 1585 (s, Ar). – 1H NMR (90 MHz, CDCl3): δ ϭ 2.50
(s, 3 H, 7-Me), 3.91 (s, 6 H, 4-OMe, 5-OMe), 3.95 (s, 3 H, 1-OMe),
6.72 (br s, 1 H, 8-H), 6.83 (s, 1 H, 3-H), 7.46 (br s, 1 H, 6-H). –
13C NMR (100 MHz, CDCl3): δ ϭ 22.2, 56.4, 56.7, 61.1, 108.8,
108.9, 112.7, 113.8, 115.7, 131.7, 137.7, 146.2, 153.8, 157.3. –
C14H15BrO3 (311.2): calcd. C 54.04, H 4.86; found C 54.18, H 4.80.
1
Ar), 1575 (s, Ar). – H NMR (90 MHz, CDCl3): δ ϭ 2.56 (s, 3 H,
7-Me), 3.93 (s, 3 H, 5-OMe), 6.89 (s, 2 H, 2-H, 3-H), 7.80 (s, 1 H,
8-H). – 13C NMR (100 MHz, CDCl3): δ ϭ 24.4, 61.5, 122.7, 124.6,
130.1, 131.7, 136.7, 140.3, 146.7, 156.9, 183.3, 184.6. – C12H9BrO3
(281.1): calcd. C 51.27, H 3.23; found C 51.34, H 3.16.
6-Bromo-5-methoxy-7-methyl-1,4-naphthalenediol (12): To a stirred
suspension of 11 (4.02 g, 14.3 mmol) in ethanol (160 mL) at 50 °C
was added a solution of tin(II) chloride (9.45 g, 50.1 mmol) in con-
centrated HCl (10.0 mL). After 30 min at the same temperature, it
was poured into cold water (600 mL). The precipitated product was
separated by filtration and washed with water. The resulting crude
product 12 (3.94 g, 97%) was obtained as a white solid and was
used in the next reaction without further purification. – IR (KBr):
ν˜max ϭ 3420 cm–1 (s, OH), 3380 (s, OH), 3275 (s, OH), 3000 (w, C–
H), 2950 (w, C–H), 2850 (w, C–H), 1630 (m, Ar), 1600 (s, Ar). –
1H NMR (90 MHz, CDCl3): δ ϭ 2.57 (d, J ϭ 0.8 Hz, 3 H, 7-Me),
4.04 (s, 3 H, 5-OMe), 6.73 (s, 2 H, 2-H, 3-H) 7.86 (d, J ϭ 0.8 Hz,
1 H, 8-H), 8.86 (s, 1 H, -OH).
2-Bromo-1-methoxy-3-methyl-1-trimethylsilyloxy-1,3-butadiene (8):
The known methyl 2-bromo-senecioate (7) was prepared from sene-
cioic acid.[21] A solution of lithium diisopropylamide (LDA) was 2-Bromo-1,5,8-trimethoxy-3-methylnaphthalene (13): To a stirred
prepared from 13.1 mL (93.2 mmol) of diisopropylamine in 120 mL
of dry THF and 37.0 mL of a 2.52  solution of n-butyllithium in
hexane. The LDA solution was cooled to –78 °C and a solution of
suspension of sodium hydride (60% dispersion in mineral oil,
1.72 g, 42.9 mmol) in DMF (160 mL) at room temperature under
argon was added a solution of 12 (3.94 g, 13.9 mmol) in DMF
7 (15.0 g, 77.7 mmol) in 90 mL of dry THF was added dropwise (40 mL). The mixture was then stirred at room temperature for
over 1 h. The mixture was stirred for 0.5 h at the same temperature
and trimethylsilyl chloride (11.8 mL, 93.2 mmol) was then added.
The temperature was allowed to rise to room temperature, stirring
was continued for 2 h, the solvent was then removed under reduced
pressure, and the residue redissolved in hexane. The solution was
filtered to remove the precipitated LiCl, the solvent removed from
the filtrate in vacuo, and the residue distilled to afford 14.1 g (65%)
of 8 as a colorless oil, b.p. 54.0–56.0 °C/1.5 Torr. – IR (film): ν˜max ϭ
1615 cm–1. – 1H NMR (90 MHz, CDCl3): δ ϭ 0.24 (s, 9 H, 1-
OTMS), 1.95 (s, 3 H, 3-Me), 3.65 (s, 3 H, 1-OMe), 5.00–5.12 (m,
45 min. After cooling to 0 °C, methyl iodide (2.60 mL, 41.7 mmol)
was added and the resulting mixture was stirred at room temper-
ature for 12 h. It was then diluted with chloroform, washed with
water and brine, dried with MgSO4, and concentrated under re-
duced pressure. The residue was chromatographed on silica gel
(200 g, hexane/ethyl acetate 10:1) to afford 4.08 g (92% based on
11) of 13 as a colorless solid. An analytical sample of 13 was ob-
tained by recrystallization from hexane as colorless needles, m.p.
123–125 °C. – IR (KBr): ν˜max ϭ 3000 cm–1 (w, C–H), 2950 (w, C–
H), 2910 (m, C–H), 2850 (m, C–H), 1620 (m, Ar), 1590 (s, Ar). –
Eur. J. Org. Chem. 2000, 1313Ϫ1317
1315

M. Yoshida, K. Mori
1H NMR (90 MHz, CDCl3): δ ϭ 2.56 (s, 3 H, 3-Me), 3.88 (s, 3 H, The extract was washed with brine, dried with MgSO4, and evapor-
FULL PAPER
1-OMe),3.94 (s, 6 H, 5-OMe, 8-OMe), 6.73 (s, 2 H, 6-H, 7-H), 7.92
(s, 1 H, 4-H). – 13C NMR (125 MHz, CDCl3): δ ϭ 24.0, 55.8,
57.1, 61.6, 104.2, 106.5, 118.8, 120.29, 120.32, 127.2, 136.4, 149.20,
149.25, 152.9. – C14H15BrO3 (311.2): calcd. C 54.04, H 4.86; found
C 54.01, H 4.77.
ated to afford 352 mg (quant.) of 16 as a yellow solid. The crude
product was used in the next reaction without further purification.
An analytical sample of 16 was obtained by recrystallization from
petroleum ether/dichloromethane as yellow needles, m.p. 256–
258°C (ref.[3] 256 °C). – IR (KBr): ν˜max ϭ 3050 cm–1 (w, C–H),
3000 (w, C–H), 2950 (w, C–H), 2850 (w, C–H), 1655 (s, CϭO),
1630 (m, CϭO), 1600 (s, Ar), 1580 (s, Ar), 1455 (m), 1405 (w), 1350
(m), 1335 (m), 1305 (s), 1290 (m), 1280 (m), 1260 (s, C–O), 1165
(w), 1135 (w), 1100 (m), 1075 (w), 1050 (s, C–O), 855 (m). – 1H
NMR (90 MHz, CDCl3): δ ϭ 2.30 (d, J ϭ 0.7 Hz, 3 H, 7Ј-Me),
2.50 (s, 3 H, 7-Me), 3.69 (s, 3 H, 5Ј-OMe), 4.03 (s, 3 H, 5-OMe),
6.77 (s, 1 H, 3-H), 6.89 (s, 1 H, 2Ј-H or 3Ј-H), 6.90 (s, 1 H, 3Ј-H
or 2Ј-H), 7.16 (br s, 1 H, 6-H), 7.57–7.63 (m, 1 H, 8-H), 7.84 (d,
J ϭ 0.7 Hz, 1 H, 8Ј-H). – 13C NMR (125 MHz, CDCl3): δ ϭ 20.8,
22.4, 56.5, 62.5, 117.7, 118.5, 120.7, 121.6, 124.4, 133.6, 133.9,
135.9, 136.7, 139.9, 140.5, 143.4, 144.8, 146.8, 158.1, 159.9, 183.3,
183.7, 184.1, 184.8. – C24H18O6 (402.4): calcd. C 71.63, H 4.51;
found C 71.35, H 4.38.
1,5,8-Trimethoxy-3-methylnaphthalene-2-boronic Acid (14): A solu-
tion of 13 (1.90 g, 6.11 mmol) in dry THF (200 mL) under argon
was cooled to –78 °C. Over the course of 10 min, a 1.54  solution
of n-butyllithium in hexane (4.36 mL, 6.72 mL) was added, and
the reaction mixture was stirred for 1 h to give a yellow solution.
Trimethyl borate (3.43 mL, 30.6 mmol) was then added, and the
reaction mixture was allowed to warm to room temperature for
about 12 h. The mixture was diluted with water (100 mL), and ex-
tracted with dichloromethane. The combined organic extracts were
dried with MgSO4 and concentrated under reduced pressure. The
residue was refluxed with hexane and the insoluble residue was
collected on a filter to give 14 (1.11 g, 66%) as a white solid, m.p.
122–124 °C. – IR (KBr): ν˜max ϭ 3340 cm–1 (s, OH), 3000 (m, C–
H), 2970 (m, C–H), 2950 (m, C–H), 2850 (m, C–H), 1625 (s, Ar), 2,6Ј-Bis(5-hydroxy-7-methyl-1,4-naphthoquinone) (1) [Diospyrin]: To
1
1600 (s, Ar), 1580 (s, Ar). – H NMR (90 MHz, CDCl3): δ ϭ 2.60
a solution of 16 (50.0 mg, 0.12 mmol) in dry dichloromethane
(s, 3 H, 3-Me), 3.85 (s, 3 H, 1-OMe), 3.95 (s, 6 H, 5-OMe, 8-OMe), (10 mL) at room temperature under argon was added aluminum
5.90 [s, 2 H, B(OH)2], 6.71 (s, 2 H, 6-H, 7-H), 7.92 (s, 1 H, 4-H). –
trichloride (628 mg, 4.71 mmol). The mixture was stirred at room
13C NMR (125 MHz, CDCl3): δ ϭ 23.2, 55.8, 56.3, 63.8, 104.6, temperature for 24 h, poured into water, then acidified with dil.
104.7, 117.8, 118.8, 129.6, 140.1, 140.4, 149.1, 149.5, 161.3. – HCl, and extracted with chloroform. The extracted was dried with
C14H17BO5 (276.1): calcd. C 60.90, H 6.21; found C 58.60, H 6.01. MgSO4 and concentrated under reduced pressure. The residue was
Due to the hygroscopic nature of 14, correct combustion analytical
data could not be obtained. – C14H17BO5: calcd. 276.1169; found
276.1185 (HRMS).
chromatographed on silica gel and refluxed with acetone. The in-
soluble residue gave 38 mg (82%) of 1 as an orange/red solid. An
analytical sample of 1 was obtained by recrystallization from chlo-
roform as orange plates, m.p. 256–258 °C (ref.[1] 258 °C); authentic
1, m.p. 256–258 °C; mixture m.p. 256–258°C. – EI-MS (70 eV); m/z
(%): 374 (100)[Mϩ], 359 (16), 357 (11), 356 (12), 328 (10), 187 (9),
2-(1Ј,4Ј,5Ј-Trimethoxy-7Ј-methylnaphthalen-6Ј-yl)-5-methoxy-7-
methyl-1,4-naphthoquinone (15): To a stirred mixture of Pd(PPh3)4
(124 mg, 0.11 mmol) and 5 (300 mg, 1.07 mmol) in toluene (5 mL)
were added successively an aqueous Na2CO3 solution (2 ,
0.93 mL) and 14 (325 mg, 1.18 mmol) in ethanol (1.3 mL) under
argon. The mixture was refluxed for 3 h with vigorous stirring. The
resulting mixture was extracted with chloroform. The extract was
washed with brine, dried with MgSO4, and concentrated under re-
duced pressure. The residue was chromatographed on silica gel
(20 g, benzene/ethyl acetate 10:1) to afford 245 mg (53%) of 15 as
an orange/red solid. An analytical sample of 15 was obtained by
recrystallization from benzene/ethyl acetate as orange red needles,
m.p. 195.0–196.0 °C. – IR (KBr): ν˜max ϭ 2950 cm–1 (w, C–H), 2840
(w, C–H), 1655 (s, CϭO), 1630 (m, CϭO), 1600 (s, Ar), 1460 (m),
1425 (m), 1340 (s), 1300 (m), 1260 (s), 1235 (m), 1110 (m), 1070
(s), 1045 (m). – 1H NMR (90 MHz, CDCl3): δ ϭ 2.27 (d, J ϭ
0.9 Hz, 3 H, 7Ј-Me), 2.49 (s, 3 H, 7-Me), 3.64 (s, 3 H, 5Ј-OMe),
3.92 (s, 3 H, 1Ј-OMe or 4Ј-OMe), 3.96 (s, 3 H, 4Ј-OMe or 1Ј-OMe),
4.03 (s, 3 H, 5-OMe), 6.73 (s, 2 H, 2Ј-H, 3Ј-H), 6.86 (s, 1 H, 3-H),
7.13 (br s, 1 H, 6-H), 7.62 (br s, 1 H, 8-H), 7.93 (d, J ϭ 0.9 Hz, 1
H, 8Ј-H). – 13C NMR (100 MHz, CDCl3): δ ϭ 20.6, 22.4, 55.9,
56.41, 56.44, 62.7, 104.5, 105.0, 118.1, 118.5, 118.8, 120.7, 126.7,
128.3, 128.8, 134.28, 134.34, 139.9, 145.3, 146.3, 149.2, 149.8,
153.7, 159.7, 184.2, 184.8. – C26H24O6 (432.5): calcd. C 72.21, H
5.91; found C 72.35, H 5.96.
163 (8), 135 (10), 134 (10), 106 (13), 99 (10). – IR (KBr): ν˜max
ϭ
3350 cm–1 (br w, C–H), 1670 (m, CϭO), 1645 (s, CϭO), 1610 (m,
Ar), 1595 (m, Ar), 1385 (m), 1360 (m), 1335 (m), 1260 (s, C–O),
1210 (m), 1090 (m), 1050 (w), 855 (m). – UV/Vis (MeOH): λmax
(log ε) ϭ 252 nm (4.34), 432 (3.90); (ϩNaOH) 260, 546. – 1H NMR
(500 MHz, CDCl3): δ ϭ 2.31 (s, 3 H, 7Ј-Me), 2.46 (s, 3 H, 7-Me),
6.90 (s, 1 H, 3-H), 6.96 (s, 2 H, 2Ј-H, 3Ј-H), 7.13 (s, 1 H, 6-H), 7.51
(s, 1 H, 8-H), 7.57 (s, 1 H, 8Ј-H), 11.88 (s, 1 H, 5-OH), 12.14 (s, 1
H, 5Ј-OH). – 13C NMR (100 MHz, CDCl3): δ ϭ 21.1, 22.3, 113.0,
113.2, 120.8, 121.3, 124.3, 128.9, 131.4, 131.6, 138.81, 138.84,
139.5, 145.8, 146.5, 148.7, 159.2, 161.7, 182.6, 184.1, 188.9, 189.8. –
C22H15O6 H2O (392.4): calcd. C 67.35, H 4.11; found C 67.24, H
4.09. – C22H15O6: calcd. 374.0790; found 374.0806 (HRMS).
Acknowledgments
Our thanks are due to Dr. B. Hazra (Jadapur University, Calcutta)
for discussions and also for her kind gift of the natural diospyrin.
We thank Mr. K. Mochizuki for his early attempts to prepare 1 by
the Stille reaction. We acknowledge the financial support of this
work by a Grant-in-Aid for Scientific Research (No. 11480165)
from the Japanese Ministry of Education, Science, Sports and Cul-
ture.
2,6Ј-Bis(5-methoxy-7-methyl-1,4-naphthoquinone) (16): A suspen-
sion of 15 (378 mg, 0.87 mmol) in a mixture of acetonitrile (25 mL)
and water (10 mL) was cooled to 0 °C. Over the course of 10 min,
a cooled solution of ceric ammonium nitrate (1.44 g, 2.62 mmol)
in a mixture of acetonitrile (15 mL) and water (15 mL) was added
to the suspension. The reaction mixture was stirred at 0 °C for
20 min, and allowed to warm to room temperature over 30 min.
The mixture was diluted with water, and extracted with chloroform.
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