Synthesis of naturally occurring naphthoquinone epoxides and application in the synthesis of β-lapachone

Article abstract of DOI:10.1039/c004580b

Optimized epoxidation conditions of mono- and dialkylated naphthoquinones are presented. Based on the epoxidation protocol making use of H ₂O₂/Na₂CO₃, naphthoquinone epoxides are obtained in high yields. The optimized epoxidation conditions are applied in a short and high yielding synthesis of the pharmaceutically important β-lapachone.

Full text of DOI:10.1039/c004580b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of naturally occurring naphthoquinone epoxides and application in
the synthesis of b-lapachone
Sven Claessens, Pascal Habonimana and Norbert De Kimpe*
Received 24th March 2010, Accepted 28th May 2010
First published as an Advance Article on the web 24th June 2010
DOI: 10.1039/c004580b
Optimized epoxidation conditions of mono- and dialkylated naphthoquinones are presented. Based on
the epoxidation protocol making use of H2O2/Na2CO3, naphthoquinone epoxides are obtained in high
yields. The optimized epoxidation conditions are applied in a short and high yielding synthesis of the
pharmaceutically important b-lapachone.
has additionally an anti-growth activity against human colon
Introduction
carcinoma.4 Phosphatoquinone A 4, an antibiotic produced
Quinones and quinone epoxides have been shown to exhibit im-
by Streptomyces sp., is a potent protein-tyrosine phosphatase
inhibitor, an immunosuppressant and an allergy inhibitor.5 2,3-
Epoxynaphthomevalin A80915G 5 is a member of the napyra-
diomycin family of antibiotics, isolated from the culture broth of
Chainia rubra MG802-AF1, which inhibits the growth of gram-
positive bacteria including drug-resistant strains.6 b-Lapachone 6
(Fig. 1) is an orthoquinone which has been isolated from the heart-
wood of the tropical tree Tabebuia avellanedae (Bignoniaceae)
and related species.7,8 b-Lapachone 6 has been reported to exhibit
antimicrobial activity.9 b-Lapachone 6 was found to be cytotoxic
to a variety of human cancers.10 b-Lapachone 6 has recently
been under investigation for the treatment of specific cancers
associated with elevated NQO1 levels, such as breast, non-small
cell lung, pancreatic, colon, and prostate cancers,11 and is currently
portant biological activities and play an essential role in metabolic
processes.1 The class of quinone epoxides shows important family
members from which natural products 1 to 5 are examples (Fig. 1).
Epoxide 1 has been isolated from rubiaceous herbs and is
believed to be an intermediate of mollugin biosynthesis.2 2-(3-
Methylbut-2-enyl)-2,3-epoxy-1,4-naphthoquinone or deoxylapa-
chol epoxide 2 has been shown to exhibit antifungal, antimicrobial,
anti-inflammatory, antiparasitic, anticancer and molluscicidal
activities.3 2,3-Epoxysesamone 3 has been isolated from Sesamum
indicum (Pedaliaceae) and is an antifungal metabolite which
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent
University, Coupure links 653, B-9000, Ghent, Belgium
Fig. 1 Important naphthoquinone epoxides.
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in phase II clinical trials for the treatment of pancreatic cancer.12
Particularly promising is the synergistic lethality of b-lapachone
with taxol13 and genistein14 on several tumour cell lines implanted
into mice. Furthermore, b-lapachone 6 has in vitro activity against
Chagas’ disease, caused by Trypanosoma cruzi, a parasite infecting
about eight million South Americans every year.15 In the present
research, optimized conditions to obtain quinone epoxides are
investigated and an application of these quinone epoxides in the
synthesis of b-lapachone 6 is presented.
The best conditions for the epoxidation of vitamin K2(1) 9
to afford vitamin K2(1) epoxide 11 were found to be using 6
equivalents of 30% H2O2 and 1.5 equivalents of Na2CO3 and
heating in ethanol at 45 ◦C. 2,3-Diprenyl-1,4-naphthoquinone 10
was epoxidized to 12 in 78% yield with 9 equivalents of 30% aq.
H2O2 and 2.35 equivalents of Na2CO3 in ethanol at 45 ◦C.
Mechanistically, 1,4-naphthoquinones can be considered as
electron-deficient olefins and their 2,3-epoxidation can be com-
pared with epoxidation of a,b-unsaturated ketones. The Michael
addition of the hydroperoxide anion (HOO-) to a carbon-carbon
double bond of 1,4-quinones is of second order kinetics and is
influenced by electronic and steric effects. Electron-donating or
bulky substituents such as alkyl groups at C-2 and/or C-3 tend
to decrease the rate of epoxidation.21 On the contrary, transition-
state-stabilizing substituents such as phenyl and carbonyl moieties
at the 2- and/or 3-positions tend to increase the rate of nucleophilic
epoxidation.22 The observation that the epoxidation gave different
yields in acetone as compared to ethanol is ascribed to solubility
issues of naphthoquinone and not through in situ formation of
dimethyldioxirane (DMDO) in acetone. Formation of DMDO
should result in epoxidation of olefinic double bonds which is
not occurring. Alternatively, the formation of percarbonate by
reaction of sodium carbonate with hydrogen peroxide must be
taken into account. However the literature reveals that in aqueous
solutions this equilibrium reaction is in favor of the dissociated
carbonate and hydrogen peroxide.23
Results and discussion
Screening of the literature shows that epoxidation of 1,4-quinones
has been carried out using the urea-hydrogen peroxide complex
(H2NCONH2·H2O2, UHP).16 This system has some advantages
such as easy handling and easy workup. However, this system
has been reported to provide only good yields in reactions with
non-substituted 1,4-naphthoquinones.17
2,3-Dialkyl-2,3-epoxy-1,4-naphthoquinones can be prepared
by NaOCl/pyridine epoxidation18 whereas monoalkyl-substituted
2,3-epoxy-1,4-naphthoquinones can be prepared by an epox-
idation with NaOCl/dioxane.19 The method by Fieser20 and
the method by Jacobsen and Torssell18b focus on the use of
the environmentally benign system H2O2/Na2CO3/H2O. This
epoxidation protocol was the starting point of our investigation
towards the optimized conditions for the synthesis of novel phys-
iologically important mono- and disubstituted naphthoquinone
epoxides.
As an application of these synthesized quinone epoxides, a high
yielding synthesis of the interesting anticancer natural product
b-lapachone 6 was achieved making use of the above mentioned
epoxidation reaction to form 2,3-epoxydeoxylapachol 2.
The method by Fieser,20 using hydroge◦n peroxide in ethanol at
◦
40 C for 5 min, instead of acetone at 0 C, gave only 10% yield
of the targeted natural product and lots of degradation products
probably due to further reactions of the formed naphthoquinone
epoxide at higher temperatures (Scheme 1).
The method by Jacobsen and Torssell,18b using 3 equivalents of
30% aq. H2O2 and 1.5 equivalents of Na2CO3 in acetone at 0 ◦C
for 40 min, rendered possible the preparation of compound 1 only
in 30% along with unreacted starting material.
Subsequently, it was found that the yield of the epoxidation
could be increased to 80% by reaction of quinone 7 with 6
equivalents of aq. 30% H2O2 and 1.5 equivalents of Na2CO3 in
acetone and keeping the reaction at 0 ◦C for 40 min.
Epoxidation of deoxylapachol 8 under the aforementioned con-
ditions using 3 equivalents of aq. 30% H2O2 in the presence of 1.5
equivalents of Na2CO3 in acetone at 0 ◦C for 40 min gave a better
result of the deoxylapachol epoxide 2 as compared to epoxidation
of compound 1 (68% vs. 30% yield), presumably because of
lower steric hindrance. By the reaction of deoxylapachol 8 with
6 equivalents of aq. 30% H2O2 and 1.5 equivalents of Na2CO3 in
acetone at 0 ◦C for 40 min, deoxylapachol epoxide 2 was obtained
in 82% yield. These conditions are an improvement of the existing
method in which deoxylapachol epoxide 2 was obtained using 30%
hydrogen peroxide and aqueous sodium hydroxide in toluene in a
yield of 53%.21
Applying the above reaction conditions for the epoxidation of
2,3-dialkyl-1,4-naphthoquinones 9 and 10, using 6 equivalents of
aq. 30% H2O2 and 1.5 equivalents of Na2CO3 in acetone at 0 ◦C,
resulted only in starting materials, even after two hours. This result
is explained by the electron-donating properties and bulkiness of
alkyl groups which hamper the reaction.21
b-Lapachone 6 has already been synthesized in an eight-step
sequence starting from a-naphthol with an overall yield of 23%.15
Treatment of lapachol 13 with H2SO4 in water has been
shown to yield 39% of b-lapachone 6 together with 34% of the
isomeric a-lapachone 14 (Scheme 2).24 Another report has shown
that microwave irradiation of lapachol 13 in the presence of
montmorillonite clay K10 provided 10% yield of b-lapachone 6
and 70% yield of a-lapachone 14.25 Drawbacks of these methods
are the limited availability of lapachol 13, which is obtained in
40% yield starting from 2-hydroxy-1,4-naphthoquinone,26 and the
formation of mixtures of a-lapachone 14 and b-lapachone 6.
It was reasoned that the reaction of deoxylapachol epoxide 2
with sulfuric acid would lead selectively to b-lapachone 6 without
the formation of a-lapachone 14, if the olefinic double bond
is faster activated then the epoxide. Therefore, deoxylapachol
epoxide 2 was reacted with 15 equivalents of 96% H2SO4, in acetic
acid at room temperature for 20 min which cleanly resulted, after
aqueous workup, in the formation of b-lapachone 6 in an excellent
isolated yield (90%) (Scheme 3).
Mechanistically, two possible routes leading to b-lapachone 6
can be considered (Scheme 4). In route A, the olefinic double bond
is first activated. As previously encountered in the synthesis of the
natural product mollugin,2a this activation easily leads to pyran
ring closure with formation of benzochromene intermediate 16.
Subsequently, rearrangement of the epoxide occurs, which leads
after keto-enol tautomerism to b-lapachone 6. Evidence for the
rearrangement of the epoxide is found in the related rearrangement
of a,b-epoxy-ketones to 1,2-diketones under acidic conditions.27
An alternative mechanism (Route B) starts with the activation
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Scheme 1
of the epoxide and subsequent rearrangement towards lapachol
Conclusion
13. Next, the olefinic double bond is activated by protonation,
resulting in pyran ring formation. However, from earlier reports
it is known that lapachol 13 under acidic conditions leads to
the formation of a mixture of a-lapachone 14 and b-lapachone
6. Therefore, the observation that no a-lapachone 14 and no
lapachol 13 was traced back in the reaction mixture, leads to the
conclusion that route A was most probably followed. In this way,
a very short, high yielding and selective synthesis of the important
natural product b-lapachone 6 was established.
The
synthesis
of
3-(3-methylbut-2-enyl)-2,3-epoxy-1,4-
naphthoquinone-2-carboxylate 1 was achieved for the first
time via a high yielding epoxidation of the corresponding
naphthoquinones using hydrogen peroxide as oxidant in acetone at
0 ◦C in the presence of Na2CO3. 2,3-Dialkyl-1,4-naphthoquinones
resisted epoxidation with hydrogen peroxide in acetone at low
temperature. However, 2,3-dialkyl-1,4-naphthoquinone epoxides
are obtained in high yield at 45 ◦C in ethanol, using an increased
3792 | Org. Biomol. Chem., 2010, 8, 3790–3795
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Scheme 2
resulting mixture was extracted with ethyl acetate, washed 3 times
with water, dried (MgSO4) and the solvent removed in vacuo.
Purification by chromatography (petroleum ether/ethyl acetate
9/1) afforded 0.44 g of methyl 3-(3-methyl-but-2-enyl)-2,3-epoxy-
1,4-naphthoquinone-2-carboxylate 1 (80%).
Methyl 3-(3-methyl-but-2-enyl)-2,3-epoxy-1,4-naphthoquinone-
2-carboxylate 1. 1H NMR (CDCl3, 300 MHz) d: 1.70 (6H, s, 2 ¥
CH3), 2.54 (1H, dd, J = 15.3 Hz, J = 6.4 Hz, CHaHb), 3.02 (1H, dd,
J = 15.3 Hz, J = 7.7 Hz, CHaHb), 3.93 (3H, s, OCH3), 5.14 (1H,
m, CH), 7.77 (2H, m, 2 ¥ CHar), 8.02 (2H, m, 2 ¥ CHar). 13C NMR
(CDCl3, 75 MHz) d: 18.2 (CH3), 25.9 (CH3), 26.2 (CH2), 53.2
(OCH3), 66.5 (Cquat), 115.5 (CH2–CH), 127.4 (CHar), 127.8 (CHar),
131.8 (Cquat), 131.8 (Cquat), 134.7 (CHar), 135.1 (CHar), 136.8 (Cquat),
Scheme 3
amount of hydrogen peroxide. A high yielding, straightforward
and selective synthesis of b-lapachone 6 was described by reaction
of deoxylapachol epoxide 2 with conc. sulfuric acid in acetic
acid. A mechanism of this rearrangement via initial pyran
ring formation was proposed based on the observance that
no a-lapachone 14 and no lapachol 13 were isolated from the
reaction mixture.
=
=
163.8 (COOMe), 187.5 (C O), 189.0 (C O). IR (NaCl) nmax: 1758
+
+
=
=
(C O), 1698 (C O). MS (ES ) m/z (%): 301 (M+H , 100). Anal.
Calcd for C17H16O5: C, 67.99; H, 5.37. Found: C, 70.21; H, 5.48.
2-(3-Methyl-but-2-enyl)-2,3-epoxy-1,4-naphthoquinone 2. 1H
NMR (CDCl3, 300 MHz) d: 1.69 (3H, s, CH3), 1.73 (3H, d, J =
0.8 Hz, CH3), 2.69 (1H, dd, J = 15.4 Hz, J = 6.9 Hz, CHaHb),
3.03 (1H, dd, J = 15.4 Hz, J = 8.0 Hz, CHaHb), 3.85 (1H, s,
Experimental part
1H NMR spectra (300 MHz) and 13C NMR (75 MHz) spectra were
recorded on a Jeol Eclipse FT 300 MHz Spectrometer. IR spectra
were recorded on a Perkin-Elmer Spectrum One Spectrometer.
Mass spectra were recorded on an Agilent 1100 Series VLL mass
Spectrometer (ES 70 eV). Melting points were measured with a
Bu¨chi Melting Point B-540 apparatus. Flash chromatography was
performed with ACROS silica gel (particles size 0.035–0.070, pore
diameter ca 6 nm) using a glass column.
=
OCH) 5.08–5.11 (1H, m, CH2CH ), 7.75 (2H, m, 2 ¥ CHar), 7.92
(CHar), 7.99 (CHar). 13C NMR (CDCl3, 75 MHz) d: 18.1 (CH3),
=
25.9 (CH3), 26.2 (CH2), 59.1 (OCH), 63.6 (Cquat), 115.5 ( CH),
126.8 (CHar), 127.5 (CHar), 132.0 (Cquat), 132.4 (Cquat), 134.1 (CHar),
=
=
134.3 (CHar), 137.2 (Cquat), 191.8 (C O), 192.1 (C O). IR (KBr)
+
+
=
n
max: 1696 (C O). MS (ES ) m/z (%): 243 (M+H , 100). Anal.
Calcd for C15H14O3: C, 74.36; H, 5.82. Found: C, 74.25; H, 6.01.
2-Methyl-3-(3-methyl-but-2-enyl)-2,3
epoxy-1,4-naphthoqui-
The general procedure for epoxidation of naphthoquinones is
exemplified by the synthesis of methyl 3-(3-methyl-but-2-enyl)-2,3-
epoxy-1,4-naphthoquinone-2-carboxylate 1
none 11. 1H-NMR (CDCl3, 300 MHz) d: 1.71 (3H, s, CH3), 1.75
(3H, s, CH3), 1,76 (3H, s, CH3), 2.42 (1H, dd, J = 15.14 Hz,
J = 7.15 Hz, CHaHb), 3.23 (1H, dd, J = 15.14 Hz, J = 7.15 Hz,
=
A
mixture
of
methyl
3-(3-methyl-but-2-enyl)-1,4-
(0.52 g, 1.83 mmol) in
CHaHb), 5.10 (1H, m, CH), 7.71 (2H, m, 2 ¥ CHar), 7.95 (2H,
naphthoquinone-2-carboxylate
7
m, 2 ¥ CHar). 13C NMR (CDCl3, 75 MHz) d: 11.9 (CH3), 18.2
acetone (15 ml) and aqueous Na2CO3 (0.39 g, 2.74 mmol,
4 ml H2O) was cooled at 0 ◦C, then 30% aq. H2O2 (1.25 ml,
10.98 mmol) was slowly added by syringe. The reaction mixture
was allowed to stir at 0 ◦C for 40 min. H2O2 was quenched by
adding an equivalent amount of 1 M aq. Na2S2O3 (11 ml). The
(CH3), 25.7 (CH2), 25.9 (CH3), 65.1 (C–O), 67.5 (C–O), 117.0
=
( CH), 127.0 (2 ¥ CHar), 132.0 (Cquat), 132.2 (Cquat), 133.9 (CHar),
=
=
134.2 (CHar), 135.5 Cquat), 192.1 (C O), 193.0 (C O). IR (NaCl)
+
+
=
n
max: 1694 (C O). MS (ES ) m/z (%): 257 (M+H , 100). Anal.
Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 75.18; H, 6.47.
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Scheme 4
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2,3-Bis(3-methyl-but-2-enyl)-2,3-epoxy-1,4-naphthoquinone 12.
1H NMR (CDCl3, 300 MHz) d 1.71 (6H, s, 2 ¥ CH3), 1.74 (6H, s,
2 ¥ CH3), 2.62 (2H, dd, J = 15.13 Hz, J = 7.15 Hz, 2 ¥ CHaHb),
3.06 (2H, dd, J = 15.13 Hz, J = 7.15 Hz, 2 ¥ CHaHb), 5.18 (2H,
Pinto, M. C. R. F. Pinto, M. O. F. Goulart and A. E. G. Sant’Ana,
Int. J. Parasitol., 2000, 30, 1199–1202; (f) N. B. Perry, J. W. Blunt and
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m, 2 ¥ CH), 7.70 (2H, m, 2 ¥ CHar), 7.95 (2H, m, 2 ¥ CHar). 13C
=
NMR (CDCl3, 75 MHz) d: 18.2 (2 ¥ CH3), 25.9 (2 ¥ CH2), 26.1 (2 ¥
=
CH3), 67.9 (2 ¥ Cquat), 117.4 (2 ¥ CH), 127.1 (2 ¥ CHar), 132.2
=
(Cquat), 134.2 (2 ¥ CHar), 135.2 (Cquat), 192.5 (C O). IR (NaCl)
+
+
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1184–1189.
=
n
max: 1695 (C O). MS (ES ) m/z (%): 311 (M+H , 100). Anal.
Calcd for C20H22O3: C, 77.39; H, 7.14. Found: C, 77.72; H, 7.43.
8 A. V. Pinto and S. L. De Castro, Molecules, 2009, 14, 4570–4590.
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b-Lapachone 6
2,3-Epoxydeoxylapachol 2 (1.5 g, 6.2 mmol) was dissolved in
glacial acetic acid (10 ml) and concentrated H2SO4 (96%, 10 ml)
was added. The resulting mixture was stirred at room temperature
for 20 min. The reaction mixture was poured into water and
extracted with diethyl ether, washed with 1M sodium hydroxide,
dried over MgSO4 and the solvent was evaporated in vacuo.
Flash chromatography on silica gel with ethyl acetate/petroleum
ether (1/9) afforded b-lapachone 6 (1.2 g) as an orange powder
which crystallizes from petroleum ether/ethyl acetate (1/9) in red
needles. The spectral data (1H NMR, 13C NMR, IR, MS) were in
agreement with tho◦se found in the literature.7,28
mp: 152.2–153.7 C. (Lit.:28 mp: 154–156 ◦C) 1H NMR (CDCl3,
300 MHz) d: 1.47 (6H, s, 2 ¥ CH3), 1.85 (2H, t, J = 6.7 Hz, CH2),
2.57 (2H, t, J = 6.7 Hz, CH2), 7.50 (1H, m, CHar), 7.64 (1H, m,
CHar), 7.81 (1H, m, CHar), 8.06 (1H, m, CHar). 13C NMR (CDCl3,
75 MHz) d: 16.2 (CH2-4), 26.8 (2 ¥ CH2), 61.6 (CH2-3), 79.3
=
=
=
(Cquat), 112.7 (Cquat), 124.1 ( CH), 128.5 ( CH), 130.2 ( Cquat),
13 C. J. Li, Y. Z. Li, A. V. Pinto and A. B. Pardee, Proc. Natl. Acad. Sci.
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=
=
=
=
130.6 ( CH), 132.6 ( Cquat), 134.8 ( CH), 162.0 ( C–O), 178.6
=
=
=
=
(C O), 179.9 (C O). IR (NaCl) nmax: 1694 (C O), 1638 (C O).
MS (ES+) m/z (%): 243 (M+H+, 100). Anal. Calcd for C15H14O3:
C, 74.36; H, 5.82. Found: C, 74.20; H, 5.91.
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Acknowledgements
The authors are indebted to the I.W.T. (Flemish Institute for
Promotion of Scientific – Technological Research in Industry) and
the Burundian Government for financial support.
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