Enantioselective epoxidation of 2-substituted 1,4-naphthoquinones using gem-dihydroperoxides

Article abstract of DOI:10.1016/j.tetlet.2009.05.096

New gem-dihydroperoxides were successfully used for DBU-promoted enantioselective epoxidation of 2-substituted 1,4-naphthoquinones. The corresponding 1,4-naphthoquinone epoxides were obtained in yields up to 97% and ee's up to 82%.

Full text of DOI:10.1016/j.tetlet.2009.05.096

Tetrahedron Letters 50 (2009) 4629–4632
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Tetrahedron Letters
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Enantioselective epoxidation of 2-substituted 1,4-naphthoquinones using
gem-dihydroperoxides
*
*
Alexander Bunge, Hans-Jürgen Hamann , Eve McCalmont, Jürgen Liebscher
Institut für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Straße 2, D-12489 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
New gem-dihydroperoxides were successfully used for DBU-promoted enantioselective epoxidation of 2-
substituted 1,4-naphthoquinones. The corresponding 1,4-naphthoquinone epoxides were obtained in
yields up to 97% and ee’s up to 82%.
Received 23 April 2009
Revised 25 May 2009
Accepted 27 May 2009
Available online 30 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
gem-Dihydroperoxides
Enantioselective epoxidation
1,4-Naphthoquinones
Thujone
Epoxides
1. Introduction
et al. to achieve 51% ee in the epoxidation of Vitamin K3.12 Re-
cently, a hydroperoxide derived from a chiral diketopiperazindione
Enantiomerically pure epoxides are of great importance in or-
ganic chemistry. They are versatile building blocks, for example,
in the synthesis of pharmaceutical and natural products.1 While
a number of different reliable methods exist for the asymmetric
epoxidation of electron-rich alkenes2,3 and electron-deficient
trans-alkenes of the chalcone type,4 enantioselective epoxidations
of quinones are not so abundant. In 1980, Pluim and Wynberg re-
ported the synthesis of optically active epoxynaphthoquinones by
epoxidation with 30% hydrogen peroxide, aqueous sodium hydrox-
ide and benzylquininium chloride as phase-transfer catalyst
(PTC).5 Enantiomeric excesses up to 45% were realized. In a similar
way, Arai et al. achieved up to 76% ee and 47% yield with chincho-
nium phase-transfer catalysts.6 Very recently Berkessel et al. re-
ported the epoxidation of 2-methylnaphthoquinone (Vitamin K3)
using modified cinchona alkaloid phase-transfer catalysts too, but
applying sodium hypochlorite instead of hydrogen peroxide.7 High
enantiomeric excesses (up to 85% ee at 73% yield) were obtained.
In another methodology, Taylor et al. used carbohydrate-de-
rived anomeric hydroperoxides (AHPs) as stoichiometric oxidizing
agents for the asymmetric epoxidation of 2-methylnaphthoqui-
none; a maximum ee of 78% was achieved, however in low yield
(32%).8,9 Chmielewski and co-workers also prepared AHPs and
used them for the same purpose, obtaining 47% ee.10,11 (+)-Nor-
camphor-derived hydroperoxides were employed by Lattanzi
was used in our group in the epoxidation of 1,4-naphthoquinones,
but unsatisfactory ee’s were achieved (maximum 14%).13
gem-Dihydroperoxides (DHPs) have received considerable
interest because of their relevance as peroxidic antimalarial
agents.14–16 Recently, Iskra and co-workers reported a versatile
method for the preparation of DHPs from ketones and H2O2 under
iodine catalysis.17,18 Other methods were described, for example,
by Terent’ev,19 Das20 and Dussault.21 Primary aliphatic gem-DHPs
were not obtained by these methods, but were reported very re-
cently by us.22 In the series of gem-dihydroperoxides cyclo-
hexylidenedihydroperoxide was the only example successfully
used as oxygen source for the epoxidation of
a,b-unsaturated ke-
tones23 and the oxidation of sulfides.24 Optically active DHPs are
rare. All reported examples were derived from steroids (see for
example16,17,25). However, to the best of our knowledge, they have
not been utilized as oxidants. Because of our continued involve-
ment in epoxidation chemistry,26 we became interested in using
enantiomerically pure DHPs as potential oxidants for asymmetric
epoxidation. Herein, we report the synthesis of novel enantiomeri-
cally pure DHPs and the first enantioselective epoxidation using
optically active DHPs.
2. Results and Discussion
Aside from commercially available enantiopure ketones and ke-
tones with a steroidal structure, a good source for naturally occur-
ring and enantiomerically pure starting materials for the synthesis
* Corresponding authors. Tel.: +49 30 2093 7550; fax: +49 30 2093 7552 (J.L.).
E-mail address: liebscher@chemie.hu-berlin.de (J. Liebscher).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.096

4630
A. Bunge et al. / Tetrahedron Letters 50 (2009) 4629–4632
of DHPs is monoterpenones. Thus we prepared dihydroperoxide 2a
from (3R)-3-methylcyclohexanone 1a analogous to Iskra and co-
OOH
OOH
OOH
O
O
workers17 while 2b–e were obtained from cis-verbanone 1b, 5
a-
H2O2
+
O
cholestan-3-one 1c, stanolone 1d, or (ꢀ)-a-thujone 1e and 70%
HOO
CSA
hydrogen peroxide in the presence of camphorsulfonic acid
(CSA), adopting an earlier protocol of ours (Scheme 1, Supplemen-
tary data).22
19%
DHP 2e was obtained in 57% yield from (ꢀ)-a-thujone (1e)
57%
(Scheme 2). Like the other DHPs, it shows distinctive signals in
the NMR spectra, including a signal at 121.4 ppm in the 13C NMR
spectrum and one typical proton signal (intensity two protons) at
9.79 ppm in the 1H NMR spectrum. In addition to the DHP 2e the
bis(hydroperoxy)peroxide 3e was isolated in 19% yield as a mix-
ture of diastereomers as by-product in this reaction (Scheme 2).
By crystallization from ethanol one diastereomer could be isolated
and characterized. In the synthesis of other gem-DHPs 2 only traces
of the bis(hydroperoxyperoxides) were found.
1e
2e
3e
Scheme 2. Transformation of (ꢀ)-
a-thujone 1e into the gem-dihydroperoxide 2e.
conversion. Thus the effect of reaction conditions on the conver-
sion and enantiomeric excess was investigated.
Performing the reaction without the use of 4 Å molecular sieves
resulted in a higher conversion but lower ee (Table 1, entry 8).
Monitoring the reactions by TLC revealed that the reaction mixture
without molecular sieves contained hydrogen peroxide, which
could not be detected when mole sieves were used. We assume
that the hydrogen peroxide is formed by decomposition of the
hemiacetal-like perhydrate 5 which is the primary reaction prod-
uct of dihydroperoxide 2 after transferring one oxygen atom to
naphthoquinone 4 (Scheme 3). The deliberated hydrogen peroxide
competes with the dihydroperoxide 2 for the naphthoquinone 4
but leads to racemic products, that is, it lowers the ee of 6. Obvi-
ously, the hydrogen peroxide can be trapped by the molecular
sieves, preventing it from non-stereoselective epoxidation of 4
(Scheme 3). As checked in some cases (e.g., 1f), ketone 1 formed
by decomposition of perhydrate 5 can be isolated from the reaction
mixture and recycled. Changing the ratio of DHP: substrate 4 af-
fected the conversion without much change of the ee. Reduction
of the reaction time (to 1 day) did not significantly change the de-
gree of conversion. To counteract a probable inactivation of the
DBU by N-oxide formation an additional equivalent of DBU was
added after 7 h (solvent dichloromethane). This led to higher con-
version, but side products were formed.
The hydroxymethyl-substituted gem-DHP 2f was synthesized
using a slightly modified procedure starting with the correspond-
ing hydroxymethyl-b-thujone 1f which is easily available from
(ꢀ)-
a
-thujone and formaldehyde in high yields.27 1f can also be
obtained even in larger quantities from naturally occurring cheap
essential oil of thuja occidentalis. The gem-DHP 2f was isolated in
35% yield after column chromatography with dichloromethane/
methanol.
As primary substrate for epoxidation we chose 2-methyl-1,4-
naphthoquinone 4a (R2 = Me) (Scheme 3). The reaction conditions
were adopted from a previously described procedure,11 using tolu-
ene as the solvent and DBU as the base. The DHPs 2a–e provided
unsatisfactory ee’s of 6a, as did the peroxide 3e (Table 1, entries
1–6).
The hydroxymethyl-substituted thujone-derived gem-DHP 2f
can be expected to form additional hydrogen bonds via the alco-
holic OH group and thus may give rise to a more rigid transition
state and higher stereoselectivity in the epoxidation of 1,4-naph-
thoquinones. Indeed, 2-methyl-1,4-naphthoquinone
4 formed
epoxide 6a in 59% ee (Table 1, entry 7), albeit with a rather low
aqu. H2O2, CSA or I2
R
R
OOH
OOH
O
R'
R'
2
1
OOH
OOH
H
OOH
OOH
H
H
HOO
HOO
H
2a
(60%)
2b
(58%)
2c
(82%)
HO
OH
OOH
OOH
OOH
OOH
H
H
H
HOO
HOO
H
2d
(31%)
2e
(57%)
2f
(35%)
Scheme 1. Synthesis and examples of gem-dihydroperoxides 2.

A. Bunge et al. / Tetrahedron Letters 50 (2009) 4629–4632
4631
O
O
R
OOH
OOH
R
OOH
OH
base
+
O
+
solvent
R'
R'
O
O
2
4a
5
6a
R
H2O2
O
+
R'
1
Scheme 3. Asymmetric epoxidation of 2-methylnaphthoquinone 4a.
Table 1
In some of these experiments we observed changes in colors prob-
ably due to unknown decomposition reactions.
Epoxidation of 4a using DHPs 2a or 3e
Entry
DHP
Solvent
Conversion
ee of 6ab (%)
Configuration of major
enantiomer
Changing the base from DBU to other organic and inorganic
bases also affected the reaction strongly. Contrary to the reports
of Chmielewski11 and Taylor,8 the use of alkali metal bases showed
a very low conversion with dihydroperoxide 2f, as did the use of
DABCO. The stronger basic N,N-diethyl-N0,N0-dipropyl-N00-hexyl-
guanidine gave a rather high conversion (81%), however the forma-
tion of unidentified side products was observed. The use of n-BuLi
similar to the procedure of Lattanzi28 gave a relatively high conver-
sion (ca. 70%), but low enantiomeric excess (10%).
Thus we concluded that the best conditions are the use of DBU
as the base, dichloromethane as solvent, molecular sieves and a ra-
tio of substrate:oxidant:base = 1:2:2. It further turned out that stir-
ring of the reaction mixture for the whole reaction period is
of 4ab (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2a
2b
2c
2d
2e
3e
2f
2f
2f
2f
2f
2f
2f
2f
2f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Et2O
DCM
EtOAc
MeCN
MeOH
Hexane
THF
31
100
8
ꢁ0
6
8
—
(2S,3R)
(2S,3R)
(2S,3R)
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3S)
11
14
14
16
6
10
17
59
c
c
24
45
36
51
44
100
93
49
56
66
66
46
10
33
40
´
important for high ees, in particular when batch sizes are larger.
29
Most likely, the drop of ee observed otherwise is caused by the for-
mation of free hydrogen peroxide (Scheme 3) which cannot be ad-
sorbed by the molecular sieves fast enough.
These optimum reaction conditions were employed to epoxi-
dize a range of 2-substituted 1,4-naphthoquinones 4 using 2f.
(Scheme 4, Table 2)
a
Reaction conditions: 2:4a:DBU = 1:1:1, temperature ꢀ30 °C, molecular sieves
4 Å, 3 d.
b
c
Determined by HPLC.
Without molecular sieves.
It turned out that substituents larger than methyl gave usually
higher enantioselectivities. High to moderate yields and enantiose-
lectivities were achieved. Our results successfully compete with
those reported in the literature for the epoxidation of 1,4-naphtho-
quinones applying either asymmetric phase-transfer catalysis or
using chiral hydroperoxides.
In summary, we have demonstrated for the first time that enan-
tiomerically pure dihydroperoxides can be used in enantioselective
epoxidation. Moderate to good ee’s and yields were achieved in the
DBU-promoted epoxidation of 2-substituted 1,4-naphthoquinones.
Further studies to extend the scope of the application of the thu-
jone-derived dihydroperoxide as well as seeking for other useful
chiral dihydroperoxides are currently under way in our
laboratories.
Conversions of 4 and the ee’s of epoxide 6 were found highly
solvent dependent as can be seen from Table 1 (entries 7, 9–15).
While highly polar or typical unpolar solvents (hexane) decrease
the ee notably, the best ee values were obtained by using ethyl ace-
tate or dichloromethane. Methanol as protic solvent is especially
detrimental to ee but results in high conversion. The application
of acetonitrile resulted in full conversion but only in 46% ee.
It should be noted that while conversions are generally higher
in other solvents than toluene, colored side products (deeply blue
turning to brownish) were observed in these cases.
Variation of temperatures revealed an optimal enantiomeric ex-
cess in a temperature range from ꢀ30 to 0 °C. Higher temperatures
increased the degree of conversion but resulted in a decrease of ee.
O
HO
+
O
HO
O
R
O
OOH
OOH
R
DBU
+
DCM
O
O
1f
6
4
2f
Scheme 4. Asymmetric epoxidation of 2-substituted naphthoquinones with hydroxymethyl-substituted thujone-derived gem-DHP 2f.

4632
A. Bunge et al. / Tetrahedron Letters 50 (2009) 4629–4632
Table 2
GmbH for donation of hydrogen peroxide and Prof. Willi Kantleh-
ner for supply of N,N-diethyl-N0,N0-dipropyl-N00-hexylguanidine.
A. Bunge gratefully acknowledges a grant from DFG.
Epoxidation of 1,4-naphthoquinones 4 using DHP 2f under optimized conditionsa
Entry 1,4-Naphtho-
R
6/Yield
ee
Configurationd
quinones 4
(%)b
(%)c
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
Me
Et
Bn
Ph2CH
t-Butyl
6a/92
6b/67
6c/64
6d/97
6e/38e
66
70
74
78
82
60
ꢀ(2R,3S)
ꢀ(2R,3S)
ꢀ(2R,3S)
ꢀ(2R,3S)
+(2R,3S)
+(2R,3S)
Supplementary data
Supplementary data (general procedures and NMR data of com-
pound) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2009.05.096.
Cyclohexyl 6f/96
a
Reaction conditions: 2f:4:DBU = 1:2:2, DCM, molecular sieves 4 Å, temperature
References and notes
ꢀ20 °C, 16 h, continuous stirring.
b
Isolated yield after column chromatography.
c
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General procedure for epoxidation (analytical scale): dihydroper-
oxide 2 or 3e (0.02 mmol) was added to the corresponding solvent
(5 ml), followed by the addition of powdered 4 Å molecular sieves
(100 mg). After addition of 0.1 ml of a solution of DBU (0.2 mmol)
in the respective solvent (1 ml) the flask was cooled down to ꢀ50
to ꢀ40 °C and stirred for 10 min. A solution of 2-methylnaphtho-
quinone (0.1 ml, 0.2 mmol) in the respective solvent (1 ml) was
then added and the reaction mixture was stirred at ꢀ50 to
ꢀ40 °C for 1 h. Afterwards the flask was put in a freezer (ꢀ30 °C)
overnight. The reaction mixture was poured into water (20 ml), ex-
tracted with dichloromethane (2 ꢂ 20 ml) and dried (sodium sul-
fate). After evaporation of the solvent the mixture was analyzed
by HPLC on a chiral column.
General procedure for asymmetric epoxidation (preparative scale):
Into a flask with dihydroperoxide 2f (0.4 mmol) DCM (50 ml) was
added, followed by powdered 4 Å molecular sieves (1 g) and DBU
(0.4 mmol). The mixture was stirred at ꢀ20 °C for 10 min, naphtho-
quinone 4 (0.2 mmol) dissolved in DCM (1 ml) was added slowly
and the reaction continued to stir overnight. The mixture was then
filtered through a pad of CeliteÒ and washed with water (50 ml).
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Acknowledgments
We wish to thank Dipl.-Ing. Angela Thiesies for imidiate mea-
surement of many NMR samples. We further thank Solvay Interox