New amino endoperoxides belonging to the antimalarial G-factor series

Article abstract of DOI:10.1002/ejoc.200700086

In the search for new antimalarial endoperoxides we developed a direct route for the preparation of new amino compounds belonging to the G-factor series. During the synthesis, a significant difference in reactivity between two series of diastereoisomers was observed. The final amino endoperoxides were obtained with 58 to 70 % yields, depending on the starting amine, in the "anti" series, but with the "syn" diastereoisomers an unexpected rearrangement occurred during the deprotection step. This was attributed to a transient hexacoordinate fluorosilicon complex allowing the formation of a 1,2-dioxetane. Its decomposition gave aldehyde 12 and 4-hydroxybutan-2-one; these compounds were also identified when acidic conditions were used in the deprotection step. The anti amino compounds obtained were tested, but in vitro activities were found to be lower than initially expected, and fitted poorly with the previous biological hypothesis. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700086

FULL PAPER
DOI: 10.1002/ejoc.200700086
New Amino Endoperoxides Belonging to the Antimalarial G-Factor Series
Cécile Givelet,[a] Virginie Bernat,[a] Mathieu Danel,[a] Christiane André-Barrès,*[a] and
Henri Vial[b]
Keywords: Endoperoxide / Malaria / Autoxidation / Hexacoordinate fluorosilicon complex / 1,2-Dioxetane
In the search for new antimalarial endoperoxides we devel-
oped a direct route for the preparation of new amino com-
pounds belonging to the G-factor series. During the synthe-
sis, a significant difference in reactivity between two series
of diastereoisomers was observed. The final amino endo-
peroxides were obtained with 58 to 70% yields, depending
on the starting amine, in the “anti” series, but with the “syn”
diastereoisomers an unexpected rearrangement occurred
mation of a 1,2-dioxetane. Its decomposition gave aldehyde
12 and 4-hydroxybutan-2-one; these compounds were also
identified when acidic conditions were used in the deprotec-
tion step. The anti amino compounds obtained were tested,
but in vitro activities were found to be lower than initially
expected, and fitted poorly with the previous biological hy-
pothesis.
during the deprotection step. This was attributed to a tran- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
sient hexacoordinate fluorosilicon complex allowing the for-
Germany, 2007)
Introduction
Malaria is one of the major parasitic diseases in many
tropical and subtropical regions, causing more than a mil-
lion deaths each year. As malaria parasites are developing
resistance to drugs such as chloroquine, the development of
new classes of antimalarials is becoming a matter of ur-
gency.[1] Artemisinin is used clinically in China for the treat-
ment of multidrug-resistant Plasmodium falciparum ma-
laria. The search for a new generation of artemisinin-based
therapeutics is being pursued and modification at the C10
position has received the most attention.[2] Synthetic perox-
Figure 1. Syncarpic acid, G-factors.
ide-containing compounds – 1,2,4-trioxanes,[3–5] 1,2,4-tri-
product G3 and the methyl ether analogue G3Me. The lat-
ter compound was found to be one hundred times more
active than the G3, indicating the crucial role of the ether
function in relation to the hydroxy one. In a tentative at-
tempt to improve the antimalarial activities of new modi-
fied G-factor compounds, we decided to synthesize endo-
peroxides bearing a mono- or a diamine group to improve
bioavailability. It was believed that the presence of these
substituents should result in accumulation in the parasite
food vacuole. Introduction of substituted piperazines and
morpholine on the lateral chain was planned with regard to
the recent results of O’Neill[15] and Haynes.[16–17] A retro-
synthetic strategy (Scheme 1) that appeared to be simple
enough to be developed on a larger scale if necessary was
designed, its key step being the incorporation of the perox-
ide. We had already developed a smooth method in this
series, allowing endoperoxide formation by spontaneous
oxygen uptake into a dienol system existing in equilibrium
with the ene form,[18] the introduction of a lateral chain on
the compound requiring the preparation of a five-carbon
hydroxy aldehyde from γ-butyrolactone.
[8–9]
oxolanes,[6] cyclic peroxyketals,[7] and endoperoxides
–
acting against Plasmodium falciparum have also been devel-
oped. We were interested in antimalarial agents that should
act in a similar way to artemisinin and we focused on the
syntheses of modified endoperoxide G-factors (G1, G2,
G3). These natural endoperoxides are easily extracted from
the leaves of Eucalyptus grandis,[10] as is their biological pre-
cursor 2,2,4,4-tetramethylcyclohexane-1,3,5,-trione, called
syncarpic acid (Figure 1). Some previously synthesized de-
rivatives show moderate to good antimalarial activities.[11]
We have previously reported the crucial role of the per-
oxyketal function for this activity,[12–14] but the most signifi-
cant differences were those observed between the natural
[a] Synthèse et Physicochimie de Molécules d’Intérêt Biologique,
UMR CNRS 5068, Université Paul Sabatier,
118 route de Narbonne, 31062 Toulouse cedex 04, France
Fax: +33-5-61-55-82-55
E-mail: candre@chimie.ups-tlse.fr
[b] Dynamique Moléculaire des Interactions Membranaires, UMR
CNRS 5539, Université Montpellier 2,
cc107, Place E. Bataillon, 34095 Montpellier Cedex 5, France
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provided the endoperoxides 9a/9b as a 60:40 mixture of dia-
stereomers, a result expected from earlier work.[11] These
were separated by column chromatography and individually
methylated with butyllithium and methyl trifluoromethane-
sulfonate at low temperature to give the endoperoxides 10a
and 10b, respectively, bearing the crucial ether function, in
72–78% yields.
Scheme 1. Retrosynthetic approach.
Results and Discussion
The synthesis started with the preparation of the alde-
hyde. α-Methyl-γ-butyrolactone (1) (Scheme 2) was classi-
cally saponified with ethanolic sodium hydroxide. After
protection of both alcohol and acid with tert-butyldiphenyl-
silyl chloride, the silyl ester 2 was reduced with diisobutyl-
aluminium hydride to give alcohol 3, which was oxidized to
furnish the desired aldehyde 4. The aldehyde reacted with
one equivalent of piperidine to give the Schiff base 5, which
added to syncarpic acid (6) to give a quantitative yield of
Mannich base 7, stabilized in aprotic solvents by the intra-
molecular H-bond.
Scheme 3. Preparation of the diastereoisomeric protected endo-
peroxides 10a and 10b.
Endoperoxides 10a (syn: defined by OMe and
CH2CH2OTBDPS being on the same side of the heterocy-
cle) and 10b (anti) were characterized and differentiated by
HMBC (Heteronuclear Multiple Bond Correlation), HSQC
(Homonuclear Single Quantum Correlation), and NOESY
(Nuclear Overhauser Effect Spectroscopy) for the stereo-
chemistry.
An NOE was observed between OMe and 15-Me for en-
doperoxide 10b, while for endoperoxide 10a an NOE was
observed between OMe and CH2. This result was also con-
firmed in modelling studies. For example, the optimal con-
formations obtained through energy minimisation[19] is pre-
sented in Figure 2. Spatial proximity between the two
methyl groups OMe and 15-Me (2.57 Å) is clearly shown in
the endoperoxide 10b, while the interaction appears be-
tween OMe and CH2 in 10a (2.75 Å).
The main problem in the synthesis appeared where it was
least expected (Scheme 4). While the compound 10b was
easily deprotected in the presence of Et3N·3HF complex
and gave the endoperoxide 11 in 85% yield (after purifica-
tion by column chromatography on silica gel), treatment of
Scheme 2. Synthesis of Mannich base 7.
Treatment with aqueous acid resulted in elimination of 10a under the same conditions resulted in the formation of
the piperidine to form an enone 8, which existed in equilib- a mixture of polar by-products with aldehyde 12 as the
rium with a dienol (Scheme 3). Spontaneous oxygen uptake major component.
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New Amino Endoperoxides
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Figure 2. Modelling and NOESY experiments for 10a and 10b endoperoxides.
times: after 48 h, the endoperoxide 10a had totally disap-
peared, and the final products due to the fragmentation
were exclusively the aldehyde 12, the 4-hydroxybutane-2-
one and methanol. A mechanism is tentatively proposed in
Scheme 4. In an acidic medium, protonation occurs on the
peroxo group; the C1–O bond is then probably broken, and
the liberated hydroperoxide adds onto the double bond, in
a Michael-type reaction, to give a dioxetane. The dioxetane
is then fragmented to give the aldehyde 12 (2-oxosyncarpic
acid) and the 4-hydroxybutane-2-one.
In the anti series, treatment of the endoperoxide 10b in
methanolic acid does not result in this rearrangement and
fragmentation. Only a trace of aldehyde was actually ob-
served after 24 h under the same conditions.
Aldehyde 12 was also observed when Et3N·3HF complex
was used for removal of OTBDPS in the syn series. Forma-
tion of a transient hexacoordinate fluorosilicon complex
could be invoked[20] and explain the formation of 12 by a
similar mechanism (Figure 3). It is noteworthy that a com-
Scheme 4. Acidic fragmentation of the syn endoperoxide 10a
through formation of a 1,2-dioxetane.
Desilylation of 10a was also attempted under acidic con-
ditions (two equivalents of H+ in MeOH/H2O). In this case,
a surprising fragmentation also occurred, producing the
same aldehyde as observed previously.
This peculiar rearrangement could be followed in the
Figure 3. Proposal for a transient hexacoordinate fluorosilicon
NMR tube by recording 1H NMR spectra at different complex.
Eur. J. Org. Chem. 2007, 3095–3101
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FULL PAPER
Scheme 5. Synthesis of 14a, 14b, 14c and 14d endoperoxides via monochlate 13.
parable transient fluorosilicon complex has also been pos-
Conclusions
tulated during the TBDPS deprotection step in other endo-
peroxides that present the same relative configuration (the
syn series), but another rearrangement was identified.[12]
The difference in reactivity between the two diastereoiso-
meric endoperoxides on treatment with Et3N·3HF complex
can be explained by structural analysis: in the case of the
anti diastereoisomer 10b the presence of a π–π interaction
(donor/acceptor) between the conjugated double bond and
the phenyl group on silicon helps the addition of fluoride
to silicon, producing a more labile TBDPS group. In ad-
dition, the formation of a hexacoordinate fluorosilicon
complex is precluded in this series whereas it is possible in
the syn series (for 10a endoperoxide).
The hydroxy group in endoperoxide 11 was then acti-
vated with a monochlate group by treatment with chlo-
romethyl sulfonyl chloride in dichloromethane in the pres-
ence of lutidine. The monochlate derivative 13, obtained in
a 77–97% yield, was then treated with several amines in
toluene at 60 °C to give 14a–d endoperoxides in 58–70%
yields after purification (Scheme 5).
Despite a disappointing antimalarial result, we have
identified a new approach for functionalizing new endo-
peroxides related to the G factor series. Special attention
was paid to the differences in reactivity between diastereo-
isomers and to the mechanisms involved in an intriguing
hydroxy deprotection step. In the trans series, the amino
endoperoxides were obtained in good yields, whilst in the
syn series a fragmentation mechanism was elucidated by
NMR studies. The formation of a transient dioxetane inter-
mediate in the syn series was responsible for the fragmenta-
tion of the endoperoxides to give a hydroxybutanone and
aldehyde 12, which could serve as a precursor for the natu-
ral products obtained from Eucalyptus and Myrtaceae.
Experimental Section
tert-Butyldiphenylsilyl 4-(tert-Butyldiphenylsilyloxy)-2-methylbut-
anoate (2): The lactone (2 g, 19.97 mmol) was dissolved in ethanol
(80 mL). NaOH solution in water (1 , 40 mL) was added and the
mixture was heated at reflux for 3 h 30 min. The solvent was then
evaporated, and water was removed by azeotropic evaporation with
Compounds 14a–d were tested in vitro against the Nige-
rian strain of Plasmodium falciparum. The activity was de-
termined by the method of Desjardins et al. by use of [3H]
hypoxanthine incorporation to assess parasite growth.
Parasitic viability was expressed as IC50, the drug concen- benzene. After drying, the crude mixture was dissolved in DMF
(180 mL). Imidazole (4.08 g, 59.91 mmol) and tert-butyldiphenylsi-
lyl chloride (15.6 mL, 59.91 mmol) were added. After 15 h at room
temperature, the product was extracted with ethyl acetate, washed
with water, dried on MgSO4 and filtered, and the solvents were
evaporated. The final product was purified on silica gel (eluent: EP/
Et2O, 99:1 then 97:3) as an oil (9.04 g, 15.2 mmol) in 76% yield.
1H NMR (250 MHz, CDCl3): δ = 1.06 (s, 9 H, tBu), 1.11 (s, 9 H,
tration causing 50% parasite growth inhibition.
Using a similar approach, O’Neill and Haynes observed
significant improvements in the antimalarial effect. The re-
sults in our case, however, were disappointing, since the ac-
tivity completely disappeared when an amine function was
introduced on the G factors’ endoperoxide structure
(Table 1). The accumulation of amino endoperoxides in the
parasite food vacuole probably depends on more complex
factors than the presence of an amino function (possibly
3
tBu), 1.24 (d, JHH = 6.25 Hz, 3 H, CH3), 1.66 and 2.11 (AB sys-
3
3
tem, JHH = 6.25 Hz, 2 H, CH2–CH), 2.91 (q, JHH = 6.25 Hz, 1
H, CH3CH), 3.75 (td, JHH = 6.25 Hz, 4JHH = 2.08 Hz, 2 H, CH2–
severe steric requirements) and the question will have to be OSi), 7.39 (m, 12 H, arom.), 7.68 (m, 8 H, arom.) ppm. 13C NMR
3
(75.48 MHz, CDCl3): δ = 17.02 (CH3CH), 19.29 [C(CH3)3], 19.31
[C(CH3)3], 26.95 [C(CH3)3], 27.04 [C(CH3)3], 36.35 (O-CH2-CH2),
37.62 (CH-C=O), 61.57 (CH2–O), 127.36 (CH arom.), 129.68 (CH
arom.), 130.05 (CH arom.), 132.11 (C arom.), 133.86 (C arom.),
re-examined.
Table 1. IC50 values for several endoperoxides on the Nigerian
strain of Plasmodium falciparum.
135.35 (CH arom.), 145.54 (CH arom.), 175.74 (C=O) ppm. IR: ν
˜
= 3071, 3050, 2959, 2858, 1725 cm–1. SMBR: [IC, MeOH, m/z (%)]:
595 [M + H]+, 617 [M + Na]+, 633 [M + K]+. Rf (EP/Et2O, 99:1)
= 0.33.
9a
9b
10a 10b 11
14a 14b 14c 14d
7.7 28 36 54
IC50 [µM] 0.74 0.73 1.4 1.6 73
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New Amino Endoperoxides
FULL PAPER
4-(tert-Butyldiphenylsilyloxy)-2-methylbutan-1-ol (3): The bis-
silylated product 2 (9 g, 15 mmol) was dissolved in anhydrous
CH2Cl2 (200 mL) and the mixture was cooled to 0 °C under argon.
DIBAL-H (1  in toluene, 33 mL, 33 mmol) was added dropwise.
After 2 h 30 min the reaction was quenched with saturated NH4Cl
solution (12.5 mL). After filtration through celite and concentra-
tion, the crude mixture was purified on silica gel (eluent: EP/Ac-
OEt, 7:1 then 5:1 and then 3:1). The alcohol 3 was obtained as an
oil in 76% yield (2.554 g, 7.46 mmol). 1H NMR (250 MHz,
CDCl3): δ = 0.90 (d, 3JHH = 7.35 Hz, 3 H, CH3), 1.05 (s, 9 H, tBu),
Endoperoxides 9a and 9b: No precautions are required for handling
these endoperoxides, as they are very stable. The above oil was dis-
solved in ethyl acetate (100 mL) and kept for three days at 25 °C
under air. After concentration the mixture was purified on silica
gel (eluent: EP/Et2O, 100:5). Two diastereoisomers were separated:
syn-9a (oil), 500 mg, 0.93 mmol) and anti-9b (oil, 360 mg,
0.67 mmol), in 52% yield over the three steps.
Isomer 9a: 1H NMR (300 MHz, CDCl3): δ = 1.05 [s, 9 H,
C(CH3)3], 1.07 (s, 3 H, CH3-11 or CH3-12), 1.35 (s, 3 H, CH3-11
or CH3-12), 1.39 (s, 3 H, CH3-13 or CH3-14), 1.40 (s, 3 H, CH3-
13 or CH3-14), 1.50 (s, 3 H, CH3-15), 1.92 (m, 2 H, CH2CH2O),
3.76 (m, 2 H, CH2OSi), 7.31 (s, 1 H, C=CH), 7.43 (m, 6 H, CH
arom., on meta and para positions), 7.64 (m, 4 H, CH arom., on
ortho position) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 15.11
(CH3, C-11 or C-12), 19.01 [C, C(CH3)3], 20.80 (CH3, C-11 or C-
12), 22.97 (CH3, C-15), 23.87 (CH3, C-13 or C-14) 26.53 (CH3, C-
13 or C-14), 26.81 [3 CH3, C(CH3)3], 40.09 (CH2, CCH2CH2O),
51.52 (C, C-10), 54.98 (C, C-8), 59.32 (CH2, CH2CH2O), 81.07 (C,
C-4), 97.37 (C, C-1), 127.83, 129.88, 135.52 (10 CH, CH arom.)
131.77 (C, C=CH), 133.08 (2 C, C arom.), 142.46 (CH, C=CH),
3
1.56 (m, 2 H, CH2CH), 1.84 (m, JHH = 7.35 Hz, 1 H, CH3-CH),
3.52 (m, 2 H, CH2–OSi), 3.74 (m, 2 H, CH2–OH), 7.41 (m, 6 H,
arom.s), 7.69 (m, 4 H, arom.s) ppm. 13C NMR (75.48 MHz,
CDCl3): δ = 17.14 (CH3–CH), 19.18 [C(CH3)3], 26.67 [C(CH3)3],
33.77 (CH–CH3), 36.75 (CH2–CHCH3), 62.53 (CH2–OSi), 68.21
(CH2–OH), 127.36 (CH arom.), 129.75 (CH arom.), 133.55 (C
arom.), 135.61 (CH arom.) ppm. IR: ν = 3350 (CH –OH), 3070,
˜
2
3049, 2957, 2857, 1472, 1112 (Si–O) cm–1. SMBR: [IC, MeOH,
m/z (%)]: 343 [M + H]+, 365 [M + Na]+, 381 [M + K]+. C21H30O2Si
(342.55): calcd. (%) C 73.63, H 8.83; found C 73.72, H 9.10. Rf
(EP/AcOEt, 7:1) = 0.33.
197.89 (C=O, C-7), 210.90 (C=O, C-9) ppm. IR: ν = 3453 (O–H
˜
stretching), 3072 and 3050 (arom. C–H stretching), 2958 to 2858
(C–H stretching for CH2 and CH3), 1726 (C=O), 1692 (C=O, α,β-
unsaturated), 1471 to 1376 (C–H deformation band for CH2 and
CH3), 1112 (Si–O), 895 (O–O), 823 (Si–tBu), 702 and 504 (mono-
substituted arom. C–H deformation) cm–1. SMBR: [DCI, NH3, in
CH2Cl2, m/z (%)]: 537 [M + H]+, 554 [M + NH4]+. Rf (CH2Cl2) =
0.25.
4-(tert-Butyldiphenylsilyloxy)-2-methylbutanal (4): The alcohol 3
(2.54 g, 7.42 mmol) was dissolved in anhydrous dichloromethane
(12 mL). Anhydrous dimethyl sulfoxide (15 mL) was then intro-
duced, followed by triethylamine (5.2 mL, 37.1 mmol).
SO3·pyridine complex was added in small portions. After 30 min
the mixture was diluted with ether (83 mL). The organic phase was
washed with water (100 mL) and then with brine (100 mL). After
drying on magnesium sulfate, filtration and concentration, the al-
dehyde was obtained as a yellow oil, in 94% yield (2.34 g,
1
Isomer 9b: H NMR (300 MHz, CDCl3): δ = 0.97 (s, 3 H, CH3-11
or CH3-12), 1.05 (s, 9 H, tBu), 1.30 (s, 3 H, CH3-11 or CH3-12),
1.36 (s, 3 H, CH3-15), 1.37 (s, 6 H, CH3-13, CH3-14), 2.08 (m, 2
H, CH2CH2O), 3.55 (s, 1 H, OH), 3.80 (m, 2 H, CH2OSi), 7.25 (1
H, C=CH), 7.39 (m, 6 H, H arom. on meta and para positions),
7.65 (m, 4 H, H arom. on ortho position) ppm. 13C NMR
(75.47 MHz, CDCl3): δ = 15.20 (CH3, C-11 or C-12), 19.07 [C,
C(CH3)3], 20.99 (CH3, C-11 or C-12), 21.56 (CH, C-15), 24.21
(CH3, C-13 or C-14), 26.59 (CH3, C-13 or C-14), 26.82 [C(CH3)3],
39.73 (CH2, CH2CH2O), 51.65 (C, C-10), 54.94 (C, C-8), 59.77
(CH2, CH2OSi), 80.98 (C, C-4), 97.40 (C, C-1), 127.78 and 135.54
(8 CH, CH arom. on meta and para positions), 129.81 (2 CH, CH
arom. ortho), 131.44 (Cq, C=CH), 133.32 (2 Cq, C arom.), 142.85
(CH, C=CH), 198.20 (C=O, C-7), 210.80 (C=O, C-9) ppm. IR
1
6.9 mmol) and 95% purity as indicated by H NMR spectroscopy.
3
1H NMR (250 MHz, CDCl3): δ = 1.03 (s, 9 H, tBu), 1.07 (d, JHH
= 7.35 Hz, 3 H, CH3), 1.65 and 1.98 (m, 2 H, AB system, CH2CH),
3
2.56 (m, JHH = 7.35 Hz, 1 H, CHCH3), 3.71 (m, 2 H, CH2–OSi),
7.27 (m, 6 H, arom.), 7.65 (m, 4 H, arom.), 9.68 (d, 3JHH = 7.35 Hz,
1 H, CHO) ppm. 13C NMR (75.48 MHz, CDCl3): δ = 13.13 (CH3–
CH), 19.18 [C(CH3)3], 26.83 [C(CH3)3], 33.46 (CH2–CH), 43.53
(CH–CH3), 61.19 (CH2–OSi), 127.73 and 129.73 (CH arom.),
133.53 and 135.55 (C arom.), 135.58 (CH arom.), 204.83
(CHO) ppm. IR: ν = 3071 and 3049 (arom. C–H stretching), 2959
˜
to 2857 (C–H stretching for CH2 and CH3), 1727 (C=O), 1472 to
1361 (C–H deformation for CH2 and CH3), 1112 (Si–O), 823 (Si–
tBu), 702 and 505 (monosubstituted arom. C–H deformation)
cm–1. SMBR: [DCI, NH3, in CH2Cl2, m/z (%)]: 341 [M + H]+, 358
[M + NH4]+. Rf (EP/CH2Cl2, 1:3) = 0.33.
(KBr): ν = 3448 (OH), 3071 and 3050 (arom. C–H stretching), 2958
˜
to 2857 (C–H stretching for CH2 and CH3), 1725 (C=O), 1691
(C=O, α,β-unsaturated), 1471 to 1376 (C–H deformation for CH2
and CH3), 1113 (Si-O), 893 (O–O), 823 (Si–tBu), 702 and 505
(monosubstituted arom. C–H deformation) cm–1. SMBR: [DCI,
NH3, CH2Cl2, m/z (%)]: 537 [M + H]+, 554 [M + NH4]+.
C31H40O6Si (536.73): calcd. (%) C 69.37, H 7.51; found C 69.14, H
7.81. Rf (CH2Cl2) = 0.20.
Mannich Base 7: A solution of aldehyde 4 (2.41 g, 6.8 mmol) and
piperidine (0.67 mL, 6.8 mmol) in dichloromethane (30 mL) was
added at room temperature to a solution of syncarpic acid 6
(1.23 g, 6.8 mmol) and piperidine (335 µL, 3.4 mmol) in anhydrous
dichloromethane (30 mL). After 20 min the mixture was concen-
trated. The crude compound (4.44 g, 7.5 mmol) was used without
any purification for next step.
Methylated Endoperoxides 10a or 10b: A solution of BuLi (1.4  in
hexanes, 350 µL, 0.49 mmol) was added at –78 °C to a solution of
diastereoisomer 9a or 9b (0.262 g, 0.49 mmol) in anhydrous THF
(5 mL). After the mixture had been stirred for 15 min, methyl trifl-
ate (56 µL, 0.49 mmol) was added dropwise. After three hours at
–78 °C, the reaction was quenched with a saturated solution of
NH4Cl. The organic phase was extracted with dichloromethane,
dried on MgSO4 and filtered, and the solvents were evaporated.
The methylated product was obtained as a white powder in 83–
100% yield, with a purity estimated as 95% by 1H NMR spec-
troscopy.
Ene-one 8: The Mannich base 7 (1.92 g, 3.2 mmol) was dissolved
in dichloromethane (75 mL). A saturated solution of NH4Cl in HCl
(1 , 100 mL) was added and the mixture was stirred for 30 min-
utes. After extraction with dichloromethane (3ϫ25 mL), drying on
MgSO4, filtration and concentration, a yellow oil was obtained. 1H
NMR (250 MHz, CDCl3): δ = 1.05 (s, 9 H, tBu), 1.13 (d, 3 H,
CH3), 1.24, 1.30, 1.32 and 1.34 (4ϫs, 4 ϫ3 H, CH3-11, CH3-12,
CH3-13, CH3-14), 1.72 (m, 2 H, CH2CH2O), 3.47 (m, 1 H,
1
CHCH3), 3.65 (m, 2 H, CH2–OSi), 7.32 (d, 1 H, C=CH), 7.41 (m, Isomer 10a: H NMR (300 MHz, CDCL3): δ = 1.03 (s, 3 H, CH3-
6 H, arom.), 7.63 (m, 4 H, arom.) ppm.
11 or CH3-12), 1.06 [s, 9 H, (CH3)3], 1.28 (s, 6 H, 2ϫCH3, CH3-
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C. Givelet, V. Bernat, M. Danel, C. André-Barrès, H. Vial
FULL PAPER
11 or CH3-12 and CH3-13 or CH3-14), 1.34 (s, 3 H, CH3-13 or
(C=O, α,β-unsaturated), 1465 to 1376 (C–H deformation band for
3
CH3-14), 1.44 (s, 3 H, CH3-15), 1.94 (t, JHH = 6.75 Hz, 2 H, CH2 and CH3), 1102 (O–CH3), 867 (O–O) cm–1. SMBR: [APCI,
3
CH2CH2O), 3.32 (s, 3 H, OCH3), 3.74 (t, JHH = 6.75 Hz, 2 H, CH3CN, formic acid (50:50), m/z (%)]: 313 [M + H]+, 295 [M +
CH2OSi), 7.39 (m, 6 H, CH arom. on meta and para positions), H – H2O]+, 281 [M + H – OMe]+. C16H24O6 (312.36): calcd. (%)
7.52 (s, 1 H, C=CH), 7.63 (m, 4 H, CH arom. on ortho posi-
tion) ppm. 13C NMR (75.47 MHz, CDCL3): δ = 15.59 (CH3, C-13
or C-14), 19.05 [C, C(CH3)3], 21.65 (CH3, C-13 or C-14), 22.50
(CH3, C-15), 24.70 (CH3, C-11 or C-12), 26.09 (CH3, C-11 or C-
12), 26.82 (3 CH3, tBu), 40.15 (CH2, CH2CH2O), 53.24 (C, C-10),
54.47 (CH3, OCH3), 54.68 (C, C8), 59.07 (CH2, CH2OSi), 80.21 (C,
C-4), 100.45 (C, C-1), 127.76, 129.82, 135.54 (10 CH, CH arom.),
127.92 (C, C=CH), 133.23 (2 C, C arom.), 145.61 (CH, C=CH),
C 61.52, H 7.74; found C 61.59, H 7.64. Rf (EP/AcOEt, 7:3) = 0.19.
Compound 12: 1H NMR (300 MHz, CD3OD): δ = 1.34 (12 H,
4ϫMe), 9.66 (1 H, CHO) ppm. 13C NMR (75.46 MHz, CDCl3): δ
= 23.79 (4 CH3), 53.78 (2 C, CH3CCH3), 109.94 [C, COC-
(CHO)=C], 190.51 (CH, CHO), 196.16 [2 C, C(OH)=C and
COC=C], 210.4 (C, CO) ppm.
Compound 13: Lutidine (100 µL, 0.85 mmol) was added at 0 °C un-
der argon to compound 11 (38 mg, 0.12 mmol) in dichloromethane
(5 mL) and chloromethylsulfonyl chloride was added (22 µL,
0.24 mmol). After twelve hours of stirring, the mixture was ex-
tracted with ethyl acetate and washed with water (3ϫ10 mL) and
then with saturated NaCl solution. After drying on MgSO4, fil-
tration and concentration, the product was quantitatively obtained
as a yellow oil. 1H NMR (300 MHz, C6D6): δ = 0.75, 077, 1.33,
1.41, 1.50 (5ϫs, 5 ϫMe), 1.71 (m, 2 H, CH2CH2O), 3.13 (s, 3 H,
OCH3), 3.61 (s, 2 H, CH2Cl), 4.10 (m, 2 H, CH2CH2O), 7.02 (s, 1
H, C=CH) ppm. Rf (EP/EtOAc, 8:2) = 0.30.
198.31 (C=O, C-7), 210.44 (C=O, C-9) ppm. IR (KBr): ν = 3071
˜
(arom. C–H stretching), 2984 to 2877 (C–H stretching for CH2 and
CH3), 1726 (C=O), 1692 (C=O, α,β-unsaturated), 1469 to 1344 (C–
H deformation band for CH2 and CH3), 1109 (Si–O and O–CH3),
895 (O–O), 822 (Si–tBu), 706 (monosubstituted arom. C–H defor-
mation) cm–1. SMBR: (DCI, NH3): 551 [MH]+, 568 [MNH4]+.
Rf (EP/Et2O, 9:1) = 0.39.
1
Isomer 10b: H NMR (250 MHz, CDCL3): δ = 0.97 (s, 3 H, CH3-
11 or CH3-12), 1.04 (s, 9 H, 3ϫCH3, tBu), 1.27 (s, 3 H, CH3-13
or CH3-14), 1.29 (s, 3 H, CH3-11 or CH3-12), 1.33 (s, 3 H, CH3-
13 or CH3-14), 1.36 (s, 3 H, CH3-15), 1.99 (m, 2 H, CH2CH2O),
3.44 (s, 3 H, OCH3), 3.81 (m, 2 H, CH2OSi), 7.43 (m, 6 H, arom.
H, on meta and para positions), 7.48 (s, 1 H, H on C5), 7.64 (m, 4
H, arom. H on ortho position) ppm. 13C NMR (75.47 MHz,
CDCL3): δ = 15.88 (CH3 on C-11 or C-2), 19.27 (C, C-19), 21.46
(CH3,C-15), 21.95 (CH3, C-11 or C-12), 25.07 (CH3, C-13 or C-
14), 26.14 (CH3, C-13 or C-14), 27.03 (3CH3, tBu), 39.83
(CH2,CH2CH2O), 53.35 (C, C-10), 54.92 (C, C-8), 54.95 (CH3,
OMe), 59.91 (CH2, CH2CH2O), 80.52 (C, C-4), 101.82 (C, C-1),
127.99 (4 CH, CH arom.), 128.01 (C, C=CH), 130.02, 130.04,
135.74, 135.77 (CH, CH arom.), 133.46, 133.50 (C, C arom.),
143.80 (CH, C=CH), 198.98 (C=O, C7), 210.73 (C=O, C9) ppm. IR
Typical Procedure for the Formation of Diamine Endoperoxides 14a,
14b, and 14c, and Morpholine Endoperoxide 14d: Piperazine
(morpholine) (8 equiv.) was added at 60 °C to the chloromethylsul-
fonyl endoperoxide 13 (25 mg, 0.06 mmol) dissolved in anhydrous
toluene. After seven hours stirring at 60 °C, saturated NaHCO3
solution was added. The organic phase was extracted with dichlo-
romethane, dried and filtered, and the solvents were evaporated.
Compound 14a: A yellow oil was obtained in 67% yield, after puri-
fication on silica gel (eluent: EP/EtOAc, 6:4). 1H NMR (250 MHz,
CDCl3): δ = 1.06 (s, 3 H, CH3-11 or CH3-12), 1.29 (s, 3 H, CH3-
13 or CH3-14), 1.30 (s, 3 H, CH3-11 or CH3-12), 1.34 (s, 3 H, CH3-
13 or CH3-14), 1.37 (s, 3 H, CH3-15), 2.01 (m, 2 H, CH2CH2N),
2.62 (m, 2 H, CH2CH2N), 2.64 [m, 4 H, CH2N(CH2CH2)2N], 3.26
[m, 4 H,CH2N(CH2CH2)2N], 3.46 (s, 3 H, OCH3), 7.06–7.09 (m, 3
H, H arom.), 7.34 (m, 1 H, H arom.), 7.45 (s, 1 H, C=CH) ppm.
13C NMR (75.46 MHz, CDCl3): δ = 15.66 (CH3, C-11 or C-12),
20.69 (CH3, C-11 or C-12), 21.79 (CH3, C-13 or C-14), 24.17 (CH3,
C-15), 25.91 (CH3, C-13 or C-14), 33.17 (CH2, CCH2CH2N),
49.84, 50.12 [2ϫCH2, CH2N(CH2CH2)2N], 52.50 (CH2,
CCH2CH2N), 53.09, 53.13 [2ϫCH2, CH2N(CH2CH2)2N], 53.26
(C, C-10), 54.77 (C, C-8), 54.79 (CH3, OCH3), 84.74 (C, C-4),
100.36 (C, C-1), 116.27 (CH, CH=CCF3), 119.03 (CH,
NC=CHCH=CH), 122.75 (CH, CH=CHCCF3), 128.17 (C,
C=CH), 130.87 (CH, CHCHCH), 132.39 (C, CCF3), 154.08
(C,CN), 145.08 (CH, C=CH), 198.75 (C=O, C-9), 0.25 (C=O, C-
7) ppm. 19F NMR (376.44 MHz, CDCL3) δ = 13.65 ppm (refer-
(KBr): ν = 3070 (arom. C–H stretching), 2926 to 2854 (C–H
˜
stretching for CH2 and CH3), 1726 (C=O), 1695 (C=O, α,β-unsatu-
rated), 1471 to 1377 (C–H deformation band for CH2 and CH3),
1112 (Si–O), 1101 (O–CH3), 885 (O–O), 822 (Si–tBu), 707 and 508
(monosubstituted arom. C–H deformation) cm–1. SMBR: [DCI,
NH3, CH2Cl2, m/z (%)]: 551 [M + H]+, 568 [M + NH4]+.
C32H42O6Si (550.76): calcd. (%) C 69.78, H 7.69; found C 69.61, H
7.71. Rf (EP/Et2O 9:1) = 0.67.
Compound 11: EtN3·HF complex (257 µL, 2.828 mmol) was added
under argon at room temperature to methylated diastereoisomer
anti-10b (0.223 g, 0.404 mmol), dissolved in anhydrous dichloro-
methane (8 mL). After the mixture had been allowed to stand for
three days at room temperature, saturated NH4Cl solution was
added. The organic phase was extracted with dichloromethane,
dried on MgSO4, filtered and concentrated to give crude product,
which was purified on silica gel (eluent: EP/AcOEt, 7:3). The
alcohol was obtained in 78% yield (0.99 g, 0.32 mmol) as a colour-
ence: CF COOH). IR: ν = 2979 to 2833 (C–H stretching for CH
˜
3
2
and CH3), 2870 (O–CH3), 1716 (C=O), 1656 (C=O, α,β-unsatu-
rated), 1608 (C=C), 1496 (CH arom.), 1451 and 1380 (C–H defor-
mation band for CH2 and CH3), 1238 (N–Ph), 1165 (N–CH), 1100
(O–CH3), 788 (disubstituted arom.) cm–1. SMBR: [APCI,
MeOH, formic acid 0.1%, 50:50, m/z (%)]: 525 [M + H]+. Rf (EP/
EtOAc, 7:3) = 0.39. Log P (I-LAB Service: ACD/Log P v8.02):
5.56Ϯ0.78.
1
less oil. H NMR (300 MHz, C6D6): δ = 0.81 (s, 3 H, CH3-11 or
CH3-12), 0.89 (s, 3 H, CH3-15), 1.36 (s, 3 H, CH3-13 or CH3-14),
1.41 (s, 3 H, CH3-13 or CH3-14), 1.53 (s, 3 H, CH3-11 or CH3-12),
1.64 (m, 2 H, CH2CH2O), 3.21 (s, 3 H, OCH3); 3.34 (m, 2 H,
CH2OH), 7.23 (s, 1 H, C=CH) ppm. 13C NMR (75.46 MHz,
C6D6): δ = 15.85 (CH3, C-11 or C-12), 20.49 (CH3, C-15), 21.24 Compound 14b: A yellow oil was obtained in 58% yield after purifi-
1
(CH3, C-11 or C-12), 24.63 (CH3, C-13 or C-14), 25.80 (CH3, C- cation on silica gel. (eluent: PE/EtOAc, 6:4). H NMR (250 MHz,
13 or C14), 36.86 (CH2, CH2CH2O), 53.32 (C, C-10), 54.53 (CH3, CDCl3): δ = 1.06 (s, 3 H, CH3-11 or CH3-12), 1.30 (s, 3 H, CH3-
OCH3), 54.82 (C, C-8), 57.76 (CH2, CH2O), 80.39 (C, C-4), 100.87 13 or CH3-14), 1.31 (s, 3 H, CH3-11 or CH3-12), 1.35 (s, 3 H, CH3-
(C, C-1), 126.85 (C, C=CH), 144.93 (CH, C=CH), 197.84 (C,
C=O), 209.09 (C, C=O, C-9) ppm. IR (ν): 3442 (CH –OH), 2936
13 or CH3-14), 1.38 (s, 3 H, CH3-15), 2.04 (m, 2 H, CH2CH2N),
2.63 (m, 2 H, CH2CH2N), 2.68 [m, 4 H, CH2N(CH2CH2)2N] 3.14
˜
2
to 2870 (C–H stretching for CH2 and CH3), 1726 (C=O), 1692 [m, 4 H, CH2N(CH2CH2)2N], 3.46 (s, 3 H, OCH3), 6.91–7.07 (m,
3100
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3095–3101

New Amino Endoperoxides
FULL PAPER
4 H, CH arom.), 7.45 (s, 1 H, C=CH) ppm. 13C NMR (75.46 MHz,
CDCl3): δ = 15.67 (CH3, C-11 or C-12), 20.72 (CH3, C-15), 21.81
(CH3, C-11 or C-12), 23.97 (CH3, C-13 or C-14), 26.92 (CH3, C-
13 or C-14), 33.47 (CH2, CCH2CH2N), 50.24 [2 CH2,
CH2N(CH2CH2)2N], 53.12 (CH2, CCH2CH2N), 53.18 (C, C-10),
53.28 [2 CH2, CH2N(CH2CH2)2N], 54.78 (C, C-8), 54.80 (OCH3),
80.22 (C, C-4), 100.37 (C, C-1), 116.13, 118.97, 122.66, 124.50 (4
CH, arom.), 128.15 (C, C=CH), 145.13 (CH, C=CH), 154.75 and
156.70 (d, 1JCF = 245.9 Hz, CF), 198.77 (C=O, C-9), 210.27 (C=O,
C-7) ppm. 19F NMR (376.44 MHz, CDCL3) δ = 46.58 ppm (refer-
Acknowledgments
We thank Liliane Gorrichon for helpful discussions.
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710.
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P. G. Bray, J. Davies, C. H. Oh, G. H. Posner, ChemBioChem
2005, 6, 2048–2054.
ence: CF COOH). IR (ν): 2978 to 2937 (C–H stretching for CH
˜
3
2
[4] G. H. Posner, J. N. Cumming, S.-H. Woo, P. Ploypradith, S.
Xie, T. Shapiro, J. Med. Chem. 1998, 41, 940–951.
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F. C. K. Chiu, J. Chollet, Y. Dong, A. Dorn, D. Hunziker, H.
Matile, K. McIntosh, M. Padmanilayam, J. SantoTomas, C.
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Xie, T. Shapiro, J. Med. Chem. 1998, 41, 2164–2167.
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pradith, S. Xie, T. Shapiro, G. Posner, J. Med. Chem. 2003, 46,
2516–2533.
[9] P. M. O’Neill, P. A. Stocks, M. D. Pugh, N. C. Araujo, E. E.
Korshin, J. F. Bickley, S. A. Ward, P. G. Bray, E. Pasini, J. Dav-
ies, E. Verissimo, M. D. Bachi, Angew. Chem. Int. Ed. 2004, 43,
4193–4197.
[10] E. Ghisaberti, Phytochemistry 1996, 41, 7–22.
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Vial, C. André-Barrès, Eur. J. Org. Chem. 2003, 17, 3335–3343.
[12] F. Najjar, L. Gorrichon, M. Baltas, H. Vial, T. Tzedakis, C.
André-Barrès, Bioorg. Med. Chem. Lett. 2003, 14, 1433–1436.
[13] C. André-Barrès, F. Najjar, A.-L. Bottalla, S. Massou, C.
Zedde, M. Baltas, L. Gorrichon, J. Org. Chem. 2005, 70, 6921–
6924.
[14] F. Najjar, L. Gorrichon, M. Baltas, C. André-Barrès, H. Vial,
Org. Biomol. Chem. 2005, 3, 1612–1614.
[15] S. Hindley, S. A. Ward, R. C. Storr, N. L. Searle, P. G. Bray,
B. K. Park, J. Davies, P. M. O’Neill, J. Med. Chem. 2002, 45,
1052–1063.
and CH3), 2870 (O–CH3), 1716 (C=O), 1655 (C=O, α,β-unsatu-
rated), 1600 (C=C), 1502 (arom. ring), 1456 and 1379 (C–H defor-
mation band for CH2 and CH3), 1240 (Ar–N), 1169 (N–CH), 1104
(O–CH3), 756 (disubstituted arom.) cm–1. SMBR: [APCI, MeOH,
formic acid 0.1%, 50:50, m/z (%)]: 459 [M + H]+. Rf (EP/EtOAc,
7:3) = 0.27. Log P (I-LAB Service: ACD/Log P v8.02): 4.60Ϯ0.79.
Compound 14c: A yellow oil was obtained in 70% yield, after purifi-
1
cation on silica gel (eluent: EtOAc). H NMR (250 MHz, CDCl3):
δ = 1.05 (s, 3 H, Me-11 or Me-12), 1.28 (s, 3 H, Me-13 or Me-14),
1.30 (s, 3 H, Me-11 or Me-12), 1.34 (s, 3 H, Me-13 or Me-14), 1.37
(s, 3 H, Me-15), 2.03 (m, 2 H, CH2CH2N), 2.54 (m, 2 H,
CH2CH2N), 2.58 [m, 4 H, CH2N(CH2CH2)2N], 3.45 (s, 3 H,
3
OCH3), 3.85 [m, 4 H, CH2N(CH2CH2)2N], 6.50 (t, JHH cis
=
4.75 Hz, 1 H, H arom.), 7.47 (s, 1 H, C=CH), 8.29–8.31 (d, 3JHH cis
= 4.75 Hz, 2 H, H arom.) ppm. 13C NMR (75.46 MHz, CDCl3): δ
= 15.67 (CH3, C-11 or C-12), 20.69 (CH3, C-15), 21.77 (CH3, C-
11 or C-12), 24.77 (CH3, C-13 or C-14), 25.91 (CH3, C-13 or C-
14), 33.39 (CH2, CCH2CH2), 43.41 [CH2, CH2N(CH2CH2)2N],
52.94 (C, C-10), 53.08 [CH2, CH2N(CH2CH2)2N], 53.18 (CH2,
CCH2CH2N), 53.68 (C, C-8), 53.78 (CH3, OCH3), 80.21 (C, C-4),
100.35 (C, C-1), 110.03 (CH, arom.), 128.10 (C, C=CH), 145.14
(CH, C=CH), 157.73 (2 CH, arom.), 161.55 (C, arom.), 198.75
(C=O, C-9), 210.26 (C=O, C-7) ppm. IR (ν): 2928 to 2854 (C–H
˜
stretching for CH2 and CH3), 2870 (O–CH3), 1716 (C=O), 1652
(C=O, α,β-unsaturated), 1586 (C=N), 1551 (C=C arom.), 1261
(Ar–N), 1103 (O–CH3), 639, 506 and 451 (2-substituted pyrimi-
dine) cm–1. SMBR: [APCI, MeOH, formic acid 0.1%, 50:50, m/z
(%)]: 459 [M + H]+. Rf (EtOAc) = 0.37. Log P (I-LAB Service:
ACD/Log P v8.02): 3.40Ϯ0.74.
[16] R. K. Haynes, W. Y. Ho, H.-W. Chan, B. Fugmann, J. Stetter,
S. L. Croft, L. Vivas, W. Peters, B. L. Robinson, Angew. Chem.
Int. Ed. 2004, 43, 1381–1385.
[17] R. K. Haynes, B. Fugmann, J. Stetter, K. Rieckmann, H.-D.
Heilmann, H.-W. Chan, M.-K. Cheung, W.-L. Lam, H.-N.
Wong, S. L. Croft, L. Vivas, L. Rattray, L. Stewart, W. Peters,
B. L. Robinson, M. D. Edstein, B. Kotecka, D. E. Kyle, B.
Beckermann, M. Gerish, M. Radtke, G. Schmuck, W. Steinke,
U. Wollborn, K. Schmeer, A. Römer, Angew. Chem. Int. Ed.
2006, 45, 2082–2088.
Compound 14d: A yellow oil was obtained in 70% yield, after puri-
fication on silica gel. (eluent: EP/EtOAc 6:4). 1H NMR (250 MHz,
CDCl3): δ = 1.03 (s, 3 H, CH3-11 or CH3-12), 1.28 (s, 3 H, CH3-
13 or CH3-14), 1.29 (s, 3 H, CH3-11 or CH3-12), 1.33 (s, 3 H, CH3-
3
13 or CH3-14), 1.35 (s, 3 H, CH3-15), 1.96 (t, JHH = 6.75 Hz, 2
H, CCH2CH2), 2.47 [t, 3JHH = 4.25 Hz, 4 H, 2ϫCH2, N(CH2CH2)
[18] F. Najjar, C. André-Barrès, R. Lauricella, L. Gorrichon, B.
Tuccio, Tetrahedron Lett. 2005, 46, 2117–2119.
3
2O], 2.51 (m, JHH = 6.75 Hz, 2 H, CCH2CH2N), 3.45 (s, 3 H,
OCH3), 3.71 [t, 3JHH = 4.25 Hz, 4 H, N(CH2CH2)2O], 7.43 (s, 1 H,
C=CH) ppm. 13C NMR (75.46 MHz, CDCl3): δ = 15.64 (CH3, C-
11 or C-12), 20.71 (CH, C-15), 21.75 (CH3, C-11 or C-12), 24.74
(CH3, C-13 or C-14), 25.91 (CH3, C-13 or C-14), 33.19 (CH2,
CCH2CH2), 53.14 (C, C-10), 53.50 (CH2, CCH2CH2), 53.68 [CH2,
N(CH2CH2)2O], 54.75 (C, C-8), 54.78 (CH3, OCH3), 66.78 [CH2,
N(CH2CH2)2O], 80.21 (C, C-4), 100.33 (C, C-1), 128.08 (C,
C=CH), 145.15 (CH, C=CH), 198.76 (C=O, C-9), 210.24 (C=O,
[19] Molecular mechanic calculations were run with the Insight
(2000) program with use of the Discover 3 calculation mode
(Accelerys, San Diego, USA). Consistence valence force fields
(CVFF) were used. Energetically optimised conformations
were determined by sampling structures during molecular dy-
namic simulations. They were run for 10 ps at 800 K by the
NVT method, with a 1 fs time step. From the energy/time
curves, six to seven minima were chosen and minimised. The
same iterative operations (dynamic simulations and minimis-
ation) were undertaken on these minima until no energy varia-
tion occurred. For each minimisation rms Ͻ 0.001.
[20] C. R. Chuit, J. P. Corriu, C. Reye, J. C. Young, Chem. Rev.
1993, 93, 1371.
C-7) ppm. IR: ν = 2977 to 2837 (C–H stretching for CH and CH ),
˜
2
3
2870 (O–CH3), 1716 (C=O), 1651 (C=O, α,β-unsaturated), 1599
(C=C), 1461 and 1377 (C–H deformation band for CH2 and CH3),
1170 (N–CH), 1100 (CH2–O–CH2) cm–1. SMBR: [APCI, MeOH,
formic acid 0.1%, 50:50, m/z (%)]: 382 [M + H]+. Rf (EtOAc) =
0.31. Log P (I-LAB Service: ACD/Log P v8.02): 2.11Ϯ0.70.
Received: February 1, 2007
Published Online: May 4, 2007
Eur. J. Org. Chem. 2007, 3095–3101
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3101