Total synthesis of the proposed structure of the anthrapyran metabolite δ-indomycinone

Article abstract of DOI:10.1002/chem.200700823

The first total synthesis of the proposed structure of δ-indomycinone has been accomplished. The key steps involve the Diels-Alder reaction of a bromonaphthoquinone (6) and 1-methoxy-3-methyl-1-trimethylsiloxy-1,3-butadiene (7) to access the anthraquinone

Full text of DOI:10.1002/chem.200700823

FULL PAPER
DOI: 10.1002/chem.200700823
Total Synthesis of the Proposed Structure of the Anthrapyran Metabolite
d-Indomycinone
Lutz F. Tietze,* Ramakrishna Reddy Singidi, and Kersten M. Gericke[a]
Dedicated to Professor Klaus Müllen on the occasion of his 60th birthday
Abstract: The first total synthesis of
the proposed structure of d-indomyci-
none has been accomplished. The key
steps involve the Diels–Alder reaction
of a bromonaphthoquinone (6) and 1-
methoxy-3-methyl-1-trimethylsiloxy-
1,3-butadiene (7) to access the anthra-
ics, regioselective bromination of an-
thraquinone (14) and a highly diaste-
reoselective alkylation of enantiomeri-
cally pure dioxolanone 8. The reported
synthetic approach has the advantage
of high yields, excellent selectivity and
a remarkable general applicability for
the total synthesis of other anthrapyran
natural products. The spectroscopic
data obtained for the synthetic com-
pounds 2 and 36 are not in agreement
with those reported for the natural
product, and therefore revision of the
assigned structure is required.
Keywords:
antibiotics
·
quinone skeleton, representing
a
cycloaddition · natural products ·
total synthesis
common building block of other natu-
rally occurring anthraquinone antibiot-
Introduction
against B. subtilis[3] and as well as antioxidative properties in
a test carried out using the DPPH method.[5]
Pluramycin antibiotics[1] containing the 4H-anthra
A
Thus, the observation of strong biological activities of an-
thrapyran antibiotics and the possibility of their application
in the treatment of various diseases such as cancer as well as
bacterial and viral infections should have made them attrac-
tive synthetic targets. However, from the synthetic point of
view the anthrapyran antibiotics were rather neglected thus
far and only a few approaches can be found in literature.[6]
A general access to anthrapyran antibiotics, especially those
with stereogenic centers in the side chain, has only recently
been accomplished within the total synthesis of the anthra-
pyran natural products AH-1763 IIa,[7] g-indomycinone,[8a–c]
and (S)-espicufolin.[8d]
b]pyran-4,7,12-trione nucleus 1 (Figure 1) to which amino
sugars such as angolosamine and vancosamine are typically
attached by C-glycosidic linkage at C-8 and C-10, are found
to have versatile and strong antimicrobial and anticancer ac-
tivities. These antibiotics, first described in 1956 by Umeza-
wa et al.,[2] are most commonly isolated from terrestrial
Streptomyces sp.; however, d-indomycinone (2), also con-
taining the skeleton 1, has recently been obtained by
Laatsch et al.[3] as a new member of the pluramycin family
from the culture broth of a marine actinomycete identified
as Streptomyces sp. (strain B 8300)[3] along with the known
b-indomycinone.[4] In contrast to the normal pluramycin an-
tibiotics, the indomycinones lack the amino sugar moieties
attached to the chromophore. It was mentioned that the
newly isolated compound exhibits antimicrobial activity
[a] Prof. L. F. Tietze, Dr. R. R. Singidi, Dr. K. M. Gericke
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität, Tammannstrasse 2
37077 Gçttingen (Germany)
E-mail: ltietze@gwdg.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Figure 1. Structural core of 4H-anthra
products (1) and proposed structure of d-indomycinone (2).
A
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9939

The constitution of d-indomycinone was established by
spectroscopic methods, but its relative as well as absolute
configuration in the side chain remained unknown. For that
reason, a total synthesis was necessary, not only to deter-
mine the absolute and relative stereochemistry of the com-
pound, but also to provide material for further biological
studies. In our continuous efforts toward the total synthesis
and structure determination of anthrapyran antibiotics,
herein, we disclose our approach toward the first enantiose-
lective total synthesis and structure determination of
(14R,18S)-d-indomycinone (2) and its (14R,18R)-diastereo-
mer (36).
product juglone (11).[9,10] Regioselective bromination[11] of
the latter was carried out using a literature-known proce-
dure to give 3-bromojuglone (12) as a pure isomer, which
was protected under mild conditions utilizing Agi2O and
benzyl bromide to furnish the desired benzyl ether of 3-bro-
mojuglone (6).[12] A Diels–Alder reaction of a naphthoqui-
none such as 6 and a diene such as 1-methoxy-3-methyl-1-
trimethylsiloxy-1,3-butadiene (7)[13] was chosen for the
straightforward construction of chrysophanol-8-benzyl ether
(14), a strategy which has been developed by Brassard and
Savard.[13] Thus, addition of diene 7 to the 3-bromojuglone
derivative 6 in benzene yielded the cycloaddition product
13, which was converted without further isolation into the
thermodynamically more stable anthraquinone derivative 14
by treatment with silica gel as mild acid. The regioselectivity
of this step was controlled by the bromine atom of the dien-
Results and Discussion
À
The retrosynthetic analysis of (14R,18S)-d-indomycinone (2)
is outlined in Scheme 1. The first disconnection in the
pyrone ring moiety envisions an intramolecular 6-endo-digo-
ophil which directed the carbon carbon bond formation
during the Diels–Alder reaction.[14] This method turned out
to be operationally simple and suitable for scaled up prepa-
rations of anthraquinone building block 14, which represents
a common precursor of other naturally occurring anthraqui-
none antibiotics. The yield of this two-step procedure could
be improved up to 94% yield, without observing the possi-
ble formation of O-methyl ether 17, a major side product in
Brassardꢁs protocol. The following regioselective bromina-
tion of anthraquinone 14 was feasible using NBS in the pres-
ence of a catalytic amount of a secondary amine[15] by
taking advantage of the strong ortho-directing effect of the
hydroxyl group under these conditions. Hence, the mono-
bromoanthraquinone (15) could be obtained in nearly quan-
titative yield (96%). The regioselectivity of both the bromi-
nation and the Diels–Alder reaction was unambiguously de-
1
duced from HMBC H NMR experiments. To complete the
synthesis of the building block 4 a protection of both the hy-
droxyl group and the quinone moiety was necessary. Follow-
ing an orthogonal protecting-group strategy the hydroxyl
group of bromoanthraquinone (15) was converted into the
corresponding isopropyl ether 16 in 90% yield by treatment
with iPrI and Cs2CO3 in a mixture of acetone and N,N-dime-
thylformamide.[16] Finally, the reductive methylation[17] of
the quinone was realized using aqueous sodium dithionite to
furnish the air- and light-sensitive hydroquinone, which un-
derwent methylation by subsequent treatment with KOH
and dimethylsulfate to obtain the air- and light-sensitive di-
methoxyanthracene (4) in an excellent overall yield of 90%.
The use of two different protecting groups in the building
block 4 has the advantage over the corresponding building
block with two isopropyl ether moieties[7] that deprotection
of the less activated A-ring as one of the last steps should
not cause any problems.
As outlined in Scheme 3, our synthesis of the propargylic
aldehyde 5 started from commercially available (S)-3-hy-
droxybutanoic acid. Treatment of the b-hydroxy ester 18
with benzyl 2,2,2-trichloroacetimidate under acidic condi-
tions[18] afforded benzyl ether 19. Reduction of the ester
moiety in 19 with LiAlH4 yielded the primary alcohol 20 in
92% yield and its tosylation[19] utilizing TosCl and pyridine
Scheme 1. Retrosynthetic analysis of (14R,18S)-d-indomycinone (2).
nal cyclization of ynone derivative 3, which in turn should
result from a nucleophilic attack of an aryllithium species
generated from the bromodimethoxyanthracene derivative 4
onto the propargylic aldehyde 5.
The desired dimethoxyanthracene derivative 4 was divid-
ed into two fragments 6 and 7, which were planned to be
coupled by a Diels–Alder cycloaddition. Finally, the propar-
gylic aldehyde 5 should be accessible by the usage of a ste-
reoselective alkylation employing the enantiopure dioxola-
none 8 and alkyl iodide 9.
The first step of our synthesis was the CuICl-mediated air
oxidation of commercially available 1,5-dihydroxynaphtha-
lene 10 (Scheme 2) yielding the naphthoquinone natural
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Chem. Eur. J. 2007, 13, 9939 – 9947

d-Indomycinone
FULL PAPER
bromide 27 with nBuLi fol-
lowed by formylation with N,N-
dimethylformamide furnished
the desired propargylic alde-
hyde 5 in 82% yield.[25]
With building blocks 4 and 5
in hand, we next turned our at-
tention to the coupling of these
intermediates. After conversion
of 4 to the lithium derivative by
bromine lithium exchange using
nBuLi at low temperature, the
subsequent reaction with prop-
argylic aldehyde 5 proceeded
smoothly to give the corre-
sponding alcohol 28 in 80%
yield (Scheme 4) as a mixture
of both possible diastereomers
Scheme 2. a) O2, CuiCl, CH3CN, RT, 8 h, 55%; b) 1) Br2, AcOH, RT, 10 min, 2) EtOH, reflux, 15 min, 80%;
c) AgiiO, BnBr, CH2Cl2, RT, 24 h, 99%; d) benzene, RT, 6 h; e) SiO2, CH2Cl2, RT, 24 h, 94% overall yield for
two steps; f) NBS, cat. iPr2NH, CH2Cl2, RT, 12 h, 96%; g) Cs2CO3, iPrI, acetone/DMF 3:1, reflux, 12 h, 90%;
h) Na2S2O4, TBABr, KOH, H2O, DMSO4, THF, RT, 8 h, 90%.
1
in a ratio of 1:1 according to H
and 13C NMR spectra of the
product. The missing selectivity
at this point has no further con-
sequence since the formed ste-
furnished the tosylate 21, which was transformed into the
alkyl iodide 9 in 86% overall yield over two steps by treat-
ment with NaI.[19] Our attention was next turned to the dia-
stereoselective alkylation of the enantiomerically pure diox-
olanone 8[20] using LDA with alkyl iodide 9. Generation of
the lithium enolate derived from dioxolanone 8 employing
LDA followed by addition of the alkyl iodide 9 cleanly pro-
vided coupling product 22 in excellent 96% yield with high
diastereoselectivity (94%).[20,21] The structure was assigned
to the product 22 based on liter-
reogenic alcohol is later removed by oxidation to the corre-
sponding ketone. It was important to add aldehyde 5 imme-
diately after generation of the organolithium compound to
avoid the formation of the debrominated compound as side
product. Oxidative demethylation of anthracene derivative
[26]
28 using AgiiO/HNO3 yielded anthraquinone derivative 29
in 90% yield, which was subsequently subjected to IBX oxi-
dation[23] to afford ynone derivative 30 in 95% yield. The
ature precedent.[20] It is worth-
while to note that deprotona-
tion of 8 using bases such as
LiHMDS,
KHMDS
and
NaHMDS followed by treat-
ment with the iodide 9 did not
yield the desired product 22;
only starting material was re-
covered under these conditions.
The transesterification[22] of di-
oxolanone 22 with sodium
methoxide in absolute metha-
nol followed by benzyl protec-
tion of the resulting tertiary al-
cohol 23 gave methyl ester 24.
Reduction of the latter using
LiAlH4 delivered the primary
alcohol 25. The following oxida-
tion utilizing the very mild
IBX[23] reagent gave the alde-
hyde 26 in 90% yield, which
was subjected to a Corey–Fuchs
homologation[24] affording vinyl
dibomide 27 in 86% yield. Sub-
Scheme 3. a) Benzyl trichloroacetimidate, cat. TfOH, cyclohexane/CH2Cl2 2:1, RT, 1 h, 87%; b) LiAH4, THF,
08C, 30 min, 92%; c) TsCl, pyridine, DMAP, 08C, 5 h; d) NaI, NaHCO3, acetone, RT, 24 h, 86%; e) LDA,
THF, À78 to 08C, 4 h, 96%; f) NaOMe, MeOH, 08C, 2 h, 88%; g) BnBr, NaH, cat. TBAI, THF, 08C to RT,
12 h, 92%; h) LiAH4, THF, 08C, 30 min, 96%; i) IBX, CH2Cl2, DMSO, RT, 4 h, 90%; j) PPh3, CBr4, Zn,
sequent treatment of vinyl di- CH2Cl2, RT, 12 h, 86%; k) nBuLi, THF, DMF, À78 to 08C, 6 h, 82%.
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L. F. Tietze et al.
Unfortunately, comparison of
1
the H NMR spectroscopic data
of synthetic (14R,18S)-d-indo-
mycinone (2) with those report-
ed for the isolated d-indomyci-
none revealed that they were
not identical. It should be noted
that due to the low solubility of
the synthetic compound 2 in
CDCl3 it was difficult to obtain
13C NMR spectroscopic data in
CDCl3 for comparison. A care-
ful examination of the chemical
shifts of the synthetic and natu-
ral product revealed that 2-H
and 18-H of (14R,18S)-d-indo-
mycinone (2) resonate at d=
6.62 and 3.88–3.96 ppm, respec-
tively, whereas the reported
data for these protons in the
isolated compound are d=6.30
and 3.22 ppm.
Scheme 4. a) nBuLi, THF, À788C, 10 min, 80%; b) AgiiO, dioxane, 4n HNO3, RT, 30 min, 90%; c) IBX,
CH2Cl2, DMSO, RT, 4 h, 95%; d) AcOH, cat. H2SO4, 558C, 30 min, 86%; e) Cs2CO3, acetone, 0 to 58C,
30 min, 42%; f) TiCl4, CH2Cl2, À78 to À208C, 2 h, 80%.
For that reason we synthe-
sized the other possible diaste-
reomer 36 as a mixture with 2
planned approach was to remove the isopropyl protecting
group at the anthraquinone moiety and perform the ring
closure under acidic conditions in a domino process.[27] How-
ever, treatment of a solution of 30 in acetic acid at 558C
with a catalytic amount of sulfuric acid led to cleavage of
the benzyl and isopropyl ethers at the anthraquinone to give
3, but a cyclization was not observed under these conditions.
Moreover, raising the tempera-
in order to compare again the analytical data. Thus,
(14R,18S)-d-indomycinone (2) and (14R,18R)-d-indomyci-
none (36; Scheme 5) were prepared starting from racemic b-
hydroxy ester 32 following the synthetic route established
for the synthesis of (14R,18S)-d-indomycinone (2).
As expected, the 1H NMR data of the diastereomer
(14R,18R)-d-indomycinone (36) were different from those
ture and increasing the reaction
time did not lead to a cycliza-
tion but induced an elimination
of the benzyloxy group in the
side chain. Finally, the pyron
ring construction could be ach-
ieved under basic conditions.
Thus, treatment of compound 3
in acetone with Cs2CO3 yielded
compound 31 in 42% yield via
an intramolecular 6-endo-digo-
nal cyclization.[28] The pyrone
ring construction in compound
31 was unambiguously deduced
from HMBC 1H NMR experi-
ments. The final step in the syn-
thesis of (14R,18S)-d-indomyci-
none (2) was the removal of the
benzyl protecting groups which
were effected in 80% yield by
treatment of 31 with TiCl4 in
CH2Cl2 at À788C and then slow
warming up to À208C.[15d]
Scheme 5. a) Benzyl trichloroacetimidate, cat. TfOH, cyclohexane/CH2Cl2 2:1, RT, 1 h, 87%; b) LiAH4, THF,
08C, 30 min, 92%; c) TsCl, pyridine, DMAP, 08C, 5 h; d) NaI, NaHCO3, acetone, RT, 24 h, 86%; e) LDA,
THF, À78 to 08C, 4 h, 90%; f) NaOMe, MeOH, 08C, 2 h, 88%; g) BnBr, NaH, TBAI, THF, 08C to RT, 12 h,
92%; h) LiAH4, THF, 08C, 30 min, 96%; i) IBX, CH2Cl2, DMSO, RT, 2 h, 90%; j) PPh3, CBr4, Zn, CH2Cl2,
RT, 12 h, 86 %; k) nBuLi, THF, DMF, À78 to 08C, 3 h, 82%; l) nBuLi, THF, À788C, 10 min, 80%; m) AgiiO,
dioxane, 4n HNO3, RT, 30 min, 90%; n) IBX, CH2Cl2, DMSO, RT, 4 h, 95%; o) AcOH, cat. H2SO4, 558C,
30 min, 84%; p) Cs2CO3, acetone, 0 to 58C, 30 min, 42%; q) TiCl4, CH2Cl2, À78 to À208C, 2 h, 75%.
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d-Indomycinone
FULL PAPER
duced pressure. The crude product was purified in a Soxhlet extractor
with n-heptane (1.6 L) as solvent to afford 11 (53.7 g, 55%) as orange-
red needles.[9,10] M.p. 1548C; 1H NMR (300 MHz, CDCl3): d=11.91 (s,
1H, OH), 7.69–7.60 (m, 2H, 7-H, 8-H), 7.29 (dd, J=7.3, 2.5 Hz, 1H, 6-
H), 6.96 ppm (s, 2H, 2-H, 3-H); 13C NMR (50.3 MHz, CDCl3): d=190.2,
184.2, 161.4, 139.5, 138.59, 136.5, 131.7, 124.4, 119.1, 114.9 ppm; IR
(KBr): n˜ =3386, 3070, 1665, 1644, 1600, 1486, 1451, 1364, 1338, 1290,
found for 2, but they also did not match with the signals
published for the proposed natural d-indomycinone (2).
Thus, 2-H and 18-H in 36 resonate at d=6.67 and 4.03–
4.14 ppm, respectively (see the Supporting Information for
NMR spectra), whereas signals at d=6.30 and 3.22 ppm, re-
spectively, were reported for the natural compound.
1226 cmÀ1
; UV (CH3CN): lmax (lg e)=207.5 (4.508), 248.5 (4.128),
1
Since the comparison of the H NMR data published for
the isolated d-indomycinone with those of the two possible
420.0 nm (3.540); MS (EI, 70 eV): m/z (%): 174.0 (100) [M]+, 146.0 (10)
[MÀCO]+, 118 (36) [MÀC2O2]+; elemental analysis calcd (%) for
C10H6O3 (174.15): C 68.97, H 3.47; found: C 69.09, H 3.38.
diastereomers
(14R,18S)-d-indomycinone
(2)
and
(14R,18R)-d-indomycinone (37) unequivocally demonstrated
that neither of them are consistent with the data reported
for the natural product, we have to presume that the isolat-
ed compound does not have the proposed structure 2.
Compound 12: A suspension of juglone 11 (12.0 g, 68.9 mmol) in acetic
acid (180 mL) was treated in the dark at 258C with bromine (68.9 mmol,
3.60 mL). After stirring for 15 min, the reaction mixture was poured onto
ice. The resultant slurry was stirred for 10 min after which the dibromi-
nated intermediate was filtered off under reduced pressure. The pale-
orange solid was washed with a little amount of ice-water and then im-
mediately treated with ethanol (80 mL) and stirred for 10 min under
reflux using a pre-heated oil bath. The mixture was cooled down to 208C
and the red precipitate was filtered off under reduced pressure. The resi-
due was washed with a small amount of cold ethanol and then subjected
to silica gel flash chromatography (CH2Cl2). Concentration of the appro-
priate fractions in vacuo furnished 3-bromojuglone 12 (14.0 g, 80%) as
an orange solid. M.p. 1688C; 1H NMR (300 MHz, CDCl3): d=11.73 (s,
1H, OH), 7.68 (t, J=7.4 Hz, 1H, 7-H), 7.64 (dd, J=7.4, 2.0 Hz, 1H, 8-
H), 7.50 (s, 1H, 2-H), 7.31 ppm (dd, J=7.5, 2.0 Hz, 1H, 6-H); 13C NMR
(50.3 MHz, CDCl3): d=182.8, 181.6, 162.0, 141.2, 139.3, 137.2, 131.6,
124.7, 119.9, 113.9 ppm; IR (KBr): n˜ =3421, 3051, 1655, 1630, 1582, 1487,
1458, 1363, 1291, 1275, 1214 cmÀ1; UV (CH3CN): lmax (lg e)=212.0
(4.462), 247.5 (3.705), 282.0 (4.041), 426.5 nm (3.515); MS (EI, 70 eV): m/
Conclusion
In summary, based on the unambiguous synthesis of the two
possible diastereomers 2 and 36 having the proposed consti-
tution of d-indomycinone it is concluded that the originally
anticipated structure for the natural product is untenable
and that structural revision will be necessary. The strategy
for the synthesis of the proposed structure of d-indomyci-
none presented here can easily be adopted for the synthesis
of other pluramycin antibiotics described in the literature,
and furthermore it also allows the preparation of unnatural
analogues with possibly higher biological activity.
z
(%): 253.9, 251.9 (100) [M]+, 173.0 (50) [MÀBr]+, 145.0 (46)
[MÀBrÀCO]+; HRMS (EI): m/z: calcd for C10H5BrO3: 251.9422; found:
251.9422; elemental analysis calcd (%) for C10H5BrO3 (253.05): C 47.46,
H 1.99; found: C 47.72, H 2.05.
Compound 6: Benzylbromide (0.47 mL, 4.00 mmol) was added to a mix-
ture of 3-bromojuglone 12 (506 mg, 2.00 mmol) and silver(I) oxide
(684 mg, 4.00 mmol) in CH2Cl2 (13 mL) and the resulting suspension was
stirred for 12 h at 258C. Then, additional silver(I) oxide (342 mg,
2.00 mmol) and benzylbromide (0.23 mL, 2.00 mmol) was added and stir-
ring was continued for another 12 h (TLC control). The mixture was fil-
tered trough a plug of Celite and the filter cake was rinsed carefully with
CH2Cl2. After removal of the solvent under reduced pressure, the crude
product was subjected to silica gel flash chromatography (CH2Cl2). Con-
centration of the appropriate fractions in vacuo afforded naphthoquinone
6 (672 mg, 98%) as a yellow solid. M.p. 1078C; 1H NMR (300 MHz,
CDCl3): d=7.73 (dd, J=7.8, 1.0 Hz, 1H, 8-H), 7.66 (t, J=8.1 Hz, 1H, 7-
H), 7.58 (brd, J=7.8 Hz, 2H, 2”o-Ph-H), 7.46–7.30 (m, 5H, p-Ph-H, 6-
H, 2”m-Ph-H, 2-H), 5.29 ppm (s, 2H, CH2Ph); 13C NMR (50.3 MHz,
CDCl3): d=182.5, 176.0, 159.2, 142.6, 138.3, 135.6, 135.4, 133.9, 128.7,
128.0, 126.7, 119.7, 119.6, 119.0, 70.95 ppm; IR (KBr): n˜ =3063, 2923,
1671, 1583, 1452, 1310, 1281, 1204, 1149, 1026 cmÀ1; UV (CH3CN): lmax
(lg e)=238.0 (4.108), 277.0 (4.058), 347.0 (3.334), 402.5 nm (3.496); MS
(EI, 70 eV): m/z (%): 344.0, 342.0 (14) [M]+, 91.0 (100) [C7H7]+; elemen-
tal analysis calcd (%) for C17H11BrO3 (343.17): C 59.50, H 3.23; found: C
59.25, H 3.09.
Experimental Section
General: All reactions were performed in flame-dried glassware under
an atmosphere of argon and the reactants were introduced by syringe.
Solvents were dried and purified according to the method defined by
Perrin and Armarego.[29] Commercial reagents were used without further
purification. Thin-layer chromatography (TLC) was carried out on pre-
coated Alugram SIL G/UV254 (0.25 mm) plates from Macherey-Nagel.
Column chromatography was carried out on silica gel 60 from Merck
with particle size 0.063–0.200 mm for normal pressure and 0.020–
0.063 mm for flash chromatography (P=pentane). Melting points were
recorded on a Mettler FP61 and are uncorrected. IR spectra were deter-
mined on a Bruker Vektor 22 (KBr pellets or films), UV/Vis spectra on a
Perkin-Elmer Lambda 2 (CH3CN), and mass spectra on a Finnigan MAT
95, and a Bioapex fourier transformation ion cyclotron resonance mass
1
spectrometer for ESI-HRMS. H NMR spectra were recorded either on a
Varian Mercury 300, Unity 300 or Inova 600 spectrometer. 13C NMR
spectra were recorded at 50 or 75 MHz. Spectra were taken at room tem-
perature in deuterated solvents as indicated using the solvent peak or
TMS as internal standard. Elemental analysis was performed at the Mik-
roanalytisches Labor des Institutes für Organische und Biomolekulare
Chemie der Universität Gçttingen.
Compound 14: Diene 7 (1.10 g, 5.88 mmol) was added at 08C dropwise
with stirring within 10 min to a solution of juglone derivative 6 (672 mg,
1.96 mmol) in benzene (19 mL). After being stirred for 1 h at 08C, the
mixture was warmed to 208C and stirring was continued for additional
5 h. Afterwards, the reaction mixture was poured onto silica gel (40 g),
CH2Cl2 (200 mL) was added, and then the suspension was stirred for
24 h. After removing the solvent under reduced pressure, the silica gel
was eluted carefully with CH2Cl2/MeOH 10:1 and the combined organic
fractions were concentrated in vacuo to afford the crude product. This
material was subjected to silica gel flash chromatography (CH2Cl2) and
concentration of the appropriate fractions in vacuo furnished anthraqui-
Compound 11:
A suspension of freshly recrystallized CuCl (12.0 g,
0.121 mol) in acetonitrile (500 mL) was placed in a 4 L three-neck flask
fitted with a mechanical stirrer and a gas inlet tube and a strong current
of air was bubbled through it. A suspension of 1,5-dihydroxynaphthalene
10 (30.0 g, 0.187 mol) in acetonitrile (500 mL) was added with vigorous
stirring at 208C in the dark over 30 min. Afterwards, another amount of
CuCl (12.0 g, 0.121 mol) was added followed by the addition of 10
(30.0 g, 0.187 mol) in acetonitrile (500 mL) over 30 min. This procedure
was carried out again with the same amount of reactants (CuCl, 12.0 g,
0.121 mol; 10, 30.0 g, 0.187 mol in 500 mL acetonitrile). The resulting
mixture was stirred for 8 h and then the solvent was removed under re-
none 14 (633 mg, 94%) as
(300 MHz, CDCl3): d=13.03 (s, 1H, OH), 7.93 (m, J=7.6, 0.8 Hz, 1H, 5-
a
yellow solid. M.p. 2188C; 1H NMR
Chem. Eur. J. 2007, 13, 9939 – 9947
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9943

L. F. Tietze et al.
H), 7.65 (t, J=8.2 Hz, 1H, 6-H), 7.60 (s, 1H, 4-H), 7.57 (m, 2”o-Ph-H),
7.43 (t, J=7.3 Hz, 2H, 2”m-Ph-H), 7.38–7.30 (m, 2H, 7-H, p-Ph-H), 7.08
(s, 1H, 2-H), 5.33 (s, 2H, OCH2Ph), 2.42 ppm (s, 3H, Ar-CH3); 13C NMR
(50.3 MHz, CDCl3): d=188.2, 182.9, 162.7, 159.7, 147.4, 136.1, 135.9,
135.3, 132.4, 128.7, 128.0, 126.7, 124.5, 121.5, 120.4, 118.0, 119.9, 115.1,
71.22, 22.0 ppm; IR (KBr): n˜ =3035, 1672, 1638, 1585, 1489, 1.444, 1365,
1301, 1271, 1240, 1205 cmÀ1; UV (CH3CN): lmax (lg e)=192.5 (4.721),
223.0 (4.469), 257.0 (4.258), 412.5 nm (3.834); MS (EI, 70 eV): m/z (%):
344.3 (42) [M]+, 91.1 (100) [C7H7]+; HRMS (ESI): m/z: calcd for
C22H16O4+H+: 345.11214; found: 345.11219; elemental analysis calcd
(%) for C22H16O4+Na+: 367.09408; found: 367.09419.
fractions in vacuo afforded anthracene 4 (681 mg, 1.38 mmol, 90%) as a
yellow oil. H NMR (300 MHz, CDCl3): d=7.89 (s, 1H, 4-H), 7.85 (d, J=
8.4 Hz, 1H, 5-H), 7.70–7.65 (m, 2H, 2”m-Ph-H), 7.47–7.33 (m, 4H, 6-H,
2”o-Ph-H, p-Ph-H), 6.87 (d, J=8.4 Hz, 1H, 7-H), 5.28 (s, 2H, OCH2Ph),
1
4.79–4.68 (m, 1H, OCH
ACHTREUNG
2.63 (s, 3H, Ar-CH3), 1.22–1.47 ppm (brs, 6H, OCH
AHCTREUNG
(125 MHz, CDCl3): d=156.20, 150.47, 149.37, 147.22, 137.37, 135.97,
128.39, 127.67, 127.56, 127.21, 126.06, 125.77, 120.28, 120.01, 119.32,
117.65, 115.14, 106.54, 78.07, 71.43, 63.87, 62.72, 24.76, 22.05 ppm; HRMS
(ESI): calcd for C27H27BrO4 + H+: 495.11655; found: 495.11674.
Compound 20: A solution of ester 19 (772 mg, 3.48 mmol) in THF
(4 mL) was added at 08C to a stirred suspension of LiAH4 (128 mg,
3.48 mmol) in THF (12 mL) and stirring was continued at the same tem-
perature for 30 min. The reaction mixture was diluted with diethyl ether
and quenched by adding ice. The reaction mixture was passed through a
small pad of Celite and the filtrate evaporated under reduced pressure to
afford the crude product which was purified by silica gel column chroma-
tography using 20% EtOAc/pentane to yield the alcohol 20 (576 mg,
Compound 15: A solution of anthraquinone 14 (633 mg, 1.84 mmol) in
CH2Cl2 (25 mL) was treated at 258C with a catalytic amount of diisopro-
pylamine (6 drops) and then a solution of NBS (480 mg, 2.70 mmol) in
CH2Cl2 (20 mL) was added dropwise during 10 min. After being stirred
for 8 h (TLC control), additional NBS (81 mg, 0.46 mmol) was added and
stirring was continued for another 4 h. Afterwards, the reaction mixture
was diluted with CH2Cl2 (100 mL) and washed subsequently with aque-
ous 0.2n HCl (250 mL) and H2O (250 mL). The organic layer was dried
(MgSO4), filtered, and concentrated under reduced pressure. The crude
product was subjected to silica gel flash chromatography (CH2Cl2) and
concentration of the appropriate fractions in vacuo afforded anthraqui-
none 15 (730 mg, 96%) as an orange solid. M.p. 2388C; 1H NMR
(300 MHz, CDCl3): d = 13.95 (s, 1H, OH), 7.95 (d, J=7.6 Hz, 1H, 5-H),
7.73–7.66 (m, 2H, 6-H, 4-H), 7.61–7.55 (m, 2H, 2”o-Ph-H), 7.47–7.31
(m, 4H, 7-H, 2”m-Ph-H, p-Ph-H), 5.37 (s, 2H, OCH2Ph), 2.56 ppm (s,
3H, Ar-CH3); 13C NMR (75 MHz, CDCl3): d=187.99, 182.44, 159.85,
159.23, 147.33, 136.25, 135.83, 135.81, 135.58, 130.46, 128.76, 128.11,
126.65, 121.68, 120.91, 120.52, 120.43, 120.23, 120.04, 115.20, 71.15,
24.20 ppm; IR (KBr): n˜ =2869, 1670, 1633, 1582, 1479, 1442, 1382, 1365,
1263, 1240, 1188, 1139, 1055, 1010 cmÀ1; UV (CH3CN): lmax (lg e)=228.5
(4.476), 261.5 (4.385), 416.0 nm (3.976); HRMS (ESI): m/z: calcd for
C22H15BrO4+H+: 423.01541; found: 423.01538.
1
92%) as viscous oil. [a]2D0 =+18.6 (c=1.1 in CHCl3); H NMR (300 MHz,
CDCl3): d=7.59–7.08 (m, 5H, Ph), 4.63 (d, J=11.7 Hz, 1H, C-3-
OCHaPh), 4.43 (d, J=11.7 Hz, 1H, C-3-OCHbPh), 3.86–3.60 (m, 3H, 1-
H2, 3-H1), 2.79–2.30 (brs, 1H, OH), 1.83–1.68 (m, 2H, 2-H2), 1.24 ppm
(d, J=6.8 Hz, 3H, 4-H3); 13C NMR (125 MHz, CDCl3): d=138.28,
128.44, 127.70, 127.66, 74.61, 70.38, 60.84, 38.65, 19.29 ppm; IR (KBr):
n˜ =1453, 1376, 1279, 1054 cmÀ1; UV (CH3CN): lmax (lg e)=251.0 (2.628),
256.5 (2.622), 261.5 nm (2.586); MS (EI, 70 eV): m/z (%): 181.1 (16)
[M+H]+, 179.1 (43), 123.1 (25), 107.1 (100), 105.0 (50), 79.0 (30).
Compound 21: pTsCl (912 mg, 4.80 mmol) was added at 08C to a stirred
solution of 20 (576 mg, 3.20 mmol) in pyridine (5 mL), and the mixture
was stirred at 08C for 5 h. After addition of crashed ice, the resulting
mixture was stirred vigorously for 10 min, poured into ice water, and
then extracted with Et2O. The extracts were washed successively with
water, cold 1n HCl solution, water, sat. NaHCO3 solution, water, and
brine and concentrated to yield the tosylate 21 (1.00 g), which was used
without further purification in the next step. [a]2D0 =+40.0 (c=1.3 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.78 (d, J=8.9 Hz, 2H, 2”m-
Tol-H), 7.34–7.21 (m, 7H, Ph, 2”o-Tol-H), 4.50 (d, J=11.4 Hz, 1H, C-3-
OCHaPh), 4.26 (d, J=11.4 Hz, 1H, C-3-OCHbPh), 4.21–4.09 (m 2H, 1-
H2), 3.69–3.58 (m, 1H, 3-H1), 2.40 (s, 3H, Tol-CH3), 1.85–1.79 (m, 2H, 2-
H2), 1.17 ppm (d, J=6.1 Hz, 3H, 4-H3); 13C NMR (125 MHz, CDCl3): d=
144.69, 138.38, 132.95, 129.80, 128.30, 127.87, 127.55, 127.52, 70.93, 70.60,
67.56, 36.14, 21.59, 19.46 ppm; IR (KBr): n˜ =1356, 1179, 939, 887,
555 cmÀ1; UV (CH3CN): (lg e)=257.5 (2.971), 272.5 (2.802), 261.5 nm
(2.990); MS (EI, 70 eV): m/z (%): 334.2 (8) [M]+, 250.1 (6), 172.1 (35),
155.1 (18), 91.1 (100).
Compound 16: A solution of anthraquinone 15 (730 mg, 1.72 mmol) in a
mixture of acetone (57 mL) and DMF (17 mL) was treated subsequently
at 208C with Cs2CO3 (1.68 g, 5.16 mmol) and 2-iodopropane (0.34 mL,
3.44 mmol). After being stirred for 12 h under reflux, the reaction mix-
ture was filtered through a plug of Celite. The filter cake was rinsed care-
fully with CH2Cl2 and then the combined organic phases were concen-
trated under reduced pressure. The residue was dissolved in CH2Cl2
(150 mL) and washed subsequently with aqueous 2m Na2CO3 (100 mL)
and brine (100 mL). The organic layer was dried (MgSO4), filtered, and
concentrated under reduced pressure. The crude product was subjected
to silica gel flash chromatography (CH2Cl2) and concentration of the ap-
propriate fractions in vacuo afforded anthraquinone 16 (719 mg, 90%) as
a yellow solid. M.p. 1658C; 1H NMR (300 MHz, CDCl3): d=7.88–7.83
(m, 2H, 4-H, 5-H), 7.67–7.60 (m, 3H, 6-H, 2”o-Ph-H), 7.45–7.29 (m, 4H,
7-H, 2”m-Ph-H, p-Ph-H), 5.29 (s, 2H, OCH2Ph), 4.52–4.39 (m, 1H,
Compound 9: A mixture of tosylate 21 (1.00 g), NaI (715 mg, 4.80 mmol)
and NaHCO3 (391 mg, 5.40 mmol) in dry acetone (10 mL) was stirred for
24 h at 208C. Afterwards, the solution was concentrated in vacuo and the
residue was diluted with water and extracted with Et2O. The extract was
washed successively with water, 10% Na2S2O3 solution, water, brine and
evaporated under reduced pressure to afford the crude product which
was purified by silica gel column chromatography using 10% EtOAc/
pentane to yield alkyl iodide 9 (800 mg, 86% overall yield for two steps)
as liquid. [a]2D0 =+67.3 (c=2.1 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=7.34–7.24 (m, 5H, Ph), 4.50 (d, J=11.3 Hz, 1H, C-3-OCHaPh), 4.43
(d, J=11.3 Hz, 1H, C-3-OCHbPh), 3.70–3.56 (m, 1H, 3-H1), 3.30–3.24
(m, 2H, 1-H2), 1.05–2.92 (m, 2H, 2-H2), 1.18 ppm (d, J=6.4 Hz, 3H, 4-
H3); 13C NMR (50 MHz, CDCl3): d=138.71, 128.53, 127.90, 127.73, 74.60,
70.80, 40.65, 18.93, 2.92 ppm; IR (KBr): n˜ =1453, 1374, 1252, 1127, 1066,
734, 697 cmÀ1; UV (CH3CN): lmax (lg e)=252.0 (2.871), 257.0 nm (2.869);
MS (EI, 70 eV): m/z (%): 290.1 (14) [M]+, 135.1 (30), 91.1 (100),
65.0(12).
OCH
A
ACHTREUNG
145.04, 136.30, 134.85, 134.02, 132.53, 130.53, 128.49, 127.82, 127.16,
126.83, 126.71, 123.54, 119.73, 119.36, 79.44, 70.90, 24.47, 22.28 ppm; IR
(KBr): n˜ =2973, 1672, 1583, 1498, 1446, 1352, 1312, 1291, 1233, 1102,
788 cmÀ1; UV (CH3CN): lmax (lg e)=263.0 (4.453), 372.5 nm (3.792);
HRMS (ESI): m/z: calcd for C25H21BrO4
+
H+: 465.06960; found:
465.06987.
Compound 4: A solution of anthraquinone 16 (719 mg, 1.54 mmol) and
tetra-n-butylammonium bromide (148 mg, 0.46 mmol) in THF (22 mL)
was treated at 208C with a solution of Na2S2O4 (1.60 g 9.24 mmol) in
H2O (4 mL) and stirred for 25 min. Afterwards, a solution of KOH
(1.98 g, 35.0 mmol) in H2O (2 mL) was added (the yellow solution turned
into deep-red) and stirring was continued for additional 15 min. After ad-
dition of dimethyl sulfate (1.5 mL), the reaction mixture was stirred for
8 h (the solution turned back into yellow) and then poured into H2O
(50 mL). The resulting solution was extracted with CH2Cl2 (3”50 mL)
and the combined organic layers were dried (MgSO4), filtered and con-
centrated under reduced pressure. The crude product was subjected to
silica gel column filtration (CH2Cl2) and concentration of the appropriate
Compound 22: nBuLi (2.5m in hexane, 2.1 mL, 5.25 mmol) was added
dropwise at À788C to
a solution of diisopropyl amine (0.78 mL,
5.51 mmol) in THF (35 mL). After 10 min, the white slurry was warmed
to À108C for 30 min. After the solution was cooled back to À788C, a so-
lution of dioxolanone 8 (790 mg, 5.00 mmol) in THF (2 mL) was added
dropwise to the solution. After 40 min, a solution of alkyl iodide 9
9944
www.chemeurj.org
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Chem. Eur. J. 2007, 13, 9939 – 9947

d-Indomycinone
FULL PAPER
(727 mg, 2.50 mmol) in THF (2 mL) was added dropwise. After 30 min,
the reaction was warmed slowly to À108C over 3 h and quenched by the
addition of a sat. aq. NH4Cl solution. The aqueous layer was extracted
with Et2O and the organic layer washed with water, brine and dried over
Na2SO4. The solvent was evaporated under reduced pressure to afford
the crude product which was purified by silica gel chromatography using
25% EtOAc/pentane to yield compound 22 (768 mg, 96%) as a liquid.
[a]2D0 =+39.7 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.35–
7.32 (m, 5H, Ph), 5.17 (s, 1H, CH-tBu), 4.54 (d, J=11.3 Hz, 1H, C-6-
OCHaPh), 4.44 (d, J=11.3 Hz, 1H, C-6-OCHbPh), 3.58–3.47 (m, 1H, 6-
H1), 1.99–1.90 (m, 1H, 4-Ha), 1.75–1.59 (m, 3H, 4-Hb, 5-H2), 1.43 (s, 3H,
3-H3), 1.21 (d, J=6.0 Hz, 3H, 7-H3), 0.94 ppm (s, 9H, tBu); 13C NMR
(75 MHz, CDCl3): d=175.71, 138.72, 128.33, 127.59, 127.48, 108.30, 79.61,
74.31, 70.33, 34.51, 31.89, 30.37, 23.29, 22.50, 19.44 ppm; IR (KBr): n˜ =
2965, 1796, 1376, 1075, 982, 736 cmÀ1; UV (CH3CN): lmax (lg e)=252.0
(2.341), 258.0 (2.341), 263.5 nm (2.292); HRMS (ESI): calcd for C19H28O4
+ H+: 321.20604; found: 321.20603.
Compound 25: A solution of ester 24 (690 mg, 1.94 mmol) in THF
(4 mL) was added at 08C to a stirred suspension of LiAH4 (143 mg,
3.88 mmol) in THF (6 mL) and stirring was continued at the same tem-
perature for 30 min. The reaction mixture was diluted with Et2O and
quenched by adding ice. The reaction mixture was passed through a
small pad of Celite and the filtrate evaporated under reduced pressure to
afford the crude product which was purified by silica gel column chroma-
tography using 25% EtOAc/pentane to yield alcohol 25 (610 mg, 96%)
as viscous oil. [a]2D0 =+11.7 (c=1.1 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.34–7.25 (m, 10H, 2”Ph), 4.58 (d, J=11.4 Hz, 1H, C-6-
OCHaPh), 4.46–4.42 (m, 3H, C-6-OCHbPh, C-2-OCH2Ph), 3.58–3.45 (m,
3H, 6-H1, 1-H2), 2.05–1.99 (m, 1H, 4-Ha), 1.83–1.72 (m, 1H, 4-Hb), 1.65–
1.52 (m, 2H, 5-H2), 1.24 (s, 3H, 3-H3), 1.21 ppm (d, J=6.4 Hz, 3H, 7-H3);
13C NMR (75 MHz, CDCl3): d=139.05, 138.84, 128.39, 128.33, 127.64,
127.46, 127.41, 127.38, 77.58, 75.06, 70.37, 67.23, 63.59, 30.74, 30.48, 2026,
19.57 ppm; IR (KBr): n˜ =2968, 1651, 1453, 1067 cmÀ1; UV (CH3CN): lmax
(lg e)=252.0 (2.463), 257.5 (2.563), 263.0 nm (2.476); HRMS (ESI): m/z:
calcd for C21H28O3 + H+: 329.21111; found: 329.21104.
Compound 34: Compound 34 was prepared from the dioxolanone 8 and
alkyl iodide 33 following the procedure described for the preparation of
the compound 22. 1H NMR (300 MHz, CDCl3): d=7.24–7.38 (m, 10H,
2”Ph), 5.17 (s, 1H, CH-tBu), 5.14 (s, 1H, CH-tBu), 4.54 (d, J=11.3 Hz,
2H, 2”C-6-OCHaPh), 4.44 (d, J=11.3 Hz, 2H, 2”C-6-OCHaPh), 3.57–
3.48 (m, 2H, 2”6-H1), 2.01–1.88 (m, 2H, 2”4-Ha), 1.79–1.52 (m, 6H, 2”
4-Hb, 2”5-H2), 1.43 (s, 6H, 2”3-H3), 1.21 (d, J=6.0 Hz, 6H, 2”7-H3),
0.98–0.90 ppm (m, 18H, 2”tBu); 13C NMR (75 MHz, CDCl3): d=175.82,
175.75, 138.68, 128.33, 127.60, 127.57, 127.49, 108.39, 108.30, 79.75, 79.61,
74.29, 74.19, 70.31, 34.53, 34.51, 31.92, 31.89, 30.41, 30.35, 23.27, 22.63,
22.50, 19.51, 19.43 ppm.
Compound 26: A solution of 25 (610 mg, 1.86 mmol) in CH2Cl2 (6 mL)
was added to a stirred solution of IBX (625 mg, 2.23 mmol) in DMSO
(1.5 mL). The reaction mixture was stirred at 258C for 4 h and quenched
by the addition of an aq. sat. Na2S2O3 solution. The aqueous layer was
extracted with CH2Cl2 and the organic layer washed with aq. sat.
NaHCO3 solution, water, brine and dried over Na2SO4. The solvent was
evaporated under reduced pressure to afford the crude product which
was purified by silica gel chromatography using 15% EtOAc/pentane to
yield compound 26 (548 mg, 90%) as a liquid. [a]2D0 =+30.4 (c=0.9 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=9.64 (s, 1H, CHO), 7.35–7.23
(m, 10H, 2”Ph), 4.55 (d, J=11.6 Hz, 1H, C-6-OCHaPh), 4.44 (s, 2H, C-
2-OCH2Ph), 4.41 (d, J=11.6 Hz, 1H, C-6-OCHbPh), 3.56–3.44 (m, 1H, 6-
H1), 1.99–1.88 (m, 1H, 4-Ha), 1.73–1.52 (m, 3H, 4-Hb, 5-H2), 1.57 (s, 3H,
3-H3), 1.19 ppm (d, J=6.2 Hz, 3H, 7-H3); 13C NMR (125 MHz, CDCl3):
d=204.92, 138.82, 138.22, 128.39, 128.30, 127.65, 127.54, 127.40, 82.45,
74.56, 70.27, 66.09, 30.54, 29.61, 19.43, 18.32 ppm; IR (KBr): n˜ =1715,
1453, 1065 cmÀ1; UV (CH3CN): lmax (lg e)=247.5 (2.710), 251.5 (2.736),
257.0 nm (2.717); MS (EI, 70 eV): m/z (%): 326.3 (6) [M]+, 164.1 (40),
Compound 23: Sodium methoxide (5.5m in methanol, 0.52 mL,
2.88 mmol) was added at 08C to
a stirred solution of 22 (768 mg,
2.40 mmol) in absolute methanol (4.8 mL), and the mixture was stirred at
08C for 2 h before quenching by the addition of ice. The aqueous layer
was extracted with ethyl acetate and the organic layer was washed with
water, brine and dried over Na2SO4. The solvent was evaporated under
reduced pressure to afford the crude product which was purified by silica
gel chromatography using 30% EtOAc/pentane to yield compound 23
(561 mg, 88%) as a liquid. [a]2D0 =+0.8 (c=1.5 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.38–7.32 (m, 5H, Ph), 4.55 (d, J=11.5 Hz, 1H,
C-6-OCHaPh), 4.44 (d, J=11.5 Hz, 1H, C-6-OCHbPh), 3.76 (s, 3H,
OCH3), 3.57–3.47 (m, 1H, 6-H1), 2.0–1.89 (m, 1H, 4-Ha), 1.72–1.58 (m,
3H, 4-Hb, 5-H2), 1.41 (s, 3H, 3-H3), 1.18 ppm (d, J=6.1 Hz, 3H, 7-H3);
13C NMR (75 MHz, CDCl3): d=177.59, 138.83, 128.29, 127.58, 127.41,
74.63, 74.45, 70.26, 52.69, 35.90, 30.54, 26.19, 19.44 ppm; IR (KBr): n˜ =
1732, 1454, 1213, 1069 cmÀ1; UV (CH3CN): lmax (lg e)=253.5 (2.380),
107.1 (40), 91.1 (100), 43.1 (18); HRMS (ESI): m/z: calcd for C21H26O3
+
NH4+: 344.22202; found: 344.22201.
Compound 27: Ph3P (880 mg, 3.36 mmol) in CH2Cl2 (2 mL) was added at
08C to a stirred mixture of CBr4 (1.12 g, 3.36 mmol) and zinc (218 mg,
3.36 mmol) in CH2Cl2 (2 mL) and stirring was continued at 258C for
60 min. After cooling back to 08C a solution of the aldehyde 26 (548 mg,
1.68 mmol) in CH2Cl2 (4 mL) was added. The reaction mixture was
stirred at 258C for 12 h and then diluted with pentane with vigorous stir-
ring. A precipitate is formed which was removed by filtration through
florisil. The filtrate was evaporated under reduced pressure to afford the
crude product which was purified by chromatography using 10% EtOAc/
pentane to yield compound 27 (700 mg, 86%) as a liquid. [a]2D0 =+4.0
(c=0.7 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.38–7.25 (m, 10H,
2”Ph), 6.66 (s, 1H, 2-H1), 4.57 (d, J=11.6 Hz, 1H, C-3-OCHaPh), 4.47–
4.39 (m, 3H, C-3-OCHbPh, C-7-OCH2Ph), 3.58–3.46 (m, 1H, 7-H1), 2.08–
1.97 (m 1H, 5-Ha), 1.82–1.57 (m, 3H, 5-Hb, 6-H2), 1.48 (s, 3H, 4-H3),
1.21 ppm (d, J=6.3 Hz, 3H, 8-H3); 13C NMR (75 MHz, CDCl3): d=
142.47, 138.95, 138.81, 128.31, 128.29, 127.56, 127.46, 127.39, 127.31, 88.25,
79.38, 74.79, 70.28, 64.75, 34.73, 30.03, 23.19, 19.59 ppm; IR (KBr): n˜ =
1453, 1066, 734 cmÀ1; UV (CH3CN): lmax (lg e)=247.5 (2.887), 251.5
257.5 (2.435), 263.0 nm (2.384); HRMS (ESI): m/z: calcd for C15H22O4
+
H+: 267.15909; found: 267.15918.
Compound 24: Methyl ester 23 (561 mg, 2.11 mmol) dissolved in THF
(2 mL) was added to a solution of the NaH (50% in paraffin oil, 200 mg,
4.22 mmol) in THF (3 mL). The reaction mixture was stirred at 08C for
30 min. To the above solution was added benzyl bromide (0.37 mL,
3.16 mmol) followed by tetra-n-butylammonium iodide (30 mg,
0.20 mmol). The reaction mixture was stirred at 258C for 12 h and
quenched with aq. saturated NaHCO3. The layers were separated and the
organic layer was washed successively with water, brine and dried over
Na2SO4. The organic layer was evaporated under reduced pressure to
afford the crude product which was purified by column chromatography
on silica gel using 10% EtOAc/pentane to yield 24 (690 mg, 92%) as a
liquid. [a]2D0 =+7.8 (c=1.8 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
7.40–7.25 (m, 10H, 2”Ph), 4.55 (d, J=11.7 Hz, 1H, C-6-OCHaPh), 4.48–
4.42 (m, 3H, C-6-OCHbPh, C-2-OCH2Ph), 3.75 (s, 3H, OCH3), 3.57–3.46
(m, 1H, 6-H1), 2.08–1.96 (m, 1H, 4-Ha), 1.87–1.76 (m, 1H, 4-Hb), 1.65–
1.57 (m, 2H, 5-H2), 1.50 (s, 3H, 3-H3), 1.20 ppm (d, J=6.4 Hz, 3H, 7-H3);
13C NMR (75 MHz, CDCl3): d=174.80, 138.98, 128.27, 128.24, 127.54,
127.50, 127.37, 127.34, 80.31, 74.75, 70.26, 66.62, 51.94, 34.48, 30.25, 21.64,
19.58 ppm; IR (KBr): n˜ =1739, 1453, 1092, 697 cmÀ1; UV (CH3CN): lmax
(lg e)=252.5 (2.588), 257.5 (2.661), 263.5 nm (2.588); HRMS (ESI): calcd
for C22H28O4 + H+: 357.20604; found: 357.20604 [M+H]+.
(2.904), 257.0 nm (2.892); HRMS (ESI): m/z: calcd for C22H26Br2O2
+
NH4+: 498.06378; found: 498.06388.
Compound 5: nBuLi (2.5m in hexane, 1.20 mL, 3.02 mmol) was added at
À788C to a stirred solution of compound 27 (700 mg, 1.44 mmol) in dry
THF (5.5 mL). After being warmed to À208C over 2 h, the mixture was
recooled to À788C and DMF (0.10 mL) was added. After being gradually
warmed to 258C over 4 h, the mixture was quenched by the addition of
aq. sat. NH4Cl solution. The reaction mixture was diluted with diethyl
ether and washed with water, brine and dried over Na2SO4. The solvent
was evaporated under reduced pressure to afford the crude product
which was purified by silica gel column chromatography. Elution with
15% EtOAc/pentane provided product 5 (410 mg, 82%) as a liquid.
Chem. Eur. J. 2007, 13, 9939 – 9947
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9945

L. F. Tietze et al.
[a]2D0 =+5.2 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=9.25 (s,
1H, CHO), 7.36–7.26 (m, 10H, 2”Ph), 4.68–4.56 (m, 3H, C-8-OCHaPh,
C-4-OCH2Ph), 4.44 (d, J=12.1 Hz, 1H, C-8-OCHbPh), 3.60–3.49 (m, 1H,
8-H1), 2.08–1.95 (m 1H, 6-Ha), 1.91–1.66 (m, 3H, 6-Hb, 7-H2), 1.58 ppm
(s, 3H, 5-H3), 1.22 (d, J=6.4 Hz, 3H, 9-H3); 13C NMR (75 MHz, CDCl3):
d=176.41, 138.87, 138.27, 128.35, 128.31, 127.60, 127.57, 127.55, 127.43,
97.45, 84.95, 74.52, 73.59, 70.34, 66.77, 37.0, 31.05, 25.65, 19.63 ppm; IR
1H NMR (300 MHz, CDCl3): d=7.83 (dd, J=7.6, 1.2 Hz, 1H, 5’-H), 7.79
(s, 1H, 4’-H), 7.65–7.59 (m, 2H, 7’-H, 6’-H), 7.41–7.15 (m, 15H, 3”Ph),
5.27 (s, 2H, C-8’-OCH2Ph), 4.60–4.37 (m, 5H, OCH(CH3)2, C-4-OCH2Ph,
R
C-8-OCH2Ph), 3.56–3.49 (m, 1H, 8-H), 2.38 (s, 3H, Ar-CH3), 1.05–2.93
(m, 1H, 6-Ha), 1.89–1.62 (m, 3H, 6-Hb, 7-H2), 1.56 (s, 3H. 5-H3), 1.30–
1.24 (m, 6H, C-1’-OCH(CH3)2), 1.18 ppm (d, J=6.3 Hz, 3H, 9-H3);
G
13C NMR (75 MHz, CDCl3): d=183.22, 182.07, 180.76, 158.15, 155.68,
141.69, 141.49, 138.92, 138.43, 136.35, 134.87, 134.03, 128.50, 128.25,
127.85, 127.66, 127.57, 127.39, 127.34, 126.71, 126.56, 124.02, 119.94,
119.52, 96.82, 85.76, 79.20, 77.20, 74.55, 73.83, 71.00, 70.21, 66.88, 36.86,
30.92, 25.57, 22.26, 19.64 ppm; IR (KBr): n˜ =2929, 1673, 1585, 1453, 1280,
1063 cmÀ1; UV (CH3CN): lmax (lg e)=258.5 (4.399), 379.0 nm (3.773);
(KBr): n˜ =1669, 1454, 1068, 697 cmÀ1
; UV (CH3CN): lmax (lg e)=
257.0 nm (3.006); MS (EI) m/z (%): 351.4 (6) [M]+, 270.2 (25), 179.2
(68), 99.1 (20), 91.1 (100); HRMS (ESI): m/z: calcd for C23H26O3 + H+:
351.19547; found: 351.19559.
Compound 28: To a stirred solution of compound 4 (247 mg, 0.50 mmol)
in THF (3 mL) at À788C was added nBuLi (2.5m in hexane, 0.24 mL,
0.60 mmol) followed by propargylic aldehyde 5 (230 mg, 0.60 mmol) dis-
solved in THF (1 mL). Stirring was continued at À788C for 10 min and
the reaction was quenched by the addition of aq. sat. NH4Cl solution.
The reaction mixture was diluted with CH2Cl2 and washed with water,
brine and dried over Na2SO4. The solvent was evaporated under reduced
pressure to afford the crude product which was purified by silica gel
column chromatography. Elution with 20% EtOAc/pentane provided
HRMS (ESI): m/z: calcd for C48H46O7
+
H+: 735.33163; found:
735.33168.
Compound 3: H2SO4 (0.01 mL) was added at 258C to a stirred solution
of compound 30 (250 mg, 0.34 mmol) in AcOH (2 mL) and stirring was
continued at 558C for 30 min. The mixture was diluted with CH2Cl2 and
the organic layer washed with water and brine. Drying over Na2SO4 and
evaporation of the solvent under reduced pressure afforded the crude
product which was purified by silica gel chromatography using 15%
EtOAc/pentane to yield compound 3 (174 mg, 86%) as a viscous oil.
[a]2D0 =À13.8 (c=1.1 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.80
(dd, J=7.6, 1.2 Hz, 1H, 5’-H), 7.71–7.60 (m, 2H, 6’-H, 4’-H), 7.37–7.13
(m, 11H, 7’-H, 2”Ph), 4.66 (d, J=11.0 Hz, 1H, C-4-OCHaPh), 4.60 (d,
J=11.0 Hz, 1H, C-4-OCHbPh), 4.51 (d, J=11.7 Hz, 1H, C-8-OCHaPh),
4.40 (d, J=11.7 Hz, 1H, C-8-OCHbPh), 3.59–3.48 (m, 1H, 8-H), 2.44 (s,
3H, Ar-CH3), 1.06–2.48 (m, 7H, 6-H2 7-H2, 5-H3), 1.19 ppm (d, J=
6.1 Hz, 3H, 9-H3); 13C NMR (125 MHz, CDCl3): d=192.28, 181.22,
178.35, 162.51, 160.41, 146.71, 138.81, 138.41, 137.38, 133.93, 133.62,
133.25, 128.26, 128.23, 127.53, 127.43, 127.39, 127.37, 127.25, 124.91,
121.97, 120.21, 115.64, 114.22, 96.87, 85.49, 85.49, 74.46, 73.96, 70.19,
66.84, 36.91, 30.93, 25.58, 20.45, 19.65 ppm; IR (KBr): n˜ =1734, 1455,
1384, 1160, 1067 cmÀ1; UV (CH3CN): lmax (lg e)=257.5 (4.385), 320.0
(3.922), 425.5 nm (3.867); HRMS (ESI): m/z: calcd for C38H34O7 + H+:
603.23742; found: 603.23748.
product 28 (305 mg, 0.40 mmol, 80%) as
a
viscous oil. 1H NMR
(300 MHz, CDCl3): d=7.86–7.73 (m, 4H, 2”6’-H, 2”4’-H), 7.66 (d, J=
7.4 Hz, 2H, 2”5’-H), 7.45–7.14 (m, 30H, 6”Ph), 6.85 (d, J=7.4 Hz, 2H,
2”7’-H), 6.59–6.18 (brs, 2H, 2”1-H), 5.30–5.19 (brs, 4H, 2”C-8’-
OCH2Ph), 4.66–4.34 (m, 10H, 2”OCH(CH3)2, 2”C-4-OCH2Ph, 2”C-8-
C
OCH2Ph), 4.01 (s, 6H 2”OMe), 3.69 (s, 6H, 2”OMe), 3.55–3.43 (m, 2H,
2”8-H), 2.86–2.68 (brs, 6H, 2”Ar-CH3), 1.96–1.65 (m, 8H, 2”6-H, 2”7-
H), 1.59–1.12 ppm (m, 24H, 2”5-H3, 2”9-H3, 2”C-1’-OCH(CH3)2);
A
13C NMR (75 MHz, CDCl3): d=156.33, 150.57, 146.99, 139.12, 139.03,
139.0, 137.48, 128.37, 128.24, 128.22, 128.19, 127.86, 127.65, 127.53, 127.51,
127.31, 127.29, 127.23, 127.20, 125.74, 119.09, 119.02, 115.18, 106.38, 87.20,
77.20, 74.83, 73.77, 71.43, 70.19, 70.17, 66.31, 63.60, 62.62, 37.51, 31.16,
26.32, 26.29, 20.76, 19.69 ppm; IR (KBr): n˜ =2930, 1617, 1556, 1452,
1357 cmÀ1; UV (CH3CN): lmax (lg e)=362.5 (3.731), 380.0 (3.995), 397.0
(3.897), 419.0 nm (3.738); HRMS (ESI): calcd for C50H54O7
784.42078; found: 784.42045.
+
H+:
Compound 31: Cs2CO3 (78 mg, 0.24 mmol) was added at 08C To a stirred
solution of compound 3 (120 mg, 0.20 mmol) in acetone (1.5 mL). The re-
action mixture was brought to 158C over 30 min, then diluted with dieth-
yl ether and filtered through a small pad of Celite. The filtrate was
evaporated under reduced pressure to afford the crude product which
was purified by silica gel column chromatography using 20% EtOAc/
Compound 29: To a stirred solution of compound 28 (305 mg, 0.40 mmol)
in dioxane (8 mL) was added AgO (247 mg, 2.0 mmol) followed by 4n
HNO3 until the silver oxide has completely dissolved. The resulting solu-
tion was stirred for 30 min and then diluted with CH2Cl2. The organic
layer was washed with water, brine, dried over Na2SO4 and the solvent
evaporated under reduced pressure to afford the crude product which
was purified by silica gel chromatography using 35% EtOAc/pentane to
yield compound 29 (265 mg, 90%) as a viscous oil. 1H NMR (300 MHz,
CDCl3): d=7.85–7.76 (m, 4H, 2”5’-H, 2”4’-H), 7.65–7.58 (m, 4H, 2”7’-
H, 2”6’-H), 7.44–7.17 (m, 30H, 6”Ph), 6.28 (s, 2H, 2”1-H), 5.27 (s, 4H,
pentane to provide compound 31 (48 mg, 42%) as a viscous oil. [a]D20
=
+29.7 (c=0.32 in CHCl3); 1H NMR (600 MHz, CDCl3): d=12.93–12.84
(brs, 1H, C-11-OH), 8.03 (s, 1H, 6’-H), 7.80 (dd, J=7.6, 1.2 Hz, 1H, 8’-
H), 7.66 (t, J=7.6 Hz, 1H, 9’-H), 7.39–7.09 (m, 11H, 10’-H, 2”Ph), 6.64
(s, 1H, 3-H), 4.58 (d, J=11.7 Hz, 1H, C-14-OCHaPh), 4.55 (d, J=
11.7 Hz, 1H, C-14-OCHbPh), 4.47 (d, J=12.1 Hz, 1H, C-18-OCHaPh),
4.36 (d, J=12.1 Hz, 1H, C-18-OCHbPh), 3.54–3.47 (m, 1H, 18-H), 3.0 (s,
3H, Ar-CH3), 2.38–2.32 (m, 1H, 16-Ha), 2.16–2.08 (m, 1H, 16-Hb), 1.80
(s, 3H, 15-H3), 1.67–1.46 (m, 2H, 17-H2), 1.16 ppm (d, J=6.1 Hz, 3H, 19-
H3); 13C NMR (75 MHz, CDCl3): d=187.07, 181.88, 179.22, 170.48,
162.56, 156.28, 149.76, 138.79, 138.21, 136.31, 135.95, 132.22, 128.14,
127.48, 127.28, 127.25, 127.06, 126.43, 125.62, 125.27, 119.79, 119.29,
116.76, 111.13, 78.67, 74.52, 70.18, 64.73, 33.91, 30.36, 24.23, 22.52,
19.50 ppm; IR (KBr): n˜ =2927, 1673, 1454, 1269 cmÀ1; UV (CH3CN): lmax
(lg e)=257.5 (4.271), 419.0 nm (3.763); MS (ESI): m/z: 625.2 [M+Na]+,
601.3 [M+H]+; HRMS (ESI): m/z: calcd for C38H34O7 + H+: 603.23773;
found: 603.2380.
2”C-8’-OCH2Ph), 4.61–4.29 (m, 10H, 2”OCH(CH3)2, 2”C-4-OCH2Ph,
A
2”C-8-OCH2Ph), 3.56–3.45 (m, 2H, 2”8-H), 3.16–3.04 (brs, 2H, 2”
OH), 2.68 (s, 6H, 2”Ar-CH3), 1.95–1.63 (m, 8H, 2”6-H, 2”7-H), 1.49–
1.10 ppm (m, 24H, 2”5-H3, 2”9-H3, 2”C-1’-OCH
(CH3)2); 13C NMR
A
(125 MHz, CDCl3): d=183.26, 183.23, 157.91, 154.60, 144.27, 139.77,
139.74, 138.92, 138.91, 138.90, 138.87, 136.32, 134.91, 133.96, 133.50,
128.47, 128.24, 128.23, 128.20, 127.83, 127.53, 127.39, 127.37, 127.34,
127.33, 127.26, 126.74, 126.50, 124.88, 119.61, 119.39, 87.56, 87.54, 84.54,
84.46, 79.23, 74.73, 74.71, 73.63, 70.90, 70.18, 66.24, 66.22, 58.13, 37.43,
37.39, 31.13, 31.10, 26.23, 26.20, 22.42, 22.28, 20.52, 20.50, 19.66 ppm; IR
(KBr): n˜ =2928, 1672, 1585, 1453, 1277 cmÀ1; UV (CH3CN): lmax (lg e)=
260.5 (4.446), 375.5 nm (3.783); HRMS (ESI): calcd for C48H48O7 + H+:
737.34728; found: 737.34718.
Compound 2: TiCl4 (1m in CH2Cl2, 0.30 mL, 0.30 mmol) was added at
À788C to a stirred solution of compound 31 (36 mg, 0.06 mmol) in
CH2Cl2 (1 mL) and the mixture was allowed to warm to À208C over 2 h.
Then, the mixture was diluted with CH2Cl2, washed successively with 1m
HCl, water, brine and dried over Na2SO4. The solvent was evaporated
under reduced pressure to afford the crude product which was purified
by column chromatography on silica gel using 5% MeOH/CH2Cl2 to
yield compound 2 (20 mg, 80%) as yellow solid. [a]2D0 =+18.6 (c=0.22 in
DMSO); 1H NMR (300 MHz, CDCl3): d=12.84 (s, 1H, C-11-OH), 8.08
(s, 1H, 6-H), 7.83 (dd, J=7.8, 1.2 Hz, 1H, 8-H), 7.69 (t, J=7.8 Hz, 1H, 9-
Compound 30: Compound 29 (265 mg, 0.36 mmol) in CH2Cl2 (2.5 mL)
was added to a stirred solution of IBX (120 mg, 0.43 mmol) in DMSO
(0.5 mL). The mixture was stirred at 208C for 4 h and quenched by addi-
tion of an aq. saturated Na2S2O3 solution. The aq. layer was extracted
with CH2Cl2 and the organic layer washed with aq. saturated NaHCO3
solution, water, brine, dried over Na2SO4 and the solvent was evaporated
under reduced pressure. The obtained crude product was purified by
silica gel chromatography using 25% EtOAc/pentane to yield compound
30 (250 mg, 95%) yield as a viscous oil. [a]2D0 =À13.8 (c=1.1 in CHCl3);
9946
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9939 – 9947

d-Indomycinone
FULL PAPER
H), 7.36 (dd, J=7.8, 1.2 Hz, 1H, 10-H), 6.62 (s, 1H, 3-H), 3.96–3.88 (m,
1H, 18-H), 3.03 (s, 3H, Ar-CH3), 2.34–2.25 (m, 1H, 16-Ha), 1.14–2.65 (m,
3H, 16-Hb, 17-H2), 1.70 (s, 3H, 15-H3), 1.23 ppm (d, J=6.6 Hz, 3H, 19-
H3); 1H NMR (600 MHz, [D6]DMSO): d=12.71 (s, 1H, C-11-OH), 7.95
(s, 1H, 6-H), 7.79 (t, J=7.8 Hz, 1H, 9-H), 7.70 (dd, J=7.8, 1.2 Hz, 1H, 8-
H), 7.41 (dd, J=8.2, 1.2 Hz, 1H, 10-H), 6.48 (s, 1H, 3-H), 5.56 (s, 1H, C-
14-OH), 4.27 (d, J=4.8 Hz, 1H, C-18-OH), 3.57–3.50 (m, 1H, 18-H), 2.91
(s, 3H, Ar-CH3), 2.20–2.12 (m, 1H, 16-Ha), 1.83–1.75 (m, 1H, 16-Hb),
1.62 (s, 3H, 15-H3), 1.56–1.42 (m, 2H, 17-H2), 1.01 ppm (d, J=6.1 Hz,
3H, 19-H3); 13C NMR (150 MHz, [D6]DMSO): d=186.89, 181.32, 178.30,
173.98, 161.33, 155.53, 148.26, 136.60, 135.75, 132.09, 125.49, 124.65,
124.62, 119.72, 118.65, 116.69, 108.83, 72.35, 65.97, 36.57, 32.91, 27.11,
23.34, 23.31 ppm; IR (KBr): n˜ =1734, 1455, 1384, 1160, 1067 cmÀ1, UV
(CH3CN): lmax (lg e)=238.5 (4.041), 266.0 (3.780), 415.5 nm (3.253); MS
(EI, 70 eV): m/z (%): 422.2 (20) [M]+, 349.2 (60), 324.2 (28), 281.1 (100),
McDonald, Org. Lett. 2005, 7, 3617–3620; h) D.-S. Hsu, T. Matsu-
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[10] The yield of this oxidizing step strongly depends on the quality of
the 1,5-dihydroxynaphthaline (10) as well as on the purity of the
copper(I) chloride. The 1,5-dihydroxynaphthaline (10) should be
light-brown coloured (not black) whereas it is recommended to use
freshly recrystallized copper(I) chloride having a pure white colour.
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99.1 (45), 43.1 (22); HRMS (ESI): m/z: calcd for C24H22O7
423.14383; found: 423.14398.
+
H+:
Compounds 2 and 36: A mixture of compound 2 and 36 was prepared
from the compounds 35 and 4 following the procedure described for the
synthesis of the compound 2. 1H NMR (300 MHz, CDCl3): d=12.87 (s,
1H, C-11-OH), 12.84 (s, 1H, C-11-OH), 8.08 (s, 2H, 2”6-H), 7.85–7.81
(m, 2H, 2”8-H), 7.73–7.63 (m, 2H, 2”9-H), 7.38–7.33 (m, 2H, 2”10-H),
6.67 (s, 1H, 3-H), 6.62 (s, 1H, 3-H), 4.14–4.03 (m, 1H, 18-H), 3.88–3.96
(m, 1H, 18-H), 3.03 (s, 6H, 2”Ar-CH3), 2.36–2.23 (m, 2H, 2”16-Ha),
2.15–1.92 (m, 6H, 2”16-Hb, 2”17-H2), 1.70 (s, 3H, 15-H3), 1.68 (s, 3H,
15-H3), 1.23 (d, J=6.6 Hz, 3H, 19-H3), 1.19 ppm (d, J=6.6 Hz, 3H, 19-
1
H3); H NMR (600 MHz, [D6]DMSO): d=12.72–12.68 (brs, 2H, 2”C-11-
OH), 7.95 (s, 2H, 6-H), 7.79 (t, J=8.2 Hz, 2H, 2”9-H), 7.70 (d, J=
8.2 Hz, 2H, 2”8-H), 7.41 (d, J=8.2, 2H, 2”10-H), 6.48 (s, 2H, 2”3-H),
5.60 (s, 1H, C-14-OH), 5.56 (s, 1H, C-14-OH), 4.36 (d, J=4.8 Hz, 1H, C-
18-OH), 4.27 (d, J=4.8 Hz, 1H, C-18-OH), 3.61–3.50 (m, 2H, 2”18-H),
2.91 (s, 6H, 2”Ar-CH3), 2.21–2.10 (m, 2H, 2”16-Ha), 1.84–1.72 (m, 2H,
2”16-Hb), 1.62 (s, 3H, 15-H3), 1.60 (s, 3H, 15-H3), 1.58–1.42 (m, 4H, 2”
17-H2), 1.01 (d, J=6.1 Hz, 3H, 19-H3), 0.99 ppm (d, J=6.1 Hz, 3H, 19-
H3).
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Acknowledgements
The authors are grateful to the Fonds der Chemischen Industrie for sup-
porting this work and R.R.S. thanks the Alexander von Humboldt Foun-
dation for a post-doctoral grant.
[18] G. E. Keck, J. A. Murry, J. Org. Chem. 1991, 56, 6606–6611.
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1
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Received: June 30, 2007
Published online: September 21, 2007
Chem. Eur. J. 2007, 13, 9939 – 9947
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9947