Dimeric orsellinic acid derivatives: Valuable intermediates for natural product synthesis

Article abstract of DOI:10.1002/ejoc.200600899

Herein we report on the synthesis of dimeric orsellinates by the Ullmann reaction as well as by biomimetic oxidative phenolic coupling. The Ullmann reaction gives the 5,5′- and 3,3′-coupled dimeric orsellinates 9 and 10 regioselectively. Oxidative phenoli

Full text of DOI:10.1002/ejoc.200600899

FULL PAPER
DOI: 10.1002/ejoc.200600899
Dimeric Orsellinic Acid Derivatives: Valuable Intermediates for Natural
Product Synthesis
Daniel Drochner,[a] Wolfgang Hüttel,[a][‡] Silke E. Bode,[a][‡] Michael Müller,*[a][‡]
Ulrich Karl,[b] Martin Nieger,[c][‡‡] and Wolfgang Steglich*[b][‡‡‡]
Keywords: Biaryls / Dihydroanthracenones / Regioselective synthesis / Atropisomers / Oxidative phenolic coupling
Herein we report on the synthesis of dimeric orsellinates by
the Ullmann reaction as well as by biomimetic oxidative phe-
nolic coupling. The Ullmann reaction gives the 5,5Ј- and 3,3Ј-
coupled dimeric orsellinates 9 and 10 regioselectively. Oxi-
dative phenolic coupling reaction of methyl 2-hydroxy-4-
methoxy-6-methylbenzoate (2) affords the regioisomeric di-
meric orsellinates 11 (3,3Ј), 12 (5,5Ј) and 13 (3,5Ј) simulta-
neously, which can be separated easily by column
dimeric biaryl 11 could be obtained in pure form by derivatiz-
ing racemic 11 with chiral auxiliaries, separating the dia-
stereomers by column chromatography and cleaving the aux-
iliary groups. Thereby the absolute configuration of the bi-
aryl axis in camphanate ester (M)-18 could be determined by
X-ray structure analysis. The dimeric orsellinates rac-10 and
(P)-10 were used for the synthesis of the dimeric dihydro-
anthracenones 21a–b by a tandem Michael–Dieckmann reac-
chromatography. The atropisomers of the 5,5Ј- and 3,3Ј-cou- tion.
pled dimers 9 and 10 were partially resolved using chiral col-
umn chromatography. Additionally, the enantiomers of 3,3Ј-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
The biaryl axis plays an important role as central struc-
tural element of diverse natural products. In fungi and
plants a significant number of dimeric dihydroanthra-
cenones (pre-anthraquinones), like flavomannin, phlegma-
cin, pseudophlegmacin, atrovirin or tricolorin,[1] can be
found (Scheme 1). These substances differ not only in the
linkage of their molecular halves (regiochemistry) but also
in the configuration of the biaryl axis (stereochemistry). Al-
though a general regio- and stereoselective approach to this
class of natural products is desirable, the asymmetric syn-
thesis of biaryls affords tedious synthesis strategies.[2]
[a] Institut für Biotechnologie 2, Forschungszentrum Jülich
GmbH,
52425 Jülich, Germany
[b] Kekulé-Institut für Organische Chemie und Biochemie, Rheini-
sche Friedrich-Wilhelms-Universität,
53121 Bonn, Germany
Scheme 1. Polyketide natural products containing a dimeric dihy-
droanthracenone structure.
[c] Institut für Anorganische Chemie, Rheinische Friedrich-
Wilhelms-Universität,
53121 Bonn, Germany
[‡] Present address: Institut für Pharmazeutische Wissenschaften,
Albert-Ludwigs-Universität Freiburg,
79104 Freiburg, Germany
Herein, we report on the synthesis and racemic resolu-
tion of regioisomeric dimeric orsellinates and their use in
natural product synthesis.
Fax: +49-761-2036351
E-mail: michael.mueller@pharmazie.uni-freiburg.de
[‡‡] Present address: Laboratory of Inorganic Chemistry, Depart-
ment of Chemistry,
Results and Discussion
00014 University of Helsinki, Finland
[‡‡‡] Present address: Department Chemie, Ludwig-Maximilians-
Universität,
Dimeric Orsellinates via Ullmann Reaction
81377 München, Germany
For the synthesis of 3,3Ј- and 5,5Ј-coupled dimeric orsel-
Fax: +49-89-218077756
E-mail: wos@cup.uni-muenchen.de
linates[3] an Ullmann reaction[4] of the corresponding iodin-
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M. Müller, W. Steglich et al.
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ated monomeric precursors was envisaged. Since the prepa- and H2O2 were added to a solution of compound 3 in
ration of monomeric orsellinic acid derivatives is well estab- EtOH and the product was precipitated with water afford-
lished, the main task was the regioselective iodination of ing 7 in 96% yield (Scheme 2, A).
the substrates. For this purpose we applied a strategy which
For the synthesis of methyl 3-iodo-2,4-dimethoxy-6-
uses methyl 2,4-dihydroxy-6-methylbenzoate[5] (1) as start- methylbenzoate (8) compound 1 was monomethylated re-
ing material for the synthesis of the monoiodinated re- gioselectively at C-4 with iodomethane in presence of anhy-
gioisomeric orsellinates 7 and 8 (Scheme 2). The prepara- drous K2CO3 delivering methyl 2-hydroxy-4-methoxy-6-
tion of methyl 5-iodo-2,4-dimethoxy-6-methylbenzoate (7)[6] methylbenzoate[9] (2) in 72% yield. Phenol 2 was iodinated
starts with the complete methylation of ester 1 using di- with iodine and H2O2 to afford a 4:1 mixture of the two
methyl sulfate in aqueous KOH to yield methyl 2,4-dimeth- regioisomeric iodoorsellinates 4 and 5 in 40% yield.[10] The
oxy-6-methylbenzoate (3).[7] The latter was iodinated exclu- crude product was permethylated with dimethyl sulfate, and
sively at the C-5 atom applying a method formerly used by the resulting regioisomers 7 and 8 were separated by col-
Marsh[8] for the iodination of naphthol. Accordingly, iodine umn chromatography (Scheme 2, B).[11]
Scheme 2. Synthesis of iodinated monomeric methyl orsellinates 7 and 8.
Scheme 3. Ullmann coupling of iodinated monomeric methyl orsellinates 7 and 8, followed by selective demethylation with BBr3.
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Dimeric Orsellinic Acid Derivatives
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To avoid the problem of separating these regioisomers five steps for the 3,3Ј-coupled dimeric orsellinate 11 and
benzyltrimethylammonium dichloroiodate was used for the four steps for the 5,5Ј-coupled dimeric orsellinate 12 start-
regioselective iodination of compound 1 at position 3 ing from 1, the oxidative coupling proceeds in only two
(Scheme 2, C).[12] The best results were achieved by con- steps. Another advantage of this approach is the facile avail-
verting crude 6 directly into compound 8. No further purifi- ability of the unsymmetrically 3,5Ј-coupled product, which
cation of 8 was required.
requires a multistep approach when regioselective coupling
For the Ullmann reaction each of the iodoorsellinic acid methods are used. The oxidative phenolic coupling, how-
derivatives 7 and 8 were heated separately with activated ever, appears to be limited to methyl 2-hydroxy-4-methoxy-
copper powder to 230–280 °C.[13] The 5,5Ј- and 3,3Ј-cou- 6-methylbenzoate (2) as substrate. Neither 1 nor 3 gave any
pled dimeric orsellinates, 9 and 10, were obtained in 54 and detectable dimerization product under various conditions.
65% yield, respectively (Scheme 3). Finally, compounds 9 Since the Ullmann reaction is incompatible with hydroxy
and 10 were regioselectively demethylated using boron tri- groups or sterically demanding substituents this route is
bromide.
limited to the O-methylated iodoorsellinates 7 and 8 as sub-
strates. Moreover, the unsymmetrical 3,5Ј-dimer 13 or its
tetramethoxy derivative are hardly accessible by using this
strategy.[16]
Dimeric Orsellinates via Oxidative Phenolic Coupling
In addition to the Ullmann procedure a solid state oxi-
dative phenolic coupling reaction was used to synthesize the
dimeric orsellinates. Methyl 2-hydroxy-4-methoxy-6-methyl-
benzoate (2) was oxidized with ferric chloride adsorbed on
silica gel as described by Keinan and Mazur.[14] Best results
were obtained by heating a mixture of orsellinate 2 with
2.8 equiv. FeCl3/silica gel at 60 °C for 24 h. After flash
chromatography, the 3,3Ј-, 5,5Ј- and 3,5Ј-coupling products,
11, 12 and 13, were obtained in 17, 33 and 30% yield,
respectively (Scheme 4). This reaction could also be per-
formed on a 2 g scale of 2 with a total yield of 70% dimer-
ized products. Coinciding with our results, two published
procedures describing selective[15a] and unselective coup-
ling[15b] of analogous substrates reveal that the electronic
effect of the substituent at C-6 determines the (un-)selectiv-
ity of the oxidative phenolic coupling: with a methoxy sub-
stituent at C-6, the 3,3Ј-dimer is the only coupling product,
whereas without substituent at C-6 all possible regioisomers
are formed.
Resolution of Atropisomers
The resolution of the racemic dimeric orsellinates 9 and
10 was performed by column chromatography with triace-
tylcellulose as stationary phase and EtOH as eluent. How-
ever, due to the large tailing of the eluting compounds the
enantiomeric excess, which was determined by 1H NMR
with Pr(hfc)3 as shift reagent, was below 15%.
Alternatively, the atropisomers of the 3,3Ј-coupled race-
mic dimeric orsellinate 11 were resolved by formation of
diastereomeric dilactones.[17] For this purpose, the sodium
dianion of the racemic biaryl 11 was treated with (M)-6,6Ј-
dinitro-2,2Ј-diphenoyl dichloride[18] [(M)-14] to give dilac-
tone (M,M)-15 in 13% isolated yield, in addition to unre-
acted starting material (P)-11. Vice versa the reaction of the
racemic biaryl 11 with (P)-14 gave the dilactone (P,P)-15
and unreacted dimeric orsellinate (M)-11. The enantioen-
richment of the reisolated starting materials was not deter-
mined. After purification by preparative TLC, the lactones
15 were saponified with KOH to yield the atropisomeric
dimeric orsellinates (P)-11 and (M)-11, respectively, and
Comparison of the two Coupling Methods
In the case of the Ullmann reaction the 3,3Ј- and 5,5Ј- 6,6Ј-dinitro-2,2Ј-diphenic acid (16) in quantitative yield
coupling products 11 and 12 are formed regioselectively di- (Scheme 5).
rected by the position of the iodo atom in the substrates.
The optically active compounds 10 and 11 were corre-
In contrast, there is no selectivity in the oxidative phenolic lated by regioselective demethylation of 10 with boron tri-
coupling of methyl 2-hydroxy-4-methoxy-6-methylbenzoate bromide.[19] Demethylation of dimeric orsellinate (+)-10 af-
(2). Compared to the reductive coupling, which requires forded compound (M)-11; and the reaction with (–)-10 gave
Scheme 4. Unselective oxidative phenolic coupling of 2.
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M. Müller, W. Steglich et al.
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Scheme 5. Racemic resolution of dimeric orsellinate 11 by formation of diastereomeric dilactones.
(P)-11. This proved the (M)-configuration for (+)-10 and
the (P)-configuration for (–)-10, respectively.
Therefore, an alternative route for the racemic resolution
was applied. The racemic 3,3Ј-coupled dimeric orsellinate
The dinitrodiphenic acid method provides an effective ra- 11 was treated with (1S,4R)-(–)-camphanoyl chloride (17)
cemic resolution of the dimeric orsellinate 11. Due to the to yield a mixture of diastereomeric camphanate esters 18
low yield, however, this procedure is not practicable on a and 19 (Scheme 6).[15a] On separation by flash chromatog-
preparative scale.
raphy with a silica gel column the ester (–)-18 (47%) was
Scheme 6. Racemic resolution of dimeric orsellinate 11 by chromatographic separation of diastereomeric camphanate esters 18 and 19.
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Dimeric Orsellinic Acid Derivatives
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first eluted followed by (+)-19 (45%). The diastereomers Syntheses of Dimeric Dihydroanthracenones
can be distinguished by their chemical shifts in the 1H
NMR spectra. As no signal of the other diastereomer was
observed in the spectra of isolated (–)-18 or (+)-19, the dia-
stereomeric excess was estimated as at least 95%.
Recrystallization of the ester (–)-18 from n-hexane/
EtOAc provided crystals suitable for X-ray diffraction.[20,21]
The absolute configuration of the biphenyl moiety of the
ester (–)-18 was determined as (M) by using the known ab-
solute configuration of the camphanate ester auxiliary as
internal reference (Figure 1).
The retrosynthetic analysis of dimeric dihydroanthra-
cenones reveals that they might be synthesized either by a
biomimetic dimerisation of their monomeric precursors[22]
or by a tandem Michael–Dieckmann reaction of dimeric
orsellinates with the corresponding Michael acceptors.[23]
Monomeric dihydroanthracenones can be iodinated or bro-
minated selectively, however, the dimerization of the re-
sulting halogenides by the classical Ullmann reaction or
palladium-catalyzed Stille coupling fails.
The 3,3Ј-dimeric orsellinates rac-10 and (P)-10 were used
for the syntheses of several flavomannin analogues by tan-
dem-Michael–Dieckmann condensation.[23] This reaction
includes Michael addition of a benzyl anion derived from
the dimeric orsellinate 10, to a Michael acceptor, here the
cyclohexenone derivative 20, followed by an intramolecular
Dieckmann condensation, which establishes the desired ring
system.
The dimeric orsellinate 10 was deprotonated to the corre-
sponding benzyl dianion at –78 °C with an excess of lithium
diisopropylamide (Scheme 7). The nucleophile attacks the
cyclohexenone 20 exclusively through an 1,4-addition to
form an intermediate enolate, which then reacts with the
ester group to provide, after warming to room temperature,
the anellated product. Two types of cyclohexenones were
used. Type A containing a β-methoxy moiety is able to
eliminate spontaneously MeOH after the tandem Michael–
Dieckmann reaction to provide directly the aromatic sys-
tem. Type B cyclohexenones lack this β-methoxy moiety.
Figure 1. Molecular structure of (M)-(–)-18 (non-hydrogen atoms
shown at 50% probability level).
Cleavage of the camphanic acid moiety was performed After the tandem Michael–Dieckmann reaction, a dehydro-
with sodium methoxide to give the atropisomeric 3,3Ј-cou- genation reaction with 2,3-dichloro-5,6-dicyano-1,4-benzo-
pled biaryls (M)-11, and (P)-11, in 75% yield each quinone (DDQ) is required in this case. Three different flav-
(Scheme 6). This outcome corresponds with the absolute omannin analogues were synthesized. Using 5,5-dimethyl-
configurations determined by the dinitrodiphenic acid 3-methoxycyclohex-2-en-1-one[24] (20a) the substituted flav-
method (see above). The camphanic acid method allows an omannin analogue 21a was prepared in a single-step with
efficient approach to both atropisomers of 11 in good 27% isolated yield. The two step conversion with cyclohex-
yields.
2-en-1-one (20b) to compound 21b was performed also with
Scheme 7. Synthesis of dimeric dihydroanthracenones.
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M. Müller, W. Steglich et al.
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series GC-system fitted with a HP 5973 mass selective detector
[Hewlett–Packard; column HP-5MS, 30 mϫ250 µm; TGC(injector)
enantioenriched (P)-10, which afforded (P)-21b (Scheme 7).
The circular dichroism (CD) of this compound reveals a
typical split CD curve with a positive Cotton effect at
280 nm first and a second negative Cotton effect at 260 nm.
Through exciton coupling methodology this allows the de-
termination of the absolute configuration at the chiral bi-
aryl axis in natural occurring flavomannins.[25]
= 250 °C, TMS(ion source) = 200 °C, time program (oven): T0min
=
60 °C, T3min = 60 °C, T14 min = 280 °C (heating rate 20 °Cmin–1),
T19min = 280 °C]. HRMS (EI) was performed on an A.E.I. MS 50,
MS (FAB) with a Finnigan MAT 95 Q in a m-nitrobenzyl alcohol
matrix and elemental analysis with a Vario EL (Heraeus) at the
Institut für Anorganische Chemie, Rheinische Friedrich-Wilhelms-
Universität, Bonn. Optical rotations were measured with a polari-
meter 241 (Perkin–Elmer) and with a polarimeter P-1020 (Jasco).
UV/Vis spectra were recorded with a Zeiss spectral photometer
DMR 10 (Carl Zeiss Jena GmbH, Germany). Absorption coeffi-
cients ε are reported relative to the highest peak. CD spectra were
recorded with a CNRS Roussel-Jouan Dichrographe III (Jobin
Yvon) and on a Jasco J-720 spectral polarimeter. Molar circular-
dichroic absorptions ∆ε are reported in cm2 ϫmmol–1. Melting
points were measured with a Büchi B-540 heating unit.
Conclusions
Two different strategies for the preparation of enantio-
merically pure dimeric orsellinates were elaborated. Both
start from easily available methyl 2,4-dihydroxy-6-methyl-
benzoate (1), but differ in the dimerisation method. The
Ullmann reaction requires a substrate which is iodinated at Methyl 2,4-Dimethoxy-6-methylbenzoate (3): Methyl 2,4-dihydroxy-
6-methylbenzoate (1) (1.00 g, 5.50 mmol) and dimethyl sulfate
(2.1 mL, 22.2 mmol) were added to a solution of sodium methoxide
(0.89 g, 16.5 mmol) in dry MeOH (15 mL). After stirring for 5 h at
65 °C, the solvent was evaporated under reduced pressure and
water (100 mL) was added. The mixture was acidified to pH 1.5–
2.0 with 2  HCl and extracted with EtOAc (3ϫ100 mL). The
combined organic layers were dried (MgSO4) and the solvent was
removed in vacuo. The residue was purified by column chromatog-
raphy (isohexane/EtOAc, 4:1) to give 3 (740 mg, 64%, Rf = 0.24)
the desired coupling position and lacks free hydroxy groups.
Unlike that, the oxidative phenolic coupling reaction re-
quires a hydroxy function at C-2, but shows no regioselec-
tivity regarding the coupling position.
The atropisomers of the dimeric orsellinates were re-
solved by column chromatography with triacetylcellulose as
stationary phase, by the dinitrodiphenic acid method and
by separation of the diastereomeric camphanate esters,
whereupon the latter method is more practicable due to
higher yields.
The value of dimeric orsellinates in natural product syn-
theses is emphasized by the synthesis of the flavomannin
analogues 21a–b using a tandem Michael–Dieckmann reac-
tion with cyclohexenone derivatives 20a–b.
Moreover, (M)- and (P)-11 were applied in the synthesis
of both atropisomers of vioxanthin[26] and dimeric couma-
rins of the kotanin type.[27] In the latter case all possible
regioisomeric dimeric coumarins were synthesized starting
from 11 (3,3Ј), 12 (5,5Ј) and 13 (3,5Ј), thus pinpointing the
high potential of unselective phenol coupling in biomimetic
natural product synthesis.
1
as a colourless solid, m.p. 41.6 °C. H NMR (400 MHz, CDCl3): δ
= 2.27 (s, 3 H, CH3), 3.78 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3),
3.87 (s, 3 H, OCH3), 6.30 (s, 2 H, Har) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.9 (CH3), 52.0 (OCH3), 55.3 (OCH3), 55.9 (OCH3),
96.2 (CHar), 106.7 (CHar), 116.4 (Cq), 138.3 (Cq), 158.2 (Cq), 161.4
(Cq), 168.7 (Cq) ppm. MS (EI): m/z (%) = 210 (89) [M+], 179 (100)
[C10H11O4+]. GC-MS: Rt = 10.78 min, m/z (%) = 210 (44) [M+],
179 (100) [C10H11O4+].
Methyl 2-Hydroxy-3-iodo-4-methoxy-6-methylbenzoate (4)* and
Methyl 2-Hydroxy-5-iodo-4-methoxy-6-methylbenzoate (5)*
Unselective Iodination: A solution of iodine (6.48 g, 25.51 mmol) in
EtOH (50 mL) and 30% H2O2 (1000 mL) were added to a solution
of methyl 2-hydroxy-4-methoxy-6-methylbenzoate (2) (5.00 g,
25.51 mmol) in EtOH (150 mL) subsequently. The solid was com-
pletely precipitated by addition of water (1000 mL) and then sepa-
rated by filtration. The title compounds 4 and 5 were obtained as
a 4:1 mixture of colourless solids (3.29 g, 40%).
Experimental Section
1
4: H NMR (300 MHz, CDCl3): δ = 12.64 (s, 1 H, OH), 6.30 (s, 1
General Remarks: All reagents were used in analytical grade. Sol-
vents were desiccated by standard methods if necessary. Methyl 2,4-
dihydroxy-6-methylbenzoate (1),[5] methyl 2-hydroxy-4-methoxy-6-
methylbenzoate (2),[10] methyl 2,4-dimethoxy-6-methylbenzoate
(3),[7] (M)- and (P)-6,6Ј-dinitro-2,2Ј-diphenoyl dichloride, (M)-(14)
and (P)-(14),[16] and 3-methoxy-5,5-dimethylcyclohex-2-en-1-one[17]
(20a) were synthesised according to published procedures. New
compounds are marked with an asterisk. Thin-layer chromatog-
raphy (TLC) was carried out on aluminium sheets precoated with
silica gel 60F254 (Merck). Detection was performed under UV light
(λ = 254 nm). Preparative column chromatography was carried out
on silica gel 60 (Merck) (particle size 40–63 µm) or Sephadex LH-
20 (Pharmacia). NMR spectra were recorded on a AMX 300
(Bruker Physik AG, Germany) or a Varian VXR 400 S (Varian
GmbH, Germany). Chemical shifts δ are reported in ppm relative
H, ar-H), 3.97 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 2.56 (s, 3 H,
CH3) ppm. GC-MS: Rt = 12.60 min, m/z (%) = 322 (38) [M+], 290
(100) [C9H7IO3+], 247 (13) [C7H4IO2+], 163 (13) [C9H7O3+].
1
5: H NMR (300 MHz, CDCl3): δ = 11.53 (s, 1 H, OH), 6.37 (s, 1
H, ar-H), 3.96 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 2.78 (s, 3 H,
CH3) ppm. GC-MS: 5, Rt = 12.97 min, m/z (%) = 322 (32) [M+],
290 (100) [C9H7IO3+], 247 (11) [C7H4IO2+], 163 (12) [C9H7O3+].
Methyl 5-Iodo-2,4-dimethoxy-6-methylbenzoate (7) and Methyl 3-
Iodo-2,4-dimethoxy-6-methylbenzoate (8)*: Anhydrous K2CO3
(9.00 g, 65.22 mmol) and dimethyl sulfate (4.13 mL, 43.48 mmol)
were added to a solution of methyl 2-hydroxy-3-iodo-4-methoxy-6-
methylbenzoate (4) and methyl 2-hydroxy-4-methoxy-5-iodo-6-
methylbenzoate (5) (7.00 g, 21.74 mmol) in acetone (500 mL). After
stirring for 24 h at 56 °C, the solvent was evaporated under reduced
to CHCl3 (1H, δ = 7.26 ppm) and CDCl3 (13C, δ = 77.0 ppm) as pressure and water (700 mL) was added. The mixture was extracted
internal standard. GC-MS spectra were determined on a HP 6890 with EtOAc (3ϫ500 mL), the combined organic layers were dried
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Dimeric Orsellinic Acid Derivatives
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(MgSO4), and the solvent was removed in vacuo. The residue was
purified by column chromatography (isohexane/EtOAc = 4:1) to
give 7 (2.43 g, 30%, Rf = 0.16) and 8 (4.87 g, 60%, Rf = 0.31) as
colourless solids.
14.88 mmol) and activated copper bronze (5 g) was heated under
nitrogen at 280 °C for 1 h. The cooled mixture was exhaustively
extracted with boiling EtOAc, the extracts were filtered and the
solvent was removed under reduced pressure. The crude product
was purified by column chromatography (isohexane/EtOAc, 2:1; Rf
7: M.p. 133 °C. IR (KBr): ν = 1720, 1585, 1323, 1262, 1205, 1072,
˜
= 0.24) to give 9 (1.71 g, 55%) as a colourless solid, m.p. 209 °C.
1
940, 807 cm–1. H NMR (300 MHz, CDCl3): δ = 6.31 (s, 1 H, ar-
1
IR (KBr): ν = 1720, 1587, 1315, 1205, 1095, 1080 cm–1. H NMR
˜
H), 3.90 (s, 6 H, OCH3), 3.84 (s, 3 H, OCH3), 2.40 (s, 3 H, CH3)
ppm. 13C NMR (75.5 MHz, CDCl3): δ = 168.29 (C=O), 159.45
(Cq), 157.74 (Cq), 139.98 (Cq), 117.41 (Cq), 92.76 (CH), 82.84 (Cq),
56.44 (OCH3), 55.95 (OCH3), 52.31 (OCH3), 25.95 (CH3) ppm.
GC-MS: Rt = 12.76 min, m/z (%) = 336 (100) [M+], 305 (70)
[C10H10IO3+]. C11H13IO4 (336.12): calcd. C 39.31, H 3.90; found C
39.58, H 3.77.
(300 MHz, CDCl3): δ = 6.38 (s, 2 H, 2ϫar-H), 3.86 (s, 6 H,
2ϫOCH3), 3.84 (s, 6 H, 2ϫOCH3), 3.66 (s, 6 H, 2ϫOCH3), 1.82
(s, 6 H, 2ϫCH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 169.10
(2ϫC=O), 158.84 (2ϫCq), 156.97 (2ϫCq), 136.83 (2ϫCq), 117.9
(2ϫCq), 116.63 (2ϫCq), 93.00 (2ϫCH), 55.80 (2ϫOCH3), 55.65
(2ϫOCH3), 51.94 (2ϫOCH3), 16.69 (2ϫCH3) ppm. MS: m/z (%)
= 418 (100) [M+], 387 (59) [C21H23O7+], 355 (13) [C20H19O6+].
C22H26O8 (418.16): calcd. C 63.15, H 6.26; found C 63.51, H 6.33;
HRMS: calcd. for C22H26O8 418.1628; found 418.1623.
8: M.p. 72 °C. IR (KBr): ν = 1715, 1210, 1085 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 6.44 (s, 1 H, ar-H), 3.89 (s, 3 H, OCH3),
3.85 (s, 1 H, OCH3), 3.82 (s, 3 H, OCH3), 2.29 (s, 3 H, CH3) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 167.51 (C=O), 159.81 (Cq),
158.34 (Cq), 138.45 (Cq), 121.67 (Cq), 108.41 (CH), 80.23 (Cq),
62.14 (OCH3), 56.45 (OCH3), 52.14 (OCH3), 19.73 (CH3) ppm.
GC-MS: Rt = 12.35 min, m/z (%) = 336 (85) [M+], 305 (100)
[C10H10IO3+], 290 (28) [C9H7IO3+]. C11H13IO4 (336.12): calcd. C
39.31, H 3.90; found C 39.62, H 4.07.
Dimethyl 2,2Ј,6,6Ј-Tetramethoxy-4,4Ј-dimethyl-3,3Ј-biphenyldicar-
boxylate (10)*: An intimate mixture of the iodo compound 8
(5.00 g, 14.88 mmol) and activated copper bronze (5 g) was heated
under nitrogen at 240 °C for 2 h. The cooled mixture was exhaus-
tively extracted with boiling EtOAc, the extracts were filtered and
the solvent was removed under reduced pressure. The crude prod-
uct was purified by column chromatography (isohexane/EtOAc,
7:2; Rf = 0.24) to give 10 (2.03 g, 65%) as a colourless solid, m.p.
Methyl 2,4-Dihydroxy-3-iodo-6-methylbenzoate (6)*
185 °C. IR (KBr): ν = 1720, 1595, 1295, 1207, 1190, 1165,
˜
Selective Iodination: Benzyltrimethylammonium dichloroiodate
(191 mg, 0.55 mmol) and KHCO3 (330 mg, 3.30 mmol) were added
1
1105 cm–1. H NMR (300 MHz, CDCl3): δ = 6.53 (s, 2 H, 2ϫar-
H), 3.84 (s, 6 H, 2ϫOCH3), 3.68 (s, 6 H, 2ϫOCH3), 3.41 (s, 6
H, 2ϫOCH3), 2.34 (s, 6 H, 2ϫCH3) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 168.70 (2ϫC=O), 159.09 (2ϫCq), 157.02 (2ϫCq),
137.67 (2ϫCq), 121.02 (2ϫCq), 114.42 (2ϫCq), 108.24 (2ϫCH),
61.45 (2ϫOCH3), 55.81 (2ϫOCH3), 51.89 (2ϫOCH3), 20.15
to
a solution of methyl 2,4-dihydroxy-6-methylbenzoate (1)
(100 mg, 0.55 mmol) in CH2Cl2 (10 mL). After stirring the mixture
for 24 h, a NaHCO3 solution (20 mL) was added and the aqueous
phase extracted with CH2Cl2 (3ϫ50 mL). The combined organic
layers were dried (MgSO4) and the solvent was removed under re-
duced pressure. The crude product was purified by column
chromatography on silica gel (toluene/acetone, 60:1; Rf = 0.23) to
(2ϫCH3) ppm. MS: m/z (%)
=
418 (81) [M+], 386 (100)
[C21H22O7+], 355 (24) [C20H19O6+]. C22H26O8 (418.16): calcd. C
63.15, H 6.26; found C 63.31, H 6.20. HRMS: calcd. for C22H26O8
418.1628; found 418.1619.
give 6 (75 mg, 44%) as a colourless solid, m.p. 143 °C. IR (KBr):
ν = 3406, 1630, 1408, 1316, 1267, 798 cm–1. H NMR (300 MHz,
1
˜
CDCl3): δ = 12.77 (s, 1 H, OH), 6.45 (s, 1 H, ar-H), 5.82 (s, 1 H,
OH), 3.93 (s, 3 H, OCH3), 2.47 (s, 3 H, CH3) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 171.76 (C=O), 163.35 (Cq), 159.45 (Cq),
143.90 (Cq), 110.26 (CH), 105.61 (Cq), 74.12 (CH), 52.36 (OCH3),
24.10 (CH3) ppm. GC-MS: Rt = 12.03 min, m/z (%) = 308 (33)
[M+], 276 (100) [C8H5IO3+], 248 (9) [C7H5IO2+], 149 (16)
[C8H5O3+]. C9H9IO4 (308.07): calcd. C 35.09, H 2.94; found C
35.38, H 2.88; HRMS: calcd. for C9H9IO4 307.9546; found
307.9541.
Alternative Synthesis of 10: To a solution of 11 (79 mg, 0.2 mmol)
in 30 mL acetone were added anhydrous K2CO3 (112 mg,
0.8 mmol) and methyl iodide (38 µL, 0.6 mmol). After reflux for
24 h, the reaction mixture was concentrated in vacuo, the residue
distributed between water and EtOAc, and the aqueous phase ex-
tracted with EtOAc. The organic phase was washed with brine,
dried (MgSO4), and the solvent was removed under reduced pres-
sure. The crude product was purified by column chromatography
on silica gel (cyclohexane/EtOAc, 2:1; Rf = 0.20) to give 10 (79 mg,
94%) as a colourless solid.
Methyl 5-Iodo-2,4-dimethoxy-6-methylbenzoate (7)
Racemic Resolution: The atropisomers (+)-10 and (–)-10 could be
separated by column chromatography on triacetylcellulose: Crys-
talline triacetylcellulose was heated under reflux in EtOH for
30 min, then filtered, slurried in EtOH, degassed by sonification
and, under slight pressure, filled in a column. Racemic 10 was dis-
solved in EtOH and eluted under slight pressure. Both enantiomers
were eluted in overlapping broad bands. First the dextrorotatory
(+)-10 was eluted, then (–)-10.[19]
The enantiomeric excess was determined by 1H NMR with shift
reagent [Pr(hfc)3] in CDCl3. Optically active samples obtained by
racemic resolution showed ee values in the range from 7–13%.
Selective Iodination: A solution of iodine (6.05 g, 20.81 mmol) in
EtOH (50 mL) and 30% H2O2 (1000 mL) was added subsequently
to a solution of methyl 2,4-dimethoxy-6-methylbenzoate (3) (5.00 g,
23.81 mmol) in EtOH (150 mL). The solid was completely precipi-
tated by addition of water (1000 mL) and then separated by fil-
tration. The residue was recrystallized (cyclohexane/EtOAc) to give
7 (7.68 g, 96%) as a colourless solid. All spectral characteristics
were identical with those of compound 7, obtained by unselective
iodination and methylation (see above).
Methyl 3-Iodo-2,4-dimethoxy-6-methylbenzoate (8)*: An excess of
methyl iodide was added to a solution of methyl 2,4-dihydroxy-3-
iodo-6-methylbenzoate (6) (300 mg, 1.47 mmol) and NaH in dry
THF. Compound 8 was obtained in quantitative yield. All spectral
characteristics were identical with those of compound 8 obtained
by unselective iodination and methylation (see above).
(+)-10: [α]578 = +0.6 (c = 0.2, dioxane/CH2Cl2, 1:1), [α]546 = +1.4
(c = 0.2, dioxane/CH2Cl2, 1:1), [α]436 = +2.8 (c = 0.2, dioxane/
CH2Cl2, 1:1), [α]365 = +6.1 (c = 0.2, dioxane/CH2Cl2, 1:1).
(–)-10: [α]578 = –0.6 (c = 0.9, dioxane/CH2Cl2, 1:1), [α]546 = –1.3 (c
= 0.9, dioxane/CH2Cl2, 1:1), [α]436 = –5.7 (c = 0.9, dioxane/CH2Cl2,
1:1), [α]365 = –10.8 (c = 0.9, dioxane/CH2Cl2, 1:1).
Dimethyl 4,4Ј,6,6Ј-Tetramethoxy-2,2Ј-dimethyl-3,3Ј-biphenyldicar-
boxylate (9): An intimate mixture of the iodo compound 7 (5.00 g,
Eur. J. Org. Chem. 2007, 1749–1758
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1755

M. Müller, W. Steglich et al.
FULL PAPER
(M)-Dimethyl 2,2Ј,6,6Ј-Tetramethoxy-4,4Ј-dimethyl-3,3Ј-biphenyl-
dicarboxylate [(M)-10]*: The synthesis of (M)-(+)-10 was per-
formed analogously to the synthesis of rac-10 starting with a solu-
tion of (M)-11 (120 mg, 0.3 mmol) in 50 mL acetone, anhydrous
K2CO3 (171 mg, 1.2 mmol) and methyl iodide (58 µL, 0.9 mmol).
After purification by column chromatography on silica gel (isohex-
ane/EtOAc, 2:1; Rf = 0.20), (M)-10 was obtained as a colourless
16 h incubation at room temperature, the 3,3Ј-coupling product 11
crystallized (24% isolated yield). The mother liquor was concen-
trated and, after flash column chromatography on silica gel
(isohexane/EtOAc, 3:1, 1:1), the 5,5Ј- and 3,5Ј-coupling products
12 and 13 were obtained in 16 and 31% isolated yield, respectively.
11: Rf = 0.22 (isohexane/EtOAc, 2:1), m.p. 246 °C. 1H NMR
(300 MHz, CDCl3): δ = 11.81 (s, 2 H, 2ϫOH), 6.41 (s, 2 H, 2ϫar-
H), 3.91 (s, 6 H, 2ϫOCH3), 3.77 (s, 6 H, 2ϫOCH3), 2.59 (s, 6 H,
solid (112 mg, 86%), m.p. 113.1 °C. [α]2D6 = –6.30 (c = 1.4, CHCl3),
20
[α]2D0 = +14.58 (c = 0.2, dioxane/CH2Cl2, 1:1), [α] = +15.42 (c =
2ϫCH3) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 172.37
578
20
0.2, dioxane/CH2Cl2, 1:1), [α]
= +17.50 (c = 0.2, dioxane/
546
(2ϫC=O), 161.90 (2ϫCq), 161.50 (2ϫCq), 143.10 (2ϫCq), 107.84
(2ϫCq), 106.69 (2ϫCH), 105.97 (2ϫCq), 55.82 (2ϫOCH3), 51.85
(2ϫOCH3), 24.96 (2ϫCH3) ppm. MS: m/z (%) = 390 (67) [M+],
358 (70) [C19H18O7+], 327 (65) [C18H15O6+], 295 (100) [C17H11O5+].
HRMS: calcd. for C20H22O8 390.1315; found 390.1311.
20
CH2Cl2, 1:1), [α]
= +32.50 (c = 0.2, dioxane/CH2Cl2, 1:1),
436
20
[α] = +62.08 (c = 0.2, dioxane/CH2Cl2, 1:1); CD (acetonitrile): λ
365
= (∆ε) [nm] = 197 (+20.6), 214 (–26.9), 240 (+8.7), 263 (+0.3), 274
(+0.8). All other spectral characteristics were identical with those
of racemic 10.
12: Rf = 0.33 (isohexane/EtOAc, 2:1), m.p. 183 °C. 1H NMR
(300 MHz, CDCl3): δ = 11.77 (s, 2 H, 2ϫOH), 6.41 (s, 2 H, 2ϫar-
H), 3.91 (s, 6 H, 2ϫOCH3), 3.67 (s, 6 H, 2ϫOCH3), 2.10 (s, 6 H,
(P)-Dimethyl 2,2Ј,6,6Ј-Tetramethoxy-4,4Ј-dimethyl-3,3Ј-biphenyl-
dicarboxylate [(P)-10]*: The synthesis of (P)-(–)-10 was performed
analogously to that of rac-10 starting with a solution of (P)-11
(120 mg, 0.3 mmol) in 50 mL acetone, K2CO3 (171 mg, 1.2 mmol)
and methyl iodide (58 µL, 0.9 mmol). After purification by column
chromatography on silica gel (isohexane/EtOAc, 2:1; Rf = 0.20),
(P)-10 was obtained as a colourless solid (112 mg, 86%), m.p.
2ϫCH3) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 172.49
(2ϫC=O), 164.47 (2ϫCq), 162.25 (2ϫCq), 141.41 (2ϫCq), 119.15
(2ϫCq), 105.55 (2ϫCq), 97.29 (2ϫCH), 55.69 (2ϫOCH3), 51.83
(2ϫOCH3), 19.36 (2ϫCH3) ppm. MS: m/z (%) = 390 (47) [M+],
358 (31) [C19H18O7+], 327 (100) [C18H15O6+], 295 (100)
[C17H11O5+]. HRMS: calcd. for C20H22O8 390.1315; found
390.1314.
13: Rf = 0.24 (isohexane/EtOAc, 2:1), m.p. 190 °C. 1H NMR
(300 MHz, CDCl3): δ = 11.79 (s, 1 H, OH), 11.74 (s, 1 H, OH),
6.44 (s, 1 H, ar-H), 6.38 (s, 1 H, ar-H), 3.92 (s, 3 H, OCH3), 3.90
(s, 3 H, OCH3), 3.75 (s, 3 H, OCH3), 3.70 (s, 3 H, OCH3), 2.60 (s,
3 H, CH3), 2.22 (s, 3 H, CH3) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 172.53 (C=O), 172.41 (C=O), 164.74 (Cq), 162.34 (Cq), 161.90
(Cq), 161.35 (Cq), 142.80 (Cq), 141.64 (Cq), 115.71 (Cq), 111.16
(Cq), 106.45 (CH), 105.87 (Cq), 105.65 (Cq), 97.50 (CH), 55.81
(OCH3), 55.69 (OCH3), 51.91 (OCH3), 51.78 (OCH3), 24.94 (CH3),
19.67 (CH3) ppm. MS: m/z (%) = 390 (53) [M+], 358 (66)
[C19H18O7+], 326 (100) [C18H14O6+]. HRMS: calcd. for C20H22O8
390.1315; found 390.1323.
131.0 °C. [α]2D6 = +4.56 (c = 1.6, CHCl3), [α]2D2 = +7.48 (c = 0.2,
20
CHCl3), [α]2D4 = –13.81 (c = 0.2, dioxane/CH2Cl2, 1:1), [α]
=
578
20
–14.29 (c = 0.2, dioxane/CH2Cl2, 1:1), [α]
= –16.90 (c = 0.2,
= –32.38 (c = 0.2, dioxane/CH2Cl2,
1:1), [α] = –63.81 (c = 0.2, dioxane/CH2Cl2, 1:1); CD (acetoni-
546
20
dioxane/CH2Cl2, 1:1), [α]
436
20
365
trile): λ = (∆ε) [nm] = 197 (–20.6), 214 (–26.9), 240 (+8.8), 263
(+0.3), 274 (+0.8). All other spectral characteristics were identical
with those of compound rac-10.
Dimethyl 2,2Ј-Dihydroxy-6,6Ј-dimethoxy-4,4Ј-dimethyl-3,3Ј-biphen-
yldicarboxylate (11), Dimethyl 4,4Ј-Dihydroxy-6,6Ј-dimethoxy-2,2Ј-
dimethyl-3,3Ј-biphenyldicarboxylate (12) and Dimethyl 2,4Ј-Dihy-
droxy-6,6Ј-dimethoxy-2Ј,4-dimethyl-3,3Ј-biphenyldicarboxylate (13).
Oxidative Phenolic Coupling: The silica gel-bound FeCl3 was pre-
pared as follows. Silica gel (7.24 g) was added to a solution of
FeCl3·6H2O (3.52 g, 13.02 mmol) in Et2O (190 mL) and MeOH Resolution of the Atropisomers via the DNPS Method
(10 mL). The solvents were evaporated and the yellow solid was
dried in vacuo at 70 °C (0.4 mbar) for 8 h. The silica gel bound
FeCl3 was obtained as a yellow-green solid. The oxidative coupling
reaction was carried out by adding this reagent (1.40 g) to a solu-
tion of methyl 2-hydroxy-4-methoxy-6-methylbenzoate (2) (146 mg,
0.74 mmol) in CH2Cl2 (30 mL). After efficient mixing, the solvent
was removed under reduced pressure to give a dark solid, which
was heated at 60 °C for 24 h. MeOH (50 mL) was added and the
dichloride [(M)-(+)-14] (71 mg, 0.19 mmol) in dry THF (80 mL)
(M,M)-Dimethyl 4,5-Dimethoxy-2,7-dimethyl-14,15-dinitro-10,19-
dioxo-10,19-dihydro-9,20-dioxa-tetrabenzo[a,c,g,i]cyclododecene-
1,8-dicarboxylate [(M,M)-15]*: Dimethyl 2,2Ј-dihydroxy-6,6Ј-di-
methoxy-4,4Ј-dimethyl-3,3Ј-biphenyldicarboxylate (11) (75 mg,
0.19 mmol) was added to a suspension of sodium hydride (30 mg,
0.76 mmol) in dry THF (80 mL). After stirring for 30 min at 67 °C,
this solution and a solution of (M)-(+)-6,6Ј-dinitro-2,2Ј-diphenoyl
mixture filtered through Celite. The solvent was removed in vacuo
and the dark residue purified by column chromatography (isohex-
ane/EtOAc, 5:1, 4:1, 3:1, 2:1) to yield the biphenyldiols 11 (22 mg,
17%), 12 (42 mg, 33%) and 13 (38 mg, 30%) as colourless solids.
From fractions containing 11 and 13 the symmetric compound 11
crystallized quantitatively while the unsymmetric compound 13 re-
mained in solution. After separation by centrifugation, analytically
pure (NMR) 11 and 13 were obtained.
were transferred simultaneously within 1 h to boiling THF.[28] After
stirring for 3 h at 67 °C, the reaction mixture was acidified with 2 
HCl. The aqueous phase was extracted with EtOAc (3ϫ150 mL),
the organic layers were dried (MgSO4), and the solvent was re-
moved under reduced pressure. The crude product was purified by
preparative TLC (isohexane/EtOAc, 2:3; Rf = 0.26) to give (M,M)-
15 (17 mg, 13%) as a colourless solid, m.p. 149 °C. IR (KBr): ν =
˜
1750, 1715, 1530, 1260, 1100 cm–1. [α]2D5 = –21.8 (c = 0.06, dioxane/
CH2Cl2, 1:1); CD (dioxane): λ = (∆ε) [nm] = 239 (+1.0), 262 (–0.8);
1H NMR (300 MHz, CDCl3): δ = 8.31 (dd, 3J = 7.8 Hz, 4J =
1.4 Hz, 1 H, 2ϫar-H), 8.06 (dd, 3J = 7.8 Hz, 4J = 1.4 Hz, 1 H,
Alternatively, for the oxidative coupling in larger scale, orsellinate
2 (4.73 g, 24.1 mmol) and silica gel bound FeCl3 (47.00 g) were
suspended in 20 mL CH2Cl2, and the solvent was removed at 40 °C
under reduced pressure within 60 min. The cycle of suspending and
drying was repeated four times until formation of by-products was
detected by TLC. The dark residue was filtered through a short
silica gel column (chloroform/2-propanol, 40:1), and the eluate was
concentrated in vacuo. The residue was dissolved in boiling EtOAc
(200 mL) and the solution mixed with cyclohexane (800 mL). After
3
2ϫar-H), 7.58 (t, J = 7.8 Hz, 1 H, 2ϫar-H), 6.63 (s, 1 H, 2ϫar-
H), 3.69 (s, 3 H, 4ϫOCH3), 2.46 (s, 3 H, 2ϫCH3) ppm. MS: m/z
(%) = 686 (100) [M+], 654 (34) [C33H22N2O13+]. HRMS: calcd. for
C34H26N2O14 686.1384; found 686.1377.
(P,P)-Dimethyl 4,5-Dimethoxy-2,7-dimethyl-14,15-dinitro-10,19-di-
oxo-10,19-dihydro-9,20-dioxa-tetrabenzo[a,c,g,i]cyclododecene-1,8-
1756
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1749–1758

Dimeric Orsellinic Acid Derivatives
FULL PAPER
dicarboxylate [(P,P)-15]*: According to the foregoing procedure
starting from 2,2Ј-dihydroxy-6,6Ј-dimethoxy-4,4Ј-dimethyl-3,3Ј-bi-
(5 mL). After stirring for 2 h at room temperature, the solvent was
evaporated in vacuo and 2  HCl (5 mL) was added. The mixture
phenyldicarboxylate (11) (75 mg, 0.19 mmol) and (P)-(–)-6,6Ј-dini- was extracted with EtOAc (3ϫ10 mL), the combined organic lay-
tro-2,2Ј-diphenoyl dichloride [(P)-(–)-14] (71 mg, 0.19 mmol) the ti-
tle compound was obtained as a colourless solid. [α]2D0 = +51.2 (c
= 0.3, CHCl3). All other spectral characteristics were identical with
those of compound (M,M)-15.
ers were dried (MgSO4), and the solvent was removed under re-
duced pressure. The crude product was purified by preparative TLC
(isohexane/EtOAc, 2:1; Rf = 0.22) to give (M)-11 (7 mg, 90%) as a
colourless solid, m.p. 229 °C. All other spectral characteristics were
identical with those of compound rac-11.
Resolution of the Atropisomers via the Camphanate Method
Camphanate Ester Method: A solution of camphanate ester (M)-18
(28 mg, 0.04 mmol) and sodium methoxide (20 mg, 0.36 mmol) in
dry MeOH (5 mL) was refluxed until no more starting material
was detectable by TLC (1 h). The reaction mixture was quenched
with 1  H2SO4 (2 mL), and the aqueous phase was extracted with
CH2Cl2 (3ϫ10 mL). The combined organic layers were washed
with brine (2ϫ15 mL), dried (MgSO4), and the solvent was re-
moved under reduced pressure. The crude product was purified by
column chromatography on silica gel (isohexane/EtOAc, 2:1; Rf =
0.22) to give (M)-11 (11 mg, 75 %) as a colourless solid, m.p.
228 °C. [α]2D0 = –53.3 (c = 0.15, CHCl3); CD (trifluoroethanol): λ =
(∆ε) [nm] = 205 (+96.6), 224 (–56.1), 260 (+37.9), 278 (–17.1), 311
(–5.0). All other spectral characteristics were identical with those
of compound rac-11.
Dimethyl 2,2Ј-Bis(camphanyloxy)-4,4Ј-dimethoxy-6,6Ј-dimethyl-
3,3Ј-biphenyldicarboxylates [(M)-(–)-18 and (P)-(+)-19]*: 4-(Di-
methylamino)pyridine (100 mg, 0.81 mmol) was added to a solu-
tion of dimethyl 2,2Ј-dihydroxy-6,6Ј-dimethoxy-4,4Ј-dimethyl-3,3Ј-
biphenyldicarboxylate rac-(11) (964 mg, 2.474 mmol) and (1S,4R)-
(–)-camphanoyl chloride (17) (4.42 g, 19.76 mmol) in dry pyridine
(60 mL). After refluxing for 4 h, CH2Cl2 (500 mL) was added and
the reaction mixture washed with 2  HCl (2ϫ250 mL), saturated
aqueous NaHCO3 (100 mL), and water (100 mL). The combined
organic layers were dried (MgSO4) and the solvent was removed
under reduced pressure. The crude product was purified by column
chromatography on silica gel (isohexane/EtOAc, 1:1) to yield the
camphanate esters (–)-18 (871 mg, 47%), and (+)-19 (834 mg, 45%)
as colourless solids.
(P)-Dimethyl 2,2Ј-Dihydroxy-6,6Ј-dimethoxy-4,4Ј-dimethyl-3,3Ј-bi-
phenyldicarboxylate [(P)-11]
(M)-(–)-18: Rf = 0.38 (isohexane/EtOAc, 1:1), m.p. 209 °C. [α]2D4
=
–26.1 (c = 1.0, CHCl3); CD (acetonitrile): λ = (∆ε) [nm] = 211
1
Dinitrodiphenic Acid Method: According to the foregoing procedure
starting from (P,P)-15 (17 mg, 0.02 mmol) the title compound was
prepared in 90% yield (7 mg) as a colourless solid, m.p. 229 °C.
[α]2D0 = +27.0 (c = 0.2, CHCl3). All other spectral characteristics
were identical with those of compound rac-11.
(–55.92), 243 (+13.9), 261 (–5.6), 280 (+1.9). H NMR (300 MHz,
CDCl3): δ = 6.67 (s, 2 H, 2ϫar-H), 3.77 (s, 6 H, 2ϫOCH3), 3.76
(s, 6 H, 2ϫOCH3), 2.41 (s, 6 H, 2ϫCH3), 2.19 (ddd, J = 13.6 Hz,
J = 10.9 Hz, J = 4.5 Hz, 2 H, 2ϫCH), 1.97 (ddd, J = 13.6 Hz, J
= 9.3 Hz, J = 4.5 Hz, 2 H, 2ϫCH), 1.81 (ddd, J = 13.6 Hz, J =
10.9 Hz, J = 4.5 Hz, 2 H, 2ϫCH), 1.60 (ddd, J = 13.6 Hz, J =
9.3 Hz, J = 4.5 Hz, 2 H, 2ϫCH), 0.99 (s, 6 H, 2ϫCH3), 0.81 (s, 6
H, 2ϫCH3), 0.47 (s, 6 H, 2ϫCH3) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 178.22 (2 ϫ C=O), 166.34 (2 ϫ C=O), 164.75
(2ϫC=O), 159.63 (2ϫCq), 147.70 (2ϫCq), 140.65 (2ϫCq), 118.43
(2ϫCq), 113.40 (2ϫCq), 111.29 (2ϫCH), 90.81 (2ϫCq), 56.26
(2ϫOCH3), 54.83 (2ϫCq), 54.05 (2ϫCq), 52.12 (2ϫOCH3), 31.00
(2ϫCH2), 28.80 (2ϫCH2), 21.51 (2ϫCH3), 16.00 (2ϫCH3), 15.10
(2ϫCH3), 9.57 (2ϫCH3) ppm. MS: m/z (%) = 750 (7) [M+], 718
(100) [C39H42O13+], 341 (14) [C18H13O7+]. HRMS: calcd. for
C40H46O14 750.2888; found 750.2940.
Camphanate Ester Method: According to the foregoing procedure
starting from camphanate ester (P)-18 (28 mg, 0.04 mmol) the title
compound was prepared in 75% yield (11 mg) as a colourless solid,
m.p. 223 °C. [α]2D0 = +36.4 (c = 0.11, CHCl3); CD (trifluoro-
ethanol): λ = (∆ε) [nm] = 206 (–51.0), 223 (+35.3), 260 (–18.5), 279
(+12.6), 312 (+6.3). All other spectral characteristics were identical
with those of compound rac-11.
Syntheses of Dimeric Dihydroanthracenones
General Procedure for the Tandem Michael–Dieckmann Reaction: A
solution of dimethyl 2,2Ј,6,6Ј-tetramethoxy-4,4Ј-dimethyl-3,3Ј-bi-
phenyldicarboxylate (10) (105 mg, 0.25 mmol) in dry THF (5 mL)
was added at –78 °C to a solution of lithium diisopropylamide in
dry THF (30 mL), prepared from diisopropylamine (0.35 mL,
2.5 mmol) and a 2.5  solution of n-butyllithium (0.8 mL,
2.0 mmol). The red solution was stirred for 10 min at –78 °C, then
warmed to –40 °C for 5 min and cooled again to –78 °C. Then a
solution of the cyclohexenone 20 (2.0 mmol) in dry THF (5 mL)
was added. The reaction mixture was stirred for 15 min at –78 °C,
before it was hydrolyzed with dry EtOH (1 mL) and warmed to
room temperature. After addition of AcOH (1 mL) and saturated
aqueous NH4Cl (200 mL), the aqueous phase was extracted with
Et2O (3ϫ100 mL). The combined organic layers were washed with
brine (100 mL), dried (MgSO4), and concentrated under reduced
pressure.
(P)-(+)-19: Rf = 0.31 (isohexane/EtOAc, 1:1), m.p. 223 °C. [α]2D5
=
+19.4 (c = 1.0, CHCl3); CD (acetonitrile): λ = (∆ε) [nm] = 211
(+71.23), 243 (–21.5), 261 (+4.7), 280 (–0.34); 1H NMR (300 MHz,
CDCl3): δ = 6.70 (s, 2 H, 2ϫar-H), 3.80 (s, 6 H, 2ϫOCH3), 3.74
(s, 6 H, 2ϫOCH3), 2.44 (s, 6 H, 2ϫCH3), 2.15 (ddd, J = 13.6 Hz,
J = 10.9 Hz, J = 4.5 Hz, 2 H, 2ϫCH), 1.80 (ddd, J = 13.6 Hz, J
= 9.3 Hz, J = 4.5 Hz, 2 H, 2ϫCH), 1.50 (m, 4 H, 2ϫCH2), 1.03
(s, 6 H, 2ϫCH3), 0.88 (s, 6 H, 2ϫCH3), 0.82 (s, 6 H, 2ϫCH3)
ppm. 13C NMR (75.5 MHz, CDCl3): δ = 178.21 (2ϫC=O), 166.50
(2 ϫ C=O), 164.56 (2 ϫ C=O), 159.43 (2 ϫCq), 147.33 (2ϫ Cq),
139.99 (2ϫCq), 119.18 (2ϫCq), 113.33 (2ϫCq), 111.20 (2ϫCH),
90.99 (2ϫCq), 56.22 (2ϫOCH3), 54.90 (2ϫCq), 54.10 (2ϫCq),
52.19 (2 ϫ OCH3), 30.41 (2 ϫ CH2), 28.80 (2 ϫ CH2), 21.33
(2ϫCH3), 16.04 (2ϫCH3), 15.94 (2ϫCH3), 9.59 (2ϫCH3) ppm.
MS: m/z (%) = 750 (5) [M+], 718 (100) [C39H42O13+], 341 (19)
[C18H13O7+]. HRMS: calcd. for C40H46O14 750.2888; found
750.2871.
(؎)-3,3Ј,4,4Ј-Tetrahydro-9,9Ј-dihydroxy-6,6Ј,8,8Ј-tetramethoxy-
3,3,3Ј,3Ј-tetramethyl-7,7Ј-bianthracene-1,1Ј(2H,2ЈH)-dione (rac-
21a)*: The title compound was prepared according to the general
procedure starting from dimeric orsellinate rac-10 (105 mg,
0.25 mmol) and 5,5-dimethyl-3-methoxycyclohex-2-en-1-one (20a)
(308 mg, 2.0 mmol). The crude product was purified by column
chromatography on Sephadex LH-20 (acetone/MeOH, 4:1) to give
rac-21a (40 mg, 26%) as a yellow solid, m.p. 255 °C. UV (MeOH):
(M)-Dimethyl 2,2Ј-Dihydroxy-6,6Ј-dimethoxy-4,4Ј-dimethyl-3,3Ј-bi-
phenyldicarboxylate [(M)-11]
Dinitrodiphenic Acid Method: A catalytic amount of KOH was
added to a solution of (M,M)-15 (17 mg, 0.02 mmol) in dry THF
Eur. J. Org. Chem. 2007, 1749–1758
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1757

M. Müller, W. Steglich et al.
FULL PAPER
1
[10] The H-NMR signal for the methyl group of the 3-iodo com-
pound 4 is shifted towards higher field than for the 5-iodo com-
pound 5. The structural assignment was made by analogy with
the bromination of compound 2: J. R. Cannon, T. M. Cresp,
B. W. Metcalf, M. V. Sargent, G. Vinciguerra, J. A. Elix, J.
Chem. Soc. C 1971, 3495–3504.
[11] F. M. Hauser, P. J. F. Gauuan, Org. Lett. 1999, 1, 671–672.
[12] a) S. Kajigaeshi, T. Kakinami, H. Yamasaki, S. Fujisaki, M.
Kondo, T. Okamoto, Chem. Lett. 1987, 2109–2112; b) cf. H.
Tsujimori, M. Bando, K. Mori, Eur. J. Org. Chem. 2000, 297–
302.
λ = (ε) [nm] = 220 (0.34), 279 (0.90), 315 (0.20), 332 (0.18), 392
(0.26). 1H NMR (400 MHz, CDCl3): δ = 15.01 (s, 2 H, 2ϫOH),
6.96 (s, 2 H, 2 ϫ ar-H), 6.87 (s, 2 H, 2 ϫ ar-H), 3.80 (s, 6 H,
2ϫOCH3), 3.70 (s, 6 H, 2ϫOCH3), 2.84 (s, 4 H, 2ϫCH2), 2.57
(s, 4 H, 2ϫCH2), 1.12 (s, 6 H, 2ϫCH3), 1.10 (s, 6 H, 2ϫCH3)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 203.89 (2 ϫ C=O),
164.77 (2ϫCq), 160.51 (2ϫCq), 158.43 (2ϫCq), 141.30 (2ϫCq),
138.05 (2ϫCq), 117.90 (2ϫCq), 116.70 (2ϫCH), 113.51 (2ϫCq),
109.95 (2 ϫ Cq), 101.90 (2 ϫ CH), 61.96 (2 ϫ OCH3), 55.73
(2ϫOCH3), 52.15 (2ϫCH2), 43.94 (2ϫCH2), 32.95 (2ϫCq), 28.22
(2ϫCH3), 28.01 (2ϫCH3) ppm. MS (FAB): m/z (%) = 599 (100)
[MH+], 598 (67) [M+], 584 (10) [C35H36O8+], 583 (21) [C35H35O8+],
567 (7) [C35H35O7+], 553 (10) [C34H33O7+], 552 (10) [C34H32O7+],
391 (3) [C20H23O8+], 307 (13) [C16H19O6+], 289 (9) [C16H17O5+].
C36H38O8 (598.69): calcd. C 72.22 H 6.40; found C 71.74 H 6.45.
[13] R. C. Fuson, E. A. Cleveland, Org. Synth. Coll. Vol. III 1955,
339–340.
[14] a) E. Keinan, Y. Mazur, J. Org. Chem. 1978, 43, 1020–1022; b)
cf. T. C. Jempty, L. L. Miller, Y. Mazur, J. Org. Chem. 1980,
45, 749–751.
[15] a) cf. H.-Y. Li, T. Nehira, M. Hagiwara, N. Harada, J. Org.
Chem. 1997, 62, 7222–7227; b) M. R. Parthasarathy, S. Gupta,
Indian J. Chem., Sect. B 1984, 23, 227–230.
[16] The tetramethoxy derivative of the 3,5Ј-coupled dimer 13 was
obtained by Ullmann reaction of the 3,5-diiodo orsellinate as
a minor side product (15% yield): U. Karl, Dissertation, Uni-
versity of Bonn, 1988.
[17] a) S. Miyano, S. Handa, M. Tobita, H. Hashimoto, Bull. Chem.
Soc. Jpn. 1986, 59, 235–238; b) cf. S. Miyano, K. Shimizu, S.
Sato, H. Hashimoto, Bull. Chem. Soc. Jpn. 1985, 58, 1345–
1346; c) cf. S. Miyano, S. Handa, K. Shimizu, K. Tagami, H.
Hashimoto, Bull. Chem. Soc. Jpn. 1984, 57, 1943–1947; d) cf.
S. Miyano, M. Tobita, H. Hashimoto, Bull. Chem. Soc. Jpn.
1981, 54, 3522–3526.
(؎)-3,3Ј,4,4Ј-Tetrahydro-9,9Ј-dihydroxy-6,6Ј,8,8Ј-tetramethoxy-7,7Ј-
bianthracene-1,1Ј(2H,2ЈH)-dione (rac-21b)*: The title compound
was prepared according to the general procedure starting from di-
meric orsellinate rac-10 (105 mg, 0.25 mmol) and cyclohex-2-en-1-
one (20b) (192 mg, 2.0 mmol). The crude product was directly de-
hydrogenated by refluxing with DDQ in dry benzene for 6 h. After
column chromatography on silica gel (isohexane/EtOAc, 4:1), rac-
21b was obtained as a yellow solid. IR (KBr): ν = 2930, 1610, 1560,
˜
1450, 1370, 1210, 1165, 1110, 1095, 710 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 15.07 (s, 2 H, 2ϫOH), 6.97 (s, 2 H, 2ϫar-H), 6.84 (s,
2 H, 2ϫar-H), 3.76 (s, 6 H, 2ϫOCH3), 3.65 (s, 6 H, 2ϫOCH3),
2.97 (s, 4 H, 2ϫCH2), 2.72 (s, 4 H, 2ϫCH2), 2.07 (s, 4 H, 2ϫCH2)
ppm. MS: m/z (%) = 542 (8) [M+], 527 (4) [C31H27O8+], 494 (9)
[C30H22O7+], 480 (100) [C30H14O6+], 449 (24) [C29H11O5+], 433 (10)
[C29H11O4+], 417 (25) [C29H11O3+]. HRMS: calcd. for C32H30O8
542.1940; found 542.1942.
[18] a) G. H. Christie, A. Holderness, J. Kenner, J. Chem. Soc. 1926,
671–676; b) cf. A. W. Ingersoll, J. R. Little, J. Am. Chem. Soc.
1934, 56, 2123–2125.
[19] The optical rotation of (+)-10 and (–)-10 shows a strong sol-
vent dependence. For the description of (+)-10 and (–)-10 the
optical rotation measured in dioxane/CH2Cl2 (1:1) with a Hg
lamp (578 nm, 546 nm, 436 nm, 365 nm) was used. In CHCl3
as solvent each enantiomer shows the opposite sign.
[20] D. Drochner, W. Hüttel, M. Nieger, M. Müller, Angew. Chem.
2003, 115, 961–963; Angew. Chem. Int. Ed. 2003, 42, 931–933.
[21] Colourless prism (0.40ϫ0.35ϫ0.30 mm), monoclinic; space
group P21. CCDC-197800 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
The two-step reaction with cyclohex-2-en-1-one (20b) to compound
21b was also performed with enantioenriched (P)-10, which af-
forded (P)-21b*. The CD of this sample is in accordance with the
known configuration of the starting material. Comparison of the
CD of model compound (P)-21b with that of natural occurring
flavomannins enabled us to determine the configuration at the chi-
ral biaryl axis in the natural products.
[22] D. H. R. Barton, T. Cohen, Festschrift: Prof. A. Stoll zum sieb-
zigsten Geburtstag, Birkhäuser, Basel, 1957.
Acknowledgments
[23] a) J. H. Dodd, S. M. Weinreb, Tetrahedron Lett. 1979, 20,
3593–3596; b) cf. J. H. Dodd, R. S. Garigipati, S. M. Weinreb,
J. Org. Chem. 1982, 47, 4045–4049; c) cf. G. E. Evans, F. J.
Leeper, J. A. Murphy, J. Staunton, J. Chem. Soc., Chem. Com-
mun. 1979, 205–206.
D. D. thanks Fonds der Chemischen Industrie (FCI) and DE-
CHEMA for financial support, M. N. thanks the Deutscher Akad-
emischer Austausdienst (DAAD) for financial support. Financial
support by Deutsche Forschungsgemeinschaft (DFG) in the scope
of SPP 1152 is gratefully acknowledged.
[24] W. F. Gannon, H. O. House, Org. Synth. Coll. Vol. V 1973,
539–541.
[25] Flavomannins of the B series[1a] correspond in their CD couplet
to compound (P)-21 and possess therefore (P)-configuration at
the chiral axis (see also: G. Billen, U. Karl, T. Scholl, K. D.
Stroech, W. Steglich in Natural Products Chemistry III (Eds.:
P. W. Le Quesne Atta-ur Rahman), Springer, Berlin, Heidel-
berg, 1988, p. 305–315).
[1] a) M. Gill, W. Steglich, Prog. Chem. Org. Nat. Prod. 1987, 51,
1–317; b) Römpp Lexikon Naturstoffe (Eds.: W. Steglich, B.
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[26] S. E. Bode, D. Drochner, M. Müller, Synthesis biosynthesis and
absolute configuration of vioxanthin, manuscript in preparation.
[27] W. Hüttel, M. Müller, ChemBioChem, in press.
[28] The formation of open chain or cyclic oligomers can be sup-
pressed by adequate dilution. To this end both, the dianion
formed by reaction of 11 with NaH and the acyl chloride 14,
are provided in two dropping funnels and added slowly to THF
within 1 h.
[3] R. G. F. Giles, M. V. Sargent, Aust. J. Chem. 1986, 39, 2177–
2181.
[4] P. E. Fanta, Synthesis 1974, 9–21.
[5] J. Chiarello, M. M. Joullié, Tetrahedron 1988, 44, 41–48.
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[8] J. E. Marsh, J. Chem. Soc. 1927, 3164.
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Received: October 13, 2006
Published Online: February 20, 2007
1758
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1749–1758