Novel strategies for the synthesis of anthrapyran antibiotics: Discovery of a new antitumor agent and total synthesis of (S)-espicufolin

Article abstract of DOI:10.1039/b700838d

Two high-yielding strategies for the synthesis of 4H-anthra[1,2-b]pyran antibiotics have been developed giving access to novel antitumor agent 24 (ED₅₀ 1.5 m) and to (S)-espicufolin (3). A key step for the assembly of the tetracyclic 4H-anthra[1,2-b]pyran-4,7,12-trione skeleton is the nucleophilic addition of an aryl lithium species onto an aldehyde which allows the introduction of either an ynone or 1,3-diketo side chain, serving as precursors for an acid-catalysed cyclisation. The Royal Society of Chemistry.

Full text of DOI:10.1039/b700838d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Novel strategies for the synthesis of anthrapyran antibiotics: discovery of a
new antitumor agent and total synthesis of (S)-espicufolin†
Lutz F. Tietze,* Kersten M. Gericke, Ramakrishna Reddy Singidi and Ingrid Schuberth
Received 18th January 2007, Accepted 20th February 2007
First published as an Advance Article on the web 14th March 2007
DOI: 10.1039/b700838d
Two high-yielding strategies for the synthesis of 4H-anthra[1,2-b]pyran antibiotics have been developed
giving access to novel antitumor agent 24 (ED50 1.5 lM) and to (S)-espicufolin (3). A key step for the
assembly of the tetracyclic 4H-anthra[1,2-b]pyran-4,7,12-trione skeleton is the nucleophilic addition of
an aryl lithium species onto an aldehyde which allows the introduction of either an ynone or 1,3-diketo
side chain, serving as precursors for an acid-catalysed cyclisation.
exhibiting interesting biological activites. Rohr and Salas et al.5
Introduction
have shown significant antitumor activity (e.g. IC50 12.9 lg mL−1,
Anthrapyran antibiotics represent a broad class of natural
lung carcinoma cells A549) of premithramycinone H (2, Fig. 1), a
hybrid natural product6 which was discovered during biosynthetic
investigations of the aureolic acid antibiotic mithramycin and that
has recently been synthesised by Krohn and Vitz.7 In contrast,
espicufolin (3), which has been isolated from a Streptomyces sp.
cu39 strain by Seto et al.,8 possesses remarkable neuronal cell
protecting properties, displaying an inhibitory activity against
glutamic acid toxicity.9
Despite the multitude of isolated compounds from the an-
thrapyran class, few procedures for their synthesis have so far
been reported. In 1979, Hauser and Rhee10,11 were successful in
synthesising the kidamycinone methyl ether, whereas 20 years
later Uno and coworkers accomplished the total synthesis of (S)-
espicufolin (3).12,13 In addition, an elegant access to the aglycons
of altromycins and kidamycin has been reported by McDonald
and Fei.14 Recently, we described the first enantioselective total
synthesis of the antiherpetic anthrapyran AH-1763 IIa15 and of
the antibiotic c-indomycinone.16
products which can be isolated from various terrestrial and
marine Streptomyces sp. strains as secondary metabolites. These
compounds comprise a characteristic 4H-anthra[1,2-b]-pyran-
4,7,12-trione nucleus 1 (Fig. 1). Furthermore, they show versa-
tile and potent biological activities making them an attractive
synthetic target. For example, the pluramycin antibiotics,1,2 first
described in 1956 by Umezawa et al.,3 are known for their
strong anticancer activities, due to a specific alkylation at N-7
of the guanine base in DNA. Pluramycin antibiotics have amino
sugars typically attached at C-8 and C-10 positions, which play
a major role in sequence recognition during intercalation of the
planar tetracyclic chromophore into DNA.4 There are also many
anthrapyrans known lacking the amino sugars but nonetheless
Herein we report in full our novel strategies for the assembly
of anthrapyrans and their application in the course of the
total synthesis of (S)-espicufolin (3). The retrosynthetic analysis
(Scheme 1) envisions as the first disconnection the cleavage of the
pyrone ring moiety leading to either an anthraquinone with a 1,3-
diketo7 or ynone side chain which are both suitable for a final
ring closure.12,13,17 The introduction of the side chains was planned
to be realised by a nucleophilic attack of an aryl lithium species
derived from a bromodimethoxyanthracene onto the appropriate
aldehyde. In turn, the anthracene derivative should be accessible
by a Diels–Alder reaction of a juglone derivative and a silylketene
acetal, followed by bromination of the resulting anthraquinone
and final reductive methylation.
Fig. 1 Common structural core 1 of 4H-anthra[1,2-b]pyran-4,7,12-trione
natural products, premithramycinone H (2) and (S)-espicufolin (3).
Results and discussion
Institut fu¨r Organische und Biomolekulare Chemie, Georg-August-
Universita¨t, Tammannstraße 2, 37077, Go¨ttingen, Germany. E-mail:
ltietze@gwdg.de; Fax: +49 551 399476; Tel: +49 551 393271
† Electronic supplementary information (ESI) available: performance and
conditions of the HTCFA (cytotoxicity) test, general and full experimental
procedures and analytical data for compounds 5–7, 9–10, 16–20, 31–34 and
36–41. See DOI: 10.1039/b700838d
Synthesis of anthrapyran 24
The synthesis commences from commercially available 1,5-
dihydroxynaphthalene (4) which was oxidised with air in the
I
presence of Cu Cl to yield juglone (5) in 55% yield (Scheme 2).18,19
Regioselective bromination of 5 was accomplished using a known
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Scheme 1 Key stages in the retrosynthetic analysis of the anthrapyran core structure.
Scheme 2 Reagents and conditions: (i) CuCl, air, CH3CN, 20 ◦C (55%); (ii)
(a) Br2, HOAc, 20 ◦C, 15 min, (b) EtOH, reflux, 10 min (80%); (iii) iPrI,
Ag2O, CHCl3, 20 ◦C, 36 h, (iv) MeOH, cat. H2SO4, reflux, 16 h (92%);
(v) LDA, THF, −78 ◦C, 2 h then TMSCl, −78 ◦C, 1.5 h, −78 ◦C → 20 ◦C,
1.5 h (94%).
Scheme 3 Reagents and conditions: (i) (a) benzene, 20 ◦C, 8 h, (b) SiO2,
CH2Cl2, 20 ◦C, 24 h then removal of solvent (94%); (ii) NBS, cat. iPr2NH,
CH2Cl2, 20 ◦C, 9 h (97%); (iii) iPrI, Cs2CO3, acetone–DMF (3 : 1), reflux,
16 h (94%); (iv) (a) Na2S2O4, cat. TBABr, THF–H2O, 20 ◦C, 25 min,
(b) KOH, H2O, 20 ◦C, 15 min, (c) Me2SO4, 20 ◦C, 12 h (98%).
procedure furnishing isomeric pure 3-bromojuglone (6) in 80%
I
yield.20 The OH group was protected utilizing Ag 2O and iPrI to
deliver isopropyl ether 7 in nearly quantitative yield.21 Starting
from 3,3-dimethylacrylic acid (8) a classical acid-catalysed con-
version into the corresponding methyl ester followed by treatment
with LDA and TMSCl gave the desired 1-methoxy-3-methyl-1-
trimethylsiloxy-1,3-butadiene (10)22 in very high yield.
With 7 and 10 in hand, we next turned our focus to the
subsequent Diels–Alder reaction applying the strategy of Brassard
and Savard.22 To our delight, the addition of diene 10 to the 3-
bromojuglone derivative 7 in benzene provided the cycloaddition
product, which was converted in 94% yield into the thermody-
namically more stable chrysophanol-8-isopropyl ether 11 using
silica gel as a mild source of acid (Scheme 3).‡ As a special
feature, this reaction proceeds with excellent regioselectivity and
without the unwanted formation of the 1-methyl ether derivative,
a major side-product in Brassard’s synthesis. The use of NBS
in dichloromethane in the presence of catalytic amounts of
a secondary amine allowed, due to the strong ortho-directing
effect of the hydroxyl group, the regioselective bromination of
anthraquinone 11.23 Thus, 12, whose structure was unambiguously
deduced from HMBC-1H-NMR experiments, could be isolated
in 97% yield. To complete the synthesis of the building block
14, we protected the remaining phenolic hydroxyl group as its
isopropyl ether 13 in 94% yield by treatment with iPrI and Cs2CO3
in a mixture of acetone and DMF.24 Finally, protection of the
quinone moiety was accomplished by reductive methylation using
aq. sodium dithionite to furnish the air-sensitive hydroquinone,
which underwent methylation upon treatment with KOH and
dimethylsulfate to obtain the dimethoxyanthracene 14 in an
excellent overall yield.
The synthesis of aldehyde 18 was achieved from commercially
available b-hydroxy ester 15 which was first protected as TBS ether
‡ The use of toluene instead of benzene in the Diels–Alder reaction led to
the desired product in slightly lower yields.
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16 applying standard conditions (Scheme 4).25 The reduction of
the ester moiety using lithium borohydride in THF afforded the
corresponding primary alcohol 17 in good yield.26 Oxidation was
carried out under Parikh–Doering conditions which led to the for-
mation of required aldehyde 18 in 86% yield.27 Manganese dioxide
was the appropriate agent for the oxidation of propargylic alcohol
19 providing the aldehyde 20 which serves as an alternative unit
for the implementation of the side chain.
formation of the corresponding debrominated compound as side
product (Scheme 5). Following this strategy, the alcohol 21
could be afforded in 89% yield as a nearly 1 : 1-mixture of
the two possible diastereomers. Oxidative demethylation of the
II
28
anthracene derivative 21 using Ag O–HNO3 and subsequent
TBS-deprotection with TBAF after a short work-up procedure
furnished the anthraquinone 22 in an excellent yield over two steps.
The bis-oxidation of the 1,3-diol unit was accomplished in a single
step using Dess–Martin periodinane.29 Thus, the desired 1,3-diketo
compound 23 could be obtained in remarkable 80% yield. It is of
great importance to mention that only old batches of Dess–Martin
reagent led to a satisfying conversion, a phenomenon which has
been already described by Schreiber and Meyer.30 However, when
freshly prepared Dess–Martin reagent was used, the reaction could
efficiently be accelerated by adding catalytic amounts of water. For
the final conversion of the 1,3-diketone into the pyranone moiety
we assumed that deprotection of the isopropyl ethers and the
following cyclisation–condensation reaction could be achieved in
a domino-like procedure31 under acidic conditions. Hence, simply
heating of 23 in the presence of catalytic amounts of sulfuric acid
in conc. acetic acid gave after only 5 min reaction time the desired
cyclised product 24 in excellent yield.
Scheme 4 Reagents and conditions: (i) TBSCl, imidazole, cat. DMAP,
DMF, 20 ◦C, 18 h, (100%); (ii) LiBH4, THF, reflux, 3 h (80%); (iii) SO3·py,
Hu¨nig-base, DMSO, 0 ◦C, 1 h (86%); (iv) MnO2, CH2Cl2, 20 ◦C, 18 h
(67%).
Encouraged by these results, we next investigated the alternative
route to 24 via introduction of the ynone side chain (Scheme 5).
Using the same conditions as for the synthesis of 21 but replacing
aldehyde 18 by compound 20, we could isolate the desired
coupling product 25 in 73% yield. Reoxidation of the latter
into anthraquinone 26 was again realised by utilising Ag O–
HNO3 in high yield. Dess–Martin reagent was again found to
be appropriate for the oxidation of the benzylic alcohol moiety
Having effectively synthesised building blocks 14, 18 and 20,
we next considered the coupling of these intermediates. The
conversion of 14 to the corresponding lithium derivative could
be carried out via bromine lithium exchange using nBuLi at low
temperature. This reaction was observed to proceed very fast (0.5–
1 min), so it was important to add the aldehyde 18 immediately
after generation of the organolithium compound to avoid the
II
Scheme 5 Reagents and conditions: (i) nBuLi, 17, THF, −78 ◦C → 20 ◦C, 1 h (89%); (ii) (a) AgO, 4N HNO3, dioxane, 20 ◦C, 10 min, (b) TBAF·3H2O,
THF, 0 ◦C → 20 ◦C, 30 min (97%); (iii) DMP, CH2Cl2, 0 ◦C → 20 ◦C, 3 h (80%); (iv) HOAc, cat. H2SO4, reflux, 5 min (97%); (v) nBuLi, 19, THF, −78 ◦C
→ 20 ◦C, 1 h (73%); (vi) AgO, 4N HNO3, dioxane, 20 ◦C, 10 min (88%); (vii) DMP, CH2Cl2, 0 ◦C → 20 ◦C, 4.5 h (98%); (viii) HOAc, cat. H2SO4, reflux,
40 min (95%).
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into the ynone side chain affording compound 27 in 98% yield.
For the final deprotection–6-endo-dig cyclisation we first tested
the previously established HOAc–cat.H2SO4 conditions. Although
the conversion was in comparison to the 1,3-diketo system
significantly slower (40 min), the yield of the anthrapyran 24 was
again nearly quantitative.
Antitumor activity
Due to the significant antitumor activity of both premithramyci-
none H (2) and compound 28 synthesised by Krohn (IC50 8.8 lM,
cell line A-431, P-glycoprotein, 3 days exposition) (Fig. 2),7 we
were highly interested in the biological properties of anthrapyran
24. The cytotoxicity was studied by in vitro growth inhibition of
human lung carcinoma cells of line A549. The adherent cells were
sown in different numbers and, after incubation with different
concentrations of the compound, the numbers of formed colonies
were counted. Using this methodology we observed a remarkably
low IC50 value of 1.5 lM for the relative colony-forming rate of 24,
therefore turning it into a potential lead structure for continuing
pharmacological investigations.
Scheme 6 Reagents and conditions: (i) (a) benzene, reflux, 6 h, (b) SiO2,
CH2Cl2, 20 ◦C, 24 h then removal of solvent (50%); (ii) NBS, cat. iPr2NH,
CH2Cl2, 20 ◦C, 4.5 h (97%); (iii) iPrI, Cs2CO3, acetone–DMF (3:1), reflux,
16 h (94%); (iv) (a) Na2S2O4, cat. TBABr, THF–H2O, 20 ◦C, 25 min,
(b) KOH, H2O, 20 ◦C, 15 min, (c) Me2SO4, 20 ◦C, 12 h (99%).
The synthesis of the enantiopure coupling partner 39 com-
mences from commercially available (S)-2-methyl-butanol (35)
which was first oxidised to the corresponding aldehyde 36 in 79%
yield using Swern-conditions (Scheme 7).34 Further addition of
allylmagnesium bromide provided homoallyl alcohol 37 in 68%
yield as a nearly 1 : 1 mixture of the two possible diastereoisomers.
Since one of the stereogenic centres was planned to be destroyed
via oxidation at a later stage of the synthesis, both diastereoisomers
were used as a mixture for the following steps. However, due to
their high volatility they were immediately transformed into the
TBS-ether 38 using TBSOTf and 2,6-lutidine. Finally, cleavage of
the terminal double bond utilising a one-pot osmium tetroxide–
sodium periodate oxidation led to the formation of the desired
aldehyde 39 in 77% yield.35 Due to its high sensitivity, the latter
was directly used within the following coupling reaction.
Fig. 2 Krohn’s anthrapyran 28 with antitumor properties.
Synthesis of (S)-espicufolin (3)
Having successfully synthesised the anthrapyran 24 by utilizing
two simple and highly efficient strategies, we were also interested
to demonstrate the general synthetic value by applying these novel
methodologies in the course of the synthesis of a more complex
structure. As a target molecule, we chose (S)-espicufolin (3), which
exhibits a stereogenic centre in the side chain and in addition, a
benzylic alcohol functionality on the anthraquinone moiety. We
planned to introduce this alcohol group protected as its methyl
ether in the beginning of the synthesis via Diels–Alder reaction
using an appropriate diene. Therefore, we tried to synthesise
diene 29 (Scheme 6) starting from methyl 3,3-dimethylacrylate (9)
employing a literature-known procedure.32 Unfortunately, we only
obtained a complex mixture of diene 29 and 30 together with their
double bond isomers, a result which has already been observed by
33
Brassard et al. Due to a lower steric demand of trisubstituted
diene 29 in comparison to tetrasubstituted diene 30, we assumed
a higher reactivity of 29 during the Diels–Alder cycloaddition. As
a consequence, we decided to use the mixture of the dienes in the
following step. Thus, the reaction of naphthoquinone 7 and the
mixture of dienes 29 and 30 afforded, after aromatisation of the
cycloadduct by the use of silica gel, the desired anthraquinone
31 in 50% yield (based on 7). The amine-catalysed bromination
furnished compound 32 in 97% yield, whereas the formation of
the isopropyl ether derivative 33 could be realised in 94% yield.
Finally, reductive methylation provided the desired anthracene 34
in nearly quantitative yield.
Scheme 7 Reagents and conditions: (i) (COCl)2, DMSO, Et3N, CH2Cl2,
−78 ◦C → 20 ◦C, 2.5 h (79%); (ii) allylmagnesium bromide, Et2O, −78 ◦C,
30 min (68%); (iii) TBSOTf, 2,6-lutidine, CH2Cl2, 0 ◦C, 30 min (80%);
(iv) (a) cat. OsO4, NMO, t-BuOH–THF–H2O, 20 ◦C, 2 h, (b) NaIO4,
20 ◦C, 45 min (77%).
The lithium-mediated coupling of bromoanthracene 34 and
aldehyde 39 again proceeded very smoothly delivering the required
product 40 in 93% yield as a complex mixture of diastereoiso-
mers (Scheme 8). The following oxidative demethylation of
II
anthracene derivative 40 utilizing Ag O–HNO3 and subsequent
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Scheme 8 Reagents and conditions: (i) nBuLi, 39, THF, −78 C → 20 ◦C, 1 h (93%); (ii) (a) AgO, 4N HNO3, dioxane, 20 ◦C, 10 min, (b) TBAF·3H2O,
THF, 0 ◦C → 20 ◦C, 30 min (85%); (iii) DMP, cat. H2O, CH2Cl2, 0 ◦C → 20 ◦C, 1 h (77%); (iv) HOAc, cat. H2SO4, reflux, 5 min (97%); (v) (a) HOAc,
cat. H2SO4, reflux, 1 h, (b) NaOMe, MeOH, 20 ◦C, 1 h, then IR-120 (23% over 2 steps).
TBS-deprotection using TBAF led to the formation of 1,3-diol
41 in a combined yield of 85%. Afterwards, the bis-oxidation
into the 1,3-diketo compound 42 could be realised in 77% yield
via Dess–Martin oxidation with water as additive. The acid-
catalysed cyclisation procedure was again very simple and highly
efficient. Thus, exposure of 1,3-diketone 42 to catalytic amounts
of sulfuric acid in boiling acetic acid triggered the pyranone
formation to afford anthrapyran 43 in excellent 97% yield. To
complete the total synthesis of (S)-espicufolin (3) we only had
to cleave the remaining methyl ether as the final step. Many
attempts to complete this transformation using different Lewis-
acids or aqueous hydrogen chloride turned out to be ineffective.
Finally, we observed that a prolonged reaction time (1 h) during
the cyclisation step led to a partial transformation of the methyl
ether 43 into the corresponding acetate (43: OAc instead of
OMe) due to the presence of acetic acid. Unfortunately, further
increase of the reaction time led to complete decomposition of the
starting material. However, the acetate group could be removed
by solvolysis according to Zemple´n using catalytic amounts of
sodium methoxide in methanol.36 In the end, (S)-espicufolin (3)
could be obtained by acidic work up with ion exchange resin IR-
120 in 23% yield over both reaction steps. All physical data for the
synthetic sample of 3 were in good agreement with those reported
in literature.8,9,12,13 Despite the low yield in the last transformation,
the above outlined reaction sequence represents an overall yield of
2.7% and only 13 steps starting from 1,3-dihydroxynaphthalene
4, the most efficient and shortest access to (S)-espicufolin (3)
reported to date.
general method for the construction of other anthrapyran natural
products and their analogues.
Experimental
Electronic supplementary material
Details about the performance and conditions of the HTCFA
(cytotoxicity) test, general and full experimental procedures and
analytical data for compounds 5–7, 9–10, 16–20 and 36–41 have
been deposited as ESI.†
Synthesis of anthrapyran 24
1-Hydroxy-8-isopropoxy-3-methylanthraquinone (11). To a so-
lution of juglone derivative 7 (840 mg, 2.85 mmol) in benzene (40
◦
mL) was added, at 0 C dropwise with stirring, diene 10 (1.59 g,
8.55 mmol) within 10 min. After being stirred for 1 h at 0 ◦C,
the mixture was warmed to 20 ◦C and stirring was continued for
an additional 7 h. Afterwards, the reaction mixture was poured
onto silica gel (50 g), CH2Cl2 (250 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
anthraquinone 11 (7.94 g, 2.68 mmol, 94%) as a yellow solid,
◦
Rf 0.44 (P–EtOAc, 4 : 1); mp 163 C; (Found: C, 72.69; H, 5.49.
C18H16O4 requires C, 72.96; H, 5.44%); kmax (CH3CN)/nm 192.5
(lge/dm3 mol−1 cm−1 4.446), 224.0 (4.580), 257.5 (4.351) and 413.5
(3.963); mmax (KBr)/cm−1 2979, 1670, 1638, 1585, 1491, 1441, 1384,
1368, 1321, 1286, 1270, 1239 and 1208; dH (300 MHz, CDCl3)
13.07 (1 H, s, 8-OH), 7.92 (1 H, dd, J7.8 and 1.4, 5-H), 7.67 (1 H,
t, J7.8, 6-H), 7.56 (1 H, d, J1.1, 4-H), 7.34 (1 H, brd, J7.8, 7-H),
7.07 (1 H, d, J1.1, 2-H), 4.74 (1 H, sept., J6.0, CH(CH3)2), 2.43
(3 H, s, Ar–CH3) and 1.50 (6 H, d, J6.0, CH(CH3)2); dC (75.5 MHz,
CDCl3) 188.2, 183.1, 162.6, 159.5, 147.2, 135.9, 135.1, 132.3,
124.5, 121.8, 121.6, 120.1, 119.8, 115.0, 72.66, 22.07 and 22.00;
m/z (EI) 296.1 (22%, [M]+), 254.0 (100%, [M − C3H6]+), 250.0
(47%, [M − C2H4O2]+) and 222.0 (37%, [M − C2H4O2 − CO]+);
Conclusions
The present work reveals the efficient construction of the 4H-
anthra[1,2-b]pyran ring system by two different cyclisation strate-
gies. We have shown that the side chain units of the required
cyclisation precursors could be easily introduced via a nucleophilic
addition of an aryl lithium species onto an appropriate aldehyde.
Thus, we obtained the novel anthrapyran 24; its biological investi-
gation revealed a remarkable antitumor activity, in very high yield.
The versatility of this methodology was also demonstrated by the
synthesis of the more complex (S)-espicufolin (3), thus disclosing a
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Found (ESI) [M + H]+ 297.11235. C18H16O4 + H+ requires
297.11214.
H+ requires 417.06960. [M + Na]+ 439.05166. C21H21BrO4 + Na+
requires 439.05154.
2-Bromo-1,8-diisopropoxy-9,10-dimethoxy-3-methylanthracene
(14). A solution of anthraquinone 13 (8.53 g, 20.4 mmol) and
tetra-n-butylammonium bromide (3.29 g, 10.2 mmol) in THF
(300 mL) was treated at 20 ◦C with a solution of Na2S2O4 (21.3 g
122 mmol) in H2O (150 mL) and stirred for 25 min. Afterwards,
a solution of KOH (34.5 g, 0.614 mol) in H2O (100 mL) was
added (the yellow solution turned into deep-red) and stirring was
continued for an additional 15 min. After addition of dimethyl
sulfate (20 mL), the reaction mixture was stirred for 12 h (the
solution turned back into yellow) and then poured into H2O
(600 mL). The resulting solution was extracted with CH2Cl2 (3 ×
250 mL) and the combined organic layers were dried (MgSO4),
filtered and concentrated under reduced pressure. The crude
product was subjected to silica gel column filtration (CH2Cl2)
and concentration of the appropriate fractions in vacuo afforded
anthracene 14 (8.94 g, 98%) as a yellow oil, Rf 0.49 (P–EtOAc,
20 : 1); (Found: C, 61.50; H, 5.84. C23H27BrO4 requires C, 61.75;
H, 6.08%); kmax (CH3CN)/nm 202.5 (lge/dm3 mol−1 cm−1 4.361),
229.5 (4.112), 269.5 (4.986), 363.0 (3.736), 381.5 (4.011), 400.5
(3.904) and 423.0 (3.768); mmax (KBr)/cm−1 2977, 2931, 1616, 1556,
1510, 1449, 1417, 1396, 1352, 1305, 1288 and 1255; dH (300 MHz,
CDCl3) 7.88 (1 H, d, J 1.0, 4-H), 7.83 (1 H, dd, J8.8 and 0.9,
5-H), 7.35 (1 H, dd, J8.8 and 7.5, 6-H), 6.82 (1 H, brd, J7.5,
7-H), 4.67 (2 H, sept., J5.9, 2 × CH(CH3)2), 4.04 (3 H, s, OCH3),
3.84 (3 H, s, OCH3), 2.63 (3 H, d, J 1.0, Ar–CH3), 1.47 (6 H, d,
J5.9, C-8-OCH(CH3)2) and 1.36 (6 H, brs, C-1-OCH(CH3)2); dC
(75.5 MHz, CDCl3) 154.8, 150.4, 149.2, 147.2, 135.7, 127.8, 125.8,
125.8, 2 × 120.2, 119.9, 117.6, 115.1, 109.9, 77.92, 71.87, 63.65,
62.65, 24.73, 22.16 and 21.90; m/z (EI) 448.0, 446.0 (14%, [M]+);
Found (ESI) [M + H]+ 447.11673. C23H27BrO4 + H+ requires
447.11655. [M + Na]+ 469.09849. C23H27BrO4 + Na+ requires
469.09870.
2-Bromo-1-hydroxy-8-isopropoxy-3-methylanthraquinone (12).
A solution of anthraquinone 11 (1.50 g, 5.60 mmol) in CH2Cl2
(60 mL) was treated at 20 ◦C with a catalytic amount of diisopropyl
amine (10 drops) and then a solution of NBS (1.35 g, 7.59 mmol)
in CH2Cl2 (60 mL) was added dropwise during 10 min. After
being stirred for 6 h (TLC-control), additional NBS (450 mg,
2.53 mmol) was added and stirring was continued for another
3 h. Afterwards, the reaction mixture was diluted with CH2Cl2
(100 mL) and washed subsequently with aqueous 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 anthraquinone 12 (1.85 g, 97%) as an orange solid, Rf
0.47 (P–EtOAc, 4 : 1); mp 228 ◦C; (Found: C, 57.64; H, 4.24.
C18H15BrO4 requires C, 57.62; H, 4.03%); kmax (CH3CN)/nm 195.0
(lge/dm3 mol−1 cm−1 4.409), 228.5 (4.535), 262.0 (4.410), 286.5
(4.011) and 416.5 (4.013); mmax (KBr)/cm−1 2978, 1673, 1636, 1582,
1480, 1440, 1383, 1366, 1344, 1299, 1263 and 1237; dH (300 MHz,
CDCl3) 13.93 (1 H, s, 8-OH), 7.92 (1 H, dd, J8.1 and 1.0, 5-H),
7.70 (1 H, t, J8.1, 6-H), 7.64 (1 H, s, 4-H), 7.35 (1 H, brd, J8.1,
7-H), 4.75 (1 H, sept., J6.0, CH(CH3)2), 2.54 (3 H, s, Ar–CH3)
and 1.50 (6 H, d, J6.0, CH(CH3)2); dC (75.5 MHz, CDCl3) 187.9,
182.5, 159.7, 159.2, 147.1, 135.6, 135.6, 130.5, 121.6, 121.5, 121.3,
2 × 120.0, 115.2, 72.79, 24.14 and 22.06; m/z (EI) 376.0, 374.0
(26%, [M]+) and 334.0, 332.0 (100%, [M − C3H6]+); Found (ESI)
[M + H]+ 375.02267. C18H15BrO4 + H+ requires 375.02265.
2-Bromo-1,8-diisopropoxy-3-methylanthraquinone (13). A so-
lution of anthraquinone 12 (1.80 g, 4.80 mmol) in a mixture of
acetone (90 mL) and DMF (30 mL) was treated subsequently
at 20 ◦C with Cs2CO3 (4.69 g, 14.4 mmol) and 2-iodopropane
(0.96 mL, 9.60 mmol). After being stirred for 16 h under reflux, the
(1RS, 3RS)-3-(tert-Butyl-dimethyl-silanyloxy)-1-(1,8-diisopro-
poxy-9,10-dimethoxy-3-methylanthracene-2-yl)-butan-1-ol (21).
A solution of anthracene 14 (1.03 g, 3.30 mmol) in THF (30
mL) was treated at −78 ◦C dropwise during 1 min with nBuLi
(1.01 mL, 2.53 mmol, 2.5M in n-hexane). After being stirred
for 30 s, aldehyde 18 (699 mg, 3.45 mmol) in THF (5 mL) was
added quickly. Stirring was continued for 15 min at −78 ◦C, and
R
reaction mixture was filtered through a plug of celiteꢀ. The filter
cake was rinsed carefully with CH2Cl2 and then the combined
organic phases were concentrated under reduced pressure. The
residue was dissolved in CH2Cl2 (150 mL) and washed subse-
quently 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 appropriate fractions in vacuo afforded anthraquinone 13
(1.88 g, 94%) as a yellow solid, Rf 0.49 (P–EtOAc, 4 : 1); mp
163 ◦C; (Found: C, 60.33; H, 4.84. C21H21BrO4 requires C, 60.44;
H, 5.07%); kmax (CH3CN)/nm 222.5 (lge/dm3 mol−1 cm−14.468),
263.0 (4.457) and 370.5 (3.766); mmax (KBr)/cm−1 2978, 1681, 1580,
1464, 1440, 1380, 1348, 1309, 1277, 1260 and 1238; dH (300 MHz,
CDCl3) 7.84 (1 H, d, J 0.6, 4-H), 7.79 (1 H, dd, J8.0 and 0.8, 5-H),
7.60 (1 H, t, J8.0, 6-H), 7.30 (1 H, dd, J8.0 and 0.8, 7-H), 4.66 (1 H,
sept., J6.2, CH(CH3)2), 4.41 (1 H, sept., J6.2, CH(CH3)2), 2.54
(3 H, s, Ar–CH3), 1.44 (6 H, d, J6.2, CH(CH3)2) and 1.40 (6 H,
d, J6.2, CH(CH3)2); dC (75.5 MHz, CDCl3) 183.4, 182.4, 157.6,
154.6, 144.7, 135.0, 133.6, 132.6, 130.2, 127.7, 125.9, 123.4, 122.0,
119.2, 79.69, 72.71, 24.40, 22.26 and 22.02; m/z (ESI) 856.8 (100%,
2 × M + Na+); Found (ESI) [M + H]+ 417.06965. C21H21BrO4 +
◦
then the reaction mixture was warmed to 20 C during 1 h. The
reaction mixture was treated with sat. NH4Cl (10 mL), stirred
for 5 min and then poured into H2O (100 mL). Afterwards, the
resulting solution was extracted with CH2Cl2 (3 × 50 mL) and
the combined organic layers were dried (MgSO4), filtered and
concentrated under reduced pressure. The crude material was
subjected to silica gel flash chromatography (P–EtOAc, 20 : 1 →
10 : 1) and concentration of the appropriate fractions in vacuo
afforded a diastereomeric mixture (dr ≈ 1 : 1) of alcohol 21
(1.17 g, 89%) as a yellow foam, Rf 0.35 (P–EtOAc, 10 : 1); (Found:
C, 69.21; H, 8.58. C33H50O6Si requires C, 69.43; H, 8.83%); kmax
(CH3CN)/nm 202.0 (lge/dm3 mol−1 cm−1 4.380), 229.0 (4.107),
267.0 (4.996), 362.5 (3.731), 380.5 (3.896), 398.0 (3.896) and
420.5 (3.742); mmax (KBr)/cm−1 3499, 2972, 2930, 2857, 1556,
1510, 1451, 1420, 1394, 1359, 1281 and 1255; mixture of two
diastereoisomers: dH (300 MHz, CDCl3) 7.88 (1 H, dt, J 8.7 and
1.0, 5ꢀ-H), 7.73 (0.5 H, d, J1.0, 4ꢀ-H), 7.71 (0.5 H, d, J1.0, 4ꢀ-H),
1196 | Org. Biomol. Chem., 2007, 5, 1191–1200
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7.31 (1 H, dd, J8.7 and 7.6, 6ꢀ-H), 6.80 (1 H, d, J7.6, 7ꢀ-H),
5.71–5.54 (1 H, m, 1-H), 4.71–4.51 (2 H, m, 2 × OCH(CH3)2),
4.38–4.23 (1 H, m, C-3), 4.03 (1.5 H, s, OCH3), 4.02 (1.5 H, s,
OCH3), 3.96 (1 H, brs, OH, disappears after H/D-exchange
with D2O), 3.77 (1.5 H, s, OCH3), 3.76 (1.5 H, s, OCH3), 2.70
(1.5 H, brs, Ar–CH3), 2.62 (1.5 H, d, J0.8Hz, Ar–CH3), 2.43–2.29
(0.5 H, m, 2-Ha), 2.18 (0.5 H, mc, 2-Ha), 1.82–1.68 (1 H, m, 2-Hb),
1.45 (9 H, mc, C-8ꢀ-OCH(CH3)2, C-1ꢀ-OCH(CH3)2), 1.29 (3 H,
t, J6.6, 4-H3), 1.10 (3 H, brs, C-1ꢀ-OCH(CH3)2), 0.95 (4.5 H, s,
SiC(CH3)3, TBS), 0.94 (4.5 H, s, SiC(CH3)3, TBS) and 0.20, 0.16,
0.12 (6 H, 3 × s, Si(CH3)2, TBS); dC (150.8 MHz, CDCl3) 154.8,
154.8, 149.7, 149.5, 146.8, 135.2, 135.0, 127.7, 127.6, 126.4, 126.3,
125.3, 125.3, 119.7, 119.7, 118.8, 118.8, 118.7, 118.4, 115.3, 115.2,
110.3, 110.0, 76.41, 72.09, 71.99, 66.45, 63.16, 63.06, 62.57, 62.55,
46.36, 46.31, 46.11, 25.90, 23.90, 23.81, 22.23, 22.17, 22.06, 21.99,
21.79, 21.72, 21.60, 21.52, 21.29, 18.04, 18.02, −4.03, −4.58,
−4.68 and −4.78; m/z (EI) 570.4 (100%, [M]+), 552.4 (42%, [M −
H2O]+) and 420.3 (46%, [M − H2O − OTBS]+); Found (ESI) [M
+ Na]+ 593.32685. C33H50O6Si + Na+ requires 593.32689. [M +
K]+ 609.30082. C33H50O6Si + K+ requires 609.30082.
[M + NH4]+) and 427.4 (100%, [M + H]+); Found (ESI) [M + H]+
427.21152. C25H30O6 + H+ requires 427.21152.
2-(1-Hydroxy-3-oxo-but-1-enyl)-1,8-diisopropoxy-3-methylanthra-
quinone (23).
A solution of anthraquinone 22 (300 mg,
0.703 mmol) in CH2Cl2 (70 mL) was treated at 0 ◦C with
Dess–Martin periodinane (1.19 g, 2.81 mmol) and stirred for 4.5 h
(if the conversion was too slow, one drop of H2O was added).
Afterwards, the reaction mixture was directly subjected to silica
gel (containing 4% NaH2PO4) flash chromatography (CH2Cl2)
and concentration of the appropriate fractions in vacuo afforded
a enol–ketone mixture (∼10 : 1) of anthraquinone 23 (238 mg,
80%) as a yellow oil, Rf 0.27 (P–EtOAc, 4 : 1); kmax (CH3CN)/nm
222.0 (lge/dm3 mol−1 cm−1 4.472), 261.5 (4.455) and 373.5 (3.829);
mmax (KBr)/cm−1 3331, 2978, 2931, 1676, 1585, 1463, 1441, 1383,
1312, 1277 and 1230; dH (300 MHz, CDCl3) enol: 15.5 (1 H,
brs, enol-OH), 7.85–7.70 (2 H, m, 5-H, 4-H), 7.60 (1 H, t, J8.2,
6-H), 7.30 (1 H, brd, J8.2, 7-H), 5.85 (1 H, s, 2ꢀ-H), 4.66 (1 H,
sept., J6.1, OCH(CH3)2), 4.27 (1 H, sept., J6.1, OCH(CH3)2),
2.41 (3 H, s, Ar-CH3), 2.16 (3 H, s, 4ꢀ-H3), 1.44 (6 H, d, J6.1,
CH(CH3)2) and 1.28 (6 H, d, J6.1, CH(CH3)2); ketone: 4.09
(2H, s, 2ꢀ-CH2) and 2.30 (3H, s, 4ꢀ-H3) (the other signals are
covered); dC (50.3 MHz, CDCl3) enol: 190.6, 187.7, 183.5, 182.7,
157.6, 154.8, 142.2, 139.1, 135.0, 134.4, 133.6, 127.4, 126.0, 123.7,
122.2, 119.3, 103.8, 79.68, 72.74, 59.02, 22.12, 22.02, 20.01 and
24.70; ketone: 133.9, 124.4, 119.4, 80.02, 77.20 and 59.02 (the
other signals are covered); m/z (ESI) 423.2 ([M + H]+); Found
(ESI) [M + H]+ 423.18009. C25H26O6 + H+ requires 423.18022.
(1RS, 3RS)-2-(1,3-Dihydroxy-butyl)-1,8-diisopropoxy-3-methyl-
anthraquinone (22). A solution of anthracene 21 (770 mg,
1.35 mmol) in 1,4-dioxane (60 mL) was treated at 20 ◦C with
silver(II) oxide (835 mg, 6.74 mmol) and stirred for 5 min until a
suspension was formed. Afterwards, 4N HNO3 (10 mL) was added
dropwise within 5 min until the silver(II) oxide was completely
dissolved. After being stirred for another 10 min, the reaction
mixture was poured into H2O (200 mL) and extracted with
CH2Cl2 (3 × 50 mL). The combined organic layers were dried
(MgSO4), filtered and concentrated under reduced pressure. The
residue was dissolved in THF (100 mL) and treated at 0 ◦C
with a solution of TBAF·3H2O (852 mg, 2.70 mmol) in THF
(10 mL). The temperature was raised to 20 ◦C and stirring was
continued for additional 30 min. The reaction was then poured
into half-sat. NaCl and extracted with CH2Cl2 (3 × 100 mL).
The combined organic layers were dried (MgSO4), filtered and
concentrated under reduced pressure. The crude material was
subjected to silica gel flash chromatography (CH2Cl2–EtOAc, 4 :
1 → 1 : 1) and concentration of the appropriate fractions in vacuo
afforded a diastereomeric mixture (dr ≈ 1 : 1) of anthraquinone
22 (565 mg, 97%) as a yellow foam, Rf 0.17 (diastereomer 1),
0.24 (diastereomer 2) (P–EtOAc, 1 : 1); kmax (CH3CN)/nm 222.0
(lge/dm3 mol−1 cm−1 4.491), 261.5 (4.403) and 373.0 (3.747);
mmax (KBr)/cm−1 3443, 2975, 2931, 2857, 1674, 1584, 1463,
1442, 1384, 1309 and 1275; mixture of two diastereoisomers: dH
(300 MHz, CDCl3) 7.77 (1 H, d, J7.9, 5-H), 7.59 (1 H, d, J7.9,
6-H), 7.72 (1 H, s, 4-H), 7.28 (1 H, d, J7.9, 7-H), 5.60–5.51 (1
H, m, 1ꢀ-H), 4.67 (1 H, sept., J6.0, C-8-OCH(CH3)2), 4.53–4.31
(1 H, m, C-1-OCH(CH3)2), 4.31–3.66 (3 H, m, 3ꢀ-H, 2 × OH),
2.57 (1.5 H, s, Ar–CH3), 2.53 (1.5 H, s, Ar–CH3), 2.28–2.04
(1 H, m, 2ꢀ-Ha), 1.80–1.56 (1 H, m, 2ꢀ-Hb), 1.47–1.37 (9 H, m,
C-8-OCH(CH3)2, C-1-OCH-(CH3)2) and 1.34–1.20 (6 H, m,
4ꢀ-H3, C-1-OCH(CH3)2); dC (75.5 MHz, CDCl3) 184.2, 184.0,
183.3, 157.2, 157.1, 154.8, 154.6, 143.0, 142.6, 142.2, 141.6, 135.1,
135.0, 133.5, 132.7, 132.5, 127.0, 126.9, 126.1, 126.0, 124.6, 124.3,
121.5, 121.4, 119.0, 78.76, 78.27, 72.44, 72.39, 70.43, 68.78, 67.11,
65.27, 44.15, 43.65, 23.64, 23.32, 22.42, 22.05, 21.99, 20.79 and
20.63; m/z (DCI) 870.8 (1%, 2 × [M + NH4]+), 444.4 (12%,
(1RS)-1-(1,8-Diisopropoxy-9,10-dimethoxy-3-methylanthracene-
2-yl)-but-2-yn-1-ol (25). A solution of anthracene 14 (500 mg,
1.12 mmol) in THF (20 mL) was treated at −78 ◦C dropwise
during 1 min with nBuLi (0.51 mL, 1.29 mmol, 2.5M in n-hexane).
After being stirred for 1 min, aldehyde 20 (305 mg, 4.48 mmol)
in THF (4 mL) was added quickly. Stirring was continued for
10 min at −78 ◦C until the reaction was warmed to 20 ◦C during
1 h. The reaction mixture was treated with sat. NH4Cl (5 mL),
stirred for 5 min and then poured into H2O (50 mL). Next,
the resulting solution was extracted with CH2Cl2 (3 × 30 mL)
and the combined organic layers were dried (MgSO4), filtered
and concentrated under reduced pressure. The crude material
was subjected to silica gel flash chromatography (P–EtOAc, 9 :
1 → 4 : 1) and concentration of the appropriate fractions in
vacuo afforded alcohol 25 (359 mg, 73%) as a yellow oil, Rf 0.25
(P–EtOAc, 6 : 1); kmax (CH3CN)/nm 202.0 (lge/dm3 mol−1 cm−1
4.364), 229.0 (4.093), 267.5 (5.003), 362.0 (3.735), 380.0 (3.999),
398.0 (3.891) and 420.0 (3.740); mmax (KBr)/cm−1 3454, 2974,
2930, 1617, 1556, 1512, 1450, 1420, 1394, 1359 and 1256; dH
(300 MHz, CDCl3) 7.83 (1 H, dd, J 8.6 and 0.5, 5ꢀ-H), 7.80 (1
H, s, 4ꢀ-H), 7.34 (1 H, dd, J 8.6 and 7.3, 6ꢀ-H), 6.82 (1 H, d, J7.3,
7ꢀ-H), 6.26 (1 H, brs, OH), 4.71–4.52 (2 H, m, 2 × OCH(CH3)2),
4.04 (3 H, s, OMe), 3.79 (3 H, s, OMe), 2.78 (3 H, brs, Ar–CH3),
1.87 (3 H, d, J2.0, 4-H3), 1.58–1.01 (12 H, m, C-1ꢀ-OCH(CH3)2,
C-8ꢀ-OCH(CH3)2); dC (75.5 MHz, CDCl3) 154.8, 150.4, 2 × 150.1,
146.9, 129.9, 128.0, 126.6, 125.6, 119.9, 118.8, 115.2, 109.9, 109.7,
82.05, 77.34, 77.20, 71.91, 63.36, 62.57, 53.41, 22.79, 22.65, 22.53,
22.41, 22.32, 22.28, 22.01, 21.91, 21.66, 20.70 and 3.79; m/z (ESI)
459.2 ([M + Na]+) and 419.2 ([M + H − H2O]+); Found (ESI)
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[M + Na]+ 459.21420. C27H32O5 + Na+ requires 459.21420. [M +
H − H2O]+ 419.22169. C27H32O5 + H+ − H2O requires 419.22169.
11-Hydroxy-2,5-dimethyl-1-oxa-benzo[a]anthracen-4,7,12-trion
(24).
Procedure A. A solution of anthraquinone 23 (100 mg,
0.237 mmol) in conc. acetic acid (10 mL) was treated with
a catalytic amount of conc. H2SO4 (10 drops) and stirred for
5 min under reflux. The reaction mixture was poured into H2O
(100 mL) and extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were dried (MgSO4), filtered and concentrated
under reduced pressure. The crude material was subjected to silica
gel filtration (CH2Cl2, CH2Cl2–EtOAc, 10 : 1) and concentration
of the appropriate fractions in vacuo afforded the target compound
24 (74 mg, 97%) as a yellow solid.
(1RS)-2-(1-Hydroxy-but-2-ynyl)-1,8-diisopropoxy-3-methyl-
anthraquinone (26). A solution of anthracene 25 (380 mg,
0.870 mmol) in 1,4-dioxane (30 mL) was treated at 20 ◦C with
silver(II) oxide (553 mg, 4.47 mmol) and stirred for 5 min until
a suspension was formed. Next, 4N HNO3 solution (6 mL)
was added dropwise within 5 min until the silver(II) oxide was
completely dissolved. After being stirred for another 10 min, the
reaction mixture was poured into H2O (150 mL) and extracted
with CH2Cl2 (3 × 50 mL). The combined organic layers were dried
(MgSO4), filtered and concentrated under reduced pressure. The
crude material was subjected to silica gel flash chromatography
(CH2Cl2, CH2Cl2–EtOAc, 20 : 1 → 4 : 1) and concentration of the
appropriate fractions in vacuo afforded alcohol 26 (312 mg, 88%)
as a yellow foam, Rf 0.53 (P–EtOAc, 2 : 1); kmax (CH3CN)/nm
222.5 (lge/dm3 mol−1 cm−1 4.556), 260.5 (4.471) and 373.0 (3.795);
mmax (KBr)/cm−1 3462, 2976, 2930, 1674, 1584, 1463, 1442, 1384,
1307, 1276 and 1236; dH (300 MHz, CDCl3) 7.78 (1 H, dd, J 8.0
and 0.5, 5-H), 7.76 (1 H, s, 4-H), 7.59 (1 H, t, J 8.0, 6-H), 7.29 (1 H,
d, J8.0, 7-H), 6.04 (1 H, brd, J2.2, 1ꢀ-H), 4.66 (1 H, sept., J6.2,
CH(CH3)2), 4.43 (1 H, sept., J6.2, CH(CH3)2), 3.47 (1 H, brs, OH),
2.65 (3 H, s, Ar–CH3), 1.83 (3 H, d, J2.2, 4-H3), 1.48–1.40 (9 H,
m, C-1-OCH(CH3)2, C-8-OCH(CH3)2) and 1.33 (3 H, d, J6.2, C-
1-OCH(CH3)2); dC (75.5 MHz, CDCl3) 2 × 183.4, 157.4, 154.6,
143.4, 140.0, 135.1, 133.5, 133.2, 127.0, 126.1, 124.5, 121.8, 119.2,
82.29, 79.09, 78.49, 72.64, 58.90, 22.43, 22.04, 21.99, 20.39 and
3.67; m/z (ESI) 429.2 ([M + Na]+) and 407.2 ([M + H]+); Found
(ESI) [M + H]+ 407.18518. C25H26O5+H+ requires 407.18530.
[M + Na]+ 429.16718. C25H26O5 + Na+ requires 429.16725.
Procedure B. A solution of anthraquinone 27 (120 mg,
0.297 mmol) in conc. acetic acid (10 mL) was treated with
a catalytic amount of conc. H2SO4 (10 drops) and stirred for
40 min under reflux. The reaction mixture was poured into H2O
(100 mL) and extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were dried (MgSO4), filtered and concentrated
under reduced pressure. The crude material was subjected to silica
gel filtration (CH2Cl2, CH2Cl2–EtOAc, 10 : 1) and concentration of
the appropriate fractions in vacuo afforded the target compound 24
(90 mg, 95%) as a yellow solid, Rf 0.17 (P–EtOAc, 4 : 1); mp 271 ◦C;
(Found: C, 71.45; H, 4.03. C19H12O5 requires C, 71.25; H, 3.78%),
kmax (CH3CN)/nm 203.5 (lge/dm3 mol−1 cm−1 4.365), 238.5 (4.678)
and 266.0 (3.934); mmax (KBr)/cm−1 2925, 1652, 1626, 1586, 1465,
1453, 1386, 1344, 1311 and 1272; dH (300 MHz, CDCl3) 12.79
(1 H, s, OH), 8.00 (1 H, s, 6-H), 7.78 (1 H, dd, J8.0 and 1.1,
8-H), 7.65 (1 H, t, J8.0, 9-H), 7.33 (1 H, d, J8.0 and 1.1, 10-
H), 6.24 (1 H, s, 3-H), 2.99 (3 H, s, Ar–CH3) and 2.51 (3 H, s,
2-CH3); dC (75.5 MHz, CDCl3) 187.1, 181.8, 178.9, 165.8, 162.5,
156.6, 149.7, 136.3, 135.8, 132.1, 126.2, 125.6, 125.3, 119.5, 119.2,
116.7, 112.8, 24.19 and 20.12; m/z (EI) 320.1 (100%, [M]+); (EI)
320.0685. C19H12O5 requires 320.0685.
1,8 - Diisopropoxy - 3-methyl-2-(1-oxo-but-2-ynyl)anthraquinone
(27). A solution of anthraquinone 26 (280 mg, 0.689 mmol)
in CH2Cl2 (30 mL) was treated at 20 ◦C with Dess–Martin
periodinane (438 mg, 1.03 mmol) and stirred for 3 h. Afterwards,
the reaction mixture was simultaneously treated with sat. NaHCO3
(5 mL) and 1M Na2S2O3 (5 mL) and stirred for 15 min until
the solution became clear. The reaction mixture was poured
into H2O (100 mL) and extracted with CH2Cl2 (3 × 30 mL).
The combined organic layers were dried (MgSO4), filtered and
concentrated under reduced pressure. The crude material was
subjected to silica gel flash chromatography (CH2Cl2–EtOAc, 10 :
1) and concentration of the appropriate fractions in vacuo afforded
ketone 27 (274 mg, 98%) as a yellow solid, Rf 0.24 (P–EtOAc,
Total synthesis of (S)-espicufolin (3)
2-(4S)-(1-Hydroxy-4-methyl-3-oxo-hex-1-enyl)-1,8-diisopropoxy-3-
methoxymethylanthraquinone (42). A solution of anthraquinone
41 (190 mg, 0.381 mmol) in CH2Cl2 (50 mL) was treated at
0
◦C with Dess–Martin periodinane (1.19 g, 1.52 mmol) and
stirred for 0.5 h. Afterwards, a drop of H2O was added and
the solution was warmed to 20 ◦C. Next, another amount of
Dess–Martin periodinane (600 mg, 0.760 mmol) was added and
stirring was continued for 30 min. The reaction mixture was then
directly subjected to silica gel flash chromatography (CH2Cl2 +
5% EtOAc + 1% HOAc) and concentration of the appropriate
fractions in vacuo afforded an enol–ketone mixture (∼6 : 1)
of anthraquinone 42 (145 mg, 77%) as a yellow oil, Rf 0.53
(P–EtOAc, 4 : 1); [a]D20 +12.3◦ (c = 1.0, CHCl3); kmax (CH3CN)/nm
221.0 (lge/dm3 mol−1 cm−1 4.430), 260.0 (4.398) and 370.5 (3.815);
mmax (KBr)/cm−1 3337, 3097, 2973, 2930, 1680, 1586, 1460, 1384,
1371, 1305, 1278 and 1228; dH (300 MHz, CDCl3) enol: 15.5 (1 H,
brs, enol-OH), 8.13 (1 H, s, 4-H), 7.81 (1 H, brd, J7.2, 5-H), 7.61
(1 H, t, J8.3, 6-H), 7.31 (1 H, brd, J8.3, 7-H), 5.92 (1 H, s, 2ꢀ-H),
4.68 (1 H, sept., J6.1, OCH(CH3)2), 4.55 (2 H, s, CH2OCH3),
4.28 (1 H, sept., J6.7, OCH(CH3)2), 3.42 (3 H, s, OCH3), 2.33
(1 H, mc, 4ꢀ-H), 1.81–1.63 (1 H, m, 5ꢀ-Ha), 1.60–1.40 (1 H, m,
5ꢀ-Hb), 1.44 (6 H, d, J2.8, C-8-OCH(CH3)2), 1.28 (3 H, d, J2.8,
C-1-OCH(CH3)a), 1.26 (3 H, d, J2.8, C-1-OCH(CH3)b), 1.20
◦
4 : 1); mp 126 C; kmax (CH3CN)/nm 222.0 (lge/dm3 mol−1 cm−1
4.552), 260.0 (4.435) and 376.0 (3.799); mmax (KBr)/cm−1 2976,
2931, 2203, 1678, 1653, 1585, 1465, 1440, 1384, 1312, 1280 and
1228; dH (300 MHz, CDCl3) 7.82–7.77 (2 H, m, 4-H, 5-H), 7.61
(1 H, t, J7.9, 6-H), 7.31 (1 H, d, J7.9, 7-H), 4.67 (1 H, sept., J6.2,
CH(CH3)2), 4.40 (1 H, sept., J6.2, CH(CH3)2), 2.40 (3 H, s, Ar–
CH3), 2.08 (3 H, d, J2.2, 4ꢀ-H3), 1.44 (3 H, d, J6.2, CH(CH3)2)
and 1.33 (3 H, d, J6.2, CH(CH3)2); dC (75.5 MHz, CDCl3) 183.3,
182.5, 181.5, 157.6, 155.0, 141.9, 140.9, 134.9, 134.5, 133.6, 127.0,
125.7, 123.7, 122.1, 119.2, 94.52, 81.29, 79.36, 72.68, 22.05, 21.97,
19.40 and 4.58; m/z (EI) 404.3 (30%, [M]+), 361.2 (15%, M-C3H7 ),
+
320.2 (100%) and 304.2 (50%); Found (ESI) [M + H]+ 405.16955.
C25H24O5 + H+ requires 405.16965.
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(3 H, d, J7.0, 1ꢀꢀ-H3) and 0.95 (3 H, t, J7.6, 6ꢀ-H3); ketone: 8.02
(1 H, s, 4-H), 4.53 (2 H, s, CH2OCH3), 3.41 (3 H, s, OCH3) and
2.64 (1 H, mc, 4ꢀ-H) (the other signals are covered); dC (75.5 MHz,
CDCl3) enol: 196.5, 188.1, 183.2, 182.7, 157.6, 154.7, 142.8, 138.0,
135.0, 134.9, 133.7, 128.7, 125.9, 122.0, 121.2, 119.3, 102.7, 79.73,
72.61, 71.35, 58.79, 43.66, 27.13, 22.12, 22.11, 22.00, 17.23 and
11.78; ketone: 29.65, 25.31, 22.22 and 14.98 (the other signals are
covered); m/z (ESI) 1010.9 (100%, [2 × M + Na]+), 517.1 (70%,
[M + Na]+) and 1009.1 (26%, [2 × M − 2 × H + Na]−), 493.1
(100%, [M − H]−); Found (ESI) [M + H]+ 495.23818. C29H34O7 +
H+ requires 495.23773.
(S)-espicufolin (3, 6.8 mg, 23% over two steps) as a yellow solid,
Rf 0.22 (P–EtOAc, 7 : 3); [a]20 −5.0◦ (c = 0.2, CHCl3); kmax
D
(CH3CN)/nm 206.5 (lge/dm3 mol−1 cm−1 4.338), 238.5 (4.644),
266.0 (4.319) and 416.0 (3.869); mmax (KBr)/cm−1 3472, 2965,
2929, 1681, 1649, 1625, 1584, 1554, 1459, 1392, 1344, 1314, 1300,
1275 and 1224; dH (300 MHz, CDCl3) 12.8 (1 H, s, OH), 8.28
(1 H, s, 6-H), 7.83 (1 H, dd, J7.6 and 1.0, 8-H), 7.70 (1 H, t, J7.6,
9-H), 7.38 (1 H, dd, J8.4 and 1.0, 10-H), 6.39 (1 H, s, 3-H), 5.07
(2 H, s, CH2OH), 4.67 (1 H, brs, OH), 2.80 (1 H, mc, 1ꢀ-H), 1.99
(1 H, mc, 2ꢀ-Ha), 1.83 (1 H, mc, 2ꢀ-Hb), 1.45 (3 H, d, J7.0, 1ꢀꢀ-H3)
and 1.00 (3 H, t, J7.5, 3ꢀ-H3); dC (75.5 MHz, CDCl3) 187.0, 181.5,
178.2, 172.5, 161.3, 155.6, 153.2, 136.6, 136.0, 132.1, 124.6, 124.0,
119.8, 118.7, 118.7, 110.5, 116.7, 62.19, 40.00, 26.68, 17.49 and
11.34; m/z (ESI) 379.1 (100%, [M + H]+); Found (ESI) [M + H]+
379.11766. C22H18O6 + H+ requires 379.11761.
(S)-2-(2-Methyl-propyl)-11-hydroxy-5-methoxymethyl-1-oxa-
benzo[a]anthracen-4,7,12-trion (43). A solution of anthraqui-
none 42 (35.0 mg, 70.8 lmol) in conc. acetic acid (5 mL) was
treated with conc. H2SO4 (5 drops) and stirred for 5 min under
reflux. The reaction mixture was poured into H2O (30 mL) and
sat. NaCl (30 mL) was added. After extraction with CH2Cl2 (3 ×
30 mL), the combined organic layers were dried (MgSO4), filtered
and concentrated under reduced pressure. The crude material was
subjected to silica gel filtration (CH2Cl2 + 2% EtOAc + 0.5%
HOAc) and concentration of the appropriate fractions in vacuo
afforded the target compound 43 (27 mg, 97%) as a yellow solid,
Acknowledgements
The authors are grateful to the Fonds der Chemischen Industrie
for supporting this work. R. R. S. thanks the Alexander von
Humboldt Foundation for a postdoctoral grant.
Rf 0.51 (P–EtOAc, 4 : 1); [a]20 +2.0◦ (c = 1.0, CHCl3); kmax
D
Notes and references
(CH3CN)/nm 206.5 (lge/dm3 mol−1 cm−1 4.370), 238.5 (4.683),
266.0 (4.350) and 416.0 (3.914); mmax (KBr)/cm−1 2979, 2932, 1673,
1651, 1582, 1556, 1453, 1390, 1373, 1298, 1271 and 1218; dH
(300 MHz, CDCl3) 12.9 (1 H, s, OH), 8.57 (1 H, s, 6-H), 7.79
(1 H, dd, J7.9 and 1.0, 10-H), 7.66 (1 H, t, J7.9, 9-H), 7.33 (1 H,
dd, J7.9, 1.0 Hz, 8-H), 6.26 (1 H, s, 3-H), 5.19 (2 H, s, CH2OCH3),
3.61 (3 H, s, OCH3), 2.11 (1 H, mc, 1ꢀ-H), 1.98 (1 H, mc, 2ꢀ-Ha), 1.81
(1 H, mc, 2ꢀ-Hb), 1.45 (3 H, d, J7.0, 1ꢀꢀ-H3) and 1.00 (3 H, t, J7.6,
3ꢀ-H3); dC (75.5 MHz, CDCl3) 187.4, 181.9, 179.3, 173.6, 162.7,
156.4, 150.4, 136.7, 136.5, 132.5, 125.3, 124.9, 120.3, 120.2, 119.6,
117.0, 111.2, 73.34, 59.26, 40.68, 27.56, 18.04 and 11.95; m/z (ESI)
806.7 (100%, [2 × M + Na]+), 415.1 (30%, [M + Na]+) and 805.2
(100%, [2 × M − 2 × H + Na]−), 391.3 (20%, [M − H]−); Found
(ESI) [M + H]+ 393.13316. C23H20O6 + H+ requires 393.13326. [M
+ Na]+ 415.11513. C23H20O6 + Na+ requires 415.11521.
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