Total synthesis of graphislactones A, C, D, and H, of ulocladol, and of the originally proposed and revised structures of graphislactones e and F

Article abstract of DOI:10.1002/ejoc.200801278

Graphislactones A-H and the structurally related ulocladol are highly oxygenated resorcylic lactones produced by lichens and fungi. We present total syntheses of graphislactones A, C-F, H and of ulocladol. Graphislactones E, F, and H were synthesized for the first time. The spectra of graphislactones E and F synthesized as the originally proposed structures were not in agreement with published data. Consequently, revised structures for these compounds are proposed, whose correctness is unambiguously proven by total synthesis and comparison of the spectroscopic data. Key steps in all syntheses are Suzuki couplings for the construction of the central biaryl bond and Dakin reactions to supply further hydroxy groups required in these highly oxygenated substrates. Graphislactones A, C, and H, acylated graphislac- tone D and ulocladol were prepared in 8-11 steps with 7-20% yield starting with purchasable compounds, where the longest linear sequence consists of 5-9 steps. The syntheses are thus significantly shorter than the previously published syntheses of graphislactones A-D and of ulocladol. Graphis- lactones E and F were synthesized in 8 steps, where the longest linear sequences consist of 6 and 5 steps, respectively. They were isolated as the respective acetylated compounds with 25 and 10% yield.

Full text of DOI:10.1002/ejoc.200801278

FULL PAPER
DOI: 10.1002/ejoc.200801278
Total Synthesis of Graphislactones A, C, D, and H, of Ulocladol, and of the
Originally Proposed and Revised Structures of Graphislactones E and F
Martina Altemöller,[a] Timo Gehring,[a] Judith Cudaj,[a] Joachim Podlech,*[a]
Helmut Goesmann,[b][‡] Claus Feldmann,[b][‡] and Alexander Rothenberger[b][‡]
To the memory of Prof. Dr. Maximilian Steiner
Keywords: Polyketides / Lichen metabolites / Resorcylic lactones / Cross-coupling / Dakin reaction / Total synthesis
Graphislactones A–H and the structurally related ulocladol
are highly oxygenated resorcylic lactones produced by li-
chens and fungi. We present total syntheses of graphislac-
tones A, C–F, H and of ulocladol. Graphislactones E, F, and
H were synthesized for the first time. The spectra of graphis-
lactones E and F synthesized as the originally proposed
structures were not in agreement with published data. Con-
sequently, revised structures for these compounds are pro-
posed, whose correctness is unambiguously proven by total
synthesis and comparison of the spectroscopic data. Key
steps in all syntheses are Suzuki couplings for the construc-
tion of the central biaryl bond and Dakin reactions to supply
further hydroxy groups required in these highly oxygenated
substrates. Graphislactones A, C, and H, acylated graphislac-
tone D and ulocladol were prepared in 8–11 steps with 7–
20% yield starting with purchasable compounds, where the
longest linear sequence consists of 5–9 steps. The syntheses
are thus significantly shorter than the previously published
syntheses of graphislactones A–D and of ulocladol. Graphis-
lactones E and F were synthesized in 8 steps, where the long-
est linear sequences consist of 6 and 5 steps, respectively.
They were isolated as the respective acetylated compounds
with 25 and 10% yield.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
H have been isolated from the endophytic fungus Cephalos-
porium acemonium IFB-E007.[7] The structurally related
botrallin was isolated from Botrytis allii[5a,5b,6e] and ulocla-
dol was isolated from the marine sponge-derived fungus
Ulocladium botrytis (Figure 1).[6e,8a,8b] The biosynthesis of
graphislactones is strongly related to that of Alternaria me-
tabolites,[6d,9] in fact, 3-desmethylgraphislactone A was
identified in the metabolism of Alternaria toxins.[10a,10b]
A number of biological activities have been reported for
graphislactones and the related compounds. Graphislactone
A is an antioxidant and a scavenger of free radicals,[11]
graphislactones A, G, and H were found to be active
against the SW1116 cell line (IC50 8.5, 21, and 12 mg/mL,
respectively),[7] graphislactone A and botrallin are moderate
inhibitors of AChE,[6e] and ulocladol is a tyrosine kinase
(p56lck) inhibitor.[8b] Total syntheses of graphislactones A–
D[12] and of ulocladol have been published previously,[13]
though neither experimental details nor spectroscopic data
have been provided for the syntheses of graphislactones A–
D. These graphislactones have been prepared in 10–12 steps
with 9–20% yield starting with 3,5-dimethoxyaniline and
methyl 3-O-methylgallate, where the longest linear sequence
consisted of 7–9 steps. Ulocladol has been prepared in 13
steps with 2–6% yield, where the longest linear sequence
consisted of 10 steps. The synthetic strategy in the pub-
Introduction
Nature has long been identified as a cornucopia of biolo-
gically active compounds. While bacteria,[1] fungi,[2] marine
organisms[3] and many other organisms have been thor-
oughly investigated in that context, lichens have been signif-
icantly less considered.[4] As a symbiosis of algae and fungi,
the latter supply the lichens with secondary metabolites; the
metabolism is consequently similar to that of fungi. Graphis-
lactone A was identified as reduction product of botrallin
in 1968,[5] but it was first isolated as a natural product from
the lichen Graphis scripta var. pulverulenta[6] in the late
1990s together with graphislactones B, C, and D.[6a–6d]
Graphislactones E and F have been isolated from Graphis
scripta and Graphis prunicola[6d] and graphislactones G and
[a] Institut für Organische Chemie, Universität Karlsruhe (TH),
Karlsruher Institut für Technologie (KIT),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49-721-608-7652
E-mail: joachim.podlech@ioc.uka.de
[b] Institut für Anorganische Chemie, Universität Karlsruhe (TH),
Karlsruher Institut für Technologie (KIT),
Engesserstraße 15, 76131 Karlsruhe, Germany
[‡] X-ray crystallographic analyses.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Total Synthesis of Several Graphislactones and Ulocladol
Scheme 1. Synthesis of the boronates suitable for Suzuki coupling.
Total Synthesis of Ulocladol and Graphislactone D
Bromide 11, which was assumed to be suitable for the
synthesis of ulocladol was obtained starting with pur-
chasable methyl 3,4-dihydroxy-5-methoxybenzoate (8)
(Scheme 2). A published two-step sequence[17] with subse-
quent reduction using lithium aluminium hydride yielded
benzyl alcohol 11. The desired regioselectivity in the bromi-
nation was unambiguously clarified by X-ray crystallo-
graphic analysis of intermediate 9.[18] An alternative ap-
proach to benzyl alcohol 11 starting with purchasable 3,4-
dihydroxy-5-methoxybenzaldehyde (12) gave significantly
lower yields.[19] Suzuki coupling was achieved with a proto-
col, which already proved to be suitable for the construction
of the related resorcylic lactones altenuene and isoalten-
uene.[20] The best results for the C–C coupling were ob-
tained with palladium(II) acetate as a catalyst, caesium car-
bonate as a base and S-Phos[14b] as a ligand, which is espe-
cially suitable for sterically hindered couplings. With these
conditions a concomitant formation of the lactone moiety
was achieved, a pleasant side effect already observed in pre-
vious syntheses.[20] X-ray crystallographic analysis proved
the correct constitution for ulocladol derivative 14 (Fig-
ure 2).[18] As expected, the structure is significantly dis-
Figure 1. Structure of graphislactones and of related compounds.
a Originally proposed structures; for corrected structures vide infra.
lished procedures commenced with the installation of the
ester bond from suitable precursors with subsequent palla-
dium-mediated couplings.
Results and Discussion
Retrosynthesis and Construction of the Boronates
Retrosynthesis of the target compounds suggested Su-
zuki couplings[14] as key steps for the construction of the
central biaryl bonds. Boronates suitable for these transfor-
mations could be prepared according to published pro-
cedures[15] and a subsequent palladium-catalyzed Miyaura
cross coupling[16] starting with commercially available ace-
tal-protected phloroglucinic acid 1 (Scheme 1). No bo-
ronate was isolated in the Miyaura reaction when bis(pi-
nacolato)diborane was used as boron component and a
poor 34% yield was observed with pinacolborane and
PdCl2(dppf) as a catalyst. The significant amount of re-
duced side products 6 and 7, respectively, obtained in the
initial experiments was suppressed with Pd(PPh3)4 as a cat-
alyst and a reduced reaction time (2 h rather than 4 h). The
boronates 4 and 5 were thus accessible from protected phlo-
roglucinic acid 1 in three steps with 65 and 56% yield,
respectively. Graphislactone F bearing a free hydroxy group
in position C-9 was prepared starting with a boronate 5
protected as benzyl ether while the methyl ether as needed
in the other natural products was introduced with boronate
4.
Scheme 2. Attempted synthesis of ulocladol starting with substi-
tuted gallate 8 (cyHe: cyclohexyl).
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J. Podlech, et al.
FULL PAPER
torted from planarity, an effect similarly observed in NMR
spectra, where the diastereotopic methylene groups (2-H2
1
and 7-H2) gave sets of two signals. Coalescence in the H
NMR spectra was observed at 65 °C (500 MHz). Neverthe-
less, ulocladol could not be liberated from precursor 14 with
any tested method. Neither utilization of Lewis acids like
[21]
PCl5
or BCl3,[22] nor oxidative cleavage with lead tetra-
acetate[23] led to a clean cleavage of the methylene acetal.
Figure 2. Structure of ulocladol derivative 14 in the crystal.[18]
Consequently, we followed a different strategy starting
with commercially available 3,4-dihydroxy-5-methoxybenz-
aldehyde (12). Bromide 15 was obtained by conventional
bromination with bromine in acetic acid.[19] Dibenzylation
only afforded a poor 50% yield due to significant amounts
of monobenzylated product isolated and other non-speci-
fied side reactions. Subsequent reduction with diisobutylal-
uminium hydride (DIBAL-H) furnished a suitably pro-
tected bromide 17 (Scheme 3).
Scheme 4. Total synthesis of ulocladol and of graphislactone D.
poses. The total synthesis of graphislactone D was thus
achieved in 9 steps, where the longest linear sequence con-
sisted of 6 steps. The respective acylated compound 20 was
obtained with 7% overall yield.
Total Synthesis of Graphislactones E and F
A first strategy for the total synthesis of graphislactones
E and F started with purchasable 2-methoxyhydroquinone
(21). Bromination and oxidation with sodium periodate
yielded quinone 23, which was subjected to a Thiele acyl-
ation (Scheme 5).[24] Nevertheless, the resulting highly oxy-
genated bromide 24 could not be reacted in a Suzuki coup-
ling with any of the reaction conditions we applied. Conse-
quently, we tested a different strategy using intermediate 23
in a Suzuki coupling with an intended subsequent Thiele
Scheme 3. Synthesis of the brominated benzyl alcohol 17.
Suzuki coupling of boronate 4 and bromide 17 using the acylation. But again, the targeted aryl-quinone 26 was not
standard protocol yielded dibenzyl-protected ulocladol 18 formed, but instead a reduced substrate 27, which did not
with 65% yield, once again with immediate lactonization of seem to be suitable for further transformations.
the intermediate coupling product (Scheme 4). Hydro-
Aldehyde 16, used for the synthesis of ulocladol, was as-
genolytic cleavage of the benzyl groups furnished ulocladol sumed to be a suitable alternate starting material for the
with 60% yield. The total synthesis could thus be com- synthesis of graphislactones E and F. For the preparation
pleted in 8 steps and 15% yield starting with 3,4-dihydroxy- of these compounds, a protected tetrahydroxylated bromo-
5-methoxybenzaldehyde (12) and protected phloroglucinic benzene was needed (Scheme 6). For this purpose the car-
acid 1, where the longest linear sequence consisted of 5 baldehyde function in brominated aldehyde 16 was oxidized
steps. Our approach is thus significantly shorter and more with a Dakin reaction.[25] From the tested protocols, meta-
effective than the previously published synthesis.[13]
chloroperbenzoic acid afforded the highest yields.[26] The
Graphislactone D was similarly obtained by O4-methyl- crude phenol was formed with 97% yield, and was used
ation of dibenzyl-protected ulocladol 18 and subsequent hy- without further purification. The hydroxy group was pro-
drogenolysis. NMR spectra showed that graphislactone D tected as tetrahydropyranyl (THP) ether, but Suzuki coup-
was essentially pure after deprotection. Nevertheless, it de- ling of the resulting THP-protected substrate with boronate
composed during chromatography on silica gel. Conse- 4 failed even with a protocol optimized for sterically hin-
quently we acetylated this compound for analytical pur- dered substrates.[14b]
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Total Synthesis of Several Graphislactones and Ulocladol
Scheme 7. Total synthesis of the originally proposed structures of
graphislactones E and F.
Scheme 5. Attempted synthesis of graphislactones E and F with
Thiele acylation and Suzuki coupling as key steps.
gen 2-H. Because re-evaluation of the published data in-
cluding data from NOE experiments suggested a misassign-
ment of the substrates’ constitutions, we now wish to cor-
rect the misassignment by giving revised structures in Fig-
ure 3, which are in full accordance with the NOE data given
in the original paper.
Table 1. Comparison of significant NMR spectroscopic data for
acetylated graphislactone E in the originally proposed structure 35
and in the revised structure 41. Major deviations are given in bold-
face.[28]
Proposed structure 35[a] Synthetic 35
Revised structure 41
Signal
δ [ppm]
δ [ppm][b]
Signal[c]
δ [ppm]
8-H
2-H
6.72
6.85
7.82
6.66
6.74
7.86
4-H
8-H
6.74
6.84
7.82
99.1
10-H
C-2
C-10b
C-6a
C-10
C-8
10-H
C-4
C-10b
C-6a
C-10
C-8
C-2
C-10a
C-1
C-4a
C-3
C-7
C-6
C-9
Scheme 6. Attempted cross coupling of a highly hindered tetra-
hydroxyphenyl bromide. DHP: 3,4-dihydro-2H-pyrane, PPTS: pyr-
idinium p-toluenesulfonate.
99.1
104.3
105.3
106.5
108.5
109.4
125.2
136.8
145.3
145.8
152.5
154.9
156.2
165.0
105.1
106.6
107.7
109.5
129.8
136.8
141.0
150.4
153.4
154.8
156.9
164.9
105.1
106.7
107.7
109.6
129.9
136.8
141.1
150.5
153.4
154.8
156.9
164.9
In a reversed strategy, boronates 4 and 5, respectively,
were coupled with aldehyde 16 yielding biaryls 31 and 32
with 80 and 90% (Scheme 7). Hydrogenolysis of the benzyl
groups, saponification with concomitant translactonization
and benzylation of the hydroxy groups yielded a tricyclic
carbaldehyde suitable for a Dakin reaction. Oxidative de-
gradation was here best achieved with magnesium mono-
perphthalate (MMPP).[27] Debenzylation with hydro-
genolytic conditions yielded graphislactones E and F,
respectively, which were immediately protected as acetates
due to their low stability.
C-4
C-10a
C-4a
C-1
C-3
C-7
C-6
C-9
[a] Assignment as given in the original literature.[6d] [b] Signals
given in increasing order. [c] Assignment was made according to
C,H- and H,H-COSY, NOESY, and HMBC spectra.
It turned out that NMR spectroscopic data of the syn-
Due to our modular synthetic strategy it was no signifi-
thesized acetylated graphislactones E (35) and F (36) are cant additional effort to synthesize these revised structures.
not identical with data published by Tanahashi et al. Graphislactones E and F were thus obtained starting with
(Table 1 and Table 2).[6d] Significant deviations were de- boronates 4 and 5 and with phenol 28. Though Suzuki
tected especially in the 13C NMR spectra for carbons C-1, coupling was only achieved with poor 30 and 36% yield,
1
C-2, C-4, and C-4a and in the H NMR spectra for hydro- the acetylated revised structures of graphislactones E (41)
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J. Podlech, et al.
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Table 2. Comparison of significant NMR spectroscopic data for sisted of 5 steps. The corresponding acylated compounds 41
acetylated graphislactone F in the originally proposed structure 36
and 42 were obtained with 8 and 10% yield. The alternative
and in the revised structure 42. Major deviations are given in bold-
approach to acylated graphislactone E (42) via carbal-
face.[28]
dehyde 31 afforded an overall yield of 26%, though an ad-
Proposed structure 36[a]
Synthetic 36
δ [ppm][b]
Revised structure 42
ditional step was necessary in this sequence.
Data for the revised structures are in full accordance with
data given in the original publication (see Tables 1 and 2)
giving unambiguous evidence for the revised structures as
depicted in Figure 3.
Signal
δ [ppm]
Signal[c]
δ [ppm]
2-H
8-H
6.86
6.99
6.70
7.00
8.36
4-H
8-H
6.85
6.99
10-H
C-2
C-10b
C-6a
C-10
C-8
8.33
10-H
C-4
C-10b
C-6a
C-10
C-8
C-2
C-10a
C-1
C-4a
C-3
C-7
C-9
C-6
8.33
99.0
100.0
104.9
110.8
114.8
116.5
130.1
136.6
141.1
150.2
153.71
153.74
155.7
156.5
104.5
105.1
110.7
115.5
116.7
125.1
136.6
145.1
145.8
152.8
153.9
104.9
110.8
114.8
116.6
130.0
136.6
141.1
150.2
153.7
153.8
155.7
156.5
Total Synthesis of Graphislactone C
C-4
Graphislactone C was accessible in two steps starting
with intermediate 33 by reduction of the carbaldehyde func-
tion and deprotection in 56% yield (Scheme 9). The total
synthesis could thus be completed with 11 steps and 16%
yield, where the longest linear sequence consisted of 9 steps.
C-10a
C-4a
C-1
C-3
C-7
C-9
C-6
155.8
[d]
[a] Assignment as given in the original literature.[6d] [b] Signals
given in increasing order. [c] Assignment was made according to
C,H- and H,H-COSY, NOESY-, and HMBC-spectra. [d] One sig-
nal is covered.
Scheme 9. Total synthesis of graphislactone C.
Total Synthesis of Graphislactones A and H
Figure 3. Revised structures of graphislactones E (37) and F (38).
The total synthesis of graphislactone A was achieved
starting with bromide 11 used for the unsuccessful ap-
proach towards the synthesis of ulocladol (Scheme 10). The
benzyl alcohol was degraded to a methyl group by a Bar-
ton–McCombie protocol with 76% yield. Suzuki coupling
was achieved with 83% yield, where formation of a reduced
side product 6 made it advantageous to use an excess of the
boronate 4. Subsequent cleavage of the dioxolane ring with
boron trichloride furnished graphislactone A. With these
conditions, a partial cleavage of the methoxy groups was
observed causing a reduced yield of only 39%. Crystals
suitable for X-ray crystallographic analysis were obtained,
proving the identity of the proposed and synthesized struc-
tures (Figure 4).[18] The total synthesis of graphislactone A
could thus be completed in 10 steps and with 16% yield,
where the longest linear sequence consisted of 7 steps. The
synthesis of graphislactone H was achieved for the first time
by careful methylation of graphislactone A with diazometh-
ane in quantitative yield. Over-methylation was avoided by
portionwise addition of diazomethane with monitoring by
thin layer chromatography. The identity of the proposed
structure was unambiguously confirmed by comparison of
published spectroscopic data,[6a] which are in full agreement
with those of the synthesized compound. Here the total
synthesis could be completed with 11 steps and 16% yield,
where the longest linear sequence consisted of 8 steps.
and F (42) were obtained after protection group manipula-
tions with 70 and 77% yield, respectively (Scheme 8). Pre-
cursor 39 can furthermore be prepared in superior 70%
yield by Dakin degradation of carbaldehyde 31 with con-
comitant translactonization. Compounds corresponding to
the revised structures of graphislactones E and F were syn-
thesized in 8 steps, where the longest linear sequences con-
Scheme 8. Total synthesis of the revised structures of acetylated
graphislactones E (41) and F (42).
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Total Synthesis of Several Graphislactones and Ulocladol
General Procedure 1 for Suzuki Cross Couplings: Degassed solvent
(dioxane/H2O, 6:1, 7 mL/mmol) was added under an argon atmo-
sphere to a mixture of aryl bromide (1 equiv.), boronate (4 or 5,
1.3 equiv.), Cs2CO3 (3 equiv.), Pd(OAc)2 (0.03 equiv.) and S-Phos
(0.06 equiv.). The solution was heated to 80 °C for 2–6 h (monitor-
ing with tlc). After cooling to room temperature, saturated aqueous
NH4Cl solution was added, and the mixture was extracted with
EtOAc. The organic layers were dried (Na2SO4) and concentrated,
and the residue was purified by chromatography (silica gel).
General Procedure 2 for Dakin Reactions:[26] m-CPBA (70%,
1.6 equiv.) in CH2Cl2 (0.1 ) was added to the respective aromatic
aldehyde (1 equiv.) and heated for 18 h to 60 °C. The organic layer
was extracted with saturated aqueous NaHCO3 solution and with
brine, dried (Na2SO4), and concentrated. The residue was dissolved
in 10% aqueous KOH solution; the solution was stirred for 2 h at
room temperature, acidified to pH 2 with 6  HCl and extracted
with CH2Cl2. The organic layer was dried (Na2SO4), and concen-
trated to yield the respective phenol.
Scheme 10. Total synthesis of graphislactones A and H.
General Procedure 3 for the Hydrogenolytical Cleavage of Benzyl
Groups: Pd/C (10–15 mol-%) and MeOH (2 mL) was added to the
protected substrate (0.10 mmol). The mixture was stirred under a
H2 atmosphere for 2–24 h at room temperature (monitoring with
tlc) and filtered. The filtrate was concentrated to yield the crude
product.
Synthesis of Boronates
5-Hydroxy-7-methoxy-2,2-dimethylbenzo[1,3]dioxin-4-one:[15a] Ace-
tonide 1 (2.50 g, 11.9 mmol) was methylated following a published
procedure yielding the title compound (2.09 g, 9.32 mmol, 78%).
Figure 4. Structure of graphislactone A in the crystal.[18]
7-Methoxy-2,2-dimethyl-5-(trifluoromethylsulfonyloxy)benzo[1,3]-
dioxin-4-one (2):[15a] Following a published procedure, the phenol
synthesized as given above (2.96 g, 13.2 mmol) was converted into
triflate 2 (4.44 g, 12.5 mmol, 95%).
Experimental Section
General Remarks: Experimental procedures and spectroscopic data
for the preparation of 1 starting with phloroglucinic acid, for 12
starting with vanillin, and an alternative synthesis of alcohol 11
starting with vanillin are given in the supplemental material. Ab-
breviations: 3,4-Dihydro-2H-pyran, (DHP), pyridinium p-toluene-
sulfonate (PPTS), tetrahydropyran (THP). Tetrahydrofuran (THF)
and Et2O were distilled from sodium benzophenone ketyl radical,
and CH2Cl2 was distilled from CaH2. All moisture-sensitive reac-
tions were carried out under oxygen-free nitrogen atmosphere using
oven-dried glassware and a vacuum line. Flash column chromatog-
raphy was carried out using Merck SiO2 60 (230–400 mesh) and
thin layer chromatography (tlc) was carried out using commercially
available Merck F254 pre-coated sheets. Medium pressure liquid
chromatography (MPLC): Detection by UV absorption (Latek
UVIS 200). 1H and 13C NMR spectra were recorded with a Bruker
Cryospek WM-250, an AM-400, a DRX 500, or with an Avance
600 instrument. Chemical shifts are given in ppm downfield of tet-
ramethylsilane. 13C NMR spectra were recorded with broad band
proton decoupling and were assigned using DEPT 135 and DEPT
90 experiments. Melting points were measured with a Büchi appa-
ratus and were not corrected. IR spectra were recorded with a
Bruker IFS-88 spectrometer. Elemental analyses were performed
with a Heraeus CHN-O-rapid and with an Elementar vario
MICRO instrument. EI, FAB and high resolution mass spectra
were recorded with a Finnigan MAT-90 mass spectrometer. UV/
Vis spectra were recorded on a Perkin–Elmer Lambda 2 spectrome-
ter. The extinction coefficient ε is given for quantitative measure-
ments.
7-Methoxy-2,2-dimethyl-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-
2-yl)benzo[1,3]dioxin-4-one (4) and 7-Methoxy-2,2-dimethylbenzo-
[1,3]dioxin-4-one (6): Freshly distilled Et3N (1.18 mL, 8.41 mmol)
and Pd(PPh3)4 (162 mg, 5 mol-%) were added to a solution of tri-
flate 2 (1.00 g, 2.80 mmol) in anhydrous dioxane (50 mL). Oxygen
was expelled by ultrasonication under argon for 10 min, and pinac-
olborane (1.07 mg, 8.41 mmol) was added dropwise within 5 min.
The solution was stirred for 2 h at 80 °C, and the solvent was re-
moved in vacuo. The residue was purified by chromatography (hex-
anes/EtOAc, 10:1) yielding boronate 4 (709 mg, 2.12 mmol, 75%)
and the reduced compound 6 (69 mg, 0.33 mmol, 12%).
7-Benzyloxy-5-hydroxy-2,2-dimethylbenzo[1,3]dioxin-4-one:[15b] Fol-
lowing a published procedure, phenol 1 (2.57 g, 12.2 mmol) was
converted into the title compound (3.28 g, 10.9 mmol, 90%).
7-Benzyloxy-2,2-dimethyl-5-(trifluoromethylsulfonyloxy)benzo[1,3]-
dioxin-4-one (3):[15a] Following a published procedure, the phenol
synthesized as given above (2.71 g, 9.04 mmol) was converted into
triflate 3 (3.74 g, 8.63 mmol, 95%).
7-Benzyloxy-2,2-dimethyl-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-
2-yl)benzo[1,3]dioxin-4-one (5) and 7-Benzyloxy-2,2-dimethylbenzo-
[1,3]dioxin-4-one (7): Freshly distilled Et3N (5.00 mL, 8.65 mmol)
and Pd(PPh3)4 (490 mg, 5 mol-%) were added to a solution of tri-
flate 3 (3.74 g, 8.65 mmol) in anhydrous dioxane (100 mL). Oxygen
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J. Podlech, et al.
FULL PAPER
was expelled by ultrasonication under argon for 10 min and pinac-
olborane (2.51 mL, 17.3 mmol) was added dropwise within 5 min.
The solution was stirred for 2 h at 80 °C and the solvent was re-
moved in vacuo. The residue was purified by chromatography (hex-
anes/EtOAc, 10:1) yielding boronate 5 (2.30 g, 5.61 mmol, 65%)
and the reduced compound 7 (849 mg, 2.98 mmol, 34%).
10,11-Bis(benzyloxy)-4-hydroxy-2,9-dimethoxy-7H-dibenzo[c,e]oxe-
pin-5-one (18) and 7,7Ј-Dimethoxy-2,2,2Ј,2Ј-tetramethyl[5,5Ј]bi-
[benzo[1,3]dioxinyl]-4,4Ј-dione: According to general procedure 1,
bromide 17 (430 mg, 1 mmol) and boronate 4 (434 mg, 1.3 mmol)
were reacted for 2 h. Purification by chromatography (hexanes/
EtOAc, 10:1 to 6:1) yielded 18 (325 mg, 0.65 mmol, 65%) as a
colourless solid. Homocoupling resulted in a biphenyl derivative
(84 mg, 0.22 mmol, 20%) as a side product.
Synthesis of Ulocladol
Methyl 2-Bromo-3,4-dihydroxy-5-methoxybenzoate (9):[17] N,NЈ-Di-
bromo-5,5-dimethylhydantoin (DBDMH, 20.7 g, 67.7 mmol) was
added portionwise to a solution of methyl ester 8 (26.2 g,
133 mmol) in CHCl3 (700 mL). Every addition led to a red-brown
colour, and the next portion was added after a significant decol-
ouration. The mixture was stirred overnight, washed with 10%
aqueous Na2S2O4 solution (3ϫ300 mL), dried (Na2SO4), and the
solvent was removed under reduced pressure to yield a brownish
residue of 9 (35.7 g, 129 mmol, 97%).
Methyl 4-Bromo-7-methoxybenzo[1,3]dioxole-5-carboxylate (10):[17]
A mixture of 9 (10.0 g, 36.1 mmol), KF (10.5 g, 181 mmol), CH2I2
(4.31 mL, 54.1 mmol), and anhydrous DMF (350 mL) was stirred
for 2 h at 110 °C and extracted with Et2O (3ϫ200 mL) after cool-
ing. The combined organic layers were washed with brine
(3ϫ150 mL), dried (Na2SO4), concentrated and the residue was
purified by chromatography (hexanes/EtOAc, 4:1) yielding 10 as a
colourless solid (7.50 g, 25.9 mmol, 72%).
4,10,11-Trihydroxy-2,9-dimethoxy-7H-dibenzo[c,e]oxepin-5-one
(Ulocladol): According to general procedure 3, protected ulocladol
18 (96.0 mg, 0.192 mmol) was reacted for 2 h and purified by
chromatography (CH2Cl2/MeOH, 20:1) to yield ulocladol as a
colourless solid (36.0 mg, 0.11 mmol, 60%). NMR spectroscopic
data were assigned according to H,H-COSY, C,H-COSY, and
HMBC spectra; m.p. 180–182 °C. Rf (CH2Cl2/MeOH, 10:1) = 0.55.
IR (DRIFT): ν = 3429 (s), 2949 (m), 1652 (s, C=O), 1616 (s), 1569
˜
1
(m) cm–1. H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H, 9-OMe),
2
3.93 (s, 3 H, 2-OMe), 4.79 (d, J = 12.0 Hz, 1 H, CHaHb), 5.11 (d,
2J = 12.0 Hz, 1 H, CHaHb), 5.98 (br. s, 2 H, 10-OH, 11-OH), 6.57
4
(d, 4J = 2.6 Hz, 1 H, 3-H), 6.59 (s, 1 H, 8-H), 6.94 (d, J = 2.6 Hz,
1 H, 1-H), 10.30 (s, 1 H, 4-OH) ppm. 13C NMR (101 MHz,
CDCl3): δ = 55.5 (q, 2-OMe), 56.3 (q, 9-OMe), 70.3 (t, C-7), 100.7
(d, C-3), 103.4 (d, C-9), 106.5 (s, C-4a), 110.2 (d, C-1), 118.7 (s, C-
11a), 126.9 (s, C-7a), 133.9 (s, C-10), 135.9 (s, C-11), 142.2 (s, C-
1a), 146.4 (s, C-8), 162.9 (s, C-4), 163.2 (s, C-2), 172.5 (s, C-5) ppm.
UV/Vis: λEtOH (ε) = 204 (Ͼ100,000), 235 (29,000), 286 (3,800) nm.
MS (EI, 130 °C): m/z (%) = 318 (100) [M+], 301 (12) [[M – OH]+],
300 (63), 274 (12), 273 (17), 259 (14), 254 (16), 84 (33), 66 (36), 43
(4-Bromo-7-methoxybenzo[1,3]dioxol-5-yl)methanol (11) and (7-
Methoxybenzo[1,3]dioxol-5-yl)methanol: A solution of 10 (1.00 g,
3.46 mmol) in anhydrous Et2O (50 mL) was added within 10 min
at 0 °C under an argon atmosphere to a suspension of LiAlH4
(147 mg, 3.76 mmol) in anhydrous Et2O (20 mL), and the mixture
was stirred for 15 min. H2O (0.15 mL), 5  NaOH (0.15 mL), and
H2O (0.45 mL) were added very carefully, and the mixture was
stirred for 30 min and filtered through celite. Extraction with Et2O
(4ϫ30 mL), combination of the organic layers, concentration and
purification of the residue with chromatography (hexanes/EtOAc,
2:1) yielded 11 as a colourless solid (696 mg, 2.67 mmol, 77%).
Debrominated substrate was obtained as a side product.
(27). HRMS (12C16 H1416O7, FAB): calcd. 318.0740; found
1
318.0737. Analytical data are in full accordance with published da-
ta.[8a]
Synthesis of Graphislactone D
10,11-Bis(benzyloxy)-2,4,9-trimethoxy-7H-dibenzo[c,e]oxepin-5-one
(19): K2CO3 (113 mg, 0.820 mmol) and MeI (116 mg, 0.82 mmol)
were added to a solution of phenol 18 (203 mg, 0.41 mmol) in an-
hydrous acetone. The mixture was heated to reflux for 12 h, concen-
trated and purified by chromatography (CH2Cl2) to yield methyl
ether 19 (169 mg, 0.33 mmol, 81%) as a colourless solid.
6,8-Dihydro-9-hydroxy-4,11-dimethoxybenz[1,3]dioxolo[4,5-e]benzo-
[c]oxepin-8-one (14): Bromide 11 (130 mg, 0.5 mmol) and boronate
4 (217 mg, 0.65 mmol) were reacted according to general procedure
1 for 3 h. Purification by MPLC (CH2Cl2) yielded 14 (101 mg,
0.31 mmol, 61%) as a colourless solid.
10,11-Dihydroxy-2,4,9-trimethoxy-7H-dibenzo[c,e]oxepin-5-one
(Graphislactone D): Bisbenzyl ether 19 (16 mg, 0.031 mmol) was
treated with Pd/C (10 mol-%) for 2 h according to general pro-
cedure 3. The crude graphislactone D contained only small
amounts of impurities. Chromatographic purification led to decom-
position. Rf (CH2Cl2/MeOH, 10:1) = 0.23. 1H NMR (250 MHz,
CDCl3): δ = 1.50–2.00 (br. s, 2 H, OH), 3.87 (s, 3 H, OMe), 3.89
3,4-Bis(benzyloxy)-2-bromo-5-methoxybenzaldehyde (16): A suspen-
sion of NaH (60% in paraffin, 910 mg, 26.2 mmol) was placed with
exclusion of air and moisture in anhydrous DMF (15 mL). At
–78 °C, bromide 15 (3.00 g, 12.2 mmol) in anhydrous DMF
(15 mL) and BnBr (5.19 g, 30.3 mmol) were added successively. Af-
ter stirring for an additional 15 min at –78 °C, the mixture was
warmed to room temperature. H2O (200 mL) was added, and the
mixture was extracted with EtOAc (4ϫ20 mL). The organic layers
were dried (Na2SO4) and concentrated, and the residue was puri-
fied by chromatography (hexanes/EtOAc, 10:1) to yield 16 as a
colourless solid (2.55 g, 5.97 mmol, 50%).
2
(s, 3 H, OMe), 3.93 (s, 3 H, OMe), 4.72 (d, J = 11.9 Hz, 1 H, 7-
2
4
CH2), 4.97 (d, J = 11.9 Hz, 1 H, 7-CH2), 6.53 (d, J = 2.3 Hz, 1
H, Ar-H), 6.58 (s, 1 H, 8-H), 6.95 (d, 4J = 2.3 Hz, 1 H, Ar-H) ppm.
Analytical data are in full accordance with published data.[6a]
10,11-Diacetoxy-2,4,9-trimethoxy-7H-dibenzo[c,e]oxepin-5-one
(Acetylated Graphislactone D, 20): Bisbenzyl ether 19 (183 mg,
0.031 mmol) was treated with Pd/C (10 mol-%) for 2 h according
to general procedure 3. Ac2O (100 µL, 1.06 mmol) and anhydrous
pyridine (86 µL, 1.06 mmol) were added to the crude graphislac-
tone D dissolved in CH2Cl2 (5 mL). The mixture was stirred for
[3,4-Bis(benzyloxy)-2-bromo-5-methoxyphenyl]methanol (17):
DIBAL-H (1  in toluene, 3.28 mL, 3.28 mmol) was added at
–78 °C within 5 min to a solution of aldehyde 16 (700 mg, 12 h at room temperature under argon, then it was washed with
1.64 mmol) in anhydrous THF (10 mL). After stirring for 2 h at
–78 °C, HCl (1 , 3 mL) and H2O (10 mL) were added, and the
mixture was extracted with EtOAc (3ϫ10 mL). The organic layers
were dried (Na2SO4) and concentrated, yielding crude alcohol 17
(695 mg, 1.62 mmol, 99%) as a colourless solid, which was used
without further purification.
HCl (0.1 , 3 mL) and saturated aqueous NaHCO3 solution
(3 mL). The organic layers were dried (Na2SO4), concentrated and
purified by precipitation from H2O/MeCN. Lyophilisation yielded
acetylated graphislactone D (20) (50 mg, 0.120 mmol, 34%) as a
colourless solid. NMR spectroscopic data were assigned according
to H,H-COSY, C,H-COSY, and HMBC spectra; m.p. 223–225 °C.
2136
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2130–2140

Total Synthesis of Several Graphislactones and Ulocladol
R (CH Cl /MeOH, 10:1) = 0.30. IR (DRIFT): ν = 2935 (m), 2849
0.23 mmol) and boronate 4 (99 mg, 0.30 mmol) were reacted ac-
˜
f
2
2
(m), 1784 (s, C=O), 1725 (C=O), 1599 (s), 1504 (s), 1457 (s), 1415 cording to general procedure 1 for 1.5 h. Purification by MPLC
(s), 1373 (s), 1328 (s), 1294 (m), 1265 (m), 1243 (m), 1209 (s), 1187 (hexanes/EtOAc, 8:1) yielded 31 (103 mg, 0.18 mmol, 80%) as a
1
(s), 1159 (s), 1083 (s) cm–1. H NMR (400 MHz. CDCl3): δ = 2.18
colourless solid.
(s, 3 H, OAc), 2.31 (s, 3 H, OAc), 3.82 (s, 3 H, 2-OMe), 3.89 (s, 6
3,4-Bis(benzyloxy)-2-(7-benzyloxy-2,2-dimethyl-4-oxo-4H-benzo[1,3]-
dioxin-5-yl)-5-methoxybenzaldehyde (32): Bromide 16 (106 mg,
0.25 mmol) and boronate 5 (135 mg, 0.33 mmol) were reacted ac-
cording to general procedure 1 for 1.5 h. Purification by MPLC
(hexanes/EtOAc, 8:1) yielded 32 (144 mg, 0.23 mmol, 90%) as a
colourless solid.
2
H, 4-OMe, 9-OMe), 4.81 (d, J = 12.1 Hz, 1 H, CHaHb), 4.96 (d,
4
2J = 12.1 Hz, 1 H, CHaHb), 6.55 (d, J = 2.3 Hz, 1 H, 3-H), 6.59
(d, 4J = 2.3 Hz, 1 H, 1-H), 6.96 (s, 1 H, 8-H) ppm. 13C NMR
(100 MHz. CDCl3): δ = 20.3 (q, OAc), 20.4 (q, OAc), 55.5 (q, OMe-
2), 56.2 (q, OMe), 56.4 (q, OMe), 68.5 (t, C-7), 99.1 (d, C-3), 104.8
(d, C-1), 110.0 (d, C-8), 113.5 (s), 124.7 (s), 133.6 (s), 134.6 (s),
134.8 (s), 141.5 (s), 152.1 (s, C-9), 159.8 (s, C-4), 161.7 (s, C-2),
165.6 (s), 167.3 (s), 167.5 (s) ppm. UV/Vis: λEtOH = 202, 251 nm.
MS (FAB): m/z (%) = 417 (83) [[M + H]+], 136 (58). HRMS
3,4-Dihydroxy-5-methoxy-2-(7-methoxy-2,2-dimethyl-4-oxo-4H-
benzo[1,3]dioxin-5-yl)benzaldehyde: Aldehyde 31 (56.0 mg,
0.10 mmol), Pd/C (5%, 21 mg, 10 mol-%), and EtOAc (3 mL) were
stirred under a hydrogen atmosphere for 2 h at room temperature.
The mixture was filtered, and the filtrate was concentrated to yield
the title compound (31.0 mg, 0.098 mmol, 98%) as a colourless so-
lid, which was used without further purification.
(12C21 H2116O9, FAB): calcd. 417.1185; found 417.1183. Analytical
1
data are in full accordance with published data.[6d]
Synthesis of Graphislactones E and F
2-Methoxybenzene-1,4-diol (2-Methoxyhydroquinone, 21):[29] Vanil-
lin (5.00 g, 32.9 mmol) was reacted according to a published pro-
cedure to yield hydroquinone 21 (3.22 g, 22.9 mmol, 70%) as a yel-
lowish solid.
4,7-Bis(benzyloxy)-3,9-dimethoxy-6-oxo-6H-benzo[c]chromene-1-
carbaldehyde (33): The catechol synthesized as given above
(100 mg, 0.27 mmol) was dissolved in KOH solution (1  in EtOH,
15 mL) and stirred for 1 h at 60 °C. The mixture was cooled to
room temperature, acidified with aqueous 1  HCl (pH 2), and
extracted with EtOAc (3ϫ15 mL). The organic layers were dried
(Na2SO4) and concentrated to yield lactone 30 (56 mg, 0.17 mmol,
66%). To this residue was added under argon K2CO3 (71.0 mg,
0.51 mmol), anhydrous DMF (5 mL), and BnBr (87.0 mg,
0.51 mmol), and the solution was stirred at room temperature over-
night. The mixture was diluted with H2O (35 mL) and extracted
with EtOAc (3ϫ15 mL). The organic layers were dried (Na2SO4),
concentrated, and purified by chromatography (hexanes/EtOAc,
8:1 to 2:1) yielding 33 (74.0 mg, 0.15 mmol, 82%, 55% over 3 steps)
as a colourless solid.
2-Bromo-5-methoxybenzene-1,4-diol (22):[30] Bromination of hydro-
quinone 21 (3.00 g, 21.4 mol) was achieved according to a pub-
lished procedure yielding 22 as brown crystals (2.96 g, 13.5 mmol,
63%)after recrystallization from benzene.
2-Bromo-5-methoxy[1,4]benzoquinone (23):[30] Bromide 22 (1.56 g,
7.12 mmol) was oxidized according to a published procedure yield-
ing quinone 23 (1.46 g, 6.73 mmol, 95%).
1,3,4-Triacetoxy-2-bromo-5-methoxybenzene (24):[31] Thiele acyl-
ation of quinone 23 (4.03 g, 18.6 mmol) was achieved following a
published procedure. Purification by chromatography (hexanes/
EtOAc, 4:1) triacetate yielded 24 (2.70 g, 7.48 mmol, 40%) as a
colourless solid and starting material (1.20 g, 5.53 mmol, 30%).
1,2,9-Tris(benzyloxy)-3-methoxy-6-oxo-6H-benzo[c]chromene-1-
carbaldehyde (34): Aldehyde 32 (200 mg, 0.38 mmol) was depro-
tected in EtOAc overnight according to general procedure 3, and
the crude product was treated with KOH (1  in EtOH, 15 mL)
and stirred for 1 h at 60 °C. The mixture was cooled to room tem-
perature, acidified with aqueous 1  HCl to pH 2, and extracted
with EtOAc (3ϫ15 mL). The organic layers were dried (Na2SO4)
and concentrated to yield the debenzylated substrate as a crude
product (84 mg, 0.28 mmol, 88%), which was treated under argon
with K2CO3 (192 mg, 1.39 mmol), anhydrous DMF (5 mL), and
BnBr (238 mg, 1.39 mmol) and stirred at room temperature over-
night. The mixture was diluted with H2O (35 mL), extracted with
EtOAc (3ϫ15 mL) and the organic layers were dried (Na2SO4),
concentrated and purified by chromatography (hexanes/EtOAc, 8:1
to 2:1) to yield 34 (124 mg, 0.22 mmol, 78%, 70% over 3 steps) as
a colourless solid.
2,7-Dihydroxy-3,9-dimethoxybenzo[c]chromen-6-one (27): Bromo-
quinone 23 (109 mg, 0.50 mmol) and boronate 4 (334 mg, 1 mmol)
were reacted according to general procedure 1 for 5 h. Purification
by chromatography (hexanes/EtOAc, 8:1) yielded lactone 27
(28 mg, 0.10 mmol, 20%) as a colourless solid.
3,4-Bis(benzyloxy)-2-bromo-5-methoxyphenol (28): According to ge-
neral procedure 2 aldehyde 16 (1.62 g, 3.79 mmol) was oxidized,
yielding phenol 28 (1.52 g, 3.67 mmol, 97%) as reddish brown oil,
which could not be further purified because it decomposed during
chromatography. It was thus used as crude material.
2-[3,4-Bis(benzyloxy)-2-bromo-5-methoxyphenoxy]tetrahydro-2H-
pyran (29): Phenol 28 (831 mg, 1.96 mmol), DHP (495 mg,
5.87 mmol) and PPTS (25 mg, 0.10 mmol) were dissolved in
CH2Cl2 (10 mL) and stirred for 12 h at room temperature. Satu-
rated aqueous NaHCO3 solution (10 mL) was added, and the mix-
ture was extracted with CH2Cl2 (3ϫ10 mL). The organic layers
were dried (Na2SO4), concentrated and purified by chromatog-
raphy (hexanes/EtOAc, 10:1), yielding THP-protected product 29
(724 mg, 1.45 mmol, 75%) as a colourless oil.
4,7-Bis(benzyloxy)-1-hydroxy-3,9-dimethoxybenzo[c]chromen-6-one:
MMPP (152 mg, 0.30 mmol) and MeOH (3 mL) were added to al-
dehyde 33 (51 mg, 0.10 mmol), and the mixture was stirred for 18 h
at room temperature. The organic layer was diluted with CH2Cl2
(5 mL), washed with saturated aqueous NaHCO3 solution (5 mL),
dried (Na2SO4), and concentrated. Aqueous KOH solution (10%,
5 mL) was added, and the mixture was stirred for 2 h at room tem-
perature, brought to pH 2 with 6  HCl, and extracted with
CH2Cl2. The organic layers were dried (Na2SO4) and concentrated
to yield the title compound (20 mg, 0.040 mmol, 40%) as a colour-
less solid.
The unsucessful reaction of 29 towards coupling product 30 is given
in the Supporting Information.
3,4-Bis(benzyloxy)-5-methoxy-2-(7-methoxy-2,2-dimethyl-4-oxo-
1,4,7-Triacetoxy-3,9-dimethoxy-6H-benzo[c]chromen-6-one (Acety-
4H-benzo[1,3]dioxin-5-yl)-benzaldehyde (31): Bromide 16 (100 mg, lated Graphislactone E, Originally Proposed Structure, 35): The pre-
Eur. J. Org. Chem. 2009, 2130–2140
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2137

J. Podlech, et al.
FULL PAPER
cursor synthesized as given above (22 mg, 0.042 mmol) was treated
with Pd/C (15 mol-%) according to general procedure 3. The crude
product was reacted after workup with Ac2O (32 µL, 0.33 mmol)
and anhydrous pyridine (27 µL, 0.33 mmol) and dissolved in anhy-
drous CH2Cl2 (5 mL). The mixture was stirred for 12 h at room
temperature under argon, concentrated, and purified by
chromatography (hexanes/EtOAc, 2:1) and by subsequent precipi-
tation from H2O/MeCN. Lyophilisation yielded acetylated graphis-
lactone E (35, 13 mg, 0.030 mmol, 73%) as a colourless solid; m.p.
[ M – C 2 H 2 O + ] , 3 7 5 ( 2 1 ) , 1 5 5 ( 2 5 ) , 1 3 6 ( 7 7 ) . H R M S
(12C22 H19 O11, FAB): calcd. 459.0927; found 459.0930.
1
16
1,2-Bis(benzyloxy)-7-hydroxy-3,9-dimethoxy-6H-benzo[c]chromen-
6-one (39). Method 1: Bromide 28 (118 mg, 0.280 mmol) and bo-
ronate 4 (123 mg, 0.360 mmol) were reacted according to general
procedure 1 for 2.5 h. Purification by chromatography (hexanes/
EtOAc, 10:1) yielded product 39 (42 mg, 0.090 mmol, 30%) as a
colourless solid.
Method 2: Aldehyde 31 (49 mg, 0.09 mmol) was reacted according
to general procedure 2 for 18 h at 45 °C. The resulting crude prod-
uct was purified by chromatography (hexanes/EtOAc, 10:1) yield-
ing product 39 (30 mg, 0.06 mmol, 70%) as a colourless solid.
168–170 °C. R (hexanes/EtOAc, 1:1) = 0.11. IR (DRIFT): ν = 2962
˜
f
(s), 2852 (m), 1775 (s, C=O), 1737 (s, C=O), 112 (s), 1566 (m), 1451
(m), 1369 (m), 1343 (m), 1260 (s), 1244 (s), 1179 (s), 1021 (s) cm–1.
Assignment of NMR spectroscopic data was made according to
H,H-COSY, C,H-COSY, NOESY, and HMBC spectra. 1H NMR
(600 MHz, CDCl3): δ = 2.40 (s, 3 H, 4-OAc), 2.41 (s, 3 H, 7-OAc),
2.47 (s, 3 H, 1-OAc), 3.88 (s, 3 H, 3-OMe), 3.93 (s, 3 H, 9-OMe),
1,2,7-Triacetoxy-3,9-dimethoxy-6H-benzo[c]chromen-6-one (Acety-
lated Graphislactone E, Revised Structure, 41): Bisbenzyl ether 39
(80 mg, 0.14 mmol) was treated with Pd/C (15 mol-%) according to
general procedure 3. The crude product was reacted after workup
with Ac2O (105 µL, 1.11 mmol) and anhydrous pyridine (90 µL,
1.11 mmol), and dissolved in anhydrous CH2Cl2 (5 mL). The mix-
ture was stirred for 12 h at room temperature under argon, concen-
trated, and purified by chromatography (hexanes/EtOAc, 2:1) to
yield acetate 41 (25 mg, 0.057 mmol, 70%) as a colourless solid;
4
6.66 (s, 1 H, 2-H), 6.74 (d, J = 2.4 Hz, 1 H, 8-H), 7.86 (d, 4J =
2.4 Hz, 1 H, 10-H) ppm. 13C NMR (101 MHz, CDCl3): δ = 20.4
(q, OAc-4), 21.2 (q, OAc-7), 21.6 (q, OAc-1), 55.9 (q, OMe-9), 56.5
(q, OMe-3), 104.3 (d, C-2), 105.3 (s, C-10b), 106.5 (s, C-6a), 108.5
(d, C-10), 109.4 (d, C-8), 125.2 (s, C-4), 136.8 (s, C-10a), 145.3 (s,
C-4a), 145.8 (s, C-1), 152.5 (s, C-3), 154. 9 (s, C-7), 156.2 (s, C-6);
165.0 (s, C-9), 168.2 (s, 2 C, OAc-2 and OAc-4), 169.5 (s, OAc-7)
ppm. UV/Vis: λEtOH = 193, 234, 258, 284, 325 nm. MS (FAB): m/z
(%) = 431 (12) [[M + H]+], 389 (36), 136 (48), 133 (100). HRMS
m.p. 183–185 °C. R (hexanes/EtOAc, 1:1) = 0.12. IR (DRIFT): ν
˜
f
= 2943 (m), 1789 (s, C=O), 1734 (s, C=O), 1607 (s, C=O), 1560
(m), 1505 (m), 1419 (s), 1373 (s), 1350 (s), 1301 (m), 1240 (s), 1194
(s), 1153 (s), 1118 (m) cm–1. Assignment of NMR spectroscopic
data was made according to H,H-COSY, C,H-COSY, NOESY, and
1
16
(12C21 H19 O10, FAB): calcd. 431.0978; found 431.0974.
4,7,9-Tris(benzyloxy)-1-hydroxy-3-methoxybenzo[c]chromen-6-one:
MMPP (237 mg, 0.48 mmol) and MeOH (3 mL) were added to al-
dehyde 34 (90 mg, 0.16 mmol), and the mixture was stirred for 18 h
at room temperature. The organic layer was diluted with CH2Cl2
(5 mL), washed with saturated aqueous NaHCO3 solution (5 mL),
dried (Na2SO4), and concentrated. Aqueous KOH solution (10%,
5 mL) was added, and the mixture was stirred for 2 h at room tem-
perature, brought to pH 2 with 6  HCl, and extracted with
CH2Cl2. The organic layers were dried (Na2SO4) and concentrated
to yield the title compound (32 mg, 0.057 mmol, 35%) as a colour-
less solid.
1
HMBC spectra. H NMR (500 MHz, CDCl3): δ = 2.33 (s, 3 H, 2-
OAc), 2.43 (s, 3 H, 7-OAc), 2.45 (s, 3 H, 1-OAc), 3.90 (s, 3 H, 9-
OMe), 3.92 (s, 3 H, 3-OMe), 6.84 (s, 1 H, 4-H), 6.74 (d, 4J = 2.4 Hz,
1 H, 8-H), 7.82 (d, 4J = 2.4 Hz, 1 H, 10-H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 20.2 (q, OAc-2), 20.8 (q, OAc-1), 21.2 (q,
OAc-7), 55.8 (q, OMe-3), 56.5 (q, OMe-9), 99.1 (d, C-4), 105.1 (s,
C-10b), 106.7 (s, C-6a), 107.7 (d, C-10), 109.6 (d, C-8), 129.9 (s, C-
2), 136.8 (s, C-10a), 141.1 (s, C-1), 150.5 (s, C-4a), 153.4 (s, C-3),
154.8 (s, C-7), 156.9 (s, C-6), 164.9 (s, C-9), 167.0 (s, OAc-1), 167.6
(s, OAc-2), 169.6 (s, OAc-7) ppm. UV/Vis: λEtOH = 194, 225, 256,
300, 323 nm. MS (FAB): m/z (%) = 431 (29) [[M + H]+], 389 (75)
[ M – C2 H2 O+ ] , 3 4 7 ( 3 5) , 3 0 4 ( 3 9) , 1 3 6 (1 00 ). HR MS
1,4,7,9-Tetraacetoxy-3-methoxy-6H-benzo[c]chromen-6-one (Acety-
lated Graphislactone F, Originally Proposed Structure, 36): The pre-
cursor synthesized as given above (17 mg, 0.028 mmol) was treated
with Pd/C (15 mol-%) according to general procedure 3. The crude
product was reacted after workup with Ac2O (32 µL, 0.34 mmol)
and anhydrous pyridine (27 µL, 0.34 mmol), and dissolved in anhy-
drous CH2Cl2 (5 mL). The mixture was stirred for 12 h at room
temperature under argon, concentrated, and purified by
chromatography (hexanes/EtOAc, 2:1) to yield acetylated graphis-
lactone F (36, 9.2 mg, 0.020 mmol, 71%) as a colourless solid; m.p.
1
16
(12C19 H17 O10, FAB): calcd. 389.0872; found 389.0869. Analytical
data are in full accordance with published data.[6d]
1,2,9-Tris(benzyloxy)-7-hydroxy-3-methoxy-6H-benzo[c]chromen-6-
one (40): Bromide 28 (204 mg, 0.490 mmol) and boronate 5
(263 mg, 0.640 mmol) were reacted for 2.5 h according to general
procedure 1. Chromatography (hexanes/EtOAc, 10:1) yielded prod-
uct 40 (98 mg, 0.18 mmol, 36%) as a colourless solid.
1,2,7,9-Tetraacetoxy-3-methoxy-6H-benzo[c]chromen-6-one (Acety-
lated Graphislactone F, Revised Structure, 42): Bisbenzyl ether 40
200–203 °C. R (hexanes/EtOAc, 1:1) = 0.09. IR (DRIFT): ν = 2940
˜
f
(m), 1772 (s, C=O), 1626 (s, C=O), 1608 (s, C=O), 1519 (m), 1438 (35 mg, 0.061 mmol) was treated with Pd/C (15 mol-%) according
(s), 1390 (m), 1367 (s), 1346 (m), 1239 (m), 1187, (s), 1139 (s) cm–1.
Assignment of NMR spectroscopic data was made according to
H,H-COSY, C,H-COSY, NOESY, and HMBC spectra. 1H NMR
to general procedure 3. The crude product was reacted after
workup with Ac2O (73 µL, 0.74 mmol) and anhydrous pyridine
(60 µL, 0.74 mmol), and dissolved in anhydrous CH2Cl2 (5 mL).
(600 MHz, CDCl3): δ = 2.36 (s, 3 H, 9-OAc), 2.41 (s, 3 H, 4-OAc), The mixture was stirred for 12 h at room temperature under argon,
2.42 (s, 3 H, 7-OAc), 2.47 (s, 3 H, 1-OAc), 3.90 (s, 3 H, 3-OMe),
concentrated, and purified by chromatography (hexanes/EtOAc,
2:1) to yield acetate 42 (21 mg, 0.047 mmol, 77%) as a colourless
solid; m.p. 208–210 °C. Rf (hexanes/EtOAc, 2:1) = 0.11. IR
4
6.70 (s, 1 H, 2-H), 7.00 (d, J = 2.2 Hz, 1 H, 8-H), 8.36 (d, 4J =
2.2 Hz, 1 H, 10-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 20.4
(q, OAc-4), 21.1 (q, 2 C, OAc-1 and 9), 21.4 (q, OAc-7), 56.5 (q,
OMe-3), 104.5 (s, C-2), 105.1 (s, C-10b), 110.7 (s, C-6a), 115.5 (d,
(DRIFT): ν = 1781 (s, C=O), 1764 (s, C=O), 1625 (s), 1609 (s),
˜
1427 (m), 1370 (s), 1350 (s), 1300 (m), 1200 (s), 1142 (s) cm–1.
C-10), 116.7 (d, C-8), 125.1 (s, C-4), 136.6 (s, C-10a), 145.1 (s, C- Assignment of NMR spectroscopic data was made according to
4a), 145.8 (s, C-1), 152.8 (s, C-3), 153.9 (s, C-7), 155.8 (s, C-6), H,H-COSY, C,H-COSY, and HMBC spectra. 1H NMR (600 MHz,
167.8 (s, OAc-9), 168.1 (s, OAc-4), 168.3 (s, OAc-1), 169.3 (s, OAc- CDCl3): δ = 2.33 (s, 3 H, 2-OAc), 2.35 (s, 3 H, 9-OAc), 2.43 (s, 3
7) ppm; the signal for C-9 is covered. UV/Vis: λEtOH = 195, 229,
H, 7-OAc), 2.46 (s, 3 H, 1-OAc), 3.91 (s, 3 H, 3 OMe), 6.85 (s, 1
4
251, 323 nm. MS (FAB): m/z (%) = 459 (23) [[M + H]+], 417 (38) H, 4-H), 6.99 (d, 4J = 2.2 Hz, 1 H, 8-H), 8.33 (d, J = 2.2 Hz, 1 H,
2138
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2130–2140

Total Synthesis of Several Graphislactones and Ulocladol
10-H) ppm. 13C NMR (101 MHz, CDCl3): δ = 20.2 (q, OAc-7),
7-Methoxy-5-(7-methoxy-5-methylbenzo[1,3]dioxol-4-yl)-2,2-dimeth-
20.6 (q, OAc-9), 21.0 (q, OAc-2), 21.4 (q, OAc-1), 56.5 (q, OMe- yl-4H-benzo[1,3]dioxin-4-one (45): A solution of bromide 44
3), 99.0 (d, C-4), 104.9 (s, C-10b), 110.8 (s, C-6a), 114.8 (d, C-10),
116.6 (d, C-8), 130.0 (s, C-2), 136.6 (s, C-10a), 141.1 (s, C-1), 150.2
(s, C-4a), 153.7 (s, C-3), 153.8 (s, C-7), 156.5 (s, C-6), 167.1 (s, OAc-
2), 167.5 (s, OAc-1), 167.7 (s, OAc-9), 169.2 (s, OAc-7) ppm. UV/
(39 mg, 0.16 mmol), boronate 4 (107 mg, 0.320 mmol), Cs2CO3
(158 mg, 0.485 mmol) and Pd(PPh3)4 (9.2 mg, 8.0 µmol) in anhy-
drous dioxane (5 mL) was stirred for 4 h under an argon atmo-
sphere at 95 °C. The mixture was concentrated and purified by
Vis: λMeOH = 221, 243, 278, 299, 328 nm. MS (FAB): m/z (%) = 459 chromatography (hexanes/EtOAc, 10:1) to yield 45 (49 mg,
(40) [[M + H]+], 417 (100). HRMS (12C22 H19 O11, FAB): calcd. 0.13 mmol, 83 %) as a white solid and reduced side product 6
1
16
459.0927; found 459.0932. Analytical data are in full accordance
(24 mg, 0.12 mmol).
with published data.[6d]
4,7-Dihydroxy-3,9-dimethoxy-1-methyl-6H-benzo[c]chromen-6-one
(Graphislactone A): BCl3 (1  in CH2Cl2, 3.5 mL, 3.5 mmol) was
Synthesis of Graphislactone C
4,7-Bis(benzyloxy)-1-hydroxymethyl-3,9-dimethoxybenzo[c]chromen- added dropwise at room temperature under argon to a solution of
6-one: DIBAL-H (1  in toluene, 0.20 mL, 0.20 mmol) was added
dropwise at –78 °C with exclusion of air and moisture to a solution
of aldehyde 33 (50 mg, 0.10 mmol) in anhydrous THF (6 mL). The
reaction was quenched after stirring for 2 h at –78 °C by addition
of aqueous HCl (1 , 2 mL) and H2O (3 mL). The mixture was
extracted with EtOAc (3ϫ3 mL), and the organic layers were dried
(Na2SO4), concentrated and purified by chromatography (CH2Cl2/
MeOH, 50:1) to yield the title compound as a colourless solid
(35 mg, 0.07 mmol, 70%).
45 (110 mg, 0.295 mmol) in anhydrous CH2Cl2 (10 mL). The yel-
low-turning solution was stirred for 24 h, MeOH (5 mL) was
added, and the mixture was stirred for an additional 2 h and con-
centrated. The brownish residue was purified by chromatography
(CH2Cl2/MeOH, 10:1) and by MPLC (CH2Cl2) to yield graphislac-
tone A (35 mg, 0.12 mmol, 39 %); m.p. 221–223 °C (ref.[6a] 236–
237 °C; ref.[6e] 220–225 °C). Rf (CH2Cl2/MeOH, 40:1) = 0.16. IR
(KBr): ν = 3092 (m), 2987 (m), 2949 (m), 2853 (m), 1742 (m), 1657
˜
(m), 1638 (m), 1575 (m), 1462 (m), 1446 (m), 1376 (m), 1345 (m),
1303 (m), 1236 (m), 1184 (m), 1148 (m), 1046 (m), 989 (m), 966
4,7-Dihydroxy-1-hydroxymethyl-3,9-dimethoxybenzo[c]chromen-6-
one (Graphislactone C): Protected graphislactone C as synthesized
above (16 mg, 0.03 mmol) in EtOAc (3 mL) was deprotected ac-
cording to general procedure 3 at room temperature overnight,
yielding graphislactone C as a colourless solid (8.00 mg,
0.025 mmol, 79%); m.p. 213–215 °C. Rf (CH2Cl2/MeOH, 20:1) =
1
(m), 838 (m), 794 (m), 707 (m), 669 (m), 611 (m) cm–1. H NMR
(400 MHz, [D6]DMSO): δ = 2.70 (s, 3 H, ArMe), 3.88 (s, 3 H,
4
OMe), 3.90 (s, 3 H, OMe), 6.60 (d, J = 2.2 Hz, 1 H, ArH), 6.92
4
(s, 1 H, ArH), 7.20 (d, J = 2.2 Hz, 1 H, ArH), 9.24 (s, 1 H, OH),
11.87 (s, 1 H, OH) ppm. 13C NMR (101 MHz, [D6]DMSO): δ =
24.6 (q), 55.7 (q), 55.9 (q), 98.4 (s), 99.4 (d), 103.8 (d), 110.5 (s),
112.9 (d), 126.1 (s), 132.3 (s), 137.9 (s), 140.6 (s), 148.1 (s), 164.0
(s), 164.4 (s), 166.0 (s) ppm. UV/Vis: λMeOH = 200, 235, 259, 285,
297, 338 nm. MS (EI, 70 eV): m/z (%) = 302 (2) [M+], 276 (8),
274 (8) [[M – CO]+], 245 (20), 243 (21), 58 (38), 43 (100). HRMS
0.54. IR (DRIFT): ν = 3326 (s, OH), 3142 (s, OH), 1663 (s, C=O),
˜
1609 (s), 1585 (m), 1471 (m), 1413 (s), 1325 (s), 1249 (s), 1123 (s)
cm–1. Assignment of NMR spectroscopic data was made according
to H,H-COSY, C,H-COSY, and HMBC spectra. 1H NMR
(400 MHz, CDCl3): δ = 3.91 (s, 6 H, 2 OMe), 4.78 (d, 3J = 4.9 Hz,
1
(12C16 H1416O6, EI, 70 eV): calcd. 302.0790; found 302.0794. Ana-
3
4
2 H, CH2OH), 5.65 (t, J = 4.9 Hz, 1 H, CH2OH), 6.66 (d, J =
lytical data are in full accordance with published data.[6a]
4
2.1 Hz, 1 H, ArH), 7.18 (s, 1 H, 2-H), 7.62 (d, J = 2.1 Hz, 1 H,
ArH), 9.48 (s, 1 H, 4-OH), 11.76 (s, 1 H, 7-OH) ppm. 13C NMR
(101 MHz, CDCl3): δ = 56.3 (q), 56.6 (q), 63.6 (t), 99.2 (s), 100.5
(d), 105.2 (d), 111.8 (s), 112 (d), 129.8 (s), 133.9 (s), 137.5 (s), 140.9
7-Hydroxy-3,4,9-trimethoxy-1-methyl-6H-benzo[c]chromen-6-one
(Graphislactone H): Graphislactone A (3.6 mg, 12 mmol) was dis-
solved in CH2Cl2/MeOH (1:2, 3 mL). A solution of CH2N2 (Cau-
tion!) in Et2O (0.4 ) was added in portions of 50–100 µL, each
addition followed by stirring for 3 min. After addition of 475 µL,
the reaction was complete (monitoring with tlc), and the solvents
(s), 148.6 (s), 164.3 (s), 164.9 (s), 166.9 (s) ppm. UV/Vis: λMeOH
=
193, 235, 259, 288, 299, 340 nm. MS (FAB): m/z (%) = 319 (20)
1
[[M + H]+], 217 (45), 136 (68). HRMS (12C16 H1516O7, FAB): calcd.
319.0818; found 319.0815. Analytical data are in full accordance
were removed in vacuo, yielding graphislactone
12 mmol, quant.) as a pale yellow solid; m.p. 179–181 °C (ref.[7]
165–166 °C). R (CH Cl /MeOH, 40:1) = 0.57. IR (KBr): ν = 2965
H (3.7 mg,
with published data.[6a]
Synthesis of Graphislactones A and H
˜
f
2
2
(m), 2941 (m), 2845 (m), 1734 (s), 1664 (m), 1626 (s), 1603 (s), 1581
(s), 1519 (m), 1459 (m), 1441 (m), 1402 (m), 1350 (m), 1315 (m),
1297 (m), 1275 (m), 1248 (s), 1212 (s), 1164 (m), 1140 (s), 1115 (m),
1070 (m), 1024 (m), 1000 (m), 987 (m), 970 (m), 896 (m), 831 (m),
800 (m), 781 (m), 702 (m), 675 (m), 651 (m), 586 (m), 542 (m), 504
O-[(4-Bromo-7-methoxybenzo[1,3]dioxol-5-yl)methyl] S-Methyl Di-
thiocarbonate (43): NaH (60%, 97 mg, 2.25 mmol) was added at
room temperature to a solution of 11 (307 mg, 1.18 mmol) in anhy-
drous THF (9 mL), and the mixture was stirred for 30 min. CS2
(15 mL, 2.4 mmol) was added, and the yellow-turning mixture was
stirred for 1 h. MeI (0.45 mL, 7.23 mmol) was added, and the mix-
ture was stirred for 45 min, diluted with CH2Cl2 (15 mL), carefully
(!) extracted with H2O (30 mL), dried (Na2SO4) and concentrated.
The resulting yellow solid was purified by chromatography (hex-
anes/EtOAc, 4:1) to yield xanthogenate 43 (374 mg, 1.06 mmol,
91%) as a white solid.
1
(m) cm–1. H NMR (400 MHz, CDCl3): δ = 2.80 (s, 3 H, ArMe),
3.91 (s, 3 H, OMe), 3.95 (s, 3 H, OMe), 3.96 (s, 3 H, OMe), 6.55
(d, 4J = 2.1 Hz, 1 H, ArH), 6.73 (s, 1 H, ArH), 7.24 (d, 4J = 1.9 Hz,
1 H, ArH), 11.95 (s, 1 H, OH) ppm. 13C NMR (101 MHz, CDCl3):
δ = 25.8 (q), 55.7 (q), 56.1 (q), 61.5 (s), 99.1 (d), 99.2 (s), 104.8 (d),
111.7 (s), 112.9 (d), 131.7 (s), 135.2 (s), 137.9 (s), 146.0 (s), 152.6
(s), 164.9 (s), 165.2 (s), 166.3 (s) ppm. UV/Vis: λMeOH = 200, 224,
258, 287, 397, 339 nm; λCHCl3 = 231, 260, 288, 298, 332, 342 nm.
4-Bromo-7-methoxy-5-methylbenzo[1,3]dioxole (44): A solution of
Bu3SnH (3.22 mL, 11.6 mmol) and AIBN (161 mg, 0.74 mmol) in
toluene (50 mL) was added at 85 °C to a degassed solution of 43
(2.57 g, 7.31 mmol) in toluene (50 mL), and the solution was stirred
for 40 min at this temperature. After cooling to room temperature,
the mixture was concentrated and purified by chromatography
(hexanes/EtOAc, 4:1) to yield 44 as a white solid (1.49 g,
6.08 mmol, 83%).
1
MS (FAB): m/z = 317 [[M + H]+]. HRMS (12C17 H1616O6, EI,
70 eV): calcd. 316.0947; found 316.0949. Analytical data are in full
accordance with published data.[7]
Supporting Information (see also the footnote on the first page of
this article): Detailed NMR spectroscopic data of originally pro-
posed and revised structures of graphislactones E and F. X-ray
Eur. J. Org. Chem. 2009, 2130–2140
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2139

J. Podlech, et al.
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Received: December 22, 2008
Published Online: March 12, 2009
2140
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Eur. J. Org. Chem. 2009, 2130–2140