What Is the Structure of the Antitubercular Natural Product Eucapsitrione?

Article abstract of DOI:10.1021/acs.joc.7b00863

1,5,7-Trihydroxy-6H-indeno[1,2-b]anthracene-6,11,13-trione (1), proposed to be the antitubercular natural product eucapsitrione, has been synthesized in 43% overall yield and six steps, including a key Suzuki-Miyaura biaryl coupling and a directed remote

Full text of DOI:10.1021/acs.joc.7b00863

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Article
What is the Structure of the Antitubercular Natural Product Eucapsitrione?
Glenn A. Pullella, Duncan Andrew Wild, Gareth L. Nealon, Mikhail Elyashberg, and Matthew J. Piggott
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00863 • Publication Date (Web): 21 Jun 2017
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What is the Structure of the Antitubercular Natural Product Eucapsitrione?
†
†
‡
₽
Glenn A. Pullella, Duncan A. Wild, Gareth L. Nealon, Mikhail Elyashberg and Matthew
†
J. Piggott *
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†
Chemistry, School of Molecular Sciences, University of Western Australia, Perth, Australia
‡
Centre for Microscopy, Characterisation and Analysis, University of Western Australia,
Perth, Australia
₽
Moscow Department, Advanced Chemistry Development Ltd., 6 Akademik Bakulev St.,
Moscow 117513, Russian Federation
*
Corresponding author: Eꢀmail: matthew.piggott@uwa.edu.au
Table of Contents/Abstract Graphic
Suzuki−Miyaura
OH
O
HO
HO
O
DReM/cyclisation
O
not eucapsitrione!
ABSTRACT
,5,7ꢀTrihydroxyꢀ6Hꢀindeno[1,2ꢀb]anthraceneꢀ6,11,13ꢀtrione (1), proposed to be the
1
antitubercular natural product eucapsitrione, has been synthesised in 43% overall yield, and
six steps, including a key Suzuki–Miyaura biaryl coupling and a directed remote metalation
(DReM)ꢀinitiated cyclisation. The physical and spectroscopic properties of 1 do not match
the data reported for the natural product. At this time there is insufficient information
available to enable a structure reassignment. During the optimization of the Suzuki–Miyaura
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coupling an unprecedented biaryl coupling ortho to the borono group was observed. The
scope of this unusual reaction has been investigated.
INTRODUCTION
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In 2010, an investigation of a cyanobacterium of the previously unexplored genus Eucapsis
1
was conducted with the aim of isolating and identifying new antitubercular agents. The study
led to the isolation of a novel natural product, which was named eucapsitrione and assigned
1
structure 1 (Scheme 1) on the basis of spectroscopic and mass spectrometric data.
Scheme 1. The proposed structure 1 of eucapsitrione and anomalous NMR data compared to
chrysazin (2), a potential precursor for total synthesis.
6
.59 ppm
11.98 ppm
177.2 ppm
OH
O
HO
OH
O
HO
5
162.3 ppm
HO
O
O
O
1
2
Eucapsitrione exhibits potent activity against rapidly growing M. tuberculosis with a
minimum inhibitory concentration of 3.1 ꢁM. Importantly, the natural product was also
2
active at a similar concentration in the lowꢀoxygenꢀrecovery assay (LORA), which has been
developed to mimic the nonꢀreplicating persistent (NRP) state that makes tuberculosis (TB)
3
difficult to treat, and contributes to antimicrobial resistance in M. tuberculosis. Conversely,
eucapsitrione did not affect the viability of Staphylococcus aureus, Escherichia coli, Candida
albicans, or Mycobacterium smegmatis at 55 ꢁM, and had an IC50 >28 ꢁM against the
mammalian Vero cell line, suggesting a mode of action that is selective for M. tuberculosis.
These properties make eucapsitrione a promising lead for the discovery of novel drugs for the
4
ꢀ8
treatment of TB infection, as noted in several reviews. In addition, no fluorenones, and
9
only a few anthraquinones, have ever been isolated from a cyanobacterium. Indeed, the
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fused pentacyclic 6Hꢀindeno[1,2ꢀb]anthraceneꢀ6,11,13ꢀtrione skeleton of 1 is unique amongst
natural products. Thus, 1 was an attractive candidate for synthesis.
Our interest in eucapsitrione was further piqued because several of the natural product’s
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spectroscopic data did not seem to fit the proposed structure. Most noticeable amongst these
1
was the assignment of a signal at 6.59 ppm in the H NMR spectrum (in d
6
ꢀDMSO) to the C5
phenolic proton. Such protons, peri to carbonyl groups, are typically strongly hydrogenꢀ
bonded and thus resonate considerably downfield of nonꢀhydrogen bonded phenols. For
example, in chrysazin (2) (Scheme 1), the analogous protons resonate at 11.98 ppm in d6ꢀ
13
DMSO. Furthermore, a signal in the C NMR spectrum of eucapsitrione at 177.2 ppm was
10
assigned to C5. Such carbons generally resonate in the range 150–160 ppm. Indeed, the
11
corresponding carbons of chrysazin (2) give rise to a signal at 162.3 ppm (Scheme 1).
−1
The report that 1 produces only one carbonyl absorption band in its IR spectrum (1616 cm )
also seemed incongruous with the proposed structure. The absorption frequency of a carbonyl
group is typically lowered when hydrogenꢀbonded to a peri phenolic proton, as evident in the
−1 12
infrared spectrum of chrysazin (2, 1678 and 1621 cm ),
and related αꢀ
As such it would be reasonable to expect the structure 1 to give
rise to at least two distinct carbonyl absorption bands. It is also worth noting that the exact
12,13
hydroxyanthraquinones.
–
1
mass determined for eucapsitrione [M–H] (357.04291) is 6.7 ppm out from the calculated
–
mass (357.0405) of the C21
H
9
O
6
ion, raising some doubt about the molecular formula.
The irregularities in the mass spectrometric and spectroscopic data discussed above suggested
that the proposed structure 1 required validation.
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RESULTS AND DISCUSSION
Synthesis of the ring system represented by 1 has only been reported a handful of times, often
14,15
16
without substitution;
otherwise, substituted derivatives have been produced in low yield
1
7
and as reaction byproducts. With no existing practical routes upon which to base the
synthesis of the structure 1, two novel pathways were devised beginning from the cheap and
readily available chrysazin (2) (Scheme 1).
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The first approach is outlined in Scheme 2. The known iodide 3, prepared simply in two steps
18,19
from chrysazin (2),
was subjected to a Heck reaction with methyl acrylate, under standard
20
conditions, initially providing a mixture of the expected coupling product 4 and the
corresponding phenol 5 resulting from deacetylation. Deprotection of the phenol was actually
desired, and was forced to completion by addition of water to the reaction mixture once the
Heck coupling was complete, affording 5 exclusively, in excellent yield. Our intention was to
effect a regioselective Diels–Alder cycloaddition of 5 with 2ꢀmethoxyfuran to provide adduct
7a, which we assumed would aromatise upon acidic workup to give the biaryl 8a. Subsequent
electrophilic ring closure could then provide access to 1.
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Scheme 2. An unsuccessful approach to eucapsitrione involving key Heck and Diels–Alder
reactions.
O
OH
O
OAc
O
OH
O
OR
I
O
O
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1. Pd(OAc)
2
NEt
3
, MeCN
O
O
2
. H
2
O
3
4, R = Ac
, R = H (96%)
5
O
O
1
. NaOH
OH
O
OH
MeOH/dioxane 82%
+
O
3
2. H O
O
O
OR
O
O
O
7a, R = Me
b, R = H
7
O
OH
OH
O
OH
OH
HO
+
3
H O
O
6
OH
O
O
OH
O
O
O
OR
HO
O
O
8
a, R = Me
8b, R = H
1
21ꢀ24
Although 2ꢀmethoxyfuran reacts readily with very good dienophiles,
and with some less
2
5
electronꢀdeficient dienophiles in the presence of Lewis acid catalysts, our attempts to
induce a Diels–Alder reaction with 5 were unsuccessful. Heating the pair under reflux in
toluene led to partial decomposition of 2ꢀmethoxyfuran and no trace of a Diels–Alder adduct
1
by H NMR spectroscopy.
It was reasoned that addition of a Lewis acid catalyst may be able to activate the dienophile
through coordination to both the ester carbonyl group and chelation with the anthraquinone
carbonyl/peri hydroxy moiety in 5, the latter mitigating the electronꢀdonating effects of the
phenol. With multiple potential coordination sites in the dienophile 5, experiments were
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therefore conducted in the presence of both subꢀ and superꢀstoichiometric quantities of Lewis
acids, and a range of temperatures. The attempted Diels–Alder reaction of 5 in the presence
26ꢀ29
of Yb(OTf)3;
4
a silicaꢀsupported TiCl ꢀbased catalyst that has been used previously with
2
5
2
ꢀmethoxyfuran; and phenylboronic acid, which was expected to form a chelate borate
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complex with αꢀhydroxyquinone moiety;
decomposition of the diene.
were all unsuccessful, leading only to
Arylboronic acids have successfully catalysed a number of Diels−Alder cycloadditions of
31,32
furan, though where the dienophile is an α,βꢀunsaturated carboxylic acid.
In these cases,
orthoꢀbromoꢀ and ꢀiodobenzeneboronic acids are noted as being amongst the most effective
31ꢀ33
catalysts,
and the carboxylic acid group of the dienophile is key to their mode of
31,34,35
activation.
Thus the acrylic acid 6 was prepared and, the cycloaddition with 2ꢀ
methoxyfuran was attempted in the presence of orthoꢀbromobenzeneboronic acid. The
reaction was first tried in 1,2ꢀdichloroethane (DCE); however, 6 is poorly soluble in DCE and
32
other solvents compatible with arylboronic acid catalysis, so, lastly, solventꢀfree
experiments with a tenꢀfold excess of diene were attempted. In all cases, only decomposition
of 2ꢀmethoxyfuran was observed with no evidence for a Diels–Alder reaction.
With further experimentation, and judicious choice of catalyst, and/or phenol protecting
groups that render the dienophile more electronꢀdeficient, it may have been possible to
achieve the desired cycloaddition. However, with no indication of any cycloadduct formation
across all attempts, an alternative synthetic pathway was pursued.
In the second, and ultimately successful synthetic route to 1, a Suzuki−Miyaura crossꢀ
coupling of iodide 3 was used to construct the key biaryl bond (Scheme 3 and Table 1).
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Initially the boronic acid 9a, derived via directed orthoꢀlithiation/borylation of the
corresponding diisopropylamide, was investigated for this purpose.
Suzuki−Miyaura coupling of halophenols can be carried out under very convenient
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3
7,38
conditions (aqueous K CO , Pd/C),
and we thought these should be applicable to the
2
3
current synthesis. Following workꢀup and chromatography, the reaction of boronic acid 9a
1
with iodide 3 under these conditions yielded a product that displayed twice the number of H
NMR resonances expected of biaryl 11a. Initially, this observation was tentatively attributed
to atropisomerism about the biaryl and arylꢀcarboxamide bonds, giving rise to a mixture of
1
diastereomers. A simplification of the H NMR spectrum of this material at high temperature
would have confirmed our hypothesis; however, there was little change in the spectrum on
heating. Similarly, cleavage of the very bulky diisopropylamide should lead to a simplified
1
H NMR spectrum in the resulting carboxylic acid if atropisomerism was at play, but the
amide was remarkably resistant to hydrolysis under basic conditions, with only starting
material recovered after nine days of heating under reflux in 1 M NaOH/dioxane.
An attempt to effect hydrolysis under strongly acidic conditions instead resulted in a mixture
3
9
of products arising from Nꢀdealkylation. Analysis of this mixture made it clear that our
atropisomerism hypothesis was incorrect and, rather, the Suzuki–Miyaura coupling had
produced two constitutional isomers. Two of the products isolated from this reaction
1
appeared, by H NMR spectroscopy, to possess a 1,2,4ꢀtrisubstituted benzene moiety.
Ultimately, NOESY and 2D NMR spectroscopic experiments confirmed the unexpected
substitution pattern in compounds 13 and 14 (Scheme 3).
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This revelation prompted a reinvestigation of the Suzuki–Miyaura coupling of 3 and 9a, and
careful preparative TLC allowed the separation of the two isomeric products of this reaction.
Thus, in addition to the expected biaryl 11a, this reaction gave the minor regioisomer 12a,
which must arise from direct arylation of the aromatic methine para to the methoxy group – a
process which must either be preceded or followed by a deboronation step in order to furnish
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12a.
Scheme 3. Suzuki coupling of iodide 3 and boronic acid 9a produces two regioisomers 11a
and 12a, discovered after isolation of the Nꢀdealkylation products 13 and 14. Yields of 11a
and 12a are NMR yields.
OH
O
OAc
I
O
B(OH)
2
+
i-Pr
2
N
O
O
9
a
3
10% Pd/C (2 mol%)
K
2
CO , H O, reflux
3
2
O
N
OH
O
O
OH
OH
O
O
OH
O
O
+
i-Pr
2
N
O
R1
R2
1
1a (54%)
12a, R
1
= R
2
= i-Pr (18%)
H
3
O+
1
1
1
3, R = H, R2 = i-Pr (33%)
4, R = R2 = H (21%)
1
40ꢀ49
Reports of Pd/Cꢀcatalysed C−H activations,
whilst still relatively uncommon, have
become more prevalent in recent years, as palladium on carbon is being applied to
5
0ꢀ
transformations previously reserved for more complicated homogeneous catalytic systems.
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53ꢀ58
Amongst these, direct arylations remain limited,
and are rarely reported for nonꢀ
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heteroaromatic systems. The formation of a significant proportion of 12a from the reaction
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of 3 and 9a under simple conditions therefore presented as an interesting side reaction worth
investigating further (Table 1).
The Suzuki–Miyaura reaction conditions were applied to 2ꢀiodochrysazin (10a), which
confirmed that the direct arylation to give 12a was not an aberration, and that the acetyl
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group of 3 likely has no role in the reaction (entry 2). These initial experiments revealed that
60ꢀ62
9a is readily deboronated under the reaction conditions,
as a significant quantity of amide
9b was observed in the crude reaction product in both cases. Therefore, to assess the
importance of the borono group, the arylation with 9b was attempted (entry 3). This reaction
gave only a trace of biaryl 12a. Whilst this result is informative, hinting at a mechanism
involving electrophilic attack at the most activated positon paraꢀto the methoxy substituent in
both 9a and 9b, the increased yield of 12a in entry 1 suggests that the borono group directs
orthoꢀarylation of 9a, prior to deboronation. To the best of our knowledge, this
*
transformation is unique amongst metalꢀcatalysed arylation reactions.
*
63
However, a similar transformation has been achieved with a hypervalent iodine.
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1
1
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2
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2
2
2
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5
5
5
5
5
6
Table 1. Scope and mechanism investigation of the direct arylation of arylboronic acid 9a
and related compounds.
i-Pr
2
N
1
.3 eq.
O
O
O
1
0% Pd/C (2 mol%)
OH
OH
O
Ar-I
+
O
X
O
R
Ar
+
2
R N
B
K
2
CO
3
(4 eq.), H
2
O
Ar
O
O
O
OH
R
2
N
O
reflux, 72 h
2
N
O
I
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
or 10
9a, R = i-Pr, X = B(OH)
b, R = i-Pr, X = H
2
11
12
9
1
5
9
c, R = Et, X = B(OH)
2
a
a
Entry
Iodide
9
11
Yield %
12
Yield %
b
1
3
9a
11a
54
12a
18
OH
O
OH
I
2
9a
9b
11a
54
−
12a
12a
13
2
O
10a
3
11a
O
O
O
O
OAc
O
O
OH
O
O
O
OH
I
2
i-Pr N
O
i-Pr
3
4
9a
9a
−
−
2
N
O
O
12b
11b
O
1
0b
O
O
OH
I
11b
−
12b
−
2
O
1
0c
OH
O
O
OH
O
OH
O
OH
O
79
86 (82)
2
Et N
5
6
7
3
9c
9a
9a
c
c
1
Et N
O
O
2
1
1c
1
2c
O
OH
OH
O
I
OH
O
56 (51)
i-Pr
2
N
−
−
i-Pr
2
N
O
O
O
10d
1
1d
12d
12e
OH
OH
I
OH
NO
O
i-Pr N
2
7
i-Pr
2
N
O
O
NO
2
1
1e
NO
2
1
0e
2
OH
O
OH
O
O
I
OH
O
O
O
OH
OH
2
i-Pr N
8
9
O
9a
60
OH
OH
−
i-Pr2N
O
O
O
11f
O
12f
1
0f
O
d
10de
10d
9a
9a
11d
11d
21
51
12d
12d
−
−
1
0
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9
a
1
Yields determined by H NMR spectroscopy using 1,3,5ꢀtrimethoxybenzene as an internal
b
c
standard. Reaction time 7 d instead of 72 h. 3 mol % of Pd/C used, reaction time 36 h
d
e
instead of 72 h. BQ (1 eq.) added to the reaction mixture. Chrysazin (1 eq.) added to the
reaction mixture.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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45
46
47
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50
51
52
53
54
55
56
57
58
59
60
The regioselectivity of the reaction, and prevalence of intramolecular direct arylation
64ꢀ69
reactions in the literature,
suggest that the borono substituent is acting as a directing
group, perhaps via an intermediate phenyl boronate such as 15. Protection of the free
hydroxyl of iodide 3 should preclude formation of such an intermediate, and so the methyl
7
0
ethers 10b and 10c were prepared (entries 3 and 4). Unfortunately, neither iodide 10b nor
0c underwent any reaction with 9a, (i.e. the normal Suzuki–Miyaura coupling was also
1
completely supressed), providing no insight into the mechanism by which the borono
substituent activates the ortho position.
Before conducting more intensive investigations regarding the mechanism of this direct
arylation, the scope of the reaction was probed. It was apparent from the reaction of the less
hindered N,Nꢀdiethylamidoboronic acid 9c that the extremely bulky substituent ortho to the
boronic acid is required for the direct arylation to compete with conventional crossꢀcoupling
as only a trace of the direct arylation product 12c was observed (entry 5). The hindered
boronic acid 9a was therefore retained in subsequent reactions with selected alternative aryl
iodides 10d−f. The reaction of 2ꢀiodophenol (10d) gave only the expected Suzuki–Miyaura
coupling product 11d in modest yield (entry 6). This suggested that the anthraquinone moiety
in the iodochrysazins 3 and 10a played a role in the direct arylation reaction. The carbonyl
groups in the anthraquinones enhance the acidity of the phenolic hydroxyl, decrease the
electron density of the aryl iodide and provide some steric encumbrance. We thus chose other
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
iodides that mimicked these properties. 4ꢀNitroꢀ2ꢀiodophenol (10e) gave only a low yield of
the normal Suzuki–Miyaura product 11e (entry 7), indicating that enhanced phenol acidity is
not sufficient to promote direct arylation. The Suzuki–Miyaura coupling of dimethyl
iodophthalate 10f, which should quite closely mimic the stereoelectronic properties of the
iodochrysazins, was accompanied by saponification to give the phthalic acid 11f, but again,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
no direct arylation product 12f was observed (entry 8). The importance of oxidative
71,72
properties of the chrysazin anthraquinone moiety
benzoquinone (BQ) promotes a variety of C−H activations,
of 3 were also considered;
73ꢀ75
and so was also tested as an
additive in the reaction with 2ꢀiodophenol (entry 9), but this only led to a reduction in yield of
the expected Suzuki–Miyaura product 11d. And, finally, addition of an equivalent of
chrysazin (2) to the experiment with 2ꢀiodophenol (10d) had no significant effect on the
outcome of that reaction.
Thus, while an interesting diversion, the scope of this direct arylation appears to be limited.
Moreover, the sideꢀreaction detracted from the efficiency of the desired synthesis of 1.
Fortunately, the Suzuki−Miyaura coupling of iodide 3 with the less hindered N,Nꢀ
diethylamide 9c produced biaryl 11c in good yield with only traces of the undesired direct
arylation product. The yield of 11c was improved simply by increasing the loading of Pd/C to
3 mol%, which furnished the biaryl in 82% isolated yield.
With a good yield of the biaryl intermediate 11c in hand, our attention turned to the end game
(
Scheme 4). Cyclisation of 11c via an electrophilic mechanism (e.g., Friedel−Crafts
acylation) was considered, but predicted to be troublesome for several reasons. The amide is
not reactive enough, and hydrolysis was likely to be very difficult. In addition, acylation
would be required at the deactivated 3ꢀposition on the pendant anthraquinone moiety.
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9
Therefore, we set out to employ the powerful directing ability of the diethylamido group of
76ꢀ79
11c in a directed remote metalation (DReM).
Literature precedents suggested that both
the phenolic hydroxyls and quinone carbonyl groups of 11c required protection for a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
6,78
successful DReMꢀinitiated cyclisation.
ether 16, and treated with excess LDA a drastic colour change resulted, but returned only
starting material on workꢀup. A subsequent D O quench experiment revealed that no
lithiation of 16 had occurred. It was reasoned that LDA was reducing the quinone through αꢀ
Indeed, when 11c was converted to the dimethyl
2
80
hydride transfer, and the hydroquinone dianion was responsible for the intense colour.
Lithium hexamethyldisilazide (LHMDS) or lithium 2,2,6,6ꢀtetramethylpiperidide (LTMP)
cannot effect reduction through this mechanism; however, treatment of 16 with these bases
delivered the same results as treatment with LDA. We surmise that the lithium amide bases
form an electronꢀtransfer complex with 16 in a similar manner to alkyllithiums with
8
1
quinones, resulting in a colour change but no apparent reaction post workꢀup.
Relenting, we prepared the anthracene 17 in excellent yield by reductive methylation of 16
82
(
Scheme 4). Methyl tosylate proved to be as effective as dimethyl sulfate for this reaction,
which was fortunate given the scheduling of the latter. DReM−cylisation of 17 proceeded
smoothly, though attempts to purify fluorenone 18 resulted in significant degradation – likely
83,84
via photooxidation to its corresponding endoperoxide
– and as a result it was not isolated.
85
Instead, freshly prepared, crude 18 was subjected to global demethylation, and aerial
86
oxidation furnished the target structure 1 in modest yield across two steps from 17. The
remarkably poor solubility of 1 complicated purification, contributing to the low yield.
Therefore, oxidative demethylation of crude 18, followed by demethylation of 19 proved a
more convenient and higher yielding route to 1.
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 4. Completion of the total synthesis of the proposed structure 1 of eucapsitrione, by
DReM/cyclisation and deprotection.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OH
O
OH
O
O
O
O
O
O
O
O
Na
2 2 4
S O , NaOH
MeI, K
DMF
2%
2 3
CO
MeOTs, TBAC
O
O
O
2
THF, H O
Et
2
N
O
Et
2
N
O
Et
2
N
O
O
9
94%
11c
16
17
base (6 eq.)
THF, −50°C → r.t.
LDA (6 eq.)
THF, −50°C → r.t.
OH
O
O
OH
O
O
O
O
O
O
O
O
HBr
AcOH, reflux
1%
AgO, HNO
3
HO
O
dioxane
O
O
O
O
9
66%
1
19
, PhNO
(2 steps)
18
1
. AlCl
3
2
; 2. air
30% (2 steps)
The first empirical evidence indicating that 1 does not represent the structure of the natural
product eucapsitrione relates to solubility. The spectroscopic data for the natural product
were obtained in d ꢀDMSO, a solvent in which the synthetic material was practically
6
1
insoluble. Even at elevated temperature, a H NMR spectrum of 1 in DMSO could not be
obtained, thus a direct comparison of synthetic 1 with the natural product could not be
5
achieved. The recalcitrant insolubility of 1 forced us to acquire NMR spectra in d ꢀpyridine.
1
3
C resonances are typically less solvent dependent than those for protons, and occur over a
8
7,88
13
wide spectral range;
thus, comparison of the C NMR spectrum of 1 with that of the
1
natural product (Figure 1) is more useful than comparing H NMR resonances, though the
latter is included for completeness (Table 2). To estimate the effect of the solvent on the
13
NMR chemical shifts of 1, chrysazin (2) was used as a comparator. Indeed the C resonances
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1
1
of chrysazin in d ꢀpyridine and in d ꢀDMSO were very similar, having a mean absolute
5
6
difference of 0.3 ppm, and a maximum difference of 0.7 ppm (Table S1).
13
The C NMR spectroscopic data obtained for 1 vary significantly from those reported for
eucapsitrione, with the majority of the resonances differing by > 0.7 ppm (the maximum
solventꢀdependent difference observed with chrysazin) (Table S1), and a number even
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
deviating by > 5 ppm (Figure 1). As predicted, 1 does not give rise to a resonance close to
13
1
77.2 ppm, the signal in the C NMR spectrum of eucapsitrione that raised our suspicions
about the assigned structure of the natural product.
3
4
OH
O
OH
2
5
7
8
9
6
1
13
11
HO
1
2
10
O
O
1
13
1
Figure 1. C NMR chemical shift differences between eucapsitrione (d
synthetic 1 (d ꢀpyridine). The mean |ꢂδ| is 3.7 ppm and the maximum is 14.0 ppm. A C
NMR resonance of C11a or C12a in 1 could not be experimentally observed (ND = No Data);
6
ꢀDMSO) and
13
5
1
3
it is likely obscured by the solvent peak at 136.5−135.5 ppm based upon C NMR chemical
shift predictions (see Table S2 and experimental for 1), and so was excluded from these shift
difference calculations.
1
Although less meaningful, comparison of the H NMR data (Table 2) did reveal a particularly
significant discrepancy. The distinctive singlet at 8.34 ppm, arising from H12, peri to two
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
carbonyl groups in 1, is reported to appear much further upfield at 7.15 ppm in
1
eucapsitrione.
1
1
Table 2. H NMR and IR spectroscopic data for 1 versus those reported for eucapsitrione.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
−1 a
H NMR (ppm)
IR (νmax cm )
b, c
b
1
1
1
(d ꢀpyr)
1 (CDCl
3
)
eucapsitrione
(d ꢀDMSO)
6
1
eucapsitrione
5
d
e
1
2.48 (s, OH)
13.99 (s, OH)
3380
1696
1669
1628
e
1
1.95 (s, OH)
13.28 (s, OH)
e
8
.39 (s, OH)
8
.34 (s)
8.16 (s)
7.60 (t)
1616
1559
1457
1372
1331
1273
1210
1152
7.91 (dd)
7.89 (dd)
7.75 (dd)
7.56 (m)
7.56 (m)
7.52 (dd)
7.15 (s)
7
7
.78 (d)
.67 (app. t) 7.60 (dd)
7.51 (dd)
7.49 (dd)
7.35 (dd)
6.88 (dd)
7
7
.39 (d)
.13 (d)
7.14 (dd)
7.12 (dd)
6.59 (s, OH)
a
b
c
Neat, ATR 500 MHz. Exchangeable protons not observed due to exchange with residual
89 d
e
D
2
O.
600 MHz. Confirmed by deuterium exchange experiment.
In contrast the NMR spectroscopic data, the infrared spectra are directly comparable, and the
spectrum of synthetic 1 shows considerable disparity with that of eucapsitrione (Table 2). As
predicted, 1 gives rise to three distinct carbonyl absorption bands. The absorptions at 1669
−1
and 1628 cm are, respectively, characteristic of the free and hydrogenꢀbonded carbonyl
1
2,13
−1
groups of an αꢀhydroxyanthraquinone.
The remaining peak at 1696 cm is therefore
attributed to the fluorenone carbonyl group. The lack of an absorption band at this frequency
in the IR spectrum of eucapsitrione suggests that it is not a fluorenone.
Though the discrepancies between their physical and spectroscopic properties are already
strong evidence that eucapsitrione does not possess structure 1, the inability to directly
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3
compare the NMR spectroscopic data is rather unsatisfying. Accordingly, the C NMR
frequencies for 1 in DMSO solution were calculated.
To determine a suitable computational methodology to apply to 1, chrysazin (2) reprised its
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
role as a standard, as the experimental C NMR spectrum could be compared with calculated
frequencies (Table 3). Several methodology and basis set combinations were employed for
these calculations, of which HF 6ꢀ31G* proved to be the most accurate for chrysazin (2),
13
giving a mean absolute difference between calculated and experimental C shifts of 2.9 ppm,
and a maximum difference of 7.0 ppm.
1
3
Table 3. Comparison of experimental and calculated C NMR chemical shifts for chrysazin
(
2).
1
1
δ
6
exp
2
δ
calc
2
δ
calc
2
calc
δ 2
B3LYP/
(d
ꢀDMSO)
HF/6ꢀ31G*
(DMSO)
B3LYP/6ꢀ31G*
//HF/6ꢀ311+G(2d,p) 6ꢀ31G*
(DMSO)
196.2
194.0
166.8
166.8
144.9
144.9
142.0
142.0
128.9
128.9
126.1
126.1
124.5
124.5
6.2
(DMSO)
186.4
177.4
157.1
157.1
131.9
131.9
128.3
128.3
119.5
119.5
116.3
116.3
112.3
112.3
5.3
1
1
1
1
1
1
92.9
82.2
62.3
62.3
38.3
38.3
134.1
134.1
125.3
25.3
20.2
20.2
16.8
16.8
192.7
178.8
160.2
160.2
137.0
137.0
133.3
133.3
120.3
120.3
118.1
118.1
109.8
109.8
2.9
1
1
1
1
1
Mean |ꢀδ|
Maximum |ꢀδ
All values in ppm.
|
7.0
11.8
6.5
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3
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
Using this basis set, the mean and maximum differences between the C NMR chemical
shifts calculated for 1 and those reported for eucapsitrione were 5.3 and 18.9 ppm,
respectively (Figure 2; see also Table S2 for calculations carried out using alternative
methodology and basis set combinations). Notably, HF 6−31G* most poorly predicted the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
shift of the most upfield Cꢀresonances in chrysazin, whilst for eucapsitrione, the
significantly larger maximum shift difference again arose from the carbon resonating at 177.2
ppm.
3
4
OH
5
O
OH
7
2
8
9
6
1
13
11
HO
1
2
10
O
O
1
13
1
Figure 2. C NMR chemical shift differences between eucapsitrione (d
calculated shifts for 1 in DMSO (HF 6−31G*). The mean |ꢂδ| is 5.3 ppm and the maximum is
8.9 ppm.
6
ꢀDMSO) and the
1
CONCLUSION
In conclusion, 1,5,7ꢀtrihydroxyꢀ6Hꢀindeno[1,2ꢀb]anthraceneꢀ6,11,13ꢀtrione (1) has been
synthesised in 43% overall yield, and six steps, from the known boronic acid 9c and iodide 3
(
eight steps from commercially available starting materials). The physical characteristics and
spectroscopic data for 1 do not match those reported for the natural product eucapsitrione.
Unfortunately, we believe the existing, published spectra of eucapsitrione do not permit a
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reassignment of structure, partly because of uncertainty about whether spurious peaks in the
NMR spectra arise from the natural product, or significant impurities. Given the promising
biological activity of the eucapsitrione, another isolation and reinvestigation of its structure is
warranted.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
During the course of the synthesis of 1, an unprecedented direct arylation reaction was
observed, in which a borono group appears to act as a traceless orthoꢀactivator. At this stage
the reaction appears to have rather specific substrate requirements, but with optimization and
broadening of scope, this reaction could prove valuable.
EXPERIMENTAL SECTION
Materials and Methods
All solvents were distilled prior to use. Anhydrous THF was obtained from a Pure Solv 5ꢀ
Mid Solvent Purification System (Innovative Technology Inc.). ‘Dry DMF’ and ‘dry MeCN’
90
refers to solvent that was stored over activated 3A molecular sieves for at least 24 h. ‘Dry
acetone’ refers to acetone that was stirred over anhydrous CaSO for 4 h before being
distilled under N . Tetramethylethylenediamine (TMEDA) and diisopropylamine were dried
over and distilled from CaH
Triisopropyl borate was distilled and stored under N . The concentrations of solutions of nꢀ
4
2
77,90
2
2 2
under N onto KOH pellets and stored as such under N .
2
9
1
and secꢀBuLi were determined by titration with Nꢀbenzylbenzamide. 1ꢀHydroxyꢀ8ꢀacetoxyꢀ
18
9
,10ꢀathraquinone was prepared from chrysazin (2) by a known method. N,Nꢀdiethylꢀ2ꢀ
9
2
93
methoxybenzamide and N,Nꢀdiisopropylꢀ2ꢀmethoxybenzamide (9b) were prepared by
94
known methods from oꢀanisic acid. Dimethyl 3ꢀhydroxyꢀ6ꢀmethylphthalate was prepared
according to a known method. All other reagents and materials were purchased from
commercial suppliers and used as received.
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2
3
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
All reactions, excepting the preparations of 1ꢀhydroxyꢀ8ꢀacetoxyꢀ9,10ꢀanthraquinone and 1ꢀ
hydroxyꢀ2ꢀiodoꢀ8ꢀacetoxyꢀ9,10ꢀanthraquinone (3) were conducted in flameꢀdried glassware
under an atmosphere of N with the use of syringe and septumꢀcap techniques. Where
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
indicated, reaction temperatures refer to the temperature of the heating or cooling bath. All
organic extracts were dried over MgSO
0−45°C. Trace residual solvent was removed under a stream of N
using high vacuum.
4
, filtered and evaporated under reduced pressure at
4
2
or, where indicated,
Reaction progress was monitored by thin layer chromatography (TLC) using Merck
aluminiumꢀbacked TLC silica gel 60 F254 plates, which were also used for preparative TLC.
Spots were visualised directly (coloured compounds) or using ultraviolet light. Flash column
chromatography was performed using Davisil chromatographic silica media LC60A 40–63
µm.
1
13
H and C nuclear magnetic resonance (NMR) spectra were acquired using Bruker Avance
1
13
1
IIIHD (600 MHz for H and 150 MHz for C), Bruker Avance IIIHD (500MHz for H and
1
3
1
13
1
25 MHz for C), and Varian (400 MHz for H and 100 MHz for C) spectrometers, as
indicated. Deuterochloroform (CDCl ) was used as the solvent for NMR samples unless
3
1
otherwise indicated. Spectra were calibrated against CHCl (for H spectra; δ 7.26 ppm) or
3
13
CDCl
3
(for C spectra; δ 77.16 ppm) peaks. Where d
5
ꢀpyridine was used as a solvent, spectra
1
were calibrated against the most upfield peaks of C
5
D
4
HN (for H spectra; δ 7.22 ppm) and
13
C
5
D
5
N (for C spectra; δ 123.90). Where d
6
ꢀDMSO was used as a solvent, spectra were
1
13
calibrated against CD SOCD H (for H spectra; δ 2.50) or (CD ) SO (for C spectra; δ
3
2
3 2
1
13
3
9.52). H and C NMR assignments were made based upon 2D and NOE NMR
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experiments, as noted for each assigned compound. Complete atomꢀnumbered structures of
each compound synthesised can be found in the Supporting Information.
High resolution mass spectra were recorded on a Waters Liquid Chromatograph Premier
mass spectrometer with timeꢀofꢀflight mass analyser, using atmospheric pressure chemical
ionisation (APCI) in positive or negative mode as indicated. Infrared spectra were recorded
on a PerkinꢀElmer Spectrum One FTꢀIR spectrometer with Attenuated Total Reflectance
10
11
12
13
14
15
16
17
18
19
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(ATR) using neat samples. Melting points were determined using a Reichert hot stage
melting point apparatus.
Synthesis
19
1
ꢀHydroxyꢀ2ꢀiodoꢀ8ꢀacetoxyꢀ9,10ꢀanthraquinone (3). Iodic acid (4.38 g, 24.9 mmol) was
18
added to a stirred mixture of 1ꢀhydroxyꢀ8ꢀacetoxyꢀ9,10ꢀanthraquinone (7.06 g, 25.0 mmol)
in water (60 mL) and dioxane (190 mL). Iodine (3.17 g, 12.5 mmol) was added, and the
resulting mixture was heated at reflux for 18 h before being cooled to room temperature. The
3
mixture was then poured into water (2 L) and extracted with CHCl (3 × 900 mL). The
organic extract was washed with 1M aqueous Na solution (500 mL), water (500 mL)
2 2 3
S O
and brine (500 mL), dried and evaporated. The crude solid residue was subjected to flash
chromatography. Elution with PhMe gave 3 (2.38 g) as an orange solid. Additionally, impure
fractions were recrystallised from PhMe to give 3 as orange needles (2.06 g, total yield 44%),
19
−1
mp 224–226°C [lit. 222–224°C]. R
f
(PhMe): 0.25; IR (ATR) νmax cm : 1765 (OC=O), 1667
1
(
C10=O), 1639 (C9=O); H NMR (400 MHz, CDCl
3
) δ 13.50 (s, 1H), 8.28 (dd, J = 7.6, 1.2
Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.84 (dd [app. t], J
1
= J
2
= 8.0 Hz, 1H), 7.56 (d, J = 8.0
1
3
Hz, 1H), 7.45 (dd, J = 8.0, 1.2 Hz, 1H), 2.47 (s, 3H); C NMR (100 MHz, CDCl ) δ 187.8,
3
181.5, 169.6, 161.4, 150.9, 146.5, 136.1, 135.3, 132.8, 130.6, 126.2, 124.3, 120.5, 116.0,
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2
2
2
2
3
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3
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3
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4
4
4
4
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5
5
5
5
5
5
5
6
•
−
95.7, 21.3; HRMS (APCI−) m/z: [M] Calcd for C16
H
IO
5
407.9495; Found 407.9510. This
9
1
19
1
compound has been reported previously, but only with H NMR data provided. The H
NMR data obtained match those in literature.
0
1
2
3
4
5
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8
9
0
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2
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7
8
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(E)ꢀMethyl 3′ꢀ(8ꢀacetoxyꢀ1ꢀhydroxyꢀ9,10ꢀanthraquinonꢀ2ꢀyl)acrylate (
iodide 3 (0.410 g, 1.00 mmol) in MeCN (45 mL) was sparged with N before methyl acrylate
0.29 mL, 3.2 mmol), NEt (0.43 mL, 3.1 mmol) and Pd(OAc) (45 mg, 0.20 mmol, 20
mol%) were added. The reaction mixture was then stirred at 70°C under N for 14 h before
being cooled to room temperature. The mixture was diluted with CH Cl (200 mL), and the
4). A mixture of
2
(
3
2
2
2
2
solution was washed with brine (3 × 30 mL), vacuum filtered through Celite, dried and
evaporated. The residue was subjected to flash chromatography. Elution with CH Cl
afforded 5 (77 mg, 24%) identical with the material described below. Further elution with
CH Cl gave 4 (52 mg, 14%), which crystallised from EtOAc as red prisms, mp 226−230°C.
R (CH Cl ): 0.25; IR (ATR) ν cm : 1765 (OC=O), 1716 (C1′=O) , 1667 (C10=O), 1633
2
2
2
2
−1
f
2
2
max
1
(
C9=O); H NMR (400 MHz, CDCl ) δ 13.39 (s, 1H), 8.28 (dd, J = 7.6, 1.2 Hz, 1H), 8.00 (d,
3
J = 16.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.84 (dd [app. t], J
1 2
= J = 8.0 Hz, 1H), 7.81 (d, J
=
8.0 Hz, 1H), 7.44 (dd, J = 8.0, 1.2Hz, 1H), 6.77 (d, J = 16.4 Hz, 1H), 3.84 (s, 3H), 2.49 (s,
1
3
3
H); C NMR (100 MHz, CDCl
3
) δ 188.4, 181.4, 169.7, 167.3, 161.7, 150.8, 137.7, 136.0,
135.6, 135.4, 133.2, 130.6, 130.1, 126.2, 124.7, 122.4, 119.0, 116.9, 52.1, 21.3; HRMS
•
−
(
APCI−) m/z: [M] Calcd for C H O 366.0740; Found 366.0735.
20 14 7
(
E)ꢀMethyl 3′ꢀ(1,8ꢀdihydroxyꢀ9,10ꢀanthraquinonꢀ2ꢀyl)acrylate (
5
). A mixture of iodide 3
(0.404 g, 0.990 mmol) in dry MeCN (60 mL) was sparged with N
2
before NEt (0.43 mL, 3.1
3
mmol), methyl acrylate (0.29 mL, 3.2 mmol) and Pd(OAc) (42 mg, 0.19 mmol, 19 mol%)
2
were added. The resulting mixture was stirred at 70°C under N for 5 h then water (3 mL)
2
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was added and stirring was continued at 70°C 64 h. The reaction mixture was cooled to room
2 2
temperature, diluted with CH Cl (300 mL) and washed with brine (3 × 50 mL). The organic
phase was vacuum filtered through Celite, washed with saturated aqueous citric acid (2 × 100
mL), brine (100 mL) and then dried and evaporated. The residue was dissolved in CH Cl ,
2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
filtered through a plug of silica gel and washed through with CH Cl , affording 5 (0.308 g,
2
2
−1
9
6%) as an orange solid, mp 215−218°C. R
(CH
Cl
2
): 0.45; IR (ATR) νmax cm : 1716
f
2
1
(
C1′=O), 1668 (C10=O), 1621 (C9=O); H NMR (400 MHz, CDCl
3
) δ 12.86 (s, 1H), 11.96
(
s, 1H), 8.00 (d, J = 16.4 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.844 (dd, J = 7.2, 1.2 Hz, 1H),
.842 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 8.4, 7.6 Hz, 1H), 7.32 (dd, J = 8.6, 1.0 Hz, 1H), 6.77
7
1
3
(d, J = 16.0 Hz, 1H), 3.84 (s, 3H); C NMR (100 MHz, CDCl ) δ 193.4, 181.3, 167.2, 162.8,
3
161.5, 137.7, 137.5, 136.0, 134.2, 133.6, 130.0, 125.0, 122.6, 120.4, 119.7, 116.3, 115.9,
• −
5
2.1; HRMS (APCI−) m/z: [M] Calcd for C18
H O 324.0634; Found 324.0635.
12 6
(E)ꢀ3′ꢀ(1,8ꢀDihydroxyꢀ9,10ꢀanthraquinonꢀ2ꢀyl)acrylic acid (6). 4 M NaOH (0.29 mL) was
added to a suspension of acrylate 5 (91 mg, 0.28 mmol) in 3:1 dioxane:MeOH (4 mL), and
the resulting purple mixture was heated under reflux for 24 h. The reaction mixture was
acidified with 1 M HCl (5 mL), forming an orange precipitate, which was collected by
vacuum filtration, washed with water (ca. 300 mL) and dried. The aqueous washes were
extracted with EtOAc (3 × 60 mL). The extract was dried and evaporated, giving an orange
solid, which was combined with the collected precipitate and triturated with boiling CH Cl
2
2
to give 6 (72 mg, 83%) as a dark orange solid, mp 291−293°C. R
(1:49 AcOH:CH
Cl
) 0.25;
f
2
2
−
1
1
IR (ATR) νmax cm : 3200−2400 (COOH), 1684 (C1′=O), 1662 (C10=O), 1623 (C9=O); H
NMR (500 MHz, d
6
ꢀDMSO) δ 12.43 (br s, 3H, 3 × OH), 8.23 (d, J = 8.0 Hz, 1H, H3), 7.86
(d, J = 16.2 Hz, 1H, H3′), 7.83 (dd, J = 8.2, 7.7 Hz, 1H, H6), 7.72 (dd, J = 7.5, 1.0 Hz, 1H,
H5), 7.69 (d, J = 8.0 Hz, 1H, H4), 7.40 (dd, J = 8.4, 1.0 Hz, 1H, H7), 6.79 (d, J = 16.2 Hz,
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1H, H2′); C NMR (125 MHz, d
6
ꢀDMSO) δ 192.1 (C9), 181.1 (C10), 167.3 (C1′), 161.4
(
C8), 160.1 (C1), 137.6 (C6), 136.0 (C3′), 135.5 (C3), 133.7 (C4a), 133.3 (C10a), 129.0 (C2),
1
24.6 (C7), 123.1 (C2′), 119.4 (C5), 118.6 (C4), 116.4 (C9a), 116.0 (C8a); HRMS (APCI−)
•
−
m/z: [M] Calcd for C H O 310.0477; Found 310.0480. NMR assignments were made
1
7
10
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
with the assistance of COSY, HQSC and HMBC experiments.
95
(
2ꢀ(Diisopropylcarbamoyl)ꢀ3ꢀmethoxyphenyl)boronic acid (9a). A stirred solution of
TMEDA (1.30 mL, 8.67 mmol) in anhydrous THF (30 mL) at −78°C under N was treated
with a 0.96 M solution of secꢀBuLi in cyclohexane (8.60 mL, 8.26 mmol). To this was added
2
93
a solution of N,Nꢀdiisopropylꢀ2ꢀmethoxybenzamide (1.76 g, 7.50 mmol) in anhydrous THF
15 mL) dropwise over 10 min. The resulting mixture was stirred at −78°C for 2 h before
being treated with B(OiꢀPr) (5.20 mL, 22.5 mmol) and allowed to warm to room temperature
overnight. The mixture was cooled and neutralised with saturated NH Cl (10 mL), then most
(
3
4
of the THF was evaporated. The residue was diluted with water (30 mL), acidified to pH 3−4
with 1 M HCl (ca. 20 mL) and extracted with CH Cl (3 × 50 mL). The extract was
2
2
evaporated and the residue was dissolved in Et
2
O (150 mL) and extracted with 1 M NaOH (3
O (50 mL) then cooled to 0°C and
×
50 mL). The basic extracts were backꢀextracted with Et
2
acidified to pH 3−4 with 5 M HCl (ca. 35 mL), forming a white suspension, which was
extracted with CH Cl (5 × 50 mL). The extract was dried and evaporated, affording 9a (1.49
2
2
9
6
g, 71%) as a white solid, which did not require further purification, mp 233−234°C [lit.
1
1
49−150°C]. H NMR (500 MHz, CDCl
3
) δ 7.46 (dd, J = 7.3, 0.8 Hz, 1H), 7.34 (dd, J = 8.0,
7
.5 Hz, 1H), 6.97 (dd, J = 8.3, 0.8 Hz, 1H), 5.91 (s, 2H), 3.81 (s, 3H), 3.61 (sept., J = 6.7 Hz,
1
1H), 3.52 (sept., J = 6.8 Hz, 1H), 1.57 (d, J = 6.5 Hz, 6H), 1.08 (d, J = 7.0 Hz, 6H). The H
9
6
NMR data match those in literature.
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General procedure for the Suzuki−Miyaura Crossꢀcouplings. The selected iodide 3 or 10
(
2 3
1 equiv.), boronic acid 9 (or amide in the case of 9b) (1.3 equiv.), K CO (4 equiv.) and 10
wt% Pd/C (2 mol%) were suspended in water (10 mL/mmol of iodide). The suspension was
stirred with heating under reflux under N for 72 h before being cooled to room temperature,
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
acidified with 1 M HCl, diluted with water and extracted with CH Cl . The extract was
2
2
filtered through a pad of Celite, washed with water and brine, dried and evaporated to give
1
the crude product. Table 1 yields were determined via H NMR spectroscopy of the crude
product with use of 1,3,5ꢀtrimethoxybenzene as the internal standard.
Suzuki−Miyaura Crossꢀcoupling of 1ꢀhydroxyꢀ2ꢀiodoꢀ8ꢀacetoxyꢀ9,10ꢀanthraquinone (
3)
with (2ꢀ(Diisopropylcarbamoyl)ꢀ3ꢀmethoxyphenyl)boronic acid (9a). The general procedure
19
95
was used with iodide 3 (1.63 g, 4.00 mmol) and boronic acid 9a (1.43 g, 5.12 mmol),
except that the reaction time was 7 d instead of 72 h. The crude product was subjected to
flash chromatography. Elution with 1:199 MeOH:CH Cl gave a tertiary mixture of 11a, 12a
2
2
and N,Nꢀdiisopropylꢀ2ꢀmethoxybenzamide (1.69 g, 72% yield of 11a and 12a with a 3:1 ratio
1
of 11a:12a by H NMR) as an orange solid. A sample of the mixture was subjected to
preparative thinꢀlayer chromatography. Development with 2:3 EtOAc:hexanes gave a pure
sample of 12a; the sample of 11a still contained N,Nꢀdiisopropylꢀ2ꢀmethoxybenzamide,
which was removed by crystallisation from 1:1 EtOAc:EtOH.
2
′ꢀ(1,8ꢀDihydroxyꢀ9,10ꢀanthraquinonꢀ2ꢀyl)ꢀN,Nꢀdiisopropylꢀ6′ꢀmethoxybenzamide (11a).
−1
Yellowꢀorange solid, mp 263−264°C. R
(2:3 EtOAc:hexanes): 0.5; IR (ATR) νmax cm :
f
1
1
671 (C10=O), 1623 (C9=O, NC=O); H NMR (500 MHz, CDCl
3
) δ 12.55 (s, 1H), 12.04 (s,
1H), 8.01 (d, J = 8.0 Hz, 1H), 7.87 (dd, J = 7.5, 1.0 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.71
(
dd [app. t], J = J = 8.0 Hz, 1H), 7.39 (dd [app. t], J = J = 8.0 Hz, 1H), 7.32 (dd, J = 8.5,
1 2 1 2
1.0 Hz, 1H), 7.07 (dd, J = 7.8, 0.8 Hz, 1H), 6.97 (dd, J = 8.3, 0.8 Hz, 1H), 3.87 (s, 3H), 3.70
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(sept., J = 6.7 Hz, 1H), 3.22 (sept., J = 6.8 Hz, 1H), 1.48 (d, J = 7.0 Hz, 3H), 1.03 (d, J = 7.0
1
3
Hz, 3H), 1.02 (d, J = 7.0 Hz, 3H), 0.70 (d, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl
3
) δ
93.4, 181.6, 166.6, 162.8, 160.3, 156.0, 140.3, 137.5, 135.1, 133.9, 133.0, 132.9, 128.4,
28.2, 124.8, 123.0, 120.3, 119.6, 116.1, 115.6, 110.9, 55.9, 51.0, 45.7, 21.0, 20.6, 20.3;
1
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
•
−
HRMS (APCI−) m/z: [M] Calcd for C H NO 473.1838; Found 473.1848.
28
27
6
5
′ꢀ(1,8ꢀDihydroxyꢀ9,10ꢀanthraquinonꢀ2ꢀyl)ꢀN,Nꢀdiisopropylꢀ2′ꢀmethoxybenzamide (12a).
−1
Redꢀorange solid, mp 222−223°C. R
(2:3 EtOAc:hexanes): 0.4; IR (ATR) νmax cm : 1731,
f
1
1
666 (C10=O), 1621 (C9=O), 1606 (NC=O); H NMR (500 MHz, CDCl
3
) δ 12.79 (s, 1H),
12.07 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.86 (dd, J = 7.5, 1.0 Hz, 1H), 7.76 (d, J = 7.5 Hz,
1H), 7.72 (dd, J =8.5, 7.5 Hz, 1H), 7.67 (dd, J = 8.5, 2.5 Hz, 1H), 7.46 (d, J = 2.5 Hz, 1H),
7
1
=
.33 (dd, J = 8.5, 1.0 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 3.89 (s, 3H), 3.80 (sept., J = 6.7 Hz,
H), 3.53 (sept., J = 6.7 Hz, 1H), 1.58 (d, J = 6.5 Hz, 3H), 1.56 (d, J = 7.0 Hz, 3H), 1.19 (d, J
13
3
6.5 Hz, 3H), 1.09 (d, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl ) δ 193.7, 181.6, 168.1,
162.8, 160.2, 155.5, 137.6, 137.5, 136.6, 133.9, 132.3, 130.6, 128.8, 128.4, 128.1, 124.8,
120.4, 120.2, 116.2, 116.1, 110.8, 55.8, 51.2, 46.0, 20.93, 20.90, 20.7, 20.6; HRMS (APCI−)
• −
6
m/z: [M] Calcd for C28H27NO 473.1838; Found 473.1841.
5
′ꢀ(1,8ꢀDihydroxyꢀ9,10ꢀanthraquinonꢀ2ꢀyl)ꢀNꢀisopropylꢀ2′ꢀmethoxybenzamide
(13).
A
tertiary mixture of biaryl amides 11, 12 and N,Nꢀdiisopropylꢀ2ꢀmethoxybenzamide was finely
divided and then washed with cold 1:1 EtOH:EtOAc, giving a binary mixture of 11 and 12.
1
This mixture (92 mg, 0.19 mmol, containing 0.078 mmol of 12 by H NMR spectroscopy)
2 4
was treated with conc. H SO (2 mL), forming a dark purple mixture. After stirring at 80°C
for 24 h, the resulting mixture was cooled to room temperature, poured into ice/water (40
mL) and extracted with CH Cl (5 × 25 mL). The combined extracts were washed with water
2
2
(30 mL), dried and evaporated to give an orange solid, which was subjected to flash
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chromatography. Elution with 3:7 EtOAc:hexanes afforded 13 (11 mg, 33%) as a redꢀorange
−1
solid, mp 232−234°C. R
(3:7 EtOAc:hexanes): 0.3; IR (ATR) νmax cm : 3331 (N−H), 1664
f
1
(
C10=O), 1619 (C9=O, NC=O); H NMR (600 MHz, CDCl
3
) δ 12.76 (s, 1H, OH1), 12.06 (s,
1H, OH8), 8.46 (d, J = 2.4 Hz, 1H, H6′), 7.90 (d, J =7.8 Hz, 1H, H4), 7.86 (dd, J = 7.2, 1.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hz, 1H, H5), 7.83 (dd, J = 8.4, 2.4 Hz, 1H, H4′), 7.80 (d, J = 7.8 Hz, 1H, H3), 7.70 (dd, J =
8
.4, 7.8 Hz, 1H, H6), 7.69 (br d, J = 7.8 Hz, 1H, N−H), 7.31 (dd, J = 8.4, 0.6 Hz, 1H, H7),
.08 (d, J = 9.0 Hz, 1H, H3′), 4.31 (m [pseudo oct], J = 6.8 Hz, 1H, NCH), 4.03 (s, 3H,
7
1
3
3 3 3
OCH ), 1.28 (d, J = 6.6 Hz, 6H, 2 × CH ); C NMR (150 MHz, CDCl ) δ 193.6 (C9), 181.6
(C10), 164.0 (NC=O), 162.7 (C8), 160.2 (C1), 157.6 (C2'), 137.7 (C3), 137.5 (C6), 136.2
(C2), 133.9 (C10a), 133.6 (C4′), 133.3 (C6′), 132.5 (C4a), 129.0 (C5′), 124.7 (C7), 122.2
(C1′), 120.3 (C4), 120.2 (C5), 116.2 (C8a or C9a), 116.1 (C8a or C9a), 111.5 (C3′), 56.3
• −
(
3 3 6
OCH ), 41.8 (NCH), 23.0 (2 × CH H21NO
); HRMS (APCI−) m/z: [M] Calcd for C25
4
31.1369; Found 431.1379. NMR assignments were made with the assistance of COSY,
HSQC, HMBC and NOESY experiments.
Further elution with 1:99 MeOH:CH Cl afforded 5′ꢀ(1,8ꢀDihydroxyꢀ9,10ꢀanthraquinonꢀ2ꢀ
2
2
yl)ꢀ2′ꢀmethoxybenzamide (14) (6.5 mg, 21%) as a redꢀorange solid, mp 288−290°C. R
(1:49
f
−1
MeOH:CH
620 (C9=O); H NMR (600 MHz, CDCl
= 2.4 Hz, 1H, H6′), 7.92 (d, J = 7.8 Hz, 1H, H3 or H4), 7.90 (dd, J = 8.4, 2.4 Hz, 1H, H4′),
2 2
Cl
): 0.2; IR (ATR) νmax cm : 3442 (N−H), 3168, 1686 (C=O), 1674 (C=O),
1
1
3
) δ 12.79 (s, 1H, OH), 12.07 (s, 1H, OH), 8.49 (d, J
7.88 (dd, J = 7.5, 0.9 Hz, 1H, H5), 7.81 (d, J = 7.8 Hz, 1H, H3 or H4), 7.74 (br s, 1H, NH),
7.71 (dd, J = 8.4, 7.8 Hz, 1H, H6), 7.32 (dd, J = 8.4, 0.6 Hz, 1H, H7), 7.13 (d, J = 9.0 Hz, 1H,
1
H3′), 5.79 (br s, 1H, NH), 4.06 (s, 3H, OCH
3
); H NMR (600 MHz, d
5
ꢀpyridine) δ 9.03 (d, J
= 2.4 Hz, 1H, H6′), 8.62 (br s, 1H, NH), 8.32 (br s, 1H, NH), 7.99 (d, J = 7.8 Hz, 1H, H4),
7
.97 (dd, J = 9.0, 2.4 Hz, 1H, H4′), 7.95 (d, J = 7.2 Hz, 1H, H5), 7.80 (d, J = 7.8 Hz, 1H, H3),
.66 (dd, J = 8.4, 7.8 Hz, 1H, H6), 7.39 (d, J = 8.4 Hz, 1H, H7), 7.19 (d, J = 9.0 Hz, 1H, H3′),
7
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5
5
5
5
5
6
1
3
3.85(s, 3H, OCH
3
); C NMR (150 MHz, d
5
ꢀpyridine) δ 193.8 (C9), 181.9 (C10), 167.4
(
(
(
NC=O), 163.1 (C8), 160.6 (C1), 158.7 (C1′), 138.1 (C3 or C6), 138.0 (C3 or C6), 136.6
†
C2), 134.6 (C10a), 134.5 (C4′), 134.1 (C6′), 133.1 (C4a), 129.4 (C5′), 125.1 (C7), 123.7
C1′), 120.4 (C4), 120.3 (C5), 117.0 (C8a or C9a), 116.9 (C8a or C9a), 112.6 (C3′), 56.5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
•
−
(OCH ); HRMS (APCI−) m/z: [M] Calcd for C H NO 389.0899; Found 389.0898. NMR
3
22 15
6
assignments were made with the assistance of COSY, HSQC and HMBC experiments.
1
2 4
,8ꢀDihydroxyꢀ2ꢀiodoꢀ9,10ꢀanthraquinone (10a). Conc. H SO (80 mL) was added to 1ꢀ
1
9
hydroxyꢀ8ꢀacetoxyꢀ2ꢀiodoꢀ9,10ꢀanthraquinone (3) (2.05 g, 5.02 mmol) and the resulting
mixture was stirred for 45 min. The mixture was poured into iceꢀwater (400 mL) and
extracted with CHCl
3
(3 × 250 mL). The extract was dried and evaporated affording 10a as
an orange solid (1.82 g, 99 %), which crystallised from EtOAc as orange needles, mp 200–
−
1
1
202°C. R
f
(PhMe): 0.65; IR (ATR) νmax cm : 1660 (C10 C=O), 1620 (C9 C=O); H NMR
(400 MHz, CDCl ) δ 12.97 (s, 1H, OH), 11.91 (s, 1H, OH), 8.22 (d, J = 8.0 Hz, 1H), 7.84
3
(
dd, J = 7.6, 1.0 Hz, 1H), 7.71 (dd, J = 8.4, 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H, H3), 7.33
13
(
dd, J = 8.4, 1.0 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ 192.8, 181.4, 162.9, 161.2, 147.0,
•
−
1
37.9, 133.7, 133.6, 125.1, 121.1, 120.4, 115.6, 115.4, 95.3; HRMS (APCI−) m/z: [M]
Calcd for C14 IO 365.9389; Found 365.9376.
H
7
4
1
ꢀMethoxyꢀ2ꢀiodoꢀ8ꢀacetoxyꢀ9,10ꢀanthraquinone (10b). A mixture of 1ꢀhydroxyꢀ2ꢀiodoꢀ8ꢀ
19
acetoxyꢀ9,10ꢀanthraquinone (3) (0.15 g, 0.37 mmol) and K
2
CO
3
were suspended in dry
acetone (8 mL). MeOTs (0.24 mL, 1.6 mmol) was then added, and the mixture was heated
under reflux under N with stirring for 12 h. Additional dry acetone (2 mL), and MeOTs
0.24 mL, 1.6 mmol) were added, and the mixture was stirred with heating under reflux for a
2
(
†
This chemical shift is reported based upon the observed correlation to H3′ in the HMBC spectrum, as the
signal was obscured by solvent in the C NMR spectrum.
1
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further 24 h. The reaction mixture was cooled to room temperature, filtered, and concentrated
2 2
under reduced pressure, and the residue was dissolved in CH Cl (20 mL). The organic phase
was washed with 1 M HCl (3 × 5 mL), water (5 mL), and brine (5 mL), dried and evaporated.
The residue was subjected to flash chromatography. Elution with CH Cl gave 10b (0.11 g,
2
2
10
11
12
13
14
15
16
17
18
19
20
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−
1
69%) as a yellow solid, mp 170−173°C. R (CH Cl ): 0.4; IR (ATR) ν cm : 1752
max
f
2
2
1
(
OC=O), 1668 (C9=O, C10=O); H NMR (500 MHz, CDCl
3
) δ 8.21 (d, J = 8.0 Hz, 1H, H3),
8
1
.19 (dd, J = 8.0, 1.2 Hz, 1H, H5), 7.79 (d, J = 8.0 Hz, 1H, H4), 7.76 (dd [app. t], J = 8.0 Hz,
1
3
3 3
H, H6), 7.43 (dd, J = 8.0, 1.2 Hz, 1H, H7), 3.92 (s, 3H, OCH ), 2.49 (s, 3H, CH ); C NMR
(
125 MHz, CDCl ) δ 182.3 (C10), 181.2 (C9), 169.9 (OC=O), 159.8 (C1), 149.9 (C8), 144.7
3
(C3), 135.1 (C4a), 134.6 (C6), 134.4 (C10a), 130.2 (C7), 126.8 (C9a), 126.2 (C8a), 125.4
•−
(
C5), 124.5 (C4), 104.5 (C2), 62.3 (OCH
421.9651; Found 421.9643. NMR assignments made with the assistance of COSY,
HSQC and HMBC experiments.
3 3
), 21.4 (CH
); HRMS (APCI−) m/z: [M] Calcd for
17 5
C H11IO
1
ꢀMethoxyꢀ2ꢀiodoꢀ8ꢀhydroxyꢀ9,10ꢀanthraquinone (10c). Conc. H SO (1.5 mL) was added
2 4
to acetate 10b (63 mg, 0.15 mmol) and the mixture was stirred for 45 min then poured into
ice/water (15 mL) and extracted with CH Cl (3 × 20 mL). The extract was dried and
2
2
evaporated, giving a yellowꢀgreen solid, which was subjected to flash chromatography.
Elution with 7:3 PhMe:hexanes afforded 10c (43 mg, 75%) as a yellow solid, mp 164−166°C.
−
1
1
R (7:3 PhMe:hexanes): 0.25; IR (ATR) νmax cm : 1672 (C10=O), 1636 (C9=O); H NMR
f
(500 MHz, CDCl
3
) δ 12.77 (s, 1H, OH), 8.28 (d, J = 8.0 Hz, 1H, H3), 7.86 (d, J = 8.0 Hz, 1H,
H4), 7.80 (dd, J = 7.5, 1.0 Hz, 1H, H5), 7.67 (dd, J = 8.5, 7.5 Hz, 1H, H6), 7.33 (dd, J = 8.5,
13
1.0 Hz, 1H, H7), 3.98 (s, 3H, OCH
3
); C NMR (125 MHz, CDCl
3
) δ 187.9 (C9), 182.1
(
(
C10), 162.8 (C8), 160.3 (C1), 145.7 (C3), 136.7 (C6), 136.0 (C4a), 132.7 (C10a), 125.6
C9a), 125.3 (C4), 125.2 (C7), 119.3 (C5), 116.7 (C8a), 105.0 (C2), 62.0 (OCH ); HRMS
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