Divergent approach to the bisanthraquinone natural products: Total synthesis of (S)-bisoranjidiol and derivatives from binaphtho- para -quinones

Article abstract of DOI:10.1021/jo302364h

The development of the first asymmetric synthesis of a chiral anthraquinone dimer is outlined, resulting in the first total synthesis of (S)-bisoranjidiol. Rather than a biomimetic dimerization retrosynthetic disconnection, the anthracenyl ring systems ar

Full text of DOI:10.1021/jo302364h

Article
pubs.acs.org/joc
Divergent Approach to the Bisanthraquinone Natural Products: Total
Synthesis of (S)‑Bisoranjidiol and Derivatives from
Binaphtho‑para‑quinones
Erin E. Podlesny and Marisa C. Kozlowski*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
S
* Supporting Information
ABSTRACT: The development of the first asymmetric
synthesis of a chiral anthraquinone dimer is outlined, resulting
in the first total synthesis of (S)-bisoranjidiol. Rather than a
biomimetic dimerization retrosynthetic disconnection, the
anthracenyl ring systems are generated after formation of the
axially chiral binaphthalene framework. This synthetic strategy
has enabled the synthesis of several analogues. Key features of
the synthesis include the enantioselective coupling of a
hindered 2-naphthol containing substitution peri to the site
of C−C bond formation, the regioselective oxidation of 8,8′-
hydroxylated binaphthols to binaphtho-para-quinones, and a tandem regioselective Diels−Alder/aromatization reaction.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Over the last several decades, many natural bisanthraquinones
and related polyoxygenated biaryl aromatic systems have been
isolated and identified.1 The bisanthraquinone family of natural
products is partly composed of a collection of axially chiral
symmetrical anthraquinone dimers possessing a 1,1′-biaryl
linkage (Figure 1). With one exception, all of these
bisanthraquinones have a meta-substitution pattern on the
distal rings, as well as 2,2′-, 4,4′-, and 5,5′-hydroxyl groups.
Examples include skyrin (1a),2 bislunatin (1d),3 disolorinic acid
(1e),4 trachypone (1h),5 etc. The exception to this general
pattern is (S)-bisoranjidiol [(S)-2, Figure 1]. Unlike disolorinic
acid (1e) and the other members, (S)-bisoranjidiol lacks the
4,4′-hydroxyl groups and contains an ortho-substitution pattern
on the distal rings. In 2006, the dimer was isolated from the
leaves of the South American shrub, Heterophyllaea pustulata.6
Useful properties of the compound include its ability to
generate singlet oxygen and the ground-state radical anion
upon exposure to light,7 which contributes to the photo-
dynamic activity of the compound against bacteria8 and cancer
cells,9 leading to potential applications in photodynamic
therapy.10−13 Other bisanthraquinones are also active against
cancer14 and have shown potential for the treatment of
diabetes,15 depression,16 etc. Despite the interesting biological
activity of bisoranjidiol and related bisanthraquinones, no
stereoselective syntheses of a 1,1′-linked bisanthraquinone had
been achieved until recently, when we reported the first total
synthesis of (S)-bisoranjidiol.17 Herein we disclose a full
description of the development of the synthesis of (S)-
bisoranjidiol as well as the synthesis of a number of potentially
bioactive analogues.
Previous approaches toward the synthesis of 1,1′-bisanthraqui-
nones have generally concentrated on biomimetic pathways,
such as the oxidative coupling of anthraquinones or anthrones
(low yields)18−20 and Ullman couplings of brominated
anthraquinones. Good yields have been achieved with the
Ullman reaction, but harsh conditions were required that are
incompatible with highly functionalized substrates.21−24 We
initially proposed a biomimetic synthesis involving late-stage
oxidative asymmetric coupling of an anthraquinone. Enantio-
selective binaphthol couplings have been a vital part of many
syntheses of biaryl natural products containing axial or helical
chirality, both by our group and others.25−27 However,
preliminary results revealed that a biomimetic approach was
not feasible because of the high oxidation potential of
anthraquinones. For example, the coupling of 3 using copper
catalyst 4 did not proceed (Scheme 1).
We therefore considered a nonbiomimetic approach, which
would allow for the enantioselective synthesis of both (S)-
bisoranjidiol and a variety of derivatives via three major
retrosynthetic steps (Scheme 2). The first key disconnection of
bisoranjidiol or analogues is a regioselective tandem Diels−
Alder/aromatization reaction between an alkyl trimethylsilyl-
vinyl ketene acetal or other diene and a binaphtho-para-
quinone (7). This chiral p-quinone intermediate could be
formed via a selective oxidation of an 8,8′-dihydroxylated
binaphthol (8). The binaphthol could in turn be generated via
an enantioselective biaryl coupling reaction of a hindered 8-
Received: October 24, 2012
Published: December 18, 2012
© 2012 American Chemical Society
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Figure 1. Examples of bisanthraquinone natural products.
Scheme 1. Attempted Biomimetic Coupling of
Anthraquinones
Scheme 3. Enantioselective Biaryl Coupling of an 8-
Substituted 2-Naphthol
Scheme 2. Retrosynthesis
and the monomer of 13b was prepared by diacetylation of
naphthalene-1,7-diol, followed by monodeprotection of the 2-
acetoxy group. The chiral vanadium-catalyzed couplings of
either monomer, however, produced only low conversions and
selectivities. Apparently, substitution at the C8-position of the
substrate greatly slows coupling at the C1-position and lowers
selectivity. On the other hand, the copper-catalyzed reactions
were more promising. The 8-substituted 2-naphthol 11a,
prepared via a Fischer esterification and selective methylation,
was selectively coupled in 59% yield and 88% ee with a 1,5-
diaza-cis-decalin copper catalyst37−40 (Scheme 3). To the best
of our knowledge, this represents the first catalyzed
enantioselective coupling reaction of a 2-naphthol with
considerable steric hindrance peri to the site of C−C bond
formation. One other enantioselective reaction of an 8-
substituted 2-naphthol was reported in the literature with
good yield and selectivity (50% yield, 75% ee), but required
superstoichiometric copper.41
Although the coupling of 11a proved proof of concept, the
methoxy-protected phenols at the 8,8′-positions were not
suitable for the synthesis of (S)-bisoranjidiol because they could
not be easily removed without affecting the methyl ester or
protecting groups on the 2,2′-hydroxyl groups. Thus, the
synthesis was adjusted to incorporate an 8-benzyloxy
substituent (11b, Scheme 3). The synthesis of this substrate
was accomplished via selective benzylation to afford the
coupling substrate in 73% yield. The enantioselective biaryl
substituted 2-naphthol. The formation of hindered biaryls have
been demonstrated recently with Suzuki−Miyaura cross-
coupling,28−31 Ullmann−Ziegler coupling,32 C−H arylation,33
and other approaches, such as the domino reaction with
alkynes.34
In choosing the appropriate catalyst for the biaryl coupling
reaction, both chiral vanadium and copper catalysts were
examined. A brief screen of vanadium-catalyzed couplings35,36
to form either biaryl 13a or 13b (Scheme 3) from their
corresponding monomers was investigated. The monomer of
13a was prepared by monobenzylation of naphthalene-1,7-diol,
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coupling reaction worked well with this substrate, providing
(S)-12b in 62% yield and 87% ee [61% yield, 92% ee with
(S,S)-4].42 The enantiopurity could readily be enhanced to
>99% ee with one trituration. The racemate of 12b could also
be generated in 91% yield using CuCl(OH)TMEDA as the
catalyst.
With a successful synthesis of biaryl (S)-12b in hand, we
chose to examine the regioselective oxidation and Diels−Alder/
aromatization reaction with a racemic model substrate that
retained the 3,3′-methyl esters. Methylation, followed by
hydrogenolysis of rac-12b, yielded 8,8′-hydroxylated binaphthol
15 (Scheme 4). Selective oxidation to the binaphtho-para-
ethylene during the aromatization step. Noncyclic dienes, such
as Danishefsky’s diene or Brassard-type dienes (alkyl silylvinyl
ketene acetals), have also been employed.45−48 For alkyl
silylvinyl ketene acetals, in general, formation of the
hydroxylated anthraquinone involves a [4 + 2] cycloaddition
reaction with the p-naphthoquinone, followed by acid- or base-
mediated aromatization. Aromatization involves loss of the silyl
groups, elimination of the alkoxy group, tautomerization, and
air oxidation to yield the aromatic ring. An imposing challenge
of this Diels−Alder/aromatization strategy is control over the
regioselectivity of the cycloaddition reaction when an unsym-
metrically substituted p-naphthoquinone is the electrophile. For
example, with a 2-alkoxy-p-naphthoquinone, as shown in Figure
2, or as proposed in our retrosynthetic scheme (7, Scheme 2),
Scheme 4. Synthesis of Binaphtho-para-quinones
Figure 2. Diels−Alder regioselectivity.
two possible regioisomers could result in which the newly
formed peri-hydroxyl group is either syn or anti to the 2-alkoxy
(Figure 2A).
It has been suggested with juglone (5-hydroxynaphthalene-
1,4-dione) derivatives that the polarization of the diene imparts
a larger influence on the regiochemical outcome than the
substituent effects of the dienophile, except for strongly
polarized dienes.49 As alkyl silylvinyl ketene acetals are strongly
polarized dienes, prediction of the regiochemical outcome of
the cycloaddition can be rationalized through charge affinity
patterns. Influences, such as hydrogen bonding and resonance
of substituents on the naphthoquinone, can affect the
regioselectivity. For example, with a 2-methoxy-p-naphthoqui-
none or similar quinone with an electron-donating group
(EDG) at the 2-position, donation of electron density into the
5-carbonyl polarizes the dienophile (Figure 2B). In this case,
the 8-carbonyl is more electrophilic and will exert greater
control over the regioselectivity, so that the syn isomer
predominates. Extrapolation of this analysis to the retrosyn-
thesis of bisoranjidiol (Scheme 2) reveals an unfavorable
outcome in which the bis-syn-adduct (in-in-isomer) is the major
product. However, formation of the bis-anti-adduct (out-out-
isomer) is necessary for the natural product. Two methods for
controlling the regioselectivity beyond substituent effects are to
use Lewis acids (LA)49,50 or directing groups.46−48,51 The LA
will coordinate to the more basic carbonyl, resulting in a more
electrophilic 7-carbon and leading to the anti-isomer in this
example (Figure 2C). Alternatively, directing groups such as
quinone43 via a Co-salen catalyzed oxidation proceeded well, as
compound 15 was transformed into model Diels−Alder
substrate 16 in 57% yield. Since the selective oxidation was
successful, the binaphtho-para-quinone intermediate [(S)-19]
to bisoranjidiol was synthesized in a similar manner from (S)-
14, following removal of the ester groups. The ester groups
were efficiently removed via a three-step sequence involving
transformation of the esters to aldehydes and decarbonylation.
Notably, oxidation of (S)-18 provided quinone (S)-19 without
loss of enantiopurity.
The next major challenge following the synthesis of
binaphtho-para-quinones was the regioselective Diels−Alder
reaction. Use of a tandem Diels−Alder/aromatization reaction
to form hydroxylated anthraquinones, particularly with a
hydroxyl group peri to one of the anthraquinone carbonyls, is
well-known. Many different types of alkyl- and silyloxy dienes
have been reported for this transformation, including 2-pyrones
or cyclohexadiene derivatives,44 which lose carbon dioxide or
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Scheme 5. Synthesis of Bisanthraquinones and Effect of LA on Regioselectivity on Model Binaphtho-para-quinone
halogens, sulfoxides, and acetoxy groups on the quinone can
provide a similar outcome (Figure 2D).
Table 1. Diels−Alder Regioselectivity on a Monomeric
System
Initial evaluation of the Diels−Alder reaction was pursued
between the model substrate 16 and diene 20 (Scheme 5).
Diene 20, with meta-substitution, was chosen over the ortho-
substituted diene necessary for bisoranjidiol because it is more
stable than many of the other vinyl ketene acetals.47 Based on
the charge affinity patterns of binaphtho-para-quinone 16, the
in-in-isomer, 21c, was expected to be favored. A LA or directing
group would be necessary to achieve selectivity for the required
out-out-isomer. This hypothesis was supported by the results of
the control reaction. Without a LA, the cycloaddition reaction
highly favored 21c (4:22:74 ratio for 21a:21b:21c), providing
the bisanthraquinone mixture in 56−66% yield. When 2 equiv
of ZnCl2 were added, improvement in the selectivity was
observed. With 4 equiv of the LA, 21a was obtained as the
major isomer and none of 21c was observed.52 Unfortunately,
the yields were consistently poor (<10%) when a LA was added
due to the formation of numerous byproducts and decom-
position.
mixture yield
(%)
ratio
entry
R
X
additive
(a:b)
a
1
2
H
H
H
H
-
-
-
65
9:91
13:87
24:76
a
Me
Me
62
b
3
78
(no ester)
4
5
6
H
H
H
H
H
Br
ZnCl2 (2 equiv)
17
38
84
19:81
12:88
24:76
Since the yields were poor with the dimer, we decided to
optimize conditions on the monomer and explore directing
groups. The monomer, 23, was synthesized from 22 in 52%
yield (Scheme 6). Methylation under mild conditions, using
MeI and Ag2O, provided 24 in 79% yield.
c
Ti(OMe)4(2 equiv)
d
-
a
b
Includes peri-methoxys. Benzene reflux then O2, 5% aq NaOH; ref
51c. In toluene. 25:75 ratio of bromoquinone regioisomers.
c
d
For the thermal Diels−Alder reaction, like the dimer,
preferential formation of the syn-isomer (27b, 28b) and good
anthraquinone yields were observed (62−78%, entries 1−3,
Table 1). The substrate lacking the 3-methyl ester was reported
to give better selectivity51c (24:76, entry 3) than either of the
ester substrates. For both the monomer and dimer,
regioisomeric ratios could be determined by analysis of the
1H NMR spectrum. The chemical shifts of the newly formed
peri-hydroxyl groups differ by at least 0.2 ppm between the syn
and anti isomers. The peri-hydroxyl group for the anti-isomer,
27a, is shifted downfield relative to 27b because it is hydrogen-
bonded to the more basic carbonyl. This analysis also extended
to the dimers. A crystal structure of 27b confirmed that the
correct regioisomeric assignments were being made.
Scheme 6. Synthesis of p-Naphthoquinone Monomers
Interestingly, significant amounts of peri-methoxyanthraqui-
nones (Figure 3) were also isolated from the reactions in
entries 1 and 2 (Table 1). This material arises from elimination
of the trimethylsiloxy group instead of the methoxy group on
Figure 3. Anthraquinones with peri-methoxy substituents.
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the cyclohexene ring of the cycloadduct during the aromatiza-
tion portion of the transformation. The mixture yields for these
entries include the peri-methoxyanthraquinone isomers. To
confirm that the ratios of peri-hydroxy- and peri-methoxyan-
thraquinones were the same, it was necessary to deprotect the
methoxy groups, since the regioisomeric ratio could not be
determined from the 1H NMR spectrum of the mixture.
Following BCl3 deprotection, analysis confirmed that the
regioisomeric ratios were identical. Thus, measurement of the
peri-hydroxyanthraquinone isomer ratio was sufficient to
determine the overall selectivity. No formation of the peri-
methoxy products 29a,b (Figure 3) was observed for the other
entries in Table 1.
When Lewis acids were screened, yields were low due to
decomposition and side reactions (entries 4 and 5, Table 1). In
particular, ZnCl2 led to 33% of a side product resulting from
Michael addition of the diene. In addition, the undesired syn
product (27b) was still predominant. Other Lewis acids, such
as Ti(OMe)4, BF3·Et2O, and Ti(Oi-Pr)4, were also unsuccess-
ful. Because of the low yields and undesired selectivity observed
with Lewis acids, directing groups were explored, particularly a
bromine group which could easily be added to the quinone.
Formation of bromoquinones 25a,b was accomplished by
bromination followed by dehydrobromination (Scheme 6). The
bromoquinones were obtained in 90% yield as an inseparable
25:75 mixture of 25a and 25b. Alternatively, hydrobromination
of 24, followed by oxidation of the ensuing hydroquinone,
provided a promising bromoquinone ratio of 93:7 (26a:26b) in
a 56% yield. For the Diels−Alder reaction, bromine-directing
groups looked promising (entry 6, Table 1). Anthraquinones
27a and 27b were obtained in high yields (84%), and the ratio
of regioisomers of the starting material was reflected in the
products. This result prompted us to explore bromine as a
directing group for the dimeric compounds.
monobrominated species. More vigorous reaction conditions
led to demethylation of the methoxy groups and a complex
mixture rather than dibromination. Bromination of 16 or (S)-
19, followed by dehydrohalogenation, proved more promising.
The ester substrate could be brominated in 87% yield,
providing 31a−c in a 37:50:13 ratio. As with the monomer
(entry 6, Table 1), we were encouraged that the isomer ratio of
dibrominated quinones 31a−c (37:50:13) was reflected in the
bisanthraquinone products 21a−c (39:47:14), following the
Diels−Alder/aromatization reaction.
With these results in hand, we turned to the synthesis of (S)-
bisoranjidiol. Bromination of (S)-19 provided a mixture of
bromoquinone regioisomers (S)-32 in 95% yield and a ratio of
43:47:10 (Table 2). This material could be used to synthesize a
significant amount of the natural product as well as an
unnatural regioisomer. On the basis of the results observed with
diene 20 and binaphtho-para-quinones 31a−c, it was
anticipated that the regioisomer ratio of the starting quinones
would be reflected in the product bisanthraquinones (see Table
1, entry 6). However, when binaphtho-para-quinone rac-32a−c
was treated with ortho-substituted diene 33,53 followed by
aromatization using silica as the Lewis acid, almost no product
was observed. It appeared that the aromatization process was
much slower for this diene. The silica source proved key to
success in this transformation, with silica from TLC plates
(Silicycle) proving more efficient than the bulk silica gel
(Silicycle, 40−63 μm) used previously. Even so, the ratio of
bisanthraquinone products did not reflect the starting material
(Scheme 7) as had consistently been the case with diene 20.
Scheme 7. Reactivity Differences in the Diels−Alder
Reaction
Unfortunately, the success of the hydrobromination/
reoxidation reaction of naphthoquinone monomer 24 to form
26 (Scheme 6) could not be extended to the biaryl system
(Table 2). While the desired out-out-regioisomer was favored in
the reaction, the majority of the isolated material was the
a
Table 2. Bromination of Binaphtho-para-quinones
product
R
conditions
mixture yield (%)
ratio (a:b:c)
b
The same problem was also encountered when dienophile
31a−c was combined with diene 33, indicating that the change
in product distribution was not due to the binaphtho-para-
31
CO2Me
CO2Me
H
A
B
B
30
66:33:<1
37:50:13
43:47:10
31
87
c
(S)-32
95 (75)
1
quinone structure. The H NMR spectrum of the reaction
a
mixture showed predominantly the out-out-bisanthraquinone
regioisomer, 34a. The yield (52%) suggested that the other
bromoquinone regioisomers or monocycloadducts were either
Conditions: A = (1) HBr/AcOH, −15 °C, (2) Ag2O, Na2SO4, dark;
b
B = Br2, AcOH then NaOAc, AcOH, reflux. Incomplete reaction;
longer times result in demethylation. After semipreparative HPLC.
c
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not reacting well with diene 33 and/or were decomposing in
the Diels−Alder reaction.
To investigate the observed reactivity difference, each of the
bromoquinone regioisomers (S)-32a−c were separated via
semipreparative HPLC and reacted individually with diene 33
(Scheme 8). Formation of (S)-34a from (S)-32a proceeded
Scheme 8. Synthesis of (S)-Bisoranjidiol and Regioisomer
Figure 4. Racemization of (S)-2 in MeOH (25 °C).
eroded during isolation, which involved heating to 80 °C as
well as exposure to acid and base.
A pathway for racemization may arise through formation of
enone 36 (Scheme 9, path A). Although the enone is highly
strained, structurally similar compounds, such as binaphthone
41 (Figure 5) with an extended quinone, have been isolated.54
In addition, binaphthone 41 was atropisomerically unstable due
to equilibration between twisted and stacked conformations.54
It is conceivable that enone 36 may proceed through an
analogous equilibration toward conformation 38 and ultimately
(R)-2. An alternate pathway for racemization is also possible
through bishemiketal intermediate 39 (Scheme 9, path B).
Formation of this type of structure has been observed with a
binaptho-p-quinone under neutral conditions43 as well as an
anthraquinone upon treatment with sulfuric acid.23 Formation
of the bishemiketal introduces a bridged biaryl bond, which is
known to lower the barrier for atropisomerization.55 Ring flip of
the pyrans lead to intermediate 40, which forms the opposite
enantiomer of bisoranjidiol, (R)-2, upon ring-opening.
Because of the interesting biological properties of bisor-
anjidiol and bisanthraquinones in general, several analogues
were synthesized by varying the diene for the Diels−Alder
reaction (Scheme 10). A mixture of dibromoquinones 31a−c
was treated with either 2,3-dimethyl-1,3-butadiene or 1-
(trimethylsiloxy)-1,3-butadiene, followed by NEt3 to generate
bisanthraquinones 44 and 46 in 71% and 65% yield,
respectively. Sultine 43,56 which degrades above 80 °C to the
exocyclic diene, and SO2 could also be used to generate a
bisanthraquinone with an extended ring system. All three of
these compounds were deprotected with BCl3 to yield
analogues 42, 45, and 47 in good overall yields.
well (80% yield), which was consistent with observations from
reaction of the bromoquinone mixture. Notably, the two
reaction sequences, cycloaddition and aromatization, on both
quinones of the dimer must proceed with high efficiency
(∼95% per transformation) to generate the observed overall
80% yield. The unsymmetrical dibromoquinone, (S)-32b,
required nearly three times longer for the cycloaddition
reaction to reach completion because it stalled at the
monocycloadduct stage. More decomposition was also
observed compared to formation of (S)-34a, resulting in
lower yields of (S)-34b (46−71% yield). The more sterically
congested product (S)-34c did not form readily; primarily,
decomposition was observed.
To complete the synthesis of bisoranjidiol, and its unnatural
regioisomer, both (S)-34a and (S)-34b were deprotected with
BBr3 to yield the natural product (S)-2 and the regioisomer
(S)-35 with no erosion of the enantiomeric excess (Scheme 8).
The NMR spectroscopic data of synthetic-(S)-2 corre-
sponded well with the literature.6 Using an authentic sample
of bisoranjidiol kindly provided by Dr. Cabrera,6 the
configuration of the natural product isolate was analyzed
using HPLC with a chiral stationary phase. This analysis
revealed that the natural product isolate was 5% ee (S).
Evaluation of the atropisomeric stability of (S)-2 revealed that
the enantiopurity of bisoranjidiol degrades in MeOH (25 °C,
t1/2 = 3.8 months; 80 °C, t1/2 = 1.8 h, ΔG⧧ (rt) = 27.20 kcal/
mol), eroding from >99% ee to 71% ee after 26 days (Figure 4).
Notably, over the same period of time a sample of the solid did
not show any degradation. In view of the observed
racemization, it is possible that any naturally occurring
enantiopurity of bisoranjidiol could have been significantly
CONCLUSION
■
In summary, chiral binaphtho-para-quinones, generated via
enantioselective oxidative naphthol coupling followed by
regioselective oxidation, were used effectively to complete the
first enantioselective synthesis of a 1,1′-linked bisanthraquinone
and the first synthesis of bisoranjidiol. The Diels−Alder/
aromatization cascades of binaphthoquinones are highly
efficient (∼95% per transformation). Overall, bromines were
found to be superior activators and directing groups in quinone
Diels−Alder reactions relative to Lewis acids or electron-
donating substituents. This approach described herein also
permitted the generation of several analogues, including the
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Scheme 9. Proposed Pathways for Racemization
Scheme 10. Synthesis of Bisanthraquinone Analogues
Figure 5. Known binaphthone compound.
regioisomer of bisoranjidiol and four other bisanthraquinones
for further study (21, 42, 45, and 47).
EXPERIMENTAL SECTION
■
General Considerations. All reactions were carried out under an
atmosphere of dry argon, unless otherwise noted. Dienes 20 and 33
were prepared according to reported procedures,57,53 distilled under
reduced pressure, and stored at −20 °C under argon. Diene 33 was
used within two weeks of preparation, and diene 20 was used within a
month. Compounds 2, 11b, 12b, 14−19, 22, 32, 34, and 35 were
reported previously.17,43
Multiplicity for 1H NMR data are reported as follows: s = singlet, d
= doublet, t = triplet, br = broad, m = multiplet. 1H NMR spectra were
referenced to the residual solvent peaks: CDCl3 (7.26 ppm), acetone-
d6 (2.05 ppm), and C6D6 (7.16 ppm). 13C NMR spectra were
referenced to CDCl3 (77.16 ppm) and acetone-d6 (29.84 ppm). High-
resolution mass spectra were measured on a LC-TOF mass
spectrometer (ionization mode: ESI+ or ESI−). Enantiomeric excesses
were determined using analytical HPLC with UV detection at 254 nm
and analytical Chiralpak AD column (4.6 mm × 250 mm, 10 μm).
Reactions were monitored via analytical thin layer chromatography
(TLC) and visualization was accomplished with UV light and/or ceric
ammonium molybdate stain. Column chromatography was performed
with silica gel (40−63 μm particle size).
Methyl 3-Hydroxy-5-methoxy-2-naphthoate (11a). In a
modified procedure,58 anhydrous K2CO3 (4.59 g, 33.2 mmol) was
added to a solution of 22 (5.00 g, 22.9 mmol) in acetone (78 mL).
Following dropwise addition of Me2SO4 (2.4 mL, 25.4 mmol), the
reaction was heated at reflux. After 4 h, water was added and the
aqueous layer extracted with CH2Cl2. The organic extract was washed
with brine and dried over Na2SO4. Following filtration and
concentration, the crude solid was combined with crude solid from
two 15.00 g scale reactions and recrystallized from MeOH to afford
1
11a as a yellow solid (26.2 g, 70% yield): mp 145−148 °C; H NMR
(500 MHz, CDCl3) δ 10.38 (s, 1H), 8.44 (s, 1H), 7.72 (s, 1H), 7.39
(d, J = 8.3 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H),
4.02 (s, 3H), 3.99 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.5,
156.5, 154.4, 132.0, 130.7, 128.2, 124.0, 121.4, 114.6, 107.1, 106.4,
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55.8, 52.7; IR (film) 3159, 3024, 2962, 1686, 1284, 1198 cm−1; HRMS
(ESI) m/z 233.0815 [M + H]+ (calcd for C13H13O4, 233.0814).
(S)-Dimethyl 2,2′-Dihydroxy-8,8′-dimethoxy-1,1′-binaphth-
yl-3,3′-dicarboxylate [(S)-12a]. To a solution of 11a (40 mg, 0.17
mmol) in ClCH2CH2Cl (2 mL) was added (R,R)-4 (6.3 mg, 10 mol
%). Following sonication, the solution was placed under an oxygen
atmosphere and heated in a 40 °C oil bath. After 20 h, the mixture was
diluted with water and extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4, and concentrated. The residue
was chromatographed (30% EtOAc/hexanes) to afford (S)-12a as a
yellow solid (47 mg, 59% yield, 88% ee): mp >250 °C; [α]26D −80 (c
149.1, 146.5, 132.8, 129.8, 127.4, 125.9, 125.4, 122.0, 118.9, 112.5,
21.3, 21.2.
To a solution of the diacetate (652 mg, 2.67 mmol) in CH2Cl2/
MeOH (13 mL/13 mL) at 0 °C was added anhydrous K2CO3 (462
mg, 3.34 mmol). After the solution was stirred for 1 h, the reaction was
quenched with 1 M HCl and extracted with CH2Cl2. The organic layer
was washed with brine and dried over Na2SO4, followed by filtration
and concentration. The residue was chromatographed (10−20%
EtOAc/hexanes) to yield 7-hydroxynaphthalen-1-yl acetate as a yellow
solid (226 mg, 42% yield): 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J =
8.7 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.21 (d,
J = 7.5, 1H), 7.13 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.7 Hz, 2.4 Hz,
1H), 2.44 (s, 3H).
CuCl(OH)TMEDA (27 mg, 10 mol %) was added to a solution of
the monoacetate (237 mg, 1.17 mmol) in ClCH2CH2Cl (11.7 mL)
and the reaction mixture stirred under an oxygen atmosphere. After 2
h, the mixture was concentrated and suspended in hexanes. Following
sonication, the solids were collected via vacuum filtration and washed
thoroughly with 1 M HCl, followed by water. Then the solid was
washed carefully with cold EtOAc and a minimal amount of acetone to
remove pinkish color, leaving 13b as a white solid (140.5 mg, 59%):
mp >200 °C dec; 1H NMR (500 MHz, acetone-d6) δ 7.88 (d, J = 8.9
Hz, 2H), 7.78 (dd, J = 8.2, 1.1 Hz, 2H), 7.61 (bs, 2H), 7.29 (t, J = 7.8
Hz, 2H), 7.29 (d, J = 8.9, 2H), 6.99 (dd, J = 7.5, 1.2 Hz, 2H), 0.93 (s,
6H); 13C NMR (125 MHz, acetone-d6) δ 169.1, 154.4, 147.6, 132.3,
130.7, 129.0, 127.1, 123.1, 121.7, 119.9, 114.7, 19.6; IR (film) 3344,
1730, 1514, 1220 cm−1; HRMS (ESI) m/z 425.1007 [M + Na]+ (calcd
for C24H18O6Na, 425.1001).
1
0.061, 88% ee, CH2Cl2); H NMR (500 MHz, CDCl3) δ 10.51 (s,
2H), 8.50 (s, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.19 (t, J = 7.9 Hz, 2H),
6.70 (d, J = 7.2 Hz, 2H), 4.02 (s, 6H), 3.13 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 170.8, 156.6, 152.9, 131.1, 129.8, 128.7, 123.4, 122.8,
120.9, 113.5, 108.9, 56.2, 52.7; IR (film) 3175, 3013, 2949, 1676, 1260,
1127 cm−1; HRMS (ESI) m/z 463.1391 [M + H]+ (calcd for
C26H23O8 463.1393).
Racemate (rac-12a). To a solution of 11a (5.00 g, 21.5 mmol) in
2:1 MeCN/ClCH2CH2Cl (375 mL) was added CuCl(OH)TMEDA
(0.500 g, 10 mol %). The reaction mixture was warmed in a 35 °C oil
bath and stirred under an oxygen atmosphere. After 10 h, the mixture
was cooled and diluted with CH2Cl2. The organic layer was washed
with 0.5 M HCl, followed by water and brine. After the organic layer
over was dried over Na2SO4, the mixture was filtered and
concentrated. The residue was triturated with cold 1:1 EtOAc/
hexanes to afford rac-12a as a yellow solid (4.44 g, 87% yield): CSP
HPLC (Chiralpak AD, 1.0 mL/min, 90:10 hexanes:i-PrOH): tR(S) =
12.0 min, tR(R) = 23.1 min.
Bisanthraquinones [21a, 21b, 21c (Major)]. To a suspension of
16 (30 mg, 0.062 mmol) in dry benzene (1.0 mL) was added diene 20
(46 μL, 4 equiv). Additional diene (4 equiv) was added after 6 and 24
h. After a total of 32 h, the reaction mixture was diluted with CH2Cl2
and poured over silica (1200 mg). The solvent was allowed to
evaporate open to air. More silica was added as needed. When
complete, the silica was loaded directly onto a column and
chromatographed (CH2Cl2−2.5% EtOAc/CH2Cl2) to afford 21 as a
mixture of regioisomers in a 4:22:74 ratio (a, b, c; 56%, 10% mono-
8,8′-Bis(benzyloxy)-1,1′-binaphthalene-2,2′-diol (13a). To a
solution of commercially available naphthalene-1,7-diol (1.00 g, 6.24
mmol) in acetone (25 mL) were added anhydrous K2CO3 (1.25 g,
9.05 mmol) and BnBr (0.89 mL, 7.5 mmol). After the reaction mixture
was heated to reflux for approximately 8 h, the solids were removed via
vacuum filtration and washed with acetone. The filtrate was
concentrated and the residue chromatographed (5% EtOAc/hexanes)
1
to yield 8-(benzyloxy)naphthalen-2-ol as a light brown oil: H NMR
1
peri-methyl ether also isolated): H NMR (500 MHz, CDCl3) 21a
(500 MHz, CDCl3) δ 7.73 (d, J = 6.7 Hz, 1H), 7.62 (d, J = 2.6 Hz,
1H), 7.53 (d, J = 7.3 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.40−7.36 (m,
2H), 7.23 (d, J = 7.9 Hz, 1H), 7.12 (dd, J = 8.8 Hz, 2.6 Hz, 1H), 6.88
(d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 4.92 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 153.6, 153.3, 137.3, 130.1, 129.7, 128.8, 128.1, 127.7, 127.0,
123.6, 120.6, 118.1, 105.9, 104.6, 70.3.
(out-out-OH): δ 12.51 (s, 2H), 8.91 (s, 2H), 7.30 (s, 2H), 7.07 (s,
2H), 4.00 (s, 6H), 3.59 (s, 6H), 2.33 (s, 6H). 21b (out-in-OH): δ
12.52 (s, 1H), 11.99 (s, 1H), 8.90 (s, 1H), 8.88 (s, 1H), 7.66 (d, J =
1.5 Hz, 1H), 7.32 (d, J = 1.5 Hz, 1H), 7.08 (s, 1H), 7.00 (s, 1H), 4.01
(s, 3H), 3.99 (s, 3H), 3.61 (s, 3H), 3.57 (s, 3H), 2.43 (s, 3H), 2.34 (s,
3H); 21c (in-in-OH): δ 12.01 (s, 2H), 8.87 (s, 2H), 7.67 (d, J = 1.0
Hz, 2H), 7.01 (s, 2H), 4.00 (s, 6H), 3.59 (s, 6H), 2.44 (s, 6H). Major
isomer 21c (in-in-OH): 13C NMR (125 MHz, CDCl3) δ 188.2, 181.6,
165.4, 163.1, 161.8, 149.1, 134.7, 134.1, 132.8, 131.6, 129.9, 128.7,
124.4, 120.9, 114.8, 62.8, 53.0, 22.4; HRMS (ESI) m/z 673.1355 [M +
Na]+ (calcd for C36H26O12Na, 673.1322).
VO(acac)2 (9 mol %, 8.0 mg) was added to a solution of 8-
(benzyloxy)naphthalen-2-ol (83 mg, 0.33 mmol) in CH2Cl2 (3.3 mL)
and the reaction mixture stirred under an oxygen atmosphere. After 3
h, the mixture was concentrated. The residue was chromatographed
(15% EtOAc/hexanes) to yield 13a as an off-white solid (30 mg, 36%,
68% based on recovered starting material): mp 188−190 °C; 1H NMR
(500 MHz, CDCl3) δ 7.47 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.2 Hz,
2H), 7.15 (t, J = 7.7 Hz, 2H), 7.13 (d, J = 6.7 Hz, 2H), 7.04 (d, J = 8.9
Hz, 2H), 7.03 (t, J = 7.6 Hz, 4H), 6.73 (d, J = 7.2 Hz, 2H), 6.57 (d, J =
7.2 Hz, 4H), 5.00 (s, 2H), 4.55 (d, J = 11.4 Hz, 2H), 4.51 (d, J = 11.4
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 155.2, 151.5, 136.2, 131.3,
130.3, 128.2, 127.6, 127.4, 125.4, 123.3, 121.7, 117.2, 113.4, 107.3,
70.5; IR (film) 3483, 3059, 2920, 2873, 1583, 1514, 1452, 1259 cm−1;
HRMS (ESI) m/z 521.1711 [M + Na]+ (calcd for C34H26O4Na,
521.1729).
2,2′-Dihydroxy-1,1′-binaphthalene-8,8′-diyl Diacetate
(13b). A solution of naphthalene-1,7-diol (500 mg, 3.12 mmol) in
pyridine (3.1 mL) was cooled to 0 °C before addition of Ac2O (1.2
mL, 12.5 mmol). After being stirred for 3 h, the reaction mixture was
diluted with EtOAc and washed with 1 M HCl, followed by brine. The
organic layer was dried over Na2SO4, filtered, and concentrated. The
residue was chromatographed (10−20% EtOAc/hexanes) to yield the
diacetate as a white solid (652 mg, 86%): 1H NMR (500 MHz,
CDCl3) δ 7.79 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.69 (d, J
= 1.9 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.31−7.27 (m, 2H), 2.46 (s,
3H), 2.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.6, 169.4,
Methyl 3-Hydroxy-5,8-dioxo-5,8-dihydronaphthalene-2-car-
boxylate (23). To a solution of 22 (100 mg, 0.458 mmol) in DMF (9
mL) was added Co-salen (30 mg, 20 mol %). After being stirred under
an oxygen atmosphere for 3 h, the mixture was diluted with Et2O and
washed with saturated aqueous NH4Cl. The organic layer was dried
over Na2SO4, filtered, and concentrated. The crude solid was
chromatographed (30−60% EtOAc/hexanes) to afford 23 as a yellow
1
solid (55.3 mg, 52%): mp 218−220 °C dec; H NMR (500 MHz,
CDCl3) δ 11.37 (s, 1H), 8.64 (s, 1H), 7.62 (s, 1H), 6.99 (s, 2H), 4.04
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 184.3, 183.3, 169.8, 165.8,
139.8, 138.9, 137.3, 130.7, 124.0, 116.5, 115.9, 53.3; IR (film) 3159,
3082, 2966, 2927, 1668, 1568, 1452, 1313, 1244 cm−1; HRMS (ESI)
m/z 233.0440 [M + H]+ (calcd for C12H9O5, 233.0450).
Methyl 3-Methoxy-5,8-dioxo-5,8-dihydronaphthalene-2-
carboxylate (24). To a suspension of 23 (35.7 mg, 0.154 mmol)
in CH2Cl2 (1 mL) was added Ag2O (30 mg, 0.8 equiv), followed by
MeI (20 μL, 2 equiv). After the mixture was stirred for 21.5 h in the
dark, additional Ag2O (30 mg, 0.8 equiv) and MeI (20 μL, 2 equiv)
were added. When the reaction was complete, the mixture was filtered
through Celite with CH2Cl2 and concentrated. The residue was
chromatographed (15−30% EtOAc/hexanes) to afford 24 as a yellow
473
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solid (30 mg, 79%): mp 163−164 °C dec; 1H NMR (500 MHz,
CDCl3) δ 8.45 (s, 1H), 7.59 (s, 1H), 6.98 (s, 1H), 6.97 (s, 1H), 4.06
(s, 3H), 3.93 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 184.6, 183.4,
165.2, 163.0, 139.5, 138.5, 135.7, 130.9, 125.6, 124.9, 109.0, 57.0, 52.7;
IR (film) 3066, 2958, 2858, 1730, 1668, 1599, 1321, 1236 cm−1;
HRMS (ESI) m/z 247.0609 [M + H]+ (calcd for C13H11O5,
247.0606).
5 °C before addition of diene 20 (2 equiv). When complete, as
determined by TLC, the reaction mixture was poured over silica (200
mg) and allowed to evaporate open to air. After 1 day, the silica was
filtered with CH2Cl2−2.5% MeOH/CH2Cl2 and the residue
chromatographed (30−50% EtOAc/hexanes) to afford the anthraqui-
none as a 13:87 mixture of regioisomers 28a (anti-OH) and 28b (syn-
OH). Isomers containing peri-methyl ethers instead of hydroxyl groups
1
Bromoquinone Monomers (26a and 26b). Naphthoquinone 24
(5.0 mg, 0.020 mmol) was dissolved in propionic acid (1 mL) flushed
with Ar and cooled to −10 °C. The addition of HBr/AcOH (33 wt %,
50 μL) turned the solution green. After 10 min, the reaction mixture
was diluted with water, extracted with EtOAc, and washed several
times with water and brine. The organic layer was dried over Na2SO4,
filtered, and concentrated. The residue was reconstituted in THF (0.7
mL), followed by the addition of Na2SO4 (44 mg) and Ag2O (7.7 mg,
0.033 mmol). After the mixture was stirred in the dark for 12.5 h, it
was filtered through Celite and chromatographed on a short column of
silica (CH2Cl2) to afford 26 as an inseparable 93:7 mixture of
were also isolated (62% combined anthraquinone yield): H NMR
(500 MHz, CDCl3) 28a (anti-OH) δ 12.58 (s, 1H), 8.65 (s, 1H), 7.79
(s, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.12 (m, 1H), 4.10 (s, 3H), 3.96 (s,
3H), 2.47 (s, 3H). 28b (syn-OH) δ 12.38 (s, 1H), 8.63 (s, 1H), 7.80
(s, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.10 (m, 1H), 4.10 (s, 3H), 3.96 (s,
3H), 2.47 (s, 3H). 13C NMR (125 MHz, CDCl3) 28b (syn-OH) δ
187.3, 181.1, 165.2, 163.1, 149.5, 148.5, 137.3, 133.3, 131.8, 126.4,
125.8, 124.0, 121.2, 114.4, 109.0, 57.0, 52.7, 22.5; HRMS (ESI) m/z
327.0865 [M + H+] (calcd for C18H15O6, 327.0869).
Bishaloquinones (31a−c). To a suspension of 16 (250 mg, 0.509
mmol) in glacial AcOH (2.5 mL) was added bromine (2 mL, 0.5 M in
AcOH). After the mixture was stirred for 10 min, ice/water was added
and the mixture extracted with EtOAc. The organic layer was washed
with saturated aqueous sodium thiosulfate, followed by water and
brine. After concentrating, the residue was reconstituted in AcOH (10
mL). Anhydrous NaOAc (417 mg, 5.09 mmol) was added and the
mixture heated to reflux for 3 min. After the mixture was cooled to 0
°C, the solid was collected via vacuum filtration and washed well with
water. The crude solid was chromatographed (CH2Cl2−5% EtOAc/
CH2Cl2) to afford a yellow solid as an inseparable 37:50:13 mixture of
1
bromoquinones 26a and 26b (3.7 mg, 56% yield): H NMR (300
MHz, CDCl3) 26a (anti-Br) δ 8.53 (s, 1H), 7.60 (s, 1H), 7.53 (s, 1H),
4.07 (s, 3H), 3.95 (s, 3H). 26b (syn-Br) δ 8.46 (s, 1H), 7.68 (s, 1H),
7.52 (s, 1H), 4.08 (s, 3H), 3.94 (s, 3H); major isomer 26a (anti-Br)
13C NMR (125 MHz, CDCl3) δ 182.0, 176.3, 165.0, 163.3, 141.5,
140.2, 135.6, 132.2, 125.0, 123.6, 109.4, 57.1, 52.9; HRMS (ESI) m/z
324.9723 [M + H]+ (calcd for C13H10O5Br, 324.9712).
Anthraquinone Monomers 27a and 27b (Entry 6, Table 1).
Naphthoquinone 23 (20 mg, 0.081 mmol) was suspended in glacial
acetic acid (0.2 mL), and a solution of Br2 in AcOH was added
dropwise (1 equiv). When the reaction was complete as determined by
TLC, it was diluted with cold water and quenched with NaHSO3. The
mixture was extracted with EtOAc, washed with brine, and dried over
Na2SO4. The residue was chromatographed (15% EtOAc/hexanes) to
remove any over brominated material and dissolved in AcOH (5 mL).
Following the addition of NaOAc (100 mg), the solution was heated
to reflux for 5 min. After being cooled to room temperature, the
reaction mixture was diluted with water and extracted with EtOAc.
The organic layer was washed with water and brine, followed by drying
over Na2SO4. The product was obtained as an inseparable mixture of
bromoquinones 25a and 25b (25:75 ratio) and used without further
1
31a, 31b, and 31c (287 mg, 87%): H NMR (500 MHz, C6D6) 31a
(out-out-Br) δ 8.78 (s, 2H), 6.68 (s, 2H), 3.41 (s, 6H), 3.35 (s, 6H).
31b (out-in-Br) δ 8.80 (s, 1H), 8.78 (s, 1H), 6.83 (s, 1H), 6.61 (s, 1H),
3.41 (s, 3H), 3.40 (s, 3H), 3.35 (s, 3H), 3.34 (s, 3H); 31c (in-in-Br) δ
8.81 (s, 2H), 6.79 (s, 2H), 3.39 (s, 6H), 3.35 (s, 6H); 13C NMR (500
MHz, acetone-d6) 31a (out-out-Br) δ 183.1, 177.5, 165.8 (overlap with
b and c), 162.8, 142.2, 140.0, 133.8, 133.2, 131.9, 129.1, 127.9, 63.1
(overlap with b and c), 53.3 (overlap with b and c); 31b (out-in-Br) δ
183.2, 181.7, 178.6, 177.4, 165.8 (2 peaks, overlap with a and c), 162.7,
162.4, 142.2, 141.1, 140.9, 140.1, 134.6, 133.9, 133.2, 132.3, 131.9,
130.9, 129.6, 129.1, 128.8, 128.0, 63.1 (2 peaks, overlap with a and c),
53.3 (2 peaks, overlap with a and c); 31c (in-in-Br) δ 181.7, 178.6,
165.8 (overlap with a and b), 162.4, 141.2, 140.8, 134.6, 132.3, 131.0,
129.5, 128.9, 63.1 (overlap with a and b), 53.3 (overlap with a and b);
HRMS (ESI) m/z 646.9209 [M + H]+ (calcd for C26H17O10Br2,
646.9188).
1
purification: H NMR (300 MHz, CDCl3) 25a (anti-Br) δ 11.42 (bs,
1H), 8.71 (s, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 4.06 (s, 3H). 25b (syn-
Br) δ 11.42 (bs, 1H), 8.63 (s, 1H), 7.72 (s, 1H), 7.53 (s, 1H), 4.04 (s,
3H).
To a 0 °C solution of a 25:75 mixture of bromoquinones 25a and
25b (5.4 mg, 0.016 mmol) in dry toluene (2 mL) was added diene 20
(8 μL, 2.6 equiv). After 1 h, the reaction mixture was concentrated,
diluted with CH2Cl2, and poured over silica (50 mg). The solvent was
allowed to evaporate open to air. After overnight, the silica was filtered
to afford 27 as a 24:76 mixture of anthraquinones 27a and 27b (4.2
Dimethyl 2,2′-Dihydroxy-5,5′,12,12′-tetraoxo-5,5′,12,12′-
tetrahydro-1,1′-bitetracene-3,3′-dicarboxylate (42). A solution
of 31a−c (20 mg, 0.031 mmol) and sultine 4356 (15 mg, 0.089 mmol)
in toluene (0.5 mL) was heated to 85−90 °C. Additional 43 (30 mg,
0.178 mmol) was added after 16 h. After 25 h total, the reaction
mixture was concentrated and reconstituted in toluene, and NEt3 (200
μL) was added with the flask open to air. When the reaction was
complete as judged by TLC, the mixture was diluted with CH2Cl2 and
washed with 1 M HCl. The organic layer was passed through Na2SO4
and used without further purification: 1H NMR (300 MHz, CDCl3) δ
9.06 (s, 2H), 8.90 (s, 2H), 8.54 (s, 2H), 8.11 (d, J = 8.1 Hz, 2H), 7.93
(d, J = 8.1 Hz, 2H), 7.72−7.61 (m, 4H), 4.04 (s, 6H), 3.65 (s, 6H);
HRMS (ESI) m/z 713.1420 [M + Na]+ (calcd for C42H26O10Na,
713.1424).
1
mg, 84%): H NMR (300 MHz, CDCl3) 27a (anti-OH): δ 12.65 (s,
1H), 11.40 (s, 1H), 8.84 (s, 1H), 7.80 (s, 1H), 7.65 (s, 1H), 7.11 (s,
1H), 4.06 (s, 3H), 2.47 (s, 3H). 27b (syn−OH): δ 12.43 (s, 1H),
11.38 (s, 1H), 8.83 (s, 1H), 7.83 (s, 1H), 7.67 (d, J = 1.3 Hz, 1H), 7.11
(d, J = 0.7 Hz, 1H), 4.06 (s, 3H), 2.47 (s, 3H).
Isomer 27b (syn-OH) was purified via chromatography (8%
EtOAc/hexanes): mp 224−226 °C; 13C NMR (500 MHz, CDCl3) δ
187.1, 181.0, 169.8, 165.8, 163.2, 149.5, 139.0, 133.5, 131.6, 125.5,
124.1, 121.2, 117.0, 116.0, 114.7, 53.3, 22.5; IR (film) 3128, 3082,
2927, 2858, 1692, 1645, 1568, 1444, 1298, 1251 cm−1; HRMS (ESI)
m/z 313.0713 [M + H]+ (calcd for C17H13O6, 313.0712). X-ray quality
crystals were obtained by suspending 27b in 1:1 EtOAc/hexanes and
adding a minimal amount of CH2Cl2 until fully dissolved, followed by
slow evaporation. The crystallographic data for 27b have been
deposited at the Cambridge Crystallographic Data Centre with the
deposition number 914772. Copies of the data can be obtained, free of
charge, on application to the Director, CCDC, 12 Union Road,
Cambridge CB21EZ, UK [fax: +44(0)-1233-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
The crude anthraquinone was dissolved in CH2Cl2 (3 mL) and
cooled to 0 °C, followed by the dropwise addition of BCl3 (1 M in
hexanes, 90 μL). After 40 min the reaction was quenched with cold
water and extracted with CH2Cl2. The organic layer was washed with
brine, dried over Na2SO4, and concentrated. The residue was
chromatographed (30% EtOAc/hexanes) to yield 42 as a yellow
1
solid (9.3 mg, 45%, two steps): mp >250 °C; H NMR (500 MHz,
CDCl3) δ 11.63 (s, 2H), 9.18 (s, 2H), 8.88 (s, 2H), 8.56 (s, 2H), 8.09
(d, J = 8.3 Hz, 2H), 7.91 (d, J = 8.1 Hz, 2H), 7.68−7.65 (m, 2H),
7.63−7.59 (m, 2H), 4.09 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
183.4, 181.8, 170.3, 163.4, 136.6, 135.4, 135.2, 131.2, 130.5, 130.2
(overlapped peaks), 130.1, 129.71, 129.68, 129.5, 129.4, 128.2, 127.5,
116.2, 53.3; IR (film) 2923, 2852, 1725, 1676, 1444, 1287, 1252 cm−1;
Anthraquinone Monomers 28a and 28b (Entry 2, Table 1). A
solution of 24 (20 mg, 0.081 mmol) in benzene (1 mL) was cooled to
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The Journal of Organic Chemistry
Article
HRMS (ESI) m/z 661.1119 [M − H−] (calcd for C40H21O10,
661.1135).
ASSOCIATED CONTENT
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S
* Supporting Information
Dimethyl 2,2′-Dimethoxy-6,6′,7,7′-tetramethyl-9,9′,10,10′-
tetraoxo-9,9′,10,10′-tetrahydro-1,1′-bianthracene-3,3′-dicar-
boxylate (44). To a suspension of 31a−c (20 mg, 0.031 mmol) in
toluene (0.5 mL) was added 2,3-dimethyl-1,3-butadiene (4 equiv).
The reaction mixture was heated to 50 °C. Additional diene was added
as needed in three portions (12 equiv total) over 44 h. After 44 h, the
solution was cooled to 0 °C, and NEt3 (>20 equiv) was added while
exposed to air. When the reaction was complete, the mixture was
concentrated and chromatographed (30% EtOAc/hexanes) to yield 44
Copies of 1H and 13C NMR spectra for new products;
crystallographic data for 27b. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: marisa@sas.upenn.edu.
Notes
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1
as a yellow solid (14 mg, 71%): mp >250 °C; H NMR (500 MHz,
The authors declare no competing financial interest.
CDCl3) δ 8.89 (s, 2H), 8.05 (s, 2H), 7.71 (s, 2H), 3.99 (s, 6H), 3.57
(s, 6H), 2.40 (s, 6H), 2.30 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
183.5, 182.2, 165.6, 161.8, 144.4, 144.2, 134.7, 134.5, 132.2, 131.4,
131.2, 130.1, 128.5, 128.4, 128.1, 62.7, 52.9, 20.31, 20.26; IR (film)
2950, 1733, 1673, 1602, 1585, 1281, 1251 cm−1; HRMS (ESI) m/z
647.1932 [M + H]+ (calcd for C38H31O10, 647.1917).
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the National
Science Foundation (CHE-1213230). E.E.P. gratefully ac-
knowledges the National Institutes of Health for both an
NRSA (F31-GM093515) and a Chemistry−Biology Interface
(T32-GM071339) predoctoral fellowship. Partial instrumenta-
tion support was provided by the NIH for MS
(1S10RR023444) and NMR (1S10RR022442) and by the
NSF for an X-ray diffractometer (CHE-0840438). We also
Dimethyl 2,2′-Dihydroxy-6,6′,7,7′-tetramethyl-9,9′,10,10′-
tetraoxo-9,9′,10,10′-tetrahydro-1,1′-bianthracene-3,3′-dicar-
boxylate (45). BCl3 (1 M in hexanes, 3.2 equiv) was added dropwise
to a solution of 44 (10 mg, 0.016 mmol) in CH2Cl2 (1.5 mL) at 0 °C.
After 15 min, the reaction was quenched with cold water, and the
layers were separated. The organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated. The residue was chromato-
graphed (CHCl3) on a short column to afford 45 as a yellow solid (8.4
́ ́
thank Dr. Jose Cabrera (Universidad Nacional de Cordoba,
Argentina) for an authentic sample of bisoranjidiol. In addition,
we greatly acknowledge Dr. Barbara J. Morgan (University of
Pennsylvania) for her contributions to the biaryl coupling
reaction and the assistance of Dr. Patrick Carroll in obtaining
1
mg, 88%): mp >250 °C; H NMR (500 MHz, CDCl3) δ 11.55 (s,
2H), 9.03 (s, 2H), 8.06 (s, 2H), 7.74 (s, 2H), 4.05 (s, 6H), 2.41 (s,
6H), 2.30 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 183.6, 182.0,
170.3, 163.3, 144.4, 143.9, 135.8, 132.3, 131.5, 130.7, 128.5, 128.1,
127.8, 126.6, 115.7, 53.2, 20.3, 20.2; IR (film) 3418, 1669, 1291 cm−1;
HRMS (ESI) m/z 619.1594 [M + H]+ (calcd for C36H27O10,
619.1604).
̈
the crystal structure of 27b. We also acknowledge Dr. Omer
Koz (visiting researcher, Ege University, Turkey) and under-
graduates Kenny Puk (University of Pennsylvania) and Xaira
Lopez Corcino (REU student) for their assistance in the scale-
up of racemic material.
Dimethyl 2,2′-Dimethoxy-9,9′,10,10′-tetraoxo-9,9′,10,10′-
tetrahydro-1,1′-bianthracene-3,3′-dicarboxylate (46). Com-
pound 31a−c (20.0 mg, 0.0309) was partially dissolved in toluene
(0.5 mL). After the addition of 1-(trimethylsiloxy)-1,3-butadiene (22
μL, 0.123 mmol), the mixture was heated to 50 °C. Additional diene
was added as necessary in three portions (12 equiv total) over 2 d.
After 2 d, the reaction mixture was concentrated and reconstituted in
CH2Cl2. Once the mixture was cooled to 0 °C, NEt3 (10 equiv) was
added while exposed to air. After 40 min, the mixture was washed with
1 M HCl and passed through Na2SO4. The residue was chromato-
graphed (CH2Cl2−5% EtOAc/CH2Cl2) to afford 46 as a yellow solid
(11.8 mg, 65%): mp >250 °C; 1H NMR (500 MHz, CDCl3) δ 8.93 (s,
2H), 8.32 (d, J = 7.6 Hz, 2H), 7.96 (d, J = 7.6 Hz, 2H), 7.77 (t, J = 7.5
Hz, 2H), 7.68 (t, J = 7.5 Hz, 2H), 4.00 (s, 6H), 3.59 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 183.3, 182.0, 165.5, 161.9, 134.7, 134.4,
134.3 (overlapped peaks), 134.2, 133.2, 131.7, 129.9, 128.7, 127.6,
127.3, 62.7, 53.0; IR (film) 1729, 1676, 1267, 1240 cm−1; HRMS
(ESI) m/z 591.1292 [M + H]+ (calcd for C34H23O10, 591.1291).
Dimethyl 2,2′-Dihydroxy-9,9′,10,10′-tetraoxo-9,9′,10,10′-
tetrahydro-1,1′-bianthracene-3,3′-dicarboxylate (47). A solu-
tion of 46 (9.1 mg, 0.016 mmol) in CH2Cl2 (1.5 mL) was cooled to 0
°C, followed by the dropwise addition of BCl3 (1 M in hexanes, 3.2
equiv). After 15 min, the reaction was quenched with cold water, and
the layers were separated. The organic layer was washed with brine,
dried over Na2SO4, and concentrated. The residue was chromato-
graphed (CH2Cl2) to afford 47 as a yellow solid (6.9 mg, 80%): mp
>250 °C; 1H NMR (500 MHz, CDCl3) δ 11.59 (s, 2H), 9.08 (s, 2H),
8.33 (dd, J = 7.8 Hz, 0.9 Hz, 2H), 7.99 (dd, J = 7.5 Hz, 0.9 Hz, 2H),
7.76 (dt, J = 7.5 Hz, 1.3 Hz, 2H), 7.67 (dt, J = 7.5 Hz, 1.3 Hz 2H),
4.07 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 183.4, 181.8, 170.2,
163.4, 135.7, 134.3 (overlapped peaks), 134.0, 133.5, 131.0, 127.8,
127.5, 127.3, 126.5, 116.0, 53.3; IR (film) 2918, 1663, 1283, 1252
cm−1; HRMS (ESI) m/z 563.0979 [M + H]+ (calcd for C32H19O10,
563.0978).
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