Total Synthesis of the Antitumor-Antitubercular 2,6′-Bijuglone Natural Product Diospyrin and Its 3,6′-Isomer

Article abstract of DOI:10.1021/acs.jnatprod.0c00800

The 2,6′-bijuglone natural product diospyrin and its unnatural 3,6′-isomer idospyrin have been synthesized in seven steps each from N,N-diethylsenecioamide in overall yields of 12% and 13%, respectively. The syntheses diverge from ramentaceone (7-methylju

Full text of DOI:10.1021/acs.jnatprod.0c00800

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Total Synthesis of the Antitumor−Antitubercular 2,6′-Bijuglone
Natural Product Diospyrin and Its 3,6′-Isomer
Glenn A. Pullella,* Daniel Vuong, Ernest Lacey, and Matthew J. Piggott*
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ABSTRACT: The 2,6′-bijuglone natural product diospyrin and its
unnatural 3,6′-isomer idospyrin have been synthesized in seven
steps each from N,N-diethylsenecioamide in overall yields of 12%
and 13%, respectively. The syntheses diverge from ramentaceone
(7-methyljuglone) and include a key Suzuki−Miyaura cross-
coupling. Diospyrin, idospyrin, and several synthetic precursors
exhibit potent and selective cytotoxicity to the murine myeloma
NS-1 cell line over neonatal foreskin cells.
ramentaceone dimers have since been found in nature,3
meaning that of the 10 possible dimers, six are confirmed
natural products. All six have been the targets of total
syntheses,4 as have two of the “unnatural” ramentaceone
dimers,4f,5 leaving only the C-2−C-8′ and C-3−C-6′ linked
dimers, 6 and 7,6 respectively (Figure 1), as yet unexplored.
Diospyrin (1) has been particularly well studied, perhaps
because of its widespread occurrence in Ebenaceae plants.7
Since its first isolation by Kapil and Dhar from the stem bark of
Diospyros montana Roxb.,2 a small tree found throughout India,
diospyrin (1) has been isolated in numerous investigations of
other members of the Ebenaceae family belonging to the
genera Diospyros2,8 and Euclea.6a,8c,9 The use of a number of
these plants, in particular D. montana Roxb.10 and E. natalensis
A.DC.,11 in traditional remedies for an array of ailments has
encouraged the assessment of diospyrin (1) for various
bioactivities.8g,12 In 1996, derivatives of diospyrin (1) were
investigated for their antiprotist properties and demonstrated
moderate inhibitory activity against the parasites Leishmania
donovani, Trypanosoma cruzi, and T. brucei brucei.13 This
finding prompted the first, and previously only, synthesis of
diospyrin (1) by Yoshida and Mori, who obtained the natural
product in nine steps and 9% overall yield.4h
iospyrin (1, Figure 1) is a naturally occurring C-2−C-6′
Dlinked dimer of ramentaceone (7-methyljuglone, 2). Its
structure was established through a series of studies1 following
its first isolation in 1961.2 Five other C−C linked
More recently, the antitumor potential of diospyrin (1) and
some of its derivatives has been explored across a number of
Received: July 18, 2020
Figure 1. Ramentaceone (2), four of its naturally occurring dimers (1,
3−5), and the two dimers yet to be characterized (6, 7).
© XXXX American Chemical Society and
American Society of Pharmacognosy
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studies from the Hazra group.14 Diospyrin (1) inhibited the
growth of the human cancer cell lines A375 (melanoma) and
Hep2 (laryngeal carcinoma) at low micromolar concentrations
(IC50 = 0.8 and 3.6 μM, respectively) and was thus derivatized
by first alkylating its phenolic hydroxyls and then modifying
one or both of the naphthoquinone units.14c−e Further
investigation of diospyrin and derivatives was severely limited
by the small quantities that could be isolated from D. montana
Roxb.14c Moreover, the influence that the position of the
dimeric bond has on the antitumor activity of ramentaceone
dimers has not been considered. Indeed, only two other
ramentaceone dimers, isodiospyrin (3) and mamegakinone (4)
(Figure 1), have been tested for antitumor activity,15 and the
data from these studies cannot be directly compared with each
other nor with data for diospyrin (1).
Scheme 1. Retrosynthetic Identification of Common
Precursors to Diospyrin (1) and Idospyrin (7)
A study by the Maxwell group, examining the inhibition of
Mycobacterium tuberculosis DNA gyrase by ramentaceone
dimers, illustrates that the connectivity of monomeric units
can affect the bioactivity of the dimer.16 Diospyrin (1)
inhibited the action of M. tuberculosis DNA gyrase (IC50 = 15
μM) with potency comparable to that of ciprofloxacin (IC50
=
10 μM),16 a fluoroquinolone antibiotic formerly used in
tuberculosis treatment.17 Meanwhile, neodiospyrin (5) and
isodiospyrin (3) showed comparatively poor activity in the
same assay (IC50 = 50 and 100 μM, respectively).
A similar evaluation of the antitumor activity of isomeric
ramentaceone dimers may determine whether the position of
the isomeric bond is important to their activity. Thus, we
elected to pursue the synthesis of diospyrin (1) and of one of
its unexplored isomers, the 3,6′-dimer, for which we propose
the name idospyrin (7) (Figure 1). Herein, we describe studies
toward the direct arylation of ramentaceone (2), eventual
success in the total synthesis of diospyrin (1) and its unnatural
3,6′-isomer idospyrin (7), and a preliminary assessment of
mammalian cytotoxicity of these compounds and several
precursors.
Scheme 2. Naphthol 9 Was Prepared by Two Routes:
Stobbe Condensation and Dienolate−Aryne Cyclization
RESULTS AND DISCUSSION
■
Synthesis. Yoshida and Mori’s synthesis of 1 constructs a
binaphthyl framework via a key Suzuki−Miyaura coupling,
with both coupling partners prepared separately via Diels−
Alder reactions of vinyl ketene acetals with benzoquinones.4h
In light of recent advances in strategies for the arylation of
quinones,18 we proposed a synthesis of diospyrin (1) and
idospyrin (7) via arylation of ramentaceone (2) (Scheme 1).
This approach was expected to yield both desired C-2−C-6′
and C-3−C-6′ linked naphthylquinones, which could be
separated and deprotected to afford diospyrin (1) and
idospyrin (7), respectively. The naphthol 9 was identified as
a key precursor from which both ramentaceone (2) and a
suitable naphthalene coupling partner 8 could be prepared
(Scheme 1).
Naphthol 9 has been a synthetic target or used to
demonstrate a methodology on a number of occasions,19 due
to its utility as a precursor to ramentaceone (2)19c and other
naturally occurring naphthoquinones.19e Most of these routes
are surprisingly lengthy,19a,c,e,f with the exception of that
developed by Sammes19b and later improved upon by
Watanabe.19d This methodology involves the reaction of a
dienolate (or equivalent) 14c,d with the benzyne derived from
a halobenzene such as 15 (Scheme 2), delivering naphthol 9 in
one step. In the current work, this strategy was modified and
applied to cheap and readily available 3,3-dimethylacrylic acid
a
b
1
Yield determined by H NMR spectroscopy. Isolated yield.
(13a), though both the derived dienediolate 14a20 and the
bis(trimethylsilyl) vinyl ketene acetal 14b21 furnished only
traces of naphthol 9 (Table S1, Supporting Information).
Subsequent attempts to improve upon the yield of 9 obtained
via ester dienolate 14c proved fruitless (Table S1, Supporting
Information). Conceding, we prepared N,N-diethylsenecioa-
mide (13c)22 and followed the precedent set by Watanabe19d
in which the use of dienolate 14d significantly increases the
B
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yield of naphthol 9, a result of the greater stability of amide
versus ester enolates.23
Arylboronic acids have recently emerged as effective
reagents for the arylation of quinones under mild reaction
conditions,18c,d,29 and methodologies have been developed that
tolerate unprotected phenolic hydroxyls in both coupling
partners.18c,d These reports prompted our pursuit of a suitable
naphthylboronic acid, which was initiated with a directed ortho
metalation (DoM)−borylation approach. Naphthol 9 was first
fitted with a methoxymethoxy (MOM) directing group
(Scheme 4), which was preferred due to ease of cleavage
An alternative route to naphthol 9 was devised and
investigated in parallel to the dienolate pathway (Scheme 2).
Naphthoate 11 was prepared by a Stobbe condensation
between 2,5-dimethoxybenzaldehyde (10) and diethyl succi-
nate, followed by intramolecular cyclization of the resultant
crude product.24 Attempts to reduce the diester 11 directly to
naphthol 9 with LiAlH4 in refluxing dioxane25 were
unsuccessful, the reduction instead stalling at diol 12. A
more appropriate room-temperature LiAlH4 reduction of 11
was employed to produce 12, which was converted to naphthol
9 by hydrogenolysis.19e This procedure26 gave 9 in four steps
and a 37% overall yield, inferior in both yield and efficiency to
the preparation of 9 via senecioamide dienolate 14d (one step,
44%).
Scheme 4. Pursuit of a Suitable Naphthylboronic Acid
Pronucleophile via DoM−Borylation
Naphthol 9 and ramentaceone (2) were the simplest
coupling partners required to trial some strategies for the
arylation of naphthoquinones directed at synthesis of diospyrin
(1). Conversion of naphthol 9 directly to ramentaceone (2) is
ineffective under standard oxidative demethylation condi-
tions,19c which instead result in the formation of the
naphthazarin derivative.27 This transformation, previously
carried out over three steps via acetylation of 9,19c was instead
performed by demethylating 9 with pyridinium chloride and
oxidizing the nascent hydroquinone with MnO2, the latter step
being incorporated into a standard workup (Scheme 3).
Scheme 3. Preparation of Ramentaceone (2) and
Unsuccessful Acid-Catalyzed Conjugate Addition Approach
a
Deuterium incorporation (not yield) as assessed by integration of
1
the crude H NMR spectrum.
later in the synthesis. Unfortunately, treatment of 17 with n-
BuLi/N,N,N′,N′-tetramethylethylenediamine (TMEDA) re-
sulted in competing metalation ortho to its methoxy groups,
as demonstrated by a deuterium quench, which provided 18
and its isomers 19 (Scheme 4). This result was somewhat
surprising given that MOM groups have been established as
superior directors of ortho metalation relative to methoxy
groups.30 In this case we surmise that the combined rate-
accelerating inductive effects of the two methoxy substituents31
and some steric hindrance from the 7-methyl group tip the
balance in favor of metalation of the dimethoxy-substituted
ring of 17.
A more powerful directing group was therefore required to
execute the desired DoM−borylation; thus the N,N-dieth-
ylcarbamate 20 was prepared (Scheme 4). Cleavage of N,N-
dialkylcarbamates is often not trivial, and we expected the
reductive32 and alkaline hydrolysis33 methods for deprotection
to be incompatible with the syntheses of 1 and 7. Before
undertaking further experiments, 20 was subjected to the
aforementioned global deprotection/oxidation sequence with
pyridinium chloride and MnO2, which resulted in conversion
to ramentaceone (2) in good yield.
The addition of electron-rich arenes to naphthoquinones
and juglones has been reported under catalysis by Lewis18a or
Brønsted18j acids, and it was predicted that naphthol 9 may be
sufficiently activated to show such reactivity; however, all
attempts to induce a conjugate addition with 2 were
unsuccessful (Scheme 3; Table S2, Supporting Information).
No reaction between 9 and either model compound juglone or
ramentaceone (2) was observed in the presence of In-
(OTf)3,18a InCl3, Yb(OTf)3,28 or H2SO4.18j Subsequent
control experiments revealed 9 was unlikely to be sufficiently
electron rich for this approach to succeed, as it failed to react
with naphthoquinone (Table S2, Supporting Information),
which is a suitable electrophile for activated arenes under
In(OTf)3 catalysis.18a Furthermore, ramentaceone (2) and its
methyl ether also appeared poorly suited to this approach, as
both juglones were unreactive toward resorcinol dimethyl
ether (Table S3, Supporting Information), which undergoes
In(OTf)3-catalyzed conjugate addition to other quinones.18a
With evidence suggesting the desired electrophilic aromatic
substitution was unlikely to be achievable, we looked toward
alternative strategies for the construction of the targeted
binaphthyl.
Having established that the carbamate directing group could
likely be cleaved late in the synthesis, 20 was lithiated with sec-
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Scheme 5. Lithium−Halogen Exchange/Borylation of Bromides 22 and 26 and Addition of Boronic Acid 27 to Ramentaceone
(2)
a
1
Conversion determined by H NMR spectroscopy. See Table S4, Supporting Information, for detailed reaction conditions and results regarding
b
1
formation of 24 and 25. Combined H NMR yield. dppp = 1,3-bis(diphenylphosphino)propane.
BuLi/TMEDA34 and quenched with triisopropyl borate at
−78 °C. However, even at this temperature, the intermediate
aryllithium underwent anionic Fries rearrangement, out-
competing borylation to cleanly afford the amide 21 (Scheme
4). Repetition of the experiment at −98 °C slowed metalation,
but did not stabilize the transient aryllithium, as only amide 21
and the starting carbamate 20 were returned upon workup.
Poor solubility of 20 in other solvents precluded lower
temperature experiments and eliminated some potential
strategies for promoting DoM−borylation over the anionic
Fries rearrangement.35 The DoM−borylation approach was
therefore abandoned in favor of borylation via the correspond-
ing aryl halide.
Iodination of 1-naphthols can be complicated by the
formation of dimeric binaphthols;36 thus 9 was instead
smoothly converted to bromonaphthol 22 with pyridinium
tribromide37 (Scheme 5). Borylation of ortho-halonaphthols
such as 22 via both Miyaura-type chemistry and deprotona-
tion/lithium−halogen exchange is unprecedented, to the best
of our knowledge. Of these two strategies, Miyaura borylation
of 22 was not pursued due to the reported difficulties
borylating the simple substrate o-bromophenol,38 for which
deprotonation followed by lithium−bromine exchange success-
fully delivers 2-hydroxyphenylboronic acid;39 additionally, the
latter strategy has also been successfully applied to m- and p-
halo-1-naphthols.40
conversion of 22 to o-lithionaphthoxide 23, as assessed by
deuterium quenching experiments. However, this change did
not translate into good yields of boronic acid 24, as deuterium
quenching also showed that 23 was unstable at 0 °C in THF,
with a half-life of approximately 90 min (Table S4, Supporting
Information). Deprotonation of THF was strongly implicated,
as the decomposition of 23 was found to be significantly slower
in ether. This finding allowed for the boronic acid 24 to be
obtained in 16% conversion following a borate ester quench of
23, with further tuning of the reaction conditions (Table S4,
Supporting Information) improving the conversion to 39%.
This already poor result was further diminished by the facile
autoxidation of 24 to ortho-naphthoquinone 25.19d This
autoxidation occurred simply during reaction workup to
varying, not-insignificant, degrees and hindered attempts to
isolate 24. This complication, coupled with the poor yields of
boronic acid 24, dictated the protection of bromonaphthol 22
as its methyl ether 26. Lithium−bromine exchange of 264h and
quenching with triisopropyl borate provided a good yield of
27, a suitable boronic acid with which to further explore
arylation of ramentaceone (2).
Of the variety of protocols using arylboronic acids for the
arylation of quinones, methodologies that did not require
expensive catalysts18b,29d or a considerable excess of either the
arylboronic acid or the quinone coupling partner29c,41 were
most appealing. The protocols reported by Baran and co-
́
Initial attempts to generate lithium ortho-lithionaphthoxide
23 (Scheme 5) with 2.2 equiv of n-BuLi in ether at −78 °C
failed to achieve lithium−bromine exchange, returning
bromonaphthol 22. This result was first attributed to the
poor solubility of the lithium bromonaphthoxide in ether,
reasoning quickly proven incorrect when the result was
duplicated upon repetition of the experiment in THF, in
which the bromonaphthoxide dissolved completely (Table S4,
Supporting Information). Increasing the reaction temperature
of the lithium−halogen exchange to 0 °C effected complete
workers18d and Csaky et al.18c were selected, as they meet the
̈
above criteria and showed added promise, having succeeded in
the arylation of juglone. The work of Baran and co-workers is
representative of a strategy that has been employed by a
number of different research groups, in which a metal catalyst
and persulfate are used to generate aryl radicals from the
arylboronic acid, and nucleophilic radical addition to the
quinone leads to the desired products.42 Accordingly, these
conditions were tested in attempts to arylate ramentaceone (2)
with boronic acid 27; however, there was no evidence that
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Scheme 6. Synthesis of Diospyrin (1) and Idospyrin (7)
naphthylquinone 28 was produced across a number of
experiments (Table S5, Supporting Information).
The binaphthyl bond of naphthyljuglones 30 and 33and
of 31, 34, diospyrin (1), and idospyrin (7)is potentially
hindered enough to restrict rotation about its axis.47 Natural
diospyrin is optically inactive,3a,48 and it remains unclear
whether this is because there is unrestricted rotation about the
binaphthyl bond of 14h,49 or because natural diospyrin is
simply racemic.47 Thus, we did not attempt to control the
stereochemistry of the Suzuki−Miyaura reactions when
preparing naphthyljuglones 30 and 33.
́
The work from the Csaky
̈
group involves arylation of
quinones with arylboronic acids under palladium/copper
catalysis; that is, conjugate addition, followed by oxidation
with FeCl3 to furnish an arylquinone.18c Application of this
protocol to our system (Scheme 5) resulted in complete
deborylation of boronic acid 27 with low conversion of
ramentaceone (2) and formed both naphthyljuglones 28 in a
combined 9% yield. An attempt to improve upon this result by
changing the phosphine ligand to 1, 1′-bis-
(diphenylphosphino)ferrocene (dppf) resulted in no reaction.
Although all avenues for the arylation of ramentaceone (2)
had not been completely exhausted, the numerous strategies
tested (Schemes 3 and 5, Tables S2, S3, and S5, Supporting
Information) had failed to provide a promising lead. Thus, our
original plan to obtain both of the naphthyljuglones required
for synthesis of 1 and 7 from a single arylation experiment was
abandoned.
The pyridinium chloride and MnO2 global deprotection/
oxidation sequence that succeeded with naphthalenes 9 and 20
failed when applied to naphthyljuglones 30 and 33, affording
an insoluble black mass in both cases. Instead, oxidative
demethylation of 30 yielded diospyrin dimethyl ether (31),
4h
which was treated with AlCl3 to furnish diospyrin (1), for
which the physical and spectroscopic data match the literature
(Table S6, Supporting Information).4h This oxidative
demethylation/deprotection sequence was repeated with 33
to give the novel isomer idospyrin (7).
Antiproliferative Activity. The activity of diospyrin (1),
idospyrin (7), and precursors was assessed against the murine
myeloma-derived NS-1 (ATCC TIB-18) cell line and non-
cancerous neonatal foreskin fibroblasts (Nff) (ATCC PCS-
201), using a resazurin assay.50 The results are presented in
Table 1. While the resazurin assay determines mitochondrial
metabolic activity as a proxy for cell viability, natural diospyrin
(1) and its semisynthetic diethyl ether have previously been
shown to induce apoptosis in a variety of cancer cell lines.14a
Diospyrin (1) and the two precursors, GAP-R370 (30) and
diospyrin dimethyl ether (31), have similar growth inhibitory
activity against the NS-1 cell line and are somewhat selective,
with 10−30-fold lower potency against Nff. The biquinone
isomer idospyrin (7) and its dimethyl ether 34 have similar
potency and selectivity to diospyrin (1) and its precursors 30
and 31. The most potent and selective compound in the series
is the partially reduced tetramethyl ether GAP-R380 (33).
Diospyrin and a number of derivatives have been shown to
be cytotoxic to a variety of cancer cell lines, and the subject has
been reviewed.51 The monomer ramentaceone (2) and
diospyrin isomer isodiospyrin (3) have also both been
reported to be cytotoxic to human colon carcinoma cells
With arylboronic acid 27 in hand, the logical approach to
complete the syntheses of diospyrin (1) and idospyrin (7) was
via Suzuki−Miyaura cross-coupling (Scheme 6). For the
synthesis of 1, the required halojuglone coupling partner was
prepared by methylation of ramentaceone (2)43 followed by
bromination, with regioselective elimination of HBr from the
intermediate juglone dibromide44 furnishing the 2-bromide 29.
Inverting this sequence45 provided access to 3-bromojuglone
32 as the major regioisomer in 62% yield across two steps from
ramentaceone (2).
Initially, naphthylboronic acid 27 and 2-bromojuglone 29
were coupled under conditions described by Yoshida and Mori
in their synthesis of diospyrin.4h In our hands this procedure
gave unsatisfactorily low yields of naphthyljuglone 30, with
competing conjugate addition of EtOH to 29 identified as a
significant side-reaction. Switching to the conditions of
Narayan and Roush in their synthetic studies toward
angelmicin B46 resulted in a significantly improved yield of
30. These conditions were also effective for the coupling of 3-
bromojuglone 32 with 27 to afford the isomeric naphthylju-
glone 33.
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Table 1. Growth Inhibition of NS-1 (Murine Myeloma) and Nff (Neonatal Foreskin Fibroblast) Cells
a
b
All results are the average of three replicates the SEM. Percentage growth inhibition at 1 mM.
with similar IC50 values (Figure 2).52 However, isodiospyrin
was later found to be inactive against a panel of cell lines,
including Col-2, which was derived from a human colon
cancer. Ramentaceone (2), on the other hand, displayed broad
activity against multiple cell lines with low μg/mL IC50
values.53 In a study of the constituents of Diospyros maritima,
ramentaceone (2), the two methoxylated congeners 35 and 36,
the isomer plumbagin (38), and the plumbagin dimers
maritinone (39), chitranone (40), and zeylanone (41) (Figure
2) were all found to have comparable cytotoxicity to four
human cell lines.54
generation of reactive oxygen species (ROS).55 ROS have
also been implicated in the antitumor activity of diospyrin (1)
and its dimethyl and diethyl ethers.51,56 Indeed, production of
ROS is the mode of action most commonly attributed to
bioactive quinones, along with conjugation with the sulfhydryl
groups of glutathione and the cysteine residues of proteins.57
The similar growth inhibitory potency of the compounds
presented herein (1, 2, 7, and 31−34), despite significant
structural changes (especially the change of biaryl linkage), is
consistent with multiple modes of action involving chemical
reactivity, rather than discrete receptor−ligand interactions.
That said, diospyrin and its precursors are not indiscriminate
cytotoxins; in our hands, none displayed toxicity to Staph-
Ramentaceone (2) was shown to induce apoptosis in the
HL-60 (promyelocytic leukemia) cell line, through the
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Figure 2. A selection of cytotoxic naphthoquinones and dimers related to diospyrin. Note, natural zeylanone is racemic.58
ylococcus aureus, Candida albicans, and Tritrichomonas fetus at
concentrations up to 100 μg/mL.
through inhibtion of M. tuberculosis DNA gyrase, is shared by
idospyrin and their precursors and derivatives.
Dimerization is an efficient way to increase chemical
diversity in secondary metabolism; in principle, one monomer
can give rise to many different, considerably more complex
dimers. Hence, it is not surprising that this biosynthetic device
has evolved in all kingdoms of life. Dimerization is particularly
effective for quinones, where the inherent chemical reactivity
of the monomer is likely to be retained in dimers. However, as
previously noted,56 structural modifications affect physico-
chemical, pharmacokinetic, and pharmacodynamic properties
of quinones. These often subtle changes alter the profile of
biomolecules directly or indirectly impacted by quinonoid
natural products, thereby modulating their bioactivity. Occa-
sionally this must provide a selective advantage to the
producing organism; hence, the biosynthetic machinery is
evolutionarily preserved.
In summary, the 2,6′-bijuglone natural product diospyrin
(1) and its novel 3,6′-isomer idospyrin (7) have both been
synthesized in seven steps, diverging from senecioamide 13c,
in overall yields of 12% and 13%, respectively. A number of
strategies for the arylation of 2,3-unsubstituted naphthoqui-
nones were tested for their application to the syntheses of 1
and 7, without success. Ultimately, the desired arylation was
realized by Suzuki−Miyaura cross-coupling of the isomeric
bromojuglones.
Given that six of the possible 10 ramentaceone (2) dimers
have already been isolated from living organisms, it seems
likely that idospyrin (7) will eventually be proven a natural
product.
While diospyrin (1) and idospyrin (7) have quite potent
cytotoxicity and display some selectivity toward a myeloma cell
line over noncancerous cells, the fact that the monomer
ramentaceone (2) and derivatives/precursors share similar
cytotoxicity suggest their activity is not mediated through
discrete ligand−receptor interactions. It remains to be
established whether the antitubercular activity of diospyrin,
EXPERIMENTAL SECTION
■
General Experimental Procedures. All solvents were distilled
prior to use. THF, pentane, PhMe, and n-hexane were obtained from
a Pure Solv 5-Mid solvent purification system (Innovative Technology
Inc.). “Anhydrous THF” refers to THF freshly distilled from a purple
solution containing sodium benzophenone ketyl. “Dry” DMF, MeCN,
and CH2Cl2 refers to solvents stored over activated type 3A molecular
sieves for at least 24 h.59 “Degassed” solvents refer to solvents that
were vigorously stirred while being sparged with N2 for at least 30
min.
The concentration of solutions of n-BuLi and sec-BuLi were
determined by titration with N-benzylbenzamide.60 TMEDA was
dried over and distilled from CaH2 under N2 onto fresh KOH pellets
and was stored as such under N2.59a Diisopropylamine was dried over
and distilled from NaH under N2 onto fresh KOH pellets and was
stored as such under N2.59a N,N-Diethylsenecioamide (13c) was
prepared by a known method from 3,3-dimethylacrylic acid and
diethylamine.22 2-Chloro-1,4-dimethoxybenzene (15) was prepared
by a known method from 1,4-dimethoxybenzene.61 A solution of
chloromethyl methyl ether in MeOAc was prepared by a known
method from dimethoxymethane and acetyl chloride.62 All other
reagents and materials were purchased from commercial suppliers and
used as received.
All reactions, except method 1 for the preparation of 2, were
conducted in oven- or flame-dried glassware under an atmosphere of
N2 with the use of syringe and septum-cap techniques. Where
indicated, reaction temperatures refer to the temperature of the
heating or cooling bath. The temperature −78 °C indicated is
approximate and refers to the temperature achieved by a dry ice−
acetone bath. All organic extracts were evaporated under reduced
pressure at 40−45 °C. Trace residual solvent was removed under a
stream of N2.
Reaction progress was monitored by TLC using Merck aluminum-
backed TLC silica gel 60 F254 plates, which were also used for
preparative TLC. Spots were visualized using ultraviolet light. Flash
column chromatography was performed using Davisil chromato-
graphic silica media LC60A 40−63 μm.
G
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1H and 13C NMR spectra were acquired using Bruker Avance
[AB], J = 10.3 Hz, 1H), 6.909 (d [AB], J = 10.3 Hz, 1H), 2.44 (s,
19c
1
1
IIIHD (600 MHz for H and 150 MHz for 13C) and Bruker Avance
3H). The H NMR data match those in the literature.
1
IIIHD (500 MHz for H and 125 MHz for 13C) spectrometers, as
Method 2. A mixture of carbamate 20 (0.254 g, 0.802 mmol) and
pyridinium chloride (1.75 g, 15.1 mmol) was stirred under reflux for
20 min. The reaction mixture was briefly allowed to cool, but while
still a liquid, it was diluted with water (15 mL) and the resulting
suspension was cooled to room temperature and extracted with
EtOAc (4 × 10 mL). The extract was treated with Na2SO4 (0.767 g,
5.40 mmol) and MnO2 (1.05 g, 12.1 mmol), and the resulting brown
suspension was stirred at room temperature for 40 min. The reaction
mixture was vacuum filtered through a pad of Celite, washing the filter
cake with EtOAc (3 × 30 mL) until the washes were colorless, and
the filtrate was evaporated. The dark orange crude solid was subjected
to flash chromatography. Elution with 3:7 CH2Cl2/hexanes afforded 2
(0.112 g, 74%) as an orange solid, identical with the product
described above.
5,8-Dimethoxy-1-(methoxymethoxy)-3-methylnaphthalene
(17). A stirred suspension of NaH (0.592 g, 24.7 mmol; prepared by
washing a 60% mineral oil dispersion of NaH (0.986 g) with n-hexane
(35 mL)) in dry DMF (30 mL) at 0 °C was treated dropwise with a
solution of naphthol 9 (1.75 g, 8.00 mmol) in dry DMF (15 mL). The
resulting mixture was stirred at 0 °C for 15 min before a ca. 6.4 M
solution of chloromethyl methyl ether in MeOAc62 (4.6 mL, ca. 29
mmol) was added slowly. The reaction mixture was allowed to warm
to room temperature and was stirred for 30 min before being cooled
to 0 °C and quenched with saturated NH4Cl (10 mL). The resulting
suspension was diluted with water (150 mL) and extracted with Et2O
(3 × 100 mL). The extract was washed with brine (75 mL), dried
over Na2SO4, filtered, and evaporated. The off-white crude solid was
subjected to flash chromatography. Elution with 1:9 EtOAc/hexanes
afforded 17 (2.02 g, 96%) as a colorless solid, mp 63−65 °C. Rf (1:9
EtOAc/hexanes) 0.25; IR (ATR) νmax cm−1 1609, 1511, 1269, 1086,
1048, 846; 1H NMR (500 MHz, CDCl3) δ 7.75 (m [pseudo dd], J =
1.6, 0.9 Hz, 1H, H-4), 6.98 (d, J = 1.6 Hz, 1H, H-2), 6.704 (d [AB], J
= 8.6 Hz, 1H, H-7), 6.696 (d [AB], J = 8.6 Hz, 1H, H-6), 5.24 (s, 2H,
OCH2O), 3.94 (s, 3H, 5-OCH3), 3.90 (s, 3H, 8-OCH3), 3.61 (s, 3H,
CH2OCH3), 2,47 (s, 3H, ArCH3); 13C NMR (125 MHz, CDCl3) δ
indicated. Spectra were acquired at 25 °C unless otherwise indicated.
1
Spectra were calibrated against CHCl3 (for H spectra; δ 7.26) or
1
CDCl3 (for 13C spectra; δ 77.16) peaks. Yields determined by H
NMR spectroscopy used 1,3,5-trimethoxybenzene as an internal
standard. At least 10 mg of internal standard and of analyte were
completely dissolved for each determination. A 1H NMR spectrum of
the solution was then obtained with a relaxation delay of 30 s, and at
least 32 scans were collected.
High-resolution mass spectra were recorded on a Waters Liquid
Chromatograph Premier mass spectrometer using ESI and APCI in
positive or negative mode, as indicated. IR spectra were recorded on a
PerkinElmer Spectrum One FT-IR spectrometer with attenuated total
reflectance (ATR) using neat samples. Assignments of IR absorption
bands were made with reference to the literature.63 Melting points
were determined using a Reichert hot stage melting point apparatus.
Synthesis. 5,8-Dimethoxy-3-methylnaphthalen-1-ol (9). Meth-
od 1. Pd/C (10 wt % Pd, 1.05 g) was added to a solution of
hydroxymethylnaphthol 12 (7.71 g, 32.9 mmol) in AcOH (160 mL),
and the resulting suspension was degassed before being stirred at
room temperature under a balloon of H2 for 40 h. The reaction
mixture was diluted with Et2O (200 mL) and vacuum filtered through
a pad of Celite, washing the filter cake with Et2O (3 × 50 mL). The
filtrate was washed with water (3 × 150 mL), and the aqueous phase
was back-extracted with Et2O (150 mL). The combined organic
phases were washed with brine (150 mL), dried over MgSO4, filtered,
and evaporated. The tan crude solid was subjected to flash
chromatography. Elution with 1:9 EtOAc/hexanes afforded impure
9 as an off-white solid (6.23 g), which recrystallized from hexanes to
give 9 (5.59 g, 78%) as colorless needles, identical with the product
described below.
Method 2. A stirred solution of iPr2NH (2.50 mL, 17.7 mmol) in
anhydrous THF (30 mL) was cooled to 0 °C, treated dropwise with
2.16 M n-BuLi in hexanes (8.20 mL, 17.7 mmol), and stirred at 0 °C
for 15 min. The resulting solution of LDA was cooled to −78 °C
before being treated dropwise with a solution of N,N-diethylsene-
cioamide (13c)22 (0.792 g, 5.10 mmol) in anhydrous THF (20 mL).
The solution was stirred at −78 °C for 1 h and warmed to −20 °C
over 15 min before a solution of 2-chloro-1,4-dimethoxybenzene
(15)61 (1.777 g, 10.29 mmol) in anhydrous THF (10 mL) was added
dropwise, causing the reaction solution to turn orange. The solution
was allowed to warm to room temperature overnight (16 h) with
stirring before being quenched with saturated aqueous NH4Cl (10
mL), acidified with 1.5 M HCl (40 mL), and extracted with CHCl3 (3
× 40 mL). The extract was dried over Na2SO4, filtered, and
evaporated. The yellow crude residue was subjected to flash
chromatography. Elution with 1:9 EtOAc/hexanes afforded 9
(0.486 g, 44%) as a colorless solid, mp 114−115 °C [lit.19e mp
116−117 °C]; 1H NMR (500 MHz, CDCl3) δ 9.37 (s, 1H), 7.50 (m
[pseudo dd], J = 1.6, 0.9 Hz, 1H), 6.77 (d, J = 1.5 Hz, 1H), 6.62 (d
[AB], J = 8.4 Hz, 1H), 6.60 (d [AB], J = 8.4 Hz, 1H), 4.00 (s, 3H),
153.6 (C-1), 150.7 (C-8), 149.4 (C-5), 136.0 (C-3), 129.1 (C-4a),
117.9 (C-8a), 116.9 (C-2), 116.2 (C-4), 106.0 (C-7), 104.2 (C-6),
97.3 (OCH2O), 57.3 (8-OCH3), 56.6 (CH2OCH3), 55.9 (5-OCH3),
+
22.0 (ArCH3); HRMS (ESI+) m/z [M + H]+ calcd for C15H19O4
263.1278; found, 263.1276. NMR assignments were made with the
assistance of COSY, HSQC, and HMBC experiments.
N,N-Diethyl-O-(5,8-dimethoxy-3-methylnaphthalen-1-yl)-
carbamate (20). A stirred suspension of naphthol 9 (0.656 g, 3.01
mmol) and K2CO3 (0.630 g, 4.56 mmol) in dry MeCN (20 mL) was
treated with ClCONEt2 (0.95 mL, 7.50 mmol) at room temperature.
The reaction mixture was stirred under reflux for 30 h before being
cooled to room temperature, diluted with water (50 mL), and
extracted with Et2O (3 × 30 mL). The extract was washed with water
(20 mL) and brine (20 mL), dried over Na2SO4, filtered, and
evaporated. The brown crude oil was subjected to flash chromatog-
raphy. Elution with 1:4 EtOAc/hexanes afforded 20 (0.933 g, 98%) as
a colorless oil that crystallized on standing to a colorless solid, mp
118−120 °C. Rf (1:4 EtOAc/hexanes) 0.3; IR (ATR) νmax cm−1 1699
1
3.94 (s, 3H), 2.44 (s, 3H). The H NMR data match those in the
literature.19d,e
1
(s, CO), 1607, 1506, 1364, 1261, 1059, 871, 812; H NMR (500
5-Hydroxy-7-methyl-1,4-naphthoquinone (7-Methyljuglone, Ra-
mentaceone) (2). Method 1. A mixture of naphthol 9 (1.09 g, 5.00
mmol) and pyridinium chloride (6.36 g, 55.0 mmol) was stirred
under reflux for 30 min. The reaction mixture was briefly allowed to
cool, but while still a liquid, it was diluted with water (40 mL), and
the resulting suspension was cooled to room temperature and
extracted with EtOAc (4 × 30 mL). The extract was treated with
Na2SO4 (4.30 g, 30.3 mmol) and MnO2 (6.52 g, 75.0 mmol), and the
resulting brown suspension was stirred at room temperature for 40
min. The reaction mixture was vacuum filtered through a pad of
Celite, washing the filter cake with EtOAc (3 × 40 mL) until the
washes were colorless. Evaporation of the filtrate gave 2 (0.785 g,
83%) as an orange solid, mp 120−122 °C [lit.19c 120.5−122 °C]. 1H
NMR (500 MHz, CDCl3) δ 11.86 (s, 1H), 7.44 (m [pseudo dd], J =
1.5, 0.3 Hz, 1H), 7.09 (m [pseudo dd], J = 1.5, 0.7 Hz, 1H), 6.918 (d
MHz, CDCl3) δ 7.89 (m [pseudo dd], J = 1.6, 0.9 Hz, 1H, H-4), 7.00
(d, J = 1.6 Hz, 1H, H-2), 6.67 (d [AB], J = 8.5 Hz, 1H, H-6), 6.63 (d
[AB], J = 8.5 Hz, 1H, H-7), 3.93 (s, 3H, 5-OCH3), 3.82 (s, 3H, 8-
OCH3), 3.55 (q, J = 7.1 Hz, 2H, NCH2)*, 3.42 (q, J = 7.1 Hz, 2H,
NCH2)∧, 2.47 (s, 3H, ArCH3), 1.32 (t, J = 7.1 Hz, 3H, NCH2CH3)*,
1.23 (t, J = 7.1 Hz, 3H, NCH2CH3)∧; 13C NMR (125 MHz, CDCl3)
δ 155.3 (CO), 149.7 (C-8), 149.1 (C-5), 147.1 (C-1), 135.8 (C-3),
128.8 (C-4a), 122.7 (C-2), 119.1 (C-4), 118.8 (C-8a), 104.2 (C-6 or
C-7), 104.1 (C-6 or C-7), 56.0 (5-OCH3), 55.8 (8-OCH3), 42.1
(NCH2)∧, 41.8 (NCH2)*, 21.6 (ArCH3), 14.2 (NCH2CH3)*, 13.6
(NCH2CH3)∧; HRMS (ESI+) m/z [M + H]+ calcd for C18H24O4N+
318.1700; found, 318.1700. NMR assignments were made with the
assistance of COSY, HSQC, and HMBC experiments. Superscripts (*,
∧) denote resonances that belong to the same spin system.
H
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N,N-Diethyl-1-hydroxy-5,8-dimethoxy-3-methyl-2-naphthamide
(21). TMEDA (40 μL, 0.27 mmol) was added to a solution of
carbamate 20 (63 mg, 0.20 mmol) in anhydrous THF (4.0 mL). The
resulting solution was cooled to −78 °C over 20 min and stirred as it
was slowly treated dropwise with 1.06 M sec-BuLi in cyclohexane
(0.27 mL, 0.29 mmol). The resulting brown solution was stirred at
−78 °C for 20 min before being quenched with triisopropyl borate
(0.11 mL, 0.48 mmol), stirred at −78 °C for a further 1 h, and
allowed to warm slowly to room temperature overnight (17 h). The
reaction mixture was acidified with 0.1 M HCl (7 mL), diluted with
water (5 mL), and extracted with EtOAc (3 × 15 mL). The extract
was washed with brine (15 mL), dried over Na2SO4, filtered, and
evaporated. The brown crude oil was subjected to flash chromatog-
raphy. Elution first with 1:4 EtOAc/hexanes and increasing polarity to
2:3 EtOAc/hexanes afforded 21 (53 mg, 84%) as a colorless residue,
which solidified on standing to give an off-white solid, mp 126−127
°C. Rf (2:3 EtOAc/hexanes) 0.2; IR (ATR) νmax cm−1 3356 (m, OH),
1′,5,5′,8′-Tetramethoxy-3′,7-dimethyl-[3,2′-binaphthalene]-1,4-
dione; GAP-R380 (33). A stirred solution of bromojuglone 32 (90 mg,
0.32 mmol), boronic acid 27 (93 mg, 0.34 mmol), and Cl2Pd(dppf)·
CH2Cl2 (40 mg, 49 μmol) in degassed THF (6.4 mL) was treated
with 1 M aqueous K3PO4 (0.64 mL, 0.64 mmol). The resulting
mixture was stirred vigorously at 60 °C for 9 h before being cooled to
room temperature, diluted with water (25 mL), and extracted with
CH2Cl2 (3 × 25 mL). The extract was washed with brine (20 mL),
dried over Na2SO4, filtered, and evaporated. The red-brown crude
residue was subjected to flash chromatography. Elution with 3:7
EtOAc/hexanes, increasing polarity to 7:13 EtOAc/hexanes, afforded
33 (0.118 g, 85%) as an orange-red solid. A sample was recrystallized
from Et2O/hexanes as orange-red granules, mp 159−160 °C. Rf (2:3
EtOAc/hexanes) 0.35; IR (ATR) νmax cm−1 1657 (s, CO), 1623,
1597, 1258, 1071, 850, 800; 1H NMR (600 MHz, CDCl3) δ 7.91 (q, J
= 0.9 Hz, 1H, H-4′), 7.62 (m [pseudo dd], J = 1.5, 0.6 Hz, 1H, H-8),
7.12 (br s, 1H, H-6), 6.86 (s, 1H, H-2), 6.74 (d [AB], J = 8.5 Hz, 1H,
H-6′), 6.72 (d [AB], J = 8.5 Hz, 1H, H-7′), 3.96 (s, 3H, 5′-OCH3),
3.95 (s, 3H, 5-OCH3), 3.92 (s, 3H, 8′-OCH3), 3.65 (s, 3H, 1′-
OCH3), 2.51 (s, 3H, 7-CH3), 2.29 (d, J = 0.9 Hz, 3H, 3′-CH3); 13C
NMR (150 MHz, CDCl3) δ 185.6 (C-1), 183.5 (C-4), 160.2 (C-5),
153.7 (C-1′), 150.2 (C-3), 150.0 (C-8′), 149.4 (C-5′), 146.4 (C-7),
135.6 (C-2), 134.6 (C-3′), 134.4 (C-8a), 128.9 (C-4a′), 127.9 (C-2′),
119.8 (C-8), 119.0 (C-8a′), 118.5 (C-6), 118.4 (C-4′), 118.3 (C-4a),
105.3 (C-7′), 104.6 (C-6′), 62.9 (1′-OCH3), 56.6 (8′-OCH3), 56.5
(5-OCH3), 56.0 (5′-OCH3), 22.5 (7-CH3), 20.7 (3′-CH3); HRMS
1
1623 (s, CO), 1606, 1497, 1362, 1246, 1065, 862; H NMR (500
MHz, CDCl3) δ 9.58 (s, 1H, OH), 7.55 (q, J = 0.8 Hz, 1H H-4), 6.64
(AB [app. s], 2H, H-6, H-7), 3.99 (s, 3H, 8-OCH3), 3.94 (s, 3H, 5-
OCH3), 3.79 (dq [pseudo sextet], J = 14.1, 7.1 Hz, 1H, NCH2)*, 3.51
(dq [pseudo sextet], J = 14.1, 7.1 Hz, 1H, NCH2)*, 3.23 (dq [pseudo
sextet], J = 14.3, 7.1 Hz, 1H, NCH2)∧, 3.18 (dq [pseudo sextet], J =
14.3, 7.1 Hz, 1H, NCH2)∧, 2.38 (d, J = 0.8 Hz, 3H, 3CH3), 1.29 (dd
[app. t], J = 7.1 Hz, 3H, NCH2CH3)*, 1.06 (dd [app. t], J = 7.1 Hz,
3H, NCH2CH3)∧; 13C NMR (125 MHz, CDCl3) δ 168.6 (CO),
150.4 (C-8), 150.0 (C-1), 149.8 (C-5), 134.1 (C-3), 127.9 (C-4a),
121.5 (C-2), 113.9 (C-8a), 113.6 (C-4), 103.7 (C-6 or C-7), 103.2
(C-6 or C-7), 56.5 (8-OCH3), 55.9 (5-OCH3), 42.8 (NCH2)∧, 38.9
(NCH2)*, 19.6 (3CH3), 14.2 (NCH2CH3)∧, 13.0 (NCH2CH3)*;
HRMS (ESI+) m/z [M + H]+ calcd for C18H24O4N+ 318.1700;
found, 318.1711. NMR assignments were made with the assistance of
+
(ESI+) m/z [M + H]+ calcd for C26H25O6 433.1646; found,
433.1664. NMR assignments were made with the assistance of COSY,
HSQC, and HMBC experiments.
5,5′-Dimethoxy-7,7′-dimethyl-[3,6′-binaphthalene]-1,1′,4,4′-tet-
raone; Idospyrin Dimethyl Ether (34). A stirred solution of GAP-
R380 (33) (78 mg, 0.18 mmol) in 5:2 MeCN/water (7.7 mL) was
cooled to 0 °C and treated dropwise with a cold (0 °C) solution of
cerium(IV) ammonium nitrate (0.301 g, 0.549 mmol) in 1:1 MeCN/
water (6.4 mL) over 10 min. The reaction mixture was stirred at 0 °C
for 70 min, forming a yellow suspension, which was diluted with water
(20 mL) and extracted with CH2Cl2 (3 × 15 mL). The extract was
washed with brine (15 mL), dried over Na2SO4, filtered, and
evaporated to give 34 (71 mg, 98%) as a yellow-orange solid, mp
188−192 °C. Rf (2:3 EtOAc/hexanes) 0.3; IR (ATR) νmax cm−1 1658
(s, CO), 1598, 1581, 1277, 1263, 1057, 1039; 1H NMR (500 MHz,
CDCl3) δ 7.82 (q, J = 0.6 Hz, 1H, H-8′), 7.63 (m [pseudo dd], J =
1.5, 0.6 Hz, 1H, H-8), 7.14 (br s, 1H, H-6), 6.92 (d [AB], J = 10.3 Hz,
1H, H-2′), 6.88 (d [AB], J = 10.3 Hz, 1H, H-3′), 6.78 (s, 1H, H-2),
3.97 (s, 3H, 5-OCH3), 3.71 (s, 3H, 5′-OCH3), 2.52 (s, 3H, 7-CH3),
2.30 (d, J = 0.6 Hz, 3H, 7′-CH3); 13C NMR (125 MHz, CDCl3) δ
185.0 (C-1 and C-1′), 183.9 (C-4′), 182.5 (C-4), 160.4 (C-5), 158.1
(C-5′), 148.1 (C-3), 147.0 (C-7), 144.9 (C-7′), 140.7 (C-3′), 137.0
(C-6′), 136.9 (C-2′), 135.5 (C-2), 134.2 (C-8a), 133.7 (C-8a′), 124.4
(C-8′), 121.7 (C-4a′), 120.1 (C-8), 118.7 (C-6), 117.8 (C-4a), 62.7
(5′-OCH3), 56.6 (5-OCH3), 22.5 (7-CH3), 20.9 (7′-CH3); HRMS
∧
COSY, HSQC, and HMBC experiments. Superscripts (*, ) denote
resonances that belong to the same spin system.
1′,5,5′,8′-Tetramethoxy-3′,7-dimethyl-[2,2′-binaphthalene]-1,4-
dione; GAP-R370 (30). Method 1.4h A mixture of bromojuglone 29
(0.114 g, 0.404 mmol) and Pd(PPh3)4 (45 mg, 39 μmol) was stirred
in degassed PhMe (5.2 mL) for 15 min and treated with a degassed 2
M aqueous Na2CO3 solution (0.33 mL, 0.66 mmol) followed by a
solution of boronic acid 27 (0.125 g, 0.453 mmol) in degassed EtOH
(1.3 mL). The resulting mixture was stirred under reflux for 6 h before
being cooled to room temperature, diluted with water (10 mL), and
extracted with CHCl3 (3 × 20 mL). The extract was washed with
brine (15 mL), dried over Na2SO4, filtered, and evaporated. The
green crude residue was subjected to flash chromatography. Elution
with CH2Cl2 afforded impure 30 as a red film (44 mg), which was
again subjected to flash chromatography. Elution with 3:7 EtOAc/
hexanes furnished 30 (19 mg) as an orange-red solid. Additionally,
impure fractions were subjected to preparative TLC. Development
with 2:3 EtOAc/hexanes afforded 30 (11 mg) as a red-orange solid
(total 30 mg, 17%), spectroscopically identical with the product
described below.
+
(ESI+) m/z [M + H]+ calcd for C24H19O6 403.1176; found,
Method 2. A stirred solution of bromojuglone 29 (0.121 g, 0.430
mmol), boronic acid 27 (0.126 g, 0.456 mmol), and Cl2Pd(dppf)·
CH2Cl2 (72 mg, 88 μmol) in degassed THF (8.6 mL) was treated
with 1 M aqueous K3PO4 (0.86 mL, 0.86 mmol). The resulting
mixture was stirred vigorously at 60 °C for 6 h before being cooled to
room temperature, diluted with water (30 mL), and extracted with
CH2Cl2 (4 × 25 mL). The extract was washed with brine (25 mL),
dried over Na2SO4, filtered, and evaporated. The red-brown crude
residue was subjected to flash chromatography. Elution first with
1:5:44 NEt3/EtOAc/hexanes and increasing polarity to 1:15:34
NEt3/EtOAc/hexanes afforded 30 (0.111 g, 60%), which crystallized
upon evaporation of relevant fractions as red prisms, mp 202−204 °C
[lit.4h 195−196 °C]. 1H NMR (500 MHz, CDCl3) δ 7.94 (q, J = 0.9
Hz, 1H), 7.63 (m [pseudo dd], J = 1.5, 0.6 Hz, 1H), 7.14 (br s, 1H),
6.86 (s, 1H), 6.74 (d [AB], J = 8.5 Hz, 1H), 6.73 (d [AB], J = 8.5 Hz,
1H), 4.04 (s, 3H), 3.96 (s, 3H), 3.92 (s, 3H), 3.64 (s, 3H), 2.50 (s,
3H), 2.28 (d, J = 0.9 Hz, 3H). The 1H NMR data match those in the
literature.4h
403.1179. NMR assignments were made with the assistance of COSY,
HSQC, and HMBC experiments.
5,5′-Dihydroxy-7,7′-dimethyl-[3,6′-binaphthalene]-1,1′,4,4′-tet-
raone; Idospyrin (7). A stirred solution of idospyrin dimethyl ether
(34) (64 mg, 0.16 mmol) in CH2Cl2 (14 mL) was cooled to 0 °C and
treated with AlCl3 (0.227 g, 1.70 mmol) added in one portion. The
reaction mixture was allowed to warm from 0 °C to room temperature
gradually over 12 h. The dark purple reaction mixture was cooled to 0
°C and quenched with water (20 mL), acidified with 10% aqueous
citric acid (20 mL), and separated. The aqueous phase was extracted
with CHCl3 (3 × 20 mL). The organic phases were combined,
washed with brine (20 mL), dried over Na2SO4, filtered, and
evaporated. The dark red crude residue was subjected to flash
chromatography. Elution first with 1:4 CHCl3/PhMe and increasing
polarity to 2:3 CHCl3/PhMe afforded impure 7 as a red solid (51
mg). Trituration of this solid with 1:9 CH2Cl2/hexanes afforded 7 (42
mg, 71%) as a red powder, mp 217−220 °C. Rf (CH2Cl2) 0.5; IR
(ATR) νmax cm−1 1664 (s, 1-CO, 1′-CO), 1632 (s, 4-CO, 4′-
I
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CO), 1612, 1592, 1379, 1364, 1342, 1259, 1216, 1095, 1052, 847;
1H NMR (600 MHz, CDCl3) δ 12.16 (s, 1H, 5′-OH), 11.84 (s, 1H,
5-OH), 7.58 (br s, 1H, H-8′), 7.52 (m [pseudo dd], J = 1.5, 0.4 Hz,
1H, H-8), 7.12 (m [pseudo dd], J = 1.5, 0.8 Hz, 1H, H-6), 6.97 (AB
[app. s], 2H, H-2′ and H-3′), 6.88 (s, 1H, H-2), 2.47 (s, 3H, 7-CH3),
2.33 (s, 3H, 7′-CH3); 13C NMR (150 MHz, CDCl3) δ 189.9 (C-4′),
187.8 (C-4), 184.3 (C-1′), 184.1 (C-1), 162.3 (C-5), 159.3 (C-5′),
149.0 (C-7), 146.7 (C-7′), 145.1 (C-3), 139.6 (C-2′ or C-3′), 139.5
(C-2), 138.9 (C-2′ or C-3′), 132.0 (C-8a), 131.6 (C-8a′), 128.5 (C-
6′), 124.5 (C-6), 120.9 (C-8′), 120.8 (C-8), 113.2 (C-4a), 113.1 (C-
4a′), 22.4 (7-CH3), 21.3 (7′-CH3); HRMS (APCI+) m/z [M + H]+
Natori, S. Chem. Pharm. Bull. 1971, 19, 851−854. (e) Van Der Vijver,
L. M.; Gerritsma, K. W. Pharm. Weekbl. 1976, 111, 1273−1285.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c00800.
■
sı
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Phytochemistry 2004, 65, 1265−1271.
Experimental procedures and characterization data for
compounds 1,4h 11,24 12,64 22,37 26,4g 27,4h 29,43,44
31,4h and 32;45,65 tables detailing additional experiments
and their results; and 13C and H NMR spectra of new
1
and known compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Glenn A. Pullella − Chemistry, School of Molecular Sciences,
University of Western Australia, Perth 6009, Australia;
orcid.org/0000-0002-8158-7936; Email: glenn.pullella@
research.uwa.edu.au
Matthew J. Piggott − Chemistry, School of Molecular Sciences,
University of Western Australia, Perth 6009, Australia;
orcid.org/0000-0002-5857-7051;
́
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Email: matthew.piggott@uwa.edu.au
Authors
Daniel Vuong − Microbial Screening Technologies, Smithfield,
NSW 2164, Australia
Ernest Lacey − Microbial Screening Technologies, Smithfield,
NSW 2164, Australia
Valentao, P.; Oliveira, J. M. A.; Andrade, P. B. PLoS One 2014, 9,
̃
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jnatprod.0c00800
e90122. (h) Uddin, G.; Rauf, A.; Siddiqui, B. S.; Muhammad, N.;
Khan, A.; Shah, S. U. A. Phytomedicine 2014, 21, 954−959.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the UWA Centre for Characterisation, Microscopy
and Analysis, in particular Drs. Gareth Nealon and Michael
Clarke, for assistance with NMR spectroscopy and mass
spectrometry, respectively. G.A.P. is the recipient of an
Australian Postgraduate Award.
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