Biomimetic synthesis of the apoptosis-inducing thiazinoquinone thiaplidiaquinone A

Article abstract of DOI:10.1021/jo301738u

A concise total synthesis of the apoptosis-inducing, marine metabolite thiaplidiaquinone A is described. The key ring forming steps are both based on biosynthetic considerations and involve the construction of the central benzo[c]chromene quinone unit by an extremely facile oxa-6π-electrocyclic ring closure reaction of an ortho-quinone intermediate, derived by tautomerization of a bis-benzoquinone, readily accessed from two simple phenolic precursors. This is followed by the installation of the 1,4-thiazine-dioxide ring by reaction of the benzo[c]chromene quinone with hypotaurine.

Full text of DOI:10.1021/jo301738u

Article
pubs.acs.org/joc
Biomimetic Synthesis of the Apoptosis-Inducing Thiazinoquinone
Thiaplidiaquinone A
Anna Carbone, Catherine L. Lucas, and Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U. K.
S
* Supporting Information
ABSTRACT: A concise total synthesis of the apoptosis-
inducing, marine metabolite thiaplidiaquinone A is described.
The key ring forming steps are both based on biosynthetic
considerations and involve the construction of the central
benzo[c]chromene quinone unit by an extremely facile oxa-6π-
electrocyclic ring closure reaction of an ortho-quinone
intermediate, derived by tautomerization of a bis-benzoqui-
none, readily accessed from two simple phenolic precursors.
This is followed by the installation of the 1,4-thiazine-dioxide
ring by reaction of the benzo[c]chromene quinone with
hypotaurine.
An alternative entry into ortho-quinone methide intermedi-
INTRODUCTION
■
ates that can undergo oxa-6π electrocyclization is by
tautomerization of ortho-prenylated quinones.11−13 Important
contributions in this field include Trauner’s syntheses of other
naturally occurring chromenes such as microphyllaquinone12
and exiguamine A,14 two compounds belonging to a rare but
biologically interesting subclass of naturally occurring chro-
menes, the benzo[c]chromene-7,10-diones (Figure 1). In
addition to the cytotoxic microphyllaquinone and the potent
inhibitor of indoleamine-2,3-dioxygenase exiguamine A, this
class also includes tecomaquinone I isolated from teak15,16 and
the antimalarial scabellone B.17 We now report the details of
the first synthesis of a structurally unique member of this family
of natural products, the 1,4-thiazine dioxide-containing,
thiaplidiaquinone A 1.
Biomimetic synthesis, or synthesis inspired by biosynthetic
consideration, is a powerful tool in organic chemistry and has
been applied in numerous routes to complex natural
products.1,2 Within this rapidly expanding arena, pericyclic
reactions (cycloadditions, electrocyclizations and sigmatropic
rearrangements), long regarded as one of the cornerstones of
synthesis, are playing an increasingly important role.3−5 One
subset of such processes, oxa-6π electrocyclizations, are of
particular interest since they usually have low activation
barriers, are often reversible, and are quite common in the
biosynthesis of oxygen heterocycles such as chromenes from
phenolic precursors.4 We now report the use of such a process
in a total synthesis of the apoptosis-inducing marine metabolite
thiaplidiaquinone A 1, a structurally unique benzo[c]chromene
quinone. The key ring forming steps are both based on
biosynthetic considerations, and involve the construction of the
central chromene unit by an extremely facile oxa-6π-electro-
cyclic ring closure reaction that occurs under neutral conditions
at room temperature, followed by installation of the 1,4-
thiazine-dioxide ring by reaction with hypotaurine.
Chromene (2H-benzopyran) natural products are widely
distributed6 and are often isoprene derived, arising by an oxa-6π
electrocyclic process on an ortho-quinone methide intermediate
(Scheme 1A).7 In nature, dehydrogenase enzymes appear to
catalyze such processes as in the case of the biosynthesis of
cannabichromenic acid (CBCA) from the corresponding ortho-
geranyl phenol (CBGA) in Cannabis sativa (Scheme 1B).8 The
reversibility of oxa-6π electrocyclizations has been invoked to
explain the observation that some chromenes such as
smenochromene A are isolated as a racemate or undergo facile
racemization via an electrocyclic ring-opening-electrocyclization
sequence (Scheme 1C).9,10
RESULTS AND DISCUSSION
■
Quinones are ubiquitous in nature occurring as secondary
metabolites in many organisms,18 as pollutants, for example, in
automobile exhaust or cigarette smoke, or as molecules that are
essential to life, being inextricably linked with oxidative
processes in cells. Thus ubiquinones (coenzymes Q) are
present in virtually all aerobic organisms from bacteria to higher
plants and animals, and play a major role in electron transport
in the respiratory chain. The closely related plastoquinones
occur in the chloroplast of green plants and are essential for
photosynthesis. As part of our ongoing studies on the synthesis
of naturally occurring quinones,19−22 we became interested in
the highly unusual thiazine-containing quinones,23 the
thiaplidiaquinones, reported in 2005 by Fattorusso and co-
workers.24 Thiaplidiaquinones A and B were isolated from the
Received: August 18, 2012
Published: September 28, 2012
© 2012 American Chemical Society
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Scheme 1. Oxa-6π Electrocyclization Reactions in
a
Biosynthesis
a
(A) General scheme for cyclization of ortho-prenylated phenols via
Figure 1. Benzo[c]chromene-7,10-dione natural products.
oxa-6π electrocyclization of an ortho-quinone methide intermediate;
(B) biosynthesis of cannabichromenic acid (CBCA) from cannabiger-
olic acid (CBGA); (C) possible route for racemization of
smenochrome A.
Mediterranean ascidian Aplidium conicum, collected off the
coast of Sardinia. The compounds were isolated as racemates
and their “unprecedented tetracyclic structures” were assigned
by extensive NMR spectroscopic studies. Structurally the
thiaplidiaquinones are related to other prenylated thiazino-
quinones isolated from the same organism, namely the
conicaquinones,25 and the aplidinones (Figure 2).26 Other
marine natural products that contain the same 1,4-thiazine-1,1-
dioxide-quinone chromophore23 are adociaquinone A,27 and
ascidiathiazone A (Figure 2).28 The thiaplidiaquinones are
interesting from the biological perspective, inducing apoptosis,
and hence cell death, in cancer cell lines by a mechanism that
involves the production of intracellular reactive oxygen species.
Our plan for the synthesis of thiaplidiaquinone A was based
on biosynthetic considerations, and involved a biomimetic late
stage construction of the 1,4-thiazine-1,1-dioxide ring by
addition of hypotaurine to the tricyclic pyranoquinone 3,
despite the fact that such an addition might be fraught with
issues of regioselectivity (see below). The key pyranoquinone 3
would arise by the pivotal biomimetic oxa-6π electrocyclic ring
closure of ortho-quinone methide intermediate 4, obtained by
Figure 2. Marine natural products containing the 1,4-thiazine-1,1-
dioxide-quinone moiety.
tautomerization of bis-benzoquinone 5 (Scheme 2). The fact
that there would be no stereocontrol in such an oxa-6π
electrocyclization is inconsequential since the natural product is
racemic. Indeed one might speculate that the reason it is
racemic is the facile reversibility of such oxa-6π electro-
cyclizations (cf. Scheme 1C). The required bis-benzoquinone 5
should be readily accessible by union of the hydroquinone
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the three phenolic groups could be manipulated separately if
necessary. This was readily prepared from 2,5-dihydroxyben-
zaldehyde by sequential protection of the two phenolic OH
groups followed by Dakin oxidation and protection of the new
OH group.30 The geranyl substituent could then be installed by
lithiation of protected 1,2,4-trihydroxybenzene 8 with n-
butyllithium, followed by alkylation with geranyl bromide.
This approach provided the desired geranylated compound 9 in
good yield. Deprotection of the THP protecting group and
methylation under standard conditions furnished diprotected
methoxybenzene 11 in near quantitative yield for the two steps
(Scheme 3). Deprotection of the two ether protecting groups
Scheme 2. Retrosynthesis of the Thiaplidiaquinones
a
Scheme 3. Synthesis of Iso-Aplidinone A 13
derivatives 6 [M = SnR3 or B(OR)2] and 7 (X = halide or OTf)
under palladium catalysis followed by oxidation.
Hypotaurine occurs widely in nature and is an intermediate
in the biosynthesis of taurine from cysteine. The co-occurrence
in the same organism of metabolites such as adociaquinone A
(Figure 2) with xestoquinone, the corresponding compound
lacking the thiazinedioxide ring, strongly suggests that the two
compounds are biosynthetically related by the addition of
hypotaurine.27,29 Indeed, such steps have been investigated in
the laboratory. Thus, for example, addition of hypotaurine to
the naturally occurring unsymmetrical naphthoquinone xesto-
quinone gives both regioisomers of the adduct, adociaquinones
A and B, with a selectivity of 2−3:1,27,29 while addition of
hypotaurine to 2-methoxycarbonylquinoline-5,8-quinone was
more selective, giving a 10:1 ratio of dioxothiazine adducts, with
the desired precursor to ascidiathiazone A predominating.28
Notwithstanding the varying outcomes with respect to the
addition to unsymmetrical quinones, one of the key steps in our
approach to thiaplidiaquinone A remained the biomimetic
addition of hypotaurine to benzoquinone 3 (Scheme 2).
However, given the uncertainty of the outcome of this key step,
we undertook a brief model study on a simpler geranyl
substituted benzoquinone 12, that contained both a geranyl
side chain and an electron donating methoxy group on the
quinone nucleus. Our route to benzoquinone 12 started with
the triply protected 1,2,4-trihydroxybenzene 8, chosen so that
a
Reagents and conditions: (a) (i) n-butyllithium, THF, 0 °C, 45 min,
(ii) geranyl bromide, 0 °C to rt, 16 h, 69%; (b) HCl(aq), EtOH, rt, 30
min, 97%; (c) (i) NaH, DMF, 0 °C, 30 min, (ii) MeI, 0 °C to rt, 3.5 h,
95%; (d) CSA, MeOH, 16.5 h, then salcomine, O2, MeCN, 50 min,
95% (2 steps); (e) hypotaurine, MeCN−EtOH, salcomine, rt (32%).
was efficiently achieved with camphorsulfonic acid in methanol
to provide the hydroquinone, which without isolation was
subsequently oxidized to quinone 12 using a catalytic amount
of salcomine under an atmosphere of oxygen (Scheme 3).
Quinone 12 was isolated as a bright yellow oil, with data
identical to those previously published.31 Addition of
hypotaurine to 2-methoxy-3-geranyl-1,4-benzoquinone 12
carried out in the presence of salcomine to aid the reoxidation
step, gave a single benzothiazine quinone in modest yield. The
structure of the product was assigned as thiazino quinone 13, a
compound we term iso-aplidinone A since it is the regioisomer
of the natural product aplidinone A,26 on the basis of NMR
spectroscopy (see Supporting Information). In particular, a
multiple bond HMBC experiment with a large number of scans
enabled correlations to be seen from the thiazine NH to
carbons in the benzoquinone structure, confirming that the NH
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is attached to the opposite quinone carbonyl compared to the
geranyl and sulfone methylene hydrogens. Hence in this model
system the addition of hypotaurine appears to be regioselective,
boding well for the crucial addition to the “real” quinone 3.
We next decided to employ a model system in order to study
the best conditions for the crucial 6π-electrocyclization,
synthesizing a simpler biaryl compound 18 containing only
one geranyl chain. This compound could be readily obtained
through a Suzuki−Miyaura reaction between the commercially
available 2,5-dimethoxybenzeneboronic acid and aryl triflate 17
(Scheme 4). Synthesis of triflate 17 began with the Dakin
yield. Suzuki coupling between triflate 17 and the boronic acid
using tetrakis(triphenylphosphine)palladium(0), cesium carbo-
nate in a mixture of dimethylformamide−water under micro-
wave irradiation gave biaryl compound 18 in 80% yield.
Oxidation of 18 with silver(II) oxide in the presence of nitric
acid33 afforded the bis-p-benzoquinone 19, a convenient
starting material for 6π-electrocyclization. Treatment of the
bis-p-benzoquinone 19 with triethylamine in dichloromethane
at room temperature for 1 h initiated tautomerization to the
ortho-quinone methide and 6π-electrocyclization to give the
desired benzo[c]chromene-7,10-dione 20 in 73% yield
(Scheme 4).
The tandem tautomerization−electrocyclization of bis-
benzoquinone 19 is extremely facile and was also observed
without the addition of the base, simply upon allowing the
quinone to stir in solution in dichloromethane at room
temperature, although the reaction proceeded very slowly (7
days) and with low yield (15%). Nevertheless the ease with
which the reaction proceeded was encouraging for the
projected synthesis of the thiaplidiaquinones. As an aside, we
also investigated the direct functionalization of benzo[c]-
chromene-7,10-dione 20 by regioselective introduction of a
geranyl side chain ortho to the phenol with a view to the
synthesis of thiaplidiaquinone B. A range of conditions was
used, including the use of geranyl bromide in the presence of
bases such as sodium hydride,34 potassium carbonate,35 or
potassium hydroxide,36 or geraniol in the presence of boron
trifluoride-diethyl etherate,37 Amberlyst-15,38 or scandium(III)
triflate,39 but unfortunately all without success.
Scheme 4. Synthesis of Model Benzo[c]chromene-7,10-
a
dione 20
Hence in order to obtain the two natural compounds, it was
necessary to introduce the second geranyl chain before
cyclization, as part of the boronic acid partner used in the
Suzuki coupling, requiring the synthesis of boronic esters 24
and 30. The synthesis of boronate 24 started with protection of
the known dibromide 2140 as its MOM-ether 22 in 73% yield.
ortho-Lithiation of 22 with n-butyllithium at −78 °C was
followed by addition of copper(I) bromide dimethylsulfide
complex and geranyl bromide to give compound 23 in modest
yield. The boronate moiety was installed via lithium−halogen
exchange of the remaining bromine and reaction with iso-
propoxypinacol boronate to provide the desired boronic ester
24, which was used in the next step without purification
(Scheme 5). With the two functionalized coupling partners, aryl
triflate 17 and boronic ester 24, we could access the oxa-6π
cyclization precursor for thiaplidiaquinone A. The Suzuki
reaction, using the same conditions described earlier, gave
biaryl compound 25 in 41% yield. The subsequent deprotection
of the MOM group with camphorsulfonic acid in methanol in
86% yield was followed by oxidation to afford bis-p-quinone 27,
the precursor for 6π-electrocyclization. However, treatment of
27 with triethylamine or other bases such as pyridine, or DBU,
or with Lewis acid (boron trifluoride-diethyl etherate) in
dichloromethane at room temperature, or at −50 °C, did not
result in the desired cascade reactions to give benzo[c]-
chromene-7,10-dione 28, but only degradation of the starting
material. However, on the basis of our observations with the
model system, we speculated that the desired cyclization was
probably quite facile, and indeed it occurred spontaneously
simply by stirring quinone 27 in solution in dichloromethane at
room temperature for 24 h in an open flask, affording the
desired benzo[c]chromene-7,10-dione 28 in 52% yield
(Scheme 5).
a
Reagents and conditions: (a) (i) m-CPBA, CH2Cl2, rt, 18 h, (ii) 2 M
aq NaOH, MeOH, 3 h, 79%; (b) tetrahydro-2H-pyran-2-ol, ADDP,
TBP, THF, rt, 18 h, 99%; (c) (i) n-BuLi, THF, rt, 30 min, (ii) geranyl
bromide, rt, 18 h, 57%; (d) Tf2O, CH2Cl2, −78 °C, 30 min, 81%; (e)
2,5-dimethoxybenzeneboronic acid, Pd(PPh3)4, Cs2CO3, DMF−H2O,
MW (300 W), 140 °C, 10 min, 80%; (f) AgO, 6 M HNO3, dioxane, rt,
30 min; (g) Et3N, CH2Cl2, rt, 1 h, 73% (over 2 steps).
oxidation of commercially available 2,5-dimethoxybenzaldehyde
in 79% yield,32 followed by protection of the phenol 14 under
Mitsunobu conditions, affording 15 in 99% yield. Directed
lithiation of 15 by treatment with n-BuLi at −78 °C followed by
addition of geranyl bromide gave compound 16 in 57% yield,
deprotection of the THP-ether also occurring during this
reaction or its workup. The subsequent reaction of 16 with
triflic anhydride produced the desired aryl triflate 17 in 81%
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a
Scheme 5. Synthesis of Benzo[c]chromene-7,10-dione Precursor 28 to Thiaplidiaquinone A
a
Reagents and conditions: (a) MOMCl, DBU, acetone, 30 min, 73%; (b) (i) n-BuLi, THF, −78 °C, 1 h, (ii) CuBr·SMe2, −78 °C, 1 h, (iii) geranyl
bromide, −78 °C to rt, 18 h, 54%; (c) (i) n-BuLi, THF, −78 °C, 30 min, (ii) 2-isopropoxy-4,4,5,5-tetramethyl-1,2,3-dioxaborolane, −78 °C, 30 min;
(d) aryl triflate 17, Pd(PPh3)4, Cs2CO3, DMF−H2O, MW (300 W, 140 °C, 10 min), 41% (over 2 steps); (e) CSA, MeOH, rt, 18 h, 86%; (f) AgO, 6
M HNO3, dioxane, rt, 30 min; (g) CH2Cl2, rt, 24 h, 52%.
a
Scheme 6. Synthesis of Benzo[c]chromene-7,10-dione Precursor 33 to Thiaplidiaquinone B
a
Reagent and conditions: (a) n-BuLi, THF, CuBr·SMe2, geranyl bromide, −78 to 0 °C, 2 h, 60%; (b) (i) n-BuLi, THF, −78 °C, 30 min, (ii) 2-
isopropoxy-4,4,5,5-tetramethyl-1,2,3-dioxaborolane, −78 °C, 30 min; (c) aryl triflate 17, Pd(PPh3)4, Cs2CO3, DMF−H2O, MW (300W), 140 °C, 10
min, 43% (over 2 steps); (d) AgO, 6 M HNO3, dioxane, rt, 30 min; (e) CH2Cl2, rt, 15 h, 52%.
The synthesis of the precursor to thiaplidiaquinone B was
carried out in a similar manner (Scheme 6). The preparation of
the boronic ester 30 followed the same method, using
commercially available 1,4-dibromo-2,5-dimethoxybenzene as
a convenient starting material, with monolithium−halogen
exchange to install the geranyl substituent and the ensuing
introduction of the boronate by a second lithium−halogen
exchange. Using the boronic ester 30 and the same aryl triflate
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a
Scheme 7. Synthesis of Thiaplidiaquinone A 1
a
Reagents and conditions: (a) hypotaurine, salcomine, MeCN−EtOH, rt, 41 h, mixture 40% (14% for 1 and 26% for 34).
17 we readily synthesized the oxa-6π cyclization precursor for
thiaplidiaquinone B. The same Suzuki conditions gave biaryl
compound 31 in 43% yield, and subsequent oxidation afforded
bis-p-quinone 32. In this case the desired tautomerization-oxa-
6π-electrocyclization sequence was even more facile, and
occurred spontaneously by leaving quinone 32 stirring in
solution with dichloromethane at room temperature for 15 h in
an open flask, affording 33 in 52% yield (Scheme 6).
With the two benzo[c]chromene-7,10-diones 28 and 33 in
hand, we were ready for the second biomimetic step, the
addition of hypotaurine. While, inexplicably, quinone 33 failed
to react with hypotaurine under a range of conditions, the
addition of hypotaurine to quinone 28 in the presence of a
catalytic amount of salcomine in acetonitrile−ethanol at room
temperature for 41 h proceeded smoothly, albeit in modest
yield to give thiaplidiaquinone A 1 and its regioisomer 34 in a
combined yield of 40% yield, thereby achieving the first
synthesis of the natural product (Scheme 7).
EXPERIMENTAL SECTION
■
For general experimental details, see the Supporting Information.
1-(2-Trimethylsilylethoxy)methoxy)-2-((tetrahydro-2H-
pyran-2-yl)oxy)-3-geranyl-4-(methoxymethoxy)benzene 9. To
a stirred solution of 1-(2-trimethylsilylethoxy)methoxy)-2-((tetrahy-
dro-2H-pyran-2-yl)oxy)-4-(methoxymethoxy)benzene 830 (1.0 g, 2.6
mmol) in anhydrous THF (9 mL) under argon at 0 °C was added n-
butyllithium (1.6 M; 1.8 mL, 2.9 mmol) dropwise, and the reaction
mixture was stirred at this temperature for 45 min. Geranyl bromide
(0.54 mL, 2.7 mmol) was added dropwise, and the reaction mixture
was stirred at rt for 16 h, diluted with water (120 mL) and extracted
with ether (3 × 50 mL). The combined organic extracts were washed
with brine (100 mL), dried (MgSO4), concentrated under reduced
pressure, and the residue was subjected to flash chromatography using
ether and light petroleum (1:9) to yield the title compound as a
colorless oil (0.93 g, 69%); (Found: C, 66.8; H, 9.3. C29H48O6Si
requires C, 66.9; H, 9.3%); (Found: M + Na+, 543.3112. C29H48O6Si +
Na+ requires 543.3112); δH (400 MHz; CDCl3) 6.93 (1H, d, J 9.0),
6.77 (1H, d, J 9.0), 5.29−5.23 (2H, m), 5.16 (2H, s), 5.12 (2H, s),
5.12−5.05 (1H, m), 4.14−4.07 (1H, m), 3.83−3.72 (2H, m), 3.58−
3.40 (3H, m), 3.47 (3H, s), 2.09−2.02 (2H, m), 2.00−1.88 (5H, m),
1.78 (3H, s), 1.66 (3H, s), 1.64−1.59 (3H, m), 1.58 (3H, s), 1.01−
0.95 (2H, m), 0.02 (9H, s); δC (100 MHz; CDCl3) 150.8 (C), 146.1
(C), 145.2 (C), 134.5 (C), 131.2 (C), 126.1 (C), 124.4 (CH), 123.1
(CH), 114.6 (CH), 109.7 (CH), 101.7 (CH), 94.9 (CH2), 94.3
(CH2), 66.1 (CH2), 63.5 (CH2), 55.8 (Me), 39.7 (CH2), 30.8 (CH2),
26.7 (CH2), 25.6 (Me), 25.3 (CH2), 23.8 (CH2), 19.7 (CH2), 18.0
(CH2), 17.6 (Me), 16.2 (Me), −1.4 (Me); m/z (ESI) 543 ([M +
Na]+, 100%), 538 ([M + Na]+, 9), 227 (10).
The formation of both regioisomers in the final addition,
while disappointing given the success of model studies (Scheme
3), was not entirely surprising given the reported fickle nature
of such reactions.27,29 The regioisomers 1 and 34 were readily
separated by chromatography, and their structures were
1
confirmed by NMR studies. While their H NMR spectra
were very similar to each other, significant differences were
observed in the chemical shift values shown in their 13C NMR
spectra. The 13C NMR spectrum of 1 was very similar to that
reported in literature for the natural product,24 while the 13C
spectrum of 34 showed very significant differences. Further
confirmation came from distinctive long-range couplings that
were observed in the HMBC spectrum of 1 between the NH
proton at δ 9.11 and the carbonyl resonance at δ 179.0 (C-12),
and between the proton at δ 5.95 (at C-6) and the other
carbonyl resonance at δ 174.8 (C-7) (see Supporting
Information), confirming the structure of this regioisomer as
that of the natural product thiaplidiaquinone A.
3-(Methoxymethoxy)-2-geranyl-6-((2-trimethylsilylethoxy)-
methoxy)phenol 10. To
a stirred solution of 1-(2-
trimethylsilylethoxy)methoxy)-2-((tetrahydro-2H-pyran-2-yl)oxy)-3-
geranyl-4-(methoxymethoxy)benzene 9 (86 mg, 0.17 mmol) in
ethanol (2.0 mL) at room temperature under argon was added
hydrochloric acid (1.0 M; 0.33 mL), and the reaction mixture was
stirred for 30 min. The reaction mixture was diluted with saturated
sodium hydrogen carbonate solution (30 mL) and extracted with ether
(3 × 25 mL). The combined organic extracts were washed with brine
(30 mL), dried (MgSO4), concentrated under reduced pressure, and
the residue was subjected to flash chromatography using ether and
light petroleum (1:9) to yield the title compound as a colorless oil (70
mg, 97%); (Found: C, 65.8; H, 9.2. C24H40O5Si requires C, 66.0; H,
9.2%); (Found: M + Na+, 459.2529. C24H40O5Si + Na+ requires
459.2537); νmax (CHCl3)/cm−1 3541; δH (400 MHz; CDCl3) 6.88
(1H, d, J 8.9), 6.54 (1H, d, J 8.9), 6.21 (1H, s), 5.27 (1H, m), 5.17
(2H, s), 5.14 (2H, s), 5.11−5.05 (1H, m), 3.82−3.76 (2H, m), 3.48
(3H, s), 3.41 (2H, d, J 7.0), 2.10−2.03 (2H, m), 2.00−1.95 (2H, m),
1.80 (3H, d, J 0.7), 1.66 (3H, d, J 0.9), 1.58 (3H, s), 1.03−0.97 (2H,
m), 0.03 (9H, s); δC (100 MHz; CDCl3) 151.1 (C), 145.4 (C), 140.2
(C), 135.1 (C), 131.2 (C), 124.4 (CH), 122.3 (CH), 118.3 (C), 113.7
(CH), 105.4 (CH), 95.5 (CH2), 94.9 (CH2), 66.8 (CH2), 55.9 (Me),
39.8 (CH2), 26.7 (CH2), 25.7 (Me), 22.9 (CH2), 18.1 (CH2), 17.6
CONCLUSIONS
■
In conclusion, a concise total synthesis of the apoptosis-
inducing marine metabolite thiaplidiaquinone A has been
described. The key ring forming steps are both based on
biosynthetic considerations and involve the construction of the
central benzo[c]chromene quinone unit by an extremely facile
oxa-6π-electrocyclic ring closure reaction that occurs under
neutral conditions at room temperature, followed by
installation of the 1,4-thiazine-dioxide ring by reaction with
hypotaurine.
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(Me), 16.1 (Me), −1.4 (Me); m/z (ESI) 459 ([M + Na]+, 100%), 454
(Found: M + Na+, 402.1353. C19H25NO5S + Na+ requires 402.1346);
λmax (MeOH)/nm 266 (log ε 3.30), 328 (3.61); νmax (CHCl3)/cm−1
3374, 1678, 1627, 1595; δH (400 MHz; CDCl3) 6.69 (1H, br. s),
5.09−5.02 (2H, m), 4.07 (2H, td, J 6.0, 3.5), 3.91 (3H, s), 3.30 (2H, t,
J 6.0), 3.22 (2H, d, J 7.3), 2.09−2.00 (2H, m), 1.99−1.92 (2H, m),
1.73 (3H, s), 1.66 (3H, s), 1.59 (3H, s); δC (100 MHz; CDCl3) 178.2
(C), 176.8 (C), 152.9 (C), 143.0 (C), 138.0 (C), 137.2 (C), 131.5
(C), 124.1 (CH), 119.0 (CH), 110.0 (C), 60.8 (Me), 48.9 (CH2), 39.9
(CH2), 39.7 (CH2), 26.6 (CH2), 25.7 (Me), 22.9 (CH2), 17.7 (Me),
16.2 (Me); m/z (ESI) 402 ([M + Na]+, 100%), 249 (6), 173 (6).
2,5-Dimethoxyphenol 14. To a solution of 2,5-dimethoxyben-
zaldehyde (2.0 g, 12.0 mmol) in dichloromethane (80 mL) was added
at 0 °C in small portions m-chloroperbenzoic acid (3.5 g, 20.3 mmol),
and the reaction mixture was stirred at room temperature for 18 h.
The organic solution was extracted with aqueous saturated sodium
hydrogen carbonate solution (3 × 40 mL) and then with aqueous
saturated sodium thiosulfate solution (3 × 40 mL). The dichloro-
methane layer was dried (MgSO4), filtered and concentrated in vacuo
to give a dark yellow oil that was dissolved in methanol (30 mL) and
stirred with acqueous sodium hydroxide solution (2 M; 12.0 mL, 24
mmol) for 3 h. Then, the reaction mixture was acidified with
hydrochloric acid (6 M) and extracted with ethyl acetate (3 × 30 mL).
The organic layers were combined, dried (MgSO4), filtered and
concentrated under reduced pressure. Column chromatography of the
residue eluting with dichloromethane and light petroleum (6:4) gave
the title compound as an oil (1.46 g, 79%); (lit.,32 colorless oil);
(Found: M + Na+, 177.0517. C8H10O3 + Na+ requires 177.0522); νmax
(CHCl3)/cm−1 3539; δH (400 MHz; CDCl3) 6.80 (1H, d, J 8.9), 6.62
(1H, d, J 3.0), 6.42 (1H, dd, J 8.9, 3.0), 5.97 (1H, s), 3.84 (3H, s), 3.78
(3H, s); δC (100 MHz; CDCl3) 154.6 (C), 146.5 (C), 141.1 (C),
111.7 (CH), 104.3 (CH), 101.9 (CH), 56.6 (Me), 55.6 (Me); m/z
(ESI) 177 (M + Na+, 100%).
2-(2,5-Dimethoxyphenoxy)tetrahydro-2H-pyran 15. To a
stirred solution of 2,5-dimethoxyphenol 14 (0.32 g, 2.08 mmol) and
tetrahydro-2H-pyran-2-ol (0.32 g, 3.10 mmol) in anhydrous
tetrahydrofuran (20 mL) under an argon atmosphere at 0 °C was
added 1,1′-(azodicarbonyl)dipiperidine (1.0 g, 4.14 mmol) and tri-n-
butylphosphine (1.0 mL, 4.14 mmol) dropwise. The reaction mixture
was warmed to room temperature and stirred for 18 h. After, the
mixture was diluted with ether (30 mL), filtered, and the filtrate was
concentrated under reduced pressure. Column chromatography of the
residue eluting with ethyl acetate and light petroleum (1:9) gave the
title compound as an oil (0.49 g, 99%); (lit.,32 colorless oil); (Found:
M + Na+, 261.1096. C13H18O4 + Na+ requires 261.1097); νmax
(CHCl3)/cm−1 1610, 1595; δH (400 MHz; CDCl3) 6.84 (1H, d, J
8.8), 6.81 (1H, d, J 2.9), 6.51 (1H, dd, J 8.8, 2.9), 5.41 (1H, t, J 3.2),
4.04−3.98 (1H, m), 3.83 (3H, s), 3.77 (3H, s), 3.65−3.60 (1H, m),
2.11−1.86 (3H, m), 1.72−1.61 (3H, m); δC (100 MHz; CDCl3) 154.3
(C), 147.3 (C), 144.6 (C), 113.7 (CH), 105.8 (CH), 105.5 (CH),
97.6 (CH), 62.2 (CH2), 57.1 (Me), 55.7 (Me), 30.4 (CH2), 25.2
(CH2), 18.9 (CH2); m/z (ESI) 261 (M + Na+, 100%).
([M + NH4]+, 6), 261 (11), 217 (11).
1-(2-Trimethylsilylethoxy)methoxy)-2-methoxy-3-geranyl-
4-(methoxymethoxy)benzene 11. To a stirred solution of 3-
(methoxymethoxy)-2-geranyl-6-((2-trimethylsilylethoxy)methoxy)-
phenol 10 (50 mg, 0.11 mmol) in DMF (1.1 mL) at room
temperature under argon was added sodium hydride (60% dispersion
in mineral oils; 5 mg, 0.13 mmol), and the reaction mixture was stirred
for 30 min. Iodomethane (8 μL, 0.13 mmol) was added dropwise, and
the reaction mixture was stirred at room temperature for a further 3.5
h. The reaction mixture was diluted with saturated ammonium
chloride solution (30 mL) and extracted with ether (3 × 15 mL). The
combined organic extracts were washed with water (2 × 20 mL), brine
(30 mL), dried (MgSO4), concentrated under reduced pressure, and
the residue was subjected to flash chromatography using ethyl acetate
and light petroleum (0:1 to 3:97) to yield the title compound as a
colorless oil (49 mg, 95%); (Found: C, 67.0; H, 9.5. C25H42O5Si
requires C, 66.6; H, 9.4%); (Found: M + Na+, 473.2697. C25H42O5Si +
Na+ requires 473.2694); δH (400 MHz; CDCl3) 6.95 (1H, d, J 9.0),
6.77 (1H, d, J 9.0), 5.23−5.18 (1H, m), 5.20 (2H, s), 5.13 (2H, s),
5.10−5.04 (1H, m), 3.82 (3H, s), 3.82−3.77 (2H, m), 3.48 (3H, s),
3.40 (2H, d, J 7.0), 2.10−2.01 (2H, m), 2.00−1.94 (2H, m), 1.79 (3H,
s), 1.65 (3H, s), 1.58 (3H, s), 1.02−0.95 (2H, m), 0.02 (9H, s); δC
(100 MHz; CDCl3) 150.6 (C), 148.8 (C), 145.6 (C), 134.7 (C), 131.3
(C), 125.9 (C), 124.4 (CH), 123.0 (CH), 114.7 (CH), 109.8 (CH),
95.0 (CH2), 94.2 (CH2), 66.1 (CH2), 60.8 (Me), 55.9 (Me), 39.8
(CH2), 26.7 (CH2), 25.6 (Me), 23.3 (CH2), 18.1 (CH2), 17.6 (Me),
16.1 (Me), −1.4 (Me); m/z (ESI) 473 ([M + Na]+, 100%), 431 (10),
413 (10), 363 (11), 301 (9), 289 (6), 227 (14).
2-Methoxy-3-geranyl-1,4-benzoquinone 12. To a stirred
solution of 1-(2-trimethylsilylethoxy)methoxy)-2-methoxy-3-geranyl-
4-(methoxymethoxy)benzene 11 (52 mg, 0.12 mmol) in methanol
(1.2 mL) at room temperature was added ( )-camphorsulfonic acid
(56 mg, 0.24 mmol), and the reaction mixture was stirred for 16.5 h.
The reaction mixture was diluted with saturated sodium hydrogen
carbonate solution (50 mL) and concentrated under reduced pressure.
The aqueous was extracted with ethyl acetate (3 × 20 mL), and the
combined organic extracts were washed with brine (40 mL), dried
(MgSO4), concentrated under reduced pressure, and the residue was
dissolved in acetonitrile (6 mL). To a stirred solution of the crude
reaction mixture under air was added salcomine (8 mg, 0.023 mmol),
and air was bubbled through the solution. The reaction mixture was
stirred for 50 min under air and concentrated under reduced pressure.
The residue was diluted with water (50 mL) and extracted with
dichloromethane (3 × 15 mL). The combined organic extracts were
washed with brine (30 mL), dried (MgSO4), concentrated under
reduced pressure, and the residue was subjected to flash chromatog-
raphy using ether and light petroleum (1:9) to yield the title
compound as a yellow oil (30 mg, 95%); (Found: M + Na+, 297.1462.
C17H22O3 + Na+ requires 297.1461); λmax (MeOH)/nm 291 (log ε
3.39); νmax (CHCl3)/cm−1 1670, 1650, 1593; δH (400 MHz; CDCl3)
6.68 (1H, d, J 10.0), 6.60 (1H, d, J 10.0), 5.09−5.02 (2H, m), 4.02
(3H, s), 3.16 (2H, d, J 7.3), 2.09−2.02 (2H, m), 2.00−1.94 (2H, m),
1.74 (3H, d, J 0.4), 1.66 (3H, d, J 0.9), 1.58 (3H, s); δC (100 MHz;
CDCl3) 187.9 (C), 183.8 (C), 155.3 (C), 137.3 (C), 136.4 (CH),
134.6 (CH), 132.2 (C), 131.4 (C), 124.1 (CH), 119.7 (CH), 60.9
(Me), 39.7 (CH2), 26.5 (CH2), 25.7 (Me), 22.3 (CH2), 17.7 (Me),
16.1 (Me); m/z (ESI) 297 ([M + Na]+, 100%), 275 ([M + H]+, 7). 1H
NMR consistent with the literature.31
2-Geranyl-3,6-dimethoxyphenol 16. A solution of n-butyl-
lithium in hexane (2.5 M; 1.0 mL, 2.52 mmol) was added dropwise at
0 °C to a solution of 2-(2,5-dimethoxyphenoxy)tetrahydro-2H-pyran
15 (0.30 g, 1.26 mmol) in dry tetrahydrofuran (10 mL) under an
argon atmosphere. The reaction mixture was stirred at room
temperature for 30 min, and then geranyl bromide (0.30 mL, 1.50
mmol) was added dropwise at 0 °C. The reaction mixture was stirred
at room temperature for 18 h, quenched with a saturated aqueous
ammonium chloride solution (10 mL), extracted with ethyl acetate (3
× 10 mL), dried (MgSO4), filtered and concentrated in vacuo.
Column chromatography of the residue eluting with dichloromethane
and light petroleum (3:7) gave the title compound as a colorless oil
(0.21 g, 57%); (Found: M + Na+, 313.1781. C18H26O3 + Na+ requires
313.1780); νmax (CHCl3)/cm−1 3539; δH (400 MHz; CDCl3) 6.68
(1H, d, J 8.8), 6.37 (1H, d, J 8.8), 5.75 (1H, s), 5.27−5.30 (1H, m),
5.12−5.09 (1H, m), 3.87 (3H, s), 3.80 (3H, s), 3.42 (2H, d, J 7.1),
2.12−1.98 (4H, m), 1.82 (3H, s), 1.68 (3H, s), 1.61 (3H, s); δC (100
MHz; CDCl3) 152.6 (C), 144.3 (C), 141.2 (C), 135.2 (C), 131.2 (C),
124.5 (CH), 122.3 (CH), 177.0 (C), 107.8 (CH), 101.1 (CH), 56.4
Iso-aplidinone A 13. To a stirred solution of methoxy-3-geranyl-
1,4-benzoquinone 12 (50 mg, 0.18 mmol) in acetonitrile/ethanol (1.8
mL; 1:1) was added a solution of hypotaurine (20 mg, 0.18 mmol) in
water (0.6 mL) and salcomine (6 mg, 0.02 mmol), and the reaction
mixture was stirred at room temperature for 43 h. The reaction
mixture was diluted with water (20 mL) and extracted with ether (3 ×
20 mL). The combined organic extracts were washed with brine (40
mL), dried (MgSO4), concentrated under reduced pressure, and the
residue was subjected to preparatory thin-layer chromatography using
ethyl acetate and light petroleum (1:1) to yield the title compound as a
deep red/orange crystalline solid (22 mg, 32%); mp 86−89 °C;
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(Me), 56.0 (Me), 39.8 (CH2), 26.8 (CH2), 25.7 (Me), 22.5 (CH2),
17.7 (Me), 16.1 (Me); m/z (ESI) 313 (M + Na+, 100%).
(4H, m), 1.86 (3H, s), 1.53 (3H s), 1.45 (3H, s); δC (100 MHz;
DMSO-d) 187.0 (C), 185.3 (C), 152.2 (C), 147.4 (C), 143.2 (C),
137.9 (CH), 135.9 (CH), 134.5 (C), 131.4 (C), 130.2 (C), 123.9
(CH), 119.9 (CH), 118.9 (CH), 118.4 (CH), 118.0 (C), 115.1 (CH),
67.0 (CH), 39.3 (CH2), 25.9 (CH2), 25.8 (Me), 17.9 (Me), 17.3
(Me); m/z (ESI) 373 (M + Na+, 100%).
2,6-Dibromo-4-methoxyphenol 21. To a stirred solution of 4-
methoxyphenol (1.21 g, 9.75 mmol) in a mixture of dichloromethane
(97.5 mL) and methanol (39.0 mL) at room temperature was added
benzyltrimethylammonium tribromide (7.60 g, 19.5 mmol). The
reaction mixture was stirred for 18 h and then concentrated in vacuo.
Column chromatography of the residue eluting with dichloromethane
and light petroleum (3:7) gave the title compound as a colorless solid:
(2.2 g, 80%); mp 90−91 °C (lit.,40 mp 89−90 °C); νmax (CHCl3)/
cm−1 3698; δH (400 MHz; CDCl3) 7.05 (2H, s), 5.50 (1H, s), 3.77
(3H, s); δC (100 MHz; CDCl3) 153.7 (C), 143.8 (C), 117.8 (CH),
109.7 (C), 56.1 (Me).
1,3-Dibromo-5-methoxy-2-(methoxymethoxy)benzene 22.
To a stirred solution of 2,6-dibromo-4-methoxyphenol 21 (0.20 g,
0.71 mmol) and chloromethyl ether (0.53 mL, 7.0 mmol) in dry
acetone (3 mL) was added a solution of 1,8-diazabicyclo[5.4.0]-
undecen-7-ene (0.5 mL, 3.56 mmol) dropwise during 30 min. After
the addition, the reaction mixture was acidified with 2 M hydrochloric
acid and extracted with ethyl acetate (3 × 10 mL). The combined
organic phases were dried (MgSO4), filtered and evaporated under
reduced pressure. Column chromatography of the residue eluting with
dichloromethane and light petroleum (3:7) gave the title compound as
an oil: (0.17 g, 73%); (Found: M + Na+, 346.8877. C9H1079Br2O3 +
Na+ requires 346.8889); δH (400 MHz; CDCl3) 7.10 (2H, s), 5.12
(2H, s), 3.79 (3H, s), 3.74 (3H, s); δC (100 MHz; δ) 156.6 (C), 145.2
(C), 118.4 (C), 118.3 (CH), 99.6 (CH2), 58.5 (Me), 56.0 (Me). m/z
(ESI) 346 (M + Na+, 51.2%), 348 (M + Na+, 100%), 350 (M + Na+,
48.7%),
1-Bromo-3-geranyl-5-methoxy-2-(methoxymethoxy)-
benzene 23. To a stirred solution of 1,3-dibromo-5-methoxy-2-
(methoxymethoxy)benzene 22 (0.25 g, 0.77 mmol) in dry
tetrahydrofuran (10 mL) at −78 °C under an argon atmosphere was
added dropwise a solution of n-butyllithium in hexane (2.7 M; 0.30
mL, 0.81 mmol), and the reaction was stirred at −78 °C for 1 h, then
copper(I) bromide dimethylsulfide complex (0.17 g, 0.83 mmol) was
added. After stirring at −78 °C for 1 h, geranyl bromide (0.16 mL,
1.10 mmol) was added, and the reaction mixture was warmed to room
temperature and stirred for 18 h. The reaction mixture was diluted
with saturated ammonium chloride solution (10 mL), extracted with
ethyl acetate (3 × 10 mL), dried (MgSO4), filtered and concentrated
under reduced pressure. Column chromatography of the residue
eluting with dichloromethane and light petroleum (4:6) gave the title
compound as a colorless oil (0.16 g, 54%); (Found: M + Na+,
405.1035. C19H2779BrO3 + Na+ requires 405.1036); δH (400 MHz;
CDCl3) 6.96 (1H, d, J 3.0), 6.71 (1H, d, J 3.0), 5.33−5.29 (1H, m),
5.05−5.05 (2H, s), 5.14−5.10 (1H, m), 3.77 (3H, s), 3.67 (3H, s),
3.46 (2H, d, J 7.1), 2.17−2.07 (4H, m), 1.72 (3H, s), 1.71 (3H, s),
1.63 (3H, s); δC (100 MHz; CDCl3) 156.4 (C), 146.4 (C), 137.8 (C),
137.3 (C), 131.6 (C), 124.1 (CH), 121.8 (CH), 117.4 (C), 115.4
(CH), 115.1 (CH), 99.9 (CH2), 57.8 (Me), 55.6 (Me), 39.7 (CH2),
29.0 (CH2), 26.6 (CH2), 25.7 (Me), 17.7 (Me), 16.2 (Me); m/z (ESI)
405 (M + Na+, 100%), 407 (M + Na+, 97.5%).
2-Geranyl-3,6-dimethoxyphenyl trifluoromethanesulfonate
17. To a stirred solution of 2-geranyl-3,6-dimethoxyphenol 16 (0.41 g,
1.41 mmol) in dry dichloromethane (7 mL) at −78 °C under an argon
atmosphere was added triethylamine (0.40 mL, 2.79 mmol) and
trifluoromethanesulfonic anhydride (0.33 mL, 1.97 mmol) dropwise,
and the reaction mixture was stirred at −78 °C for 30 min. The
reaction mixture was diluted with saturated ammonium chloride
solution (10 mL), extracted with ethyl acetate (3 × 10 mL), dried
(MgSO4), filtered and concentrated in vacuo. Column chromatog-
raphy of the residue eluting with dichloromethane and light petroleum
(4:6) gave the title compound as a colorless oil (0.48 g, 81%); (Found:
M + Na+, 445.1274. C19H25F3O5S + Na+ requires 445.1267); δH (400
MHz; CDCl3) 6.84 (1H, d, J 9.0), 6.81 (1H, d, J 9.0), 5.16−5.13 (1H,
m), 5.05−5.10 (1H, m), 3.86 (3H, s), 3.83 (3H, s), 3.45 (2H, d, J 6.9),
2.10−1.97 (4H, m), 1.76 (3H, s), 1.67 (3H, s), 1.59 (3H, s); δC (100
MHz; CDCl3) 152.0 (C), 145.3 (C), 137.8 (C), 136.4 (C), 131.3 (C),
125.5 (C), 124.2 (CH), 120.6 (CH), 118.7 (q, J 320, CF3), 110.0
(CH), 109.9 (CH), 56.3 (Me), 56.2 (Me), 39.7 (CH2), 26.6 (CH2),
25.6 (Me), 23.6 (CH2), 17.6 (Me), 16.1 (Me); m/z (ESI) 445 (M +
Na+, 100%).
2-Geranyl-3,6,2′,5′-tetramethoxybiphenyl 18. To a degassed
solution of 2-geranyl-3,6-dimethoxyphenyl trifluoromethanesulfonate
17 (10 mg, 0.024 mmol) and 2,5-dimethoxybenzeneboronic acid (5.46
mg, 0.03 mmol) in a sealed tube in dimethylformamide and water
(0.15 mL, 9:1) was added tetrakis(triphenylphosphine)palladium(0)
(5.55 mg, 20 mol %). The mixture was thoroughly degassed with
argon under sonication, and cesium carbonate (25.4 mg, 0.072 mmol)
was added. The sealed tube was subject to microwave irradiation (300
W) at 140 °C for 10 min. After cooling, the reaction mixture was
diluted with water (5 mL) and extracted with ethyl acetate (3 × 10
mL). The combined organic extracts were dried (MgSO4), filtered and
concentrated under reduced pressure. Column chromatography of the
residue eluting with ethyl acetate and light petroleum (1:9) gave the
title compound as a colorless oil (7.9 mg, 80%); (Found: M + Na+,
433.2352. C26H34O4 + Na+ requires 433.2349); δH (400 MHz;
DMSO-d) 6.95−6.88 (3H, m), 6.84 (1H, d, J 8.9), 6.71 (1H, d, J 2.9),
5.08−5.11 (2H, m) 3.87 (3H, s), 3.79 (3H, s), 3.72 (3H, s), 3.71 (3H,
s), 3.25 (1H, dd, J 14.2, 6.1), 3.09 (1H, dd, J 14.2, 6.1), 2.06−1.89
(4H, m), 1.70 (3H, s), 1.62 (3H, s), 1.37 (3H, s); δC (100 MHz;
DMSO-d) 153.3 (C), 152.0 (C), 151.6 (C), 151.5 (C), 134.1 (C),
131.1 (C), 130.6 (C), 128.8 (C), 127.3 (C), 124.6 (CH), 122.8 (CH),
117.3 (CH), 113.3 (CH), 112.1 (CH), 110.1 (CH), 109.1 (CH), 56.5
(Me), 56.3 (Me), 56.0 (Me), 55.6 (Me), 39.9 (CH2), 26.8 (2 × CH2),
25.7 (Me), 17.7 (Me), 15.7 (Me); m/z (ESI) 433 (M + Na+, 100%).
6-(2,6-Dimethylhepta-1,5-dienyl)-2-hydroxy-6H-benzo[c]-
chromene-7,10-dione 20. (a) Nitric acid (6 M; 0.08 mL) was
added at room temperature to a mixture of 2-geranyl-3,6,2′,5′-
tetramethoxybiphenyl 18 (32.8 mg, 0.08 mmol), silver(II) oxide (79
mg, 0.64 mmol) and 1,4-dioxane (2 mL), and the mixture was stirred
for 30 min. The mixture was diluted with water (10 mL) and extracted
with ethyl acetate (3 × 10 mL). The combined organic extracts were
dried (MgSO4), filtered and concentrated under reduced pressure. The
residue was quickly purified by chromatography using ethyl acetate
and light petroleum (1:9) as an eluent to give 3-geranyl-2,2′-bis-p-
benzoquinone 19 immediately used for the next step. This compound
could not be characterized because it readily cyclizes to 6-(2,6-
dimethylhepta-1,5-dienyl)-2-hydroxy-6H-benzo[c]chromene-7,10-
dione 20, simply on standing in solution.
2′,3-Digeranyl-5,3′,6′-trimethoxy-2-(methoxymethoxy)-
biphenyl 25. (a) To a stirred solution of 1-bromo-3-geranyl-5-
methoxy-2-(methoxymethoxy)benzene 23 (11.5 mg, 0.03 mmol) in
anhydrous tetrahydrofuran (4 mL) under an argon atmosphere at −78
°C was added n-butyllithium (1.6 M; 0.02 mL, 0.033 mmol) dropwise,
and the reaction mixture was stirred at this temperature for 30 min. 2-
Isopropoxy-4,4,5,5-tetramethyl-1,2,3-dioxaborolane (6.73 μL, 0.033
mmol) was added dropwise, and the reaction mixture was stirred for
30 min at −78 °C. The mixture was quenched with a saturated
aqueous ammonium chloride solution (10 mL) and extracted with
ethyl acetate (3 × 30 mL). The combined organic extracts were dried
(MgSO4), filtered and concentrated under reduced pressure. The
crude 2-[3-geranyl-5-methoxy-2-(methoxymethoxy)phenyl]-4,4,5,5-
(b) To a solution of 3-geranyl-2,2′-bis-p-benzoquinone 19 (30 mg,
0.086 mmol) in dichloromethane (4.6 mL) at 0 °C was added
triethylamine (0.06 mL, 0.43 mmol), and the mixture was stirred at
room temperature for 1 h. The resulting dark red mixture was
concentrated in vacuo. Column chromatography of the residue eluting
with ethyl acetate and light petroleum (1:9) gave the title compound
as a purple oil (22.0 mg, 73%); (Found: M + Na+, 373.1406. C22H22O4
+ Na+ requires 373.1410); νmax (CHCl3)/cm−1 1641, 1600; δH (400
MHz; DMSO-d) 9.26 (1H, s), 7.68 (1 H, s), 6.88−6.75 (4H, m),
5.90−5.87 (1H, m), 5.28 (1H, d, J 9.3), 4.88−4.85 (1H, m), 1.97−1.93
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tetramethyl-[1,3,2]dioxaborolane 24 was used in the next step without
purification.
(b) A solution of 3,6′-gigeranyl-2,2′-p-benzoquinone 27 (10 mg,
0.021 mmol, one-quarter of the material from the previous step) in
dichloromethane (2 mL) was stirred at room temperature for 24 h.
The resulting dark brown mixture was concentrated in vacuo. Column
chromatography of the residue eluting with ethyl acetate and light
petroleum (1:9) gave the title compound as a dark brown oil (5.3 mg,
52%); (Found: M + Na+, 509.2665. C32H38O4 + Na+ requires
509.2662); νmax (CHCl3)/cm−1 3691, 3603, 3048, 1653, 1602; δH
(500 MHz; DMSO-d) 9.16 (1H, s), 7.49 (1 H, d, J 2.7), 6.88 (2H, s),
6.65 (1H, d, J 2.7), 5.91 (1H, d, J 9.3), 5.26 (1H, d, J 9.3), 5.18 (1H, t,
J 7.2), 5.07−5.04 (1H, m), 4.92−4.86 (1H, m), 3.20−3.09 (2H, m),
2.05−1.92 (8H, m), 1.88 (3H, s), 1.64 (3H, s), 1.62 (3H, s), 1.55 (3H,
s), 1.53 (3H s), 1.45 (3H, s); δC (125 MHz; DMSO-d) 187.1 (C),
185.4 (C), 151.7 (C), 145.2 (C), 143.5 (C), 137.9 (CH), 135.8 (CH),
134.6 (C), 131.4 (C), 131.3 (C), 131.2 (C), 130.6 (C), 124.5 (CH),
123.8 (CH), 122.4 (CH), 120.1 (CH), 119.3 (CH), 117.9 (C), 112.8
(CH), 66.8 (CH), 79.7 (C), 39.7 (CH2), 39.3 (CH2), 28.3 (CH2),
26.6 (CH2), 26.0 (CH2), 25.9 (Me), 25.8 (Me), 18.0 (Me), 17.9 (Me),
17.3 (Me), 16.3 (Me); m/z (ESI) 509 (M + Na+, 100%).
1-Bromo-4-geranyl-2,5-dimethoxybenzene 29. To a stirred
solution of 1,4-dibromo-2,5-dimethoxybenzene (0.30 g, 1.0 mmol) in
dry tetrahydrofuran (13 mL) at −78 °C under an argon atmosphere
was added dropwise a solution of n-butyllithium in hexane (1.6 M;
0.63 mL, 1.0 mmol), copper(I) bromide dimethylsulfide complex
(0.21 g, 1.0 mmol) and a solution of geranyl bromide (0.10 mL, 0.50
mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred at
−78 °C for 1 h, and then the mixure was gradually warmed to 0 °C
and stirred at this temperature for 1 h. The reaction mixture was
diluted with saturated ammonium chloride solution (10 mL), extracted
with ethyl acetate (3 × 10 mL), dried (MgSO4), filtered and
concentrated under reduced pressure. Column chromatography of the
residue eluting with dichloromethane and light petroleum (2:8) gave
the title compound as a colorless oil (0.22 g, 60%); (lit.,41 oil) (Found:
M + Na+, 375.0927. C18H2579BrO2 + Na+ requires 375.0930); δH (400
MHz; CDCl3) 7.04 (1H, s), 6.78 (1H, s), 5.33−5.29 (1H, m), 5.12−
5.16 (1H, m), 3.86 (3H, s), 3.81 (3H, s), 3.31 (2H, d, J 7.1), 2.16−
2.07 (4H, m), 1.73 (3H, s), 1.70 (3H, s), 1.63 (3H, s); δC (100 MHz;
CDCl3) 151.8 (C), 150.0 (C), 137.0 (C), 131.5 (C), 130.5 (C), 124.2
(CH), 121.7 (CH), 108.3 (C), 115.7 (CH), 114.0 (CH), 57.0 (Me),
56.2 (Me), 39.8 (CH2), 28.2 (CH2), 26.8 (CH2), 25.7 (Me), 17.7
(Me), 16.1 (Me); m/z (ESI) 375 (M + Na+, 100%), 377 (M + Na+,
99%).
2,4′-Digeranyl-3,6-2′,5′-tetramethoxybiphenyl 31. (a) To a
stirred solution of 1-bromo-4-geranyl-2,5-dimethoxybenzene 29 (10.6
mg, 0.03 mmol) in anhydrous tetrahydrofuran (4 mL) under an argon
atmosphere at −78 °C was added n-butyllithium (1.6 M; 0.02 mL,
0.033 mmol) dropwise, and the reaction mixture was stirred for 30
min. 2-Isopropoxy-4,4,5,5-tetramethyl-1,2,3-dioxaborolane (6.73 μL,
0.033 mmol) was added dropwise, and the reaction mixture was stirred
for 30 min at −78 °C. The mixture was quenched with a saturated
aqueous ammonium chloride solution (10 mL) and extracted with
ethyl acetate (3 × 30 mL). The combined organic extracts were dried
(MgSO4), filtered and concentrated under reduced pressure. The
crude 2-(4-geranyl-2,5-dimethoxyphenyl)-4,4,5,5-tetramethyl[1,3,2]-
dioxaborolane 30 was used in the next step without purification.
(b) To a degassed solution of 2-geranyl-3,6-dimethoxyphenyl
trifluoromethanesulfonate 17 (10 mg, 0.024 mmol) and the crude 2-
(4-geranyl-2,5-dimethoxyphenyl)-4,4,5,5-tetramethyl[1,3,2]-
dioxaborolane 30 (0.03 mmol) in a sealed tube in dimethylformamide
and water (0.15 mL, 9:1) was added tetrakis(triphenylphosphine)-
palladium(0) (5.55 mg, 20 mol %). The mixture was thoroughly
degassed with argon under sonication and cesium carbonate (25.4 mg,
0.072 mmol) was added. The sealed tube was subject to microwave
irradiation (300 W) at 140 °C for 10 min. After cooling, the reaction
mixture was diluted with water (5 mL) and extracted with ethyl acetate
(3 × 10 mL). The combined organic extracts were dried (MgSO4),
filtered and concentrated under reduced pressure. Column chroma-
tography of the residue eluting with ethyl acetate and light petroleum
(1:9) gave the title compound as a colorless oil (5.6 mg, 43%);
(Found: M + Na+, 569.3600. C36H50O4 + Na+ requires 569.3601); δH
(b) To a degassed solution of 2-geranyl-3,6-dimethoxyphenyl
trifluoromethanesulfonate 17 (10 mg, 0.024 mmol) and the crude 2-
[3-geranyl-5-methoxy-2-(methoxymethoxy)phenyl]-4,4,5,5-tetrameth-
yl-[1,3,2]dioxaborolane 24 (0.03 mmol) in a sealed tube in
dimethylformamide and water (0.15 mL, 9:1) was added tetrakis-
(triphenylphosphine)palladium(0) (5.55 mg, 20 mol %). The mixture
was thoroughly degassed with argon under sonication, and cesium
carbonate (25.4 mg, 0.072 mmol) was added. The sealed tube was
subject to microwave irradiation (300 W) at 140 °C for 10 min. After
cooling, the reaction mixture was diluted with water (5 mL) and
extracted with ethyl acetate (3 × 10 mL). The combined organic
extracts were dried (MgSO4), filtered and concentrated under reduced
pressure. Column chromatography of the residue eluting with ethyl
acetate and light petroleum (1:9) gave the title compound as a
colorless oil (5.7 mg, 41%); (Found: M + Na+, 599.3706. C37H52O5 +
Na+ requires 599.3707); δH (400 MHz; CDCl3) 6.87 (1 H, d, J 8.9),
6.79 (1H, d, J 8.9), 6.77 (1H, d, J 3.2), 6.51 (1H, d, J 3.2), 5.38−5.42
(1H, m), 5.18−5.06 (3H, m), 4.64 (1H, d, J 5.2), 4.53 (1H, d, J 5.2),
3.85 (3H, s), 3.75 (3H, s), 3.72 (3H, s), 3.42−3.54 (2H, m), 3.38 (1H,
dd, J 14.2, 6.1), 3.12 (3H, s), 2.99 (1H, dd, J 14.2, 6.1), 2.19−2.39
(8H, m), 1.75 (3H, s), 1.72 (3H, s), 1.67 (3H, s), 1.65 (3H, s), 1.59
(3H s), 1.33 (3H, s); δC (100 MHz; CDCl3) 155.4 (C), 152.0 (C),
151.5 (C), 146.6 (C), 136.5 (C), 136.0 (C), 134.3 (C), 131.5 (C),
131.4 (C), 131.1 (C), 131.0 (C), 129.2 (C), 124.6 (CH), 124.3 (CH),
122.7 (CH), 122.6 (CH), 114.8 (CH), 114.1 (CH), 110.3 (CH),
108.6 (CH), 98.8 (CH2), 56.6 (Me), 56.2 (Me), 56.1 (Me), 55.3
(Me), 39.9 (CH2), 39.8 (CH2), 28.6 (CH2), 27.0 (CH2), 26.8 (CH2),
26.7 (CH2), 25.7 (Me), 25.6 (Me), 17.7 (Me), 17.6 (Me), 16.2 (Me),
15.7 (Me); m/z (ESI) 599 (M + Na+, 100%).
2′,3-Digeranyl-5,3′,6′-trimethoxy-biphenyl-2-ol 26. To a
stirred solution of 2′,3-digeranyl-5,3′,6′-trimethoxy-2-
(methoxymethoxy)biphenyl 25 (60 mg, 0.10 mmol) in methanol (1
mL), at room temperature was added camphorsulforic acid (35 mg,
0.15 mmol), and the reaction mixture was stirred at room temperature
for 18 h. Then, the mixture was diluted with saturated aqueous sodium
hydrogen carbonate solution (10 mL) and extracted with ethyl acetate
(3 × 10 mL). The combined organic extracts were dried (MgSO4),
filtered and concentrated under reduced pressure to give the title
compound as a colorless oil (46 mg, 86%); (Found: M + Na+,
555.3458. C35H48O4 + Na+ requires 555.3445); νmax (CHCl3)/cm−1
3550; δH (400 MHz; CDCl3) 6.93 (1 H, d, J 8.9), 6.85 (1H, d, J 8.9),
6.76 (1H, d, J 3.1), 6.51 (1H, d, J 3.1), 5.40−5.44 (1H, m), 5.18−5.05
(3H, m), 4.56 (1H, s), 3.87 (3H, s), 3.75 (3H, s), 3.72 (3H, s), 3.43−
3.40 (2H, m), 3.25 (1H, dd, J 14.0, 7.0), 3.11 (1H, dd, J 14.0, 7.0),
2.19−1.88 (8H, m), 1.75 (3H, s), 1.72 (3H, s), 1.68 (3H, s), 1.64 (3H,
s), 1.60 (3H s), 1.34 (3H, s); δC (100 MHz; CDCl3) 152.9 (C), 152.5
(C), 151.5 (C), 145.3 (C), 136.7 (C), 135.0 (C), 131.9 (C), 131.5
(C), 131.2 (C), 129.0 (C), 126.4 (C), 124.5 (CH), 124.3 (CH), 123.8
(C), 122.3 (CH), 122.1 (CH), 115.2 (CH), 112.9 (CH), 111.0 (CH),
109.2 (CH), 56.4 (Me), 56.1 (Me), 55.5 (Me), 39.8 (2 × CH2), 28.7
(CH2), 26.8 (CH2), 26.7 (2 × CH2), 25.7 (Me), 25.6 (Me), 17.7
(Me), 17.6 (Me), 16.2 (Me), 15.7 (Me); m/z (ESI) 555 (M + Na+,
100%).
4-Geranyl-6-(2,6-dimethylhepta-1,5-dienyl)-2-hydroxy-6H-
benzo[c]chromene-7,10-dione 28. (a) Nitric acid (6 M; 0.08 mL)
was added at room temperature to a mixture of 2′,3-digeranyl-5,3′,6′-
trimethoxy-biphenyl-2-ol 26 (40 mg, 0.08 mmol), silver(II) oxide (79
mg, 0.64 mmol) and 1,4 dioxane (2 mL), and the mixture was stirred
for 30 min. The mixture was diluted with water (10 mL) and extracted
with ethyl acetate (3 × 10 mL). The combined organic extracts were
dried (MgSO4), filtered and concentrated under reduced pressure. The
residue was quickly purified by chromatography using ethyl acetate
and light petroleum (1:9) as an eluent to give 3,6′-digeranyl-2,2′-p-
benzoquinone 27 (ca. 40 mg), immediately used for the next step.
This compound could not be characterized because it readily cyclizes
to 4-geranyl-6-(2,6-dimethylhepta-1,5-dienyl)-2-hydroxy-6H-benzo[c]-
chromene-7,10-dione 28, simply on standing in solution.
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Article
(400 MHz; CDCl3) 6.89 (1 H, d, J 8.9), 6.85−6.83 (2H, m), 6.62 (1H,
s), 5.44−5.40 (1H, m), 5.21−5.08 (3H, m), 3.87 (3H, s), 3.77 (3H, s),
3.72 (3H, s), 3.71 (3H, s), 3.48−3.35 (2H, m), 3.25 (1H, dd, J 14.0,
6.0), 3.06 (1H, dd, J 14.0, 6.0), 2.22−1.89 (8H, m), 1.79 (3H, s), 1.73
(3H, s), 1.70 (3H, s), 1.67 (3H, s), 1.61 (3H s), 1.35 (3H, s); δC (100
MHz; CDCl3) 152.0 (C), 151.7 (C), 151.1 (C), 151.0 (C), 136.2 (C),
134.0 (C), 131.4 (C), 131.1 (C), 130.8 (C), 129.7 (C), 129.1 (C),
124.6 (CH), 124.4 (CH), 124.3 (C), 123.0 (CH), 122.6 (CH), 114.2
(CH), 113.3 (CH), 110.0 (CH), 109.6 (CH), 56.5 (Me), 56.4 (Me),
56.0 (Me), 55.9 (Me), 39.9 (CH2), 39.8 (CH2), 28.6 (CH2), 28.4
(CH2), 26.9 (CH2), 26.8 (CH2), 25.8 (Me), 25.7 (Me), 17.7 (Me),
17.6 (Me), 16.2 (Me), 15.7 (Me); m/z (ESI) 569 (M + Na+, 100%).
3-Geranyl-6-(2,6-dimethylhepta-1,5-dienyl)-2-hydroxy-6H-
benzo[c]chromene-7,10-dione 33. (a) Nitric acid (6 M; 0.08 mL)
was added at room temperature to a mixture of 2,4′-digeranyl-3,6-
2′,5′-tetramethoxybiphenyl 31 (44 mg, 0.08 mmol), silver(II) oxide
(79 mg, 0.64 mmol) and 1,4-dioxane (2 mL), and the mixture was
stirred for 30 min. The mixture was diluted with water (10 mL) and
extracted with ethyl acetate (3 × 10 mL). The combined organic
extracts were dried (MgSO4), filtered and concentrated under reduced
pressure. The obtained residue was quickly purified by chromatog-
raphy using ethyl acetate and light petroleum (1:9) as an eluent to give
3,5′-digeranyl-2,2′-bis-p-benzoquinone 32, immediately used for the
next step. This compound could not be characterized because it readily
cyclizes to 3-geranyl-6-(2,6-dimethylhepta-1,5-dienyl)-2-hydroxy-6H-
benzo[c]chromene-7,10-dione 33, simply on standing in solution.
(b) A solution of 3,5′-digeranyl-2,2′-bis-p-benzoquinone 32 (10 mg,
0.021 mmol, from the above crude material) in dichloromethane (2
mL) was stirred at room temperature for 15 h. The resulting dark
brown mixture was concentrated in vacuo. Column chromatography of
the residue eluting with ethyl acetate and light petroleum (1:9) gave
the title compound as a dark brown oil (5.3 mg, 52%); (Found: M +
Na+, 509.2665. C32H38O4 + Na+ requires 509.2662); λmax (MeOH)/
nm 269 (log ε 3.4), 315 (3.67), 403 (3.29); νmax (CHCl3)/cm−1 3690,
3602, 1650, 1600; δH (500 MHz; DMSO-d) 9.31 (1H, s), 7.72 (1 H,
s), 6.86 (2H, s), 6.59 (1H, s), 5.85 (1H, d, J 9.5), 5.32−5.24 (2H, m),
5.09−5.07 (1H, m), 5.04−4.86 (1H, m), 3.21 (2H, d, J 7.2), 2.09−1.90
(8H, m), 1.84 (3H, s), 1.64 (3H, s), 1.63 (3H, s), 1.55 (3H, s), 1.52
(3H s), 1.45 (3H, s); δC (125 MHz; DMSO-d) 187.3 (C), 185.3 (C),
150.1 (C), 147.7 (C), 142.9 (C), 137.7 (CH), 136.5 (C), 135.9 (CH),
133.6 (C), 133.2 (C), 131.4 (C), 131.3 (C), 130.2 (C), 124.5 (CH),
123.9 (CH), 121.8 (CH), 119.2 (CH), 117.8 (CH), 115.4 (CH),
114.2 (C), 67.0 (CH), 39.7 (CH2), 39.3 (CH2), 28.4 (CH2), 26.5
(CH2), 25.9 (CH2), 25.9 (Me), 25.8 (Me), 18.0 (Me), 17.9 (Me), 17.2
(Me), 16.3 (Me); m/z (ESI) 509 (M + Na+, 100%).
Thiaplidiaquinone A 1. To a stirred solution of 4-geranyl-6-(2,6-
dimethyl-hepta-1,5-dienyl)-2-hydroxy-6H-benzo[c]chromene-7,10-
dione 28 (10 mg, 0.0205 mmol) in acetonitrile/ethanol (0.40 mL, 1:1)
was added a solution of hypotaurine (2.9 mg, 0.0266 mmol) in water
(0.1 mL) and salcomine (0.9 mg, 0.0028 mmol), and the reaction
mixture was stirred at room temperature for 41 h, diluted with water
(3 mL), extracted with ethyl acetate (3 × 5 mL), dried (MgSO4),
filtered and concentrated under reduced pressure. Column chroma-
tography of the residue eluting with ethyl acetate and light petroleum
(30:20 to 45:5) gave (i) the regioisomer 34 as a black oil (3.2 mg,
26%) and (ii) thiaplidiaquinone A 1 as a red oil (1.7 mg, 14%).
Regioisomer 34. (Found: M + Na+, 614.2552. C34H41N1O6S1 +
Na+ requires 614.2547); νmax (CHCl3)/cm−1 3668, 1627; δH (500
MHz; DMSO-d) 9.19 (1H, s), 9.07 (1H, br s), 7.58 (1H, d, J 3.0), 6.68
(1H, d, J 3.0), 5.92 (1H, d, J 9.3), 5.26 (1H, d, J 9.3), 5.18 (1H, t, J
7.1), 5.06 (1H, t, J 6.8), 4.89 (1H, t, J 7.1), 3.85−3.75 (2H, m), 3.20−
3.09 (2H, m), 2.04−1.90 (10H, m), 1.88 (3H, s), 1.64 (3H, s), 1.63
(3H, s), 1.55 (3H, s), 1.46 (3H, s); δC (125 MHz; DMSO-d) 178.0
(C), 176.8 (C), 151.8 (C), 146.3 (C), 145.3 (C), 143.5 (C), 135.9
(C), 132.7 (C), 132.2 (C), 131.4 (C), 131.3 (C), 127.9 (C), 124.4
(CH), 123.9 (CH), 122.3 (CH), 121.0 (CH), 119.0 (CH), 118.3 (C),
113.8 (CH), 111.0 (C), 66.9 (CH), 48.7 (CH2), 39.9, (CH2) 39.7
(CH2), 39.3 (CH2), 28.3 (CH2), 26.6 (CH2), 26.1 (CH2), 26.0 (Me),
25.8 (Me), 18.0 (Me), 17.9 (Me), 17.3 (Me), 16.3 (Me); m/z (ESI)
614 (M + Na+, 100%).
Thiapliaquinone A 1. (Found: M + Na+, 614.2571. C34H41N1O6S1
+ Na+ requires 614.2547); νmax (CHCl3)/cm−1 3668, 1628; δH (500
MHz; DMSO-d) 9.15 (1H, s), 9.11 (1H, br s), 7.44 (1H, d, J 3.0), 6.62
(1H, d, J 3.0), 5.95 (1H, d, J 9.3), 5.23 (1H, d, J 9.3), 5.18 (1H, t, J
6.9), 5.04−5.07 (1H, m), 4.92−4.90 (1H, m), 3.83−3.85 (2H, m),
3.20−3.08 (2H, m), 2.04−1.92 (8H, m), 1.88 (3H, s), 1.64 (3H, s),
1.63 (3H, s), 1.55 (6H, s), 1.46 (3H, s); δC (125 MHz; DMSO-d)
179.0 (C), 174.8 (C), 151.5 (C), 146.5 (C), 144.3 (C), 143.8 (C),
137.7 (C), 135.8 (C), 131.5 (C), 131.3 (C), 131.1 (C), 128.9 (C),
124.5 (CH), 123.9 (CH), 122.4 (CH), 119.4 (CH), 118.9 (CH),
117.8 (C), 112.2 (CH), 108.7 (C), 67.0 (CH), 48.5 (CH2), 39.8 (2 ×
CH2), 39.4 (CH2), 28.3 (CH2), 26.6 (CH2), 26.1 (CH2), 26.0 (Me),
25.8 (Me), 18.0 (Me), 17.9 (Me), 17.3 (Me), 16.3 (Me); m/z (ESI)
614 (M + Na+, 100%).
ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental details and copies of H and 13C NMR
1
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Fax: (+44) 115 951 3564. E-mail: c.j.moody@nottingham.ac.
■
uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EU for a Marie Curie Fellowship (to A.C.), the
Engineering and Physical Sciences Research Council for
support via the DTA scheme (to C.L.L.), Dr. Adrienne
Davis, Dr. Russell Kitson, and Mr. Shazad Aslam for their
contributions to NMR spectroscopy, Dr. Raffaele Pasceri for
recording UV spectra, and Professor Ernesto Fattorusso
(University of Naples) for copies of the NMR spectra of
natural thiaplidiaquinone A.
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