Synthetic studies towards the mulberry Diels-Alder adducts: H-bond accelerated cycloadditions of chalcones

Article abstract of DOI:10.1039/c2ob25115a

The methyl ether derivatives 2, 4 and 6 of the mulberry Diels-Alder adducts chalcomoracin (1) and mulberrofuran C (3) and kuwanon J (5) respectively have been synthesized by a thermal [4 + 2]-cycloaddition reaction between a chalcone and dehydroprenyl die

Full text of DOI:10.1039/c2ob25115a

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PAPER
Synthetic studies towards the mulberry Diels–Alder adducts: H-bond
accelerated cycloadditions of chalcones†‡
Sompong Boonsri,a Christian Gunawan,a Elizabeth H. Krenske*a,b and Mark A. Rizzacasa*a
Received 15th January 2012, Accepted 7th March 2012
DOI: 10.1039/c2ob25115a
The methyl ether derivatives 2, 4 and 6 of the mulberry Diels–Alder adducts chalcomoracin (1) and
mulberrofuran C (3) and kuwanon J (5) respectively have been synthesized by a thermal [4 + 2]-
cycloaddition reaction between a chalcone and dehydroprenyl diene. A H-bonded ortho OH substituent
on the chalcone was found to be essential for Diels–Alder reactivity. Density functional theory
calculations show that the OH group lowers the barrier for the Diels–Alder reaction by 2–3 kcal mol−1
compared with OMe. The acceleration by the OH group is traced to two transition-state effects: a stronger
diene–chalcone interaction and better planarity of the aryl–diene unit.
Diels–Alder reaction through an endo transition state (Fig. 1)
while the trans, trans stereochemistry, which is also observed in
Introduction
Moraceae is a family of flowering plants comprising about sixty
genera and nearly 1400 species which are found in temperate,
subtropical and tropical regions of the world. The mulberry tree
is a typical plant of the genus Morus, which are widely culti-
vated in China, Korea and Japan. The root bark of mulberry tree
has long been used in traditional Chinese medicine for anti-
inflammatory, diuretic, anti-tussive, expectorant and anti-pyretic
purposes.1 The methanol extract of Morus alba showed antioxi-
dant properties2 and inhibited the proliferation of vascular
smooth muscle cell3 while the fruit extract also showed a hypoli-
pidemic effect in rats.4 In addition, compounds isolated from the
root bark of Morus alba exhibit a hypoglycaemic effect in dia-
betic mice.5 Chemical investigations of Morus species have
resulted in the isolation of a wide range of natural products
including the so called Diels–Alder adducts.6 Some examples
are shown in Fig. 1 and include the dehydroprenylarylbenzo-
furan adducts chalcomoracin (1)7 and mulberrofuran C (3)8 and
the dehydroprenylchalcone adduct kuwanon J (5).9 The trisubsti-
tuted methylcyclohexene moiety found in these molecules
appears to originate from an intermolecular [4 + 2]-cycloaddition
reaction between a chalcone type dienophile and dehydroprenyl-
phenol diene.6 Thus, adducts bearing the cis, trans stereo-
chemistry on the cyclohexene ring would be derived from a
a number of these natural products, arises from the exo transition
aSchool of Chemistry, The Bio21 Institute, The University of Melbourne,
VIC 3010, Australia. E-mail: masr@unimelb.edu.au
bAustralian Research Council Centre of Excellence for Free Radical
Chemistry and Biotechnology, School of Chemistry, The University of
Melbourne, VIC 3010, Australia. E-mail: ekrenske@unimelb.edu.au
†Electronic supplementary information (ESI) available: NMR spectra of
all Diels–Alder adducts and computational data. See DOI: 10.1039/
c2ob25115a
‡This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
Fig. 1 Examples of mulberry Diels–Alder adducts.
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Scheme 1 Retro-Diels–Alder reaction of chalcomoracin heptamethyl-
ether (2) (ref. 16).
Scheme 3 Retrosynthesis of mulberrofuran C heptamethylether (4).
Scheme 4 Synthesis of diene 7.
Scheme 2 Retro-Diels–Alder/Diels–Alder reaction of kuwanon
octamethylether (10) (ref. 17).
G
Thermal Diels–Alder reactions of chalcones with dienes such
as myrcene have been reported for the synthesis of related
methylcyclohexene natural products such as the nicolaioidesins,
crinatusins19 and panduratins.20 In addition, Porco and co-
workers have reported cycloadditions of chalcones catalysed by
CoI2 or silver nanoparticles which are proposed to proceed via a
stepwise radical mechanism.21 However, few examples of the
[4 + 2]-cycloaddition of chalcones22 and dehydroprenyl dienes
to produce members of the mulberry Diels–Alder type family of
natural products have been disclosed.23,24 We were intrigued by
this fact and therefore elected to investigate the synthesis of
various cycloaddition partners and the subsequent Diels–Alder
reaction. In this paper, we report the full details of our study,23
including a computational investigation of the acceleration of the
Diels–Alder reaction by intramolecular H-bonding.
state. Interestingly, all these adducts are optically active with the
absolute configuration of mulberrofuran C (3) determined as 3′′
S, 4′′R, 5′′S by a combination of CD spectroscopy and X-ray
crystallography.10,11 Furthermore, all adducts with a positive
optical rotation value are cis, trans (endo)-adducts whilst the
adducts with negative values are the trans, trans (exo) adducts.10
This infers that the [4 + 2]-cycloaddition is under some type of
enzymatic control12–14 but the question of whether this process
in Nature is concerted or stepwise is a subject of debate.15,16
Early studies showed that pyrolysis of chalcomoracin hepta-
methylether (2) resulted in retro Diels–Alder reaction to afford
dehydroprenylbenzofuran 7 and chalcone 8, with the latter com-
pound quoted as highly unstable and therefore not fully charac-
terised (Scheme 1).17
Similarly, Nomura’s group reported that pyrolysis of kuwanon
G octamethylether 9 gave the diene 10 and chalcone 11 which
upon heating together at 180 °C in toluene in a sealed tube
reformed racemic 9 along with the corresponding endo-isomer in
50% yield (Scheme 2).18 Again, no experimental detail was
reported for this process.
Discussion and results
A proposed synthesis of mulberrofuran C heptamethylether (4)
is shown in Scheme 3. This compound could originate from a
[4 + 2]-cycloaddition between the simple chalcone 12 and dehy-
droprenylbenzofuran 7 as the diene (Scheme 4). Owing to its
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Scheme 5 Attempted Diels–Alder reaction between 7 & 12
reported instability,17 we first investigated the synthesis of the
diene 7. We reasoned 7 could arise from a Suzuki cross coup-
ling25 reaction between iodide 13 and a suitable boronate whilst
the benzofuran system could be synthesized by an intramolecular
cyclisation of a phenolic alkyne formed by a selective
Sonogashira coupling26 between iodoalkyne 14 and iodide 15.
The synthesis of the diene 7 is shown in Scheme 4. Alkyne 14
arose from the known aldehyde 1627 via treatment with the
Bestmann–Ohira reagent28 in the presence of base. Sonogashira
coupling with the iodide 15 was best achieved using Cs2CO3 as
base29 to afford the tolan 17. Hydrolysis gave the phenol 18
which was best cyclized to the benzofuran 13 by treatment with
TBAF in boiling THF.30
Scheme 6 Diels–Alder reaction between 7 & phenolic chalcone 24.
The pinacol boronate 2031 was synthesized from enyne 19 by
hydroboration32 with freshly prepared pinacol borane. Suzuki
coupling with iodide 13 then afforded diene 7 in high yield.
Whilst this compound was sensitive, it proved stable enough in
our hands to be fully characterised. We next embarked on the
synthesis of the chalcone dienophile as shown in Scheme 5.
Claisen–Schmidt condensation33 between acetophenone 21 and
aldehyde 22 gave the chalcone 12.34 Unfortunately, all attempts
at a thermal or Lewis acid catalysed Diels–Alder reaction
between 12 and 7 gave only traces of the desired product 4 and
large amounts of decomposition.
Fig. 2 Selected nOe interactions for endo-isomer 26.
placing these protons in a trans arrangement. This data correlated
with that for the related natural products.7,8 Methylation of endo-
isomer 26 gave mulberrofuran C heptamethylether (4) however,
since NMR data was not provided in the original report of its
synthesis from mulberrofuran C,8 a direct comparison could not
be made.
In addition, we noted that in the exo-isomer 25 the signals for
1
H6′ and H2′ in the H NMR spectrum appeared as two broad
We next examined an alternative dienophile 24 which was
synthesized as a precursor for the prenylated chalcones. Claisen–
Schmidt condensation between phenol 23 and 22 afforded the
naturally occurring chalcone 2435,36 which displayed a strong
singlets at δ 6.89 and 7.09 ppm whilst the signals for the
methoxy groups at C3′ and C5′ also appeared as broad singlets
at δ 3.71 and 4.08 ppm. These signals broadened significantly on
heating to 50 °C in d6-acetone. The corresponding signals in the
1H NMR spectrum of endo adduct appeared as two broad sing-
lets at 6.95 ppm (2H, H2′ and 6′) and 3.59 ppm (6H, C3′ and 5′
OMe). This clearly indicates that there is restricted rotation about
the C3′′–C4′ bond which is more pronounced in the exo-isomer.
This was also observed for H2′ and 6′ (6.67 and 6.83 ppm) for
the natural product mulberrofuran J37 and is possibly due to the
close proximity of the aryl groups in the all trans-arrangement
on the cyclohexene ring increasing the steric congestion.
Clearly, the presence of the H-bonded free phenol in the chal-
cone 24 was key to the success of the Diels–Alder reaction. In
addition, heating the adduct 25 in toluene at 180 °C for 24 h
resulted in little change apart form a small amount of decompo-
sition. This indicated the Diels–Alder reaction was under kinetic
1
H-bonded phenolic resonance in its H NMR spectrum. When a
solution of 24 and 7 in toluene was heated in a sealed tube for
16 h the exo product 25 (mulberrofuran J hexamethylether) and
endo isomer 26 (mulberrofuran C hexamethylether) were now
formed in a 1 : 1 ratio in 40% yield (Scheme 6).
The isomers were separated by HPLC and the stereochemistry
of each adduct was confirmed by 1H NMR analysis (Fig. 2). The
endo-isomer 26 showed a nOe in the NOESY spectrum between
the aromatic proton H14′′ and H5′′ on the cyclohexene ring indi-
cating a cis relationship while nOes between H20′′ and H3′′ and
4′′ suggested these were also in cis arrangement. A coupling con-
stant of 5 Hz between H3′′ and 4′′ indicated these were cis and
the aryl benzofuran ring (Ar3) is in a pseudoaxial orientation. In
the exo-isomer 25, the coupling between H3′′ and 4′′ is 10 Hz
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Scheme 9 Retrosynthesis of kuwanon J heptamethylether (6).
Scheme 7 Synthesis of chalcone 27.
Scheme 10 Synthesis of diene 32.
rotation) with our synthetic sample thus confirming the stereo-
chemistry of 31. The endo-isomer also had similar 1H NMR
characteristics to that described above for 26 and the exo-isomer
also displayed significant hindered rotation about the C3′′–C4′
bond with the signals for H2′ and 6′ appearing at 6.79 and
7.07 ppm whilst the C3′ and 5′ OMe signals appeared at 3.66
and 4.07 ppm.
To further probe the H-bond effect, we next targeted kuwanon
J heptamethylether (6) (Scheme 9). Kuwanon J9 (5) itself has
been shown to arise from a single prenylated chalcone starting
material which on dehydrogenation gives a diene partner.14
Thus, compound 6 could arise from a Diels–Alder reaction
between the chalcone dienophile 27 and the corresponding chal-
cone diene 32 followed by methylation. In this instance, one can
envisage the chalcone diene 32 could also react with itself as
a dienophile. However, if the H-bonded chalcone 27 reacts
fast enough as a dienophile, as suggested by our earlier results,
then little dimerization product should be observed and only the
[4 + 2]-cycloaddition product arising from a combination of 27
and 32 should be observed. Diene 32 could be obtained by a
Suzuki coupling using the same pinacol borane 20 and the
appropriate iodide.
The sequence began with the synthesis of the diene 32 as
shown in Scheme 10. Iodination of acetophenone 23 gave iodide
33 along with the 5-iodoisomer. Claisen–Schmidt condensation
with the aldehyde 22 followed by methylation gave chalcone 34
and Suzuki coupling with boronate 20 gave diene 32 albeit in
low yield. With the two cycloaddition partners in hand we next
examined the Diels–Alder reaction.
Scheme 8 Diels–Alder reaction between 7 & chalcone 27: synthesis of
chalcomoracin heptamethylether (2).
control. We therefore next investigated the synthesis chalcomora-
cin heptamethylether (2) which commenced with the production
of the requisite prenylated chalcone 27 (Scheme 7). Prenylation
of chalcone 24 with prenyl chloride gave ether 28 in good yield.
A 1,3-shift38 mediated by florisil in toluene at 100 °C yielded
the desired prenylated chalcone 27 as well as the 1,5-shift
product 29 in 28% and 22% yields respectively along with the
phenol 24.
The cycloaddition between diene 7 and chalcone 27 pro-
ceeded at 180 °C to afford a 55% overall yield of chalcomoracin
hexamethylether 31 and mongolicin F39 hexamethylether 30 in a
ratio of 2 : 1 respectively (Scheme 8). Each of these was again
separable by HPLC and compound 31 was methylated to afford
chalcomoracin heptamethylether 2.7 Fortunately, we were able to
obtain a somewhat impure authentic sample of chalcomoracin
(1) and permethylation of this crude compound gave naturally
derived chalcomoracin heptamethylether 2 in low yield. This
compound was identical in all respects (apart from optical
The [4 + 2]-cycloaddition reaction between diene 32 and chal-
cone 27 afforded kuwanon J heptamethyl ether (6) and the exo-
isomer, which corresponds to kuwanon I40 heptamethylether
(35), in a 1 : 1 ratio as the only products isolated (Scheme 11).
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Scheme 12 Model Diels–Alder reactions between diene 38 & chal-
cones 12 or 24.
Scheme 11 Diels–Alder reaction between diene 32 & chalcone 27:
synthesis of kuwanon J heptamethylether (6).
Fig. 3 Dorstenone (36) and dorstenone pentamethylether (37).
No product resulting from the Diels–Alder reaction of diene 32
with itself as the dienophile to afford kuwanon J octamethylether
was detected, again indicating the importance of the H-bond.
The exo-isomer also showed restricted rotation about the C3′–
C3′′ bond as shown by the arrow however in this case, most of
the signals in the 1H NMR spectrum were doubled (3 : 2 ratio) as
a result of atropisomerism due to the unsymmetrical nature of
the aromatic ring. When a solution of 35 in d6-DMSO was
heated to 75 °C, the signals coalesced to a single set which on
cooling to 25 °C returned to the initial 3 : 2 atropisomeric
mixture. In the original report of the isolation of the related
natural product dorstenone (36)41 (Fig. 3), a doubling of peaks
Fig. 4 Calculated transition structures for Diels–Alder reactions of
diene 38 with chalcones 24 and 12 (B3LYP geometries, distances in Å).
M06-2X activation and reaction energies are shown (kcal mol−1).
1
was observed in the H NMR spectrum of this compound after
4 h of dissolution of sample. Interestingly, others have observed
a doubling of peaks for dorstenone pentamethylether (37)24 and
attributed this to an equilibrium between the exo- and endo-
isomers i.e. by epimerisation at the C3′′ stereocentre. This heat
induced epimerisation to resolve the mixture to one exo-isomer
(which then returns to the same endo/exo mixture on cooling to
room temperature) is highly unlikely. Based on our observations
it appears that the both these reported examples are also due to
atropisomerism.42
group, we performed density functional theory calculations on
the Diels–Alder reactions of 12 and 24 with the model aryl diene
38, as shown in Scheme 12.43
Geometries of reactants, transition states, and products were
optimized at the B3LYP/6-31G(d) level, and single-point ener-
gies were then computed at the M06-2X/6-311+G(d,p) level.
The endo and exo transition structures are shown in Fig. 4,
together with their activation energies and the overall reaction
energies. The transition states are concerted, but highly asyn-
chronous. The bond to the more electrophilic β carbon of the
chalcone is 0.75–0.85 Å shorter than the bond forming at the α
carbon. The major geometrical difference between the transition
Computational studies
To determine why the Diels–Alder reactivity of the chalcones 12
and 24 is so highly dependent on the presence of the ortho OH
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states for the two chalcones is that the carbonyl oxygen is hydro-
gen-bonded to OH in chalcone 24 (TS1/TS2), while there is no
possibility for hydrogen bonding in the chalcone 12 (TS3/TS4)
which has its OMe group positioned anti to CvO to minimize
electrostatic repulsion.
Nature, however the current results do not discount the possi-
bility that a concerted [4 + 2]-cycloaddition reaction is involved
in the biogenesis of this family of natural products.
The values of ΔG‡ for TS1–TS4 predict exo selectivities of
approximately 1 kcal mol−1, but this value is lowered by
inclusion of other low-lying TS conformers. Experimentally,
little exo/endo selectivity was detected. The OH group lowers
the activation energy (ΔG‡) by 2.3–2.6 kcal mol−1 compared to
OMe. This corresponds to a 13–18-fold larger rate constant at
180 °C, in agreement with the yields of 40% and <5% obtained
from the Diels–Alder reactions of arylbenzofuran diene 7 with
the OH- and OMe-substituted chalcones 24 and 12, respectively
(Schemes 5 and 6).
Experimental
General
High resolution mass spectra (HRMS) were run using electro-
spray ionisation (ESI). Proton nuclear magnetic resonance (1H
NMR, 400 and 500 MHz) and proton decoupled carbon nuclear
magnetic resonance spectra (13C NMR, 100 and 125 MHz) were
recorded for deuteriochloroform solutions with residual chloro-
form as internal standard unless otherwise stated. Analytical thin
layer chromatography (TLC) was conducted on aluminium
backed 2 mm thick silica gel GF254. Compounds were visual-
ized with solutions of 20% w/w phosphomolybdic acid in
ethanol, 20% w/w potassium permanganate in water or under
UV (365 nm). Anhydrous tetrahydrofuran (THF) and diethyl
ether were dried using a Glass Contour cartridge solvent dispen-
sing system. Petrol refers to the fraction boiling at 40–60 °C. All
other commercial reagents were used as received. All air and
moisture sensitive reactions were performed in glassware that
was either flame dried under an atmosphere of dry argon or oven
dried at 150 °C.
As mentioned above, the diene 32 (Schemes 9–11), which
bears a pendant OMe-substituted chalcone, could undergo
Diels–Alder reaction with a second molecule of itself. However,
no self-reaction adduct was detected and we surmise that the
diene simply prefers to combine with the faster-reacting OH-sub-
stituted chalcone 27. The overall energetics for OH versus OMe
favour this explanation. There is only a ∼1 kcal mol−1 difference
in the thermodynamic stabilities of the two chalcone products,
which would require the self-reaction product to be present in a
1 : 3 ratio if an equilibrium had indeed been reached. This
suggests that the reaction is subject to kinetic control under the
conditions used.
5-Ethynyl-2-iodo-1,3-dimethoxybenzene (14)
The enhancement of reactivity by the ortho OH group can be
traced to two features. During the reaction of diene 38 with OH-
substituted chalcone 24, less energy is required to distort the
diene to its TS geometry, and the interaction between the diene
and the chalcone in the TS is stronger. An analysis44 of the OH
and OMe transition states TS2 and TS4 shows that each of these
factors contributes ∼1 kcal mol−1 to the overall difference in
barriers (ΔE‡, M06-2X). The smaller diene distortion for the OH
reaction reflects a better coplanarity between the diene and its
aryl substituent (Ar3) in the TS.45 The stronger chalcone–diene
interaction reflects the LUMO-lowering effect of the OH–
carbonyl hydrogen bond. Charge transfer from diene to dieno-
phile is 0.14 e greater in the OH-substituted TS2 than in the
OMe-substituted TS4.46
To a solution of aldehyde 16 (1.50 g, 5.08 mmol) in distilled
methanol (10 mL) were added K2CO3 (1.41 g, 10.2 mmol) and
Bestmann–Ohira reagent28 (1.23 g, 6.36 mmol). The reaction
mixture was stirred at r.t. for 16 h before the addition of water
and CH2Cl2. The aqueous phase was extracted with CH2Cl2
(2×). The organic layers were collected, washed with brine, dried
over MgSO4 and concentrated. The crude residue was purified
by flash chromatography eluting with 30% EtOAc–petrol to
afford 14 (108 mg, 98%) as a yellow crystals; m.p. 127–130 °C;
IR νmax (film): 3016, 2970, 2945, 1738, 1435, 1366, 1229,
1217, 120 cm−1; δH (500 MHz) 6.62 (s, 2H), 3.88 (s, 6H), 3.11
(s, 1H); δC (100 MHz) 159.4, 123.6, 107.8, 83.4, 77.82, 77.80,
56.7; HRMS (ESI) calcd for C10H9IO2Na [M
310.95394. Found 310.95394.
+
Na]+:
Conclusions
2-((4-Iodo-3,5-dimethoxyphenyl)ethynyl)5-methoxyphenyl
acetate (17)
A number of thermal Diels–Alder reactions between dehydropre-
nyl dienes and chalcones to afford the methyl ether derivatives
2, 4 and 6 of the mulberry Diels–Alder adducts chalcomoracin
(1) and mulberrofuran C (3) and kuwanon J (5), respectively, as
well as mulberrofuran J hexamethylether (25), mongolicin F
hexamethylether (30), and kuwanon I heptamethylether (35), are
reported. The success of the [4 + 2]-cycloaddition was depen-
dent on the presence of the H-bonded phenol in the chalcone
dienophile and density functional theory calculations suggest
that the acceleration of the cycloaddition reaction by the OH
group arises both from the LUMO-lowering effect of the OH–
carbonyl hydrogen bond and from better coplanarity between the
diene and its aryl substituent in the TS. The high temperature
conditions utilised above by no means mirror those found in
To a flame-dried 2-neck round bottom flask, under an argon
atmosphere were added tetrakis(triphenylphosphine)palladium(0)
(20 mg, 17.4 μmol), copper iodide (4.96 mg, 26.1 μmol), iodide
15 (77.3 mg, 0.26 mmol) and dry DMF (1 mL). The mixture
was degassed for 15 min and a solution of alkyne 14 (50 mg,
0.1736 mmol) in dry DMF (1 mL) was added dropwise at 0 °C.
The reaction mixture was degassed for 15 min before the
addition of cesium carbonate (84.9 mg, 0.26 mmol). The reac-
tion mixture was then stirred at r.t. for 4 h, then filtered through a
pad of celite. To the filtrate was added water and the mixture was
extracted with CH2Cl2 (2×). The organic layers were collected,
washed with brine, dried over MgSO4 and concentrated. The
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crude residue was purified by flash chromatography with 30%–
40% ether–petrol as eluent to give tolan 17 as a yellow amor-
phous solid (51 mg, 65%); νmax (film): 3016, 2971, 2946, 1738,
1441, 1366, 1229, 1217, 1206, 1157, 1119, 896 cm−1; δH
(500 MHz) 7.48 (d, J = 8.5 Hz, 1H), 6.78 (dd, J = 2.5, 8.5 Hz,
1H), 6.68 (d, J = 2.5 Hz), 6.61 (s, 2H), 3.89 (s, 6H), 3.83
(s, 3H), 2.35 (s, 3H); δC (125 MHz) 168.7, 160.9, 159.4, 152.9,
133.74, 124.8, 112.3, 109.2, 108.5, 107.2, 92.5, 85.0, 78.8,
56.78, 56.75, 21.0; HRMS (ESI): calculated for C19H17INaO5
[M + Na]+ 475.0018, found: 475.0014.
(s, 12H); δC (125 MHz) 152.3, 143.1, 120.2, 83.3, 24.92, 24.69,
17.8.
(E)-2-(3,5-Dimethoxy-4-(3-methylbuta-1,3-dienyl)phenyl)-6-
methoxybenzofuran (7)
To a flame-dried 2-neck round bottom flask containing a solution
of arylbenzofuran iodide 13 (20 mg, 0.05 mmol) and
dienylboronate 20 (39.7 mg, 0.20 mmol) in DMF (2 mL), were
added Pd2(dba)3 (3.29 mg, 3.59 μmol) and AsPh3 (2.20 mg,
7.19 μmol) under an argon atmosphere. The reaction mixture
was degassed for 15 min before the addition of a solution of
K3PO4 in water (3 M, 170 μL, 0.51 mmol). The reaction mixture
was stirred at 50 °C for 16 h, then filtered through a pad of
celite. To the filtrate was added water and CH2Cl2. The aqueous
phase was extracted with CH2Cl2 (2×). The organic layers were
collected, washed with brine, dried over MgSO4 and concen-
trated. The crude residue was purified by flash chromatography
with 10% ether–petrol (1% Et3N) as eluent to provide diene 7
(14 mg, 82%) as a light yellow amorphous solid; νmax (film):
2922, 2853, 1745, 1655, 1621, 1599, 1556, 1492, 1456, 1412,
1357, 1338, 1278, 1204, 1151, 1120, 1028, 962, 975, 878, 821,
765, 697; δH (500 MHz) 7.43 (d, J = 8.5 Hz, 1H), 7.36 (d, J =
16.5 Hz, 1H), 7.08 (d, J = 1.5 Hz, 1H), 7.01 (s, 2H), 6.97 (d, J =
0.5 Hz, 1H), 6.86 (d, J = 16.5 Hz, 1H), 6.86 (dd, J = 2.5, 8.5
Hz), 5.10 (br s, 1H), 5.05 (br s, 1H), 5.03, 3.97 (s, 6H), 3.88
(s, 3H), 2.01 (s, 3H); δC (125 MHz, d6-acetone) 159.7, 159.5,
156.8, 155.7, 144.5, 136.2, 131.1, 129.8, 129.2, 122.0, 120.6,
116.7, 113.2, 103.0, 101.0, 96.4, 56.3, 56.0, 23.3; HRMS (ESI)
calculated for C22H23O4 [M + H]+ 351.1596, found: 351.1582.
2-(4-Iodo-3,5-dimethoxyphenyl)-6-methoxybenzofuran (13)
To a solution of acetate 17 (37 mg, 0.08 mmol) in distilled
methanol (5 mL) was added K2CO3 (20 mg, 0.14 mmol). The
reaction mixture was stirred at r.t.for 3 h before the addition of
water and CH2Cl2. The aqueous phase was extracted with
CH2Cl2 (2×). The organic layers were collected, washed with
brine, dried over MgSO4 and concentrated. The crude residue
was purified by flash chromatography with 40% ether–petrol as
eluent to afford phenol 18 (26 mg, 78%) a light yellow amor-
phous solid; νmax (film): 3457, 3016, 2971, 2946, 1738, 1563,
1441, 1366, 1229, 1217, 1206, 1119, 899.5 cm−1; δC (500 MHz)
7.33 (d, J = 8.5 Hz, 1H), 6.64 (s, 2H), 6.54 (d, J = 2.5 Hz, 1H),
6.49 (dd, J = 2.5, 8.5 Hz, 1H), 3.92 (s, 6H), 3.82 (s, 3H); δC
(125 MHz) 162.0, 159.5, 158.2, 132.6, 124.2, 107.7, 107.1,
101.6, 100.3, 95.0, 83.9, 79.1, 56.8, 55.6; HRMS (ESI): calcu-
lated for C17H14IO4 [M − H+]− 408.9937, found: 408.9940.
To a solution of phenol 18 (29 mg, 0.07 mmol) in THF
(5 mL) TBAF (44.6 mg, 0.14 mmol) was added. The reaction
mixture was refluxed for 3 h before the addition of water and
CH2Cl2. The aqueous phase was extracted with CH2Cl2 (2×).
The organic layers were collected, washed with brine, dried over
MgSO4 and concentrated. The crude residue was purified by
flash chromatography with 30% ether–petrol as eluent to give
benzofuran 13 (24 mg, 82%) as a pale yellow solid; m.p.
191–192 °C; νmax (film): 3000, 2939, 2837, 1623, 1597, 1578,
1558, 1492, 1455, 1405, 1277, 1237, 1207, 1151, 1121, 1021,
962, 821 cm−1; δH (500 MHz) 7.44 (d, J = 8.5 Hz, 1H), 7.08 (d,
J = 2.5 Hz, 1H), 7.02 (d, J = 1.0 Hz, 1H), 6.95 (s, 2H), 6.88 (dd,
J = 2.5, 8.5 Hz, 1H), 3.99 (s, 6H), 3.88 (s, 3H); δC (125 MHz)
159.8, 158.5, 156.0, 154.5, 132.6, 122.5, 121.2, 112.3, 102.2,
100.4, 96.0, 56.8, 55.8; HRMS (ESI): calculated for
C17H15INaO4 [M + Na]+ 432.9913, found: 432.9908.
Mulberrofuran C hexamethyl (26) ether mulberrofuran
J hexamethyl ether (25)
Diene 7 (13 mg, 0.0371 mmol) and dienophile 24 (14 mg,
0.0445 mmol) were dissolved in distilled toluene (2 mL) in a
sealed tube. The mixture was degassed for 15 min and heated at
180 °C for 16 h. The reaction mixture was concentrated and sep-
arated by column chromatography with 30% ether–petrol as
eluent to give a mixture of diastereoisomers 25 and 26 as a
yellow solid (12 mg, 40%). The mixture of diastereoisomers
was separated by preparative HPLC (5 micron Spherex 5 silica
250 × 10 mm column, 40% EtOAc–petrol as an eluent, flow
rate: 2 mL min−1).
Endo-isomer 26 (Rt = 11.03 min) was obtained as a pale
yellow a light yellow amorphous solid; νmax (film): 2956, 2837,
1740, 1624, 1609, 1563, 1506, 1492, 1462, 1412, 1374, 1358,
1278, 1235, 1207, 1152, 1124, 1033, 962, 823; δH (500 MHz,
d6-acetone) 12.6 (s, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.46 (d, J =
8.5 Hz, 1H), 7.16 (d, J = 0.5 Hz, 1H), 7.13 (d, J = 2.5 Hz, 1H),
7.01 (d, J = 8.5 Hz, 1H), 6.95 (s, 2H), 6.86 (dd, J = 2.5, 8.5 Hz,
1H), 6.51 (dd, J = 2.5, 8.5 Hz, 1H), 6.43 (d, J = 2.5 Hz, 1H),
6.31 (dd, J = 2.5, 8.5 Hz, 1H), 6.23 (d, J = 2.5 Hz, 1H), 5.40 (br
s, 1H), 4.63 (br s, 2H), 4.24 (br d, J = 5.5 Hz, 1H), 3.86 (s, 3H),
3.77 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H), 3.65 (br s, 6H), 2.35
(dd, J = 6.5, 18.0 Hz, 1H), 2.18 (dd, J = 10.0, 18.0 Hz, 1H),
1.77 (s, 3H); δC (125 MHz, d6-acetone) 207.1, 166.3, 166.2,
165.9, 165.6, 159.9, 159.3, 159.2, 156.6, 156.0, 133.3, 133.1,
(E)-4,4,5,5-Tetramethyl-2-(3-methylbuta-1,3-dienyl)-1,3,2-
dioxaborolane (20)
To a solution of pinacolborane (325 mg, 2.54 mmol) in distilled
pentane (4 mL), under an argon atmosphere, was added
2-methyl-1-buten-3-yne 19 (139 mg, 2.10 mmol) dropwise at
0 °C. The reaction mixture was heated under reflux for 17 h and
allowed to cool to r.t. The mixture was filtered through a pad of
celite and the filtrate was concentrated to provide 20 (296 mg,
73%) as a colourless oil which was used in the next step without
further purification. δH (500 MHz) 7.08 (d, J = 18.0 Hz, 1H),
5.54 (d, J = 18.0 Hz, 1H), 5.15 (s, 2H), 1.85 (s, 3H,), 1.25
6016 | Org. Biomol. Chem., 2012, 10, 6010–6021
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131.1, 123.3, 122.9, 121.9, 119.0, 115.8, 113.0, 107.1, 105.2,
102.3, 101.32, 101.27, 101.22, 101.20, 99.5, 96.4, 56.0, 55.93,
55.91, 55.8, 55.3, 49.3, 38.3, 35.6, 23.7; HRMS (ESI): calcu-
lated for C40H40NaO9 [M + Na]+ 687.2570, found: 687.2565.
Exo-isomer 25 (Rt = 11.95 min) was obtained as a yellow
amorphous solid; νmax (film): 2999, 2970, 2938, 2836, 1738,
1609, 1563, 1506, 1492, 1454, 1439, 1412, 1371, 1277, 1230,
1207, 1151, 1111, 1031, 960, 937, 922, 822, 736 cm−1; δH
(500 MHz, d6-acetone) 13.1 (s, 1H), 7.56 (d, J = 9.0 Hz, 1H),
7.44 (d, J = 8.5 Hz, 1H), 7.13 (s, 1H), 7.11 (s, 1H), 7.08 (br s,
1H), 7.02 (d, J = 8.0 Hz, 1H), 6.87 (br s, 1H), 6.86 (dd, J = 2.0,
9.0 Hz, 1H), 6.36 (s, 1H), 6.26 (dd, J = 2.0, 8.0 Hz, 1H), 6.15
(dd, J = 2.0, 9.0 Hz, 1H), 6.05 (br s, 1H), 5.25 (s, 1H), 4.93 (br
s, 1H), 4.51 (br d, J = 10 Hz, 1H), 4.06 (br s, 3H), 3.86 (s, 3H),
3.83 (s, 3H), 3.70 (br s, 3H), 3.65 (s, 3H), 3.62 (s, 3H), 2.15 (br
s, 1H), 1.74 (s, 3H); δC (125 MHz, d6-acetone) 209.8, 166.5,
165.8, 160.7, 160.2, 159.3, 159.2, 159.0, 156.6, 155.8, 132.9,
132.3, 131.0, 125.1, 123.2, 121.9, 120.6, 116.0, 113.0, 107.1,
105.1, 102.4, 101.9, 101.3, 100.7, 99.3, 96.4, 56.6, 56.4, 56,0,
55.7, 55.3, 42.0, 38.8, 36.9, 36.8, 23.4; HRMS (ESI): calculated
for C40H41O9 [M + H]+ 665.2751, found: 665.2700.
concentrated. The crude residue was purified by flash chromato-
graphy with 40% ether–petrol as eluent to provide chalcone 28
(206 mg, 84%) as a yellow oil; νmax (film): 3016, 2971, 2949,
1738.6, 1600, 1440, 1366, 1229, 1217, 1206 cm−1; δH
(500 MHz) 7.99 (d, J = 16.0 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H),
7.59 (d, J = 16.0 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 6.56 (dd, J
= 2.5, 8.5 Hz, 1H), 6.50 (dd, J = 2.5, 8.5 Hz, 1H), 6.49 (d, J =
2.5 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 5.52 (t of sept, J = 1.5,
6.5 Hz, 1H), 4.60 (d, J = 6.5 Hz, 2H), 3.87 (s, 6H), 3.85 (s, 3H),
1.78 (s, 3H), 1.74 (s, 3H); δC (125 MHz) 190.9, 163.8, 162.6,
160.2, 159.8, 137.2, 133.0, 129.7, 125.7, 123.2, 119.6, 118.0,
105.5, 105.4, 100.0, 98.4, 65.9, 55.7, 55.6, 25.9, 18.4; HRMS
(ESI): calculated for C23H27O5 [M + H]+ 383.1858, found
383.1852.
(E)-3-(2,4-Dimethoxyphenyl)-1-(2-hydroxy-4-methoxy-3-(3-
methylbut-2-enyl)phenyl)prop-2-en-1-one (27) and (E)-3-(2,4-
dimethoxyphenyl)-1-(2-hydroxy-4-methoxy-5-(3-methylbut-2-
enyl)phenyl)prop-2-en-1-one (29)
To a solution of prenyl chalcone 28 (206 mg, 0.54 mmol) in dis-
tilled toluene (3 mL) was added 60–100 mesh Florisil®
(800 mg). The reaction mixture was stirred at 100 °C for 16 h,
then filtered through a pad of celite and the filtrate was concen-
trated. The crude residue was purified by flash chromatography
eluting with 50% CH2Cl2–petrol to give 27 (Rf = 0.5) (60 mg,
28%) as a yellow oil; νmax (film): 2963, 2922, 2840, 1680, 1626,
1606, 1557, 1505, 1494, 1458, 1438, 1417, 1372, 1314, 1297,
1266, 1235, 1210, 1161, 1072, 1031, 986, 835, 790 cm−1; δH
(500 MHz) 13.58 (s, 1H), 8.11 (d, J = 15.5 Hz, 1H), 7.79 (d, J =
9.5 Hz, 1H), 7.63 (d, J = 15.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H),
6.54 (dd, J = 2.0, 8.5 Hz, 1H), 6.48 (d, J = 9.0 Hz, 1H), 6.48
(d, J = 2.5 Hz, 1H), 5.24 (t of sept, J = 1.5, 7.0 Hz, 1H), 3.92
(s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 3.38 (d, J = 7.5 Hz, 2H), 1.79
(s, 3H), 1.68 (s, 3H); δC (125 MHz) 193.0, 163.2, 163.1, 160.6,
139.9, 131.8, 131.2, 129.2, 122.3, 118.8, 117.5, 117.3, 115.0,
105.6, 102.0, 98.6, 55.8, 55.7, 55.6, 25.9, 21.9, 17.9; HRMS
(ESI): calculated for C23H27O5 [M + H]+ 383.1858, found:
383.1851.
Further elution provided the [1,5]-rearrangement product 29
(Rf = 0.4) as a yellow oil (45 mg, 22%); IR νmax (film): 2929,
1629, 1608, 1558, 1503, 1457, 1440, 1362, 1294, 1256, 1210,
1160, 1130, 1032, 995, 834 cm−1; δH (500 MHz) 13.63 (s, 1H),
8.09 (d, J = 15.5 Hz, 1H), 7.63 (d, J = 15.5 Hz, 1H), 7.60 (s,
1H), 7.56 (d, J = 8.5 Hz, 1H), 6.55 (dd, J = 2.5, 9.0 Hz, 1H),
6.49 (d, J = 2.5 Hz, 1H), 6.43 (s, 1H), 5.31 (t of sept, J = 1.5,
7.0, 1H), 3.92 (s, 3H), 3.874 (s, 3H), 3.870 (s, 3H), 3.25 (d, J =
7 Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H); δC (125 MHz) 192.5,
165.2, 163.8, 163.0, 160.5, 139.9, 132.8, 131.5, 129.6, 122.3,
121.3, 118.8, 117.2, 105.4, 99.3, 98.5, 55.6, 55.5, 55.4, 27.8,
25.8, 17.8; HRMS (ESI): calculated for C23H27O5 [M + H]+
383.1858, found 383.1851.
Mulberrofuran C heptamethyl ether (4)
To a solution of mulberrofuran C hexamethyl ether 26 (2 mg,
3.125 mmol) in acetone (2 mL) under an argon atmosphere were
added anhydrous K2CO3 (4.3 mg, 31.25 mmol) and MeI
(4.43 mg, 31.25 mmol). The reaction mixture was heated under
reflux for 16 h and water and CH2Cl2 were added. The aqueous
phase was extracted with CH2Cl2 (2×). The organic layers were
collected, washed with brine, dried over MgSO4 and concen-
trated to afford a yellow amorphous solid 4 (2 mg, 98%); νmax
(film): 2925, 2851, 1716, 1663, 1603, 1562, 1504, 1492, 1462,
1413, 1361, 1279, 1252, 1231, 1207, 1152, 1121, 1030, 962,
936, 824, 737 cm−1; δH (500 MHz, d6-acetone) 7.46 (d, J = 8.5
Hz, 1H), 7.14 (s, 1H), 7.13 (s, 1H), 7.01 (d, J = 8.5 Hz, 1H),
6.98 (d, J = 8.5 Hz, 1H), 6.88 (br s, 2H), 6.86 (dd, J = 2.5, 9.0
Hz, 1H), 6.56 (d, J = 2.5 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H), 6.31
(dd, J = 2.0, 8.5 Hz, 2H), 5.32 (br s, 1H), 4.77 (dd, J = 8.0,
11.5, 1H), 4.75 (br s, 1H), 4.29 (dd, J = 6.3, 10.5 Hz, 1H), 3.99
(s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.69 (s, 3H),
3.61 (br s, 6H), 2.34 (dd, J = 6.0, 18.3 Hz, 1H), 2.07 (d, J = 6.5
Hz, 1H), 1.73 (s, 3H); δC (125 MHz, d6-acetone) 199.8, 164.5,
161.3, 159.5, 159.3, 159.2, 156.6, 156.3, 133.2, 132.6, 160.6,
129.2, 123.6, 123.5, 123.4, 121.8, 120.3, 112.9, 105.9, 105.2,
102.0, 99.4, 98.5, 96.4, 56.2, 56.0, 55.88, 55.82, 55.81, 55.4,
53.6, 38.8, 33.5, 32.6, 23.8; HRMS (ESI): calculated for
C41H42O9 [M + H]+ 679.2907, found: 679.2897.
(E)-3-(2,4-Dimethoxyphenyl)-1-(4-methoxy-2-(3-methylbut-2-
enyloxy)phenyl)prop-2-en-1-one (28)
To a solution of chalcone 24 (200 mg, 0.64 mmol) in acetone
(5 mL) were added K2CO3 (220 mg, 1.59 mmol) and prenyl
chloride (325 mg, 3.10 mmol). The reaction mixture was heated
under reflux for 16 h before the addition of water and CH2Cl2.
The aqueous phase was extracted with CH2Cl2 (2×). The organic
layers were collected, washed with brine, dried over MgSO4 and
Chalcomoracin hexamethyl ether (31) and mongolicin
F hexamethyl ether (30)
Diene 7 (14 mg, 0.04 mmol) and dienophile 27 (20 mg,
0.052 mmol) were dissolved in distilled toluene (2 mL) in a
This journal is © The Royal Society of Chemistry 2012
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sealed tube. The mixture was degassed for 15 min and heated at
180 °C for 16 h. The reaction mixture was concentrated and sep-
arated by column chromatography with 60% CH2Cl2–petrol as
eluent to give a mixture of diastereoisomers 30 and 31 as a
yellow solid (16 mg, 55%). The mixture was separated by pre-
parative HPLC (5 micron Spherex 5 silica 250 × 10 mm column,
40% EtOAc–petrol as an eluent, flow rate: 2 mL min−1).
2934, 2835, 1737, 1673, 1608, 1587, 1562, 1491, 1454, 1411,
1359, 1276, 1232, 1206, 1151, 1109, 1032, 962, 936, 822, 735;
δH (500 MHz, d6-acetone) 7.46 (d, J = 8.5 Hz, 1H), 7.16 (d, J =
9.0 Hz, 1H), 7.136 (d, J = 2.0 Hz, 1H), 7.134 (s, 1H), 7.11 (d, J
= 8.5 Hz, 1H), 6.87 (dd, J = 2.5, 9.0 Hz, 1H), 6.86 (s, 2H), 6.60
(d, J = 9.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.36 (dd, J = 2.5,
8.5 Hz, 1H), 5.32 (s, 1H), 5.10 (t, J = 6.5 Hz, 1H), 4.59 (s, 2H),
4.29 (br s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 3.71 (s,
3H), 3.61 (br s, 6H), 3.38 (s, 3H), 3.30 (dd, J = 7.5, 14.0 Hz,
1H), 3.19 (dd, J = 6.5, 14.0 Hz, 1H), 2.39 (dd, J = 6.0, 17.5 Hz,
1H), 2.18 (br, 1H), 1.73 (s, 3H), 1.71 (s, 3H), 1.63 (s, 3H); δC
(125 MHz, d6-acetone) 200.6, 161.7, 160.2, 159.8, 159.4, 159.3,
159.2, 156.6, 156.3, 132.4, 131.2, 130.8, 130.6, 129.6, 129.3,
128.6, 127.4, 124.2, 123.6, 123.4, 121.8, 119.9, 112.9, 106.4,
105.2, 102.0, 101.0, 99.3, 96.4, 62.9, 56.2, 56.0, 55.8, 55.7,
55.4, 52.2, 37.8, 34.2, 25.8, 23.8, 23.4, 17.9; HRMS (ESI): cal-
culated for C46H51O9 [M + H]+ 747.3533, found 747.3528.
Endo-isomer 31 (Rt = 9.75 min) was obtained as a yellow
solid; νmax (film): 2926, 2837, 1737, 1608, 1562, 1492, 1454,
1413, 1358, 1277, 1238, 1206, 1150, 1109, 1071, 1033, 962,
936, 821, 789, 735, 703; δH (500 MHz, d6-acetone) 12.7 (s, 1H),
8.03 (d, J = 9.0 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.16 (d, J =
1.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H),
6.93 (s, 2H), 6.86 (dd, J = 2.5, 8.5 Hz, 1H), 6.62 (d, J = 9.0 Hz,
1H), 6.43 (d, J = 2.0 Hz, 1H), 6.31 (dd, J = 2.5, 8.5 Hz, 1H),
5.40 (s, 1H), 5.08 (t, J = 1.5, 7.0 Hz, 1H), 4.65 (dd, J = 7.0,
10.0 Hz, 1H), 4.58 (br s, 1H), 4.26 (br d, J = 6.0, 10.0 Hz, 1H),
3.89 (s, 3H), 3.86 (s, 3H), 3.81 (s, 3H), 3.67 (s, 3H), 3.56 (br s,
6H), 3.18 (d, J = 7 Hz, 2H), 2.40 (dd, J = 18.0, 6.0 Hz, 1H),
2.17 (dd, J = 10.0, 16.0 Hz, 1H), 1.77 (s, 3H,), 1.64 (s, 3H),
1.58 (s, 3H); δC (125 MHz, d6-acetone) 207.4, 163.2, 162.1,
159.7, 159.2, 159.1, 156.5, 155.9, 133.3, 131.3, 130.8, 123.2,
122.8, 121.9, 118.7, 116.7, 116.1, 112.9, 105.1, 102.5, 102.3,
99.3, 96.2, 56.1, 55.9, 55.8, 55.7, 55.2, 49.2, 35.7, 25.8, 23.7,
22.0, 17.7; HRMS (ESI): calculated for C45H48NaO9 [M + Na]+
755.3196, found: 755.3191.
Exo-isomer 30 (Rt = 10.60 min) as a yellow amorphous solid;
νmax (film): 2999, 2927, 2837, 1738, 1611, 1563, 1492, 1454,
1438, 1414, 1366, 1276, 1206, 1150, 1109, 1068, 1032, 962,
936, 820, 792, 736 cm−1; δH (500 MHz, d6-acetone) 13.1 (s, 1H,
OH), 7.49 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.11
(s, 2H), 7.07 (br s, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.86 (dd, J =
2.5, 8.5 Hz, 1H), 6.79 (br s, 1H), 6.36 (s, 1H), 6.26 (dd, J = 2.5,
8.5 Hz, 1H), 6.25 (d, J = 9.0 Hz, 1H), 5.26 (s, 1H), 4.98 (t, J =
1.3, 7.0 Hz, 1H), 4.91 (br s, 1H), 4.45 (br d, J = 10.0 Hz, 1H),
4.07 (br s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.66 (br s, 3H), 3.64
(s, 3H), 3.63 (s, 3H), 3.08 (d, J = 7.0 Hz, 2H), 2.51 (br s, 1H),
2.14 (br d, J = 16.0 Hz, 1H), 1.74 (s, 3H), 1.62 (s, 3H), 1.53 (s,
3H); δC (125 MHz, d6-acetone) 210.1, 163.5, 162.0, 160.6,
160.2, 159.3, 159.0, 156.6, 155.9, 132.2, 131.2, 131.0, 130.9,
125.1, 123.3, 123.2, 121.9, 120.7, 116.6, 116.3, 113.0, 105.2,
102.3, 102.0, 101.1, 99.4, 96.4, 56.4, 56.0, 55.7, 55.9, 55.3,
46.9, 39.0, 25.7, 23.4, 22.0, 17.7; HRMS (ESI): calculated for
C45H49O9 [M + H]+ 733.3377, found: 733.3373.
Methylation of an authentic sample of chalcomoracin (1)
To a stirred solution of authentic sample of impure chalcomora-
cin 1 (6 mg, 9.25 μmol) in acetone (2 mL) were added anhy-
drous K2CO3 (12.7 mg, 92.5 μmol) and MeI (500 mg,
3.52 mmol). The reaction mixture was refluxed for 16 h before
and water and CH2Cl2 were added. The aqueous phase was
extracted with CH2Cl2 (2×). The organic layers were collected,
washed with brine, dried over MgSO4 and concentrated. The
crude residue was separated by column chromatography with
50% ether–petrol as eluent to give the crude product (4 mg)
which was subjected to purification using preparative HPLC
(5 micron Spherex 5 silica 250 × 10 mm column, 40% EtOAc–
petrol as eluent, flow rate: 2 mL min−1) to give chalcomoracin
heptamethyl ether 31 as a yellow solid (1 mg, 14%).
1-(2-Hydroxy-3-iodo-4-methoxyphenyl)ethanone 32 and
1-(2-hydroxy-5-iodo-4-methoxyphenyl)ethanone
To a solution of acetophenone 23 (100 mg, 0.59 mmol) in dis-
tilled MeOH was added iodosuccinimide (224 mg, 0.90 mmol)
at 0 °C. The reaction mixture was stirred at r.t. for 16 h before
the addition of a solution of Na2S2O3 and CH2Cl2. The aqueous
phase was extracted with CH2Cl2 (2×). The organic layers were
collected, washed with brine, dried over MgSO4 and concen-
trated. The crude product was purified by flash chromatography
with 20% EtOAc–petrol to provide a yellow solid (Rf = 0.6)
(66 mg, 38%) as 5-iodo-2-hydroxy-4-methoxymethylacetophe-
none; m.p. 151–152 °C; νmax (film): 2938, 1621, 1564, 1484,
1464, 1440, 1411, 1362, 1322, 1278, 1250, 1226, 1205, 1176,
1070, 1042, 950, 893, 818, 715 cm−1; δH (500 MHz) 12.6 (s,
1H), 8.07 (s, 1H), 6.40 (s, 1H). 3.91 (s, 3H), 2.55 (s, 3H); δC
(125 MHz) 201.7, 165.2, 163.7, 141.0, 115.8, 99.9, 73.2, 56.7,
26.3; HRMS (ESI): calculated for C9H10IO3 [M + H]+
292.96691, found 292.96688.
Chalcomoracin heptamethyl ether (2)
To a stirred solution of chalcomoracin hexamethyl ether 31
(7 mg, 9.88 μmol) in acetone (2 mL) under an argon atmosphere
were added anhydrous K2CO3 (10 mg, 0.072 mmol) and MeI
(500 mg, 3.52 mmol). The reaction mixture was heated under
reflux for 16 h and water and CH2Cl2 were added. The aqueous
phase was extracted with CH2Cl2 (2×). The organic layers were
collected, washed with brine, dried over MgSO4 and concen-
trated. The crude residue was purified by preparative HPLC
(5 micron Spherex 5 silica 250 × 10 mm column, 40% EtOAc–
petrol as eluent, flow rate: 2 mL min−1) to provide 2 (4 mg,
56%) as a yellow amorphous solid (Rt = 9.81 min); νmax (film):
Further elution provided the 3-iodo-2-hydroxy-4-methoxy-
methyl acetophenone 32 as a yellow solid (Rf = 0.4) (90 mg,
52%); m.p. 150–151 °C; νmax (film): 2970, 1738, 1632, 1551,
1490, 1402, 1370, 1276, 1228, 1217, 1163, 1087, 1056,
976, 938, 825, 793, 749 cm−1; δH (500 MHz) 13.5 (s, 1H), 7.74
6018 | Org. Biomol. Chem., 2012, 10, 6010–6021
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(d, J = 9.0 Hz, 1H), 6.45 (d, J = 9.0 Hz, 1H), 3.97 (s, 3H),
2.60 (s, 3H); δC (125 MHz) 202.4, 164.5, 163.4, 132.7, 114.7,
102.4, 76.9, 56.8, 26.1; HRMS (ESI): calculated for C9H10IO3
[M + H]+ 292.96691, found 292.96689.
added water and CH2Cl2. The aqueous phase was extracted with
CH2Cl2 (2×). The organic layers were collected, washed with
brine, dried over MgSO4 and concentrated. The crude residue
was purified by flash chromatography with 40% ether–petrol as
eluent to provide diene 32 (30.0 mg, 18%) as a yellow oil; νmax
(film): 3470.7, 2968.2, 2939.2, 1739.0, 1619.3, 1562.8, 1504.7,
1455.3, 1399.7, 1353.2, 1300.0, 1233.2, 1165.8, 1119.8, 1017.5,
829.9, 751.1, 732.6, 696.7 cm−1; δH (500 MHz) 7.97 (d, J =
16.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H),
7.44 (d, J = 16.0 Hz, 1H), 7.34 (d, J = 17.0, 1H), 6.77 (d, J =
16.5 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.52 (dd, J = 2.5, 8.5
Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 5.12 (br s, 1H), 5.09 (br s,
1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 3.71 (s, 3H), 2.01
(s, 3H); δC (125 MHz) 192.6, 163.0, 161.1, 160.3, 158.9, 143.4,
139.0, 137.0, 130.2, 130.1, 127.4, 124.8, 120.0, 119.4, 117.4,
106.8, 105.5, 98.5, 62.4, 56.0, 55.68, 55.62, 18.4; HRMS (ESI):
calculated for C24H27O5 [M + H]+ 395.18530, found 395.18539.
(E)-3-(2,4-Dimethoxyphenyl)-1-(3-iodo-2,4-dimethoxyphenyl)-
prop-2-en-1-one (34)
To a solution of acetophenone 33 (1.16 g, 3.97 mmol) and ben-
zaldehyde 22 (550 mg, 3.31 mmol) in distilled EtOH (20 mL)
was added KOH (3.71 g, 66.2 mmol). The reaction mixture was
refluxed for 16 h before the addition of water and CH2Cl2. The
aqueous phase was extracted with CH2Cl2 (2×). The organic
layers were collected, washed with brine, dried over MgSO4 and
concentrated. The crude residue was purified by flash chromato-
graphy eluting with 60% CH2Cl2–petrol to afford the chalcone
(1.08 g, 61%) as a yellow solid; m.p. 175–177 °C; νmax (film):
2837, 1626, 1607, 1549, 1504, 1487, 1461, 1402, 1297, 1266,
1224, 1175, 1157, 1149, 1073, 1029, 987, 949, 824, 790,
750 cm−1; δH (500 MHz) 8.16 (d, J = 15.0 Hz, 1H), 7.92 (d, J =
9.0 Hz, 1H), 7.62 (d, J = 15.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H),
6.55 (dd, J = 8.5, 2.5 Hz, 1H), 6.49 (d, J = 2.5 Hz, 1H), 6.48
(d, J = 9.0 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H); δC
(125 MHz) 192.2, 164.6, 164.1, 163.5, 160.7, 141.3, 131.6,
131.5, 117.5, 116.8, 115.2, 105.6, 102.2, 98.4, 77.1, 56.7, 55.6;
HRMS (ESI): calculated for C18H18IO5 [M + H]+ 441.01934,
found 441.01926.
To a solution of the chalcone (1.0 g, 2.27 mmol) in acetone
were added K2CO3 (627 mg, 4.54 mmol) and CH3I (644 mg,
4.54 mmol). The reaction mixture was refluxed for 18 h before
the addition of water and CH2Cl2. The aqueous phase was
extracted with CH2Cl2 (2×). The combined organic layers were
washed with brine solution and dried over MgSO4, filtered and
concentrated. The crude residue was purified by column chrom-
atography eluting with 15% EtOAc–petrol to give chalcone 34
(862 mg, 83%) as a yellow solid; m.p. 130–131 °C; νmax (film):
2970, 2940, 2838, 1738, 1649, 1583, 1503, 1456, 1421, 1385,
1329, 1276, 1267, 1228, 1209, 1161, 1120, 1079, 1029, 919,
823, 799, 734 cm−1; δH (500 MHz) 8.05 (d, J = 15.5 Hz, 1H),
7.70 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.46 (d, J =
15.5 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 6.51 (dd, J = 2.5, 8.5
Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H),
3.85 (s, 3H), 3.77 (s, 3H); δC (125 MHz) 191.1, 163.1, 162.0,
160.3, 139.5, 132.3, 130.3, 130.2, 127.4, 117.1, 106.7, 105.4,
98.4, 85.0, 62.7, 56.8, 55.6, 55.5; HRMS (ESI): calculated for
C19H20IO5 [M + H]+ 455.03510, found 455.03499.
Kuwanon J heptamethyl ether (31) and kuwanon I heptamethyl
ether (30)
Diene 32 (30.0 mg, 0.07 mmol) and dienophile 27 (34.8 mg,
0.09 mmol) was dissolved in distilled toluene (3 mL) in a sealed
tube. The mixture was degassed for 15 min and heated at 180 °C
for 16 h. The reaction mixture was concentrated and separated
by column chromatography with 50% ether–petrol as eluent to a
mixture of diastereoisomers as a yellow oil (22 mg, 37%). The
mixture was separated by preparative HPLC (5 micron Spherex 5
silica 250 × 10 mm column, 40% EtOAc–petrol as an eluent,
flow rate: 2 mL min−1).
Endo-isomer 31 (Rt = 14.80 min) was obtained as a yellow
solid; νmax (film): 2935.0, 2838.5, 1587.5, 1504.5, 1463.6,
1438.6, 1416.7, 1330.8, 1293.2, 1266.4, 1238.6, 1112.7, 1209.9,
1033.4, 939.2, 834.3, 795.6 cm−1; δH (500 MHz, d6-acetone)
12.8 (s, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 16.0 Hz, 1H),
7.56 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.30 (d, J =
16.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 2.5 Hz),
6.62 (dd, J = 8.5, 2.5 Hz, 1H), 6.61 (d, J = 8.5 Hz), 6.58 (d, J =
8.5 Hz, 1H), 6.43 (d, J = 2.5 Hz), 6.31 (dd, J = 8.5 and 2.5 Hz,
1H), 5.49 (br s, 1H), 5.06 (t, J = 7.0 Hz, 1H), 4.71 (br s, 1H),
4.57 (br s, 1H), 4.27 (br d, J = 7.5 Hz, 1H), 3.923 (s, 3H), 3.920
(s, 3H), 3.89 (s, 3H), 3.77 (s, 3H), 3.68 (s, 3H), 3.48 (s, 3H),
3.39 (s, 3H), 3.18 (d, J = 6.0 Hz, 2H), 2.41 (br s, 1H), 2.30 (br
d, J = 18.0 Hz, 1H), 1.81 (s, 3H), 1.65 (s, 3H), 1.53 (s, 3H); δC
(125 MHz, d6-acetone) 207.6, 192.7, 164.1, 163.4, 162,4, 161.2,
160.0, 159.3, 139.1, 133.7, 131.3, 130.9, 127.7, 125.3, 123.4,
123.2, 123.0, 117.8, 117.0, 116.9, 116.3, 106.8, 105.3, 102.6,
99.6, 99.1, 63.2, 56.2, 56.1, 55.9, 55.5, 55.3, 48.9, 42.1, 37.7,
36.0, 34.4, 31.2, 25.7, 23.8, 22.8, 22.1, 17.8; HRMS (ESI):
calculated for C47H52O10Na [M + Na] 799.34527, found
799.34586.
(E)-1-(2,4-Dimethoxy-3-((E)-3-methylbuta-1,3-dienyl)phenyl)-3-
(2,4-dimethoxyphenyl)prop-2-en-1-one (32)
To a flame-dried 2-neck round bottom flask containing a solution
of chalcone iodide 34 (95.0 mg, 0.21 mmol) and dienylboronate
20 (81 mg, 0.42 mmol) in DMF (3 mL) were added Pd2(dba)3
(9.55 mg, 10.5 μmol) and AsPh3 (6.4 mg, 20.9 μmol) under an
argon atmosphere. The reaction mixture was degassed for
15 min before the addition of a solution of K3PO4 in water (3M,
0.65 mL, 2.09 mmol). The reaction mixture was stirred at 50 °C
for 16 h, the filtered through a pad of celite. To the filtrate were
Exo-isomer 30 (Rt = 16.77 min) was obtained as a
3 : 2 mixture of atropisomers; νmax (film): 2960.1, 2930.2,
1727.5, 1611.4, 1588.8, 1504.8, 1463.7, 1416.7, 1380.5, 1272.1,
1209.6, 1160.1, 1119.8, 1073.1, 742.7 cm−1; δH (500 MHz) 12.9
(s, 1H), 12.8 (s, 1H), 8.01 (d, J = 15.5 Hz, 1H), 7.93 (d, J = 16.0
Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.51
(s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.33
This journal is © The Royal Society of Chemistry 2012
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(t, J = 5.0 Hz, 1H), 7.29 (d, J = 9.5 Hz, 1H), 7.05 (d, J = 8.5 Hz,
1H), 7.01 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 6.57
(dd, J = 2.0, 8.5 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 6.43 (s, 1H),
6.34 (s, 1H), 6.30 (d, J = 8.5 Hz, 1H), 6.26 (dd, J = 2.0, 9.0 Hz,
1H), 6.06 (d, J = 9.5 Hz, 1H), 6.02 (d, J = 9.0 Hz, 1H), 5.34
(s, 1H), 5.26 (s, 1H), 5.01 (t, J = 7.0 Hz, 1H), 4.95 (t, J = 7.0
Hz, 1H), 4.86 (br s, 1H), 4.74 (br s, 1H), 4.47 (d, J = 7.5 Hz,
1H), 4.43 (d, J = 7.5 Hz, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.87 (s,
3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.74
(s, 3H), 3.70 (s, 3H), 3.57 (s, 3H), 3.54 (s, 3H), 3.48 (s, 3H),
3.12 (d, J = 7.0 Hz, 2H), 3.09 (d, J = 4.0 Hz, 1H), 3.05 (d, J =
5.5 Hz, 1H), 2.25 (d, J = 18.5 Hz, 1H), 2.17 (d, J = 18.0 Hz,
1H), 1.75 (s, 3H), 1.67 (s, 3H), 1.61 (s, 3H), 1.58 (s, 3H), 1.52
(s, 3H); δC (125 MHz) 209.2, 208.8, 192.6, 192.2, 163.1, 162.5,
162.1, 161.5, 161.2, 160.6, 160.4, 160.2, 159.0, 158.3, 138.9,
138.1, 132.4, 131.8, 131.4, 130.5, 130.3, 129.8, 129.5, 126.9,
125.3, 124.7, 124.6, 124.2, 123.8, 123.6, 122.5, 122.3, 117.5,
117.4, 116.5, 116.06, 116.01, 107.4, 105.8, 105.6, 105.4, 104.4,
101.2, 99.0, 98.6, 98.5, 63.7, 63.2, 56.0, 55.9, 55.6, 55.5, 55.3,
47.8, 46.0, 38.9, 38.7, 29.8, 29.5, 25.8, 25.7, 23.4, 23.3, 21.6,
17.8; HRMS (ESI): calculated for C47H52O10Na [M + Na]
799.34527, found 799.34590.
and the ARC Centre of Excellence for Free Radical Chemistry
and Biotechnology for funding. Computational resources were
provided by the National Computational Infrastructure National
Facility (Australia) and by the University of Melbourne School
of Chemistry.
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energy conformer of each species. Stationary points were ident-
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.
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Acknowledgements
We thank the Australian Research Council Discovery Grants
Scheme (DP110100112 to M.A.R. and DP0985623 to E.H.K.)
6020 | Org. Biomol. Chem., 2012, 10, 6010–6021
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45 The Ar3 group is twisted 3.5° further out of coplanarity with the diene in
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