The synthesis of the pyranonaphthoquinones dehydroherbarin and anhydrofusarubin using Wacker oxidation methodology as a key step and other unexpected oxidation reactions with ceric ammonium nitrate and salcomine

Article abstract of DOI:10.1039/c2ob26126j

The synthesis of two closely related pyranonaphthoquinones, dehydroherbarin and anhydrofusarubin, is described. The construction of the naphthalene nuclei was achieved using the Stobbe condensation reaction using 2,4- dimethoxybenzaldehyde and 2,4,5-trime

Full text of DOI:10.1039/c2ob26126j

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PAPER
The synthesis of the pyranonaphthoquinones dehydroherbarin and
anhydrofusarubin using Wacker oxidation methodology as a key step and
other unexpected oxidation reactions with ceric ammonium nitrate and
salcomine†‡
Adushan Pillay, Amanda L. Rousseau, Manuel A. Fernandes§ and Charles B. de Koning*
Received 12th June 2012, Accepted 10th August 2012
DOI: 10.1039/c2ob26126j
The synthesis of two closely related pyranonaphthoquinones, dehydroherbarin and anhydrofusarubin,
is described. The construction of the naphthalene nuclei was achieved using the Stobbe condensation
reaction using 2,4-dimethoxybenzaldehyde and 2,4,5-trimethoxybenzaldehyde as their respective starting
materials. Two key steps en route include a PIFA-mediated addition of a methoxy substituent onto the
naphthalene skeleton and a Wacker oxidation reaction to construct the benzo[g]isochromene nucleus. Two
interesting oxidation reactions of the intermediate isochromene enol ether of 7,9-dimethoxy-3-methyl-1H-
benzo[g]isochromene-5-ol were observed. Treatment of the substrate with salcomine resulted in the
formation of (3-formyl-4-hydroxy-6,8-dimethoxynaphthalene-2-yl)methyl acetate, while treatment of the
same substrate with CAN resulted in the formation of racemic (3R,4R)-3-hydroxy-7,9-dimethoxy-3-
methyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-benzo[g]isochromen-4-yl nitrate.
reported activity was better than the anticancer standards, ellipti-
Introduction
cine and doxorubicin respectively (Scheme 1).3
The quinone dehydroherbarin 1 has been isolated from the
dematiaceous fungus Torula herbarum1 that is often found on
the dry leaves and twigs of Felia microphylla. In addition, it has
been found in the endolichenic fungal strain, Corynesspora sp.
BA-10763, which occurs in the cavern beard lichen Usnea
cavernosa.2 Dehydroherbarin 1 has been shown to exhibit anti-
microbial and antiamoebic activity, as well as cause significant
inhibition of both metastatic prostate and breast cancers (PC-3M
and MDA-MB-231 respectively).1,2 The related quinone, anhy-
drofusarubin 2, has been known for decades, and was recently
isolated from the sea-fan-derived fungus Fusarium spp
PSU-F135.3 There has been renewed interest in this quinone
owing to the excellent cytotoxic activity against oral human car-
cinoma cells (KB) and human breast cancer cells (MCF-7). The
The synthesis of dehydroherbarin 1 has been accomplished by
both the De Kimpe and Brimble groups.4,5 De Kimpe et al. uti-
lized the quinone 4 as a key intermediate which, on exposure to
Et3N, gave dehydroherbarin 1 via what is believed to be the
quinone methide 5. More recently, the Brimble group took
advantage of Staunton–Weinreb annulation methodology to
assemble the advanced intermediate 6 from 7 and the Michael
acceptor 8, albeit in poor yield (Scheme 1).
The synthesis of anhydrofusarubin 2 has not been documen-
ted, but it has been noted that anhydrofusarubin undergoes
hydration to afford the related quinone fusarubin 3, if left stand-
ing in the atmosphere.6
As part of our programme on the synthesis of pyranonaphtho-
quinones7 and, in particular, on the use of Wacker oxidation
methodology for their synthesis,8 we wished to extend this
methodology to the synthesis of both dehydorherbarin and anhy-
drofusarubin. In this paper we describe the synthesis of dehydro-
herbarin and anhydrofusarubin, as well as present some
unprecedented oxidation reactions mediated by ceric ammonium
nitrate and salcomine en route.
Molecular Sciences Institute, School of Chemistry, University of the
Witwatersrand, PO Wits 2050, Johannesburg, South Africa.
E-mail: Charles.deKoning@wits.ac.za; Fax: +27 11 7176749;
Tel: +27 11 7176724
†Dedicated to my friends and colleagues, Robin Giles and Ivan Green,
who inspired me to research quinone chemistry.
‡Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR spectra are provided. CCDC 885420, 885421 and
885422. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob26126j
Results and discussion
The Stobbe condensation is well documented9 as a key step for
the construction of naphthalene nuclei (Fig. 1).
§For correspondence regarding crystallography, Manuel.Fernandes@
wits.ac.za
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Fig. 2 Oxidation of naphthol to naphthoquinone.
Scheme 1 (i) Et3N, toluene, 84%; (ii) LDA, THF, −78 °C, 27%.
Scheme 2 Reagents and conditions: (i) (a) KOH, MeOH/H2O, rt, 6 h,
(b) aq HCl, (c) K2CO3, allyl bromide, Me2CO, reflux, 18 h, 83% over 2
steps, (ii) 170 °C, 18 h, 87%, (iii) TBDMSCl, imidazole, DMAP (cat.),
DCM, rt, 24 h, 93%, (iv) LAH, THF, 5 °C, 2 h, 96%, (v) cat PdCl2,
CuCl2·2H2O, DMF/H2O, O2(g), rt, 24 h, 52%, (vi) TBAF, THF, rt, 18 h,
73%.
Fig. 1 Stobbe condensation reaction for the assembly of naphthalenes.
The limitation with this methodology is that substituents are
introduced only at position 2 and 4 on the newly constructed
ring of the naphthalene product. However, we believed that we
would be able to construct the appropriately substituted naphtho-
quinone moiety of dehydroherbarin using this methodology, pro-
vided that we could introduce the requisite extra oxygen
substituent on the naphthalene at a later stage. Precedent for this
type of transformation has been reported for the synthesis of
dehydorherbarin,5 where a naphthol is oxidized using salcomine
to the corresponding quinone (Fig. 2).
Hence, starting from 2,4-dimethoxybenzaldehyde, the tetra-
subtituted naphthalene 9 was formed in reasonable yield by reac-
tion with diethylsuccinate in the presence of NaOEt, followed by
treatment with NaOAc in acetic anhydride.7 In our first attempt
at the synthesis of dehydroherbarin (Scheme 2), potassium
hydroxide hydrolysis of naphthalene 9 followed by exposure to
allylbromide and potassium carbonate yielded 10. A thermally
induced Claisen rearrangement on 10 followed by protection of
the naphthol 11 with TBDMSCl furnished 12. This was then fol-
lowed by reduction of the ester 12 to afford the benzylic alcohol
13. We were now in a position to attempt the Wacker oxidation
to form the isochromene ring. The desired product 14 was
formed in an acceptable yield of 52%. Removal of the silicon
protecting group of 14 with TBAF afforded the required
naphthol 15 in good yield. Now all that was required was oxi-
dation of 15 to the target quinone, dehydroherbarin 1.
As salcomine has been successfully utilised in the oxidation
of the regioisomeric naphthol, 7,9-dimethoxy-3-methyl-1H-
benzo[g]isochromen-10-ol (Fig. 2)5 we assumed that this would
be a trivial reaction. However, exposure of 15 to salcomine
[N,N′-bis(salicylidene)ethylenediaminocobalt(II)] only resulted in
the isolation of the dicarbonyl 16, formed as a result of the oxi-
dation of the enol ether of 15. The identity of the product 16 was
confirmed by X-ray crystallography (Fig. 3 and Scheme 3).10
Frustrated by this result, we tested the use of ceric ammonium
nitrate in the oxidation reaction. Although ceric ammonium
nitrate oxidation of 15 resulted in the formation of the desired
quinone, the enol ether had also undergone an addition reaction
resulting in the formation of the hemiacetal 17. In this case, a
nitrate had formally added to the other side of the double bond
of the enol ether. An X-ray crystallography study clearly ident-
ified the product with a trans-relationship between the nitrate
and hydroxyl substituents (Fig. 4).11 Precedent for this type of
reaction has been found in the work of Nair et al.12 Based on
this study, we propose that the Ce(IV) reagent is reduced by the
enol ether of 15, providing a radical cation (Fig. 4) to which
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Fig. 3 ORTEP diagram of (3-formyl-4-hydroxy-6,8-dimethoxy-
naphthalene-2-yl)methyl acetate 16.
Scheme 4 Reagents and conditions: (i) (a) PIFA, MeOH, rt, 15 min,
(b) NaOEt, EtOH, rt, 15 min, 57% over 2 steps, (ii) K2CO3, Me2SO4,
Me2CO, reflux, 18 h, 92%, (iv) LAH, Et2O, rt, 2 h, 83%, (iv) cat PdCl2,
CuCl2·2H2O, DMF/H2O, O2(g), rt, 2 h, 63%, (v) (a) PIFA, H2O/
CH3CN, rt, 2 h, 25%.
Scheme 3 Reagents and conditions: (i) salcomine, CH3CN, O2(g)
atm, rt, 24 h, 30%, (ii) CAN, H2O/CH3CN, rt, 30 min, 54%.
Armed with this newly developed methodology for the syn-
thesis of dehydroherbarin, an obvious extension was to utilise
this methodology for the synthesis of anhydrofusarubin 2 con-
taining a penta-oxygenated naphthalene nucleus.
Starting from 2,4,5-trimethoxybenzaldehyde, naphthalene 22
was prepared using the Stobbe reaction followed by acetic anhy-
dride mediated ring closure.7 Using the same methodology as
described for the synthesis of dehydroherbarin, benzylic alcohol
27 was prepared from naphthalene 22 by the uneventful
sequence of synthetic transformations shown in Scheme 5. We
were now in a position to attempt the Wacker-mediated ring
closure reaction on 27 to form the isochromene ring of anhydro-
fusarubin. Exposure of 27 to oxygen, catalytic PdCl2 and CuCl2
resulted in the formation of the desired isochromene 28. Treat-
ment of 28 with AgO resulted in the formation of both para- 29
and ortho-quinones 30 in yields of 63% and 27% respectively.
The identity of 29 was established with the aid of X-ray crystal-
lography (Fig. 5).14 Treatment of 29 with BCl3 at −78 °C
resulted in the formation of anhydrofusarubin 2 in a yield of
Fig. 4 Intermediate radical cation and ORTEP diagram of quinone 17.
both a nitrate anion and a hydroxyl substituent are able to add to
afford 17.
At this point we believed that the best way forward would be
to assemble the correctly substituted naphthalene nucleus at an
earlier stage of the synthesis of dehydroherbarin. Methodology
for the introduction of a methoxy substituent on an aromatic ring
bearing a para hydroxyl group using PIFA has recently been
reported by Kozlowski and co-workers.13 We decided to attempt
the introduction of the extra oxygen on our naphthalene system
using this methodology, prior to formation of the isochromene
ring.
Hence, exposure of 11 to PIFA in the presence of methanol,
followed by aromatization with sodium ethoxide, gave the
desired naphthol 18 containing an extra methoxy substituent
(Scheme 4). Protection of the naphthol as a methyl ether
afforded the naphthalene 19. Reduction of the allyl ester of 19
furnished the desired benzyl alcohol 20 on which to attempt our
Wacker mediated ring closure reaction. Exposure of 20 to cataly-
tic palladium(II) chloride and copper(II) chloride in the presence
of oxygen afforded the desired isochromene 21. Finally, oxi-
dation of 21 with PIFA afforded the desired product, dehydroher-
barin 1, although in a disappointing yield of 25%.
1
65%. Both the H and 13C NMR spectral data agreed with that
published.15
Finally, using this methodology a 10-deoxy derivative of
anhydrofusarubin 31 was easy to prepare as shown in Scheme 6.
Naphthol 24 was converted to the ester 32 which was reduced to
alcohol 33. Again using our Wacker reaction conditions on 33
furnished the desired product 31.
Conclusions
In summary, we have been able to synthesize two closely related
pyranonaphthoquinones, dehydroherbarin 1 and anhydrofusaru-
bin 2. Dehydroherbarin was synthesized in 10 steps from 2,4-
dimethoxybenzaldehyde in an overall yield of 4% while anhy-
drofusarubin was made from 2,4,5-trimethoxybenzaldehyde in
11 steps in an overall yield of 5%. Stobbe methodology was
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Scheme 6 Reagents and conditions: (i) K2CO3, Me2SO4, Me2CO,
reflux, 18 h, 90%; (ii) LAH, THF, rt, 2 h, 86%, (iii) cat PdCl2,
CuCl2·2H2O, DMF/H2O, O2(g) atm, rt, 24 h, 64%.
Experimental
1H NMR and 13C NMR spectra were recorded either on a Bruker
AVANCE 300 spectrometer, a Bruker AVANCE 400 spectrometer
or a Bruker AVANCE III 500 spectrometer. All spectra were
recorded in CDCl3, or d6-acetone. All chemical shift values are
reported in parts per million referenced against TMS which is
given an assignment of zero parts per million. Coupling con-
stants (J-values) are given in Hertz (Hz). For most NMR spectra
a range of 2-D experiments were done to allow for a more com-
plete assignment of 13C NMR spectra. All mass spectroscopy
data were collected on a Waters Micromass LCT TOF Mass
Spectrometer. The sample was dissolved in MeOH to a concen-
tration of 2 ng μl−1 and introduced by direct infusion. The ioniz-
ation mode was electrospray positive with a capillary voltage of
2500 V and a desolvation temperature of 250 °C using N2 gas at
250 L h−1. Infrared spectra were recorded on a Bruker Tensor 27
standard system spectrometer. Macherey-Nagel Kieselgel 60
(particle size 0.063–0.200 mm) was used for conventional silica
gel column chromatography with various EtOAc and hexane
mixtures as the mobile phase. TLC was performed on alumi-
num-backed Macherey-Nagel Alugram Sil G/UV254 plates pre-
coated with 0.25 mm silica gel 60. In vacuo refers to refers to
the solvent evaporated under reduced pressure utilizing a rotary
evaporator.
Scheme 5 Reagents and conditions: (i) (a) KOH, MeOH/H2O, rt, 6 h,
(b) aq HCl, (c) K2CO3, allyl bromide, Me2CO, reflux, 18 h, 84% over 2
steps, (ii) 170 °C, 18 h, 88%, (iii) (a) PIFA, MeOH, rt, 10 min, (b)
NaOEt, EtOH, rt, 15 min, 54% over 2 steps, (iv) K2CO3, Me2SO4,
Me2CO, reflux, 18 h, 81%; (v) LAH, THF, 5 °C, 2 h, (vi) cat PdCl2,
CuCl2·2H2O, DMF/H2O, O2(g), rt, 24 h, 49%, over 2 steps. (vii) (a)
AgO, 6 M HNO3, dioxane, 29, 63%, 30, 27%; (viii) BCl3, CH2Cl2,
−78 °C, 65%.
Ethyl 4-acetoxy-6,8-dimethoxy-2-naphthoate 9
To
a
solution of 2,4-dimethoxybenzaldehyde (4.00 g,
24.1 mmol) and diethyl succinate (5.45 g, 31.3 mmol) in dry
THF (50 ml), at 0 °C, was added NaOEt (3.28 g, 48.1 mmol).
The reaction mixture was refluxed for 2 h, cooled to rt and then
acidified to pH 3 with aqueous HCl [33% (v/v)]. The product
therefore precipitated and was extracted with EtOAc (2 × 50 ml).
The combined organic extracts were dried over anhydrous
MgSO4, filtered, and the filtrate was concentrated in vacuo. The
residue and anhydrous NaOAc (2.57 g, 31.3 mmol) were dis-
solved in acetic anhydride (50 ml) and refluxed for 3 h. The
solvent was removed in vacuo and the resulting residue was dis-
solved in EtOAc (60 ml). Aqueous NaHCO3 was slowly added
to the EtOAc layer until all the traces of acetic anhydride were
removed. The organic layer was then separated, dried over
MgSO4, filtered, and the filtrate was concentrated in vacuo. The
Fig. 5 ORTEP diagram of quinone 29.
used to assemble the core naphthalene nuclei of both natural pro-
ducts, then a PIFA-mediated addition of methanol to the two
respective naphthols, allowed for the introduction of a methoxy
substituent onto each naphthalene nucleus. This provided the
correct naphthalene substitution pattern of the target quinones.
Once the appropriate functionalities had been introduced, a
Wacker-mediated reaction allowed for the construction of the iso-
chromene ring.
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residue was purified by column chromatography (30% EtOAc–
hexane) to afford ethyl 4-acetoxy-6,8-dimethoxy-2-naphthoate 9
(8.69 g, 82%) as a yellow solid. H NMR (300 MHz, CDCl3)
dimethoxy-2-naphthoate 11 as a yellow amorphous solid (6.48 g,
90%). Mp. = 90–91 °C; IR νmax (cm−1) = 3539 (OH), 1673
(CvO), 1580 (CvC), 1461, 1291, 1249, 1158; 1H NMR
(300 MHz, CDCl3) δH = 8.43 (1H, s, H-1), 7.04 (1H, d, J 1.8,
1
δH = 8.79 (1H, d, J 1.1, H-1), 7.81 (1H, d, J 1.1, H-3), 6.66 (1H,
d, J 1.9, H-5), 6.51 (1H, d, J 1.9, H-7), 4.42 (2H, q, J 7.1,
OCH2CH3), 3.98 (3H, s, OCH3), 3.91 (3H, s, OCH3), 2.46
(CH3CO2), 1.42 (3H, t, J 7.1, OCH2CH3); 13C NMR (75 MHz,
CDCl3) δC = 169.3 (CH3CO2), 166.3 (ArCO2Et), 161.0, 157.9,
145.4 (C-4), 133.2 (C-4a), 124.4 (C-2), 123.4 (C-1), 122.2
(C-8a) 119.1 (C-3), 98.6 (C-5), 91.7 (C-7) 61.0 (OCH2CH3),
55.8 (OCH3), 55.4 (OCH3), 20.9 (CH3CO2), 14.4 (OCH2CH3).7
H-5), 6.48 (1H, d,
J 2.2, H-7), 6.20–6.01 (2H, m,
COOCH2CHvCH2 and ArCH2CHvCH2), 5.82 (1H, s, OH),
5.44 (1H, ddd, J 17.2, 3.0, 1.5, one of COOCH2CHvCH2),
5.37–5.25 (1H, m, one of COOCH2CHvCH2), 5.18 (2H, ddd,
J
5.1, 3.9, 1.7, ArCH2CHvCH2), 4.88–4.80 (2H, m,
COOCH2CHvCH2), 3.97–3.88 (2H, m, ArCH2CHvCH2,
under OCH3) 3.94 (3H, s, OCH3), 3.91 (OCH3); 13C NMR
(75 MHz, CDCl3) δC = 167.8 (CvO), 160.1, 157.3, 149.7,
136.5 (COOCH2CHvCH2), 132.5 (ArCH2CHvCH2), 128.5
(C-8a), 125.1 (C-4a), 120.3 (C-3), 119.2 (C-2), 118.9 (C-1),
118.3 (COOCH2CHvCH2), 116.1 (ArCH2CHvCH2), 98.3
(C-5), 92.1 (C-7), 65.7 (COOCH2CHvCH2), 55.7 (OCH3), 55.5
(OCH3), 31.7 (ArCH2CHvCH2); HR-TOF-MS: m/z found
329.1376 [M + H]+ (calculated for C19H21O5, 329.1389).
Allyl 4-(allyloxy)-6,8-dimethoxy-2-naphthoate 10
Ethyl 4-acetoxy-6,8-dimethoxy-2-naphthoate
9
(10.0 g,
31.4 mmol) was dissolved in MeOH (100 ml) followed by the
drop-wise addition of an aqueous KOH solution (8.81 g,
157 mmol, 200 ml H2O). The dark-orange reaction was stirred
was 6 h at rt, before the MeOH was removed in vacuo. The
aqueous solution was then carefully acidified to pH 4.0 with
aqueous HCl (30%), and then extracted with EtOAc (3 ×
150 ml). The organic layers were combined, dried over anhy-
drous MgSO4, filtered and concentrated under reduced pressure.
The crude, off-white solid was then dissolved in acetone
(150 ml), and allyl bromide (9.41 g, 78.5 mmol), anhydrous
K2CO3 (10.8 g, 78.5 mmol) were added to the reaction mixture
which was then refluxed for 18 h under a N2(g) atmosphere. The
mixture was then allowed to cool to rt, filtered through a bed of
celite, and the solvent was removed in vacuo. The light-yellow
residue was then purified via column chromatography (10%
EtOAc–hexane) to yield allyl 4-(allyloxy)-6,8-dimethoxy-2-
naphthoate 10 as a yellow amorphous solid (8.56 g, 83%). Mp.
= 64–65 °C; IR νmax (cm−1) = 1647 (CvO), 1600 (CvC),
Allyl 3-allyl-4-(tert-butyldimethylsilyloxy)-6,8-dimethoxy-
2-naphthoate 12
Allyl 3-allyl-4-hydroxy-6,8-dimethoxy-2-naphthoate 11 (7.20 g,
21.9 mmol), tert-butyldimethylsilyl chloride (4.96 g, 32.9 mmol),
imidazole (2.23 g, 32.9 mmol) and dimethylaminopyridine
(0.400 g) were dissolved in CH2Cl2 (150 ml) and stirred at rt for
24 h under a N2(g) atmosphere. The mixture was then washed
with H2O (2 × 100 ml), dried over anhydrous MgSO4, filtered,
and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (10% EtOAc–hexane) to
afford allyl 3-allyl-4-(tert-butyldimethylsilyloxy)-6,8-dimethoxy-2-
naphthoate 12 (9.01 g, 93%) as a clear oil. IR νmax (cm−1) =
1
1767 (CvO), 1589 (CvC), 1468, 1317, 1251, 1188; H NMR
1429, 1285, 1217, 1146; 1H NMR (400 MHz, CDCl3) δH
8.53 (1H s, H-1), 7.41 (1H, d, J 1.3, H-3), 7.13 (1H, d, J 2.0,
H-5), 6.51 (1H, d, 2.2, H-7), 6.26–6.01 (2H, m,
=
(300 MHz, CDCl3) δH = 8.44 (1H, s, H-1), 6.96 (1H, d, J 1.9,
H-5), 6.47 (1H, d, J 2.1, H-7), 6.08 (1H, ddd, J 16.1, 10.9, 5.7,
COOCH2CHvCH2), 5.93 (1H, ddt, J 16.3, 10.4, 5.9, ArCH2-
CHvCH2), 5.43 (1H, dd, J 17.2, 1.5, one of COOCH2-
CHvCH2), 5.29 (1H, dd, J 10.4, 1.2, one of COOCH2CHvCH2),
4.99–4.86 (2H, m, ArCH2CHvCH2), 4.82 (2H, d, J 5.7,
COOCH2CHvCH2), 3.99–3.93 (2H, m, ArCH2CHvCH2,
under OCH3), 3.95 (3H, s, OCH3), 3.92 (3H, s, OCH3), 1.13
(9H, s, OSi(CH3)2C(CH3)3), 0.23 (6H, s, OSi(CH3)2C(CH3)3);
13C NMR (75 MHz, CDCl3) δC = 168.0 (CvO), 159.6, 157.4,
148.3, 137.5 (ArCH2CHvCH2), 132.7 (COOCH2CHvCH2),
131.6, 126.4, 126.2, 120.4, 119.9, 118.1 (COOCH2CHvCH2),
114.9 (ArCH2CHvCH2), 97.9 (C-5), 94.2 (C-7), 65.6 (COO-
CH2CHvCH2), 55.7 (OCH3), 55.4 (OCH3), 31.2 (ArCH2-
CHvCH2), 26.2 (OSi(CH3)2C(CH3)3), 18.8 (OSi(CH3)2C-
(CH3)3), −2.9 (OSi(CH3)2C(CH3)3); HR-TOF-MS: m/z found
443.2248 [M + H]+ (calculated for C25H35O5Si, 443.2254).
J
COOCH2CHvCH2 and OCH2CHvCH2), 5.57–5.39 (2H, m,
COOCH2CHvCH2), 5.38–5.25 (2H, m, OCH2CHvCH2), 4.87
(2H, dt, J 5.6, 1.3, COOCH2CHvCH2), 4.75 (2H, d, J 5.2,
OCH2CHvCH2), 3.95 (3H, s, OCH3), 3.93 (3H, s, OCH3); 13C
NMR (100 MHz, CDCl3) δC = 167.0 (CvO), 160.4, 157.8,
153.3, 133.3 (OCH2CHvCH2), 132.8 (COOCH2CHvCH2),
130.2 (C-2), 124.4 (C-4a), 121.8 (C-8a), 118.4 (C-1) 118.2
(OCH2CHvCH2), 117.8 (COOCH2CHvCH2), 105.9 (C-3),
98.8 (C-4), 92.9 (C-6), 69.4 (OCH2CHvCH2) 65.7
(COOCH2CHvCH2),
55.8
(OCH3),
55.6
(OCH3);
HR-TOF-MS: m/z found 329.1389 [M + H]+ (calculated for
C19H21O5, 329.1389).
Allyl 3-allyl-4-hydroxy-6,8-dimethoxy-2-naphthoate 11
Allyl 4-(allyloxy)-6,8-dimethoxy-2-naphthoate 10 (7.20 g,
21.9 mmol) was loaded neat into in a round-bottom flask
(100 ml) equipped with a reflux condenser and a magnetic stirrer
bar. The reaction vessel was then heated to 180 °C for 18 h
under a N2(g) atmosphere. The dark viscous residue was allowed
to cool to rt and was then purified using column chromatography
(20% EtOAc–hexane) to yield allyl 3-allyl-4-hydroxy-6,8-
(3-Allyl-4-(tert-butyldimethylsilyloxy)-6,8-dimethoxynaphthalen2-
yl)methanol 13
Allyl
3-allyl-4-(tert-butyldimethylsilyloxy)-6,8-dimethoxy-2-
naphthoate 12 (7.90 g, 18.4 mmol) was dissolved dry THF
(100 ml) and cooled to 0 °C in an ice bath. Lithium aluminium
hydride (2.09 g, 55.1 mmol) was added slowly over 15 min. The
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reaction mixture was then stirred vigorously for 2 h at rt under a
N2 atmosphere. The solution was then cooled to 0 °C in an ice
bath and cold H2O (1.5 ml) was added drop-wise until the
fizzing stopped. Aqueous NaOH (1.5 ml, 15% m/v) and H2O
(4.5 ml) were then added and the resulting mixture was stirred
for 3 h at rt. EtOAc (100 ml) was then added and the organic
layer was extracted, dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. Column chromatography
(20% EtOAc–hexane) of the residue afforded (3-allyl-4-(tert-
butyldimethylsilyloxy)-6,8-dimethoxynaphthalen2-yl)methanol
hexane) to afford 7,9-dimethoxy-3-methyl-1H-benzo[g]isochro-
mene-5-ol 15 (0.256 g, 73%) as a white crystalline solid. Mp. =
156–157 °C; IR νmax (cm−1) = 3348 (OH), 1508, 1435, 1290,
1
1204, 1185; H NMR (500 MHz, acetone) δH = 7.91 (1H, br s,
OH), 7.34 (1H, s, H-10), 7.11 (1H, d, J 2.1, H-6), 6.44 (1H, d,
J 2.1, H-8), 6.15 (1H, s, H-4), 5.07 (2H, d, J 0.8, H-1), 3.91
(3H, s, OCH3), 3.84 (3H, s, OCH3), 1.91 (3H, d, J 0.6, CH3);
13C NMR (125 MHz, acetone) δC = 158.9, 157.5, 155.3 (C-3),
143.7, 127.8 (C-9a), 125.8 (C-4a), 121.5 (C-5a), 116.1 (C-10a),
109.6 (C-10), 97.7 (C-8), 96.9 (C-4), 93.5 (C-6), 69.7 (C-1),
55.9 (OCH3), 55.5 (OCH3), 20.0 (CH3); HR-TOF-MS: m/z
found 273.1118 [M + H]+ (calculated for C16H17O4, 273.1127).
1
13 as a clear oil (6.86 g, 96%). H NMR (300 MHz, CDCl3) δH
= 7.90 (1H, s, H-1), 6.97 (1H, d, J 1.9, H-5), 6.46 (1H, d, J 2.2,
H-7), 5.96 (1H, dq, J 10.3, 5.7, ArCH2CHvCH2), 4.98 (1H, dd,
J 10.2, 1.7, one of ArCH2CHvCH2), 4.91 (1H, dd, J 17.2, 1.7,
one of ArCH2CHvCH2), 4.77 (2H, s, ArCH2), 3.91 (3H, s,
(3-Formyl-4-hydroxy-6,8-dimethoxynaphthalene-2-yl)methyl
acetate 16
OCH3), 3.90 (3H, s, OCH3), 3.66 (2H, br d,
J 5.7,
ArCH2CHvCH2), 2.60 (1H, brs, OH), 1.14 (9H, s, OSi(CH3)2C-
(CH3)3), 0.25 (6H, s, OSi(CH3)2C(CH3)3); 13C NMR (75 MHz,
CDCl3) δC = 157.6, 156.6, 148.1, 137.1, 135.5, 129.0, 125.0,
121.4, 115.4, 115.0, 97.3, 94.1, 64.0, 55.4, 55.2, 30.7, 26.1,
18.8, −2.8.16
7,9-Dimethoxy-3-methyl-1H-benzo[g]isochromene-5-ol 15 (0.200 g,
0.764 mmol) and salcomine complex N,N′-bis(salicylidene)-
ethylenediaminocobalt(II) hydrate (0.148 g, 0.44 mmol) were
dissolved in CH3CN (30 ml) and stirred for 3 h at rt under an
O2(g) atmosphere. The reaction was then filtered through celite
and the solvent was removed in vacuo. The resulting residue was
purified by column chromatography (30% EtOAc–hexane) to
tert-Butyl(7,9-dimethoxy-3-methyl-1H-benzo[g]isochromene-
5-yloxy)dimethylsilane 14
afford
(3-formyl-4-hydroxy-6,8-dimethoxynaphthalene-2-yl)
methyl acetate 16 (0.070 g, 30%) as an orange solid. Mp. =
118–119 °C; IR νmax (cm−1) = 3455 (OH), 1737 (CvO), 1620
(CvO), 1578 (CvC), 1433, 1282, 1208, 1160; 1H NMR
(300 MHz, CDCl3) δH = 13.48 (1H, br s, OH), 10.26 (1H, s,
CHO), 7.64 (1H, s, H-1), 7.27 (1H, d, J 2.1, H-5), 6.67 (1H, d,
J 2.2, H-7), 5.44 (2H, s, ArCH2O), 3.96 (3H, s, OCH3), 3.95
(3H, s, OCH3), 2.10 (3H, s, OCOCH3); 13C NMR (75 MHz,
CDCl3) δC = 195.4 (CvO), 170.6 (CvO), 162.6, 159.4, 156.6,
128.5, 127.1, 124.6, 116.0, 113.1, 102.5, 94.6, 64.3 (ArCH2O),
55.9 (OCH3), 55.8 (OCH3), 21.1 (CH3); HR-TOF-MS: m/z
found 305.1027 [M + H]+ (calculated for C16H17O6, 305.1025).
Compound 13 (1.27 g, 3.27 mmol) was dissolved in a DMF–
H2O mixture (1 : 1 v/v, 40 ml). PdCl2 (0.0589 g, 0.327 mmol)
and CuCl2·2H2O (0.558 g, 3.27 mmol) were added to the solu-
tion which was stirred vigorously for 24 h at rt under an O2(g)
atmosphere. The reaction was filtered, and EtOAc (2 × 40 ml)
was added. The organic layers were combined, washed with
H2O (3 × 20 ml), separated, dried over anhydrous MgSO4,
filtered and concentrated under reduced pressure. Column
chromatography (15% EtOAc–hexane) of the residue afforded
the product 14 as a clear oil (0.657 g, 52%). IR νmax (cm−1) =
1
1504, 1450, 1367, 1257, 1154; H NMR (300 MHz, CDCl3) δH
= 7.50 (1H, s, H-10), 6.95 (1H, d, J 2.0, H-6), 6.41 (1H, d,
J 2.2, H-8), 5.99 (1H, s, H-4), 5.14 (2H, d, J 0.8, H-1), 3.92
(3H, s, OCH3), 3.90 (3H, s, OCH3), 2.01 (3H, d, J 0.5, CH3),
1.17 (9H, s, OSi(CH3)2C(CH3)3), 0.21 (6H, s, OSi(CH3)2C-
(CH3)3); 13C NMR (75 MHz, CDCl3) δC = 157.7, 156.6 (C-3),
154.6, 141.8, 129.8 (C-9a), 125.1 (C-10a), 120.9 (C-5a), 119.9
(C-4a), 110.7 (C-10), 97.9 (C-4), 96.9 (C-8), 94.0 (C-6), 69.3
(C-1), 55.6 (OCH3), 55.3 (OCH3), 26.2 (OSi(CH3)2C(CH3)3),
20.1 (CH3), 18.8 (OSi(CH3)2C(CH3)3), −3.1 (OSi(CH3)2C-
(CH3)3); HR-TOF-MS: m/z found 387.1984 [M + H]+ (calcu-
lated for C22H31O4Si, 387.1992).
(3R,4R)-3-Hydroxy-7,9-dimethoxy-3-methyl-5,10-dioxo-3,4,5,10-
tetrahydro-1H-benzo[g]isochromen-4-yl nitrate 17
7,9-Dimethoxy-3-methyl-1H-benzo[g]isochromene-5-ol 15 (0.308 g,
1.01 mmol) was dissolved in CH3CN–H2O mixture (2 : 1 v/v
ratio, 75 ml), and CAN (2.41 g, 4.40 mmol) in H2O (25 ml) was
added drop-wise. The reaction was then stirred for 1 h at rt fol-
lowed by the addition of H2O (100 ml) and EtOAc (100 ml).
The organic layer was extracted, dried over anhydrous MgSO4,
filtered, and the filtrate was concentrated in vacuo. The residue
was purified by column chromatography (30% EtOAc–hexane)
to afford the product 17 (0.201 g, 54%) as an orange solid. Mp.
= 105–106 °C; IR νmax (cm−1) = 3427 (OH), 1728 (CvO),
1658 (CvO), 1591, 1457, 1269, 1203; 1H NMR (300 MHz,
acetone-d6) δH = 7.17 (1H, d, J 2.4, H-6), 6.93 (1H, d, J 2.4,
H-8), 5.95 (1H, s, H-4), 4.62–4.56 (2H, m, H-1), 3.97 (3H, s,
OCH3), 3.94 (3H, s, OCH3), 2.87 (1H, br s, OH), 1.52 (3H, s,
CH3); 13C NMR (75 MHz, acetone-d6) δC = 183.3 (CvO),
180.6 (CvO), 166.0, 163.4, 149.0 (C-4a), 136.1 (C-5a), 131.6
(C-10a), 114.6 (C-9a), 105.0 (C-6)*, 104.8 (C-8)*, 95.9 (C-3),
73.3 (C-4), 58.6 (C-1), 56.8 (OCH3), 56.6 (OCH3), 24.1 (CH3).
*assignments may be interchanged.
7,9-Dimethoxy-3-methyl-1H-benzo[g]isochromene-5-ol 15
Tert-butyl(7,9-dimethoxy-3-methyl-1H-benzo[g]isochromene-
5-yloxy)dimethylsilane 14 (0.456 g, 1.16 mmol) was dissolved
in dry THF (3 ml) and was treated with tert-butylammonium
fluoride (0.609 g, 2.33 mmol) and stirred for 18 h at rt under a
N2(g) atmosphere. H2O (10 ml) and EtOAc (15 ml) were added
and the upper organic layer was extracted, dried over anhydrous
MgSO4, filtered, and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (10% EtOAc–
7814 | Org. Biomol. Chem., 2012, 10, 7809–7819
This journal is © The Royal Society of Chemistry 2012

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Allyl 3-allyl-4-hydroxy-1,6,8-trimethoxy-2-naphthoate 18
(COOCH2CHvCH2), 115.9 (ArCH2CHvCH2), 115.3 (C-2),
99.3 (C-5), 93.2 (C-7), 65.9 (COOCH2CHvCH2), 63.9 (OCH3),
61.5 (OCH3), 56.1 (OCH3), 55.3 (OCH3), 31.7
(ArCH2CHvCH2); HR-TOF-MS-ES: m/z found 395.1466
[M + Na]+ (calculated for C21H24O6Na, 395.1471).
Allyl 3-allyl-4-hydroxy-6,8-dimethoxy-2-naphthoate 11 (2.00 g,
6.10 mmol) was dissolved in MeOH (80 ml) in a round-bottom
flask (100 ml). PIFA (3.41 g, 7.93 mmol) was added and the
reaction was stirred for 15 min at rt. Aqueous NaHCO3 was
added until fizzing stopped and the MeOH was removed in
vacuo to leave only an aqueous medium. The H2O layer was
extracted with EtOAc (2 × 50 ml). The organic layers were com-
bined, dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. The residue was then treated with an
ethanolic solution of NaOEt (10.9 ml, 33.5 mmol) with vigorous
stirring for 20 min at rt. The reaction was then quenched with
the addition of saturated aqueous NH4Cl (10 ml). EtOAc
(30 ml) was added and the resulting upper organic layer was
removed, dried over anhydrous MgSO4, filtered and concentrated
in vacuo. Column chromatography (10% EtOAc–hexane) of the
residue afforded 18 as a brown oil (1.21 g, 60%). Mp. =
58–59 °C; IR νmax (cm−1) = 3257 (OH), 1738 (CvO), 1601
(3-Allyl-1,4,6,8-tetramethoxynaphthalen-2-yl)methanol 20
Allyl 3-allyl-1,4,6,8-tetramethoxy-2-naphthoate 19 (6.30 g,
16.9 mmol) was dissolved dry Et2O (100 ml) and cooled to 0 °C
in an ice bath. Lithium aluminium hydride (1.29 g, 33.8 mmol)
was added slowly over 5 min. The reaction mixture was then
stirred vigorously for 2 h at rt under a N2(g) atmosphere. The
solution was then cooled to 0 °C in an ice bath and cold H2O
was added drop-wise until the fizzing ceased. EtOAc (100 ml)
was added and the solution was washed with HCl (aq) (2 M,
30 ml). The organic layer was then dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure.
Column chromatography (40% EtOAc–hexane) of the residue
afforded 20 as a white crystalline solid (4.50 g, 84%). Mp. =
122–123 °C; IR νmax (cm−1) = 3481 (OH), 1580 (CvC), 1447,
1
(CvC), 1441, 1274, 1229, 1189; H NMR (300 MHz, CDCl3)
δH = 7.08 (1H, br s, H-5), 6.52 (1H, br s, H-7), 6.10–5.90 (2H, m,
COOCH2CHvCH2 and ArCH2CHvCH2), 5.57 (1H, s, OH),
5.41 (1H, ddd, J 17.2, 2.9, 1.4, one of COOCH2CHvCH2),
5.33–5.14 (3H, m, one of COOCH2CHvCH2 and ArCH2-
CHvCH2), 4.89–4.79 (2H, m, COOCH2CHvCH2), 3.94 (3H, s,
OCH3), 3.89 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.43 (2H, br d,
1
1262, 1204, 1114; H NMR (300 MHz, CDCl3) δH = 6.97 (1H,
d, J 2.3, H-5), 6.52 (1H, d, J 2.3, H-7), 6.19–5.98 (1H, m,
ArCH2CHvCH2), 5.05 (1H, dd, J 10.2, 1.7, one of ArCH2-
CHvCH2), 4.90 (1H, dd, J 17.2, 1.8, one of ArCH2CHvCH2),
4.78 (2H, s, ArCH2), 3.96 (3H, s, OCH3), 3.91 (3H, s, OCH3),
3.84 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.70 (2H, dt, J 5.3,
1.7, ArCH2CHvCH2), 2.55 (1H, br s, OH); 13C NMR
(75 MHz, CDCl3) δC = 158.7, 157.6, 152.2, 149.5, 137.9
(ArCH2CHvCH2), 131.9 (C-4a), 129.1 (C-3), 128.1 (C-2),
115.6 (C-8a), 115.4 (ArCH2CHvCH2), 99.0 (C-5), 93.2 (C-7),
63.3 (OCH3), 61.6 (OCH3), 57.5 (ArCH2), 56.1 (OCH3), 55.3
(OCH3), 30.7 (ArCH2CHvCH2); HR-TOF-MS-ES: m/z found
341.1367 [M + Na]+ (calculated for C18H22O5Na, 341.1365).
J 6.1, ArCH2CHvCH2); 13C NMR (75 MHz, CDCl3) δC
=
168.2 (CvO), 158.7, 157.4, 147.6, 145.3, 135.3 (COO-
CH2CHvCH2 and C-4a, overlapped), 131.9 (ArCH2CHvCH2),
129.5 (C-3), 124.3 (C-8a), 118.8 (COOCH2CHvCH2), 116.8
(ArCH2CHvCH2), 116.7 (C-2), 114.9, 99.4 (C-7), 92.9 (C-5),
66.0 (COOCH2CHvCH2), 63.9 (OCH3), 55.9 (OCH3), 55.2
(OCH3), 32.6 (ArCH2CHvCH2); HR-TOF-MS-ES: m/z found
381.1314 [M + Na]+ (calculated for C20H22O6Na, 381.1314).
Allyl 3-allyl-1,4,6,8-tetramethoxy-2-naphthoate 19
5,7,9,10-Tetramethoxy-3-methyl-1H-benzo[g]isochromene 21
Allyl
3-allyl-4-hydroxy-1,6,8-trimethoxy-2-naphthoate
18
(0.513 g, 1.40 mmol), anhydrous K2CO3 (0.289 g, 2.10 mmol)
and Me2SO4 (0.264 g, 2.10 mmol) were dissolved in acetone
(30 ml). The mixture was then refluxed for 18 h, cooled to rt,
filtered, and the solvent was removed in vacuo. The residue was
then dissolved in EtOAc (50 ml) and was successively washed
with aqueous NH3 (25%, 50 ml) and H2O (50 ml). The organic
layer was dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. Column chromatography (10% EtOAc–
hexane) of the residue afforded 19 as a yellow solid (0.466 g,
89%). Mp. = 60–61 °C; IR νmax (cm−1) = 1718 (CvO), 1581
(3-Allyl-1,4,6,8-tetramethoxynaphthalen-2-yl)methanol 20 (4.00 g,
12.6 mmol) was dissolved in a DMF–H2O mixture (1 : 1 v/v,
100 ml). PdCl2 (0.223 g, 1.26 mmol) and CuCl2·2H2O (2.14 g,
12.6 mmol) were added to the solution and O2(g) was bubbled
through the solution which was stirred vigorously for 2 h at rt.
The reaction was filtered, and EtOAc (2 × 50 ml) was added.
The organic layers were combined, washed with H2O (3 ×
20 ml), separated, dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. Column chromatography
(eluant 15% EtOAc–hexane) of the residue afforded 21 as a
white crystalline solid (2.62 g, 66%). Mp. = 134–135 °C; IR
νmax (cm−1) = 1601 (CvC), 1501, 1444, 1256, 1217, 1155;
1H NMR (300 MHz, CDCl3) δH = 6.96 (1H, d, J 2.3, H-6), 6.46
(1H, d, J 2.2, H-8), 5.95 (1H, s, H-4), 5.28 (2H, s, H-1), 3.94
(3H, s, OCH3), 3.91 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.76
(3H, s, OCH3), 2.02 (3H, s, CH3); 13C NMR (125 MHz, CDCl3)
δC = 158.5, 157.7, 156.1 (C-3), 147.5, 143.0, 131.9 (C-5a), 122.3
(C-4a), 116.9 (C-10a), 114.9 (C-9a), 98.3 (C-6), 95.6 (C-4), 93.1
(C-8), 64.0 (C-1), 62.2 (OCH3), 61.2 (OCH3), 56.0 (OCH3),
55.3 (OCH3), 20.1 (CH3); HR-TOF-MS-ES: m/z found
339.1209 [M + Na]+ (calculated for C18H20O5Na, 339.1208).
1
(CvC), 1450, 1299, 1214, 1191; H NMR (500 MHz, CDCl3)
δH = 6.97 (1H, s, H-5), 6.52 (1H, s, H-7), 6.07–5.90 (2H, m,
COOCH2CHvCH2 and ArCH2CHvCH2), 5.41 (1H, d, J 17.2,
one of COOCH2CHvCH2), 5.26 (1H, d, J 10.4, one of
COOCH2CHvCH2), 5.04 (2H, t, J 14.0, ArCH2CHvCH2),
4.80 (2H, dd, J 6.0, 0.8, COOCH2CHvCH2), 3.93 (3H, s,
OCH3), 3.90 (3H, s, OCH3), 3.84 (3H, s, OCH3) 3.82 (3H, s,
OCH3), 3.55 (2H, d, J 6.2, ArCH2CHvCH2); 13C NMR
(125 MHz, CDCl3) δC = 167.7 (CvO), 159.4, 157.9, 150.6,
149.2, 136.2 (COOCH2CHvCH2), 132.7 (C-4a), 132.1
(ArCH2CHvCH2), 126.6 (C-3), 124.7 (C-8a), 118.8
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7809–7819 | 7815

View Article Online
7,9-Dimethoxy-3-methyl-1H-benzo[g]isochromene-5,10-dione 1
through a bed of celite, and the solvent was removed in vacuo.
The light-yellow residue was then purified using column
chromatography (10% EtOAc–hexane) to yield allyl 4-(allyl-
oxy)-5,6,8-trimethoxy-2-naphthoate 23 as a yellow solid (4.67 g,
84%). Mp. = 70–71 °C; IR νmax (cm−1) = 1712 (CvO), 1505,
5,7,9,10-Tetramethoxy-3-methyl-1H-benzo[g]isochromene
(0.200 g, 0.632 mmol) was dissolved in a CH3CN–H2O mixture
(1 : 1 v/v, 8 ml), followed by the addition of PIFA (0.408 g,
0.948 mmol). The reaction was stirred for 2 h at rt, before being
quenched by aqueous NaHCO3 (15 ml). EtOAc was added (2 ×
30 ml), and the organic layers were separated, combined, dried
over anhydrous MgSO4, filtered, and the solvent was removed in
vacuo. The residue was purified by column chromatography
(30% EtOAc–hexane) to afford 7,9-dimethoxy-3-methyl-1H-
benzo[g]isochromene-5,10-dione 1 (0.045 g, 25%) as a dark-red
21
1465, 1258, 1201, 1180; 1H NMR (300 MHz, CDCl3) δH
=
8.57 (1H, d, J 1.2, H-1), 7.41 (1H, d, J 1.0, H-3), 6.66 (1H, s,
H-7), 6.28–5.97 (2H, m, COOCH2CHvCH2 and
OCH2CHvCH2), 5.57 (1H, dd, J 17.2, 1.4, one of COOCH2-
CHvCH2), 5.41 (1H, dd, J 17.2, 1.3, one of COOCH2CHvCH2),
5.30 (2H, dd, J 15.1, 5.7, OCH2CHvCH2), 4.84 (2H, d, J 5.6,
COOCH2CHvCH2), 4.69 (2H, d, J 5.1, OCH2CHvCH2), 3.97
(3H, s, OCH3), 3.96 (3H, s, OCH3), 3.80 (3H, s, OCH3); 13C
NMR (75 MHz, CDCl3) δC = 166.5 (CvO), 154.6, 153.5, 152.3,
137.7, 133.2 (OCH2CHvCH2), 132.6 (COOCH2CHvCH2),
124.5 (C-2), 124.2 (C-4a), 122.1 (C-8a), 118.8 (C-1), 118.1
(OCH2CHvCH2), 117.5 (COOCH2CHvCH2), 107.7 (C-3),
96.0 (C-7), 70.4 (OCH2CHvCH2) 65.6 (COOCH2CHvCH2),
62.0 (OCH3), 55.1 (OCH3), 55.9 (OCH3); HR-TOF-MS:
m/z found 359.1499 [M + H]+ (calculated for C20H23O6,
359.1495).
1
amorphous solid. H NMR (500 MHz, CDCl3) δH = 7.21 (1H,
d, J 2.4, H-6), 6.68 (1H, d, J 2.4, H-8), 5.81 (1H, s, H-4), 5.09
(2H, s, H-1), 3.93 (3H, s, OCH3), 3.92 (3H, s, OCH3), 1.98 (3H,
s, CH3); 13C NMR (125 MHz, CDCl3) δC 182.4 (CvO), 181.0
(CvO), 164.3, 163.4, 161.6 (C-3), 135.7 (C-4a), 135.5 (C-5a),
124.9 (C-10a), 114.7 (C-9a), 104.4 (C-8) 103.7 (C-6), 93.9
(C-4), 63.5 (C-1), 56.5 (OCH3), 56.0 (OCH3), 20.2 (CH3).4
Ethyl 4-acetoxy-5,6,8-trimethoxy-2-naphthoate 22
To
a solution of 2,4,5-trimethoxybenzaldehyde (4.00 g,
24.1 mmol) and diethyl succinate (5.45 g, 31.29 mmol) in dry
THF (50 ml), at 0 °C, was added NaOEt (3.28 g, 48.1 mmol).
The reaction mixture was refluxed for 2 h, cooled to rt and then
acidified to pH 3 with aqueous HCl [33% (v/v)]. The product
precipitated and was extracted with EtOAc (2 × 50 ml). The
combined organic extracts were dried over MgSO4, filtered, and
the filtrate was concentrated in vacuo. The residue, anhydrous
NaOAc (2.57 g, 31.3 mmol) were dissolved in acetic anhydride
(50 ml) and refluxed for 3 h. The solvent was removed in vacuo
and the resulting residue was dissolved in EtOAc (60 ml).
Aqueous NaHCO3 was slowly added to the EtOAc layer until no
effervesce was visible and all the traces of acetic acid were elimi-
nated. The organic layer was then separated, dried over MgSO4,
filtered, and the filtrate was concentrated in vacuo. The residue
was purified by column chromatography (30% EtOAc–hexane)
to afford ethyl 4-acetoxy-6,8-dimethoxy-2-naphthoate 22 (8.69 g,
Allyl 3-allyl-4-hydroxy-5,6,8-trimethoxy-2-naphthoate 24
Allyl 4-(allyloxy)-5,6,8-trimethoxy-2-naphthoate 23 (3.10 g,
8.65 mmol) was loaded neat into in a round-bottom flask
(50 ml) equipped with a reflux condenser and a magnetic stirrer
bar. The reaction vessel was then heated to 190 °C for 18 h
under a N2(g) atmosphere. The dark viscous residue was allowed
to cool to rt and was then purified by column chromatography
(20% EtOAc–hexane) to yield allyl 3-allyl-4-hydroxy-5,6,8-tri-
methoxy-2-naphthoate 24 as a yellow amorphous solid (2.73 g,
88%). Mp. = 68–69 °C; IR νmax (cm−1) = 3280 (OH), 1738
(CvO), 1604 (CvC), 1365, 1229, 1208, 1182; 1H NMR
(300 MHz, CDCl3) δH = 10.07 (1H, br s, OH), 8.25 (1H, s,
H-1), 6.55 (1H, s, H-7), 6.15–5.99 (2H, m, COOCH2CHvCH2
and ArCH2CHvCH2 overlapped), 5.41 (1H, dd, J 17.2, 1.5, one
of COOCH2CHvCH2), 5.27 (1H, dd, J 10.4, 1.3, one of
COOCH2CHvCH2), 5.06–4.97 (2H, m, ArCH2CHvCH2),
4.86–4.77 (2H, m, COOCH2CHvCH2), 3.98 (3H, s, OCH3),
3.97 (3H, s, OCH3), 3.95 (3H, s, OCH3), 3.88 (2H, br d, J 5.9,
ArCH2CHvCH2); (75 MHz, CDCl3) δC = 167.7 (CvO), 153.9,
151.1, 149.3, 137.4 (COOCH2CHvCH2), 135.9, 132.6
(ArCH2CHvCH2), 127.4 (C-3) 121.1 (C-4a), 120.0 (C-8a),
119.6 (C-2), 118.2 (COOCH2CHvCH2), 116.7 (C-1), 114.4
(ArCH2CHvCH2), 94.8 (C-7), 65.6 (COOCH2CHvCH2), 62.3
(OCH3), 57.0 (OCH3), 55.8 (OCH3), 30.1 (ArCH2CHvCH2);
HR-TOF-MS-ES: m/z found 381.1307 [M + Na]+ (calculated
for C20H22O6Na, 381.1314).
1
82%) as a yellow solid. H NMR (300 MHz, CDCl3) δH = 8.83
(1H, d, J 1.6, H-1), 7.68 (1H, d, J 1.6, H-3), 6.67 (1H, s, H-7),
4.39 (2H, q, J 7.1, OCH2CH3), 3.98 (3H, s, OCH3), 3.82 (3H, s,
OCH3), 2.38 (CH3CO2), 1.42 (3H, t, J 7.1, OCH2CH3).7
Allyl 4-(allyloxy)-5,6,8-trimethoxy-2-naphthoate 23
Ethyl 4-acetoxy-5,6,8-trimethoxy-2-naphthoate 22 (5.40 g,
15.5 mmol) was dissolved in MeOH (80 ml) followed by the
drop-wise addition of aqueous KOH (4.35 g, 77.5 mmol, 150 ml
H2O). The dark-orange reaction was stirred was 6 h at rt, before
the MeOH was removed in vacuo. The aqueous solution was
then carefully acidified to pH 4.0 with aqueous HCl (30%), and
then extracted with EtOAc (3 × 100 ml). The organic layers
were combined, dried over anhydrous MgSO4, filtered and con-
centrated under reduced pressure. The crude, off-white solid was
then dissolved in Me2CO (100 ml). Allyl bromide (4.69 g,
38.8 mmol), anhydrous K2CO3 (5.36 g, 38.8 mmol) was then
added to the solution which was refluxed for 18 h under a N2(g)
atmosphere. The mixture was then allowed to cool to rt, filtered
Allyl 3-allyl-4-hydroxy-1,5,6,8-tetramethoxy-2-naphthoate 25
Allyl 3-allyl-4-hydroxy-5,6,8-trimethoxy-2-naphthoate 24 (8.00 g,
22.3 mmol) was dissolved in MeOH (120 ml) in a round-bottom
flask (250 ml). PIFA (12.5 g, 29.0 mmol) was added and the reac-
tion was stirred for 10 min at rt. Aqueous NaHCO3 was added
until fizzing stopped and the MeOH was removed in vacuo to
leave only an aqueous medium. The H2O layer was extracted with
7816 | Org. Biomol. Chem., 2012, 10, 7809–7819
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5,6,7,9,10-Pentamethoxy-3-methyl-1H-benzo[g]isochromene 28
EtOAc (2 × 100 ml). The organic layers were combined, dried
over anhydrous MgSO4, filtered and concentrated under reduced
pressure. The residue was then treated with an ethanolic solution
of NaOEt (36.1 ml, 111.5 mmol) with vigorous stirring for
20 min at rt. The reaction was then quenched with the addition
of saturated aqueous NH4Cl (50 ml). EtOAc (100 ml) was added
and the resulting upper organic layer was removed, dried over
anhydrous MgSO4, filtered and concentrated in vacuo. Column
chromatography (15% EtOAc–hexane) of the residue afforded
Allyl 3-allyl-1,4,5,6,8-pentamethoxy-2-naphthoate (3.30 g,
8.20 mmol) was dissolved dry Et2O (100 ml) and cooled to 0 °C
in an ice bath. Lithium aluminium hydride (0.622 g, 16.4 mmol)
was added slowly over 5 min. The reaction mixture was then
stirred vigorously for 2 h at 40 °C under a N2(g) atmosphere.
The solution was then cooled to 0 °C in an ice bath and cold
H2O was added drop-wise until the fizzing stopped. EtOAc
(100 ml) was added and the solution was washed with aqueous
HCl (2 M, 20 ml). The organic layer was then dried over anhy-
drous MgSO4, filtered through a short pad of silica, and concen-
trated under reduced pressure to yield a yellow residue of what
was presumed to be (3-allyl-1,4,5,6,8-pentamethoxy-2-naphtha-
len-2-yl)methanol 27. This residue was dissolved in a DMF–
H2O mixture (1 : 1 v/v, 70 ml). PdCl2 (0.145 g, 0.820 mmol)
and CuCl2·2H2O (1.40 g, 8.20 mmol) were added to the solution
and O2(g) was bubbled through the solution which was stirred
vigorously for 2 h at rt. The reaction was filtered, and EtOAc
(2 × 50 ml) was added. The organic layers were combined,
washed with H2O (3 × 50 ml), separated, dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure.
Column chromatography (10% EtOAc–hexane) of the residue
afforded 28 as a white crystalline solid (1.40 g, 49% over two
steps). Mp. = 122–123 °C; IR νmax (cm−1) = 1654 (CvC), 1597
(CvC), 1339, 1178, 1134; (500 MHz, CDCl3) δH = 6.64 (1H, s,
H-8), 6.03 (1H, s, H-4), 5.26 (2H, s, H-1), 3.99 (3H, s, OCH3),
3.97 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.79 (3H, s, OCH3),
3.74 (3H, s, OCH3), 2.00 (3H, s, CH3); 13C NMR (125 MHz,
CDCl3) δC = 156.9 (C-3), 153.3, 150.0, 147.3, 142.6, 136.8,
125.8 (C-5a), 122.6 (C-10a), 117.6 (C-4a), 115.7 (C-9a), 96.1
(C-8), 95.6 (C-4), 63.8 (C-1), 62.3 (OCH3), 62.2 (OCH3), 62.0
(OCH3), 56.9 (OCH3), 56.5 (OCH3), 20.1 (CH3);
HR-TOF-MS-ES: m/z found 369.1312 [M + Na]+ (calculated
for C19H22O6Na, 369.1314).
25 as an orange amorphous solid (4.70 g, 54%). IR νmax (cm−1
)
= 3215 (OH), 1724 (CvO), 1609 (CvC), 1580 (CvC), 1287,
1
1260, 1152; H NMR (300 MHz, CDCl3) δH = 10.18 (1H, br s,
OH), 6.59 (1H, s, H-7), 6.07–5.89 (2H, m, COOCH2CHvCH2
and ArCH2CHvCH2), 5.44–5.33 (1H, m, one of
COOCH2CHvCH2), 5.24 (1H, dd, J 10.4, 1.3, one of
COOCH2CHvCH2), 5.08–4.93 (2H, m, ArCH2CHvCH2),
4.83–4.77 (2H, m, COOCH2CHvCH2), 3.92 (3H, s, OCH3),
3.91 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.74 (3H, s, OCH3),
3.42 (2H, br d, J 6.3 ArCH2CHvCH2); 13C NMR (75 MHz,
CDCl3) δC = 167.8 (CvO), 154.0, 148.3, 147.1, 145.7, 136.5
(C-4a), 135.9 (ArCH2CHvCH2), 132.1 (COOCH2CHvCH2),
126.3 (C-3), 120.2 (C-8a), 118.8 (COOCH2CHvCH2), 118.0
(C-2), 115.23 (ArCH2CHvCH2), 115.19, 96.8 (C-7), 65.9
(COOCH2CHvCH2), 63.9 (OCH3), 62.3 (OCH3), 56.8 (OCH3),
56.7 (OCH3), 31.5 (ArCH2CHvCH2); HR-TOF-MS-ES: m/z
found 411.1417 [M + Na]+ (calculated for C21H24O7Na,
411.1420).
Allyl 3-allyl-1,4,5,6,8-pentamethoxy-2-naphthoate 26
Allyl 3-allyl-4-hydroxy-1,5,6,8-tetramethoxy-2-naphthoate 25
(3.80 g, 10.09 mmol), anhydrous K2CO3 (2.09 g, 15.1 mmol)
and Me2SO4 (1.91 g, 15.1 mmol) were dissolved in acetone
(60 ml). The mixture was then refluxed for 18 h, cooled to rt,
filtered, and the solvent was removed in vacuo. The residue was
then dissolved in EtOAc (80 ml) and was successively washed
with aqueous NH3 (25%, 80 ml) and H2O (80 ml). The organic
layer was dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. Column chromatography (15% EtOAc–
hexane) of the residue afforded 26 as a yellow oil (3.30 g, 81%).
IR νmax (cm−1) = 1738 (CvO), 1603 (CvC), 1438, 1364,
1216, 1045; 1H NMR (300 MHz, CDCl3) δH = 6.69 (1H, s,
5,7,10-Trimethoxy-3-methyl-1H-benzo[g]isochromene-6,9-dione
29 and 5,9,10-trimethoxy-3-methyl-1H-benzo[g]isochromene-
6,7-dione 30
5,6,7,9,10-Pentamethoxy-3-methyl-1H-benzo[g]isochromene
(0.400 g, 1.15 mmol) was dissolved in 1,4-dioxane (30 ml) at
RT. AgO (5.77 mmol, 0.715 g) was then added to the stirred sol-
ution, followed by the drop-wise addition of HNO3 (6 M,
6.4 ml) to the solution which was the stirred for a further 5 min.
CH2Cl2 (50 ml) and H2O (50 ml) were added and the lower
organic layer was extracted, dried over anhydrous MgSO4,
filtered and concentrated under reduced pressure. Column
chromatography (20% EtOAc–hexane) of the residue afforded
2914 as an orange amorphous solid (0.230 g, 63%). Mp. =
H-7),
6.07–5.86
(2H,
m,
COOCH2CHvCH2
and
ArCH2CHvCH2), 5.38 (1H, dd,
J
17.2, 1.5 one of
COOCH2CHvCH2), 5.23 (1H, dd, J 10.4, 1.2, COOCH2-
CHvCH2), 5.07–4.93 (2H, m, ArCH2CHvCH2), 4.82–4.73
(2H, m, COOCH2CHvCH2), 3.95 (3H, s, OCH3), 3.93 (3H, s,
OCH3), 3.77 (3H, s, OCH3), 3.73 (3H, s, OCH3), 3.73 (3H, s,
OCH3), 3.53 (2H, br d, J 6.2, ArCH2CHvCH2); 13C NMR
(75 MHz, CDCl3) δC = 167.7 (CvO), 153.8, 151.1, 150.2,
149.2, 136.7 (C-4a), 136.6 (ArCH2CHvCH2), 132.1
(COOCH2CHvCH2), 127.7 (C-8a), 126.5 (C-2)*, 125.3 (C-3)*,
119.0 (COOCH2CHvCH2), 116.0 (ArCH2CHvCH2), 115.9,
97.1 (C-7), 66.1 (COOCH2CHvCH2), 63.9 (OCH3), 62.8
(OCH3), 62.1 (OCH3), 56.9 (OCH3), 56.8 (OCH3), 31.6
(ArCH2CHvCH2); *assignments may be interchanged;
HR-TOF-MS-ES: m/z found 425.1573 [M + Na]+ (calculated
for C22H26O7Na, 425.1576).
205–206 °C. IR νmax (cm−1) = 1782 (CvO), 1755 (CvO),
1
1705 (CvC), 1440, 1407; H NMR (500 MHz, CDCl3) δH
=
5.98 (1H, s, H-8), 5.96 (1H, s, H-4), 5.22 (2H, s, H-1), 3.84
(3H, s, OCH3), 3.82 (6H, s, 2 × OCH3), 2.00 (3H, s, CH3); 13C
NMR (125 MHz, CDCl3) δC = 183.7 (CvO), 179.3 (CvO),
159.8 (C-3), 159.0, 151.8, 149.8, 134.6 (C-10a), 128.2 (C-4a),
124.3 (C-5a), 122.0 (C-9a), 110.2 (C-8), 95.2 (C-4), 63.5 (C-1),
61.8 (OCH3), 61.6 (OCH3), 56.3 (OCH3), 20.0 (CH3);
HR-TOF-MS-ES: m/z found 317.1022 [M + H]+ (calculated for
This journal is © The Royal Society of Chemistry 2012
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C17H17O6, 317.1025). Further elution (50% EtOAc–hexane) led
to the isolation of 30 as a dark red solid (0.100 g, 27%). Mp. =
3.98 (3H, s, OCH3), 3.96 (5H, br s, OCH3 and ArCH2CHvCH2
overlapped), 3.79 (3H, s, OCH3), 3.79 (3H, s, OCH3);
13C NMR (75 MHz, CDCl3) δC = 167.4 (CvO), 156.6, 153.1,
152.2, 138.2 (COOCH2CHvCH2), 135.8, 132.4 (ArCH2-
CHvCH2), 130.4 (C-3) 126.3 (C-4a), 125.4 (C-8a), 122.2
(C-1), 120.7 (C-2) 118.2 (COOCH2CHvCH2), 114.7
(ArCH2CHvCH2), 94.8 (C-7), 65.5 (COOCH2CHvCH2), 62.7
(OCH3), 62.0 (OCH3), 56.9 (OCH3), 55.8 (OCH3), 30.1
(ArCH2CHvCH2); HR-TOF-MS-ES: m/z found 395.1465
[M + Na]+ (calculated for C21H24O6Na, 395.1471).
205–206 °C; IR νmax (cm−1) = 1794 (CvO), 1758 (CvO),
1
1698 (CvC), 1465, 1401; H NMR (500 MHz, CDCl3) δH
=
5.91 (1H, s, H-4), 5.88 (1H, s, H-8), 5.17 (2H, s, H-1), 3.99
(3H, s, OCH3), 3.81 (3H, s, OCH3), 3.73 (3H, s, OCH3), 2.00
(3H, s, CH3); 13C NMR (125 MHz, CDCl3) δC = 179.8 (CvO),
179.4 (CvO), 170.7, 159.4 (C-3), 152.6, 150.4, 132.8 (C-10a),
129.0 (C-4a), 123.6 (C-5a), 121.2 (C-9a), 101.9 (C-8), 95.0
(C-4), 63.5 (C-1), 62.4 (OCH3), 61.8 (OCH3), 57.0 (OCH3),
20.0 (CH3); HR-TOF-MS-ES: m/z found 317.1027 [M + H]+
(calculated for C17H17O6, 317.1025).
(3-Allyl-4,5,6,8-tetramethoxynaphthalen-2-yl)methanol 33
Allyl 3-allyl-4,5,6,8-tetramethoxy-2-naphthoate 32 (1.80 g,
4.83 mmol) was dissolved dry Et2O (50 ml) and cooled to 0 °C
in an ice bath. Lithium aluminium hydride (0.367 g, 9.67 mmol)
was added slowly over 5 min. The reaction mixture was then
stirred vigorously for 2 h at rt under a nitrogen atmosphere. The
solution was then cooled to 0 °C in an ice bath and cold H2O
was added drop-wise until the fizzing stopped. EtOAc (50 ml)
was added and the solution was washed with aqueous HCl (2 M,
10 ml). The organic layer was then dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure.
Column chromatography (40% EtOAc–hexane) of the residue
afforded (3-allyl-4,5,6,8-tetramethoxynaphthalen-2-yl)methanol
33 as a white crystalline solid (1.32 g, 86%). 1H NMR
(300 MHz, CDCl3) δH = 8.02 (1H, s, H-1), 6.64 (1H, s, H-7),
6.07 (1H, tdd, J 15.7, 10.5, 5.5, ArCH2CHvCH2), 5.05–4.94
(1H, m, one of ArCH2CHvCH2), 4.94–4.81 (1H, m, one of
ArCH2CHvCH2), 4.76 (2H, s, ArCH2OH), 3.98 (3H, s, OCH3),
3.94 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.81 (3H, s, OCH3),
3.71–3.61 (2H, m, ArCH2CHvCH2), 2.33 (1H, br s, OH); 13C
NMR (75 MHz, CDCl3) δC = 152.9, 152.6, 150.0, 138.0
(ArCH2CHvCH2), 136.2 (C-4a), 135.8, 129.3 (C-3), 123.2
(C-2), 122.0 (C-8a), 117.5 (C-1), 115.1 (ArCH2CHvCH2), 95.0
(C-7), 63.6 (ArCH2OH), 62.8 (OCH3), 62.0 (OCH3), 57.1
(OCH3), 55.8 (OCH3), 29.8 (ArCH2CHvCH2).17
Anhydrofusarubin 2
5,7,10-Trimethoxy-3-methyl-1H-benzo[g]isochromene-6,9-
dione (0.200 g, 1.15 mmol) was dissolved in dry CH2Cl2
(50 ml) and cooled to −78 °C under a N2(g) atmosphere. BCl3
(1.58 ml, 1.58 mmol) was added drop-wise to the solution
which was stirred for a further 40 min at −78 °C, and then
allowed to warm to rt. The reaction was then carefully quenched
with a few drops of cold H2O and then CH2Cl2 (50 ml) and H2O
(100 ml) were added. The lower organic layer was separated,
dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure. Column chromatography (20% EtOAc–
hexane) of the residue afforded 2 as a crystalline purple solid
(0.130 g, 65%). Mp. = 195–196 °C (199–202 °C);18 1H NMR
(500 MHz, CDCl3) δH = 13.04 (1H, s, OH), 12.65 (1H, s, OH),
6.17 (1H, s, H-8), 5.99 (1H, s, H-4), 5.22 (2H, s, H-1), 3.92
(3H, s, OCH3), 2.02 (3H, s, CH3); 13C NMR (125 MHz,
CDCl3) δC = 183.0 (CvO), 177.9 (CvO), 161.7 (C-3), 160.1,
158.1, 158.0, 133.2 (C-4a), 122.9 (C-10a), 111.1 (C-5a), 110.1
(C-8), 108.1 (C-9a), 94.9 (C-4), 63.1 (C-1), 56.8 (OCH3), 20.2
(CH3); HR-TOF-MS-ES: m/z found 288.0633 [M]+ (calculated
for C15H12O6, 288.0634).
Allyl 3-allyl-4,5,6,8-tetramethoxy-2-naphthoate 32
Allyl 3-allyl-4-hydroxy-5,6,8-trimethoxy-2-naphthoate 24 (2.60 g,
7.25 mmol), anhydrous K2CO3 (1.50 g, 10.9 mmol) and
Me2SO4 (1.37 g, 10.9 mmol) were dissolved in acetone (50 ml)
in a round-bottom flask (100 ml). The solution was then refluxed
for 12 h under a N2(g) atmosphere. The mixture was then
allowed to cool to rt, filtered through a bed of celite, and the
solvent was removed in vacuo. The residue was then dissolved in
EtOAc (50 ml) and was successively washed with aqueous NH3
(25%, 3 × 20 ml), HCl (0.5 M, 2 × 20 ml) and H2O (50 ml).
The EtOAc layer was dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. Column chromatography
(10% EtOAc–hexane) of the residue afforded allyl 3-allyl-
4,5,6,8-tetramethoxy-2-naphthoate 32 (2.43 g, 90%) as an off-
white solid. Mp. = 66–67 °C; IR νmax (cm−1) = 1740 (CvO),
1602 (CvC), 1358, 1442, 1225, 1137; 1H NMR (300 MHz,
CDCl3) δH = 8.52 (1H, s, H-1), 6.65 (1H, s, H-7), 6.13–5.95
(2H, m, COOCH2CHvCH2 and ArCH2CHvCH2 overlapped),
5.39 (1H, ddd, J 17.2, 3.0, 1.5, one of COOCH2CHvCH2),
5.26 (1H, dd, J 10.4, 1.3, COOCH2CHvCH2), 4.98–4.91 (2H, m,
ArCH2CHvCH2), 4.79 (2H, dt, J 5.6, 1.3, COOCH2CHvCH2),
5,6,7,9-Tetramethoxy-3-methyl-1H-benzo[g]isochromene 31
(3-Allyl-4,5,6,8-tetramethoxynaphthalen-2-yl)methanol 32 (1.40 g,
4.40 mmol) was dissolved in a DMF–H2O mixture (1 : 1 v/v,
20 ml). PdCl2 (0.0780 g, 0.440 mmol) and CuCl2·2H2O
(0.750 g, 4.40 mmol) were added to the solution and O2(g) was
bubbled through the solution which was stirred vigorously for
2 h at rt. The reaction was filtered, and EtOAc (2 × 30 ml) was
added. The organic layers were combined, washed with H2O
(3 × 20 ml), separated, dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure. Column chromato-
graphy (15% EtOAc–hexane) of the residue afforded 31 as a
1
white crystalline solid (0.890 g, 64%). Mp. = 101–102 °C; H
NMR (300 MHz, CDCl3) δH = 7.61 (1H, s, H-10), 6.57 (1H, s,
H-8), 6.18–6.03 (1H, m, H-4), 5.12 (2H, s, H-1), 3.97 (3H, s,
OCH3), 3.93 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.84 (3H, s,
OCH3), 2.00 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) δC
=
156.1 (C-3), 152.6, 149.9, 146.1, 136.6, 125.5 (C-4a), 123.9
(C-10a), 123.4 (C-9a), 121.4 (C-5a), 113.0 (C-10), 96.0 (C-4),
94.3 (C-8), 68.7 (C-1), 62.3 (OCH3), 62.0 (OCH3), 55.8
7818 | Org. Biomol. Chem., 2012, 10, 7809–7819
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10 The three data sets were collected using ω-scans on a APEX II CCD area
detector diffractometer. The crystals for compound 16 and 17 were pre-
pared by dissolving the samples in CH2Cl2 in a vial. These vials were put
into bigger vials filled with hexane and the whole system was sealed.
Cotton wool was used to keep the inner and outer vials apart. Crystal data
for 16: CCDC 885420, C16H16O6: Mr 304.29 g mol−1; crystal dimensions
(mm) 0.42 × 0.25 × 0.22; crystal system, monoclinic; space group, C2/m;
unit cell dimensions and volume, a = 19.2003(6) Å, b = 6.7203(2) Å, c =
11.0340(4) Å, α = 90°, β = 99.379(2)°, γ = 90°, V = 1404.70(8) Å3, no.
of formula units in the unit cell Z = 4; calculated density rcalcd 1.439 Mg
(OCH3), 55.7 (OCH3), 20.1 (CH3); HR-TOF-MS-ES: m/z
found 339.1207 [M + Na]+ (calculated for C18H20O5Na,
339.1209).
Acknowledgements
This work was supported by SABINA (Southern African Bio-
chemistry and Informatics for Natural Products Network), the
National Research Foundation (NRF, GUN 2053652 and IRDP
of the NRF (South Africa) for financial support provided by the
Research Niche Areas programme), Pretoria, and the University
of the Witwatersrand (Science Faculty Research Council). We
also gratefully acknowledge the NRF scarce skills programme
for generous funding to MMJ. Mr R Mampa (University of the
Witwatersrand) and Ms C. Janse Van Rensburg (University of
Kwa-Zulu Natal, Pietermaritzburg) are thanked for providing the
NMR and HRMS MS spectroscopy services, respectively.
Mr J. Sumani (University of the Witwatersrand) is thanked for
purification of some compounds.
m
−3; linear absorption coefficient, m 0.111 mm−1; radiation and wave-
length, MoKα = 0.71073 Å; temperature of measurement, 173(2) K, 2
Qmax 28.00°; no of measured and independent reflections, 8613 and
1842; Rint = 0.0473; R[I > 2.0σ(I)] = 0.0473, wR = 0.1176, GoF = 1.069,
refined on F; residual electron density, 0.247 and −0.363 eÅ−3
.
11 Crystal data for 17: CCDC 885421, C16H15NO9: Mr 365.29 g mol−1
;
crystal dimensions (mm) 0.32 × 0.06 × 0.03; crystal system, monoclinic;
space group, P21/c; unit cell dimensions and volume, a = 13.913(4) Å, b
= 13.475(4) Å, c = 8.404(3) Å, α = 90°, β = 94.246(9)°, γ = 90°, V =
1571.2(9) Å3, no. of formula units in the unit cell Z = 4; calculated
density rcalcd
, ; linear absorption coefficient, m
1.544 Mg m−3
0.129 mm−1; radiation and wavelength, MoKα = 0.71073 Å; temperature
of measurement, 173(2) K, 2 Qmax 28.00°; no of measured and indepen-
dent reflections, 7954 and 2722; Rint = 0.1022; R[I > 2.0σ(I)] = 0.0497,
wR = 0.0821, GoF = 0.874, refined on F; residual electron density, 0.184
and −0.196 eÅ−3
.
12 V. Nair, T. D. Suja and K. Mohanan, Synthesis, 2006, 2531–2534.
13 (a) A. N. Lowell, M. W. Fennie and M. C. Kozlowski, J. Org. Chem.,
2008, 73, 1911–1918; (b) For the initial research in this area on the intro-
duction of an hydroxyl substituent onto an aromatic ring, see for
example, the review: T. Dohi, M. Ito, N. Yamaoka, K. Morimoto,
H. Fujioka and Y. Kita, Tetrahedron, 2009, 65, 10797–10815. In our
research limited success wasmet in trying to introduce a hydroxyl substi-
tuent onto an aromatic ring with PIFA.
Notes and references
1 M. V. Kadkol, K. S. Gopalkrishnan and N. Narasimhachari, J. Antibiot.,
1971, 24, 245–248.
2 P. A. Paranagama, E. M. K. Wijeratne, A. M. Burns, M. T. Marron,
M. K. Gunatilaka, A. E. Arnold and A. A. L. Gunatilaka, J. Nat. Prod.,
2007, 70, 1700–1705.
14 The crystals for compound 29 was prepared by dissolving the sample in
CH2Cl2 in a vial and left overnight: Crystal data for 29: CCDC 885422,
3 K. Trisuwan, N. Khamthong, V. Rukachaisirikul, S. Phongpaichit,
S. Preedanon and J. Sakayaroj, J. Nat. Prod., 2010, 73, 1507–1511.
4 B. Kesteleyn and N. De Kimpe, J. Org. Chem., 2000, 65, 640–644.
5 D. Wadsworth, J. Sperry and M. A. Brimble, Synthesis, 2010, 2604–
2608.
C
17H16O6: Mr 316.30 g mol−1; crystal dimensions (mm) 0.41 × 0.40 ×
ˉ
0.06; crystal system, triclinic; space group, P1; unit cell dimensions and
volume, a = 8.4652(2) Å, b = 9.6050(2) Å, c = 9.6340(2) Å, α =
111.5360(10)°, β = 90.649(2)°, γ = 98.224(2)°, V = 719.41(3) Å3, no. of
formula units in the unit cell Z = 2; calculated density rcalcd, 1.460 Mg
6 W. S. Chilton, J. Org. Chem., 1968, 33, 4299–4300.
7 See for example: (a) C. B. de Koning, R. G. F. Giles and I. R. Green,
J. Chem. Soc., Perkin Trans. 1, 1991, 2743–2748; (b) C. B. de Koning,
J. P. Michael and W. A. L. van Otterlo, J. Chem. Soc., Perkin Trans. 1,
2000, 799–811; (c) C. B. de Koning, I. R. Green, J. P. Michael and
J. R. Oliveira, Tetrahedron, 2001, 57, 9623–9634; (d) E. M. Mmutlane,
J. P. Michael, I. R. Green and C. B. de Koning, Org. Biomol. Chem.,
2004, 2, 2461–2470.
8 (a) S. Govender, E. M. Mmutlane, W. A. L. van Otterlo and C. B. de
Koning, Org. Biomol. Chem., 2007, 5, 2433–2440; (b) For a recent
review on these types of Wacker oxidations see: J. Muzart, Tetrahedron,
2005, 61, 5955–6008.
m
−3; linear absorption coefficient, m 0.111 mm−1; radiation and wave-
length, MoKα = 0.71073 Å; temperature of measurement, 173(2) K, 2
Qmax 28.00°; no of measured and independent reflections, 17 177 and
3470; Rint = 0.0442; R[I > 2.0σ(I)] = 0.0421, wR = 0.1150, GoF = 1.017,
refined on F; residual electron density, 0.346 and −0.222 e.Å−3
.
15 I. Kurobane, L. C. Vining, A. G. McInnes and J. A. Walter,
Can. J. Chem., 1980, 58, 1380–1385.
16 G. A. Kraus and H. Ogutu, Tetrahedron, 2002, 58, 7391–7395.
17 C. B. de Koning, S. S. Manzini, J. P. Michael, E. M. Mmutlane,
T. R. Tshabidi and W. A. L. van Otterlo, Tetrahedron, 2005, 61, 555–564.
18 C.-L. Shao, W.-C. Wang, D.-S. Deng, Z. G. She, Y.-C. Gu and Y.-C. Lin,
Chin. J. Struct. Chem., 2008, 27, 824–828.
9 W. S. Johnson and G. H. Daub, “The stobbe condensation”, in Organic
Reactions, John Wiley & Sons, Inc., 1951, vol. 6, pp. 1–73.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7809–7819 | 7819