Bidirectional racemic synthesis of the biologically active quinone cardinalin 3

Article abstract of DOI:10.1039/b707187f

Readily available 2,2′,6,6′-tetramethoxy-1,1′-biphenyl was transformed in 14 synthetic steps into the natural product cardinalin 3 using a bidirectional approach. One of the key steps was the formation of the cis-1,3-dimethylnaphtho[2,3-c]pyran ring. (±)-

Full text of DOI:10.1039/b707187f

View Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Bidirectional racemic synthesis of the biologically active quinone cardinalin 3
Sameshnee Govender, Edwin M. Mmutlane,† Willem A. L. van Otterlo and Charles B. de Koning*
Received 11th May 2007, Accepted 4th June 2007
First published as an Advance Article on the web 26th June 2007
DOI: 10.1039/b707187f
Readily available 2,2ꢀ,6,6ꢀ-tetramethoxy-1,1ꢀ-biphenyl was transformed in 14 synthetic steps into the
natural product cardinalin 3 using a bidirectional approach. One of the key steps was the formation
of the cis-1,3-dimethylnaphtho[2,3-c]pyran ring. ( )-1,1ꢀ-[6,6ꢀ-Diallyl-5,5ꢀ-bis(benzyloxy)-
1,1ꢀ,3,3ꢀ-tetramethoxy-2,2ꢀ-binaphthalene-7,7ꢀ-diyl]diethanol was treated with O2 in the presence
of CuCl2 and catalytic PdCl2 to afford 5,5ꢀ-bis(benzyloxy)-7,7ꢀ,9,9ꢀ-tetramethoxy-1,1ꢀ,3,3ꢀ-
tetramethyl-1H,1ꢀH-8,8ꢀ-bibenzo[g]isochromene. Hydrogenation of this compound afforded
7,7ꢀ,9,9ꢀ-tetramethoxy-cis-1,3-cis-1ꢀ,3ꢀ-tetramethyl-3,3ꢀ,4,4ꢀ-tetrahydro-1H,1ꢀH-8,8ꢀ-
bibenzo[g]isochromene-5,5ꢀ-diol in quantitative yield, which was converted in 3 steps
to cardinalin 3.
Introduction
The New Zealand toadstool Dermocybe cardinalis,1,2 produces
interesting distinctive purple and orange fruit bodies. From these
bodies a series of biologically active pyranonaphthoquinone-type
pigments, known as the cardinalins (e.g. cardinalins 1–3, Fig. 1),
have been isolated. The simplest of this series of compounds is
cardinalin 3 3, which is a dimer of ventiloquinone L 4, itself a
naturally occurring compound isolated from Ventilago goughii
(Rhamnaceae).3 Both cardinalin 3 3 and ventiloquinone L 4
possess a cis-1,3-dimethylpyran ring fused to a naphthoquinone
nucleus.
While the synthesis of cardinalin 3 has yet to be achieved, there
are three previously reported syntheses of ventiloquinone L.4–6 In
principle, the dimerization of ventiloquinone L should provide
cardinalin 3, but in our hands this proved to be problematic.5
Therefore we sought an alternative approach.
The use of bidirectional synthesis has been used to assemble
a number of compounds that contain two equal halves.7a For
instance, a recent example is the synthesis of the central amino acid
component of chloptosin 5, a relatively complex natural product
(Fig. 2).7b This approach has also been used for the assembly of
biaryl naphthalenes.7c,7d
In this paper we wish to report on the bidirectional synthesis
Fig. 1 Cardinalins 1–3 and ventiloquinone L.
of cardinalin 3 3. The successful synthesis of cardinalin 3 was
achieved in 14 steps and in an overall yield of 2.3% starting from
readily available 2-iodo-1,3-dimethoxybenzene.
Results and discussion
As a result of our inability to convert ventiloquinone L 4
into cardinalin 3 3 using oxidative coupling methodology,5 we
reasoned that the biaryl axis could be constructed at an early stage
of the synthesis. We postulated that thereafter, using a bidirectional
Molecular Sciences Institute, School of Chemistry, University of the
Witwatersrand, PO Wits, 2050, South Africa. E-mail: Charles.deKoning@
wits.ac.za; Fax: +27 11 717 6749; Tel: +27 11 717 6724
† Current address: Discovery Chemistry, CSIR, 1 Ardeer Rd, Modder-
fontein, 1645, South Africa
Fig. 2 Bidirectional synthesis of the central amino acid of chloptosin.
Org. Biomol. Chem., 2007, 5, 2433–2440 | 2433
This journal is The Royal Society of Chemistry 2007
©

View Online
synthetic approach, methodology we had used previously
could be used to synthesize cardinalin 3 3.
15. However, what we anticipated to be a trivial reduction of the
ester of 13 into the primary benzyl alcohol, proved to be the
most problematic step in the entire synthesis! Using a variety
of reduction conditions12 gave mixtures of products resulting
from incomplete reduction of both esters. The best yield (42%)
was obtained with LiAlH4 as the reagent and using the specific
conditions outlined in the Experimental section for the work-up
of the reaction. The benzylic alcohol was then oxidized to the
aldehyde 14 using PCC (Scheme 1). Attempts to convert 13 into
aldehyde 14 directly with DIBAL also met with failure.
Starting from readily available 2-iodo-1,3-dimethoxybenzene
78 it was found that the highest yielding way to convert this
compound into the desired biaryl 8 was using literature Ullmann
type chemistry.9 As shown in Scheme 1, an in situ formation
of 2-litho-1,3-dimethoxybenzene was readily accomplished and
reaction of this with CuI in the presence of 7 yielded the desired
product 8 in excellent yield. Hence the desired biaryl bond had
now been formed at an early stage of the synthesis.
We now were set to try all the remaining reactions in the
synthesis in a bidirectional manner. All attempts using traditional
Vilsmeier–Haack conditions to form the bis-aldehyde 9 were
either unsuccessful, low yielding, or gave mixtures of the desired
product and the mono-formylated product. By contrast, using
the conditions developed by Rieche and co-workers10 the product
9 was formed in excellent yields. We were now in a position
to attempt the formation of the second aromatic ring to make
the biaryl naphthalene 10. Therefore 9 was subjected to Stobbe
condensation conditions with diethyl succinate. This was followed
by an acetic anhydride-mediated ring closure to afford the desired
naphthalene 10 in 60% yield over the two steps.
Exposure of aldehyde 14 to MeMgI afforded racemic 15
(Scheme 2). At this point some of the signals in the NMR
spectra were doubled as a result of the formation of a mixture
of diastereoisomers. For example, one of the methoxy signals
1
now appeared as two singlets at d 3.63 and 3.62 in the H NMR
spectrum. Gratifyingly, when 15 was treated with 10% PdCl2 and
stoichiometric CuCl2 under an oxygen atmosphere the reaction
proceeded in good yield (78%) to afford 16. Treatment of 16
with 10% Pd/C appeared to exclusively afford the desired cis-
1,3-dimethylpyran 17 in near quantitative yield. In addition, as
planned, the O-benzyl protecting group was removed under these
conditions.
Selective removal of the O-acetate of the bis-naphthalene 10
with guanidine gave the desired naphthol 11 in 78% yield without
touching the other ester substituent. The naphthol 11 was easily
converted into the O-allyl bis-naphthalene 12. Subjecting this com-
pound to microwave11 conditions for the Claisen rearrangement
yielded the required C-allyl bis-naphthol, which was O-benzylated
to afford 13.
We were now in a position to attempt the use of Wacker-type
conditions we have developed for specifically constructing cis-1,3-
dimethylpyrans.5 We initially had to convert the ester of the bis-
naphthalene 13 into the desired methyl substituted benzyl alcohol
All that remained in the synthesis was the oxidation of the
naphthol into the desired quinone 18 and then the removal of one
of the O-methyl protecting groups to yield cardinalin 3 3. The first
step was achieved using salcomine and oxygen to yield 18. The
second step was accomplished using BCl3 in CH2Cl2 at 0 ◦C to
afford the target cardinalin 3 3.
The NMR spectral data for 3 were in general agreement with
that reported in the literature.1 As a diastereoisomeric mixture of
products was formed, additional peaks for some of the signals in
1
the H NMR and 13C NMR spectra were noted. Two doublets
were seen at d 1.58 and 1.57 for the methyl attached to C-1. H-6
Scheme 1 Reagents and conditions: (i) (a) 1,3-dimethoxybenzene, n-BuLi, THF, 0 ◦C, 1 h, (b) CuI, 7, pyridine, reflux, 72 h, 93%; (ii) MeOCHCl2, CH2Cl2,
TiCl4, 0 ◦C, 95%; (iii) (a) diethyl succinate, t-BuOH, KOBut, reflux, 2 h, (b) Ac2O, NaOAc, 140 ◦C, 60%; (iv) guanidine·HCl, KOBut EtOH–CH2Cl2, rt,
1.5 h, 78%; (v) allyl bromide, K2CO3, Me2CO, reflux, 18 h, 84%; (vi) (a) DMF, microwave (200 W), 170 ◦C, 250 psi, 25 min, 98%, (b) BnCl, KI, K2CO3,
Me2CO, 18 h, 90%; (vii) (a) LiAlH4, THF, 0 ◦C, 18 h, 42%, (b) PCC–Al2O3, CH2Cl2, rt, 8 h, 90%.
2434 | Org. Biomol. Chem., 2007, 5, 2433–2440
This journal is
The Royal Society of Chemistry 2007
©

View Online
Scheme 2 Reagents and conditions: (i) MeMgI–Et2O–THF, rt, 18 h, 79%; (ii) 10% PdCl2, CuCl2·H2O–DMF, rt, O2, 18 h, 78%; (iii) 10% Pd/C, H2,
CH2Cl2–dioxane, rt, 48 h, cis-100%; (iv) 1.1 equiv. salcomine, DMF, O2, rt, 18 h, 51%; (v) BCl3, CH2Cl2, 15 min, 0 ◦C, 64%.
also appeared as two singlets, both very close to d 7.33 (d 7.331 and
7.329). In the expanded 1H NMR spectrum of 3 a small complex
multiplet between d 3.96–4.04 for H-3 and H-3ꢀ was observed. This
is diagnostic for trans-1,3-dimethylbenzopyrans13 and therefore it
is believed that a small amount (<5%) of this had also formed. As
there were only trace amounts of the possible trans-product, its
identity could not be confirmed. The melting point of 3 was also
measurements by electrospray-MS were conducted on a Finnigan
MAT 900 MS instrument with EBqQ configuration equipped
with an electrospray ion source. The analyte solutions (CH2Cl2
1.0 mg ml−1) were diluted with methanol to concentrations of 10−4–
10−6 mol l−1. The exact mass measurement of the molecular ions
(specified on the result form: mostly sodiated molecular ion species
[M + Na]+) experiments were conducted by peak matching with
adequate internal reference ions (respective polypropyleneglycol
PPG reference ions reported on the result forms). The solution
of PPG was added to the analyte solution prior to the ESMS
measurement (flow rate: 3 ll min−1, electrospray voltage: 3.7 kV,
temperature of the heated capillary: 230 ◦C). The resolution was
at least 9000 (resolution: 10% valley definition). The error of the
exact ion mass measurements was always smaller than 5 ppm
(relative) respectively smaller than 0.002u (absolute). The mea-
surements were repeated 100 times and the respective mean results
reported. Microwave reactions were performed in a CEM Discover
microwave. Macherey-Nagel Kieselgel 60 (particle size 0.063–
0.200 mm) was used for conventional silica gel chromatography.
All solvents used for reactions and chromatography were distilled
prior to use to remove residual non-volatiles. Anhydrous/oxygen-
free solvents (THF and Et2O) were obtained according to standard
procedures. Removal or concentration of solvent in vacuo implies
the evaporation of solvent at 20–25 Torr utilising a rotary
evaporator.
◦
different to the value of 213–220 C described in the literature.1
We observed darkening of the crystals taking place above 145 ◦C
and melting only took place between 236 and 241 ◦C.
In conclusion, the first synthesis of racemic cardinalin 3 has
been achieved. Presently we are developing methodology for
the construction of the 1,3-dimethylbenzopyran system in a
stereoselective manner that could be applied to the asymmetric
synthesis of cardinalin 3.
Experimental
1H NMR and 13C NMR spectra were recorded either on a
Bruker AVANCE 300 spectrometer or on a Bruker DRX-400
spectrometer at the frequency indicated. DEPT, C–H correlated
and COSY spectra were run on some samples to enable a more
complete assignment of signals. J Values are given in Hz. Infra-red
spectra were recorded on a Bruker Vector 22 Fourier Transform
spectrometer. Mass spectra were recorded in Ko¨ln. The EIMS
low resolution spectra were measured on a Finnigan INCOS 50
single quadrupole MS-instrument. The samples were introduced
via a direct inlet probe and ionized with electrons at 70 eV
energy. The samples were dissolved in CH2Cl2 to give solutions of
1.0 mg ml−1 and aliquots of these analyte solutions were vaporized
in respective crucibles. Approximately 1 lg of the dried compound
of interest was finally introduced to the ion source, thermally
transferred to the gas phase and analyzed by ESMS with unit
resolution of the single quadrupole analyzer. The exact mass
2-Iodo-1,3-dimethoxybenzene 7
Into a flame dried RB flask fitted with a dropping funnel was
placed dry THF (50 ml), followed by 1,3-dimethoxybenzene
(4.74 ml, 5.00 g, 36.2 mmol). The solution was cooled down
to 0 ◦C. Once cooled, the n-BuLi (1.4 M in hexane, 28.4 ml,
39.8 mmol) was slowly added using a dropping funnel. The
solution was stirred at 0 ◦C for 1 h. The dropping funnel was
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2433–2440 | 2435
©

View Online
◦
then charged with a solution of I2 (10.1 g, 39.8 mmol) in THF
(70 ml). This solution was then added dropwise to the milky white
reaction mixture. The end point of the reaction was observed by
the appearance of the light brown halogen colour. The resulting
solution was stirred for an additional 1 h at rt. Water was
then added to the product mixture and the product extracted
with CH2Cl2. The solvent was removed in vacuo and the crude
product was recrystallized from CH2Cl2–EtOH to give large white
crystals of 2-iodo-1,3-dimethoxybenzene 7 (8.84 g, 93%). Mp =
for 30 min. The resulting solution was then warmed up to 0 C
over 1 h and stirred at this temperature for an additional 15 min.
The product mixture was then poured into a separating funnel
containing crushed ice (ca. 10 g) and aqueous conc. HCl (ca. 8 ml)
and shaken vigorously. The pink–purple organic layer was then
separated, washed with water (ca. 50 ml) and brine (ca. 50 ml).
It was then dried over anhydrous MgSO4, filtered and the solvent
removed in vacuo. The crude material was purified by silica gel
column chromatography (40% EtOAc–hexane) to give 2,2ꢀ,6,6ꢀ-
tetramethoxy[1,1ꢀ-biphenyl]-3,3ꢀ-dicarbaldehyde 9 as a white solid
◦
105–106 C (CH2Cl2–EtOH) (lit.14 102–103 ◦C); IR (CHCl3):
mmax(cm ) = 1587 and 1470 (ArC C); 1H NMR (300 MHz,
(0.80 g, 95%). Mp = 147–149 ◦C; IR (CHCl3): mmax(cm−1) = 1677
−1
=
1
=
=
CDCl3): dH = 7.26 (1H, t, J = 8.3, H-5), 6.50 (2H, d, J = 8.3,
H-4 and H-6) and 3.89 (6H, s, 2 × OMe); 13C NMR (75 MHz,
CDCl3) dC = 158.4 (C-1 and C-3), 128.7 (C-5), 112.6 (C-2) 104.5
(C-4 and C-6) and 56.1 (2 × OMe); HRMS: Found M+, 263.9654.
C8H9IO2 requires M 263.9647; m/z (EI) 264 (M+, 100%), 249 (6),
221 (18), 206 (7), 122 (8), 107 (37), 92 (9), 77 (10) and 51 (8).
(ArC O), 1586 and 1463 (ArC C); H NMR (300 MHz, CDCl3):
dH = 10.17 (2H, s, 2 × CHO), 7.91 (2H, d, J = 8.8, 4- and 4ꢀ-H),
6.83 (2H, d, J = 8.8, 5- and 5ꢀ-H), 3.76 (6H, s, 2 × OMe) and 3.52
(6H, s, 2 × OMe); 13C NMR (75 MHz, CDCl3) dC = 188.8 (2 ×
CHO), 163.5 (2- and 2ꢀ-C), 162.7 (6- and 6ꢀ-C), 130.6 (4- and 4ꢀ-C),
123.1 (3- and 3ꢀ-C), 116.4 (1- and 1ꢀ-C), 107.1 (5- and 5ꢀ-C), 63.0
(2 × OMe) and 56.1 (2 × OMe); HRMS: Found M+, 330.1093.
C18H18O6 requires M 330.1103; m/z (EI) 330 (M+, 79%), 299 (100),
283 (16), 255 (28), 239 (66), 219 (17), 179 (28), 155 (10), 142 (9),
115 (10), 91 (5), 69 (19) and 51 (5).
2,2ꢀ,6,6ꢀ-Tetramethoxy-1,1ꢀ-biphenyl 8
Into a flame dried RB flask fitted with a dropping funnel was
placed dry THF (50 ml), followed by 1,3-dimethoxybenzene
(3.47 ml, 3.66 g, 26.5 mmol). The solution was cooled down to
Diethyl 5,5ꢀ-diacetoxy-1,1ꢀ,3,3ꢀ-tetramethoxy-2,2ꢀ-binaphthalene-
7,7ꢀ-dicarboxylate 10
0
◦C. Once cooled, n-butyllithium (1.6 M in hexane, 16.6 ml,
26.5 mmol) was slowly added using the dropping funnel. The
solution was stirred at 0 ◦C for 1 h. Copper(I) iodide (5.05 g,
26.5 mmol), first purified by Soxhlet extraction using THF
and then dried overnight in an oven at 110 ◦C, was added in
portions, and the mixture was stirred at rt for another 2 h. The
dropping funnel was then charged with a solution of 2-iodo-1,3-
dimethoxybenzene 7 (6.36 g, 24.0 mmol) in dry pyridine (50 ml).
Once added, the dropping funnel was replaced with a condenser,
and the mixture was heated under reflux for 72 h. The product
mixture was then poured onto ice and acidified with concentrated
aqueous HCl (ca. 25 ml). The product was then extracted with
CH2Cl2 (3 × 80 ml). The organic extracts were then combined,
dried with anhydrous MgSO4, and the solvent was removed
in vacuo. The crude product was recrystallized from CH2Cl2–EtOH
to give 2,2ꢀ,6,6ꢀ-tetramethoxy-1,1ꢀ-biphenyl 8 (6.12 g, 93%). Mp =
In a two neck RB flask, fitted with a condenser, under Ar,
dicarbaldehyde 9 (1.53 g, 4.63 mmol) and diethyl succinate
(2.31 ml, 2.42 g, 13.9 mmol) were dissolved in dry tert-butyl
alcohol (20 ml). To this mixture was slowly added KOBut (1.56 g,
13.9 mmol). The resulting solution was heated under reflux for
2 h and then allowed to cool down to rt, poured into a separating
funnel containing ice and acidified to pH 3 with aqueous conc.
HCl. The product was then extracted with EtOAc (3 × 50 ml).
The combined organic extracts were then dried over anhydrous
MgSO4, filtered, and the solvent removed in vacuo. The resultant
oil was not purified or characterized, but used immediately in the
next step.
Into a two neck RB flask, fitted with a condenser, under Ar, the
Stobbe condensation product from above was dissolved in acetic
anhydride (80 ml). To this was added anhydr◦ous NaOAc (1.89 g,
23.2 mmol). The mixture was heated at 140 C for 2 h and then
allowed to cool. The acetic anhydride was removed in vacuo, water
(ca. 100 ml) was added, and the product extracted with CH2Cl2
(3 × 100 ml). The combined organic extracts were dried over
anhydrous MgSO4, filtered and the solvent removed in vacuo. The
crude material was purified by silica gel column chromatography
(30% EtOAc–hexane) to yield the product 10 as a bright yellow
◦
175–177 C (CH2Cl2–EtOH) (lit.15 174–175 ◦C); IR (CHCl3):
−1
mmax(cm ) = 1587 and 1451 (ArC C); 1H NMR (300 MHz,
=
CDCl3): dH = 7.28 (2H, t, J = 8.3, 4- and 4ꢀ-H), 6.65 (4H, d,
J = 8.3, 3-H, 3ꢀ-H, 5-H and 5ꢀ-H) and 3.71 (12H, s, 4 × OMe);
13C NMR (75 MHz, CDCl3) dC = 158.4 (2-C, 2ꢀ-C, 6-C and 6ꢀ-
C), 128.7 (4-C and 4ꢀ-C), 112.5 (1-C and 1ꢀ-C), 104.4 (3-C, 3ꢀ-C,
5-C and 5ꢀ-C) and 56.1 (4 × OMe); HRMS: Found M+, 274.1198.
C16H18O4 requires M 274.1205; m/z (EI) 274 (M+, 100%), 243 (7),
228 (11), 155 (5), 151 (52), 115 (18) and 91 (17).
solid (1.78 g, 60% over two steps). Mp = 268–272 ◦C (with sweating
starting at 258 ◦C); IR (CHCl3): mmax(cm ) = 1770, 1716, (C O),
−1
=
1
=
1627 (ArC C), 1498 and 1459; H NMR (300 MHz, CDCl3): dH =
2,2ꢀ,6,6ꢀ-Tetramethoxy[1,1ꢀ-biphenyl]-3,3ꢀ-dicarbaldehyde 9
8.77 (2H, s, 8- and 8ꢀ-H), 7.87 (2H, s, 6- and 6ꢀ-H), 7.01 (2H, s, 4-
and 4ꢀ-H), 4.43 (4H, q, J = 7.1, 2 × CH2CH3), 3.84 (6H, s, 2 ×
OMe), 3.64 (6H, s, 2 × OMe), 2.51 (6H, s, 2 × OAc) and 1.42
(6H, t, J = 7.1, 2 × CH2CH3); 13C NMR (75 MHz, CDCl3) dC =
169.4 (2 × OAc), 166.2 (2 × CO2Et), 159.2 (2 × ArC), 156.5 (2 ×
ArC), 145.7 (2 × ArC), 130.9 (2 × ArC), 125.2 (2 × ArC), 124.7
(2 × ArC), 123.9 (8- and 8ꢀ-C), 118.9 (6- and 6ꢀ-C), 117.8 (2 ×
ArC), 94.9 (4- and 4ꢀ-C), 61.9 (2 × OMe), 61.1 (2 × CH2CH3),
55.8 (2 × OMe), 21.0 (2 × OAc) and 14.4 (2 × CH2CH3); HRMS:
Into a two neck RB flask under argon, fitted with a rubber
septum, was added 2,2ꢀ,6,6ꢀ-tetramethoxy-1,1ꢀ-biphenyl 8 (0.70 g,
2.55 mmol) in dry CH2Cl2 (50 ml). To this solution was added
TiCl4 (1.12 ml, 1.93 g, 10.2 mmol) using a syringe. The solution
immediately changed to an orange colour. The reaction mixture
was then cooled down to −78 ◦C and dichloromethyl methyl ether
(0.64 ml, 0.82 g, 7.1 mmol) was then added. The solution changed
to a dark brown colour. Stirring at this temperature was continued
2436 | Org. Biomol. Chem., 2007, 5, 2433–2440
This journal is
The Royal Society of Chemistry 2007
©

View Online
Found M+, 634.2038. C34H34O12 requires M 634.2050; m/z (EI)
634 (M+, 2%), 512 (32), 470 (27), 428 (73), 382 (5), 54 (26) and 43
(18).
HRMS (ESI): Found [M + Na]+, 653.236. C36H38O10Na requires
M 653.2363; m/z (EI) 631 (M+ + 1, 22%), 630 (M+, 54), 590 (40),
589 (100), 561 (20), 548 (41), 315 (22) and 295 (26).
Diethyl 5,5ꢀ-dihydroxy-1,1ꢀ,3,3ꢀ-tetramethoxy-2,2ꢀ-binaphthalene-
7,7ꢀ-dicarboxylate 11
Diethyl 6,6ꢀ-diallyl-5,5ꢀ-dihydroxy-1,1ꢀ,3,3ꢀ-tetramethoxy-2,2ꢀ-
binaphthalene-7,7ꢀ-dicarboxylate
To a solution of guanidine hydrochloride (0.934 g, 9.78 mmol)
in dry EtOH (70 ml), stirring at room temperature under Ar was
added KOBut (1.10 g, 9.78 mmol) and the resulting suspension
stirred for 30 min. To this mixture was added the ester 10 (2.8 g,
4.44 mmol) dissolved in CH2Cl2 (70 ml) and stirring was continued
for 1.5 h. The reaction mixture was then poured into a beaker
containing water (100 ml) and acidified to pH 4 with conc. HCl.
The solution was then extracted with EtOAc (3 × 100 ml). The
organic extracts were combined and dried over anhydrous MgSO4,
filtered and the solvent removed in vacuo. The crude product
was purified by silica gel column chromatography (40% EtOAc–
hexane) to yield a yellow solid 11 (1.89 g, 78%). Mp = 283–288 ◦C;
The allylated phenol 12 (1.92 g, 3.04 mmol) was dissolved in DMF
(3.0 ml) and the solution transferred to a microwave vessel. The
reaction mixture was then subjected to microwave radiation at
a temperature of 170 ◦C and pressure of 250 psi with 200 W
of power for a period of 25 min with stirring. The light yellow
solution changed to a dark brown colour. This was transferred
to a separating funnel and washed with water (100 ml) and the
organic product extracted with CH2Cl2 (2 × 20 ml). The extracts
were dried over anhydrous MgSO4, filtered through Celite and the
solvent removed in vacuo. The dark brown viscous oil was purified
by column chromatography (40% EtOAc–hexane) to yield a yellow
foam (1.89 g, 98%) of diethyl 6,6ꢀ-diallyl-5,5ꢀ-dihydroxy-1,1ꢀ,3,3ꢀ-
−1
1
tetramethoxy-2,2ꢀ-binaphthalene-7,7ꢀ-dicarboxylate. Mp = 93–
=
IR (CHCl3): mmax(cm ) = 3413 (OH) and 1640 (ArC O); H NMR
(300 MHz, DMSO): dH = 10.51 (2H, s, 2 × OH), 8.15 (2H, br s,
8- and 8ꢀ-H), 7.45 (2H, d, J = 1.3, 6- and 6ꢀ-H), 7.42 (2H, s, 4- and
4ꢀ-H), 4.35 (4H, q, J = 6.9, 2 × CH2CH3). 3.81 (6H, s, 2 × OMe),
3.57 (6H, s, 2 × OMe) and 1.35 (6H, t, J = 7.0, 2 × CH2CH3);
13C NMR (75 MHz, DMSO) dC = 166.0 (2 × CO2Et), 157.5 (2 ×
ArC), 155.2 (2 × ArC), 152.7 (2 × ArC), 128.4 (2 × ArC), 125.1
(2 × ArC), 123.4 (2 × ArC), 117.6 (2 × ArC), 115.5 (2 × ArC),
107.4 (2 × ArC), 96.2 (4- and 4ꢀ-C), 61.1 (2 × OMe), 60.5 (2 ×
CH2CH3), 55.7 (2 × OMe), 14.2 (2 × CH2CH3); HRMS (ESI):
Found [M + Na]+, 573.174. C30H30O10Na requires M 573.1736;
m/z (EI) 551 (M+ + 1, 32%), 550 (M+, 100), 505 (13), 504 (18),
275 (30) and 216 (28).
98 ◦C; IR (CHCl3): mmax(cm ) = 3420 (OH), 1713 (ArC O) and
−1
=
1
=
1461 (C C); H NMR (300 MHz, CDCl3): dH = 8.36 (2H, s,
8 and 8ꢀ-H), 7.41 (2H, s, 4 and 4ꢀ-H), 6.25–6.07 (2H, m, 2 ×
=
CH2CH CH2), 5.84 (2H, s, 2 × OH), 5.30–5.22 (4H, m, 2 ×
=
CH2CH CH2), 4.45–4.34 (4H, m, 2 × CH2CH3), 3.96 (2H, br d,
=
J = 5.2, 2 × CH2CH CH2), 3.86 (6H, s, 2 × OMe), 3.62 (6H, s,
2 × OMe) and 1.41 (6H, t, J = 7.1, 2 × CH2CH3); 13C NMR
(75 MHz, CDCl3) dC = 168.2 (2 × CO2Et), 158.4 (2 × ArC), 155.7
=
(2 × ArC), 150.1 (2 × ArC), 136.4 (2 × CH2CH CH2), 128.1 (2 ×
ArC), 126.4 (2 × ArC), 122.6 (2 × ArC), 119.2 (C-8 and C-8ꢀ),
=
118.3 (2 × ArC), 117.4 (2 × ArC), 116.2 (2 × CH2CH CH2),
95.6 (C-4 and C-4ꢀ), 61.6 (2 × CH2CH3), 60.9 (2 × OMe), 55.8
=
(2 × OMe), 31.8 (2 × CH2CH CH2) and 14.3 (2 × CH2CH3);
HRMS (ESI): Found [M + Na]+, 653.235. C36H38O10Na requires
M 653.2363; m/z (EI) 631 (M+ + 1, 32%), 630 (M+, 100), 585 (8),
584 (10), 315 (17), 255 (30), 87 (62) and 55 (75).
Diethyl 5,5ꢀ-bis(allyloxy)-1,1ꢀ,3,3ꢀ-tetramethoxy-2,2ꢀ-
binaphthalene-7,7ꢀ-dicarboxylate 12
Allyl bromide (0.96 ml, 1.34 g, 11.1 mmol) and K2CO3 (1.53 g,
11.1 mmol) were added to a solution of the di-naphthol 11 (2.03 g,
3.69 mmol) in acetone (100 ml), stirring in a RB flask fitted with a
condenser. The mixture was stirred under reflux for 18 h. After this
time it was then allowed to cool to rt and filtered through Celite.
The acetone was then removed in vacuo and the light brown oil
was purified using silica gel column chromatography (30% EtOAc–
hexane) to yield the diallylated product 12 as a light yellow solid
Diethyl 6,6ꢀ-diallyl-5,5ꢀ-bis(benzyloxy)-1,1ꢀ,3,3ꢀ-tetramethoxy-
2,2ꢀ-binaphthalene-7,7ꢀ-dicarboxylate 13
In a two neck RB flask fitted with a condenser was placed a so-
lution of diethyl 6,6ꢀ-diallyl-5,5ꢀ-dihydroxy-1,1ꢀ,3,3ꢀ-tetramethoxy-
2,2ꢀ-binaphthalene-7,7ꢀ-dicarboxylate (1.10 g, 1.75 mmol) in ace-
tone (70 ml). To this yellow solution was added benzyl chloride
(0.40 ml, 0.46 g, 3.7 mmol), K2CO3 (0.51 g, 3.7 mmol) and KI
(0.61 g, 3.7 mmol). The mixture was stirred under reflux for 18 h.
After cooling to rt, the mixture was filtered through Celite and
the filtrate concentrated on a rotary evaporator. The resultant oil
was purified by silica gel column chromatography (10% EtOAc–
(1.95 g, 84%). Mp = 74–78 ◦C; IR (CHCl3): mmax(cm−1) = 1713
1
=
=
(ArC O), 1622, 1495 and 1461 (C C); H NMR (300 MHz,
CDCl3): dH = 8.51 (2H, br s, 8- and 8ꢀ-H), 7.54 (2H, s, 4- and
4ꢀ-H), 7.48 (2H, d, J = 1.1, 6- and 6ꢀ-H), 6.23 (4H, ddd, J =
=
17.3, 10.5, 5.2, 2 × CH2CH CH2), 5.57 (2H, dd, J = 17.3 and
=
1.5, trans-CH2CH CH2), 5.38 (2H, dd, J = 10.5 and 1.3, 2 ×
hexane) to give the product 13 as a yellow foam (1.28 g, 90%).
cis-CH2CH CH2), 4.84 (4H, br d, J = 5.2, 2 × CH2CH CH2),
4.50–4.37 (4H, m, 2 × CH2CH3), 3.88 (6H, s, 2 × OMe), 3.64
(6H, s, 2 × OMe) and 1.43 (6H, t, J = 7.1, 2 × CH2CH3); 13C NMR
(75 MHz, CDCl3) dC = 167.1 (2 × CO2Et), 158.4 (2 × ArC), 156.1
Mp = 55–57 ◦C; IR (CHCl3): mmax(cm ) = 1736 (ArC O) and
−1
=
=
=
1
=
1456 (C C); H NMR (300 MHz, CDCl3): dH = 8.52 (2H, s, 8 and
8ꢀ-H), 7.60–7.58 (4H, m, 4 × ArH), 7.47–7.34 (8H, m, 6 × ArH
ꢀ
=
and 4 and 4 -H), 6.18–6.03 (2H, m, 2 × CH2CH CH2), 5.12–4.91
=
=
(2 × ArC), 153.5 (2 × ArC), 133.2 (2 × CH2CH CH2), 129.7
(8H, m, 2 × CH2CH CH2 and 2 × CH2Ph), 4.39 (4H, q, J =
(2 × ArC), 125.3 (2 × ArC), 124.0 (2 × ArC), 118.8 (8- and 8ꢀ-C),
6.3, 2 × CH2CH3), 4.07 (4H, br d, J = 5.6, 2 × CH2CH CH2),
=
ꢀ
=
117.8 (2 × ArC), 117.6 (2 × CH2CH CH2), 105.2 (6- and 6 -C),
3.72 (6H, s, 2 × OMe), 3.62 (6H, s, 2 × OMe) and 1.41 (6H, t,
J = 7.1, 2 × CH2CH3); 13C NMR (75 MHz, CDCl3) dC = 168.0
(2 × CO2Et), 158.8 (2 × ArC), 156.2 (2 × ArC), 152.7 (2 × ArC),
ꢀ
=
96.2 (4- and 4 -C), 69.3 (2 × CH2CH CH2), 61.7 (2 × OMe),
60.9 (2 × CH2CH3), 55.9 (2 × OMe) and 14.4 (2 × CH2CH3);
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2433–2440 | 2437
©

View Online
=
137.9 (CH2CH CH2), 137.6 (2 × ArC), 131.7 (2 × ArC), 129.4
mixture was allowed to stir at rt for 18 h. This was followed
by filtration of the mixture through Celite and concentration of
the filtrate on a rotary evaporator. The crude oil was purified by
silica gel column chromatography (20% EtOAc–hexane) to yield
(2 × ArC), 128.7 (4 × ArCH), 128.1 (2 × ArCH), 127.6 (4 ×
ArCH), 127.0 (2 × ArC), 123.0 (2 × ArC), 122.9 (2 × ArC), 117.0
ꢀ
ꢀ
=
(8 and 8 -C), 115.0 (2 × CH2CH CH2), 96.2 (4 and 4 -C), 76.1
(2 × CH2Ph), 61.7 (2 × CH2CH3), 60.9 (2 × OMe), 55.7 (2 ×
the aldehyde 14 (0.61 g, 90%). Mp = 67–71 ◦C; IR (CHCl3):
−1
OMe), 31.0 (2 × CH2CH CH2) and 14.3 (2 × CH2CH3); HRMS
mmax(cm ) = 1691 (C O), 1614 and 1455 (C C); 1H NMR
=
=
=
(ESI): Found [M + H]+, 811.347. C51H50O10requires M 811.3481;
m/z (EI) 810 (M+, 3%), 721 (2), 720 (5), 719 (13), 555 (4), 92 (5),
91 (100) and 65 (6).
(300 MHz, CDCl3): dH = 10.24 (2H, s, 2 × CHO), 8.47 (2H, s, 8 and
8ꢀ-H), 7.60–7.57 (4H, m, 4 × ArH), 7.48–7.39 (6H, m, 6 × ArH),
ꢀ
=
7.28 (2H, s, 4 and 4 -H), 6.24–6.11 (2H, m, 2 × CH2CH CH2),
=
5.15–4.98 (4H, m, 2 × CH2CH CH2), 5.11 (4H, s, 2 × CH2Ph),
=
4.12 (4H, br d, J = 5.5, 2 × CH2CH CH2), 3.73 (6H, s, 2 × OMe)
1,1ꢀ-[6,6ꢀ-Diallyl-5,5ꢀ-bis(benzyloxy)-1,1ꢀ,3,3ꢀ-tetramethoxy-2,2ꢀ-
binaphthalene-7,7ꢀ-diyl]dimethanol
and 3.66 (6H, s, 2 × OMe); 13C NMR (75 MHz, CDCl3) dC
=
192.4 (2 × CHO), 159.8 (2 × ArC), 156.8 (2 × ArC), 152.9 (2 ×
ArC), 137.6 (2 × C), 137.4 (2 × C), 133.1 (2 × C), 131.0 (2 × C),
129.2 (2 × ArCH), 128.7 (4 × ArCH), 128.2 (2 × ArCH), 127.6
(4 × ArCH), 123.3 (2 × C), 117.0 (2 × C), 115.7 (8 and 8ꢀ-C), 96.6
(4 and 4ꢀ-C), 76.3 (2 × CH2Ph), 61.9 (2 × OMe), 55.8 (2 × OMe)
The ester 13 (0.70 g, 0.86 mmol) dissolved in dry THF (150 ml)
was placed into a flame-dried two neck RB flask under Ar.
The solution was cooled to 0 ◦C by means of an ice bath and
once cooled, LiAlH4 (0.13 g, 3.5 mmol) was added portion-wise
resulting in effervescence of the solution. The reaction mixture
was analyzed by TLC at 1 h intervals for the first few hours and
still showed starting material present. It was left to proceed at rt
overnight. After 18 h the TLC revealed that the reaction was still
not complete. However the reaction mixture was cooled down to
0 ◦C and water added drop-wise (approx. 10 ml) until the evolution
of gas had stopped. The emulsion formed was broken by adding a
10% solution of HCl (aq.) (ca. 5 ml). The mixture was transferred
to a separating funnel and the product was extracted using EtOAc
(2 × 25 ml) and CH2Cl2 (2 × 25 ml). The organic extracts were
combined, dried over anhydrous MgSO4, filtered through Celite
and the solvent finally removed in vacuo. The crude oil was purified
by silica gel column chromatography (50% EtOAc–hexane) to give
1,1ꢀ -[6,6ꢀ -diallyl-5,5ꢀ -bis(benzyloxy)-1,1ꢀ,3,3ꢀ -tetramethoxy-2,2ꢀ -
binaphthalene-7,7ꢀ-diyl]dimethanol (0.264 g, 42%); Mp = 86–
=
and 29.7 (2 × CH2CH CH2), one carbon not observed; HRMS
(ESI): Found [M + H]+, 723.295. C46H43O8 requires M 723.2958;
m/z (EI) 722 (M+, 2%), 633 (4), 632 (10), 631 (22), 92 (7), 91 (100)
and 65 (12).
1,1ꢀ-[6,6ꢀ-Diallyl-5,5ꢀ-bis(benzyloxy)-1,1ꢀ,3,3ꢀ-tetramethoxy-2,2ꢀ-
binaphthalene-7,7ꢀ-diyl]diethanol 15
Into a flame-dried two neck RB flask fitted with a condenser, under
Ar was placed oven dried Mg turnings (0.034 g, 1.4 mmol) and
dry Et2O (10 ml). To this suspension was added MeI (0.082 ml,
0.19 g, 1.3 mmol). The reaction mixture immediately became
cloudy. It was slowly stirred to allow the formation of the Grignard
reagent. Once most of the Mg metal had reacted, the aldehyde 14
(0.32 g, 0.44 mmol) dissolved in dry THF (10 ml) was added
dropwise to the cloudy reaction mixture. The now yellow solution
was allowed to stir at rt under Ar for a further 18 h. At this
point it had become milky orange in colour. Water (∼5 ml) was
carefully added to the reaction to quench the excess Grignard
reagent. The mixture was then transferred to a separating funnel
and the organic product extracted with EtOAc (3 × 50 ml) and
CH2Cl2 (3 × 50 ml). The organic extracts were combined, dried
over anhydrous MgSO4 and filtered through Celite. The solvent
was removed in vacuo and the yellow oily residue was purified by
silica gel column chromatography (30% EtOAc–hexane) to give the
secondary alcohol 15 (0.26 g, 79%). Mp = 85–90 ◦C; IR (CHCl3):
91 ◦C; IR (CHCl3): mmax(cm−1) = 3417 (OH), 1600, 1496 and 1455
(C C); H NMR (300 MHz, CDCl3): dH = 7.96 (2H, s, 8 and 8ꢀ-
1
=
H), 7.60–7.56 (4H, m, 4 × ArH), 7.47–7.30 (6H, m, 6 × ArH), 7.26
ꢀ
=
(1H, s, 4 and 4 -H), 6.20–6.08 (2H, m, 2 × CH2CH CH2), 5.14–
=
4.99 (4H, m, 2 × CH2CH CH2), 5.10 (4H, s, 2 × CH2Ph), 4.84
=
(4H, s, 2 × CH2OH), 3.83–3.69 (4H, br m, 2 × CH2CH CH2),
3.70 (6H, s, 2 × OMe), 3.61 (6H, s, 2 × OMe) and 1.84 (1H, s,
2 × OH); 13C NMR (75 MHz, CDCl3) dC = 157.2 (2 × ArC),
155.4 (2 × ArC), 152.6 (2 × ArC), 137.8 (2 × ArC), 137.7 (2 ×
=
CH2CH CH2), 135.7 (2 × ArC), 129.4 (2 × ArC), 128.6 (4 ×
ArCH), 128.0 (2 × ArCH), 127.5 (4 × ArCH), 124.0 (2 × ArC),
ꢀ
=
118.7 (2 × CH2CH CH2), 117.0 (2 × ArC), 115.5 (8 and 8 -C),
96.3 (4 and 4ꢀ-C), 76.0 (2 × CH2Ph), 64.1 (2 × CH2OH), 61.4 (2 ×
mmax(cm ) = 3415 (OH), 1627, 1596, 1496 and 1455 (C C); H
NMR (300 MHz, CDCl3): dH = 8.14 (2H, s, 8 and 8ꢀ-H), 7.60–
7.24 (10H, m, 2 × Ph), 7.25 (2H, s, 4 and 4ꢀ-H), 6.22–6.09 (2H,
−1
1
=
=
OMe) and 55.6 (2 × OMe) and 30.4 (2 × CH2CH CH2); HRMS
(ESI): Found [M + H]+, 727.327. C46H47O8 requires M 727.3271;
m/z (EI) 726 (M+, 2%), 637 (2), 636 (7), 635 (15), 92 (10), 91 (100)
and 65 (12).
=
m, 2 × CH2CH CH2), 5.25 (2H, q, J = 6.2, 2 × CH3(CH)OH),
=
5.12–4.97 (4H, m, 2 × CH2CH CH2), 5.10 (4H, s, 2 × CH2Ph),
=
3.92–3.79 (2H, m, 2 × CH2CH CH2), 3.71 (6H, s, 2 × OMe),
3.62 (6H, s, 2 × OMe), 1.88 (1H, s, 2 × OH) and 1.60 (6H, d, J =
6.2, 2 × Me(CH)OH); 13C NMR (75 MHz, CDCl3) dC = 157.1
(2 × ArC), 155.4 (2 × ArC), 152.3 (2 × ArC), 140.6 (2 × ArC),
137.9 (2 × C), 137.8 (2 × C), 137.8 (2 × C), 128.9 (2 × C), 128.6
(4 × ArCH), 128.0 (2 × ArCH), 127.5 (4 × ArCH), 127.1 (2 × C),
124.2 (2 × C), 117.0 (2 × C), 115.5 (8 and 8ꢀ-C), 96.1 (4 and 4ꢀ-C),
75.9 (2 × CH2Ph), 66.7 (2 × Me(CH)OH), 61.4 (2 × OMe), 55.6
6,6ꢀ-Diallyl-5,5ꢀ-bis(benzyloxy)-1,1ꢀ,3,3ꢀ-tetramethoxy-2,2ꢀ-
binaphthalene-7,7ꢀ-dicarbaldehyde 14
Pyridinium chlorochromate (0.81 g, 3.7 mmol) was dissolved
in MeCN (20 ml) and dried onto neutral alumina (8 g) using
a rotary evaporator. This bright orange solid was then added
to a solution of 1,1ꢀ-[6,6ꢀ-diallyl-5,5ꢀ-bis(benzyloxy)-1,1ꢀ,3,3ꢀ-
tetramethoxy-2,2ꢀ-binaphthalene-7,7ꢀ-diyl]dimethanol (0.68 g,
0.94 mmol) dissolved in CH2Cl2 (50 ml). The now dark reaction
=
(2 × OMe), 30.2 (2 × CH2CH CH2) and 24.5 (2 × Me(CH)OH);
HRMS (ESI): Found [M + Na]+, 777.340. C48H50O8Na requires
2438 | Org. Biomol. Chem., 2007, 5, 2433–2440
This journal is
The Royal Society of Chemistry 2007
©

View Online
ꢀ
M 777.3403; m/z (EI) 754 (M+, 1%), 665 (2), 664 (6), 663 (11),
dd, J = 16.5, and 2.5, 4a and 4a -H), 2.61 (2H, dd, J = 16.5, and
11.3, 4b and 4bꢀ-H), 1.62 (6H, d, J = 6.3, 1 and 1ꢀ-Me), 1.42 (6H,
d, J = 6.1, 3 and 3ꢀ-Me); 13C NMR (100 MHz, CDCl3 and 4 drops
DMSO) dC = 155.7 (2 × C), 154.3, 154.2 and 153.1 (2 × C), 147.9
and 147.8 (C-5 and C-5ꢀ), 135.5 and 135.4 (2 × C), 124.4 (2 ×
C), 122.8 and 122.7 (2 × C), 116.6 and 116.7 (2 × C and 10 and
10ꢀ-C), 109.0, 108.9 and 108.8 (2 × C), 95.5 (6 and 6ꢀ-C), 73.4 and
73.3 (1 and 1ꢀ-C), 70.2 (3 and 3ꢀ-C), 60.7 and 60.6 (×2) and 60.5
(2 × OMe), 55.5 (2 × OMe), 31.5 (4 and 4ꢀ-C), 21.9 (1-Me and
1ꢀ-Me), 21.7 (3-Me and 3ꢀ-Me); HRMS (ESI): Found [M + Na]+,
597.247. C34H38O8Na requires M 597.2465; m/z (EI) 576 (M+ + 2,
12%), 575 (M+ + 1, 37), 574 (M+, 100), 560 (7), 559 (32), 558 (93),
531 (4), 530 (11), 529 (17), 272 (37) and 258 (52).
92 (8), 91 (100) and 65 (10).
5,5ꢀ-Bis(benzyloxy)-7,7ꢀ,9,9ꢀ-tetramethoxy-1,1ꢀ,3,3ꢀ-tetramethyl-
1H,1ꢀH-8,8ꢀ-bibenzo[g]isochromene 16
To a solution of the secondary alcohol 15 (0.06 g, 0.08 mmol)
in DMF (5 ml), stirred at rt under O2 (g) (balloon) in a two
neck RB flask, was added CuCl2·2H2O (0.014 g, 0.08 mmol) and
PdCl2 (0.0014 g, 0.0081 mmol, 10 mol%) in water (5 ml). The
resultant suspension slowly changed from light yellow to dark
orange in colour and was left to stir at rt for 18 h. Work-up
of the reaction was accomplished by adding a 10% solution of
HCl (aq.) (10 ml) and the mixture was transferred to a separating
funnel. The organic product was extracted with EtOAc (3 × 30 ml)
and CH2Cl2 (30 ml). The organic extracts were combined, dried
over anhydrous MgSO4, filtered through Celite and the solvent
removed in vacuo. The crude yellow residue was purified by silica
gel column chromatography (30% EtOAc–hexane) to yield the
benzoisochromene 16 (0.048 g, 78%). Mp = 87–90 ◦C; IR (CHCl3):
7,7ꢀ,9,9ꢀ-Tetramethoxy-cis-1,3-cis-1ꢀ,3ꢀ-tetramethyl-3,3ꢀ,4,4ꢀ-
tetrahydro-1H,1ꢀH-8,8ꢀ-bibenzo[g]isochromene-5,5ꢀ,10,10ꢀ-tetrone
(mixture of diastereomers) 18
To
a
solution of the benzoisochromane 17 (0.10 g,
0.17 mmol) in DMF (10 ml), stirred at rt under an
O2 atmosphere (balloon) was added the salcomine complex
N,Nꢀ-bis(salicylidene)ethylenediaminocobalt(II) hydrate (0.062 g,
019 mmol). Stirring was continued at rt for 18 h. The reaction
mixture was then poured into a beaker containing ice water
(100 ml) and acidified to pH 3 by the dropwise addition of conc.
HCl (aq.). This mixture was transferred to a separating funnel
and the organic product extracted with CH2Cl2 (3 × 50 ml). The
organic extracts were combined, dried over anhydrous MgSO4,
filtered through Celite and the product purified by silica gel column
chromatography (40% EtOAc–hexane) to yield the quinone 18
(0.54 g, 51%). Mp = 174–177 ◦C (darkens above 132 ◦C); IR
−1
1
=
mmax(cm ) = 1599, 1496 and 1455 (C C); H NMR (300 MHz,
CDCl3): dH = 7.60–7.57 and 7.46–7.35 (12H, m, overlapping
signals 6 and 6ꢀ-H and 2 × Ph), 7.21 (2H, s, 10 and 10ꢀ-H), 6.05
(2H, s, 4 and 4ꢀ-H), 5.36–5.28 (2H, m, 1 and 1ꢀ-H), 5.11 (2H, d,
J = 11.8, 2 × one of CH2Ph), 5.06 (2H, d, J = 11.8, 2 × one of
CH2Ph), 3.71 (6H, s, 2 × OMe), 3.56 and 3.54 (6H, 2 × s, 2 ×
OMe), 2.00 (6H, s, 3 and 3ꢀ-Me), 1.70 (6H, d, J = 6.5, 1 and 1ꢀ-
Me); 13C NMR (75 MHz, CDCl3) dC = 157.1 (2 × C), 155.4 and
154.6 (2 × C), 154.4 (2 × C), 145.7 (2 × C), 137.9 (2 × C), 130.0
(2 × C), 129.5 (2 × C), 128.6 (4 × ArCH), 128.0 (2 × ArCH),
127.9 (2 × ArCH) and 127.8 (4 × ArCH), 123.4 (2 × C), 121.6
and 121.5 (2 × C), 116.1 and 116.0 (2 × C), 113.2 and 113.1 (C-10
and C-10ꢀ), 96.1 (C-6 and C-6ꢀ), 95.9 and 95.8 (C-4 and C-4ꢀ), 75.7
(C-5 and C-5ꢀ), 74.3 and 74.3 (C-1 and C-1ꢀ), 61.3 and 61.2 (2 ×
OMe), 55.7 (2 × OMe), 20.5 (1-Me and 1ꢀ-Me), 20.0 (3-Me and
3ꢀ-Me), some assignments were confirmed using C–H correlation
spectra; HRMS (ESI): Found [M + Na]+, 773.309. C48H46O8Na
requires M 773.3090; m/z (EI) 750 (M+, 2%), 661 (5), 660 (13), 659
(22), 571 (3), 570 (9), 569 (10), 285 (7), 289 (18), 92 (14), 91 (100)
and 65 (19).
−1
1
=
(CHCl3): mmax(cm ) = 1659 and 1573 (C O); H NMR (400 MHz,
CDCl3): dH = 7.53 (2H, s, 6 and 6ꢀ-H), 4.90–4.82 (2H, m, 1 and
1ꢀ-H), 3.87 (6H, s, 2 × OMe), 3.64, 3.63, 3.62 and 3.61 (8H, 4 × s
and overlapping m, 2 × OMe and 3 and 3ꢀ-H), 2.78 (2H, br d,
ꢀ
J = 18.4, 4a and 4a -H), 2.22 (2H, ddd, J = 18.5, 10.3 and 3.2,
4b and 4bꢀ-H), 1.54 (6H, d, J = 6.8, 1 and 1ꢀ-Me), 1.38 (6H, d,
J = 6.0, 3-Me and 3ꢀ-Me); 13C NMR (75 MHz, CDCl3) dC = 183.7
=
=
(2 × C O), 182.7 (2 × C O), 161.7, 161.6, 161.5 and 161.4 (C-7
and C-7ꢀ)a, 159.7, 159.6, 159.5 and 159.4 (C-9 and C-9ꢀ)a, 148.7
and 148.6 (C-10a and C-10aꢀ), 140.0, 139.9 and 139.8 (C-4a and
C-4aꢀ), 135.3 and 135.2 (C-5a and C-5aꢀ), 123.5, 123.4 and 123.3
(C-8 and C-8ꢀ), 119.1, 118.9, 118.8 and 118.7 (C-9a and C-9aꢀ),
104.7 (C-6 and C-6ꢀ), 70.2 (C-1 and C-1ꢀ), 68.7 (C-3 and C-3ꢀ),
61.9, 61.8 and 61.7 (2 × OMe), 56.3 (×2) (2 × OMe), 30.0 (C-4
and C-4ꢀ), 21.2 (1-Me and 1ꢀ-Me), 20.9, 20.8 and 20.7 (3-Me and 3ꢀ-
Me), assignments with the same superscript may be interchanged;
HRMS (ESI): Found [M + Na]+, 625.205. C34H34O10Na requires
M 625.2050; m/z (EI) 604 (M+ + 2, 12%), 603 (M+ + 1, 33), 602
(M+, 100), 544 (13), 543 (34), 497 (7), 469 (9), 286 (18), 279 (25),
264 (27) and 257 (37).
7,7ꢀ,9,9ꢀ-Tetramethoxy-cis-1,3-cis-1ꢀ,3ꢀ-tetramethyl-3,3ꢀ,4,4ꢀ-
tetrahydro-1H,1ꢀH-8,8ꢀ-bibenzo[g]isochromene-5,5ꢀ-diol (mixture
of diastereomers) 17
To a solution of the benzoisochromene 16 (0.16 g, 0.021 mmol)
in a 3 : 1 CH2Cl2–dioxane mixture (40 ml), stirred at rt under
H2 (g) (balloon) was added 10% w/w palladium on charcoal
(0.016 g) and stirring was continued for 18 h. The reaction mixture
was then filtered through Celite, the filtrate concentrated on a
rotary evaporator and the resultant yellow oil purified by column
chromatography (40% EtOAc–hexane) to give the unprotected
benzoisochromane 17 (0.12 g, 100%) as a flaky off white solid.
9,9ꢀ-Dihydroxy-7,7ꢀ-dimethoxy-cis-1,3-cis-1ꢀ,3ꢀ-tetramethyl-
3,3ꢀ,4,4ꢀ-tetrahydro-1H,1ꢀH-8,8ꢀ-bibenzo[g]isochromene-
5,5ꢀ,10,10ꢀ-tetrone (mixture of diastereomers) 3 (cardinalin 3)
Mp = >300 ◦C; IR (CHCl3): mmax(cm−1) = 3424 (OH), 1601, 1495
1
=
and 1457 (C C); H NMR (400 MHz, CDCl3 + drop DMSO):
dH = 8.54 (2H, br s, 2 × OH), 7.46 (2H, s, 10 and 10ꢀ-H), 7.39 and
7.37 (2H, 2 × br s, 6 and 6ꢀ-H), 5.00–4.93 (2H, m, 1 and 1ꢀ-H),
3.89–3.83 (2H, m, 3 and 3ꢀ-H), 3.81, 3.80 and 3.80 (6H, 3 × s, 2 ×
OMe), 3.58, 3.57, 3.54 and 3.53 (6H, 4 × s, 2 × OMe), 3.04 (2H,
In a flame-dried two neck RB flask under Ar, a solution of the
dimethoxy quinone 18 (40 mg, 0.066 mmol) in dry CH2Cl2 (10 ml)
was cooled to 0 ◦C and to this was added the BCl3 solution (0.27 ml,
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2433–2440 | 2439
©

View Online
1.0 M in CH2Cl2). The reaction mixture immediately changed from
a light yellow colour to a dark red colour. Analysis of the reaction
mixture by TLC showed a new yellow spot at a slightly higher Rf
and the absence of the starting material. The reaction still at 0 ◦C
was quenched with water, transferred to a separating funnel and
the organic product extracted with CH2Cl2 (3 × 20 ml). The solvent
was dried over anhydrous MgSO4, filtered and the solvent removed
in vacuo. The crude material was dried over silica and purified by
silica gel column chromatography (30% EtOAc–hexane) to yield
racemic cardinalin 3 3 as a yellow powder (24 mg, 64%). Mp = 236–
Council) and the Mellon Postgraduate Mentoring Programme
(sponsored by the Andrew W. Mellon Foundation). SG and EMM
thank the Department of Labour (DoL) for Scarce Skills Schol-
arships. R. Mampa of this University is thanked for providing the
NMR service. Dr M. Scha¨fer of the University of Ko¨ln (Germany)
is thanked for providing the mass spectroscopy service.
References and notes
1 M. Gill, M. S. Buchanan and J. Yu, J. Chem. Soc., Perkin Trans. 1,
1997, 919.
2 M. Gill, M. S. Buchanan and J. Yu, Aust. J. Chem., 1997, 50, 1081.
3 S. R. Jammula, S. B. Pepalla, H. Telikepalli, K. V. J. Rao and R. H.
Thomson, Phytochemistry, 1991, 30, 3741.
4 D. W. Cameron, G. I. Feutrill and G. A. Pietersz, Aust. J. Chem., 1982,
35, 1481.
5 E. M. Mmutlane, J. P. Michael, I. R. Green and C. B. de Koning, Org.
Biomol. Chem., 2004, 2, 2461.
241 ◦C (darkening of the crystals above 145 ◦C) (lit.1 213–220 ◦C);
−1
=
IR (CHCl3): mmax(cm ) = 3450 (OH), 1660 and 1636 (C O);
NMR assignments were made by comparison with the literature
data. As a mixture of diastereoisomers was obtained assignments
with the same chemical shift as the natural product were assigned
1
according to the axial chirality of the natural product (S). H
NMR (400 MHz, CDCl3): dH = 12.352 and 12.349 [2H, s, (S)-2 ×
OH], 12.31 and 12.30 [2H, s, 2 × OH], 7.331 [2H, s, (S)-6 and
6ꢀ-H], 7.329 [2H, s, 6 and 6ꢀ-H], 4.95–4.80 (2H, m, 1 and 1ꢀ-H),
3.91 [6H, s, (S)-2 × OMe], 3.90 [6H, s, 2 × OMe], 3.67–3.47 (2H,
6 L. M. Tewierk, C. Dimitriadis, M. Gill and B. Willems, Org. Biomol.
Chem., 2006, 4, 3311.
7 For a review see: (a) M. Vrettou, A. A. Gray, A. R. E. Brewer and
A. G. M. Barrett, Tetrahedron, 2007, 63, 1487; (b) W.-X. Hong, L.-J.
Chen, C.-L. Zhong and Z.-J. Yao, Org. Lett., 2006, 8, 4919; (c) F. M.
Hauser and P. J. F. Gauuan, Org. Lett., 1999, 1, 671; (d) D. Drochner,
W. Huttel, S. E. Bode, M. Muller, U. Karl, M. Nieger and W. Steglich,
Eur. J. Org. Chem., 2007, 1749.
8 J. C. Anderson and D. J. Pearson, J. Chem. Soc., Perkin Trans. 1, 1998,
2023.
9 J. Hassan, M. Se´vignon, C. Gozzi, E. Schulz and M. Lemaire, Chem.
Rev., 2002, 102, 1359.
ꢀ
m, 3 and 3ꢀ-H), 2.76 (2H, dt, J = 18.7 and 2.4, 4a and 4a -H),
2.26 (2H, ddd, J = 18.6, 10.0 and 3.9, 4b and 4bꢀ-H), 1.58 [6H,
d, J = 6.5, (S)-1 and 1ꢀ-Me], 1.57 [6H, d, J = 6.5, 1 and 1ꢀ-Me],
1.37 (6H, d, J = 6.1, 3 and 3ꢀ-Me); 13C NMR (100 MHz, CDCl3)
ꢀ
=
=
dC = 187.9 (2 × C O), 183.2 (2 × C O), 163.2 (C-7 and C-7 ),
161.0, 161.0 and 160.9 (C-9 and C-9ꢀ), 146.7 and 146.7 (C-10a and
C-10aꢀ), 143.1 and 143.0 (C-4a and C-4aꢀ), 133.2 (C-5a and C-5aꢀ),
114.5 (C-8 and C-8ꢀ), 110.2 (C-9a and C-9aꢀ), 102.7 (C-6 and C-
6ꢀ), 69.8 (C-1 and C-1ꢀ), 68.7 (C-3 and C-3ꢀ), 56.6 and 56.5 (2 ×
OMe), 30.6 and 30.6 (C-4 and C-4ꢀ), 21.3 (1-Me and 1ꢀ-Me) and
21.2 (3-Me and 3ꢀ-Me); HRMS (ESI): Found [M + Na]+, 597.174.
C32H30O10Na requires M 597.1736; m/z (EI) 576 (M+ + 2, 5%),
575 (M+ + 1, 27), 574 (M+, 100), 530 (12), 515 (35), 271 (35), 244
(37), 243 (91) and 98 (87).
10 H. Gross, A. Rieche and G. Mattey, Chem. Ber., 1963, 96, 308.
11 C. J. Davis, T E. Hurst, A. M. Jacob and C. J. Moody, J. Org. Chem.,
2005, 70, 4414.
12 For example, LiBH4–MeOH, (a) K. Soai and A. Ookawa, J. Org.
Chem., 1986, 51, 4000; (b) NaBH4–MeOH, K. Luthman, M. Orbe,
T. Waglund and A. Claesson, J. Org. Chem., 1987, 52, 3777; (c) Na–
EtOH, S. G. Ford and C. S. Marrel, Org. Synth., 1943, Coll. Vol. II,
372–374; (d) LiBH4–toluene, H. C. Brown, S. Narasimhan and Y. M.
Choi, J. Org. Chem., 1982, 47, 4708; (e) L-Selectride, A. B. Bueno,
M. C. Carren˜o, J. L. G. Ruano, B. Pen˜a, A. Rubio and M. A. Hoyos,
Tetrahedron, 1994, 50, 9355.
13 For trans-1,3-dimethyl aromatic-fused pyrans the signal for H-3
appears between d 4.0–4.2, while for the corresponding cis-compound
the signal for H-3 appears between d 3.5–3.9.
Acknowledgements
14 U. Azzena, T. Denurra, G. Melloni and A. M. Piroddi, J. Org. Chem.,
This work was supported by the National Research Foundation
(NRF, GUN 2053652), Pretoria, the University of the Witwa-
tersrand (University Research Council and Faculty Research
1990, 55, 5386.
15 G. Lindson, O. Wennerstom and R. Isakson, J. Org. Chem., 1987, 52,
547.
2440 | Org. Biomol. Chem., 2007, 5, 2433–2440
This journal is
The Royal Society of Chemistry 2007
©