Wacker oxidation methodology for the synthesis of the benzo-fused acetal core of marticin

Article abstract of DOI:10.1016/j.tet.2012.06.052

Methodology for the synthesis of the benzo-fused acetal core of marticin is described in this paper. Condensation of readily available 1-(2-allyl-3,6- dimethoxyphenyl)ethanone with diethyl oxalate under Claisen condensation conditions furnished (Z)-ethyl

Full text of DOI:10.1016/j.tet.2012.06.052

Tetrahedron 68 (2012) 7116e7121
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Wacker oxidation methodology for the synthesis of the benzo-fused acetal core
of marticin
y
*
Adushan Pillay, Amanda L. Rousseau, Manuel A. Fernandes , Charles B. de Koning
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits 2050, Johannesburg, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Methodology for the synthesis of the benzo-fused acetal core of marticin is described in this paper.
Condensation of readily available 1-(2-allyl-3,6-dimethoxyphenyl)ethanone with diethyl oxalate under
Claisen condensation conditions furnished (Z)-ethyl 4-(2-allyl-3,6-dimethoxyphenyl)-2-hydroxy-4-
oxobut-2-enoate. Treatment of this with LiAlH4 resulted in the formation of the diol, 1-(2-allyl-3,6-
dimethoxyphenyl)-3,4-dihydroxybutan-1-one. Conversion of primary alcohol of the diol into the
TBDMS ether followed by further reaction with LiAlH4 and exposure to Wacker oxidation conditions
resulted in the formation of (3,6-dimethoxy-9-methyl-10,13-dioxatricyclo[7.3.1.02,7]trideca-2,4,6-trien-
11-yl)methanol, the core of marticin.
Received 23 March 2012
Received in revised form 24 May 2012
Accepted 12 June 2012
Available online 23 June 2012
Keywords:
Marticin
Wacker oxidation
Acetal-containing naphthoquinones
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
the mycotoxin aflatoxins B1 and G1,2 while isagarin 4 is a tetracyclic
naphthoquinone isolated from the roots of Pentas longiflora Oliv.
An interesting class of quinone containing compounds pos-
sessing a fused cyclic acetal is shown in Fig. 1. Thus far, four ex-
amples of these quinones have been isolated from nature,
including marticin 1 and isomarticin 2, napthazirin phytotoxins
that are produced by Fusarium solani and Fusarium martii.1 Aver-
ufin 3 is a decaketide quinone intermediate in the biosynthesis of
(Rubiaceae).3 All of these compounds contain either a 6,6-bicyclic
fused naphthopyran ring system or a 6,5-bicyclic fused ring
system.
Marticin and isomarticin are reported to be toxic at low pH to
tomatoes and peas4 causing extensive damage to plant tissue.2 The
marticins also possess some antimicrobial activity and were found
to be active against Staphylococcus aureus (128
mg/mL) and Staph-
ylococcus pyogenes (128 g/mL). The toxic mechanism of action of
m
the marticins in higher plants still remains to be elucidated, but it is
possible that inhibition of malate or citrate dehydration in the citric
acid cycle occurs.
Isagarin was first synthesized by De Kimpe et al.5 in 1999 and
more recently by Ploysuk.6 In the last two years stereoselective
syntheses of isagarin have been disclosed by De Kimpe7 and Fer-
nandes,8 while the more complex quinone averufin was first syn-
thesized in 1981.9 However, there are no reported syntheses of the
cyclic acetals, marticin or isomarticin.
With our experience in using the Wacker oxidation methodol-
ogy for the synthesis of isochromanes such as cardinalin 3,10 we
believed that it may be possible to develop this methodology for
the synthesis of the marticin and isomarticin skeletons. As such, we
planned to synthesize the triol 5 and subject this to Wacker oxi-
dation conditions for our synthesis of acetal 6 (Fig. 2). This would
represent the first synthesis of the benzo-fused acetal skeleton of
the marticins. Examination of the literature revealed that a similar
approach had been adopted for the synthesis of the cyclic acetal 8
from the non-aromatic triol 7.11
Fig. 1. Acetal-containing quinones.
* Corresponding author. Tel.: þ27 11 717 6724; fax: þ27 11 717 6749; e-mail
address: Charles.deKoning@wits.ac.za (C.B. de Koning).
y
For correspondence regarding crystallography.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.052

A. Pillay et al. / Tetrahedron 68 (2012) 7116e7121
7117
Fig. 2. Wacker oxidations for the formation of acetals.
Scheme 2. (a) LiAlH4, THF, 10 ꢀC/rt, 34%; (b) LiAlH4, THF, reflux, 62%; (c) 10% PdCl2,
CuCl2$2H2O, DMF and H2O, O2, 72%.
2. Results and discussion
selectively protected as the TBS ether to afford 16 in reasonable yield
(Scheme 3). The resulting product 16 was then treated with LiAlH4
under reflux for 2 h. The presumed intermediate triol 5 (1:1.8 ratio of
diastereoisomers by 1H NMR spectroscopy) was subjected to our
normal Wacker oxidation conditions without purification to afford
the required tricyclic acetal 6 as a mixture of diastereoisomers (1:2.3
ratio) in 67% yield over the two steps. Clear evidence for the mixture
can be found by examining the 1H NMR spectra. An X-ray crystal
structure proved the identity of the desired product (Fig. 3). Oxi-
dation of 6 with CAN yielded the quinone 17 in good yield.
As a first attempt, ketone 9, readily synthesized from 2,5-
dihydroxyacetophenone in three steps,12 was condensed with
diethyl oxalate under Claisen condensation conditions to afford 10.
Reduction of 10 with NaBH4 resulted in reduction of only one of the
ketone functional groups to yield 11. While this was not our desired
triol, we attempted Wacker oxidation of 11 in order to assess the po-
tential of this system to produce a cyclic hemiacetal. However, under
these conditions, we were only able to isolate ketone 12 (Scheme 1).
Scheme 1. (a) (i) (COOEt)2, NaOEt, THF, 0 ꢀC/rt, (ii) aq HCl, 90%; (b) NaBH4, THF,
0
ꢀC/rt, 40%; (c) 10% PdCl2, CuCl2$2H2O, DMF, O2, 67%.
Scheme 3. (a) TBDMSCl, imidazole, MeCN, 64%; (b) LiAlH4, THF, ꢁ10 ꢀC/reflux; (c)
10% PdCl2, CuCl2$2H2O, DMF and H2O, O2, 67%; (d) CAN, MeCN/H2O, 89%.
Therefore, compound 10 was treated with LiAlH4 and stirred at
rt for 2 h. This resulted in the formation of the diol 13 as shown in
Scheme 2. In an attempt to facilitate conversion to the desired triol
5, the diol 13 was treated with LiAlH4 in THF at reflux for 3 h.
Frustratingly, this resulted in the formation of the 1,4-diol 14.
With diol 14 in hand, we once again assessed the potential to
construct a cyclic acetal under Wacker oxidation conditions, al-
though for our purposes, the product would contain the wrong size
acetal rings. Nevertheless, exposure of 14 to catalytic PdCl2, CuCl2
and oxygen resulted in the formation of the tricyclic compound 15
containing a cyclic acetal. As this was successful, we believed that if
the required triol 5 could be formed, even as an intermediate, we
would be able to assemble the skeleton of marticin.
We believed that diol 14 was being formed by elimination of
water from 13 to form an enol, which would tautomerise to an al-
dehyde, followed by reduction of both the benzylic ketone and the
resulting aldehyde. As such, we decided that protection of the pri-
mary alcohol of 13 as the TBS ether may prevent the elimination of
water taking place. Fortunately, the primary alcohol of 13 was
Fig. 3. Separated ORTEP diagrams of the diastereoisomeric mixture of 6a (major) and
6b (minor) (50% probability level). Note position of hydrogen on atom labelled C9 of
both diastereoisomers.13

7118
A. Pillay et al. / Tetrahedron 68 (2012) 7116e7121
In summary, for the first time we have been able to develop
1-(2-allyl-3,6-dihydroxyphenyl)ethanone as a yellow oil (4.26 g,
methodology for the synthesis of the tricyclic core of marticin.
Starting from 2,4-dihydroxyacetophenone the tricyclic quinone
containing acetal portion of marticin 17 was synthesized in nine
steps with an overall yield of 6%. Disappointingly, the apparently
trivial reduction of 10 to 13 only proceeded in 34% yield. However,
the key Wacker step proceeded to afford compound 6 in a reason-
able yield of 67%. The synthesis of marticin using this methodology
is currently underway.
73%); 1H NMR (300 MHz, acetone) dH¼8.39 (1H, br s, OH), 7.93 (1H,
br s, OH), 6.79 (1H, d, J 8.7, H-40
*
), 6.66 (1H, d, J 8.7, H-50
), 5.92 (1H,
*
ddt, J 16.5, 10.2, 6.3, ArCH2CH]CH2), 5.00e4.88 (2H, m, ArCH2CH]
CH2), 3.36 (2H, d, J 6.3, ArCH2CH]CH2), 2.48 (3H, s, COCH3); 13C
NMR (75 MHz, acetone) dC¼205.4 (C]O), 149.0, 148.2, 137.8
(ArCH2CH]CH2), 131.3, 124.3, 117.8 (C-50), 115.3 (C-40), 115.3
(ArCH2CH]CH2), 32.6 (COCH3), 31.4 (ArCH2CH]CH2). The in-
termediate, 1-(2-allyl-3,6-dihydroxyphenyl)ethanone
(3.68 g,
19.1 mmol), anhydrous K2CO3 (7.94 g, 57.4 mmol) and Me2SO4
(9.66 g, 75.6 mmol) were dissolved in Me2CO (200 mL). The solu-
tion was then heated at reflux for 24 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 (100 mL) and was successively washed with
aqueous NH3 (25%, 3ꢂ50 mL), HCl (0.5 M, 2ꢂ50 mL) and H2O
(100 mL). The EtOAc layer was dried over anhydrous MgSO4, fil-
tered and concentrated under reduced pressure. Column chroma-
tography (10% EtOAc/hexane) of the residue afforded 1-(2-allyl-3,6-
dimethoxyphenyl)ethanone 9 as a yellow oil (3.20 g, 76%); Rf¼0.24
(30% EtOAc/hexane); 1H NMR (300 MHz, CDCl3) dH¼6.77 (1H, d, J
3. Experimental
3.1. General
1H NMR and 13C NMR spectra were recorded either on a Bruker
AVANCE 300 spectrometer or a Bruker AVANCE III 500 spectrom-
eter. All spectra were recorded in CDCl3, or acetone-d6. All chemical
shift values are reported in parts per million referenced against
TMS, which is given an assignment of zero parts per million. Cou-
pling constants (J-values) are given in Hertz (Hz). Assignments
were made using a range of 2D NMR experiments. However, as-
signments with the same superscript (
*
) may be interchanged. All
9.0, H-40
*
), 6.69 (1H, d, J 9.0, H-50
), 5.86 (1H, ddt, J 18.0, 9.3, 6.2,
*
mass spectroscopy data were collected on a Waters Micromass LCT
TOF Mass Spectrometer. The sample was dissolved in MeOH to
a concentration of 2 ng/mL and introduced by direct infusion. The
ArCH2CH]CH2), 4.96e4.86 (2H, m, ArCH2CH]CH2), 3.72 (3H, s,
OCH3), 3.70 (3H, s, OCH3), 3.28 (2H, br d, J 6.3, ArCH2CH]CH2), 2.42
(3H, s, COCH3); 13C NMR (75 MHz, CDCl3) dC¼205.1 (C]O), 151.8,
149.8, 136.5 (ArCH2CH]CH2), 132.8, 125.5, 115.1 (ArCH2CH]CH2),
111.6 (C-40), 109.4 (C-50), 55.9 (2ꢂOCH3), 32.3 (COCH3), 30.7
(ArCH2CH]CH2).14 The spectroscopic data agreed with that
reported in the literature.
ionization 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. Infrared spectra were recorded on a Bruker Tensor 27
standard system spectrometer. Macherey-Nagel Kieselgel 60 (par-
ticle size 0.063e0.200 mm) was used for conventional silica gel
column chromatography with various EtOAc and hexane mixtures
as the mobile phase. TLC was performed on aluminium-backed
Macherey-Nagel Alugram Sil G/UV254 plates pre-coated with
0.25 mm silica gel 60. In vacuo refers to the solvent evaporated
under reduced pressure utilizing a rotary evaporator.
3.4. Ethyl-(Z)-4-(2-allyl-3,6-dimethoxyphenyl)-2-hydroxy-4-
oxobut-2-enoate 10
To a stirred solution of 1-(2-allyl-3,6-dihydroxyphenyl)etha-
none 9 (3.00 g, 13.6 mmol) and diethyl oxalate (3.98 g, 27.2 mmol)
in dry THF (50 mL) at 0 ꢀC, NaOEt (1.85 g, 27.2 mmol) was slowly
added. The reaction mixture was then stirred vigorously for 3 h at rt
before being acidified with aqueous HCl (100 mL, 2.0 M). EtOAc
(100 mL) was then added to the mixture. The organic layer was
then separated, dried over anhydrous MgSO4, filtered and con-
centrated under reduced pressure. Column chromatography (10%
EtOAc/hexane) of the residue afforded ethyl-(Z)-4-(2-allyl-3,6-
dimethoxyphenyl)-2-hydroxy-4-oxobut-2-enoate 10 as a yellow
solid (3.92 g, 90%); Rf¼0.55 (20% EtOAc/hexane); mp¼65e66 ꢀC; IR
nmax (cmꢁ1)¼3007 (OH), 1738 (C]O), 1730 (C]O), 1625 (C]C),
1597 (C]C), 1228, 1216; 1H NMR (300 MHz, CDCl3) dH¼14.30 (1H,
3.2. 1-(5-Allyloxy-2-hydroxyphenyl)ethanone
2,5-Dihydroxyacetophenone (8.00 g, 52.6 mmol) was dissolved
in Me2CO (300 mL) in a round-bottom flask (500 mL) equipped
with a reflux condenser and a magnetic stirrer bar. Allyl bromide
(8.28 g, 68.4 mmol) and anhydrous K2CO3 (9.45 g, 68.4 mmol) were
added to the solution, which was then heated at reflux 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 residue was purified by column chromatography (20%
EtOAc/hexane) to afford 1-(5-allyloxy-2-hydroxyphenyl)ethanone
(8.69 g, 86%) as a yellow crystalline solid; Rf¼0.79 (20% EtOAc/
hexane); mp¼60e61 ꢀC; 1H NMR (300 MHz, CDCl3) dH¼11.84 (1H,
s, OH), 7.16 (1H, d, J 3.0, H-60), 7.08 (1H, dd, J 9.0, 3.0, H-40), 6.86 (1H,
d, J 9.0, H-30), 6.02 (1H, ddt, J 17.2, 10.5, 5.3, OCH2CH]CH2), 5.38
(1H, dt, J 17.2, 3.6, one of OCH2CH]CH2), 5.28 (1H, dd, J 10.5,1.3, one
of OCH2CH]CH2), 4.47 (2H, dt, J 5.3,1.3, OCH2CH]CH2), 2.56 (3H, s,
COCH3); 13C NMR (75 MHz, CDCl3) dC¼204.0 (C]O), 156.8, 150.6,
133.1 (OCH2CH]CH2), 124.9 (C-30), 119.2, 119.1 (C-60), 117.8
(OCH2CH]CH2), 114.9 (C-40), 69.8 (OCH2CH]CH2), 26.6 (COCH3).12
The spectroscopic data agreed with that reported in the literature.
br s, OH), 6.89 (1H, d, J 9.0, H-40
s, COCH]C(OH)CO2Et), 5.87 (1H, ddt, J 16.6, 10.3, 6.2, ArCH2CH]
CH2), 4.97e4.84 (2H, m, ArCH2CH]CH2), 4.34 (2H, q, 7.1,
*
), 6.77 (1H, d, J 9.0, H-50
), 6.57 (1H,
*
J
CO2CH2CH3), 3.78 (3H, s, OCH3), 3.75 (3H, s, OCH3), 3.35 (2H, d, J 6.2,
ArCH2CH]CH2), 1.35 (3H, t, J 7.1, CO2CH2CH3); 13C NMR (75 MHz,
CDCl3) dC¼197.6 (C]O), 164.5 (COCH]C(OH)CO2Et), 162.3 (COCH]
C(OH)CO2Et), 151.8, 150.5, 136.1 (ArCH2CH]CH2), 128.8, 127.5, 115.3
(ArCH2CH]CH2), 113.15 (C-40), 109.7 (C-50), 105.9 (COCH]C(OH)
CO2Et), 62.8 (CO2CH2CH3), 56.2 (2ꢂOCH3), 30.9 (ArCH2CH]CH2),
13.9 (CO2CH2CH3); HR-TOF-MS: m/z found 321.1338 [MþH]þ (cal-
culated for C17H21O6, 321.1342).
3.3. 1-(2-Allyl-3,6-dimethoxyphenyl)ethanone 9
3.5. Ethyl 4-(2-allyl-3,6-dimethoxyphenyl)-2-hydroxy-4-
oxobutanoate 11
1-[5-(Allyloxy)-2-hydroxyphenyl]ethanone (5.82 g, 30.3 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 140 ꢀC for 18 h under a N2(g) atmosphere.
The dark viscous residue was allowed to cool to rt and was then
purified via column chromatography (15% EtOAc/hexane) to yield
Ethyl-(Z)-4-(2-allyl-3,6-dimethoxyphenyl)-2-hydroxy-4-oxobut-
2-enoate 10 (3.00 g, 9.37 mmol) was dissolved in dry THF (50 mL)
and cooled to 0 ꢀC in an ice bath. Sodium borohydride (0.711 g,
18.7 mmol) was added to the stirred reaction solution over 15 min.
The reaction mixture was then stirred vigorously for 2 h at rt, before

A. Pillay et al. / Tetrahedron 68 (2012) 7116e7121
7119
being acidified with a dilute aqueous solution of HCl (100 mL, 0.5 M).
Once the fizzing stopped, the mixture was extracted with EtOAc
(100 mL). The organic layer was then separated, dried over anhy-
drous MgSO4, filtered and concentrated under reduced
pressure. Column chromatography (20% EtOAc/hexane) of the resi-
due afforded ethyl 4-(2-allyl-3,6-dimethoxyphenyl)-2-hydroxy-4-
oxobutanoate 11 as a yellow oil (1.20 g, 40%); Rf¼0.15 (30% EtOAc/
hexane); IR nmax (cmꢁ1)¼3015 (OH), 1738 (C]O), 1588 (C]C), 1228,
hexane); IR nmax (cmꢁ1)¼3015 (OH), 1738 (C]O), 1595 (C]C), 1255,
1228; 1H NMR (300 MHz, CDCl3) dH¼6.78 (1H, d, J 9.0, H-40)
*
, 6.69
(1H, d, J 9.0, H-50)
, 5.92e5.76 (1H, m, ArCH2CH]CH2), 4.95e4.85
*
(2H, m, ArCH2CH]CH2), 4.31e4.21 (1H, m, COCH2CH(OH)CH2OH),
3.72 (3H, s, OCH3), 3.70 (3H, s, OCH3), 3.63 (1H, dd, J 11.7, 2.8, one of
COCH2CH(OH)CH2OH and OH), 3.48 (1H, dd, J 11.3, 6.6, one of
COCH2CH(OH)CH2OH), 3.25 (2H, d, J 5.0, ArCH2CH]CH2), 2.92 (2H, d,
J 6.1, COCH2CH(OH)CH2OH); 13C NMR (75 MHz, CDCl3) dC¼207.3 (C]
O), 151.8, 149.7, 136.4 (ArCH2CH]CH2), 131.6, 126.3, 115.3
1216; 1H NMR (300 MHz, CDCl3) dH¼6.82 (1H, d, J 9.0, H-40)
*
, 6.72
(1H, d, J 9.0, H-50)
*
, 5.97e5.81 (1H, m, ArCH2CH]CH2), 5.01e4.90
(ArCH2CH]CH2), 112.1 (C-40)
*
, 109.5 (C-50)
, 68.6 (COCH2CH(OH)
*
(2H, m, ArCH2CH]CH2), 4.56 (1H, br s, COCH2CH(OH)CO2Et), 4.25
(2H, q, J 7.1, CO2CH2CH3), 3.76 (3H, s, OCH3), 3.74 (3H, s, OCH3), 3.34
(1H, dd, J 18.3, 3.7, one of COCH2CH(OH)CO2Et), 3.32 (1H, br s, OH),
3.26 (2H, d, J 6.3, ArCH2CH]CH2), 3.23 (1H, dd, J 18.3, 6.3, one of
COCH2CH(OH)CO2Et), 1.28 (3H, t, J 7.1, CO2CH2CH3); 13C NMR
(75 MHz, CDCl3) dC¼204.4 (C]O), 173.8 (CO2Et), 151.9, 149.9, 136.4
CH2OH), 65.8 (COCH2CH(OH)CH2OH), 55.8 (2ꢂOCH3), 47.7 (COCH2
-
CH(OH)CH2OH), 30.1 (ArCH2CH]CH2); HR-TOF-MS: m/z found
281.1389, [MþH]þ (calculated for C15H21O5, 281.1382).
3.8. 1-(2-Allyl-3,6-dimethoxyphenyl)butane-1,4-diol 14
(ArCH2CH]CH2), 131.1, 126.4, 115.3 (ArCH2CH]CH2), 112.2 (C-40)
*
,
1-(2-Allyl-3,6-dimethoxyphenyl)-3,4-dihydroxybutan-1-one 13
(2.20 g, 7.85 mmol) was dissolved in dry THF (50 mL). The solution
was cooled to ꢁ10 ꢀC in a Me2CO/ice bath and lithium aluminium
hydride (0.447 g, 11.8 mmol) was added slowly over 5 min. The
reaction mixture was then heated for 3 h at reflux under a N2(g)
atmosphere. The solution was then cooled to 0 ꢀC in an ice bath and
cold H2O (10 mL) was added drop-wise until the fizzing stopped.
EtOAc (50 mL) was added and the solution was washed with
aqueous HCl (2 M, 50 mL). The organic layer was then dried over
anhydrous MgSO4, filtered and concentrated under reduced pres-
sure. Column chromatography (40% EtOAc/hexane) of the residue
afforded 1-(2-allyl-3,6-dimethoxyphenyl)butane-1,4-diol 14 as
a colourless liquid (1.30 g, 62%); Rf¼0.25 (50% EtOAc/hexane); IR
nmax (cmꢁ1)¼3373 (OH), 1596 (C]C), 1228, 1217, 1051; 1H NMR
109.4 (C-50)
, 66.9 (COCH2CH(OH)CO2Et), 61.6 (CO2CH2CH3), 56.1
*
(2ꢂOCH3), 48.3 (COCH2CH(OH)CO2Et), 30.9 (ArCH2CH]CH2), 14.1
(CO2CH2CH3); HR-TOF-MS: m/z found 323.1495, [MþH]þ (calculated
for C17H23O6, 323.1484).
3.6. Ethyl 4-[3,6-dimethoxy-2-(2-oxopropyl)phenyl]-2-
hydroxy-4-oxobutanoate 12
Ethyl 4-(2-allyl-3,6-dimethoxyphenyl)-2-hydroxy-4-oxobutanoate
11 (1.10 g, 3.41 mmol) was dissolved in a DMF/H2O mixture (1:1 v/v,
20 mL). PdCl2 (0.0605 g, 0.341 mmol) and CuCl2$2H2O (0.582 g,
3.41 mmol) were added to the solution. Oxygen gas was bubbled
through the solution, which was stirred vigorously for 2 h at 70 ꢀC.
The reaction mixture was filtered, and EtOAc (30 mL) was added. The
organic layer was washed with H2O (3ꢂ30 mL), separated, dried over
anhydrous MgSO4, filtered and concentrated under reduced pressure.
Column chromatography (30% EtOAc/hexane) of the residue
afforded ethyl 4-[3,6-dimethoxy-2-(2-oxopropyl)phenyl]-2-hydroxy-
4-oxobutanoate 12 as a yellow liquid (0.773 g, 67%); Rf¼0.15 (40%
EtOAc/hexane); IR nmax (cmꢁ1)¼3015 (OH), 1738 (C]O), 1257, 1216;
(300 MHz, CDCl3) dH¼6.74 (1H, d, J 9.0, H-40)
*
, 6.70 (1H, d, J 9.0, H-
50)
, 5.88 (1H, ddt, J 16.3, 10.2, 5.8, ArCH2CH]CH2), 5.02e4.87 (2H,
*
m, ArCH2CH]CH2), 4.83 (1H, dd, J 9.6, 3.2, CH(OH)CH2CH2CH2OH),
3.80 (3H, s, OCH3), 3.73 (3H, s, OCH3), 3.68e3.58 (2H, m, CH(OH)
CH2CH2CH2OH), 3.54e3.32 (2H, m, ArCH2CH]CH2), 2.09e1.55 (4H,
m, CH(OH)CH2CH2CH2OH); 13C NMR (75 MHz, CDCl3) dC 151.8,151.7,
136.5 (ArCH2CH]CH2), 131.6, 126.4, 114.9 (ArCH2CH]CH2), 109.6
1H NMR (300 MHz, CDCl3) dH¼6.86 (1H, d, J 9.0, H-40)
*
, 6.79 (1H, d, J
(C-40)
*
, 109.5 (C-50)
, 71.3 (CH(OH)CH2CH2CH2OH), 62.7 (CH(OH)
*
9.0, H-50)
*
, 4.54 (1H, ddd, J 6.8, 5.6, 3.6, COCH2CH(OH)CO2Et), 4.24 (2H,
CH2CH2CH2OH), 55.8 (2ꢂOCH3), 34.4 (CH(OH)CH2CH2CH2OH), 30.2
(CH(OH)CH2CH2CH2OH), 29.9 (ArCH2CH]CH2); HR-TOF-MS: m/z
found 249.1488, [MꢁOH]þ (calculated for C15H21O3, 249.1491).
q, J 7.1, CO2CH2CH3), 3.77 (3H, s, OCH3), 3.73 (3H, s, OCH3), 3.68 (2H, s,
ArCH2COCH3), 3.39 (1H, dd, J 17.6, 3.6, one of COCH2CH(OH)CO2Et),
3.25 (1H, d, J 5.6, OH), 3.23 (1H, dd, J 17.6, 6.8, one of COCH2CH(OH)
CO2Et), 2.16 (3H, s, ArCH2COCH3), 1.28 (3H, t, J 7.1, CO2CH2CH3); 13C
NMR (75 MHz, CDCl3) dC¼206.3 (ArCH2COCH3), 204.3 (COCH2CH(OH)
CO2Et), 173.6 (COCH2CH(OH)CO2Et), 151.9, 150.4, 122.6, 112.5, 110.3 (C-
3.9. 3,6-Dimethoxy-9-methyl-10,13-dioxatricyclo[7.3.1.02,7
trideca-2,4,6-triene 15
]
40)
*
, 77.1 (C-50)
*
, 67.4 (COCH2CH(OH)CO2Et), 61.7 (CO2CH2CH3), 56.1
1-(2-Allyl-3,6-dimethoxyphenyl)butane-1,4-diol 14 (1.20 g,
4.51 mmol) was dissolved in a DMF/H2O mixture (1:1 v/v, 50 mL).
PdCl2 (0.0800 g, 0.451 mmol) and CuCl2$2H2O (0.768 g,
4.51 mmol) were added to the solution. Oxygen gas was bubbled
through the solution, which was stirred vigorously for 2 h at 70 ꢀC.
The reaction mixture was filtered, and EtOAc (20 mL) was added.
The organic layer was washed with H2O (3ꢂ20 mL), separated,
dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure. Column chromatography (30% EtOAc/hexane) of
the residue afforded 15 as a colourless liquid (0.858 g, 72%);
Rf¼0.54 (40% EtOAc/hexane); IR nmax (cmꢁ1)¼1254, 1228, 1065; 1H
(2ꢂOCH3), 48.0 (COCH2CH(OH)CO2Et), 41.1 (ArCH2COCH3), 29.6
(ArCH2COCH3), 14.1 (CO2CH2CH3); HR-TOF-MS: m/z found 339.1444,
[MþH]þ (calculated for C17H23O7, 339.1437).
3.7. 1-(2-Allyl-3,6-dimethoxyphenyl)-3,4-dihydroxybutan-1-
one 13
Ethyl-(Z)-4-(2-allyl-3,6-dimethoxyphenyl)-2-hydroxy-4-oxobut-
2-enoate 10 (1.00 g, 3.12 mmol) was dissolved in dry THF (20 mL).
The solution was cooled to ꢁ10 ꢀC in a Me2CO/ice bath and lithium
aluminium hydride (0.237 g, 6.24 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 (10 mL) was added drop-wise until the fizzing
stopped. EtOAc (20 mL) was added and the solution was washed
with aqueous HCl (2 M, 20 mL). The organic layer was then dried
over anhydrous MgSO4, filtered and concentrated under reduced
pressure. Column chromatography (40% EtOAc/hexane) of the resi-
due afforded 1-(2-allyl-3,6-dimethoxyphenyl)-3,4-dihydroxybutan-
1-one 13 as a yellow liquid (0.30 g, 34%); Rf¼0.26 (50% EtOAc/
NMR (300 MHz, CDCl3) dH¼6.67 (1H, d, J 9.0, H-4)
*
, 6.63 (1H, d, J
9.0, H-5) , 5.17 (1H, br d, J 4.8, H-1), 3.80 (1H, dd, J 11.8, 1.5, H-11a),
*
3.76 (3H, s, OCH3), 3.75 (3H, s, OCH3), 3.56 (1H, ddd, J 11.8, 3.3, 2.0,
H-11b), 3.05 (1H, d, J 16.8, H-8a), 2.65e2.54 (1H, m, H-13a), 2.50
(1H, d, J 16.8, H-8b), 1.90e1.76 (1H, m, H-13b), 1.64e1.54 (1H, m,
H-12a), 1.49 (3H, s, CH3), 1.47e1.32 (1H, m, H-12b); 13C NMR
(75 MHz, CDCl3) dC¼151.1, 149.4, 125.1 (C-2), 123.0 (C-7), 107.8 (C-
5)
*
, 107.4 (C-4)
*
, 97.4 (C-9), 72.2 (C-1), 61.8 (C-11), 55.4 (2ꢂOCH3),
33.6 (C-8), 32.3 (C-13), 27.6 (C-12), 25.0 (CH3); HR-TOF-MS: m/z
found 265.1440, [MþH]þ (calculated for C15H21O4, 265.1429).

7120
A. Pillay et al. / Tetrahedron 68 (2012) 7116e7121
3.10. 1-(2-Allyl-3,6-dimethoxyphenyl)-4-(tert-
A portion of the impure crystalline material, 5 as a mixture of
butyldimethylsilyloxy)-3-hydroxybutan-1-one 16
diastereoisomers (0.423 g, 2.48 mmol) was dissolved in a mixture of
DMF/H2O mixture (1:1 v/v, 40 mL). PdCl2 (0.0439 g, 0.248 mmol) and
CuCl2$2H2O (0.423 g, 2.48 mmol)were added tothe solution. Oxygen
gas was bubbled through the solution, which was stirred vigorously
for 2 h at 70 ꢀC. The reaction mixture was filtered, and EtOAc (50 mL)
was added. The organic layer was washed with H2O (3ꢂ30 mL),
separated, dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. Column chromatography (50% EtOAc/hex-
ane) of the residue afforded of mixture of diastereoisomers of 6 as
awhitesolid(0.601 g,67%from16)inaratioof2.3:1asdeterminedby
1H NMR spectroscopy; Rf¼0.58 (50% EtOAc); mp¼142e143 ꢀC; IR
nmax (cmꢁ1)¼1229, 1215, 1172; 1H NMR (500 MHz, CDCl3) major di-
1-(2-Allyl-3,6-dimethoxyphenyl)-3,4-dihydroxybutan-1-one 13
(2.44 g, 8.74 mmol) was dissolved in dry CH3CN (35 mL) at 0 ꢀC
under a N2(g) atmosphere. Imidazole (0.595 g, 8.74 mmol) and tert-
butyldimethylsilyl chloride (1.32 g, 8.74 mmol) were added in three
portions to the reaction mixture, every 15 min for a 45 min period.
Onceaddition of the reactants was complete, themixturewas stirred
for 1 h at rt. The solution was then filtered and the solvent was re-
moved in vacuo. The residue was then dissolved in EtOAc (50 mL),
and was sequentially washed with aqueous NaHCO3 (50 mL) fol-
lowed by aqueous NaCl (50 mL). The organic layer was then dried
over anhydrous MgSO4, filtered and concentrated under reduced
pressure. Column chromatography (10% EtOAc/hexane) of the resi-
due afforded 1-(2-allyl-3,6-dimethoxyphenyl)-4-(tert-butyldime-
astereomer dH¼6.67 (1H, d, J 8.8, H-4)
*
, 6.64 (1H, d, J 8.8, H-5) , 5.40
*
(1H, br d, J 3.9, H-1), 3.91e3.83 (1H, m, H-11), 3.79 (3H, s, OCH3), 3.76
(3H, s, OCH3), 3.48 (2H, br s, CH2OH), 2.98 (1H, d, J 18.8, H-8a), 2.85
(1H, d, J18.8, H-8b), 2.20(1H, br t, J5.8, OH), 2.09e2.02(1H, m, H-12a),
1.53 (3H, s, CH3), 1.40 (1H, dt, J 12.9, 2.0, H-12b); minor diastereomer
thylsilyloxy)-3-hydroxybutan-1-one 16 as
a colourless liquid
(2.20 g, 64%); Rf¼0.37 (20% EtOAc/hexane); IR nmax (cmꢁ1)¼3015
(OH), 1738 (C]O), 1255, 1228; 1H NMR (300 MHz, CDCl3) dH¼6.83
dH¼6.67 (1H, d, J 8.8, H-4)
*
, 6.63 (1H, d, J 8.8, H-5) , 5.25 (1H, br d, J 9.1,
*
(1H, d, J 9.0, H-40)
*
, 6.74 (1H, d, J 9.0, H-50)
*
, 5.90 (1H, ddt, J 16.6,10.4,
H-1), 4.09e4.03 (1H, m, H-11), 3.77 (3H, s, OCH3), 3.76 (3H, s, OCH3),
3.60e3.54 (1H, m, one of CH2OH), 3.41e3.35 (1H, m, one of CH2OH),
2.83 (1H, d, J 17.3, H-8a), 2.59 (1H, d, J 17.3, H-8b), 2.30 (1H, ddd, J 13.0,
10.1, 5.3, H-12a), 2.08 (1H, br s, OH),1.57 (1H, ddd, J 13.0, 11.1, 1.55, H-
12b),1.52 (3H, s, CH3);13C NMR (125 MHz, CDCl3) majordiastereomer
6.2, ArCH2CH]CH2), 5.01e4.90 (2H, m, ArCH2CH]CH2), 4.31e4.19
(1H, m, COCH2CH(OH)CH2OTBS), 3.78 (3H, s, OCH3), 3.75 (3H, s,
OCH3), 3.69e3.56 (2H, m, COCH2CH(OH)CH2OTBS), 3.30 (2H, dd, J
6.2, 1.4, ArCH2CH]CH2), 3.04 (1H, dd, J 17.9, 4.4, one of COCH2
-
CH(OH)CH2OTBS), 2.98 (1H, d, J 3.6, OH), 2.91 (1H, dd, J 17.9, 7.8, one
of COCH2CH(OH)CH2OTBS), 0.89 (9H, s, 3ꢂCH3), 0.07 (6H, s, 2ꢂCH3);
13C NMR (75 MHz, CDCl3) dC¼207.0 (C]O), 151.9, 149.8, 136.4, 131.5,
dC¼149.9,148.7,126.0 (C-7),124.1 (C-2),107.8 (C-5)
*
,107.3 (C-4) , 96.0
*
(C-9), 68.3 (C-11), 65.9 (CH2OH), 65.7 (C-1), 55.9 (OCH3), 55.3 (OCH3),
32.8 (C-8), 30.4 (C-12), 29.5 (CH3); minor diastereomer dC¼151.2,
148.6,128.9 (C-2),121.5 (C-7),107.9 (C-5),107.0 (C-4), 97.4 (C-9), 66.7
(C-11), 65.0 (C-1), 64.9 (CH2OH), 55.5 (OCH3), 55.4 (OCH3), 33.2 (C-8),
32.8 (C-12), 24.6 (CH3); HR-TOF-MS: m/z found 281.1389, [MþH]þ
(calculated for C15H21O5, 281.1382).
126.1 (ArCH2CH]CH2), 115.3 (ArCH2CH]CH2), 111.9 (C-40)
, 109.4
*
(C-50)
*
,
68.3 (COCH2CH(OH)CH2OTBS), 66.4 (COCH2CH(OH)
CH2OTBS), 56.1 (2ꢂOCH3), 48.1 (COCH2CH(OH)CH2OTBS), 30.9
(ArCH2CH]CH2), 25.9 (OSi(CH3)2C(CH3)3), 18.3 (OSi(CH3)2C(CH3)3),
ꢁ5.4 (OSi(CH3)2C(CH3)); HR-TOF-MS: m/z found 395.2254, [MþH]þ
(calculated for C21H35O5Si, 395.2245).
3.12. 11-(Hydroxymethyl)-9-methyl-10,13-dioxatricyclo
[7.3.1.02,7]trideca-2(7),4-diene-3,6-dione 17
3.11. (3,6-Dimethoxy-9-methyl-10,13-dioxatricyclo[7.3.1.02,7
trideca-2,4,6-trien-11-yl)methanol 6
]
Compound 6 (0.400 g, 1.44 mmol) was dissolved in a mixture of
CH3CN and H2O (40 mL, 50:50 v/v ratio). CAN (2.36 g, 4.31 mmol)
was added to the reaction mixture, which was then stirred vigor-
ously for 30 min at rt. EtOAc (40 mL) and aqueous NaCl (940 mL)
were then added and the upper organic layer was separated, dried
over anhydrous MgSO4, filtered and concentrated under reduced
pressure. Column chromatography (30% EtOAc/hexane) of the resi-
due afforded 17 as an amorphous red solid (0.320 g, 89%); Rf¼0.36
(50% EtOAc/hexane); IR nmax (cmꢁ1)¼3015 (OH), 1754 (C]O), 1111;
1H NMR (300 MHz, CDCl3) majordiastereomer dH¼6.79 (1H, d, J 10.2,
1-(2-Allyl-3,6-dimethoxyphenyl)-4-(tert-butyldimethylsilyloxy)-
3-hydroxybutan-1-one 16 (2.10 g, 5.34 mmol) was dissolved in dry
THF (80 mL). The solution was cooled to ꢁ10 ꢀC in a Me2CO/ice bath
and lithium aluminium hydride (0.303 g, 8.00 mmol) was added
slowly over 5 min. The reaction mixture was then heated for 2 h at
reflux under a N2(g) atmosphere. The solution was then cooled to
0 ꢀC in an ice bath and cold water was added drop-wise until the
fizzing stopped. EtOAc (60 mL) was added and the solution was
washed with aqueous HCl (2 M, 60 mL). The organic layer was then
dried over anhydrous MgSO4, filtered and concentrated under re-
duced pressure to afford an impure crystalline compound (0.700 g)
of 4-(2-allyl-3,6-dimethoxyphenyl)butane-1,2,4-triol 5 in a ratio of
1.8:1 as determined by 1H NMR spectroscopy. A 1H NMR spectrum of
the crude mixture confirmed that no starting material was present
as signals for the silicon-protecting group were absent. The impure
crystalline compound could not be isolated in sizable quantities after
purification by silica gel column chromatography, and was treated as
an intermediate. However, on one occasion, trace amounts (13 mg)
of a single diastereoisomer of 5 were isolated from a silica gel column
(70% EtOAc/hexane) after conducting the reaction on a 2 g scale; 1H
NMR (300 MHz, CDCl3) dH¼6.78 (2H, s, 4-H and 5-H), 5.96e5.85 (1H,
m, ArCH2CH]CH2), 5.16 (1H, dd, J 10.5, 2.8, ArCH(OH)CH2CH(OH)
CH2OH), 5.01 (1H, dd, J 10.1, 1.6, one of ArCH2CH]CH2), 4.94 (1H, dd,
J 17.1, 1.7, one of ArCH2CH]CH2), 4.06e3.97 (1H, m, ArCH(OH)
CH2CH(OH)CH2OH), 3.87 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.63 (1H,
dd, J 11.2, 3.5, one of ArCH(OH)CH2CH(OH)CH2OH), 3.55e3.45 (3H,
m, one of ArCH(OH)CH2CH(OH)CH2OH and ArCH2CH]CH2),
2.30e2.16 (1H, m, one of ArCH(OH)CH2CH(OH)CH2OH),1.69 (1H, dt, J
14.6, 2.8, one of ArCH(OH)CH2CH(OH)CH2OH).
H-4)
*
, 6.74 (1H, d, J 10.2, H-5) , 5.15 (1H, d, J 5.3, H-1), 3.90e3.80 (1H,
m, H-11), 3.55 (2H, br s, CH2OH), 2.82 (1H, d, J 20.9, H-8a), 2.82 (1H, d,
J 20.9, H-8b), 2.17e2.06 (1H, m, H-12a), 1.52 (3H, s, CH3), 1.40e1.33
*
(1H, m, H-12b); minordiastereomer dH¼6.77 (1H, d, J10.1, H-4)
*
, 6.74
(1H, d, J 10.2, H-5) , 5.03 (1H, br d, J 10.7, H-1), 4.06e3.95 (1H, m, H-
*
11), 3.58e3.69 (1H, m, one of CH2OH), 3.50e3.37 (1H, m, one of
CH2OH), 2.64 (1H, d, J 19.1, H-8a), 2.82 (1H, d, J 19.1, H-8b), 2.36e2.23
(1H, m, H-12a),1.58e1.52 (1H, m, H-12b),1.52 (3H, s, CH3); 13C NMR
(75 MHz, CDCl3) major diastereomer dC¼185.3 (C]O),184.7 (C]O),
141.3 (C-2), 141.1 (C-7), 136.1 (C-4)
*
, 136.0 (C-5) , 96.0 (C-9), 68.2 (C-
*
11), 65.6 (CH2OH), 64.4 (C-1), 32.3 (C-8), 28.8 (C-12), 29.4 (CH3);
minordiastereomer dC¼186.4 (C]O),185.3 (C]O),143.6 (C-2),137.7
(C-7),136.1 (C-4)
*
,136.0 (C-5) , 97.5 (C-9), 66.1 (C-11), 64.6 (CH2OH),
*
63.7 (C-1), 33.6 (C-8), 29.7 (C-12), 24.1 (CH3).
Acknowledgements
This work was supported by SABINA (Southern African Bio-
chemistry and Informatics for Natural Products Network), the Na-
tional Research Foundation (NRF, GUN 2053652 and IRDP of the
NRF (South Africa) for financial support provided by the Research

A. Pillay et al. / Tetrahedron 68 (2012) 7116e7121
7121
3. Van Puyvelde, L.; El Hady, S.; De Kimpe, N.; Feneau-Dupont, J.; Declercq, J.-P. J.
Nat. Prod. 1998, 61, 1020e1021.
4. Kern, H. Ann. Phytopathol. 1978, 10, 327e345.
Niche Areas programme), Pretoria, and the University of the Wit-
watersrand (Science Faculty Research Council). We also gratefully
acknowledge the NRF scarce skills programme for generous fund-
ing to AP. The funders have played no role in study design; in the
collection, analysis and interpretation of data; in the writing of the
paper; and in the decision to submit the article for publication to
Tetrahedron. Mr. R. Mampa (University of the Witwatersrand) and
Ms. C. Janse Van Rensburg (University of Kwa-Zulu Natal, Pie-
termaritzburg) are thanked for providing the NMR and HRMS MS
spectroscopy services, respectively.
5. De Kimpe, N.; Kesteleyn, B.; Van Puyvelde, L. J. Org. Chem. 1999, 64, 438e440.
6. Ploysuk, C.; Kongkathip, B.; Kongkathip, N. Synth. Commun. 2007, 37,
1463e1471.
ꢀ
ꢀ
7. Jacobs, J.; Claessens, S.; De Mol, E.; El Hady, S.; Minguillon, C.; Alvarez, M.; De
Kimpe, N. Tetrahedron 2010, 66, 5158e5160.
8. Fernandes, R. A.; Ingle, A. B. Eur. J. Org. Chem. 2011, 6624e6627.
9. Townsend, C. A.; Davis, S. G.; Christensen, S. B.; Link, J. C.; Lewis, C. P. J. Am.
Chem. Soc. 1981, 103, 6885e6888.
10. Govender, S.; Mmutlane, E. M.; van Otterlo, W. A. L.; de Koning, C. B. Org. Biomol.
Chem. 2007, 5, 2433e2440.
11. Kongkathip, B.; Sookkho, R.; Kongkathip, N.; Taylor, W. C. Chem. Lett. 1999,
1095e1096.
12. Mmutlane, E. M.; Michael, J. P.; Green, I. R.; de Koning, C. B. Org. Biomol. Chem.
2004, 2, 2461e2470.
Supplementary data
13. CCDC 882007: the data set for compound 6 was collected using u-scans on an
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.06.052.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
APEX II CCD area detector diffractometer. Crystal data for 6, C15H20O5: Mr 280.
31 g molꢁ1; crystal dimensions (mm) 0.48ꢂ0.15ꢂ0.05; crystal system, mono-
ꢁ
clinic; space group, P2(1)/c; unit cell dimensions and volume, a¼9.8703(4) A,
ꢁ
ꢁ
b¼20.4560(7) A, c¼6.8483(3) A,
a
¼90ꢀ,
b
¼93.068(2)ꢀ,
g
¼90ꢀ, V¼1380.74(9),
no. of formula units in the unit cell Z¼4; calculated density rcalcd 1.348 Mg/m3;
linear absorption coefficient, m 0.101 mmꢁ1; radiation and wavelength, Mo
¼0.71073 A; temperature of measurement, 173(2) K, 2Qmax 28.00ꢀ; no of
ꢁ
References and notes
K
a
measured and independent reflections, 15,409 and 2722; Rint¼0.0473; R[I>2.
0
s
(I)]¼0.0400, wR¼0.0400, GoF¼0.827, refined on F; residual electron density,
ꢁꢁ3
1. (a) Holenstein, J. E.; Stoessl, A.; Kern, H.; Stothers, J. B. Can. J. Chem. 1984, 62,
1971e1976; (b) Brimble, M. A.; Duncalf, L. J.; Nairn, M. R. Nat. Prod. Rep. 1999, 16,
267e281.
0.167 and ꢁ0.185 e A
.
14. Green, I. R.; Hugo, V. I.; Oosthuisen, F. J.; van Eeden, N.; Giles, R. G. F. S. Afr. J.
Chem. 1995, 48, 15e22.
2. Ogoshi, H.; Omura, T.; Yoshida, Z. J. Am. Chem. Soc. 1973, 95, 1668e1669.