Investigations towards the synthesis of xylindein, a blue-green pigment from the fungus Chlorociboria aeruginosa

Article abstract of DOI:10.1016/j.tet.2012.02.009

An approach towards the synthesis of the fungal pigment xylindein 1 is described. Synthesis of the pyranonaphthoquinone corresponding to one half of the xylindein framework is achieved over 11 steps from 1,2-epoxypentane, utilizing multiple Diels-Alder cy

Full text of DOI:10.1016/j.tet.2012.02.009

Tetrahedron 68 (2012) 2799e2805
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Investigations towards the synthesis of xylindein, a blue-green pigment
from the fungus Chlorociboria aeruginosa
,
b
,
a
a
a,
y
Christopher D. Donner a , Anthony N. Cuzzupe , Cheryl L. Falzon , Melvyn Gill
*
a School of Chemistry, The University of Melbourne, Victoria 3010, Australia
b Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
An approach towards the synthesis of the fungal pigment xylindein 1 is described. Synthesis of the
pyranonaphthoquinone corresponding to one half of the xylindein framework is achieved over 11 steps
from 1,2-epoxypentane, utilizing multiple DielseAlder cycloaddition processes. Methods for self-
coupling of dihydroxynaphthoquinones to give extended quinones are explored.
Received 2 November 2011
Received in revised form 19 January 2012
Accepted 6 February 2012
Available online 10 February 2012
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
Xylindein
Extended quinone
DielseAlder
Fungal pigment
1. Introduction
O
O
OH
O
O
The green colour of wood infected with the fungus Chlor-
ociboria aeruginosa is due to the presence of the extended qui-
none xylindein 1, a novel pigment with a long and interesting
history. A process for artificially colouring wood with C. aerugi-
nosa was patented and oak stained in this way was used for
making ‘Tunbridge ware’, a special kind of marquetry. Over one
hundred years ago Liebermann obtained the pigment in crystal-
line form for the first time by extraction of infected wood with
aqueous phenol and crystallization from the same solvent.1
However, structural studies of xylindein 1 were severely ham-
pered by its extremely low solubility in all common organic sol-
vents. In the 1920s Kogl made the first advances in the structure
elucidation of xylindein by establishing the presence of two acidic
hydroxy groups, two lactone rings, and an extended quinone
system.2,3 The complete structure of xylindein 1 was elucidated,
independently, by Todd and co-workers4,5 and by Edwards and
Kale.6 The methods relied on derivatization of the natural mate-
rial and degradative studies, the details of which have been suc-
cinctly documented by Thomson.7
O
O
O
O
HO
1
OH
O
O
O
OH OH
O
O
O
HO
HO
3
2
More recently, Saikawa and co-workers8 have established the
(3S,30S) absolute configuration of xylindein 1 using natural mate-
rial extracted from fruiting bodies of C. aeruginosa, Chlorociboria
aeruginascens and Chlorociboria omnivirens. X-ray crystallographic
analysis of the natural product confirmed that the structure 1 is
indeed the tautomeric form of natural xylindein, whilst de-
rivatization of 1 as a bis para-bromobenzyl derivative gave mate-
rial suitable for X-ray crystallographic heavy atom analysis.
* Corresponding author. Tel.: þ61 3 8344 2411; fax: þ61 3 9347 8189; e-mail
address: cdonner@unimelb.edu.au (C.D. Donner).
y
Deceased.
0040-4020/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.009

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C.D. Donner et al. / Tetrahedron 68 (2012) 2799e2805
It has been postulated that synthetically xylindein 1 could be
In order to firstly establish the viability of our proposed ap-
proach, our study began with (ꢀ)-1,2-epoxypentane 10 (Scheme 3)
that was treated with the ethylene diamine complex of lithium
acetylide to form the acetylenic alcohol 11. Treatment of the alcohol
11 with TBSCl in DMF gave the silyl ether 12 in 94% yield. Carbo-
methoxylation of the alkyne 12 was achieved by lithiation with n-
butyllithium at ꢁ78 ꢂC followed by addition of methyl chlor-
oformate to give the acetylenic ester (ꢀ)-9 in 89% yield. DielseAlder
cycloaddition between the octynoate ester 9 and 1-methoxy-1,3-
cyclohexadiene in a sealed tube at 185 ꢂC for 72 h gave exclu-
sively the benzoate 13, after loss of ethylene. Exposure of the
benzoate 13 to para-toluenesulfonic acid (p-TsOH) in CH2Cl2
effected both removal of the silyl protecting group and subsequent
lactonization to give the benzopyranone 14 in 91% yield, the
spectroscopic data (Experimental section) being in complete accord
with the structure 14.
formed by dimerization of lactone 2, a process that would involve
no change in oxidation level but rather is formally a dehydration.9
Giles and co-workers have prepared the 7,9-dideoxy analogue of 2
in racemic form.9,10 Unfortunately, attempts to apply their strategy
to the more highly oxygenated system 2 were unsuccessful.10 We
have previously prepared (ꢀ)-naphthopyranone 3, the 5-deoxo
analogue of 2, in four steps from 1,2-epoxypentane.11 However,
attempted oxidative phenolic coupling of 3 towards xylindein met
with little success.
Based on our previous work12 we doubted that the lactone 2
would itself be synthetically useful due to the unfavourable re-
activity induced by the juxtaposition of the lactone and the quinone
carbonyl groups. However, the 1-deoxo analogue of 2 may be
a more viable substrate for extended quinone formation. This
proposal is based on the work of Blackburn and co-workers who
were able to convert the aphid insect pigment derivative ‘quinone
A’ 4 directly to the extended quinone xylaphin 5 under anaerobic,
buffered aqueous conditions (Scheme 1).13 The product 5 so formed
contains the same extended quinone chromophore that occurs in
xylindein 1. Herein we report our preparation of the 1-deoxo ana-
logue of 2 as a potential precursor for the synthesis of xylindein 1.
H
CO2Me
O
a
c
( )-10
OR
OTBS
( )-9
11 R = H
b
12 R = TBS
O
HO
O
Me
MeO
O
O
MeO
aq. Na2HPO4
/
OH
O
Me
CO2Me
OTBS
O
d
e
citric acid (pH 6.2)
80 oC, N2
1
O
OH
O
Me
6
4
Me
OH
13
Scheme 3. Reagents and conditions: (a) LiC^CH/H2N(CH2)2NH2 complex, DMSO, 0 ꢂ
HO
Me
14
O
OH
O
C
to rt, overnight (50%); (b) TBSCl, imidazole, DMF, overnight (94%); (c) (i) nBuLi, THF,
4
Me OH
O
ꢁ78 ꢂC, 30 min; (ii) ClCO2Me, ꢁ78 ꢂC to rt,
2
h
(89%); (d) 1-methoxy-1,3-
cyclohexadiene, dichloromaleic anhydride, N-phenyl-
b-naphthylamine, sealed tube,
5
185 ꢂC, 72 h (84%); (e) p-TsOH$H2O, CH2Cl2, 72 h (91%).
Scheme 1. Conversion of ‘quinone A’ 4 to xylaphin 5.13
We next explored two routes to convert the benzopyranone 14
to the bromobenzoquinone (ꢀ)-7. The incorporation of a halogen at
C7 in benzoquinone 7 is required to ensure the subsequent Diel-
seAlder process occurs in a highly regioselective manner,14,15
whilst ensuing loss of HBr ensures complete aromatization. In the
first approach towards 7, outlined in Scheme 4, the hindered
methyl ether in 14 was cleaved by treatment with BCl3 in CH2Cl2 to
give the phenol (ꢀ)-8 in 94% yield. Treatment of the benzopyranone
8 with 2 equiv of NBS in DMF gave the dibromophenol 15 in 94%
yield. It was necessary to reduce the lactone at this stage as such
a structural feature is incompatible with a neighbouring quinone
moiety.12 This firstly required methylation of phenol 15, effected
using dimethyl sulfate in acetone at reflux, to give the ether 16 in
near quantitative yield.
2. Results and discussion
Our proposed approach to the synthesis of xylindein 1 is shown
retrosynthetically in Scheme 2. According to our plans phenolic
coupling of the pyranonaphthoquinone 6 followed by oxidation at
the benzylic position in both of the pyran rings would lead to
xylindein 1. The naphthoquinone 6 should, in turn, be available by
DielseAlder cycloaddition between an appropriate butadiene and
the benzoquinone 7. The bromoquinone 7 may be prepared from
the benzopyranone 8, which itself should be accessible via Diel-
seAlder reaction of the acetylene
cyclohexadiene. The octynoate ester 9 should be available from
1,2-epoxypentane 10.
9 with 1-methoxy-1,3-
OR
O
OR
O
Br
O
O
OH
O
O
b
O
Br
O
O
1
Br
HO
14 R = Me
( )-8 R = H
15 R = H
a
c
O
6
16 R = Me
7
OR
MeO
Br
OH
CO2Me
Br
OH
O
O
1
e
O
d
O
3
O
Br
Br
17
18 R = Me
19 R = H
10
f
OTBS
9
8
Scheme 4. Reagents and conditions: (a) BCl3, CH2Cl2, 0 ꢂC to rt, 12 h (94%); (b) NBS,
DMF, 18 h (94%); (c) Me2SO4, K2CO3, acetone, reflux, 45 min (98%); (d) DIBAL-H, tol-
uene, ꢁ70 ꢂC, 45 min (94%); (e) Et3SiH, TFA, CH2Cl2, 0 ꢂC to rt, 45 min (98%); (f)
(PhCH2Se)2, NaBH4, DMF, reflux, 1.5 h (82%).
Scheme 2. Retrosynthesis of xylindein 1.

C.D. Donner et al. / Tetrahedron 68 (2012) 2799e2805
2801
Reduction of the lactone carbonyl group in 16 to afford the
benzopyran 18 was achieved over two steps. Firstly, treatment of 16
with DIBAL-H in toluene at ꢁ70 ꢂC gave the lactol 17 in 94% yield as
a single diastereomer. The 1H NMR spectrum of 17 contains
a methoxy resonance at
d
3.94, an aromatic resonance at
d 7.74 and
double doublets centred at
d
2.36 and 2.74 from the C4 methylene
protons. The relative configuration of the lactol 17 is clearly
(1R*,3S*) as evidenced by the chemical shifts of both the acetal
proton (d 6.17) and C3 methine proton (d
4.28) in the 1H NMR
Fig. 1. Preferred half chair conformation in the dihydropyran ring of the pyr-
anobenzoquinone (ꢀ)-7.
spectrum, which are consistent with the C1 hydroxy group being in
an axial orientation12 as would be favoured by the anomeric ef-
fect.16 Reduction of the lactol 17 to the benzopyran 18 was achieved
by exposure of the lactol to triethylsilane in the presence of TFA.
Direct oxidation of the benzopyran 18 to the benzoquinone 7 was
unsuccessful, thus it was necessary to cleave the aromatic methyl
ether. As we have found with related benzopyrans,12 O-demethy-
lation of these systems is best achieved using the benzylselenolate
ion in hot DMF.17 Thus, treatment of the ether 18 with a mixture of
dibenzyldiselenide and sodium borohydride gave the phenol 19 in
82% yield.
and
d 2.56, ddd) due to geminal, vicinal and homoallylic coupling
consistent with the dihydropyran ring in 7 adopting a half chair con-
formationwiththeC3propylgroupinapseudo-equatorialorientation.
In order to assemble the tricyclic system present in the naph-
thopyranone 6 the benzoquinone 7 was subjected to DielseAlder
cycloaddition
with
1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-
butadiene.18 After chromatographic purification and crystalliza-
tion the naphthoquinone (ꢀ)-6 was obtained as orange needles in
43% yield. The 1H NMR spectrum of 6, which includes two meta-
coupled (J 2.5 Hz) aromatic proton signals (
d 6.51 and 6.97) and
An alternate and potentially more direct route to the phenol 19
from benzopyranone 14 was also explored in which the lactone
carbonyl group was reduced prior to bromination. In this approach
(Scheme 5) the lactone in 14 was firstly reduced by treatment with
DIBAL-H at ꢁ70 ꢂC. The intermediate lactol was not isolated but
was instead further reduced by using Et3SiH/TFA to give the ben-
zopyran 20, the physical and spectroscopic data of which was fully
consistent with the assigned structure. All attempts to brominate
the methyl ether 20 to form the dibromoether 18 led only to the
formation of mixtures of products. Therefore, the methyl ether 20
was first demethylated by using a mixture of dibenzyldiselenide
and sodium borohydride to give the phenol 21 in 70% yield. The
phenol 21 could then be smoothly brominated on treatment with
NBS in DMF to afford the dibromophenol 19 as the sole product, in
82% yield. The spectroscopic data for the phenol 19 obtained in this
way proved to be identical to those of the material prepared earlier.
This second approach to the phenol 19 (Scheme 5) proceeds in 51%
yield over four steps from 14. In comparison, the previous approach
(Scheme 4) gave the phenol 19 in 65% yield over six steps from the
same methyl ether 14.
signals from chelated ( 12.02) and free ( 10.36, broad) aromatic
d
d
hydroxy protons, along with all the other spectroscopic data (see
Experimental section) are in full accord with the assigned structure.
With the crucial dihydroxynaphthoquinone 6 in hand its possible
conversion to xylindein 1 could now be investigated.
The self-coupling ability of dihydroxynaphthoquinones to give
extended quinones has been demonstrated for the conversion of
‘quinone A’ 4 to the extended quinone xylaphin 5 by heating under
anaerobic conditions in a buffered (pH 6.2) aqueous solution
(Scheme 1).13 Additionally, when ‘quinone A’ 4 was treated with an
aqueous buffer of boric acid and sodium hydroxide (pH 9.0) the
reaction stopped at the level of the C6/C60 dimer of 4, that was
subsequently transformed to xylaphin 5 on treatment with acid.13
In order to assess the applicability of these self-coupling pro-
cedures to the synthesis of xylindein 1 the simpler model dihy-
droxynaphthoquinone system 25 was prepared as outlined in
Scheme 6. Thus, 5,6,7,8-tetrahydro-1-naphthol 22 was bromi-
nated using 2 equiv of NBS in DMF to afford the dibromophenol 23
in 96% yield. The bromophenol 23 was oxidized by using CAN in
aqueous acetonitrile to give the bromobenzoquinone 24 and sub-
sequent DielseAlder cycloaddition between the benzoquinone 24
and 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene gave the
dihydroxynaphthoquinone 25 in 83% yield.
OH
OR
MeO
O
Br
O
d
O
a, b
O
OH
OH
Br
20 R = Me
21 R = H
Br
c
14
a
19
O
O
OH
O
O
Br
22
Br
23
1
4
O
O
e
f
O
O
OH
O
HO
Br
c
b
( )-7
( )-6
HO
O
25
Scheme 5. Reagents and conditions: (a) DIBAL-H, toluene, ꢁ70 ꢂC, 1 h; (b) Et3SiH, TFA,
CH2Cl2, 0 ꢂC, 1 h (89%, two steps); (c) (PhCH2Se)2, NaBH4, DMF, reflux, 2 h (70%); (d)
NBS, DMF, 18 h (82%); (e) CAN, MeCN, THF, H2O, 30 min (91%); (f) 1-methoxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene, benzene, reflux, 1.5 h (43%).
24
Scheme 6. Reagents and conditions: (a) NBS, DMF, 18 h (96%); (b) CAN, MeCN, H2O,
30 min (87%); (c) 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene, benzene, 4 h
(83%).
Subsequent conversion of the phenol 19 to the benzoquinone
(ꢀ)-7 was achieved by addition of an aqueous solution of CAN to the
phenol 19 in acetonitrile (Scheme 5). The benzoquinone 7 was ob-
tained as a yellow oil with absorption maxima at 205 and 273 nm in
the electronic spectrum, consistent with a benzoquinone chromo-
phore.7 The 1H NMR spectrum of (ꢀ)-7, summarized in Fig. 1, shows
When the dihydroxynaphthoquinone 25 was exposed to a buff-
ered aqueous solution (pH 6) containing disodium hydrogen phos-
phate and citric acid according to Blackburn’s method13 no coupled
products were observed andthe substratewas recovered unchanged.
When the model quinone 25 was exposed to boric acid and sodium
hydroxide13 in aqueous THF at 80 ꢂC a blue precipitate, indicative of
a complexcoupling pattern forthe C4methylene protons (d 2.18, dddd

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C.D. Donner et al. / Tetrahedron 68 (2012) 2799e2805
an extended quinone chromophore, was formed in trace quantities.
Isolation of this material, however, proved fruitless. Nonetheless,
similar alkaline conditions were then applied to the functionalized
naphthoquinone 6 in an attempt to construct the complete carbon
framework of xylindein 1. Similarly, this resulted in the formation of
trace quantities of a blue precipitate and, although the electronic
spectrum of this material indicated the presence of an extended
quinone chromophore, inadequate quantities could be obtained for
complete structural assignment. The precise conditions required for
the transformation of dihydroxynaphthoquinones, such as 4, 6 and
25, to their respective extended quinone dimers appear to be ex-
tremely substrate specific. As was originally noted during the for-
mation of xylaphin 5, the most minor changes in the structure of the
substrate (e.g., inversion of the stereochemistry of the C4 hydroxy
group in 4) reduce the efficiency of the reaction, presumably due to
subtle differences in oxidationereduction potential.13
Microanalyses were carried out by Chemical and MicroAnalytical
Services Pty. Ltd., Geelong, Victoria, Australia.
4.2. Experimental procedures
4.2.1. (ꢀ)-1-Heptyn-4-ol (11). To a suspension of lithium acetyli-
deeethylene diamine complex (7.50 g, 81.5 mmol) in dimethyl
sulfoxide (100 mL) cooled to 0 ꢂC under nitrogen was added
dropwise (ꢀ)-1,2-epoxypentane 10 (4.70 g, 54.6 mmol). After
complete addition the suspension was allowed to warm slowly to
room temperature and the mixture was stirred overnight. The re-
action mixture was poured onto ice (200 mL) and the product was
extracted into ether (4ꢃ150 mL). The combined extracts were
washed sequentially with brine (6ꢃ150 mL) and water (3ꢃ150 mL)
and dried (MgSO4). Removal of the solvent under reduced pressure
followed by distillation of the residue yielded the alcohol 11 (3.05 g,
50%) as a colourless liquid, bp 66e67 ꢂC/16 mmHg (lit.20 58e59 ꢂC/
11 mmHg); nmax 3373br, 3308, 2960, 2119, 1466, 1426, 1124, 1075,
3. Summary and conclusions
1045, 1018 cmꢁ1
; dH (300 MHz) 0.93 (3H, t, J 7.1 Hz, H37), 1.32e1.56
In summary, the pyranonaphthoquinone (ꢀ)-6, an anticipated
precursor to xylindein 1, has been prepared over 11 steps from
propyl oxirane (ꢀ)-10. Preliminary attempts to couple the naph-
thoquinone 6 in order to form the complete carbon skeleton of
xylindein 1, using conditions applied in the preparation of the re-
lated extended quinone xylaphin 5,13 have met with limited suc-
cess. As such, the more readily accessible11,19 naphthopyranone
precursors, such as 3, are being considered as potentially more
robust substrates for biaryl coupling. Work in this area towards the
first total synthesis the unusual extended quinone pigment xylin-
dein 1 will be reported in due course.
(4H, m, H25 and H26), 1.96 (1H, br s, OH), 2.05 (1H, t, J 2.7 Hz, H1),
2.30 (1H, ddd, J 16.7, 6.7 and 2.7 Hz, HA3), 2.43 (1H, ddd, J 16.7, 4.8
and 2.7 Hz, HB3), 3.72e3.80 (1H, m, H4); dC (75 MHz) 13.9, 18.8,
27.3, 38.3, 69.6, 70.7, 80.9. The spectral data (1H and 13C NMR) was
identical to that reported.21
4.2.2. (ꢀ)-4-tert-Butyldimethylsilyloxyhept-1-yne (12). A solution
of (ꢀ)-1-heptyn-4-ol 11 (3.0 g, 26.7 mmol), imidazole (3.60 g,
52.9 mmol) and tert-butylchlorodimethylsilane (4.03 g, 26.7 mmol)
in N,N-dimethylformamide (25 mL) was stirred overnight. The
mixture was diluted with water (20 mL) and the product was
extracted into ether (3ꢃ20 mL) and the combined organic extracts
were washed sequentially with brine (6ꢃ20 mL) and water
(3ꢃ20 mL) and dried (MgSO4). After removal of the solvent under
reduced pressure Kugelrohr distillation of the residue yielded the
title compound 12 (5.70 g, 94%) as a colourless liquid, bp 75e78 ꢂC/
20 mmHg; nmax 3309, 2954, 2121, 1469, 1460, 1254, 1109, 836,
4. Experimental section
4.1. General
All reactions requiring anhydrous conditions were performed in
oven- or flame-dried glassware under an atmosphere of dry nitro-
gen. 1H and 13C NMR spectra were recorded on Varian Unity Plus
400, Varian Unity INOVA 400 or Varian Unity 300 spectrometers for
774 cmꢁ1
; dH (400 MHz) 0.06 and 0.08 (each 3H, s, SiMe), 0.89 (9H,
s, SiCMe3), 0.91 (3H, t, J 7.4 Hz, H37), 1.28e1.62 (4H, m, H25 and
H26), 1.97 (1H, t, J 2.7 Hz, H1), 2.30e2.32 (2H, m, H23), 3.76e3.82
(1H, m, H4); dC (100 MHz) ꢁ4.7 and ꢁ4.5 (each SiMe), 14.2, 18.1
(SiCMe3), 18.4, 25.8 (SiCMe3), 27.4, 38.9, 69.7, 70.7, 81.8. m/z (ESI)
227 ([MþH]þ); m/z (EI) 169 ([MꢁC4H9]þ, 49%), 86 (56), 84 (100).
The spectral data (1H and 13C NMR) was identical to that reported.21
solutions in deuteriochloroform with residual chloroform (
1H and 77.0 for 13C) as internal reference, unless indicated other-
wise. 1H NMR data are reported as follows: chemical shift (
) [rel-
d 7.26 for
d
d
ative integral, multiplicity, coupling constant(s) J (Hz), assignment].
Chemical shifts are given relative to tetramethylsilane with multi-
plicities indicated as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet) or br (broad) in the usual fashion. Electronic spectra
were recorded on a Varian SuperScan-3 or Shimadzu UV-2401PC
spectrometer using the solvent specified in a 10 mm quartz cell.
Infra-red spectra were obtained as KBr discs for solids and between
NaCl plates for liquids by using PerkineElmer 983G grating or 1600
series Fourier transform spectrophotometers. Electron impact (EI)
mass spectra were obtained using a V. G. Micromass 7070F or Shi-
madzu GCeMS-QP505A spectrometer. The mass of each ion is given
followed by its relative abundance. Only ions of relative intensity
greater than 50% of the base peak are reported, unless they are of
particular significance. Electrospray ionization (ESI) mass spectra
were obtained using a Micromass QUATTRO II spectrometer. Flash
column chromatography was performed over Merck Kieselgel 60
silica gel. Thin-layer chromatography was performed using pre-
coated sheets (0.25 mm, Kieselgel 60 GF254). Gel permeation chro-
matography was carried out using columns of Sephadex LH-20
(Pharmacia) suspended in and eluted with the solvent specified.
Ether refers to diethyl ether, while light petroleum refers to the
hydrocarbon fraction boiling in the range 40e60 ꢂC. Brine refers to
a saturated aqueous solution of sodium chloride. Melting points
were determined on a Kofler hot-stage and are uncorrected.
4.2.3. (ꢀ)-Methyl 5-tert-butyldimethylsilyloxyoct-2-ynoate (9). To
a stirred solution of the (ꢀ)-silyl ether 12 (4.00 g, 17.7 mmol) in THF
(60 mL) at ꢁ78 ꢂC was added n-butyllithium (8.50 mL, 2.5 M in
hexane, 21.2 mmol). After 30 min methyl chloroformate (1.64 mL,
21.2 mmol) was added dropwise and the mixture was allowed to
warm to room temperature. After 2 h the reaction mixture was
diluted with water (40 mL) and extracted with ether (3ꢃ50 mL).
The combined extracts were washed with brine (3ꢃ30 mL), dried
(MgSO4) and concentrated under reduced pressure. Kugelrohr
distillation yielded the title compound 9 (4.45 g, 89%) as a colourless
liquid, bp 95e98 ꢂC/0.3 mmHg; nmax 2954, 2239, 1716, 1250, 1073,
836, 775 cmꢁ1
; dH (400 MHz) 0.06 and 0.08 (each 3H, s, SiMe), 0.88
(9H, s, SiCMe3), 0.91 (3H, t, J 7.5 Hz, H38), 1.27e1.59 (4H, m, H26 and
H27), 2.44e2.46 (2H, m, H24), 3.75 (3H, s, CO2Me), 3.84e3.87 (1H,
m, H5); dC (100 MHz) ꢁ4.7 and ꢁ4.6 (each SiMe), 14.1 (C8), 18.0
(SiCMe3),18.3 (C7), 25.8 (SiCMe3), 27.6 (C4), 39.2 (C6), 52.6 (CO2Me),
70.1 (C5), 74.1 (C2), 87.2 (C3), 154.1 (CO2Me); m/z (EI) 284 (Mþ, 2%),
227 ([MꢁC4H9]þ, 8%), 97 (58), 85 (72), 83 (77), 81 (50), 71 (88), 69
(100), 67 (51).
4.2.4. (ꢀ)-Methyl 2-(2-tert-butyldimethylsilyloxypentyl)-6-
methoxybenzoate (13). A mixture of the (ꢀ)-octynoate 9 (4.00 g,

C.D. Donner et al. / Tetrahedron 68 (2012) 2799e2805
2803
14.1 mmol), 1-methoxy-1,3-cyclohexadiene (a commercial sample
of the 1,3- and the 1,4-dienes in a 65:35 ratio, 3.33 mL, 28.1 mmol),
compound 15 (432 mg, 94%) as a colourless oil; Rf (dichloro-
methane) 0.73; nmax 3434br, 2933, 1684, 1420, 1202 cmꢁ1
dH
;
dichloromaleic anhydride (10.0 mg, 59.9
m
mol) and N-phenyl-
b
-
(400 MHz) 0.99 (3H, t, J 7.3 Hz, H330), 1.47e1.95 (4H, m, H210 and
H220), 2.79 (1H, dd, J 17.1 and 11.8 Hz, Hax4), 3.14 (1H, dd, J 17.1 and
3.4 Hz, Heq4), 4.55e4.62 (1H, m, H3), 7.91 (1H, s, H6), 11.88 (1H, s,
OH); dC (100 MHz) 13.7 (C30), 18.0 (C20), 33.0 (C4), 36.7 (C10), 79.1
(C3), 110.4 (C), 110.5 (C), 111.2 (C), 137.9 (C), 141.7 (CH), 158.3 (C),
169.0 (C1); m/z (EI) 366 (Mþ, 81Br2, 18%), 364 (Mþ, 81Br79Br, 34%),
naphthylamine (20.0 mg, 91.2
m
mol) was heated in a sealed tube,
with stirring, at 185 ꢂC for 72 h. Flash column chromatography
using a graded solvent system (light petroleum/ether) gave the title
compound 13 (4.35 g, 84%) as a viscous colourless oil; Rf (light pe-
troleum/ether 2:1) 0.55; nmax 2951, 1727, 1468, 1267, 1073 cmꢁ1
; dH
(400 MHz) ꢁ0.25 and ꢁ0.08 (each 3H, s, SiMe), 0.83 (9H, s, SiCMe3),
0.87 (3H, t, J 7.1 Hz, H350), 1.27e1.41 (4H, m, H230 and H240), 2.64
(1H, dd, J 13.5 and 7.7 Hz, HA10), 2.72 (1H, dd, J 13.5 and 5.5 Hz,
HB10), 3.81 (3H, s, CO2Me), 3.82e3.85 (1H, m, H20), 3.90 (3H, s,
OMe), 6.77 (1H, d, J 8.2 Hz, H5), 6.85 (1H, d, J 7.6 Hz, H3), 7.22e7.26
(1H, m, H4); dC (100 MHz) ꢁ5.0 and ꢁ4.9 (each SiMe), 14.2, 18.0
(SiCMe3), 18.5, 25.9 (SiCMe3), 39.7, 41.4, 52.1 (CO2Me), 55.9 (OMe),
72.7 (C20), 108.7, 123.8, 124.0, 129.8,138.0, 156.3, 168.8 (CO2Me); m/z
(EI) 309 ([MꢁC4H9]þ, 87%), 277 (71), 73 (100).
362 (Mþ, 79Br2, 19%), 149 (67), 85 (56), 71 (100), 69 (82); HRMS
79
(ESI): [MꢁH]ꢁ, found 360.9085. C12
H Br2O3 requires 360.9080.
11
4.2.8. (ꢀ)-5,7-Dibromo-8-methoxy-3-propyl-3,4-dihydro-1H-2-
benzopyran-1-one (16). To the (ꢀ)-dibromophenol 15 (385 mg,
1.06 mmol) in acetone (20 mL) were added potassium carbonate
(750 mg, 5.43 mmol) and dimethyl sulfate (0.250 mL, 2.64 mmol)
and the reaction mixture was heated at reflux for 45 min. After
cooling to room temperature water (15 mL) was added and the
product was extracted into chloroform (3ꢃ10 mL) and the com-
bined extracts were dried (MgSO4) and concentrated under re-
duced pressure. The residue was purified by flash column
chromatography (dichloromethane) to give the title compound 16
(390 mg, 98%) as a colourless oil; Rf (dichloromethane) 0.60; nmax
4.2.5. (ꢀ)-8-Methoxy-3-propyl-3,4-dihydro-1H-2-benzopyran-1-
one (14). A solution of the (ꢀ)-benzoate 13 (2.40 g, 6.55 mmol) in
dichloromethane (40 mL) containing para-toluenesulfonic acid
monohydrate (100 mg, 52.6 mmol) was stirred at room temperature
for 72 h. After removal of the solvent under reduced pressure the
residue was purified by flash column chromatography (ether) to
give the title compound 14 (1.31 g, 91%) as a colourless oil; Rf (ether)
2956, 1726, 1453, 1413, 1266, 1217, 1101 cmꢁ1
; dH (400 MHz) 0.98
(3H, t, J 7.3 Hz, H330), 1.46e1.91 (4H, m, H210 and H220), 2.75 (1H, dd,
J 16.9 and 11.4 Hz, Hax4), 3.10 (1H, dd, J 16.9 and 2.9 Hz, Heq4), 3.98
(3H, s, OMe), 4.37e4.43 (1H, m, H3), 7.97 (1H, s, H6); dC (100 MHz)
13.8 (C30), 18.1 (C20), 34.5 (C4), 36.6 (C10), 62.3 (OMe), 77.3 (C3),
117.1 (C), 118.7 (C), 121.8 (C), 140.2 (C), 140.5 (CH), 158.4 (C), 160.9
(C1); m/z (EI) 380 (Mþ, 81Br2, 9%), 378 (Mþ, 81Br79Br, 17%), 376 (Mþ,
0.37; nmax 2953, 1720, 1473, 1232, 1086, 1057 cmꢁ1
; dH (400 MHz)
0.94 (3H, t, J 7.3 Hz, H330), 1.44e1.86 (4H, m, H210 and H220), 2.82
(1H, dd, J 16.0 and 3.3 Hz, Heq4), 2.90 (1H, dd, J 16.0 and 10.8 Hz,
Hax4), 3.93 (3H, s, OMe), 4.35e4.41 (1H, m, H3), 6.79 (1H, d, J 7.5 Hz,
H5), 6.90 (1H, d, J 8.6 Hz, H7), 7.41e7.45 (1H, m, H6); dC (100 MHz)
13.8 (C30), 18.2 (C20), 34.4 (C4), 36.7 (C10), 56.1 (OMe), 77.5 (C3),
110.7 (C7), 113.9 (C8a), 119.2 (C5), 134.3 (C6), 142.0 (C4a), 161.0 (C8),
162.8 (C1); m/z (EI) 220 (Mþ, 47%), 149 (100), 148 (66), 91 (82), 90
(52), 77 (54). The spectral data (1H NMR) was identical to that
reported.22
79Br2, 7%), 85 (53), 74 (74), 71 (81), 69 (100), 60 (75); HRMS (ESI):
79
[MþNa]þ, found 398.9218. C13
H Br2NaO3 requires 398.9202.
14
4.2.9. (ꢀ)-5,7-Dibromo-1-hydroxy-8-methoxy-3-propyl-3,4-
dihydro-1H-2-benzopyran (17). To the (ꢀ)-lactone 16 (350 mg,
0.926 mmol) in toluene (40 mL) at ꢁ70 ꢂC was added diisobuty-
laluminium hydride (1.5 M in toluene, 0.85 mL, 1.28 mmol) drop-
wise. The reaction mixture was maintained at ꢁ70 ꢂC for 45 min
and then allowed to warm to room temperature (30 min). The so-
lution was then poured into saturated potassium sodium tartrate
(40 mL) and stirred vigorously for 1 h. Extraction with chloroform
(3ꢃ10 mL), drying (MgSO4) of the combined organic extracts,
concentration under reduced pressure and crystallization from
ethyl acetate/hexane gave the title compound 17 (330 mg, 94%) as
colourless needles, mp 129e132 ꢂC; nmax 3410br, 2952, 1452, 1089,
4.2.6. (ꢀ)-8-Hydroxy-3-propyl-3,4-dihydro-1H-2-benzopyran-1-one
(8). To the (ꢀ)-methyl ether 14 (350 mg, 1.59 mmol) in dichloro-
methane (30 mL) at 0 ꢂC was added boron trichloride (1 M in
dichloromethane, 2.00 mL, 2.00 mmol) and the solution was
allowed to warm slowly to room temperature and stirred for
a further 12 h. Water (30 mL) was added and stirring was continued
for 10 min followed by extraction with dichloromethane (3ꢃ10 mL).
The combined extracts were dried (MgSO4), concentrated under
reduced pressure and purified by flash column chromatography
(ether) to give the title compound 8 (308 mg, 94%) as a colourless
oil; Rf (ether) 0.70; nmax 3109br, 2957, 1678, 1616, 1460, 1229, 1207,
984 cmꢁ1 dH (400 MHz) 0.99 (3H, t, J 7.3 Hz, H330), 1.44e1.75 (4H,
;
m, H210 and H220), 2.36 (1H, dd, J 17.4 and 11.6 Hz, Hax4), 2.74 (1H,
dd, J 17.4 and 3.4 Hz, Heq4), 2.95 (1H, d, J 3.7 Hz, OH), 3.94 (3H, s,
OMe), 4.24e4.31 (1H, m, H3), 6.17 (1H, d, J 3.7 Hz, H1), 7.74 (1H, s,
H6); m/z (EI) 382 (Mþ, 81Br2, 30%), 380 (Mþ, 81Br79Br, 60%), 378 (Mþ,
1108 cmꢁ1 dH (400 MHz) 0.98 (3H, t, J 7.3 Hz, H330), 1.46e1.92 (4H,
;
m, H210 and H220), 2.91e2.94 (2H, m, H24), 4.56e4.61 (1H, m, H3),
6.69 (1H, d, J 7.3 Hz, H5), 6.88 (1H, d, J 8.4 Hz, H7), 7.38e7.42 (1H, m,
H6), 11.03 (1H, s, OH); dC (100 MHz) 13.8 (C30), 18.1 (C20), 32.9 (C4),
36.8 (C10), 79.4 (C3), 108.5 (C), 116.1 (CH), 117.9 (CH), 136.0 (CH),
139.5 (C), 162.1 (C),170.0 (C1); m/z (EI) 206 (Mþ,100%),135 (52), 134
(65); HRMS (ESI): [MþNa]þ, found 229.0837. C12H14NaO3 requires
229.0835.
79Br2, 31%), 308 (100), 306 (60), 290 (53); HRMS (ESI): [MþNa]þ,
79
found 400.9375. C13
H Br2NaO3 requires 400.9358.
16
4.2.10. (ꢀ)-5,7-Dibromo-8-methoxy-3-propyl-3,4-dihydro-1H-2-
benzopyran (18). To the (ꢀ)-lactol 17 (300 mg, 0.789 mmol) in
dichloromethane (50 mL) at 0 ꢂC was added trifluoroacetic acid
(0.180 mL, 2.34 mmol) and the solution was stirred for 15 min.
Triethylsilane (0.380 mL, 2.38 mmol) was added and the solution
was allowed to warm slowly to room temperature then stirred for
a further 45 min. Water (20 mL) was added and the product was
extracted into chloroform (3ꢃ10 mL) and the combined extracts
were dried (MgSO4) and concentrated under reduced pressure.
Flash column chromatography (dichloromethane) and crystalliza-
tion from ether/hexane gave the title compound 18 (280 mg, 98%) as
colourless needles, mp 112e116 ꢂC; Rf (dichloromethane) 0.65; nmax
4.2.7. (ꢀ)-5,7-Dibromo-8-hydroxy-3-propyl-3,4-dihydro-1H-2-
benzopyran-1-one (15). To a solution of the (ꢀ)-phenol 8 (260 mg,
1.26 mmol) in dimethylformamide (10 mL) was added a solution of
N-bromosuccinimide (460 mg, 2.58 mmol) in dimethylformamide
(2 mL) dropwise. The reaction mixture was stirred at room tem-
perature, in the dark, for 18 h, diluted with water (20 mL), extracted
with chloroform (3ꢃ10 mL) and the combined extracts were
washed with water (5ꢃ10 mL) and dried (MgSO4). After removal of
the solvent under reduced pressure the residue was purified by
flash column chromatography (dichloromethane) to give the title
2951, 1448, 1174, 1096 cmꢁ1
H330), 1.44e1.74 (4H, m, H210 and H220), 2.42 (1H, dd, J 17.2 and
; dH (400 MHz) 0.98 (3H, t, J 7.2 Hz,

2804
C.D. Donner et al. / Tetrahedron 68 (2012) 2799e2805
10.7 Hz, Hax4), 2.70 (1H, dd, J 17.2 and 3.4 Hz, Heq4), 3.52e3.59 (1H,
m, H3), 3.80 (3H, s, OMe), 4.65 (1H, d, J 16.0 Hz, Hax1), 4.99 (1H, d, J
16.0 Hz, Heq1), 7.64 (1H, s, H6); dC (100 MHz) 14.1 (C30), 18.6 (C20),
34.7 (C4), 37.9 (C10), 60.4 (OMe), 64.8 (C1), 74.3 (C3), 114.3 (C), 119.9
(C),132.6 (C),133.7 (CH),134.6 (C),152.1 (C); m/z (EI) 366 (Mþ, 81Br2,
8%), 364 (Mþ, 81Br79Br, 15%), 362 (Mþ, 79Br2, 13%), 292 (100), 290
(61), 281 (51), 279 (54), 75 (56), 71 (64).
dimethylformamide (12 mL) was added sodium borohydride
(190 mg, 5.02 mmol). After stirring for 20 min the (ꢀ)-methyl ether
20 (170 mg, 0.824 mmol) in dimethylformamide (2 mL) was added
and the solution was heated under reflux for 2 h. After cooling to
room temperature the solution was diluted with water (20 mL),
acidified (dil aq H2SO4) and extracted with ethyl acetate (3ꢃ15 mL).
The combined organic extracts were washed sequentially with
brine (3ꢃ30 mL) and water (3ꢃ30 mL) and dried (MgSO4). Con-
centration under reduced pressure followed by flash column
chromatography using a graded solvent system (dichloromethane/
ethyl acetate) and crystallization from dichloromethane/hexane
gave the title compound 21 (110 mg, 70%) as colourless plates, mp
119e122 ꢂC; Rf (dichloromethane/ethyl acetate 1:1) 0.60; nmax
4.2.11. (ꢀ)-5,7-Dibromo-8-hydroxy-3-propyl-3,4-dihydro-1H-2-
benzopyran (19); prepared by demethylation of (ꢀ)-methyl ether
(18). To a solution of dibenzyldiselenide (150 mg, 0.44 mmol) in
dimethylformamide (8 mL) was added sodium borohydride
(115 mg, 3.04 mmol). After stirring for 15 min the (ꢀ)-methyl ether
18 (230 mg, 0.632 mmol) in dimethylformamide (2 mL) was added
and the solution was heated under reflux for 1.5 h. After cooling to
room temperature the solution was diluted with water (5 mL),
acidified (dil aq H2SO4) and extracted with ethyl acetate (2ꢃ10 mL).
The combined organic extracts were washed sequentially with
brine (3ꢃ15 mL) and water (3ꢃ15 mL) and dried (MgSO4). Con-
centration under reduced pressure followed by flash column
chromatography (dichloromethane/light petroleum) and crystalli-
zation from dichloromethane/hexane gave the title compound 19
(180 mg, 82%) as colourless needles, mp 99e100 ꢂC; Rf (dichloro-
methane/light petroleum 1:1) 0.35; nmax 3379br, 3066, 1437, 1202,
3240br, 2957, 1589, 1467, 1276, 1043, 776 cmꢁ1
; dH (400 MHz) 0.96
(3H, t, J 7.2 Hz, H330), 1.40e1.74 (4H, m, H210 and H220), 2.68e2.70
(2H, m, H24), 3.62e3.68 (1H, m, H3), 4.69 (1H, d, J 15.6 Hz, Hax1),
5.00 (1H, d, J 15.6 Hz, Heq1), 5.29 (1H, br s, OH), 6.55 (1H, d, J 7.9 Hz,
H5), 6.69 (1H, d, J 7.6 Hz, H7), 7.00e7.04 (1H, m, H6); dC (100 MHz)
14.1 (C30), 18.7 (C20), 33.9 (C4), 37.9 (C10), 64.4 (C1), 74.3 (C3), 112.1
(CH), 121.0 (CH), 122.0 (C), 126.9 (CH), 135.5 (C), 151.4 (C); m/z (EI)
192 (Mþ, 0.6%), 40 (100); HRMS (ESI): [MꢁH]ꢁ, found 191.1078.
C12H15O2 requires 191.1078.
4.2.14. (ꢀ)-5,7-Dibromo-8-hydroxy-3-propyl-3,4-dihydro-1H-2-
benzopyran (19); prepared by bromination of (ꢀ)-phenol (21). To
a solution of the (ꢀ)-phenol 21 (36.0 mg, 0.187 mmol) in
dimethylformamide (2 mL) was added a solution of N-bromo-
succinimide (68.0 mg, 0.382 mmol) in dimethylformamide
(0.5 mL) dropwise. The reaction mixture was stirred at room
temperature, in the dark, for 18 h, diluted with water (5 mL),
extracted with ethyl acetate (3ꢃ5 mL) and the combined extracts
were washed with water (4ꢃ10 mL) and dried (MgSO4). After
removal of the solvent under reduced pressure the residue was
purified by flash column chromatography (dichloromethane/
light petroleum) to give the title compound 19 (54.0 mg, 82%) as
colourless needles, mp 99e100 ꢂC, from dichloromethane/hex-
ane. All physical and spectroscopic data were identical to the
data obtained for the same product prepared from (ꢀ)-ether 18,
as described above.
1173 cmꢁ1 dH (400 MHz) 0.98 (3H, t, J 7.2 Hz, H330), 1.43e1.74 (4H,
;
m, H210 and H220), 2.42 (1H, dd, J 17.1 and 10.5 Hz, Hax4), 2.71 (1H,
dd, J 17.1 and 3.2 Hz, Heq4), 3.52e3.59 (1H, m, H3), 4.59 (1H, d, J
16.1 Hz, Hax1), 4.95 (1H, d, J 16.1 Hz, Heq1), 5.49 (1H, s, OH), 7.54 (1H,
s, H6); dC (100 MHz) 14.1 (C30), 18.7 (C20), 34.7 (C4), 37.8 (C10), 64.7
(C1), 74.1 (C3), 107.3 (C), 115.2 (C), 125.4 (C), 131.7 (CH), 134.7 (C),
147.1 (C); m/z (EI) 352 (Mþ, 81Br2, 9%), 350 (Mþ, 81Br79Br, 19%), 348
(Mþ, 79Br2, 11%), 280 (52), 278 (100), 276 (50); HRMS (ESI):
79
[MþNa]þ, found 370.9263. C12
H Br2NaO2 requires 370.9253.
14
4.2.12. (ꢀ)-8-Methoxy-3-propyl-3,4-dihydro-1H-2-benzopyran
(20). To the (ꢀ)-lactone 14 (350 mg, 1.59 mmol) in toluene (35 mL)
at ꢁ70 ꢂC, under nitrogen, was added diisobutylaluminium hydride
(1.5 M in toluene, 1.50 mL, 2.25 mmol). The reaction mixture was
maintained at ꢁ70 ꢂC for 1 h and then allowed to warm slowly to
room temperature (approx. 1 h). The mixture was poured into
a saturated aqueous solution of potassium sodium tartrate (40 mL)
and stirred vigorously (1 h). The product was extracted into chlo-
roform (4ꢃ15 mL) and the combined organic extracts were dried
(MgSO4). Concentration under reduced pressure gave an oil, which
was dissolved in dichloromethane (25 mL) and cooled to 0 ꢂC.
Trifluoroacetic acid (0.380 mL, 4.96 mmol) was added and the so-
lution was stirred for 10 min. Triethylsilane (0.760 mL, 4.76 mmol)
was added and the solution was stirred at 0 ꢂC for 1 h. Water
(20 mL) was added and the product was extracted into dichloro-
methane (3ꢃ10 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. Flash column
chromatography (dichloromethane) gave the title compound 20
(292 mg, 89%) as colourless needles, mp 40e41 ꢂC (hexane);
[Found: C, 75.59; H, 8.89. C13H18O2 requires C, 75.69; H 8.80%]; Rf
(dichloromethane) 0.60; nmax 2949, 1584, 1469, 1257, 1085, 1056,
4.2.15. (ꢀ)-7-Bromo-3-propyl-3,4-dihydro-1H-2-benzopyran-5,8-
dione (7). To
a
solution of the (ꢀ)-phenol 19 (155 mg,
0.443 mmol) in acetonitrile (10 mL) and THF (0.30 mL) was added
a solution of cerium (IV) ammonium nitrate (728 mg, 1.33 mmol
in water; 1.5 mL). The solution was stirred at room temperature
for 30 min, diluted with water (15 mL) and extracted with chlo-
roform (3ꢃ5 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. The residual
oil in dichloromethane/ethyl acetate (95:5) was filtered through
a short column (0.5 cm) of silica and the filtrate was concentrated
to give the title compound 7 (115 mg, 91%) as a yellow oil; nmax
2955, 2929, 1663, 1654, 1587, 735 cmꢁ1
; dH (400 MHz) 0.94 (3H, t,
J 7.1 Hz, H330), 1.38e1.68 (4H, m, H210 and H220), 2.18 (1H, dddd, J
19.0, 10.0, 4.4 and 2.7 Hz, Hax4), 2.56 (1H, ddd, J 19.0, 3.5 and
2.9 Hz, Heq4), 3.43e3.49 (1H, m, H3), 4.38 (1H, ddd, J 18.8, 4.4 and
3.5 Hz, Hax1), 4.68 (1H, dd, J 18.8 and 2.7 Hz, Heq1), 7.24 (1H, s,
H6); dC (100 MHz) 14.0 (C30), 18.4 (C20), 27.5 (C4), 37.4 (C10), 63.3
(C1), 73.0 (C3), 136.9 (C), 137.8 (CH), 140.4 (C), 140.5 (C), 177.9 (C),
767 cmꢁ1 dH (400 MHz) 0.97 (3H, t, J 7.2 Hz, H330),1.43e1.72 (4H, m,
;
H210 and H220), 2.67e2.68 (2H, m, H24), 3.57e3.63 (1H, m, H3), 3.80
(3H, s, OMe), 4.62 (1H, d, J 15.9 Hz, Hax1), 4.94 (1H, d, J 15.9 Hz,
Heq1), 6.67 (1H, d, J 8.3 Hz, H5), 6.71 (1H, d, J 7.6 Hz, H7), 7.11e7.15
(1H, m, H6); dC (100 MHz) 14.1 (C30), 18.7 (C20), 33.9 (C4), 38.0 (C10),
55.0 (OMe), 64.6 (C1), 73.9 (C3), 107.0 (CH), 120.8 (CH), 123.6 (C),
126.7 (CH), 135.0 (C), 155.3 (C); m/z (EI) 206 (Mþ, 23%), 134 (100).
The spectral data (1H NMR) was identical to that reported.22
183.5 (C); lmax (EtOH) 205 (log
3
4.24), 273 nm (4.02); m/z (EI)
286 (Mþ, 81Br, 20%), 284 (Mþ, 79Br, 15%), 279 (56), 216 (71), 214
(84), 77 (54), 71 (100).
4.2.16. (ꢀ)-3,4-Dihydro-7,9-dihydroxy-3-propyl-1H-naphtho[2,3-c]
pyran-5,10-dione (6). To the (ꢀ)-benzoquinone
7 (115 mg,
4.2.13. (ꢀ)-8-Hydroxy-3-propyl-3,4-dihydro-1H-2-benzopyran
(21). To a solution of dibenzyldiselenide (224 mg, 0.658 mmol) in
0.403 mmol) in benzene (2 mL) was added 1-methoxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene (210 mg, 0.806 mmol) in

C.D. Donner et al. / Tetrahedron 68 (2012) 2799e2805
2805
benzene (1 mL). The mixture was stirred at room temperature for
1 h then heated at reflux for 1.5 h. After cooling to room temper-
ature silica (200 mg) was added and the solution was stirred for
a further 15 min. After removal of the solvent under reduced
pressure the residue was filtered slowly through a short column of
silica (dichloromethane/ethyl acetate 2:1þ1% formic acid). The
yellow fractions were combined, concentrated, further chromato-
graphed (Sephadex LH-20, dichloromethane/methanol 1:1) and
crystallized from acetone/chloroform to give the title compound 6
(50.0 mg, 43%) as orange needles, mp 180e182 ꢂC (dec); nmax
242 (Mþ, 81Br, 58%), 240 (Mþ, 79Br, 44), 161 (100), 105 (53), 79 (71),
77 (73).
4.2.19. 1,3-Dihydroxy-5,6,7,8-tetrahydro-9,10-anthraquinone
(25). To the benzoquinone 24 (120 mg, 0.498 mmol) in benzene
(2 mL) was added 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-
butadiene (250 mg, 0.960 mmol). The solution was stirred at
room temperature for 4 h and then heated at reflux for 1 h. After
cooling to room temperature, silica (0.5 g) was added and the so-
lution was stirred for a further 30 min. After removal of the solvent
under reduced pressure the residue was filtered slowly through
a short column of silica (dichloromethane/ethyl acetate 1:1þ1%
formic acid). The yellow fractions were combined, concentrated,
further chromatographed (Sephadex LH-20, dichloromethane/
methanol 1:1) and crystallized from acetone/chloroform to give the
title compound 25 (100 mg, 83%) as orange needles, mp 188e191 ꢂC
3413br, 1637, 1614, 1321, 1153 cmꢁ1
; dH (400 MHz, acetone-d6) 0.94
(3H, t, J 7.2 Hz, H330), 1.40e1.61 (4H, m, H210 and H220), 2.07e2.16
(1H, m, Hax4), 2.58 (1H, ddd, J 18.8, 3.2 and 2.9 Hz, Heq4), 3.48e3.55
(1H, m, H3), 4.38 (1H, ddd, J 18.5, 3.7 and 3.2 Hz, Hax1), 4.68 (1H, dd,
J 18.5 and 2.6 Hz, Heq1), 6.51 (1H, d, J 2.5 Hz, H8), 6.97 (1H, d, J
2.5 Hz, H6), 10.36 (1H, br s, 7-OH), 12.02 (1H, s, 9-OH); dC (100 MHz,
acetone-d6) 14.2 (C30), 19.2 (C20), 28.6 (C4), 38.3 (C10), 63.3 (C1),
73.6 (C3), 108.0 (C8), 109.0 (C6), 109.2 (C9a), 134.7 (C5a), 142.9 (C4a/
10a), 143.5 (C4a/10a), 165.0 (C9), 165.6 (C7), 183.2 (C5), 187.5 (C10);
(dec); nmax 3407br, 1630, 1609, 1316, 1156 cmꢁ1
; dH (400 MHz, d6-
acetone) 1.69e1.72 (4H, m, H26 and H27), 2.45e2.51 (4H, m, H25
and H28), 6.52 (1H, d, J 2.4 Hz, H2), 6.98 (1H, d, J 2.4 Hz, H4), 9.81
(1H, br s, 3-OH), 12.31 (1H, s, 1-OH); dC (100 MHz, acetone-d6) 21.6
(C6 and 7), 23.1 (C5/8), 23.7 (C5/8), 107.8 (C2/4), 108.3 (C2/4), 109.6
(C9a), 134.9 (C4a), 145.3 (C8a/10a), 145.6 (C8a/10a), 164.9 (C1/3),
lmax (EtOH) 219 (log 4.43), 271 (4.09), 289 (3.98), 440 nm (3.45);
3
(EtOHþ1 drop 1 M aq NaOH) 208 (log
3
4.79), 232 (4.29), 295 (4.07),
530 nm (3.37); m/z (EI) 288 (Mþ, 68%), 216 (100); HRMS (ESI):
[MꢁH]ꢁ, found 287.0926. C16H15O5 requires 287.0925.
165.0 (C1/3), 184.2 (C10), 189.2 (C9); lmax (EtOH) 219 (log
3
4.44),
271 (4.12), 291 (4.05), 426 nm (3.50); (EtOHþ1 drop 1 M aq NaOH)
4.2.17. 2,4-Dibromo-5,6,7,8-tetrahydro-1-naphthol (23). To a solu-
tion of 5,6,7,8-tetrahydro-1-naphthol 22 (100 mg, 0.675 mmol) in
dimethylformamide (3 mL) was added a solution of N-bromo-
succinimide (246 mg, 1.38 mmol) in dimethylformamide (1 mL).
The solution was stirred at room temperature, in the dark, for 18 h,
diluted with water (20 mL), extracted with ethyl acetate (3ꢃ10 mL)
and the combined organic extracts were washed with water
(4ꢃ15 mL) and dried (MgSO4). Removal of the solvent under re-
duced pressure and crystallization from hexane gave the title
compound 23 (197 mg, 96%) as colourless needles, mp 54e55 ꢂC;
207 (log 4.73), 231 (4.35), 250 (4.08), 295 (4.18), 518 nm (3.48); m/
3
z (EI) 244 (Mþ, 22%), 86 (70), 84 (79), 71 (100), 70 (58), 69 (99).
Supplementary data
1H NMR and 13C NMR spectra for compounds 6e9, 11e21 and
23e25. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2012.02.009.
nmax 3398br, 2934, 1425, 1301, 1221, 689 cmꢁ1
; dH (400 MHz)
References and notes
1.73e1.80 (4H, m, H26 and H27), 2.64e2.72 (4H, m, H25 and H28),
5.48 (1H, s, OH), 7.50 (1H, s, H3); dC (100 MHz) 21.9 (CH2), 22.5
(CH2), 24.5 (CH2), 30.3 (CH2), 106.8 (C), 115.9 (C), 127.5 (C), 130.9
(CH), 137.5 (C), 149.1 (C); m/z (EI) 308 (Mþ, 81Br2, 22%), 306 (Mþ,
81Br79Br, 46%), 304 (Mþ, 79Br2, 26%), 146 (70), 84 (54), 57 (92), 55
(100), 51 (61); HRMS (ESI): [MꢁH]ꢁ, found 302.9029. C10H799Br2O
requires 302.9026.
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(MgSO4) and concentrated under reduced pressure. The residual oil
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Springer: New York, NY, 1983.
ꢀ
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3054e3065.
(120 mg, 87%) as a yellow oil; nmax 3015,1662, 1647,1213, 753 cmꢁ1
;
dH (400 MHz) 1.68e1.72 (4H, m, H26 and H27), 2.41e2.50 (4H, m,
H25 and H28), 7.20 (1H, s, H3); dC (100 MHz) 20.7 (CH2), 21.1 (CH2),
22.6 (CH2), 23.5 (CH2),137.1 (C),137.8 (CH),142.2 (C),142.9 (C),179.6
22. Giles, R. G. F.; Green, I. R.; Pestana, J. A. X. J. Chem. Soc., Perkin Trans. 1 1984,
2389e2395.
(C), 184.9 (C); lmax (EtOH) 203 (log 4.39), 275 nm (4.42); m/z (EI)
3