Synthesis of a C8 oxygenated pyranonaphthoquinone: a useful precursor to dimeric pyranonaphthoquinones

Article abstract of DOI:10.1016/j.tet.2008.01.135

The synthesis of a pyranonaphthoquinone bearing an oxygenated substituent at C8 is reported. The oxygen substituent at C8 provides a key functionality for use as a homocoupling precursor for the synthesis of a dimeric pyranonaphthoquinone.

Full text of DOI:10.1016/j.tet.2008.01.135

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3343e3350
www.elsevier.com/locate/tet
Synthesis of a C8 oxygenated pyranonaphthoquinone: a useful
precursor to dimeric pyranonaphthoquinones
*
Prabhakar Bachu, Jonathan Sperry, Margaret A. Brimble
Department of Chemistry, The University of Auckland, 23 Symonds Street, Auckland, New Zealand
Received 29 October 2007; received in revised form 14 January 2008; accepted 31 January 2008
Available online 6 February 2008
Abstract
The synthesis of a pyranonaphthoquinone bearing an oxygenated substituent at C8 is reported. The oxygen substituent at C8 provides a key
functionality for use as a homocoupling precursor for the synthesis of a dimeric pyranonaphthoquinone.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Pyranonaphthoquinone antibiotics; Intramolecular cyclization; Nanaomycin
O
OH
OH
OH
OH
O
1. Introduction
8
8'
8'
O
O
O
O
The class of compounds known as the pyranonaphthoqui-
none antibiotics are isolated from various strains of bacteria
and fungi, the majority being microbial in origin.1,2 This fam-
ily of compounds have been shown to exhibit activity against
various Gram-positive bacteria, pathogenic fungi and yeasts,
as well as antiviral activity. Several pyranonaphthoquinones
have also been proposed to act as effective bioreductive alkyl-
ating agents.3,4 More structurally complex members of this
class include actinorhodin 1 and crisamicin A 2, symmetrical
dimeric pyranonaphthoquinones linked via a common C8eC80
biaryl bond (Fig. 1). Given their significant biological activity
combined with our continued interest in this class of com-
pounds, we were attracted to the possibility of synthesizing
dimeric pyranonaphthoquinones using a late stage homocou-
pling of their respective monomers. To date, the only success-
ful synthesis of pyranonaphthoquinone dimers is based around
early stage homocoupling techniques, including an Ullman
coupling to construct the biaryl bond during a racemic synthe-
sis of cardinalin C35 and our own success6a,b using a Suzukie
Miyaura homocoupling of aryl triflates to access regioisomers
of crisamicin A. We herein report our efforts towards the
HO2C
CO2H
O
O
O
O
1
8
H
O
H
O
H
H
O
O
O
OH
OH
O
2
Figure 1.
synthesis of a monomeric pyranonaphthoquinone bearing an
appropriately positioned oxygenated substituent at C8 that
would provide an appropriate handle for subsequent late stage
homocoupling. Thus, triflate 4 was deemed a key precursor to
target model dimer 3 and the synthesis of methoxynaphthoqui-
none 5 is the focus of the work reported herein (Scheme 1).
2. Results and discussion
The retrosynthetic analysis of cis-C8 oxygenated pyrano-
naphthoquinone 5 is depicted (Scheme 2) and is based on
our recently reported enantioselective synthesis of an analogue
of deoxynanaomycin A.7,8 The chosen route hinges on the use
of homoallylic acetate 6 in which the stereochemistry at C3
* Corresponding author. Tel.: þ64 9 3737599x88259; fax: þ64 9 3737599.
E-mail address: m.brimble@auckland.ac.nz (M.A. Brimble).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.135

3344
P. Bachu et al. / Tetrahedron 64 (2008) 3343e3350
by Giles’ et al.9 Thus, regioselective bromination of p-methoxy-
O
O
O
O
8
8'
phenol 10 delivered arylbromide 11 that underwent smooth
tosylation to tosylate 12 in excellent yield. The benzyne inter-
mediate generated from bromotosylate 12 was treated with
excess furan, affording 7-methoxynaphthalen-1-ol 9. Regio-
selective bromination10,11 of naphthol 9 was achieved by treat-
ment with N-bromosuccinimide in the presence of a catalytic
quantity of diisopropylamine at ꢀ30 ꢁC affording arylbromide
13 that underwent oxidation with [bis(trifluoroacetoxy)iodo]-
benzene12 to naphthoquinone 14. Lewis acid promoted
allylation of quinone 14 in the presence of allyltrimethyl-
silane13 delivered allylnaphthoquinone 8 after reoxidation of
the crude reaction mixture with ferric chloride. Reductive
methylation14 of 8 then provided allylbromonaphthalene 15
that was subjected to immediate dihydroxylation using cata-
lytic quantities of osmium tetroxide with N-methylmorpholine
N-oxide as co-oxidant, furnishing diol 16. Sodium periodate
mediated oxidative cleavage of diol 16 gratifyingly delivered
the desired aldehyde 7 in excellent yield. With aldehyde 7
in hand, the allylation could be attempted. Thus, freshly pre-
pared allylmagnesium bromide was added to a solution of
aldehyde 7 in diethyl ether, delivering rac-17 in excellent yield
(Scheme 3).
Attention could now be focused towards an asymmetric var-
iant of the allylation reaction. Initially, the popular asymmetric
allylation method reported by Brown15 was investigated. Treat-
ment of (ꢀ)-DIP-chlorideÒ with freshly prepared allylmagne-
sium bromide at 0 ꢁC followed by the addition of aldehyde 7
to a magnesium salt free ethereal solution of the resulting
(þ)-B-allyldiisopinocampheylborane 18 at ꢀ78 ꢁC only af-
fording unreacted aldehyde 7. This result was surprising as
the demethoxy analogue of aldehyde 7 previously underwent
smooth asymmetric allylation in our hands.7 Unperturbed by
this result, attention turned to the use of our recently disclosed
microwave promoted enzymatic resolution of racemic alco-
hols16 as a possible method of preparing enantioenriched
(S)-17. Unfortunately, various attempts at resolving racemic
homoallylic alcohol rac-17 into (S)-17 and acetate (R)-6 using
our microwave assisted NovozymeÒ 435 protocol failed, with
unreacted rac-17 being the only product isolated from the
reaction (Scheme 4).
O
O
HO2C
CO2H
3
biaryl homocoupling
O
TfO
O
2 x
CO2H
O
4
O
O
MeO
1
O
8
3
CO2H
(1R,3R)-5
Scheme 1.
is established via asymmetric allylation of aldehyde 7. Alde-
hyde 7 can be accessed from allylbromonaphthalene 8, which
in turn can be prepared from naphthol 9. In the key cyclization
step, lithiumehalogen exchange of (S)-6 followed by in situ
trapping of the resulting aryllithium with the adjacent acetate
triggers an intramolecular cyclization, furnishing pyrano-
naphthoquinone 5 after oxidation of the allyl side chain
(Scheme 2).
Initially, attention focused on the synthesis of racemic
homoallylic alcohol rac-17 in order to gauge the viability of
the proposed approach. Our initial starting material, 7-methoxy-
naphthalen-1-ol 9 was accessed using the procedure reported
O
MeO
O
(1R,3R)-5
3
CO2H
O
It was decided to continue with the synthesis in racemic
form in order to test the viability of the proposed route.
Thus, homoallylic acetate rac-6 was prepared in 90% yield
from rac-17 using acetic anhydride in dichloromethane in the
presence of a catalytic quantity of perchloric acid in excellent
yield. rac-Homoallylic acetate 17 was then treated with tert-
butyllithium at ꢀ78 ꢁC, gratifyingly undergoing cyclization
in situ to afford the unstable lactol 19 that was swiftly con-
verted to the stable cis-(ꢂ)-naphthopyran 20 in 65% yield
over two steps using the triethylsilane promoted reduction
reported by Kraus.17 The NOESY spectrum recorded for 20
confirmed the cis-stereochemistry between 1-H and 3-H.
Dihydroxylation of the allylic group in naphthopyran 20
was achieved with the osmium tetroxide oxidation resulting
in an inseparable mixture of 1,2-diols 21 that underwent
smooth oxidative cleavage in the presence of sodium periodate
OMe
OMe
O
MeO
Br
MeO
Br
O
CHO
OMe
OMe
(S)-6
7
O
OH
MeO
Br
MeO
O
8
9
Scheme 2.

P. Bachu et al. / Tetrahedron 64 (2008) 3343e3350
3345
OH
MeO
MeO
MeO
Br
MeO
Br
MeO
(i)
(ii)
(iii)
OH
OH
OH
OTs
9
12
10
11
O
O
O
OMe
MeO
Br
MeO
Br
MeO
Br
Br
(vii)
(iv)
(v)
(vi)
O
8
OMe
15
13
14
OMe
OMe
OMe
MeO
Br
MeO
Br
MeO
Br
OH
(viii)
(ix)
(x)
OH
OH
CHO
OMe
rac-17
OMe
16
OMe
7
Scheme 3. (i) Br2, CH2Cl2, ꢀ5 ꢁC, 1 h, 86%; (ii) p-toluenesulfonyl chloride, Et3N, CH2Cl2, 0 ꢁC, 2 h, 93%; (iii) n-BuLi, furan, THF, 30 min, ꢀ78 ꢁC to rt, then
MeOH, HCl, 80 ꢁC, 2 h, 70%; (iv) NBS, i-Pr2NH, CH2Cl2, 1 h, ꢀ30 ꢁC, 60%; (v) PhI(OCOCF3)2, MeCNeH2O, 1 h, ꢀ5 ꢁC, 58%; (vi) allyltrimethylsilane,
MeAlCl2, CH2Cl2, 2 h, ꢀ78 ꢁC then anhydrous FeCl3, MeOH, 6 h, rt, 55%; (vii) Na2S2O4, THFeH2O, n-Bu4NF, KOH, Me2SO4, 4 h, 95%; (viii) OsO4,
NMO, acetoneeH2O, 24 h, 0 ꢁC to rt, 80% (1:1); (ix) NaIO4, MeOHeH2O, 2 h, rt, 99%; (x) allylmagnesium bromide, Et2O, 6 h, ꢀ40 ꢁC to rt, 89%.
B
2
OMe
OMe
18
MeO
Br
MeO
Br
OH
CHO
OMe
7
OMe
(S)-17
Novozyme 435
microwave
OMe
OMe
OMe
O
OMe
MeO
Br
MeO
Br
MeO
Br
OH
O
OH
+
OAc
OMe
(R)-6
OMe
rac-17
Cl
(S)-17
Scheme 4.
to furnish aldehyde cis-(ꢂ)-22. The desired transformation
into carboxylic acid cis-(ꢂ)-23 was accomplished by treat-
ment of a tert-butanol solution of aldehyde 22 with sodium
chlorite,18 with a final CAN-mediated oxidative methylation
gratifyingly providing pyranonaphthoquinone cis-(ꢂ)-5 in
76% yield over the two steps (Scheme 5). Importantly, the
NOESY spectrum recorded for 5 confirmed the cis-stereo-
chemistry between 1-H and 3-H.
OMe
OMe
O
OMe
OH
O
MeO
Br
MeO
(iv)
Br
MeO
(v)
OH
(i)
O
(ii)
OMe
rac-17
OMe
rac-6
OMe
19
OMe
OMe
OMe
OMe
MeO
MeO
MeO
(iii)
O
OH
O
O
OH
O
CHO
OMe
cis-( )-20
OMe
cis-( )-22
cis-( )-21
OMe
OMe
MeO
MeO
O
O
(vii)
(vi)
CO2H
CO2H
O
cis-( )-5
cis-( )-23
Scheme 5. (i) Ac2O, CH2Cl2, HClO4, 2 h, rt, 90%; (ii) t-BuLi, THF, 1 h, ꢀ78 ꢁC; (iii) Et3SiH, TFA, CH2Cl2, 2 h, ꢀ78 ꢁC to rt, 65% (over 2 steps); (iv) OsO4,
NMO, acetoneeH2O, 24 h, 0 ꢁC to rt, 86%; (v) NaIO4, MeOHeH2O, 2 h, rt, 70%; (vi) NaClO2, t-BuOH, NaH2PO4$2H2O, cyclohexene, 2 h, rt; (vii) CAN,
MeCNeH2O, 10 min, 0 ꢁC to rt, 76% (over 2 steps).

3346
P. Bachu et al. / Tetrahedron 64 (2008) 3343e3350
Unfortunately, all attempts to remove the methoxy group at
8.10 mmol) in dichloromethane (6 mL) dropwise at ꢀ5 ꢁC.
The reaction mixture was stirred for 1 h then quenched with
saturated Na2S2O5 solution (5 mL), washed with water (40 mL)
and dried over anhydrous MgSO4. The organic extract was
evaporated under reduced pressure and the residue purified
by flash chromatography (20% ethyl acetate/hexanes) to afford
the title compound 11 (1.60 g, 7.9 mmol, 86%) as a colourless
solid, mp 43e44 ꢁC (lit.19 mp 42e43 ꢁC); Rf (20% ethyl
acetate/hexanes) 0.45; dH (400 MHz, CDCl3) 7.01 (1H, d,
J3,5 2.9 Hz, 3-H), 6.94 (1H, d, J6,5 9.0 Hz, 6-H), 6.80 (1H,
dd, J5,6 9.0 Hz, J5,3 2.9 Hz, 5-H), 5.15 (1H, br s, OH), 3.75
(3H, s, 4-OMe); m/z (EI, %) 204 (Mþ, 81Br, 50), 202 (Mþ,
79Br, 55), 189 (50), 187 (50), 73 (57), 41 (100); HRMS (EI)
Mþ, Found 203.9614, 201.9635, C7H871BrO2, C7H779BrO2
requires 203.9609, 201.9629. The spectroscopic data was in
agreement with that reported in the literature.19
C8 using a variety of conditions led to degradation of the sub-
strate, thus its conversion to the key homocoupling precursor 4
could not be achieved.
3. Conclusions
The synthesis of a pyranonaphthoquinone bearing an
oxygen substituent at C8 has been achieved starting from
p-methoxyphenol 10. Although the key homocoupling was
not achieved due to the difficulty in removing the protecting
group at C8, the synthesis of the monomer 5 provides an im-
portant basis for further studies in this area. Synthetic efforts
towards an asymmetric synthesis of the key monomeric
coupling precursor with a suitably labile protecting group at
C8 as well studies on a late stage homocoupling strategy are
ongoing.
4.1.2. 2-Bromo-4-methoxyphenyl-p-toluenesulfonate 129
4. Experimental
To a stirred solution of 2-bromo-4-methoxyphenol 11
(1.60 g, 7.9 mmol) in dichloromethane (25 mL) was added
triethylamine (1.30 mL, 9.48 mmol) at 0 ꢁC. A solution of
p-toluenesulfonyl chloride (1.80 g, 9.48 mmol) in dichloro-
methane (35 mL) was added dropwise and stirring was contin-
ued for 2 h. The mixture was washed with water (25 mL),
saturated NaHCO3 solution (25 mL) and brine (25 mL). After
drying over anhydrous MgSO4, the solvent was removed under
reduced pressure. The crude product was purified by flash
chromatography (10% ethyl acetate/hexanes) to afford the title
compound 12 (2.62 g, 7.3 mmol, 93%) as colourless needles,
mp 74e76 ꢁC (lit.9 mp 73.5e75 ꢁC); Rf (10% ethyl acetate/
hexanes) 0.60; dH (400 MHz, CDCl3) 7.77 (2H, d, J 8.2 Hz,
Ar-H), 7.32 (2H, d, J 8.2 Hz, Ar-H), 7.22 (1H, d, J6,5
9.0 Hz, 6-H), 7.01 (1H, d, J3,5 3.0 Hz, 3-H), 6.81 (1H, dd,
J5,6 9.0 Hz, J5,3 3.0 Hz, 5-H), 3.73 (3H, s, 4-OMe), 2.46
(3H, s, Me); m/z (EI, %) 358 (Mþ, 81Br, 20), 356 (Mþ, 79Br,
20), 281 (10), 279 (10), 203 (95), 201 (100), 175 (10), 173
(10), 91 (35); HRMS (EI) Mþ, Found 357.9682, 355.9718,
4.1. General
All reactions were carried out in flame or oven dried glass-
ware under a dry nitrogen atmosphere. Tetrahydrofuran and
diethyl ether were dried over sodium wire. Dichloromethane,
pyridine and triethylamine were dried over calcium hydride,
and ethanol and methanol were dried over magnesium ethox-
ide and methoxide. All solvents were distilled prior to use.
Flash chromatography was carried out using 0.063e0.1 mm
silica gel with the desired solvent. Thin layer chromatography
was performed using silica coated aluminium plates (60 F254).
Compounds were identified using UV fluorescence and or
staining with vanillin in methanolic sulfuric acid, a solution
of ammonium heptamolybdate and cerium sulfate in aqueous
sulfuric acid, iodine or a solution of potassium permanganate
and potassium carbonate in aqueous sodium hydroxide. Low
resolution mass spectra were recorded using a VG-70SE spec-
trometer operating at a nominal accelerating voltage of 70 eV.
High resolution mass spectra were recorded at a nominal res-
olution of 5000e10,000. Infrared spectra were obtained using
a PerkineElmer Spectrum 1000 series Fourier Transform IR
spectrometer as a thin film between sodium chloride plates.
NMR spectra were recorded on either a Bruker DRX300 spec-
81
79
C14H BrO4S, C14H BrO4S requires 357.9698, 355.9718.
The spectroscopic data was in agreement with that reported
in the literature.9
13
13
4.1.3. 7-Methoxynaphthalen-1-ol 99
To a solution of tosyl ester 12 (2.8 g, 7.89 mmol) in anhy-
drous tetrahydrofuran (30 mL) under nitrogen was added furan
(5 mL). The mixture was cooled to ꢀ78 ꢁC and a solution of
n-butyllithium in hexanes (6.25 mL, 1.3 M, 8.28 mmol) was
added dropwise, stirring was continued for 30 min at ꢀ78 ꢁC
then the mixture was allowed to warm to room temperature.
The reaction was quenched with water (25 mL) and extracted
with ethyl acetate (3ꢃ25 mL). The organic layer was dried
over anhydrous MgSO4 and solvent removed under reduced
pressure. The crude material was added to a solution of concd
hydrochloric acid (2 drops) in methanol (20 mL) and was
heated to reflux for 1 h under nitrogen. After cooling to
room temperature, the methanol was removed under reduced
pressure and water (20 mL) was added. The crude product
was extracted with ethyl acetate (3ꢃ20 mL) and dried over
1
trometer operating at 300 MHz for H nuclei and 75 MHz for
13C nuclei or using a Bruker DRX400 spectrometer operating
at 400 MHz for H nuclei and 100 MHz for 13C nuclei. H
NMR data are reported as chemical shift, relative integral,
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint,
quintet), coupling constant (J Hz) and assignment. Optical
rotations were measured using a PerkineElmer 341 polarimeter
at l¼598 nm and are given in 10ꢀ1 deg cm2 gꢀ1. Melting
points were determined on a Kofler hot-stage apparatus and
are uncorrected.
1
1
4.1.1. 2-Bromo-4-methoxyphenol 1119
To a solution of 4-methoxyphenol 10 (1.00 g, 8.10 mmol)
in dichloromethane (30 mL) was added bromine (0.41 mL,

P. Bachu et al. / Tetrahedron 64 (2008) 3343e3350
3347
anhydrous MgSO4. The solvent was removed under reduced
pressure and the residue purified by flash chromatography
(10% ethyl acetate/hexanes) to afford the title compound 9
(958 mg, 5.5 mmol, 70%) as colourless needles, mp 104e
106 ꢁC (lit.9 mp 105e106 ꢁC); Rf (10% ethyl acetate/hexanes)
0.30; dH (300 MHz, CDCl3) 7.69 (1H, d, J5,6 9.0 Hz, 5-H),
7.47 (1H, d, J8,6 2.5 Hz, 8-H), 7.37 (1H, d, J3,4 7.9 Hz, 3-H),
7.17e7.10 (2H, m, 2-H and 6-H), 6.76 (1H, dd, J4,3 7.9 Hz,
J4,2 0.8 Hz, 4-H), 5.58 (1H, br s, OH), 3.91 (3H, s, 7-OMe);
dC (75 MHz, CDCl3) 157.3, 150.5, 130.3, 129.7, 125.2, 123.3,
120.4, 119.2, 109.1, 99.9, 55.4; m/z (EI, %) 174 (Mþ, 95),
131 (60), 92 (13), 77 (13); HRMS (EI) Mþ, Found 174.0683,
C11H10O2 requires 174.0681. The spectroscopic data were in
agreement with that reported in the literature.15
1601, 1588, 1309, 1265, 738 cmꢀ1; dH (400 MHz, CDCl3)
8.03 (1H, d, J5,6 8.6 Hz, 5-H), 7.59 (1H, dd, J8,6 2.6 Hz, J8,5
1.1 Hz, 8-H), 7.46 (1H, s, 3-H), 7.23 (1H, dd, J6,5 8.6 Hz,
J6,8 2.6 Hz, 6-H), 3.96 (3H, s, 7-OMe); dC (75 MHz, CDCl3)
181.5, 178.0, 164.2, 140.6, 139.1, 132.9, 129.3, 125.2,
120.8, 111.3, 56.0; m/z (EI, %) 268 (M [81Br]þ, 78), 266 (M
[79Br]þ, 80), 240 (M [81Br]þꢀO2, 10), 238 (M [79Br]þꢀO2,
10), 187 (MþꢀBr, 100), 159 (40); HRMS (EI) Mþ, Found
267.9563, 265.9574, C11H871BrO3, C11H779BrO3 requires
267.9558, 265.9579.
4.1.6. 3-Bromo-2-allyl-6-methoxy-1,4-naphthoquinone 8
To a solution of 2-bromo-1,4-naphthoquinone 14 (50 mg,
0.19 mmol) in dry dichloromethane (10 mL) at ꢀ78 ꢁC was
added allyltrimethylsilane (0.03 mL, 0.19 mmol) followed
by a solution of methylaluminium dichloride in hexanes
(0.55 mL, 1.0 M, 0.55 mmol). After stirring for 2 h at
ꢀ78 ꢁC, the reaction mixture was quenched with water
(5 mL) and allowed to warm to room temperature. The crude
product was extracted with dichloromethane (3ꢃ5 mL), dried
over anhydrous MgSO4 and the solvent removed under re-
duced pressure. The crude product was dissolved in methanol
4.1.4. 2-Bromo-7-methoxynaphthalen-1-ol 13
To a stirred solution of naphthol 9 (250 mg, 1.44 mmol)
and N,N-diisopropylamine (19.9 mL, 0.14 mmol) in dichloro-
methane (10 mL) was added a suspension of N-bromosuccini-
mide (256 mg, 1.44 mmol) in dichloromethane (10 mL) at
ꢀ30 ꢁC dropwise. After stirring for 1 h, the reaction mixture
was allowed to warm to room temperature then poured into
water (20 mL) and acidified to pH 1 with concd sulfuric
acid. The crude product was extracted with dichloromethane
(3ꢃ20 mL) and the combined organic layers were washed
with water (3ꢃ20 mL), brine (20 mL) and dried over anhy-
drous MgSO4. The solvent was removed under reduced pres-
sure and the residue purified by flash chromatography (20%
ethyl acetate/hexanes) to yield the title compound 13 (218 mg,
0.86 mmol, 60%) as an off-white solid, mp 87e89 ꢁC; Rf
(20% ethyl acetate/hexanes) 0.75; nmax (film) 3268, 1624,
1600, 1510, 1478, 1425, 1219, 1177 cmꢀ1; dH (300 MHz,
CDCl3) 8.10 (1H, d, J5,6 8.6 Hz, 5-H), 7.47 (1H, d, J8,6
2.7 Hz, 8-H), 7.42 (1H, d, J3,4 7.9 Hz, 3-H), 7.26 (1H, dd,
J6,5 8.6 Hz, J6,8 2.7 Hz, 6-H), 6.67 (1H, d, J4,3 7.9 Hz, 4-H),
3.95 (3H, s, 7-OMe); dC (75 MHz, CDCl3) 157.9, 150.3,
128.8, 128.2, 126.8, 126.7, 120.4, 113.4, 109.7, 100.5, 55.5;
m/z (EI, %) 254 (M [81Br]þ, 95), 252 (M [79Br]þ, 100), 211
(40), 209 (40), 145 (35), 102 (45); HRMS (EI) Mþ, Found
253.9774, 251.9795, C11H891BrO2, C11H979BrO2 requires
253.9765, 251.9786.
(10 mL) and
a solution of anhydrous FeCl3 (65 mg,
0.40 mmol) in methanol (2 mL) was added and the mixture
stirred for 6 h. The methanol was removed under reduced pres-
sure and the crude product was re-dissolved in dichlorome-
thane (15 mL), washed with water (10 mL) and dried over
anhydrous MgSO4. The solvent was removed under reduced
pressure and the crude mixture purified by flash chromatogra-
phy (10% ethyl acetate/hexanes) to yield the title compound 8
(32 mg, 0.10 mmol, 55%) as a yellow solid, mp 65e67 ꢁC; Rf
(10% ethyl acetate/hexanes) 0.55; nmax (film) 1677, 1589,
1497, 1423, 1265, 1067, 1026 cmꢀ1; dH (300 MHz, CDCl3)
8.05 (1H, d, J8,7 8.6 Hz, 8-H), 7.58 (1H, d, J5,7 2.6 Hz, 5-H),
7.19 (1H, dd, J7,8 8.6 Hz, J7,5 2.6 Hz, 7-H), 5.88e5.79 (1H,
m, 2-H), 5.21 (1H, dd, J3B,2 10.0 Hz, Jgem 1.4 Hz, 3-HB),
5.12 (1H, dd, J3A,2 10.0 Hz, Jgem 1.4 Hz, 3-HA), 3.94 (3H, s,
6-OMe), 3.60 (2H, dt, J1,2 6.6 Hz, J1,3 1.4 Hz, 1-H); dC
(75 MHz, CDCl3) 180.4, 177.9, 164.2, 149.2, 138.5, 131.6,
129.6, 128.6, 125.0, 120.7, 118.2, 110.9, 56.0, 35.5; m/z (EI,
%) 308 (M [81Br]þ, 60), 306 (M [79Br]þ, 60), 293 (M
[81Br]þꢀO, 18), 291 (M [79Br]þꢀO, 20), 227 (MþꢀBr,
100), 199 (15); HRMS (EI) Found Mþ, 307.9883, 305.9883,
4.1.5. 2-Bromo-7-methoxy-1,4-naphthoquinone 14
81
79
To a solution of naphthol 13 (400 mg, 1.57 mmol) in aceto-
nitrile (20 mL) and water (6 mL) at ꢀ5 ꢁC was added [bis(tri-
fluoroacetoxy)iodo]benzene (1.43 g, 3.29 mmol) portionwise
over 20 min. After stirring for 30 min at ꢀ5 ꢁC, the reaction
mixture was allowed to warm to room temperature and stirring
continued for 1 h. Saturated NaHCO3 solution (5 mL) was
added to the reaction mixture and the mixture extracted with
ethyl acetate (3ꢃ25 mL). The combined organic extracts were
washed with brine (20 mL), dried over anhydrous MgSO4
and the solvent removed under reduced pressure. The crude
product was purified by flash chromatography (10% ethyl
acetate/hexanes) to yield the title compound 14 (244 mg,
0.91 mmol, 58%) as a yellow solid, mp 122e124 ꢁC; Rf
(10% ethyl acetate/hexanes) 0.60; nmax (film) 1682, 1659,
C14H BrO3, C14H BrO3 requires 307.9871, 305.9892.
11 11
4.1.7. 2-(2,3-Dihydroxyprop-1-yl)-3-bromo-1,4,6-trimethoxy-
naphthalene 16
To a solution of 2-allyl-3-bromo-6-methoxy-1,4-naphtho-
quinone 8 (200 mg, 0.65 mmol) and tetrabutylammonium
iodide (10 mg, 0.02 mmol) in THF (15 mL) under nitrogen was
added a solution of sodium dithionite (711 mg, 4.05 mmol) in
water (7 mL) with vigorous stirring. After 30 min, a solution
of potassium hydroxide (439 mg, 7.83 mmol) in water
(7 mL) was added dropwise then the reaction mixture was
stirred for 1 h followed by addition of dimethylsulfate
(1.35 mL, 13.87 mmol). After 4 h stirring, the mixture was
quenched with aqueous ammonia (1.5 M, 5 mL) followed by

3348
P. Bachu et al. / Tetrahedron 64 (2008) 3343e3350
water (25 mL) and the product was extracted with ethyl ace-
tate (3ꢃ20 mL). The combined organic extracts were washed
with 2 M hydrochloric acid (20 mL), water (3ꢃ20 mL), dried
over anhydrous MgSO4 and the solvent removed under
reduced pressure to obtain crude allyl ether 15.
4.1.9. rac-2-(2-Hydroxy-4-penten-1-yl)-3-bromo-1,4,6-
trimethoxynaphthalene 17
To a stirred suspension of magnesium powder (14 mg,
0.58 mmol) in dry diethyl ether (7 mL) was added a solution
of allyl bromide (0.04 mL, 0.45 mmol) in dry diethyl ether
(2 mL) dropwise under nitrogen. The reaction mixture was
heated to reflux for 1 h then cooled to room temperature. In
other flask, aldehyde 7 (70 mg, 0.21 mmol) was dissolved in
diethyl ether (10 mL) and cooled to ꢀ40 ꢁC. The solution of
allylmagnesium bromide was added to aldehyde solution drop-
wise via syringe. The reaction mixture was allowed to warm to
room temperature and stirred overnight. The reaction was
quenched with H2O (40 mL) and stirred for 5 min. The mix-
ture was extracted with diethyl ether (3ꢃ20 mL), dried over
anhydrous MgSO4 and the solvent removed under reduced
pressure. The residue was purified by flash chromatography
(10% ethyl acetate/hexanes) to afford the title compound 17
(70 mg, 0.18 mmol, 89%) as a colourless liquid.; Rf (10%
ethyl acetate/hexanes) 0.60; nmax (film) 3584, 2400, 1624,
1580, 1496, 1362, 1031, 1010 cmꢀ1; dH (300 MHz, CDCl3)
7.93 (1H, d, J8,7 9.2 Hz, 8-H), 7.35 (1H, d, J5,7 2.6 Hz, 5-H),
7.18 (1H, dd, J7,8 9.2 Hz, J7,5 2.6 Hz, 7-H), 6.00e5.86 (1H,
m, 4-H), 5.22e5.12 (2H, m, 5-H), 4.07e4.01 (1H, m, 2-H),
3.95 (3H, s, 4-OMe or 1-OMe), 3.94 (3H, s, 1-OMe or 4-
OMe), 3.90 (3H, s, 6-OMe), 3.14 (2H, d, J1,2 5.9 Hz, 1-H),
2.38 (2H, t, J3,2 or 3,4 6.1 Hz, 3-H), 2.30 (1H, br s, OH); dC
(75 MHz, CDCl3) 158.5, 151.4, 149.3, 134.9, 129.5, 125.2,
124.5, 123.0, 119.4, 117.8, 117.4, 100.8, 70.8, 62.2, 60.8,
55.4, 41.9, 37.5; m/z (EI, %) 382 (M [81Br]þ, 100), 380 (M
[79Br]þ, 100), 340 (10), 338 (10), 311 (90), 309 (90), 297
(80), 295 (80); HRMS (EI) Mþ, Found 382.0610, 380.0617,
To a solution of crude allyl ether 15 (208 mg, 0.62 mmol)
in acetone (15 mL) and H2O (3 mL) was added N-methylmor-
pholine N-oxide (122 mg, 0.86 mmol) and the mixture was
cooled to 0 ꢁC. After 5 min stirring, a solution of osmium
tetroxide (0.06 mL, 0.01 mmol) was added and the mixture
gradually warmed to room temperature. The reaction mixture
was stirred for 24 h then 33% aqueous Na2SO3 solution
(5 mL) was added. The mixture was extracted with ethyl
acetate (3ꢃ20 mL) and the combined organic extracts were
washed with water (10 mL) and brine (10 mL). After drying
over anhydrous Na2SO4, the solvent was removed under re-
duced pressure and the crude product was purified by flash
chromatography (50% ethyl acetate/hexanes) to yield the title
compound 16 (183 mg, 0.54 mmol, 80%) as a colourless solid,
mp 156e157 ꢁC; Rf (50% ethyl acetate/hexanes) 0.23; nmax
(film) 3374, 2305, 1624, 1579, 1421, 1326, 1024, 746 cmꢀ1
;
dH (300 MHz, CDCl3) 7.93 (1H, d, J8,7 9.2 Hz, 8-H), 7.37
(1H, d, J5,7 2.5 Hz, 5-H), 7.21 (1H, dd, J7,8 9.2 Hz, J7,5
2.5 Hz, 7-H), 4.10e4.00 (1H, m, 2-H), 3.96 (3H, s, 4-OMe or
1-OMe), 3.95 (3H, s, 1-OMe or 4-OMe), 3.93 (3H, s, 7-OMe),
3.72e3.64 (1H, m, 3-HB), 3.56e3.49 (1H, m, 3-HA), 3.27e
3.09 (2H, m, 1-H); dC (75 MHz, CDCl3) 158.6, 151.1, 150.4,
129.7, 124.4, 122.8, 119.6, 117.2, 100.9, 94.0, 71.7, 65.7,
62.4, 60.9, 55.5, 34.1; m/z (EI, %) 372 (M [81Br]þ, 100), 370
(M [79Br]þ, 100), 354 (M [81Br]ꢀH2O, 10), 352 (M [79Br]ꢀ
H2O, 10), 311 (M [81Br]ꢀC2H5O2, 90), 309 (M [79Br]ꢀ
C2H5O2, 90); HRMS (EI) Mþ, Found 372.0398, 370.0412,
81
79
C18H BrO4, C18H BrO4 requires 382.0603, 380.0623.
21
21
81
79
C16H BrO5, C16H BrO5 requires 372.0395, 370.0416.
19
19
4.1.10. rac-2-(2-Acetoxy-4-penten-1-yl)-3-bromo-1,4,6-
trimethoxynaphthalene 6
4.1.8. 2-(3-Bromo-1,4,6-trimethoxynaphthalen-2-yl)-
ethanal 7
To a solution of homoallyl alcohol rac-17 (70 mg,
0.18 mmol) in dichloromethane (30 mL) was added acetic
anhydride (0.02 mL, 0.22 mmol) dropwise with stirring. After
stirring for 10 min, a catalytic quantity of perchloric acid (one
drop) was added to the reaction mixture and the resulting
violet mixture stirred for 2 h. The reaction mixture was
quenched with saturated NaHCO3 solution (10 mL) and
extracted with dichloromethane (3ꢃ10 mL). The combined
organic extracts were washed with saturated NH4Cl solution
(20 mL) and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the crude product was
purified by flash chromatography (30% ethyl acetate/hexanes)
to yield the title compound 6 (70 mg, 0.17 mmol, 90%) as
a colourless liquid; Rf (30% ethyl acetate/hexanes) 0.60;
nmax (film) 2936, 1738, 1622, 1578, 1495, 1227, 1076,
1030 cmꢀ1; dH (300 MHz, CDCl3) 7.93 (1H, d, J8,7 9.2 Hz,
8-H), 7.34 (1H, d, J5,7 2.5 Hz, 5-H), 7.17 (1H, dd, J7,5
2.5 Hz, J7,8 9.2 Hz, 7-H), 5.88e5.75 (1H, m, 4-H), 5.43e
5.35 (1H, m, 2-H), 5.10 (1H, dd, J5B,4 19.0 Hz, Jgem 1.3 Hz,
5-HB), 5.07 (1H, dd, J5A,4 10.9 Hz, Jgem 1.3 Hz, 5-HA), 3.94
(3H, s, 4-OMe or 1-OMe), 3.93 (3H, s, 1-OMe or 4-OMe),
3.89 (3H, s, 6-OMe), 3.29 (1H, dd, Jgem 13.6 Hz, J1B,2
To a solution of diol 16 (133 mg, 0.36 mmol) in methanol
(10 mL) and water (3 mL) at 0 ꢁC was added sodium periodate
(92 mg, 0.43 mmol) in several portions at 0 ꢁC. After 2 h stir-
ring at 0 ꢁC, the mixture was warmed to room temperature and
extracted with diethyl ether (3ꢃ15 mL). The organic extracts
were washed with brine (15 mL) and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure
and the residue purified by flash chromatography (50% ethyl
acetate/hexanes) to yield the title compound 7 (120 mg,
0.34 mmol, 99%) as a colourless liquid; Rf (50% ethyl ace-
tate/hexanes) 0.74; nmax (film) 1721, 1623, 1582, 1496, 1450,
1406, 1076, 1014 cmꢀ1; dH (300 MHz, CDCl3) 9.84 (1H, t,
J1,2 1.5 Hz, CHO), 7.95 (1H, d, J8,7 9.2 Hz, 8-H), 7.37 (1H,
d, J5,7 2.5 Hz, 5-H), 4.07 (2H, d, J2,1 1.5 Hz, 2-H), 3.97 (3H,
s, 4-OMe or 1-OMe), 3.95 (3H, s, 1-OMe or 4-OMe), 3.83
(3H, s, 6-OMe); dC (75 MHz, CDCl3) 198.8, 158.9, 152.0,
149.3, 130.2, 124.5, 123.0, 120.4, 119.6, 116.7, 100.9, 62.5,
60.9, 55.5, 45.0; m/z (EI, %) 340 (M [81Br]þ, 100), 338 (M
[79Br]þ, 100), 325 (20), 323 (20), 311 (80), 309 (80);
81
15
HRMS (EI) Mþ, Found 340.0124, 338.0163, C15H BrO4,
79
C15H BrO4 requires 340.0133, 338.0157.
15

P. Bachu et al. / Tetrahedron 64 (2008) 3343e3350
3349
8.1 Hz, 1-HB), 3.17 (1H, dd, Jgem 13.6 Hz, J1A,2 5.4 Hz, 1-HA),
and cis-(ꢂ)-(20R)-3-(2,3-dihydroxyprop-1-yl)-5,8,10-tri-
2.42 (2H, t, J 7.0 Hz, 3-H), 1.89 (3H, s, OCOMe); dC
(75 MHz, CDCl3) 170.2, 158.5, 151.8, 149.0, 133.9, 129.6,
124.5, 124.3, 123.0, 119.3, 117.6, 117.5, 100.8, 72.6, 62.3,
60.8, 55.4, 38.6, 34.4, 21.0; m/z (EI, %) 424 (Mþ, 81Br, 48),
422 (Mþ, 79Br, 50), 364 (70), 362 (70), 311 (40), 43
(MþꢀC18H20O4Br, 100); HRMS (EI) Mþ, Found 424.0705,
methoxy-1-methyl-3,4-dihydro-1H-naphtho[2,3-c]pyran 21
To a solution of allylnaphtho[2,3-c]pyran 20 (35 mg,
0.11 mmol) in acetone (10 mL) and H2O (2 mL) was added
N-methylmorpholine N-oxide (23 mg, 0.16 mmol) and cooled
to 0 ꢁC. After stirring for 5 min, a solution of osmium tetrox-
ide (2.5 wt% solution in 2-methyl-2-propanol) (0.01 mL,
0.002 mmol) was added and the mixture gradually warmed
to room temperature. The reaction mixture was allowed to
stir for 24 h then 33% aqueous Na2SO3 solution (5 mL) was
added. The mixture was extracted with ethyl acetate
(3ꢃ10 mL) and the combined organic extracts were washed
with water (5 mL) and brine (5 mL). After drying over anhy-
drous Na2SO4, the solvent was removed under reduced pres-
sure and the crude product was purified by flash
chromatography (20% ethyl acetate/hexanes) to yield the title
compounds 21 (33 mg, 0.09 mmol, 86%) as colourless viscous
oil; Rf (20% ethyl acetate/hexanes) 0.80; nmax (film) 3400,
1627, 1598, 1500, 1448, 1420, 1343, 1222 cmꢀ1; dH
(300 MHz, CDCl3) 7.95 (1H, d, J6,7 9.2 Hz, 6-H), 7.30 (1H,
d, J9,7 2.5 Hz, 9-H), 7.14 (1H, dd, J7,6 9.2 Hz, J7,9 2.5 Hz,
7-H), 5.29e5.14 (1H, m, 1-H), 4.15e4.05 (1H, m, 2-H),
3.99e3.88 (1H, m, 3-H), 3.92 (3H, s, 8-OMe), 3.86 (3H, s,
10-OMe), 3.83 (3H, s, 5-OMe), 3.74e3.56 (2H, m, 3-H),
3.23 (1H, br s, OH), 3.07e2.96 (1H, m, 4-HB), 2.77e2.59
(1H, m, 4-HA), 2.54 (1H, br s, OH), 2.00e1.91 (1H, m,
1-HB), 1.88e1.79 (1H, m, 1-HA), 1.67 (3H, d, J1,Me 6.3 Hz,
1-Me); dC (75 MHz, CDCl3) 157.7, 157.6, 149.0, 149.1,
147.3, 129.1, 128.4, 128.3, 123.7, 122.74, 122.71, 121.8,
118.6, 118.5, 99.9, 73.8 71.4, 71.3, 71.1, 69.3, 71.6, 66.5,
66.7, 61.2, 60.3, 60.2, 55.1, 38.5, 38.3, 30.2, 29.7, 22.3,
22.2; m/z (FAB, %) 362 (Mþ, 10), 307 (30), 289 (15), 154
(MþꢀC9H20O5, 100), 136 (70), 107 (25); HRMS (FAB) Mþ,
Found 362.1731, C20H26O6 requires 362.1729.
81
79
422.0732, C20H BrO5, C20H BrO5 requires 424.0708,
23
23
422.0729.
4.1.11. cis-(ꢂ)-3-Allyl-5,8,10-trimethoxy-1-methyl-3,4-
dihydro-1H-naphtho[2,3-c]pyran 20
Bromo ester rac-6 (70 mg, 0.17 mmol) was dissolved in dry
THF (7 mL) under nitrogen atmosphere and the solution
cooled to ꢀ78 ꢁC. A solution of tert-butyllithium in pentane
(0.25 mL, 1.3 M, 0.36 mmol) was added dropwise via syringe
to the above solution and the resulting dark orange reaction
mixture stirred for 1 h at ꢀ78 ꢁC. The reaction mixture was
quenched with H2O (5 mL) at ꢀ78 ꢁC, warmed to room
temperature then extracted with ethyl acetate (3ꢃ40 mL).
The combined organic extracts were washed with brine
(20 mL), dried over anhydrous Na2SO4 and the solvent was
evaporated to give crude lactol 19, which was used directly
in the next step without further purification due to its instabil-
ity on silica gel.
To a solution of the crude lactol 19 (57 mg, 0.17 mmol) in
dry dichloromethane (10 mL) at ꢀ78 ꢁC was added trifluoro-
acetic acid (0.04 mL, 0.50 mmol) dropwise and the mixture
stirred for 15 min. Triethylsilane (0.08 mL, 0.50 mmol) was
added dropwise to the reaction mixture at ꢀ78 ꢁC and the
mixture stirred for 2 h then gradually warmed to room temper-
ature. The reaction mixture was then quenched with ice-water
(10 mL) and extracted with dichloromethane (3ꢃ10 mL). The
combined organic layers were washed with brine (10 mL) and
dried over anhydrous Na2SO4. After evaporation of the sol-
vent, the residue was purified by flash chromatography (20%
ethyl acetate/hexanes) to give the title compound 20 (35 mg,
0.11 mmol, 65%) as a pale yellow viscous oil; Rf (20% ethyl
acetate/hexanes) 0.80; nmax (film) 1736, 1627, 1598, 1499,
1448, 1420, 1342, 1222 cmꢀ1; dH (300 MHz, CDCl3) 7.97
(1H, d, J6,7 9.2 Hz, 6-H), 7.31 (1H, d, J9,7 2.5 Hz, 9-H), 7.13
(1H, dd, J7,6 9.2 Hz, J7,9 2.5 Hz, 7-H), 6.04e5.90 (1H, m, 2-
H), 5.20 (1H, q, J1,Me 6.3 Hz, 1-H), 5.17e5.10 (2H, m, 3-
H), 3.93 (3H, s, 8-OMe), 3.88 (3H, s, 10-OMe or 5-OMe),
3.84 (3H, s, 5-OMe or 10-OMe), 3.64e3.56 (1H, m, 3-H),
3.06 (1H, dd, Jgem 15.5 Hz, J4ax,3 1.6 Hz, 4-Hax), 2.60 (1H,
d, Jgem 15.5 Hz, 4-Heq), 2.57e2.49 (1H, m, 1-HB), 2.46e
2.35 (1H, m, 1-HA), 1.68 (3H, d, JMe,1 6.3 Hz, 1-Me); dC
(75 MHz, CDCl3) 157.8, 149.3, 148.0, 134.7, 131.0, 128.5,
123.9, 122.9, 122.5, 118.6, 117.0, 100.1, 73.3, 71.4, 61.4,
60.4, 55.3, 40.5, 29.6, 22.4; m/z (EI, %) 328 (Mþ, 60), 313
(MþꢀMe, 8), 307 (25), 289 (15), 154 (MþꢀC9H18O3, 100),
136 (70); HRMS (EI) Mþ, Found 328.1681, C20H24O4 re-
quires 328.1675.
4.1.13. cis-(ꢂ)-2-(5,8,10-Trimethoxy-1-methyl-3,4-dihydro-
1H-naphtho[2,3-c]pyran-3-yl)ethanal 22
To a solution of diols 21 (33 mg, 0.09 mmol) in methanol
(5 mL) and water (1.5 mL) at 0 ꢁC was added sodium period-
ate (24 mg, 0.11 mmol) in several portions and stirred for 2 h.
The reaction mixture was warmed to room temperature and
extracted with diethyl ether (3ꢃ10 mL). The organic extracts
were washed with brine (10 mL) and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure
and the residue was purified by flash chromatography (30%
ethyl acetate/hexanes) to yield the title compound 22
(21 mg, 0.062 mmol, 70%) as a colourless solid, mp 129e
132 ꢁC; Rf (30% ethyl acetate/hexanes) 0.62; nmax (film)
1725, 1627, 1598, 1500, 1448, 1421, 1343 cmꢀ1; dH
(300 MHz, CDCl3) 9.91 (1H, t, J1,2 2.0 Hz, CHO), 7.95 (1H,
d, J6,7 9.2 Hz, 6-H), 7.31 (1H, d, J9,7 2.5 Hz, 9-H), 7.14 (1H,
dd, J7,6 9.2 Hz, J7,9 2.5 Hz, 7-H), 5.23 (1H, q, J1,Me 6.3 Hz,
1-H), 4.17e4.07 (1H, m, 3-H), 3.93 (3H, s, 8-OMe), 3.87
(3H, s, 10-OMe), 3.85 (3H, s, 5-OMe), 3.09 (1H, dd, Jgem
16.2 Hz, J4eq,3ax 2.2 Hz, 4-Heq), 2.85 (1H, ddd, Jgem 16.2 Hz,
J4ax,3ax 7.9 Hz, J4ax,1 2.2 Hz, 4-Hax), 2.75e2.59 (2H, m, 2-
H), 1.65 (3H, d, JMe,1 6.3 Hz, 1-Me); dC (75 MHz, CDCl3)
4.1.12. cis-(ꢂ)-(20S)-3-(2,3-Dihydroxyprop-1-yl)-5,8,10-tri-
methoxy-1-methyl-3,4-dihydro-1H-naphtho[2,3-c]pyran

3350
P. Bachu et al. / Tetrahedron 64 (2008) 3343e3350
200.9, 157.9, 149.3, 147.5, 129.3, 128.7, 123.9, 122.9, 121.5,
118.8, 100.1, 71.5, 68.9, 61.4, 60.5, 55.3, 49.5, 29.9, 22.3; m/z
(FAB, %) 330 (Mþ, 10), 154 (MþꢀC8H16O4, 100), 136 (70),
120 (15), 107 (23), 89 (20), 77 (20); HRMS (FAB) Mþ, Found
330.1461, C19H22O5 requires 330.1467.
Acknowledgements
The authors thank the Department of Chemistry, The
University of Auckland for the award of a Departmental
Scholarship (P.B.).
4.1.14. cis-(ꢂ)-2-(8-Methoxy-1-methyl-5,10-dioxo-3,4,5,10-
tetrahydro-1H-naphtho[2,3-c]pyran-3-yl)acetic acid 5
References and notes
To a solution of aldehyde 22 (20 mg, 0.06 mmol) in tert-
butanol (2 mL) were added water (0.5 mL) and cyclohexene
(1 mL). After 5 min, sodium chlorite (28 mg, 0.24 mmol) and
sodium phosphate monobasic dihydrate (42 mg, 0.31 mmol)
were added and the mixture stirred for 2 h at room tempera-
ture. The reaction mixture was cooled to 0 ꢁC and sodium
bisulfite powder (22 mg, 0.20 mmol) was added followed by
dilution with saturated sodium phosphate (5 mL). The reaction
mixture was extracted with ethyl acetate (3ꢃ10 mL), washed
with brine (5 mL) and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure to obtain the
corresponding crude carboxylic acid 23.
To a solution of crude carboxylic acid 23 (15 mg,
0.043 mmol) in acetonitrile (5 mL) at 0 ꢁC was added a solution
of ceric ammonium nitrate (59 mg, 0.11 mmol) in water (5 mL)
dropwise and the mixture allowed to warm to room tempera-
ture. The reaction mixture was poured into water (10 mL)
and extracted with ethyl acetate (3ꢃ10 mL). The combined or-
ganic extracts were washed with brine (15 mL) and dried over
anhydrous Na2SO4. After evaporation of solvent under reduced
pressure, the crude product was purified with flash chromato-
graphy (30% ethyl acetate/hexanes) to afford the title com-
pound 5 (11 mg, 0.035 mmol, 76%) as a yellow solid, mp 93e
95 ꢁC; Rf (30% ethyl acetate/hexanes) 0.25; nmax (film) 3054,
2987, 2305, 1712, 1595, 1421, 896 cmꢀ1; dH (300 MHz,
CDCl3) 8.01 (1H, d, J6,7 8.6 Hz, 6-H), 7.47 (1H, d, J9,7
2.7 Hz, 9-H), 7.16 (1H, dd, J7,6 8.6 Hz, J7,9 2.7 Hz, 7-H),
4.89e4.84 (1H, m, 1-H), 3.94e3.88 (1H, m, 3-H), 3.93 (3H,
s, 8-OMe), 2.89 (1H, dd, Jgem 18.4 Hz, J4eq,3 2.4 Hz, 4-Heq),
2.81e2.64 (2H, m, 2-H), 2.33 (1H, ddd, Jgem 18.4 Hz, J4ax,3
10.4 Hz, J4ax,1 3.8 Hz, 4-Hax), 1.53 (3H, d, JMe,1 6.6 Hz, 1-
Me); dC (75 MHz, CDCl3) 183.8, 182.7, 175.7, 164.2, 146.0,
141.9, 134.4, 128.8, 125.2, 120.2, 109.7, 70.3, 69.0, 55.9, 40.2,
28.4, 20.7; m/z (FAB, %) 317 (Mþ, 3), 154 (Mþ
ꢀC6H10O5, 100), 136 (75), 107 (25), 89 (25), 77 (20); HRMS
(FAB) Mþ, Found 317.1026,C17H16O6 requires 317.1025.
1. Thomson, R. H. Naturally Occurring Quinones, 2nd ed.; Academic:
London, 1971; p 282, see also p 597.
2. Brimble, M. A.; Dunclaf, L. J.; Nairn, M. R. Nat. Prod. Rep. 1999,
16, 267.
3. Moore, H. W. Science 1977, 197, 527.
4. Moore, H. W.; Czerniak, R. Med. Res. Rev. 1981, 1, 249.
5. Govender, S.; Mmutlane, E. M.; van Otterlo, W. A. L.; de Koning, C. B.
Org. Biomol. Chem. 2007, 5, 2433.
6. (a) Brimble, M. A.; Lai, M. Y. H. Org. Biomol. Chem. 2003, 1, 2084; (b)
Brimble, M. A.; Lai, M. Y. H. Org. Biomol. Chem. 2003, 1, 4227.
7. Brimble, M. A.; Bachu, P.; Sperry, J. Synthesis 2007, 2887.
8. For isolation: (a) Omura, S.; Tanaka, H.; Koyama, Y.; Oiwa, R.; Katagiri,
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