Synthesis of a 2-deoxyglucosyl analogue of medermycin

Article abstract of DOI:10.1039/b103080a

The synthesis of a 2-deoxyglucosyl analogue 6 of the C-glycosylpyranonaphthoquinone antibiotic medermycin 1 is described. The key 3-acetyl-6-(2-deoxyglucosyl)-1,4-naphthoquinone 7 is prepared from 6-(2-deoxyglucosyl)-1,4-naphthoquinone 21, which in turn is available by C-glycosylation of naphthol 18 with glycosyl donor 12 using BF₃·Et₂O in acetonitrile followed by oxidative demethylation of the derived methyl ether 20. An acetyl group is then introduced at C-3 on naphthoquinone 21 by reductive monomethylation to naphthol 22, ortho bromination to bromide 24, methylation to 9, followed by Stille coupling with α-ethoxyvinyltributyltin (and hydrolysis) to afford the 3-acetylnaphthalene 8. Addition of 2-(trimethylsilyloxy)furan 13 to naphthoquinone 7, formed from oxidative demethylation of the naphthalene 8, affords the furofuran adducts 25 and 26 as an inseparable mixture of diastereomers. Oxidative rearrangement of this diastereomeric mixture using cerium (IV) ammonium nitrate affords the unstable diastereomeric lactols 27 and 28 also as a 1:1 inseparable mixture. Reduction of these lactols 27 and 28 with triethylsilane and BF₃·Et₂O at - 10 °C affords ethers 29 and 30 as a 1:1 mixture. Finally, conversion of ethers 29 and 30 to a 1:1 diastereomeric mixture of medermycin analogues 6 and 31 is achieved by treatment with boron tribromide which effects removal of the methoxy group at C-7, the benzyl ethers on the 2-deoxyglucose residue, and epimerisation at C-5.

Full text of DOI:10.1039/b103080a

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Synthesis of a 2-deoxyglucosyl analogue of medermycin
Margaret A. Brimble*† and Timothy J. Brenstrum
School of Chemistry, F11, University of Sydney, Camperdown, NSW 2006, Australia
1
Received (in Cambridge, UK) 5th April 2001, Accepted 22nd May 2001
First published as an Advance Article on the web 5th July 2001
The synthesis of a 2-deoxyglucosyl analogue 6 of the C-glycosylpyranonaphthoquinone antibiotic medermycin 1 is
described. The key 3-acetyl-6-(2-deoxyglucosyl)-1,4-naphthoquinone 7 is prepared from 6-(2-deoxyglucosyl)-1,4-
naphthoquinone 21, which in turn is available by C-glycosylation of naphthol 18 with glycosyl donor 12 using
BF3ؒEt2O in acetonitrile followed by oxidative demethylation of the derived methyl ether 20. An acetyl group is
then introduced at C-3 on naphthoquinone 21 by reductive monomethylation to naphthol 22, ortho bromination
to bromide 24, methylation to 9, followed by Stille coupling with α-ethoxyvinyltributyltin (and hydrolysis) to afford
the 3-acetylnaphthalene 8. Addition of 2-(trimethylsilyloxy)furan 13 to naphthoquinone 7, formed from oxidative
demethylation of the naphthalene 8, affords the furofuran adducts 25 and 26 as an inseparable mixture of
diastereomers. Oxidative rearrangement of this diastereomeric mixture using cerium() ammonium nitrate affords
the unstable diastereomeric lactols 27 and 28 also as a 1:1 inseparable mixture. Reduction of these lactols 27 and 28
with triethylsilane and BF3ؒEt2O at Ϫ10 ЊC affords ethers 29 and 30 as a 1:1 mixture. Finally, conversion of ethers
29 and 30 to a 1:1 diastereomeric mixture of medermycin analogues 6 and 31 is achieved by treatment with boron
tribromide which effects removal of the methoxy group at C-7, the benzyl ethers on the 2-deoxyglucose residue, and
epimerisation at C-5.
Medermycin 1 was isolated1 from a strain of Streptomyces
tanashiensis and the structure shown to contain the same
skeleton as kalafungin 2 with an amino sugar moiety (-
angolosamine) on the naphthoquinone nucleus at C-8. There
was some confusion when Tanaka et al.2,3 reported the iso-
lation and structure of lactoquinomycin and suggested that
medermycin 1 could be an isomer of lactoquinomycin based
on apparent differences in their physicochemical properties
and biological activities. This was resolved, however, when a
synthesis of 1 by Tatsuka et al.4 allowed comparison of the
synthetic and natural samples thereby establishing that all three
samples were identical.
deoxyglucosyl analogue of medermycin, compound 6, using
a furofuran annulation–oxidative rearrangement strategy as
previously used for the synthesis of kalafungin 29 and related
aglycones.10 We therefore herein report the full details of
our successful synthesis of a 2-deoxyglucosyl analogue of
medermycin 611 based on this strategy.
Results and discussion
In order to realise a synthesis of a deoxyglucosyl analogue of
medermycin 6 based on the retrosynthesis outlined (Scheme 1),
a
synthesis of the acetyl substituted deoxyglucosyl-1,4-
Medermycin 1 is highly active against gram-positive organ-
isms including many species of Staphylococcus and Bacillus.2
It is also effective against neoplastic cells in vitro, antibiotic-
resistant cell lines of L5178Y lymphoblastoma and Ehrlich
carcinoma in mice, and has shown 50% inhibition of human
leukaemia K-562 cells as well as platelet aggregation.5 Lacto-
quinomycin B 3 was isolated6 from S. tanashiensis IM8442T
and shown to contain an epoxide moiety between C-5a and
C-11a, whose stereochemistry is yet to be determined. Lacto-
quinomycin B 3 inhibited gram-positive bacteria and exhibited
cytotoxicity against a range of human and murine tumour lines.
Transfer of gene sequences coding for actinorhodin bio-
synthesis into the medermycin producer, S. tanashiensis, has
also resulted in production of the hybrid C-glycosylpyrano-
naphthoquinone antibiotics mederrhodins A 4 and B 5.7,8
Given the significant biological activity exhibited by C-
glycosylpyranonaphthoquinone antibiotics such as meder-
mycin 1, we embarked on a flexible synthetic programme that
would provide access to a range of C-glycosidic pyrano-
naphthoquinones for biological evaluation. To date only one
(lengthy) synthesis of medermycin 1 has been reported,4 in
which the pyranonaphthalene skeleton was assembled by
addition of a C-glycosylsulfonylphthalide to an enone. Our
initial synthetic effort has focused on the synthesis of a 2-
naphthoquinone 7 from a C-glycosylnaphthalene 8 or 9 was
required. The bromine or acetyl substituent in C-glycosyl-
naphthalenes 8 and 9 allowed introduction of the necessary
acetyl group at C-3‡ in naphthoquinone 7, which was important
for control of the regiochemistry in the subsequent furofuran
annulation. Whilst direct C-glycosylation of the acetylnaphthol
10 or bromonaphthol 11 with tri-O-benzyl-2-deoxyglucosyl
acetate 12 would provide direct access to C-glycosyl-
naphthalenes 8 and 9, this approach met with difficulties due
to the unanticipated rearrangement12 of the glycosyl donor 12
when attempting direct C-glycosylation13 of 3-functionalised
naphthols 10 and 11.
In light of these results, the successful synthesis of the
6-deoxyglucosyl analogue of medermycin 6 by necessity com-
menced with C-glycosylation of 5-hydroxy-1,4-dimethoxy-
naphthalene 18 (Scheme 2) with glycosyl acetate 12 (Schemes 3,
4). The acetyl group was then introduced at C-3 of the naph-
thalene ring when the aryl C-glycoside linkage was already in
place. Initial attention therefore focused on the direct C-glyco-
sylation of naphthol 18.
Two different routes were used for the synthesis of naphthol
18 (Scheme 2). The first route involved three steps, which were
high yielding and able to be performed on a large scale. After
benzylation of juglone 14 using benzyl bromide and silver()
oxide in chloroform the benzyl ether 15 underwent reduction
using aq. sodium dithionite (7 equiv.) to afford the air-sensitive
† Present address: Department of Chemistry, University of Auckland,
Private Bag 92019, Auckland, New Zealand. Fax: +64 9 3737422;
email: m.brimble@auckland.ac.nz
‡ Juglone numbering, as shown in Scheme 1.
DOI: 10.1039/b103080a
1624
J. Chem. Soc., Perkin Trans. 1, 2001, 1624–1634
This journal is © The Royal Society of Chemistry 2001

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Scheme 1
hydroquinone 16. This was not purified further, but was dis-
solved immediately in dry acetone and heated at reflux with
potassium carbonate (5 equiv.) and dimethyl sulfate (3 equiv.)
to afford the bis(methyl ether) 17 in 84% yield. The benzyl ether
was then cleaved by hydrogenation of the bis(methyl ether) 17
over 10% palladium on charcoal to afford naphthol 18 in 98%
yield. The physical and spectroscopic data were in agreement
with those reported in the literature.14,15
A more direct approach to naphthol 18 was reported by
Wurm and Goeßler.14 This involved the addition of juglone 14
and tin() chloride to an ice-cooled solution of methanol
acidified with conc. sulfuric acid. The mixture was then heated
at reflux for three days. In our hands this procedure gave only a
43% yield of 18 after work-up and chromatography. The yield
increased to 70% by employing a vigorous aqueous work-up
using benzene as a co-solvent.
With naphthol 18 in hand, attention next turned to the
critical C-glycosylation step (Scheme 3). In related studies on
the C-glycosylation of naphthol 18, Larsen and co-workers16
generated the trifluoroacetate analogue of glycosyl donor 12
in situ, citing the fact that acetate 12 underwent hydrolysis upon
storage as the primary reason for doing this. We found that
acetate 12 was a convenient glycosyl donor provided that
it had been freshly prepared. Boron trifluoride–diethyl ether
(2.0 equiv.) was added to a solution of the naphthol 18 and the
glycosyl acetate 12 (1.2 equiv.) in dry acetonitrile at 0 ЊC. After
20 min the solution was quenched with water and the desired
β-C-glycoside 19 was isolated in 73% yield after chromato-
graphy. The yield for this reaction was improved by avoiding
chromatography, which resulted in decomposition of 19.
Scheme 2 Reagents, conditions and yields: (i) SnCl2, MeOH, conc.
H2SO4, C6H6, reflux, 3 days (43%) (ii) BnBr, Ag2O, CHCl3 (90%) (iii)
Na2S2O4; (iv) Me2SO4, acetone, K2CO3, reflux, 48 h (84%) (v) H2, 10%
Pd/C, EtOAc, 2h (98%).
Hence, the crude product was typically used for the subsequent
methylation step.
The spectral data for C-glycoside 19 were consistent with
those reported by Larsen and co-workers during the course of
this work.16 The anomeric proton, 1Ј-H, resonated at δ 5.01,
with coupling constants, J1Ј,2Јax 11.0 and J1Ј,2Јeq 1.8 Hz, providing
evidence that 1Ј-H was axial and hence that the glycosyl linkage
was of the desired β-stereochemistry. Likewise, the 13C NMR
data agreed well with those reported in the literature.16
With C-glycoside 19 in hand, its conversion to C-glyco-
sylnaphthoquinone 7 which contains the regiochemistry-
controlling acetyl group at C-3 was next undertaken as outlined
(Scheme 3). Methylation of naphthol 19 using sodium hydride
and iodomethane in DMF afforded methyl ether 20 which
then underwent oxidative demethylation using aq. cerium()
ammonium nitrate (CAN) to afford naphthoquinone 21 in 93%
yield after flash chromatography. Reduction of the quinone 21
using aq. sodium dithionite (7 equiv.) gave an air-sensitive
hydroquinone, which was heated under reflux with potassium
J. Chem. Soc., Perkin Trans. 1, 2001, 1624–1634
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Scheme 3 Reagents, conditions and yields: (i) BF3ؒEt2O, CH3CN, 0 ЊC, 20 min (73%) (ii) Mel, NaH, DMF, 0 ЊC, 12 h (8%) (iii) CAN, CH3CN, 0.5 h
(93%) (iv) Na2S2O4; then Me2SO4, K2CO3, acetone, reflux, 2–4 h (82%) (v) Br2, CCl4, 0 ЊC, 2 min (77%) (vi) NaOH, Me2SO4, aq. DMF, 0.5 h, 0 ЊC
(84%) (vii) Pd(PPh3)2Cl2, Bu3SnC(OEt)᎐CH2, toluene, 100 ЊC, N2, 18 h; then H3Oϩ (90%) (viii) AgO, HNO3, 1,4-dioxane, 20 min (93%).
᎐
Scheme 4 Reagents, conditions and yields: (i) CH3CN, 0 ЊC, 1 h; then MeOH, silica gel, 18 h (60%) (ii) CAN, CH3CN, 20 min (85%) (iii) CF3CO2H,
Et3SiH, CH2Cl2, Ϫ10 ЊC, 72 h (86%) (iv) BBr3, CH2Cl2, Ϫ 48 ЊC to room temp., 30 min (67%).
carbonate (5 equiv.) and dimethyl sulfate (3 equiv.) in dry
acetone for 2–4 h to give the naphthol 22 in 82% yield after flash
chromatography. It was neccessary to carefully monitor the
reaction to obtain optimum yields of naphthol 22.
Given that introduction of an acetyl group to C-3 of C-
glycosylnaphthol 22 was our next goal, it was envisaged that
acetylation followed by a Fries rearrangement would be the
normal course of action. With this in mind, acetate 23 was
readily prepared in 85% yield by treating naphthol 22 with tri-
ethylamine (3 equiv.), acetic anhydride (2 equiv.) and a catalytic
amount of 4-(dimethylamino)pyridine (DMAP) in dichloro-
methane. Unfortunately the benzyl protecting groups on the
1626
J. Chem. Soc., Perkin Trans. 1, 2001, 1624–1634

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glycosyl moiety proved to be labile under the conditions
required for the Fries rearrangement.
of the catalyst and meant that in our case the reaction was not
catalytic. Hydrolysis of the reaction mixture using dil. hydro-
chloric acid afforded the desired ketone 8 in 90% overall yield.
Care was needed in order to free the product 8 from tin residues.
Washing with aq. potassium fluoride18 removed the majority
of the tin residue and then careful chromatography allowed
further purification of the product 8.
In the light of the difficulties experienced with the Fries
rearrangement, an alternative approach to the synthesis of the
3-acetylnaphthalene 8 was sought. It was noted that the free
hydroxy group on naphthol 22 provided a convenient handle for
the regioselective introduction of bromine at the ortho-position.
The bromine substituent would then provide a suitable handle
for use of an organolithium reagent to introduce an acetyl
group at C-3.
Various conditions were tried before successful bromination
of the naphthol 22 was achieved. The addition of bromine in
tetrachloromethane to a solution of the naphthol 22 in tetra-
chloromethane at 0 ЊC and subsequent stirring for a period
of 0.5 h resulted in the formation of various highly coloured
products which were not isolated (thought to be quinonoid by-
products resulting from oxidation). It was later discovered that
immediate quenching of the reaction with aq. sodium thio-
sulfate following the addition of bromine resulted in isolation
of the desired product 24 in 77% yield after chromatography.
It was rationalised that bromination was occurring virtually
instantaneously and thus secondary oxidation was being
avoided by the rapid quench.
The 3-acetylnaphthalene 8 analyzed correctly for C42H44O8.
The IR spectrum featured a carbonyl stretch due to the ketone
at 1667 cmϪ1 and the mass spectrum exhibited a molecular ion at
m/z 676 further supporting successful acylation. The 1H NMR
spectrum of the 3-acetylnaphthalene 8 showed little change
from that of the bromide 9 in the glycosyl region; however, a
distinctive, three-proton, singlet at δ 2.71 was assigned to the
protons of a methyl ketone. 2-H resonated at δ 6.97, which was
downfield of its position (δ 6.85) in the corresponding bromide
9, due to deshielding from the neighbouring acetyl group.
With the desired ketone 8 in hand, it remained to effect
oxidative demethylation to the key naphthoquinone 7. A
solution of the ketone 8 in acetonitrile was treated with aq.
cerium() ammonium nitrate (2 equiv.) for 20 min at room
temperature to afford the 3-acetyl-1,4-naphthoquinone 7 in
91% yield. An alternative procedure was also used whereby
ketone 8 was oxidized using silver() oxide and nitric acid,
in dioxane affording the 3-acetyl-1,4-naphthoquinone 7 in a
slightly improved yield of 93%.
Bromonaphthol 24 slowly crystallised to give tan needles
which melted at 116–117 ЊC and analyzed correctly for
C39H39BrO7. The IR spectrum contained a broad hydroxy-
group stretch at 3329 cmϪ1 and the mass spectrum contained a
molecular ion at m/z 698/700 which supported the proposed
Having successfully prepared the benzyl-protected 2-deoxy-
glucosyl-1,4-naphthoquinone 7, our attention next focused on
the furofuran annulation (Scheme 4). Thus, with acetonitrile as
solvent, 2-trimethylsilyloxyfuran 13 (2 equiv.) was added to the
naphthoquinone 7 at 0 ЊC for an hour, then the mixture was
warmed to room temperature. Methanol and silica gel were
then added and the mixture was stirred for a further 18 hours
affording an inseparable mixtue of adducts 25 and 26 in 60%
yield after work-up and flash chromatography. Rapid elution
was preferable when carrying out chromatography due to the
instability of 25 and 26. The ratio of the two diastereomers 25
and 26 was 5 : 4 by integration of the 1H NMR spectrum of the
crude product mixture. Analytical HPLC (optimum conditions
1
structure. The pertinent feature of the H NMR spectrum was
that H-2 resonated as a singlet at δ 6.85 instead of a doublet,
due to substitution at the 3-position with bromine.
Methylation of bromonaphthol 24 was next attempted under
a variety of conditions. Using idomethane and sodium hydride
in dry DMF only small amounts of the desired product 9
were obtained. A purple by-product was observed which was
thought to be the result of oxidation. Using tetrahydrofuran or
mixtures of tetrahydrofuran and DMF as solvent worsened the
situation. A slight improvement was observed on using dimethyl
sulfate as the methylating agent. Finally, reasonable yields of
methyl ether 9 were obtained by the addition of an excess of
aq. sodium hydroxide to a solution of 24 and dimethyl sulfate
(2 equiv.) in dry DMF at 0 ЊC. After being stirred for 0.5 h,
the solution was quenched with dilute ammonium hydroxide
and the product 9 was obtained in 84% yield after chromato-
graphy. A key to the success of this reaction was the presence of
the methylating agent prior to the addition of the base.
Our initial strategy to effect conversion of bromide 9 to
acetylnaphthalene 8 focused on the addition of acetaldehyde
to a naphthyl anion generated from the bromide. Subsequent
oxidation of the resultant alcohol would have given the desired
acetyl compound 8. In practice, the anion formed from C-
glycosy bromide 9 was extremely reactive and only dehalogen-
ated material 20 was recovered from the reaction mixture
despite the use of strictly anhydrous conditions. This result is
thought to be due to the increased basicity of the more highly
substituted and electron-rich naphthalene which abstracted a
proton from acetaldehyde or from the solvent, tetrahydrofuran.
Fortuitously a convenient solution to the above dilemma
involves the use of α-ethoxyvinyltributyltin as a masked
acetylating agent in a palladium(0)-catalyzed reaction with aryl
bromide 9 followed by hydrolysis of the resultant aryl vinyl
ether to a ketone.17 The general acetylation procedure involves
heating a solution of the aryl bromide (5.0 equiv.), α-ethoxy-
vinyltributyltin (5.5 equiv.) and bis(triphenylphosphine)-
palladium() dichloride (0.5 equiv.) in toluene for 18 hours
followed by hydrolysis with dil. hydrochloric acid. C-Glycosyl-
bromonaphthalene 9 reacted slowly under these conditions
and it was necessary to add several more portions of both the
stannane and the palladium catalyst in order for the reaction to
proceed to completion. This was probably due to poisoning
i
1.5% PrOH–hexane; Partisil 5 column, 25 cm × 4.6 mm I.D.;
flow rate 1.5 mL minϪ1) suggested that separation of the
diastereomers 25 and 26 by HPLC would be difficult due to
poor resolution.
The high-resolution mass spectrum of the mixture of 25 and
26 exhibited a molecular ion at m/z 730.2762 consistent with the
molecular formula C44H42O10. The IR spectrum displayed a
broad band at 3333 cmϪ1 characteristic of a hydroxy group,
as well as strong bands at 1784 and 1742 cmϪ1 indicative of
the carbonyl groups of the γ-lactone and ortho-hydroxyaryl
1
ketone respectively. The H NMR spectrum was complicated
by the presence of two diastereomers, with the resonances for
the minor diastereomer denoted below by an asterisk. In the
majority of cases where there were two resonances, the reson-
ances for the minor diastereomer were further upfield, the
exception being 6b-H where the resonance for the major dia-
stereomer was further upfield. In both diastereomers, 2Ј ax-H
resonated as a doublet of doublets of doublets at δ 1.45,
whereas 2Ј eq-H resonated as overlapping doublets of doublets
of doublets at δ 2.47* and 2.51, assigned to the minor and
major diastereomers respectively. Resonances at δ 6.47 and
6.48* were assigned to 6b-H and those at δ 14.43* and 14.49 to
the aromatic hydroxyic protons. 1-H resonated as a doublet at
δ 7.76 with coupling constant J1,2 8.5 Hz, while doublets at
δ 7.88* and 7.89 were assigned as the 2-H resonances for the
minor and major diastereomer, respectively. The bridgehead
protons, 6b-H and 9a-H, resonated at similar chemical shifts
to those reported for analogous compounds.9,10 The bridge-
head coupling constant, J9a,6b 6.3 Hz, was consistent with the
presence of a cis-fused 2H-furo[3,2-b]naphtho[2,1-d]furan ring
system.9,10 Surprisingly, in the 13C NMR spectrum, resonances
J. Chem. Soc., Perkin Trans. 1, 2001, 1624–1634
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for the individual diastereomers of the mixture of adducts 25
and 26 were not observed.
ascertain which peaks belonged to an individual diastereomer
of the lactol. The methyl groups resonated at δC 27.5/27.6 and
the methoxy groups at δC 62.7/62.9. The resonance at δC 29.7
was assigned to C-3 based on comparison with similar com-
pounds, as were the bridgehead carbons, C-3a and C-11b,
resonating at δC 67.1/67.2 and 68.5/68.7, respectively.
Having prepared furo[3,2-b]naphtho[2,1-d]furans 25 and 26,
rearrangement to the corresponding furonaphthopyrans 27
and 28 was then investigated. It was anticipated that the
diastereomeric lactols 27 and 28 would be of sufficiently dif-
ferent polarity to allow their separation by chromatography.
A solution of the furonaphthofurans 25 and 26 in acetonitrile
was treated with aq. CAN (2.0 equiv.) for 20 min, resulting in
formation of a pair of more polar products. These products
were identified as the diastereomeric lactols 27 and 28 (1:1
mixture, 85% crude yield) and although separation was possible
by chromatography, they were extremely unstable on silica gel
and the majority of the product decomposed. Thus, except for
the purposes of characterisation, the crude mixture of lactols
27 and 28 was used in the next step without chromatography.
Formation of the mixture of lactols 27 and 28 was supported
by the high-resolution mass spectrum which exhibited a
molecular ion at m/z 746.2749 confirming the molecular
formula as C44H42O11. The IR spectrum featured a broad
stretch at 3276–3624 cmϪ1, indicative of the hydroxy group, as
well as carbonyl bands at 1788 cmϪ1 and 1668 cmϪ1 assigned to
the γ-lactone and quinone carbonyl groups, respectively.
The diastereomers were partially separated by low-
temperature (Ϫ10 ЊC) chromatography, using hexane–ethyl
acetate (1:2) that had been stirred with potassium carbonate
as eluent, to afford a 14% yield of lactol 27 or 28 which
was enriched in the less polar diastereomer, and a 12% yield
of a lactol 28 or 27 which was enriched in the more polar dia-
stereomer. Assignment of stereochemistry to these two lactols,
The 1H NMR data obtained for each diastereomer suggested
that only one configuration at the lactol carbon was present.
The structure assigned was that in which the hydroxy group is
axial and cis with respect to the bridgehead protons 3a-H and
11b-H. This assignment was made on the basis of the anomeric
effect and also by comparison with similar compounds from the
literature.9,10
With the desired lactols 27 and 28 in hand, albeit as a 1:1
mixture of diastereomers, the next step in the synthesis involved
reduction of the lactol to a cyclic ether. This reaction was
carried out according to the procedure of Kraus et al.,19 who
reported axial delivery of hydride from triethylsilane, to afford
products with a cis-relationship between the protons at C-5 and
C-3a. A solution of lactols 27 and 28 in dichloromethane at
Ϫ30 ЊC was treated with triethylsilane (10 equiv.) and trifluoro-
acetic acid (10 equiv.), then allowed to warm to room tem-
perature. After 6 hours none of the desired product (which
was expected to be less polar) was observed, but a substantial
quantity of baseline material was observed. With stirring for a
longer time, all the remaining starting material decomposed.
Since decomposition was occurring before the reduction could
take place it was decided to carry out the reaction at a lower
temperature and over a longer period of time. Thus a solution
of lactols 27 and 28 in dichloromethane at Ϫ30 ЊC was again
treated with triethylsilane (10 equiv.) and trifluoroacetic acid
(10 equiv.), allowed to warm to Ϫ10 ЊC and then kept at that
temperature with the aid of a cryostat. Using these conditions,
decomposition was kept to a minimum and after 3 days the
starting material had been entirely consumed and two less polar
products were formed, which were identified as the cyclic ethers
29 and 30.
1
however, was not possible using the H and 13C NMR data
obtained. Attempts to obtain a crystalline derivative suitable
for X-ray crystallography were also unsuccessful.
1
The H NMR spectrum of the less polar diastereomer 27 or
28 featured doublets of doublets of doublets at δ 1.46 and δ 2.46
assigned to 2Ј ax-H and 2Ј eq-H, respectively, while the three-
proton singlet at δ 1.73 was assigned to the methyl group. A
doublet at δ 2.67, with coupling constant Jgem 17.7 Hz, and a
doublet of doublets at δ 2.87, Jgem 17.7 and J3B,3a 4.8 Hz, were
assigned to 3-HA and 3-HB, respectively. A three-proton singlet
at δ 3.77 was assigned to the methoxy group, and a two-proton
singlet at δ 7.90 was assigned to 9-H and 10-H. There was a
characteristic upfield shift in the resonances of the bridgehead
protons relative to the adducts 25 and 26. In the less polar lactol
27 or 28 a doublet of doublets at δ 4.83, J3a,3B 4.8 and J3a,11b 2.7
Hz, was assigned to 3a-H, and a doublet at δ 5.20, J11b,3a 2.7 Hz,
was assigned to 11b-H. These protons appeared at similar
chemical shifts to those reported for analogous furo[3,2-b]naph-
tho[2,3-d]pyrans. Similar resonances were observed for 3a-H
and 11b-H in the more polar lactol 28 or 27. The bridgehead
coupling constant, J3a,11b 2.7 Hz, also supported the presence
of a cis-fused 2H-furo[3,2-b]naphtho[2,3-d]pyran system.9,10
The 1H NMR spectrum of the more polar diastereomer 28 or
27 was for the most part very similar to that observed for the
less polar diastereomer 27 or 28. While 2Ј ax-H was unchanged,
2Ј eq-H shifted upfield, resonating at δ 2.40. By contrast the
methoxy group was further downfield at δ 3.82. Of the bridge-
head protons, only 3a-H was noticeably affected, being shifted
upfield to δ 4.81, with an additional coupling constant, J3a,3A
2.0 Hz. Likewise, the 3-HA resonance at δ 2.65 was shifted
slightly upfield and the same additional coupling, J3a,3A 2.0 Hz,
was observed. The final resonances of note for this dia-
stereomer were doublets at δ 7.88 and 7.93 with coupling
constant J9,10 8.0 Hz, which were assigned to 10-H and 9-H.
The 1H NMR data obtained were in excellent agreement with
those reported for related literature compounds.9,10 The 13C
NMR data for the mixture of lactols 27 and 28 (available in
larger quantities) was collected, but was complicated by the
doubling up of most of the peaks. Moreover, since the ratio of
diastereomers was approximately 1:1 it was not possible to
Isolation of the cyclic ethers 29 and 30 was the next hurdle
since the products were unstable and the mixture decomposed
to an intractable brown tar if the solvent was removed at room
temperature. After addition of a small amount of Celite, the
solvent was removed at reduced pressure whilst the temperature
was maintained at Ϫ10 ЊC. Chromatography at room tem-
perature resulted in decomposition (presumably initiated by
opening of the γ-lactone ring) and methanol was required to
elute the extremely polar decomposition products. Chrom-
atography was then attempted at low temperature (Ϫ10 ЊC) and
this allowed partial separation of the individual diastereomers
with only partial decomposition being observed. This procedure
afforded the cyclic ethers 29 and 30 in 86% combined yield.
High-resolution mass spectrometry established the molecular
formula C44H42O10, whilst the IR spectrum featured carbonyl
stretches at 1736 and 1665 cmϪ1, corresponding to the γ-lactone
1
and quinone carbonyls respectively. In the H NMR spectrum
of the crude product mixture, complex multiplets at δ 1.29–1.38
and 2.40–2.60 were assigned to 2Ј ax-H and 2Ј eq-H, respec-
tively. A doublet at δ 2.72, with coupling constant Jgem 17.3 Hz,
was assigned to 3-HA, while a doublet of doublets at δ 2.90,
with coupling constants Jgem 17.3 and J3B,3a 4.5 Hz, was
assigned to 3-HB. Multiplets at δ 4.30–4.38 and δ 5.25–5.30 were
assigned to the bridgehead protons, 3a-H and 11b-H, respec-
tively. A multiplet at δ 4.80 was assigned to 5-H. Other
resonances of note were a doublet of doublets at δ 5.38, J1Ј,2Јax
10.8 and J1Ј,2Јeq 2.9 Hz, assigned to 1Ј-H (establishing the β-
stereochemistry of the C-glycoside bond), and two apparent
singlets at δ 7.94 and 7.96, assigned to 9-H and 10-H.
Some separation of the individual diastereomers of these
cyclic ethers 29 and 30 was achieved by low-temperature
chromatography, and 1H NMR spectra were obtained for each
diastereomer. Although there were a number of differences
1628
J. Chem. Soc., Perkin Trans. 1, 2001, 1624–1634

View Article Online
observed, assignment of stereochemistry was not possible
based on this information. A difference between the chemical
shifts for the two diastereomers was observed in the resonances
assigned to the methyl-group protons. In the less polar
diastereomer 29 or 30, the methyl group protons resonated as
a doublet at δ 1.73, Jvic 6.2 Hz, while in the the more polar
diastereomer 30 or 29 they resonated as a doublet at δ 1.57, Jvic
6.6 Hz. Likewise, differences in the chemical shifts of the pro-
tons assigned to the methoxy group and one of the benzylic
methylene protons were noticed. In the less polar diastereomer
29 or 30 these groups resonated as a singlet at δ 3.88 and a
doublet at δ 4.99, with coupling constant Jgem 10.7 Hz, respec-
tively, while in the the more polar diastereomer, 30 or 29, they
resonated as a singlet at δ 3.81 and a doublet at δ 4.96, with
coupling constant Jgem 10.9 Hz respectively.
doublet of doublets assigned to the bridgehead proton 3a-H
shifted downfield from δ 4.34 in the cis methyl ethers 29 and 30
to δ 4.81–4.99 in the trans products 6 and 31, where it resonated
as a multiplet. Similar downfield shifts were reported when
comparing epi-7-O-methylkalfungin and kalafungin 2.9,20
Assignment of the individual diastereomers of the trans
cyclic ethers 6 and 31 as the medermycin analogue 6 or the
1
alternative diastereomer 31 was not possible using H and 13C
NMR data. These compounds 6 and 31, although a mixture of
diastereomers, were isolated as a crystalline solid and exhibited
much greater stability than both the lactols 27 and 28 and the
cyclic ethers 29 and 30. All efforts to obtain a crystalline
derivative suitable for X-ray crystallography were unsuccessful.
The synthesis of medermycin analogue 6 has been achieved,
albeit as a mixture of diastereomers 6 and 31. The work
reported herein has demonstrated that the 2-(trimethylsilyloxy)-
furan addition–oxidative rearrangement methodology used for
the construction of the pyranonaphthoquinone skeleton is
viable when using a 3-acetyl-1,4-naphthoquinone bearing a
C-glycosyl moiety at C-6 as a starting point for the synthesis.
The synthetic route demonstrated provides an efficient entry for
the synthesis of a range of C-glycosylpyranonaphthoquinones
for biological evaluation.
The 13C NMR spectrum was also consistent with the pro-
posed structure. The resonances at δC 20.5/20.3 were assigned to
the C-5 methyl group, an upfield shift relative to the analogous
protons in the lactols 27 and 28, consistent with reduction to
the cyclic ether. Resonances at δC 69.4/69.5 were assigned to
C-3a, while those at δC 70.1/70.3 were characteristic of C-11b.
The methylene resonances at δC 38.2/38.4 were assigned to C-3,
and the resonances at δC 72.4/72.6 were assigned to C-5.
In the final step of the synthesis of the 2-deoxyglucosyl
analogue 6 of medermycin 1, it remained to effect deprotection
of the methyl ether as well as epimerisation of the protons
attached to C-3a or C-5 so that they adopted the more thermo-
dynamically favourable trans stereochemistry. The benzyl pro-
tecting groups on the glycosyl moiety also had to be removed.
Boron tribromide has been successfully employed by this
research group to effect demethylation and epimerisation of
epi-7-O-methylkalafungin to kalafungin 2.9 While demethyl-
ation occurred almost instantaneously, epimerisation took
much longer. If the reaction was quenched immediately, the
cis-isomer was obtained, whereas on equilibration at room
temperature for 30 min, only the trans-isomer kalafungin 2 was
isolated. A similar result was reported during the synthesis of
the arizonins.10 It was envisaged that these reaction conditions
could be used in the present work.
Excess of boron tribromide (6 equiv.) was added to a solution
of a mixture of the cyclic ethers 29 and 30, which was enriched
in the more polar diastereomer (3:1 ratio), in dichloromethane
at Ϫ48 ЊC. After 5 minutes a red-brown precipitate had formed,
presumably because debenzylation of the sugar had rendered
the boron tribromide–C-glycoside complex insoluble in
dichloromethane. When the mixture was allowed to warm to
room temperature and still failed to dissolve, acetonitrile was
added, affording partial dissolution of the solid material.
Stirring was continued for a further 30 minutes in order to allow
equilibration to the trans-isomer. Aqueous work-up followed
by trituration using hexane and diethyl ether afforded orange
crystalline C-glycosylpyranonaphthoquinones 6 and 31 as a
3:1 inseparable mixture in 67% yield.
Experimental
Mps were determined on a Kofler hot-stage apparatus and are
uncorrected. IR spectra were recorded using a Perkin-Elmer
1600 Fourier Transform IR spectrophotometer as thin films
between sodium chloride plates. Absorption spectra are
expressed in wavenumbers (cmϪ1) with the following abbrevi-
1
ations: s = strong, m = medium, w = weak and br = broad. H
NMR spectra were recorded on a Bruker AC 200 (200 MHz)
or a Bruker DRX 400 (400 MHz) spectrometer at ambient
temperature. All J-values are given in Hz. Chemical shifts are
expressed in parts per million downfield shift from tetramethyl-
silane as internal standard, and reported as position (δH),
relative integral, multiplicity (s = singlet, br s = broad singlet,
d = doublet, dd = double doublet, ddd = double double
doublet, t = triplet, q = quartet, m = multiplet) and assignment.
13C NMR spectra were recorded on a Bruker AC 200 (50.3
MHz) or a Bruker DRX 400 (100.5 MHz) spectrometer at
ambient temperature with complete proton decoupling.
Chemical shifts are expressed in parts per million downfield
shift from tetramethylsilane an internal standard and reported
as position (δ), multiplicity (aided by DEPT 135, DEPT 90,
COSY and HETCOR experiments) and assignment. When
NMR data are reported for isomeric mixtures, resonances for
the minor isomer are denoted by an asterisk (*). Low-resolution
mass spectra were recorded on a VG70-250S, a VG70-SD or
a AEI model MS902 double-focusing magnetic sector mass
spectrometer operating with an ionisation potential of 70 eV
(EI, DEI, CI and DCI). High-resolution mass spectra were
recorded at a nominal resolution of 5000 or 10 000 as appropri-
ate. Major fragments are given as percentages relative to the
base peak and assigned where possible. Ionisation methods
employed were either electron impact or chemical ionisation
with ammonia or methane as reagent gas (CI). Low-resolution
chemical ionisation mass spectra were also recorded on a
Hewlett Packard 5989A mass spectrometer using ammonia as
reagent gas with the sample dissolved in methanol. Flash
chromatography was performed using Merck Kieselgel 60 (230–
400 mesh) with the indicated solvents. TLC was performed
using 0.2 mm thick precoated silica gel plates (Merck Kieselgel
60 F254 or Riedel-de Haen Kieselgel S F254). Compounds were
visualised by UV fluorescence or by staining with iodine or
vanillin in methanolic sulfuric acid. High-performance liquid
chromatography (HPLC) was carried out using a Waters
Associates system consisting of a Model M–6000A pump,
a millipore model U6K injector, a model 440 UV detector at
The formation of C-glycosylpyranonaphthoquinones 6 and
31 was supported by the high-resolution mass spectrum which
exhibited a molecular ion at m/z 446.1217, confirming the
molecular formula as C22H22O10. The IR spectrum featured a
broad stretch at 3100–3643 cmϪ1 supporting the presence of
hydroxy groups. Prominent carbonyl stretches at 1780, 1652
and 1615 cmϪ1 were assigned to the γ-lactone and two quinone
carbonyl groups, respectively.
1
In the H NMR spectrum, evidence for the formation of
the trans isomers 6 and 31 came from the observation of the
characteristic downfield shifts of the resonances assigned to 3a-
H and 5-H. The chemical shift of a doublet of quartets assigned
to 5-H shifted from δ 4.80 in the cis methyl ethers 29 and 30 to
δ 5.04 in the trans products 6 and 31, where it resonated as a
quartet, Jvic 6.6 Hz. The observed loss of long-range coupling
between 5-H and 11b-H was also consistent with conversion of
the cis ethers 29 and 30 to the trans products 6 and 31. The
J. Chem. Soc., Perkin Trans. 1, 2001, 1624–1634
1629

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256 nm and on R401 differential refractometer. Separation was
carried out using the indicated solvents on a Partisil 10 M9
semipreparative column of the following dimensions; outer
diameter 12.80 mm, inner diameter 9.40 mm, length 500.0 mm
and particle size 10.0 µm. Optical rotations were recorded on an
Optical Activity POLAAR 2001 polarimeter using a 5 mL cell.
Samples were prepared in the solvent indicated at the con-
centration specified (measured in g/100 cm3). [α]D-Values are
given in units of 10Ϫ1 deg cm2 gϪ1.
acetate (15 mL) was stirred under an atmosphere of hydrogen
over palladium on charcoal (10%; 206 mg, 50 mg mmolϪ1).
After 4 h the reaction was complete. The mixture was filtered
through Celite and the solvent was removed at reduced pres-
sure. The crude green oil was purified by flash chromatography
using hexane–ethyl acetate (4 : 1) as eluent to afford the title
compound 18 (823 mg, 98%) as a pale green solid. Recrystal-
lisation from ethanol gave fine white needles, mp 101–102 ЊC
(lit.,15 103–104 ЊC). The data for 18 were identical to those
reported above using the previous method.
5-Hydroxy-1,4-dimethoxynaphthalene 18
(i) From juglone 14 using tin(II) chloride and methanol.14
Conc. sulfuric acid (12.5 mL) was added slowly to ice-cooled
dry methanol (75 mL). Anhydrous tin() chloride (7.50 g,
39.6 mmol) was then added and the mixture was left for 2 min
before the addition of juglone 14 (1.50 g, 8.62 mmol) and
benzene (200 mL). The mixture was heated at reflux for 3 days
after which time most of the solvent was removed under
reduced pressure. The mixture was then poured into water and
extracted with dichloromethane (3 × 200 mL). The extracts
were washed with water (3 × 60 mL) and dried (magnesium
sulfate). The crude material was then purified by flash
chromatography using dichloromethane as eluent. The product,
5-hydroxy-1,4-dimethoxynaphthalene 18 (756 mg, 43%) was
obtained as a pale green solid. Recrystallisation from ethanol
gave fine white needles, mp 101–102 ЊC (lit.,15 103–104 ЊC);
1-Hydroxy-5,8-dimethoxy-2-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-ꢀ-
D-arabino-hexopyranosyl)naphthalene 1916
Boron trifluoride–diethyl ether (241 µL, 1.96 mmol) was added
dropwise to a solution of the naphthol 18 (200 mg, 0.980 mmol)
and 3,4,6-tri-O-benzyl-2-deoxy--glucosyl acetate23 12 (562
mg, 1.18 mmol) in dry acetonitrile (18 mL) at 0 ЊC. The mixture
was stirred for 20 min then was quenched with water (5 mL).
The reaction mixture was extracted with dichloromethane
(3 × 150 mL), and the extract was washed with water (250 mL)
and dried (magnesium sulfate). The solvent was removed at
reduced pressure and the oily residue was purified by flash
chromatography using hexane–ethyl acetate (4 : 1) as eluent
to give 1-hydroxy-5,8-dimethoxy-2-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-
deoxy-β--arabino-hexopyranosyl)naphthalene 19 (444 mg,
73%) as a colourless oil, [α]2D2 ϩ 45.6 (c 1.14, CHCl3) {lit.,16
[α]2D5 ϩ 33.3 (c 0.32, CH2Cl2)}; νmax/cmϪ1 3384 (OH), 3056,
νmax/cmϪ1 3342 (OH), 2936, 2834 (C-C), 1630, 1613 (C᎐C),
᎐
1517, 1462, 1451, 1400 (C-O); δH (200 MHz; CDCl3) 3.94, 4.02
(each 3H, s, 2 × OCH3), 6.56 (1H, d, J3,2 8.0, 3-H), 6.68 (1H,
d, J2,3 8.0, 2-H), 6.92 (1H, dd, J6,7 7.7 and J6,8 1.0 Hz, 6-H),
7.37 (1H, dd, J7,8 8.3 and J7,6 7.7, 7-H), 7.71 (1H, dd, J8,7 8.3 and
J8,6 1.0, 8-H); m/z (EI) 204 (Mϩ, 12%), 149 (100).
(C-H), 1643 (C᎐C), 1419 (C-O); δ (200 MHz; CDCl3)§ 1.63
᎐
H
(1H, ddd, Jgem 12.8, J2Јax,1Ј 11.0 and J2Јax,3Ј 11.0, 2Јax-H), 2.59
(1H, ddd, Jgem 12.8, J2Јeq,3Ј 4.9 and J2Јeq,1Ј 1.8, 2Јeq-H), 3.65–4.00
(5H, m, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 3.99, 4.01 (each 3H, s,
2 × OCH3), 4.61–4.78 (5H, m, 5 × CHPh), 4.98 (1H, d, Jgem
10.7, CHPh), 5.01 (1H, dd, J1Ј,2Јax 11.0 and J1Ј,2Јeq 1.8, 1Ј-H), 6.61
(1H, d, J3,2 8.4, 3-H), 6.68 (1H, d, J2,3 8.4, 2-H), 7.20–7.43 (15H,
m, Ph), 7.65 (1H, d, J8,7 8.7, 8-H), 7.74 (1H, d, J7,8 8.7, 7-H),
9.76 (1H, s, OH); δC (50 MHz; CDCl3)§ 37.4 (CH2, C-2Ј), 55.7,
56.4 (CH3, 2 × OCH3), 69.7 (CH2, C-6Ј), 71.1 (CH, C-1Ј), 71.8,
73.4, 75.0 (CH2, 3 × CH2Ph), 78.5, 79.5, 81.4 (CH, C-3Ј, C-4Ј,
C-5Ј), 102.8, 103.6 (CH, C-2, C-3), 113.2 (CH, C-7), 115.1
(quat., C-4a), 123.7 (quat., C-8a), 124.8 (CH, C-8), 127.4–128.3
(CH, Ph), 138.6, 138.7, 138.7 (quat., 3 × ipso-Ph), 149.6, 150.0,
150.2 (quat., C-1, C-4, C-5); m/z (EI) 620 (Mϩ, 12%), 91 (C7H7,
100). The data were in agreement with those reported in the
literature.16
(ii) From juglone benzyl ether 15. 5-Benzyloxy-1,4-dimethoxy-
naphthalene 17. Juglone benzyl ether15 15 (3.56 g, 13.5 mmol)
was dissolved in dichloromethane–diethyl ether (1:3) (300 mL)
and the solution was shaken with a freshly prepared solution
of sodium dithionite (17.5 g, 101 mmol) in water (200 mL)
for 10 min. The organic layer was separated, washed with brine
(140 mL), dried (magnesium sulfate) and the solvent was
removed at reduced pressure to give the crude hydroquinone 16
as a pale brown oil. This was dissolved in dry acetone (75 mL)
and the solution was transferred by double-ended needle to a
reaction vessel containing a stirred suspension of potassium
carbonate (22 g, 160 mmol) in dry acetone (220 mL). Dimethyl
sulfate (6.36 mL, 67 mmol) was added in one portion and the
solution was heated at reflux for 48 h. The mixture was then
cooled, filtered through Celite, and the solvent was removed at
reduced pressure. The resultant red oil was dissolved in diethyl
ether (170 mL) and stirred with triethylamine (10.3 mL, 74
mmol). After 20 min the solution was washed successively with
hydrochloric acid (1 M; 2 × 85 mL), water (85 mL) and brine
(85 mL). It was then dried (sodium sulfate), and concentrated
in vacuo to give an oily residue, which was purified by flash
chromatography using hexane–ethyl acetate (6:1) as eluent to
afford 5-benzyloxy-1,4-dimethoxynaphthalene 17 (3.33 g, 84%)
as tan needles, mp 108–109 ЊC (lit.,22 108–109 ЊC); δH (200
MHz; CDCl3) 3.88, 3.94 (each 3H, s, 2 × OCH3), 5.20 (2H, s,
CH2Ph), 6.74 (1H, d, J3,2 8.4, 3-H), 6.79 (1H, d, J2,3 8.4, 2-H),
6.99 (1H, dd, J6,7 7.5, J6,8 1.0, 6-H), 7.23–7.42 (4H, m, 7-H, Ph),
7.59 (2H, d, Jor 7.5, o-Ph), 7.89 (1H, dd, J8,7 8.6 and J8,6 1.0,
8-H); δC (50 MHz; CDCl3) 55.8, 57.2 (CH3, 2 × OCH3), 71.6
(CH2, CH2Ph), 104.2, 106.8, 109.6, 115.2 (CH, C-2, C-3, C-6,
C-7), 119.0 (quat., C-4a), 125.9 (CH, C-8), 127.0 (CH, o-Ph),
127.5 (CH, p-Ph), 128.3 (CH, m-Ph), 128.9 (quat., C-8a), 137.6
(quat., ipso-Ph), 149.5, 151.0, 155.7 (quat., C-1, C-4, C-5); m/z
(EI) 294 (Mϩ, 13%), 91 (C7H7, 100). The data were in agreement
with those in the literature.22
1,5,8-Trimethoxy-2-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-ꢀ-D-
arabino-hexopyranosyl)naphthalene 20
A slurry of sodium hydride (60 mg, 2.52 mmol) in dry dimethyl-
formamide (2 mL) was added to a stirred solution of the C-
glycosylnaphthol 19 (1.04 g, 1.68 mmol) in dimethylformamide
(15 mL) at 0 ЊC. After an interval of 5 min, iodomethane
(0.54 mL, 16.8 mmol) was added and the mixture was stirred
and allowed to warm to room temperature overnight. The
solvent was removed at reduced pressure and the mixture was
redissolved in dichloromethane (50 mL). This was washed
with water (50 mL) and the aqueous layer was extracted with
dichloromethane (2 × 50 mL). The combined organic extracts
were dried (magnesium sulfate) and the solvent was removed at
reduced pressure. The crude product was purified by flash
chromatography using hexane–ethyl acetate (4 : 1) as eluent to
afford 1,5,8-trimethoxy-2-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-β--
arabino-hexopyranosyl)naphthalene 20 (904 mg, 85%) as a tan
oil; [α]1D9 ϩ 13.9 (c 0.718, CHCl3) (Found: C, 75.36; H, 7.00.
C40H42O7 requires C, 75.67; H, 6.67%); νmax/cmϪ1 2925, 2863 (C-
H), 1621, 1602, 1584 (C᎐C), 1453 (C-O); δ (200 MHz; CDCl )§
᎐
H
3
1.74 (1H, ddd, Jgem 12.5, J2Јax,1Ј 11.5 and J2Јax,3Ј 11.5, 2Јax-H), 2.51
5-Hydroxy-1,4-dimethoxynaphthalene 18 (alternative prepar-
ation). A solution of benzyl ether 17 (1.21 g, 4.11 mmol) in ethyl
§ NMR assignments follow the numbering scheme shown in Scheme 3.
1630
J. Chem. Soc., Perkin Trans. 1, 2001, 1624–1634

View Article Online
(1H, ddd, Jgem 12.5, J2Јeq,3Ј 4.8 and J2Јeq,1Ј 1.6, 2Јeq-H), 3.55–3.95
(5H, m, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 3.82, 3.89, 3.92 (each
3H, s, 3 × OCH3), 4.54–4.73 (5H, m, 5 × CHPh), 4.90 (1H,
d, Jgem 10.9, CHPh), 4.91 (1H, br d, J1,2 9.9, 1Ј-H), 6.63 (1H, d,
J3,2 8.5, 3-H), 6.69 (1H, d, J2,3 8.5, 2-H), 7.16–7.37 (15H, m,
Ph), 7.59 (1H, d, J8,7 8.9, 8-H), 7.99 (1H, d, J7,8 8.9, 7-H); δC (50
MHz; CDCl3)§ 38.3 (CH2, C-2Ј), 55.7, 56.6 (CH3, 1-OCH3,
4-OCH3), 62.9 (CH3, 5-OCH3), 69.6 (CH2, C-6Ј), 71.2 (CH2,
CH2Ph), 72.2 (CH, C-1Ј), 73.3, 75.0 (CH2, 2 × CH2Ph), 78.3,
79.5, 81.4 (CH, C-3Ј, C-4Ј, C-5Ј), 103.7 (CH, C-3), 106.0 (CH,
C-2), 118.6 (CH, C-7), 120.4 (quat., C-4a), 124.2 (CH, C-8),
127.4–128.4 (CH, Ph), 128.4 (quat., C-8a), 132.1 (quat.,
C-6), 138.6, 138.6, 138.7 (quat., 3 × ipso-Ph), 149.8, 149.8,
152.3 (C-1, C-4, C-5); m/z (EI) 634 (Mϩ, 50%), 526 (50), 436
(18), 294 (10), 189 (13), 105 (52), 91 (C7H7, 100).
sulfate), and concentrated in vacuo to give an oily residue, which
was purified by flash chromatography using hexane–ethyl
acetate (4 : 1) as eluent to afford 8-hydroxy-1,5-dimethoxy-
2-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-β--arabino-hexopyranosyl)-
naphthalene 22 (643 mg, 82%) as a tan oil; [α]1D9 ϩ 1.08 (c 0.372,
CHCl3) (Found: C, 75.03; H, 6.36. C39H40O7 requires C, 75.45;
H, 6.50%); νmax/cmϪ1 3381 br (OH), 3029, 2925, 2863 (C-H),
1634, 1608 (C᎐C), 1496, 1469, 1452, 1409, 1355 (C-O); δ (400
᎐
H
MHz; CDCl3)§ 1.95 (1H, ddd, Jgem 13.0, J2Јax,1Ј 11.5 and J2Јax,3Ј
11.5, 2Јax-H), 2.32 (1H, ddd, Jgem 13.0, J2Јeq,3Ј 4.9 and J2Јeq,1Ј 1.9,
2Јeq-H), 3.68–4.00 (5H, m, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB),
3.92, 3.92 (each 3H, s, 2 × OCH3), 4.53, 4.62 (each 1H, d, Jgem
12.3, 2 × CHPh), 4.65 (1H, d, Jgem 11.7, CHPh), 4.66 (1H, d,
Jgem 10.9, CHPh), 4.72 (1H, d, Jgem 11.7, CHPh), 4.89 (1H, dd,
J1Ј,2Јax 11.5 and J1Ј,2Јeq 1.9, 1Ј-H), 4.98 (1H, d, Jgem 10.9, CHPh),
6.74 (1H, d, J3,2 8.4, 3-H), 6.82 (1H, d, J2,3 8.4, 2-H), 7.23–7.34
(15H, m, Ph), 7.57 (1H, d, J8,7 8.9, 8-H), 8.05 (1H, d, J7,8 8.9,
7-H), 8.94 (1H, s, OH); δC (100 MHz; CDCl3)§ 37.6 (CH2,
C-2Ј), 55.9 (CH3, 1-OCH3), 64.3 (CH3, 5-OCH3), 69.6 (CH2,
C-6Ј), 71.4 (CH, C-1Ј), 71.5, 73.4, 75.1 (CH2, 3 × CH2Ph), 78.3,
79.8, 81.3 (CH, C-3Ј, C-4Ј, C-5Ј), 106.0 (CH, C-3), 109.5 (CH,
C-2), 117.0 (quat., C-4a), 119.9 (CH, C-7), 124.3 (CH, C-8),
127.5–128.4 (CH, Ph, quat., C-8a), 129.3 (quat., C-6), 138.4,
138.4, 138.5 (quat., 3 × ipso-Ph), 147.0, 148.5, 152.5 (quat., C-1,
C-4, C-5); m/z (EI) 620 (Mϩ, 20%), 230 (30), 91 (C7H7, 100).
5-Methoxy-6-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-ꢀ-D-arabino-hexo-
pyranosyl)-1,4-naphthoquinone 21
A solution of cerium() ammonium nitrate (1.49 g, 2.72 mmol)
in water (1 mL) was added dropwise to a stirred solution of
C- glycosylnaphthalene 20 (863 mg, 1.36 mmol) in acetonitrile
(15 mL). The reaction mixture was stirred for 0.5 h, then was
diluted with dichloromethane (50 mL) and washed with water
(50 mL). The combined organic phases were dried (magnesium
sulfate) and the solvent was removed under reduced pressure.
The crude product was purified by flash chromatography using
hexane–ethyl acetate (2:1) as eluent to afford 5-methoxy-
6-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-β--arabino-hexopyranosyl)
1,4-naphthoquinone 21 (765 mg, 93%) as an orange oil;
[α]1D9 Ϫ 29.6 (c 1.02, CHCl3) [Found (FAB): Mϩ, 604.2453.
C38H36O7 requires M, 604.2461]; νmax /cmϪ1 3029, 2919, 2864
8-Acetoxy-1,5-dimethoxy-2-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-ꢀ-D-
arabino-hexopyranosyl)naphthalene 23
Triethylamine (128 µL, 0.919 mmol), acetic anhydride (58 µL,
0.613 mmol) and a catalytic quantity of DMAP were added
to a solution of 22 (190 mg, 0.306 mmol) in dichloromethane
(10 mL). The solution was stirred overnight and then the
solvent was removed at reduced pressure. The residue was puri-
fied by flash chromatography using hexane–ethyl acetate (4 : 1)
to give 8-acetoxy-1,5-dimethoxy-2-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-
deoxy-β--arabino-hexopyranosyl)naphthalene 23 (172 mg,
85%) as a tan oil (Found: C, 74.12; H, 6.45. C41H42O8 requires
(C-H), 1665 (C᎐O, quin.) 1496, 1453, 1362, 1288 (C-O), 1090;
᎐
δH (200 MHz; CDCl3) 1.51 (1H, ddd, Jgem 12.5, J2Јax,1 11.4, and
J2Јax,3 11.4, 2Јax-H), 2.52 (1H, ddd, Jgem 12.5, J2Јeq,3Ј 4.8 and J2Јeq,1Ј
1.6, 2Јeq-H), 3.53–4.01 (5H, m, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB),
3.87 (3H, s, OCH3), 4.75–4.95 (5H, m, 5 × CHPh), 4.81 (1H,
dd, J1Ј,2Јax 11.4 and J1Ј,2Јeq 1.6, 1-H), 4.96 (1H, d, Jgem 10.9,
CHPh), 6.88 (1H, d, J3,210.3, 3-H), 6.94 (1H, d, J2,3 10.3, 2-H),
7.21–7.37 (15H, m, Ph), 7.94 (2H, s, 8-H and 7-H); δC (50 MHz;
CDCl3) 37.8 (CH2, C-2Ј), 62.4 (CH3, OCH3), 69.6 (CH2, C-6Ј),
71.3, 73.3, 75.0 (CH2, 3 × CH2Ph), 71.9 (CH, C-1Ј), 78.0, 79.3,
80.9 (CH, C-3Ј, C-4Ј, C-5Ј), 123.2, 132.5 (CH, C-2, C-3), 123.4
(quat., C-4a), 127.6 (CH, o-Ph), 127.9 (CH, p-Ph), 128.7 (CH,
m-Ph), 133.0 (quat., C-8a), 136.9, 140.3 (CH, C-7, C-8), 138.2,
138.3, 138.4 (quat., 3 × ipso-Ph), 143.5 (quat., C-6), 156.5
C, 74.30; H, 6.39%); νmax/cmϪ1 2927, 2862 (C-H), 1759 (C᎐O,
᎐
ester), 1603 C᎐C), 1352, 1207 (C-O); δ (400 MHz; CDCl3)§
᎐
H
1.77 (1H, ddd, Jgem 13.1, J2Јax,1Ј 11.6 and J2Јax,3Ј 11.6, 2Јax-H), 2.26
(1H, ddd, Jgem 13.1, J2Јeq,3Ј 4.8 and J2Јeq,1Ј 1.9, 2Јeq-H), 2.90 (3H, s,
COCH3), 3.50–3.90 (5H, m, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB),
3.73, 3.90 (each 3H, s, 2 × OCH3), 4.47 (1H, d, Jgem 12.3,
CHPh), 4.55–4.59 (3H, m, 3 × CHPh), 4.64 (1H, d, Jgem 11.6,
CHPh), 4.87 (1H, dd, J1Ј,2Јax 11.6 and J1Ј,2Јeq1.9, 1Ј-H), 4.90 (1H,
d, Jgem 11.0, CHPh), 6.68 (1H, d, J3,2 8.3, 3-H), 6.94 (1H, d, J2,3
8.3, 2-H), 7.17–7.26 (15H, m, Ph), 7.56 (1H, d, J8,7 8.9, 8-H),
8.03 (1H, d, J7,8 8.9, 7-H); δC (100 MHz; CDCl3)§ 20.8 (CH3,
COCH3), 37.9 (CH2, C-2Ј), 55.8, 63.2 (CH3, 2 × OCH3), 69.7
(CH2, C-6Ј), 71.4 (CH2, CH2Ph), 71.7 (CH, C-1Ј), 73.4, 75.1
(CH2, 2 × CH2Ph), 78.5, 79.7, 81.4 (CH, C-3Ј, C-4Ј, C-5Ј),
103.5 (CH, C-2), 119.4, 119.4 (CH, C-3, C-7), 121.7 (quat.,
C-4a), 124.6 (CH, C-8), 127.4–128.4 (CH, Ph and quat., C-8a),
132.3 (quat., C-6), 138.6 (quat., C-4), 138.6, 138.7, 138.8 (quat.,
3 × ipso-Ph), 151.4, 153.8 (quat., C-1, C-5), 170.1 (quat.,
COCH3); m/z (EI) 662 (Mϩ, 4%), 620 (MHϩ Ϫ COCH3, 1), 230
(26), 91 (C7H7, 100).
ϩ
(quat., C-5), 184.4, 184.7 (quat., C-1, C-4); m/z (EI) 606 (MH2 ,
4%), 604 (Mϩ, 2), 513 (7), 498 (2), 407 (47), 299 (8), 215 (7),
91 (C7H7, 100).
8-Hydroxy-1,5-dimethoxy-2-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-ꢀ-
D-arabino-hexopyranosyl)naphthalene 22
C-Glycosylnaphthoquinone 21 (765 mg, 1.27 mmol) was dis-
solved in dichloromethane–diethyl ether (1:3) (100 mL) and
shaken with a solution of sodium dithionite (1.545 g, 8.88
mmol) in water (100 mL) for 10 min. The organic layer was
washed with water (50 mL), dried (magnesium sulfate), and
the solvent was removed under reduced pressure to give the
crude hydroquinone as a brown foam. This was dissolved in dry
acetone (20 mL) and transferred by double-ended needle to
a reaction vessel containing potassium carbonate (875 mg,
6.33 mmol) and dry acetone (5 mL). Dimethyl sulfate (360 µL,
3.80 mmol) was added, the mixture was stirred and heated at
reflux until the reaction was complete (2–4 h). The mixture
was then cooled, filtered through Celite, and the solvent was
removed at reduced pressure. The residue was dissolved in
diethyl ether (50 mL) and the solution was stirred with triethyl-
amine (706 µL, 5.07 mmol). After 20 min the solution was
washed successively with hydrochloric acid (1 M; 2 × 50 mL),
water (50 mL) and brine (50 mL). It was then dried (sodium
2-Bromo-1-hydroxy-4,8-dimethoxy-7-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-
deoxy-ꢀ-D-arabino-hexopyranosyl)naphthalene 24
A solution of bromine (148 mg, 0.92 mmol) in tetrachloro-
methane (1.0 mL) was added dropwise to a stirred solution of
C-glycosylnaphthol 22 (477 mg, 0.77 mmol) in tetrachloro-
methane (4.0 mL) at 0 ЊC. The reaction mixture was stirred for
a further 2 min, then was quenched with saturated aq. sodium
thiosulfate (5 mL) and diluted with dichloromethane (50 mL).
The organic layer was washed with water (50 mL) and the
aqueous layer was extracted twice with dichloromethane
(2 × 50 mL). The combined organic phases were dried over
J. Chem. Soc., Perkin Trans. 1, 2001, 1624–1634
1631

View Article Online
magnesium sulfate and the solvent was removed at reduced
pressure. The crude product was purified by flash column
chromatography using hexane–ethyl acetate (4 : 1) as eluent
to afford 2-bromo-1-hydroxy-4,8-dimethoxy-7-(3Ј,4Ј,6Ј-tri-O-
benzyl-2Ј-deoxy-β--arabino-hexopyranosyl)naphthalene 24 as
a pale brown solid (416 mg, 77%), which was recrystallised from
hexane–ethyl acetate to give tan needles, mp 116–117 ЊC;
[α]1D9 Ϫ 4.06 (c 0.394, CHCl3) (Found: C, 66.90; H, 5.41.
C39H39BrO7 requires C, 66.95; H, 5.62%); νmax/cmϪ1 3329br
quenched with dilute aq. ammonium hydroxide (2 M; 5 mL).
The mixture was extracted with dichloromethane (3 × 150 mL),
and the extract was washed with water (100 mL) and dried
(sodium sulfate). The solvent was removed at reduced pressure
and the residue was purified by flash chromatography using
hexane–ethyl acetate (4 : 1) as eluent to afford the title com-
pound 9 (214 mg, 84%) as a colourless oil for which the spectro-
scopic data were in agreement with those described above.
(OH), 3029, 2862 (C-H), 1663, 1604 (C᎐C), 1496, 1453, 1403,
2-Acetyl-1,4,8-trimethoxy-7-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-ꢀ-
D-arabino-hexopyranosyl)naphthalene 8
A mixture of α-ethoxyvinyltributyltin24 (52 mg, 0.171 mmol),
᎐
1352 (C-O); δH (400 MHz; CDCl3)§ 1.86 (1H, ddd, Jgem 13.0 and
J2Јax,1Ј 11.5 and J2Јax,3Ј 11.5 Hz, 2Јax-H), 2.23 (1H, ddd, Jgem 13.0,
J2Јeq,3Ј 4.9 and J2Јeq,1Ј 1.8, 2Јeq-H), 3.59–3.87 (5H, 3Ј-H, 4Ј-H,
5Ј-H, 6Ј-HA, 6Ј-HA), 3.85, 3.85 (each 3H, s, 2 × OCH3), 4.45,
4.53 (each 1H, d, Jgem 12.2 2 × CHPh), 4.58 (1H, d, Jgem 10.9,
CHPh), 4.58 (1H, d, Jgem 11.7, CHPh), 4.64 (1H, d, Jgem 11.7,
CHPh), 4.80 (1H, dd, J1Ј,2Јax 11.5 and J1Ј,2Јeq 1.8, 1Ј-H), 4.90 (1H,
d, Jgem 10.9, CHPh), 6.85 (1H, s, H-2), 7.17–7.26 (15H, m, Ph),
7.52 (1H, d, J8,7 8.9, H-8), 7.94 (1H, d, J7,8 8.9, H-7), 9.53 (1H, s,
OH); δC (100 MHz; CDCl3)§ 37.6 (CH2, C-2Ј), 56.0, 64.6 (CH3,
2 × OCH3), 69.6 (CH2, C-6Ј), 71.4 (CH2, CH2Ph), 71.5 (CH,
C1Ј), 73.4, 75.1 (2 × CH2Ph), 78.3, 79.8, 81.2 (CH, C-3Ј, C-4Ј,
C-5Ј), 103.5 (quat., C-3), 109.9 (CH, C-2), 117.6 (quat., C-4a),
120.1, 124.8 (CH, C-7, C-8), 127.0 (quat., C-8a), 127.5–128.4
(CH, Ph), 130.5 (quat., C-6), 138.3, 138.4, 138.5 (quat.,
3 × ipso-Ph), 143.5, 148.5, 151.9 (quat., C-1, C-4, C-5); m/z (EI)
700, 698 (Mϩ, 3%), 621 (14), 530 (6), 309 (14), 230 (30), 91
(C7H7, 100).
C-glycosylbromonaphthalene
9 (111 mg, 0.156 mmol),
dichlorobis(triphenylphosphine)palladium (11 mg, 1.56 × 10Ϫ2
mmol) and dry toluene (2 mL) was heated at 100 ЊC. Over the
course of 18 h, two more portions of α-ethoxyvinyltributyltin
(52 mg, 0.171 mmol) and the palladium catalyst (11 mg,
1.56 × 10Ϫ2 mmol) were added due to the sluggishness of the
reaction. After hydrolysis of the reaction mixture by dilution
with dichloromethane (5 mL) and vigorous stirring with hydro-
chloric acid (1 M; 2 mL) for 0.5 h, the organic layer was
extracted with diethyl ether (3 × 100 mL). The combined
organic fractions were washed successively with water (150
mL), dil. aq. potassium fluoride (100 mL) and water (150 mL).
After drying (sodium sulfate) the solvent was removed at
reduced pressure and the residue was purified by flash chrom-
atography using hexane–ethyl acetate (4 : 1) as eluent to afford
the title compound 8 (95 mg, 90%) as a pale yellow oil; [α]D19
ϩ21.8 (c 0.330, CHCl3) (Found: C, 74.28; H, 6.66. C42H44O8
requires C, 74.52; H, 6.56%); νmax/cmϪ1 3063, 3029, 2927, 2862
2-Bromo-1,4,8-trimethoxy-7-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-ꢀ-
D-arabino-hexopyranosyl)naphthalene 9
(C-H), 1667 (C᎐O, ketone), 1603, 1568 (C᎐C), 1510, 1496, 1454,
᎐
᎐
(i) Using sodium hydride–hydrogen atmosphere. To a solution
of C-glycosylbromonaphthol 24 (251 mg, 0.359 mmol) in
dimethylformamide (5 mL) at 0 ЊC (which had been degassed
and flushed with nitrogen) was added dropwise, with stirring
a slurry of oil-free sodium hydride (17 mg, 0.718 mmol) in
dimethylformamide (1 mL) followed by dimethyl sulfate (68 µL,
0.718 mmol). The reaction mixture was stirred for 5 min, then
quenched with water (5 mL), extracted with dichloromethane
(3 × 50 mL) and the combined organic extracts was washed
with water (50 mL). The organic phase was dried (magnesium
sulfate), the solvent was evaporated at reduced pressure, and the
residue was purified by flash chromatography using hexane–
ethyl acetate (4 : 1) as eluent to afford the title compound 9
(177 mg, 69%) as a colourless oil; [α]1D9 ϩ11.4 (c 0.980, CHCl3)
[Found (FAB): Mϩ, 712.2027. C40H41 79BrO7 requires M,
1415, 1360 (C-O); δH (400 MHz; CDCl3)§ 1.72 (1H, ddd,
Jgem 12.9, J2Јax,3Ј 11.5 and J2Јax,1Ј 11.5, 2Јax-H), 2.31 (1H, ddd,
Jgem 12.9, J2Јeq,3Ј 4.9 and J2Јeq,1Ј 1.9, 2Јeq-H), 2.71 (3H, s, COCH3),
3.55–3.97 (5H, m, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 3.74, 3.76,
3.92 (each 3H, s, 3 × OCH3), 4.50, 4.59 (each 1H, d, Jgem 12.3,
2 × CHPh), 4.59 (1H, d, Jgem 10.9, CHPh), 4.61, 4.66 (each 1H,
d, Jgem 11.6, 2 × CHPh), 4.90 (1H, d, Jgem 10.9, CHPh), 4.95
(1H, dd, J1Ј,2Јax 11.5 and J1Ј,2Јeq 1.7, 1Ј-H), 6.97 (1H, s, 2-H),
7.18–7.27 (15H, m, Ph-H), 7.67 (1H, d, J8,7 8.8, 8-H), 8.01 (1H,
d, J7,8 8.8, 7-H); δC (100 MHz; CDCl3)§ 31.5 (CH3, COCH3),
38.6 (CH2, C-2Ј), 55.8 (CH3, 1-OCH3), 63.3 (CH3, 5-OCH3),
63.8 (CH3, 4-OCH3), 69.7 (CH2, C-6Ј), 71.6 (CH2, CH2Ph), 71.9
(CH, C-1Ј), 73.4, 75.1 (CH2, 2 × CH2Ph), 78.4, 79.6, 81.4 (CH,
C-3Ј, C-4Ј, C-5Ј), 102.8 (CH, C-2), 119.2, 126.5 (CH, C-7, C-8),
122.5 (quat., C-4a), 127.5–128.4 (CH, Ph), 129.4, 130.7, 133.2
(quat., C-8a, C-3, C-6), 138.5, 138.6, 138.6 (quat., 3 × ipso-Ph),
151.0, 151.8, 152.2 (quat., C-1, C-4, C-5), 201.0 (quat.,
COCH3); m/z (CI) 676 (Mϩ, 48%), 286 (16), 91 (C7H7, 100).
712.2036]; νmax/cmϪ1 2927, 2861 (C-H), 1587 (C᎐C), 1496, 1452,
᎐
1408, 1360, 1328 (C-O); δH (400 MHz; CDCl3) 1.74 (1H, ddd,
Jgem 13.0, J2Јax,1Ј 11.5 and J2Јax,3Ј 11.5, 2Јax-H), 2.51 (1H, ddd,
Jgem 13.0, J2Јeq,3Ј 4.9 and J2Јeq,1Ј 1.8, 2Јeq-H), 3.60–3.87 (5H, m,
3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 3.88, 3.75, 3.76 (each 3H, s,
3 × OCH3), 4.50 (1H, d, Jgem 12.3, CHPh), 4.56–4.67 (4H, m,
4 × CHPh), 4.90 (1H, d, Jgem 10.9, CHPh), 4.94 (1H, dd, J1Ј,2Јax
11.5 and J1Ј,2Јeq 1.8, 1Ј-H), 6.85 (1H, s, 2-H), 7.17–7.27 (15H,
m, Ph), 7.59 (1H, d, J8,7 8.8, 8-H), 8.00 (1H, d, J7,8 8.8, 7-H); δC
(100 MHz; CDCl3)§ 38.5 (CH2, C-2Ј), 55.9, 61.9, 63.4 (CH3,
3 × OCH3), 69.6 (CH2, C-6Ј), 71.5 (CH2, CH2Ph), 71.9 (CH,
C-1Ј), 73.4, 75.1 (CH2, 2 × CH2Ph), 78.4, 79.6, 81.4 (CH, C-3Ј,
C-4Ј, C-5Ј), 108.6 (CH, C-2), 114.9 (quat., C-3), 119.2 (CH,
C-7), 123.1 (quat., C-4a), 124.6 (CH, C-8), 127.5–128.4 (CH,
Ph), 127.8 (quat., C-8a), 133.3 (quat., C-6), 138.5, 138.6, 138.6
(quat., 3 × ipso-Ph), 145.7, 152.2, 152.2 (quat., C-1, C-4, C-5);
m/z (EI) 714, 712 (Mϩ, 34%), 624, 622 (M Ϫ C7H6, 12), 324 (30),
309 (21), 279 (48), 167 (16), 149 (42), 105 (17), 91 (C7H7, 100).
2-Acetyl-7-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-ꢀ-D-arabino-hexo-
pyranosyl)-8-methoxy-1,4-naphthoquinone 7
(i) Using CAN. A solution of cerium() ammonium nitrate
(308 mg, 0.562 mmol) in water (1.0 mL) was added dropwise to
a solution of C-glycosylnaphthalene 8 (190 mg, 0.281 mmol) in
acetonitrile (5.0 mL) and the mixture was stirred for 10 min.
The reaction mixture was diluted with water (10 mL) and
extracted with dichloromethane (3 × 50 mL). The combined
organic fractions were washed with water (50 mL), dried
(sodium sulfate) and the solvent was removed at reduced pres-
sure to give an orange oil. Flash chromatography using hexane–
ethyl acetate (1:1) as eluent afforded the title compound 7 (166
mg, 91%) as a yellow oil (Found: C, 73.98; H, 6.21. C40H38O8
requires C, 74.27; H, 5.93%); νmax/cmϪ1 3060, 3030, 2925, 2863
(ii) Using sodium hydroxide. To a solution of C-glycosyl-
bromonaphthol 24 (250 mg, 0.358 mmol) in dimethylform-
amide (5 mL) at 0 ЊC was added dimethyl sulfate (68 µL, 0.715
mmol) followed by aq. sodium hydroxide (2 M; 1.79 mL). The
mixture was stirred for 0.5 h at room temperature and then
(C-H), 1702 (C᎐O, ketone), 1666 (C᎐O, quin.), 1605, 1585, 1573
᎐ ᎐
(C᎐C), 1496, 1453, 1365 (C-O); δ (400 MHz; CDCl3)† 1.72
᎐
H
(1H, ddd, Jgem 12.9, J2Јax,3Ј 12.0 and J2Јax,1Ј 12.0, 2ax-H), 2.31 (1H,
ddd, Jgem 12.9, J2Јeq,3Ј 5.0 and J2Јeq,1Ј 1.0, 2eq-H), 2.53 (3H, s,
COCH3), 3.47–3.90 (5H, m, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB),
1632
J. Chem. Soc., Perkin Trans. 1, 2001, 1624–1634

View Article Online
3.81 (3H, s, OCH3), 4.47–4.60 (4H, m, 4 × CHPh), 4.63 (1H, d,
Jgem 11.8, CHPh), 4.74 (1H, dd, J1Ј,2Јax 11.6 and J1Ј,2Јeq 1.0, 1Ј-H),
4.89 (1H, d, Jgem 11.2, CHPh), 6.96 (1H, s, 2-H), 7.15–7.28
(15H, m, Ph-H), 7.85 (1H, d, J8,7 8.1, 8-H), 7.91 (1H, d, J7,8 8.1,
7-H); δC (100 MHz; CDCl3)† 30.8 (CH3, COCH3), 38.0 (CH2,
C-2Ј), 62.6 (CH3, OCH3), 69.8 (CH2, C-6Ј), 71.5 (CH2, CH2Ph),
72.0 (CH, C-1Ј), 73.5, 75.0 (CH2, 2 × CH2Ph), 78.2, 79.6,
81.0 (CH, C-3Ј, C-4Ј, C-5Ј), 123.0, 123.5 (quat., C-4a, C-3),
127.6–128.5 (CH, Ph, C-7), 133.1 (CH, C-8), 134.8 (quat.,
C-8a), 138.6, 138.6, 138.6 (quat., 3 × ipso-Ph), 147.3 (quat.,
C-6), 157.1 (quat., C-5), 183.0, 184.6 (quat., C-1, C-4), 198.0
(quat., COCH3); m/z (CI) 648 (Mϩ, 12%), 286 (16), 258 (21),
181 (16), 91 (C7H7, 100), 43 (COCH3, 55).
C-10a), 171.7 (quat., C-8), 203.0 (quat., COCH3); m/z (CI) 731
(MHϩ, 92%), 730 (Mϩ, 100), 685 (10), 640 (15), 547 (35), 391
(80), 341 (40), 305 (88), 91 (C7H7, 63).
(3aR,5S,11bR)-5-Hydroxy-7-methoxy-5-methyl-8-(3Ј,4Ј,6Ј-tri-
O-benzyl-2Ј-deoxy-ꢀ-D-arabino-hexopyranosyl)-3,3a,5,11b-
tetrahydro-2H-furo[3,2-b]naphtho[2,3-d]pyran-2,6,11-trione 27
and (3aS,5R,11bS)-5-hydroxy-7-methoxy-5-methyl-8-(3Ј,4Ј,6Ј-
tri-O-benzyl-2Ј-deoxy-ꢀ-D-arabino-hexopyranosyl)-3,3a,5,11b-
tetrahydro-2H-furo[3,2-b]naphtho[2,3-d]pyran-2,6,11-trione 28
A solution of cerium() ammonium nitrate (71 mg, 0.13 mmol)
in water (0.5 mL) was added dropwise to a stirred solution of
adducts 25 and 26 (47 mg, 0.064 mmol) in acetonitrile (5.0 mL)
until no starting material could be detected by TLC (ca. 10 min).
The mixture was diluted with dichloromethane (10 mL), washed
with water (2 × 5 mL) and dried (sodium sulfate). The solvent
was removed at reduced pressure and the resultant oil was
filtered through a plug of silica using dichloromethane as
eluent. Removal of the solvent at reduced pressure afforded a
mixture of title lactols 27 and 28 (41 mg, 85%) as an orange oily
mixture of diastereomers (1:1, 1H NMR) [Found (LSIMS): Mϩ,
746.2749. C44H42O11 requires M, 746.2727]; δC (100 MHz;
CDCl3) 27.5, 27.6 (CH3, CH3, CH3*), 29.7 (CH2, C-3), 37.9
(CH2, C-2Ј), 62.7, 62.9 (CH3, OCH3, OCH3*), 67.1, 67.2 (CH,
C-3a), 68.5, 68.7 (CH, C-11b), 69.6 (CH2, C-6Ј), 71.4 (CH2,
CH2Ph), 71.8, 72.0 (CH, C-1Ј), 73.4, 75.1 (CH2, 2 × CH2Ph),
78.0, 79.4, 80.9 (CH, C-3Ј, C-4Ј, C-5Ј), 93.2 (quat., C-5), 123.4,
123.5 (CH, C-9, C-10), 127.6–128.4 (CH, Ph and quat, C-5a,
C-6a, C-10a, C-11a), 138.2, 138.63, 138.4 (quat., 3 × ipso-Ph),
166.4, 166.5 (quat., C-2, C-2*), 171.2, 174.2 (quat., C-6, C-11);
m/z (CI) 744 (Mϩ, 1%), 686 (2), 296 (3), 105 (6), 91 (C7H7, 100).
Flash chromatography at Ϫ10 ЊC using hexane–ethyl acetate
(1:2) treated with potassium carbonate, as eluent, allowed
separation of the diastereomers to give:
(i) Using silver(II) oxide and nitric acid. To a solution of C-
glycosylnaphthalene 8 (200 mg, 0.296 mmol) in 1,4-dioxane
(10 mL) was added freshly prepared silver() oxide25 (146 mg,
1.18 mmol) followed by nitric acid (11.1 M; 106 µL). After
stirring of the mixture for 10 min further portions of silver()
oxide (146 mg, 1.18 mmol) and nitric acid (11.1 M; 106 µL)
were added. After stirring for an additional 10 min the reaction
mixture was quenched with water (5 mL) and extracted into
dichloromethane (3 × 100 mL). The organic layer was washed
with water (2 × 50 mL), dried (sodium sulfate) and the solvent
was removed under reduced pressure to yield the title compound
7 (178 mg, 93%) as a yellow oil for which the spectroscopic data
were in agreement with those reported above.
(6bR,9aR)-6-Acetyl-5-hydroxy-4-methoxy-3-(3Ј,4Ј,6Ј-tri-O-
benzyl-2Ј-deoxy-ꢀ-D-arabino-hexopyranosyl)-6b,9a-dihydro-
furo[3,2-b]naphtho[2,1-d]furan-8(9H)-one 25 and (6bS,9aS)-6-
acetyl-5-hydroxy-4-methoxy-3-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-
ꢀ-D-arabino-hexopyranosyl)-6b,9a-dihydrofuro[3,2-b]naphtho-
[2,1-d]furan-8(9H)-one 26
A solution of 2-(trimethylsilyloxy)furan 13 (33 mg, 0.21 mmol)
in dry acetonitrile (0.5 mL) was added dropwise to an ice-
cooled solution of C-glycosylnaphthoquinone 7 (69 mg, 0.107
mmol) in dry acetonitrile (1.5 mL) under an atmosphere of
nitrogen. After 1 h the reaction mixture was allowed to warm to
room temperature and methanol (0.5 mL) and silica gel (23–400
mesh; 50 mg) were added. After a further 18 h, dichloro-
methane (10 mL) was added and the solution was washed with
water (2 × 5 mL) and dried (sodium sulfate). Removal of the
solvent at reduced pressure yielded a crude oil, which was
adsorbed onto Celite (100 mg) and then purified by flash
chromatography using hexane–ethyl acetate (2:1) as eluent to
afford the title compounds 25 and 26 (47 mg, 60%) as an orange
oily mixture of diastereomers (5:4, 1H NMR) [Found (LSIMS):
Mϩ, 730.2762. C44H42O10 requires M, 730.2778]; νmax/cmϪ1
The less polar lactol 27 or 28 (6 mg, 14%) as a yellow oil;
νmax/cmϪ1 3276–3624 (OH), 1788 (C᎐O, γ-lactone) and 1668
᎐
(C᎐O, quin.); δ (200 MHz; CDCl3) 1.46 (1H, ddd, Jgem 12.7,
᎐
H
J2Јax,3Ј 11.7 and J2Јax,1Ј 11.2, 2Јax-H), 1.64–1.90 (1H, br s, OH),
1.73 (3H, s, CH3), 2.46 (1H, ddd, Jgem 12.7, J2Јeq,3Ј 4.9 and
J2Јeq,1Ј 2.0, 2Јeq-H), 2.67 (1H, d, Jgem 17.7, 3-HA), 2.87 (1H, dd,
Jgem 17.7, J3B,3a 4.8, 3-HB), 3.46–3.62 (2H, m, 6Ј-HB, 6Ј-HA),
3.68–3.75 (2H, m, 4Ј-H, 5Ј-H), 3.76–3.84 (1H, m, 3Ј-H), 3.77
(3H, s, OCH3), 4.45–4.68 (5H, m, 5 × CHPh), 4.73 (1H, dd,
J1Ј,2Јax 11.2 and J1Ј,2Јeq 2.0, 1Ј-H), 4.83 (1H, dd, J3a,3B 4.8 and
J3a,11b 2.7, 3a-H), 4.89 (1H, d, Jgem 10.9, CHPh), 5.20 (1H,
d, J11b,3a 2.7, 11b-H), 7.13–7.29 (15H, m, Ph), 7.90 (2H, s, 9-H
and 10-H).
The more polar lactol 28 or 27 (5 mg, 12%) as a yellow oil;
νmax/cmϪ1 3587–3182 (OH), 3062, 3023, 2925, 2866 (C-H), 1788
3333br (OH), 2924, 2868 (C-H), 1784 (C᎐O, γ-lactone), 1742
᎐
(C᎐O, γ-lactone), 1671 (C᎐O, quin.); δ (200 MHz; CDCl3)
᎐
᎐
H
(C᎐O, ketone), 1666 (C᎐O, quin.), 1630 (C᎐C), 1565, 1517,
᎐
᎐
᎐
1.45 (1H, ddd, Jgem 13.0, J2Јax,3Ј 11.7 and J2Јax,1Ј 11.7, 2Јax-H),
1.64–1.90 (1H, br s, OH), 1.72 (3H, s, CH3), 2.40 (1H, ddd,
Jgem 13.0, J2Јeq,3Ј 5.0 and J2Јeq,1Ј 2.0, 2Јeq-H), 2.65 (1H, dd, Jgem 17.5
and J3A,3a 2.0, 3-HA), 2.87 (1H, dd, Jgem 17.7, J3B,3a 4.7, 3-HB),
3.46–3.68 (2H, m, 6Ј-HA, 6Ј-HB), 3.68–3.75 (2H, m, 4Ј-H, 5Ј-H),
3.76–3.84 (1H, m, 3Ј-H), 3.82 (3H, s, OCH3), 4.45–4.68 (5H, m,
5 × CHPh), 4.72 (1H, dd, J1Ј,2Јax 11.7 and J1Ј,2Јeq 2.0, 1Ј-H), 4.81
(1H, ddd, J3a,3B 4.7, J3a,11b 2.8 and J3a,3A 2.0, 3a-H), 4.89 (1H, d,
Jgem 10.9, CHPh), 5.19 (1H, d, J11b,3a 2.8, 11b-H), 7.13–7.29
(15H, m, Ph), 7.88 (1H, d, J10,9 8.0, 10-H), 7.93 (1H, d, J9,10 8.0,
9-H).
1496, 1453, 1396 (C-O); δH (400 MHz; CDCl3) 1.45 (1H, ddd,
Jgem 12.9, J2Јax,3Ј 11.0 and J2Јax,1Ј 11.0, 2Јax-H), 2.47*, 2.51 (1H,
ddd, Jgem 12.9, J2Јeq,3Ј 4.9 and J2Јeq,1Ј 1.8, 2Јeq-H), 2.83*, 2.84 (3H,
s, COCH3), 3.14*, 3.15 (2H, d, J9,9a 4.1, 9-H2), 3.61–3.71 (2H,
m, 6Ј-H2), 3.79–3.84 (2H, m, 4Ј-H, 5Ј-H), 3.86–3.95 (1H, m,
3Ј-H), 3.91*, 3.93 (3H, s, OCH3), 4.56, 4.58* (1H, d, Jgem 12.3,
CHPh), 4.61–4.68 (3H, m, 3 × CHPh), 4.72 (1H, d, Jgem 11.8,
CHPh), 4.94 (1H, dd, J1Ј,2Јax 7.0 and J1Ј,2Јeq 1.8, 1Ј-H), 4.98 (1H,
d, Jgem 10.9, CHPh), 5.51 (1H, dt, J9a,6b 6.3 and J9a,9 4.1, 9a-H),
6.47, 6.48* (1H, d, J9a,6b 6.3, 6b-H), 7.25–7.35 (15H, m, Ph),
7.76 (1H, d, J1,28.5, 1-H), 7.88*, 7.89 (1H, d, J2,1 8.5, 2-H),
14.43*, 14.49 (1H, s, OH); δC (100 MHz; CDCl3) 31.2 (CH3,
COCH3), 34.0 (CH2, C-9), 38.2 (CH2, C-2Ј), 63.3 (CH3, OCH3),
69.7 (CH2, C-6Ј), 71.3 (CH2, CH2Ph), 72.0 (CH, C-1Ј), 73.4,
75.0 (CH2, 2 × CH2Ph), 78.2, 79.4, 81.2 (CH, C-3Ј, C-4Ј, C-5Ј),
81.0 (CH, C-9a), 85.8 (CH, C-6b), 107.3, 116.5 (CH, C-1, C-2),
108.4, 116.6, 121.0, 126.9 (quat., C-4a, C-6, C-6a, C-10b),
127.5-127.4 (CH, Ph), 130.0 (quat., C-3), 138.3, 138.4, 138.6
(quat., 3 × ipso-Ph), 150.2, 156.1, 162.6 (quat., C-4, C-5,
(11bR,5S,3aR)-7-Methoxy-5-methyl-8-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-
deoxy-ꢀ-D-arabino-hexopyranosyl)-3,3a,5,11b-tetrahydro-2H-
furo[3,2-b]naphtho[2,3-d]pyran-2,6,11-trione 29 and
(11bS,5R,3aS)-7-methoxy-5-methyl-8-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-
deoxy-ꢀ-D-arabino-hexopyranosyl)-3,3a,5,11b-tetrahydro-2H-
furo[3,2-b]naphtho[2,1-d]pyran-2,6,11-trione 30
To a solution of lactols 27 and 28 (1:1 mixture; 42 mg, 0.056
J. Chem. Soc., Perkin Trans. 1, 2001, 1624–1634
1633

View Article Online
mmol) in dichloromethane (4 mL), cooled to Ϫ30 ЊC under an
atmosphere of nitrogen, were added trifluoroacetic acid (43 µL,
0.56 mmol) and triethylsilane (90 µL, 0.56 mmol). The mixture
was slowly allowed to warm to Ϫ10 ЊC and was then stirred
at this temperature for 72 h with the aid of a cryostat. Celite
(250 mg) was added, and the solvent was removed at reduced
pressure while the temperature was maintained at Ϫ10 ЊC. The
unstable residue was purified by flash chromatography at
Ϫ10 ЊC using hexane–ethyl acetate (1:1) that had been stirred
over potassium carbonate as eluent to give the title lactols 29
and 30 (35 mg, 86%) as an orange oily mixture of diastereomers
to afford the title compounds 6 and 31 (13 mg, 67%) as an
orange solid mixture of diastereomers (3:1; 1H NMR); mp 151–
152 ЊC [Found (LSIMS): Mϩ, 446.1217. C22H22O10 requires M,
446.1213]; νmax/cmϪ1 3100–3643 (OH), 2934, 2890 (C-H) 1780
(C᎐O, γ-lactone), 1652, 1615 (C᎐O, quin.), 1434, 1282, 1088,
᎐
᎐
1039; δH [400 MHz; (CD3)2CO] 1.57 (0.75H, d, Jvic 7.0, CH3*),
1.58 (2.25H, d, Jvic 6.8, CH3), 1.31–1.39 (1H, m, 2Јax-H), 2.36–
2.47 (1H, m, 2Јeq-H), 2.49 (1H, d, Jgem 17.5, 3-HA), 3.19 (1H, dd,
Jgem 17.5, J3,3a 5.0, 3-HB), 3.43–3.82 (5H, m, 3Ј-H, 4Ј-H, 5Ј-H,
6Ј-HA and 6Ј-HB), 4.81–4.99 (2H, m, 3a-H, 1Ј-H), 5.04 (1H, q,
Jvic 6.6, 5-H), 5.34 (1H, d, J11b,3a 1.6, 11b-H), 5.78 (1H, br
s, OH), 7.63 (0.25H, d, J9,10 7.8, 9-H*), 7.64 (0.75H, d, J9,10 7.8,
9-H), 8.00 (0.25H, d, J9,10 7.8, 10-H*), 8.01 (0.75H, d, J9,10 7.8,
10-H), 12.20 (0.25H, br s, ArOH*), 12.30 (0.75H, br s, ArOH);
δC [100 MHz; (CD3)2CO] 18.3 (CH3, Me), 20.6 (CH3, Me*),
37.1 (CH2, C-3), 40.4 (CH2, C-2Ј), 63.0 (CH2, C-6Ј), 66.9 (CH,
C-3a*), 67.5 (CH, C-3a), 69.0 (CH, C-11b*), 69.5 (CH, C-11b),
70.7 (CH, C-5*), 72.1 (CH, C-5), 71.9, 73.3, 73.5 (CH, C-3Ј,
C-4Ј, C-5Ј), 81.6 (CH, C-1Ј), 113.7 (quat., C-10a), 119.3 (quat.,
C-8), 119.4 (CH, C-10), 134.3 (CH, C-9), 138.9 (quat., C-5a),
1
(1:1, H NMR) [Found (LSIMS): MHϩ, 731.2823. C44H42O10
requires MH, 731.2778]; νmax/cmϪ1 3027, 2923, 2865 (C-H),
1736 (C᎐O, γ-lactone), 1665 (C᎐O, quin.), 1575 (C᎐C), 1453,
᎐
᎐
᎐
1362, 1270, 1095 (C-O). The 13C NMR spectrum was obtained
for a mixture of diastereomers enriched in the more polar
diastereomer (less polar diastereomer marked with asterisk);
δC (100 MHz; CDCl3) 20.5, 20.3* (CH3, Me), 37.8 (CH2, C-2Ј),
38.4, 38.2* (CH2, C-3), 63.5, 63.2* (CH3, OMe), 69.5, 69.4*
(CH, C-3a), 69.9 (CH2, C-6Ј), 70.3, 70.1* (CH, C-11b), 71.8
(CH2, CH2Ph), 71.9 (CH, C-1Ј), 72.4, 72.6* (CH, C-5), 73.9,
75.8 (CH2, 2 × CH2Ph), 78.4, 79.7, 81.4 (CH, C-3Ј, C-4Ј, C-5Ј),
122.2, 124.7 (CH, C-9 and C-10), 123.9, 124.7* (quat., C-11a),
133.0, 132.9*, 133.4, 133.5* (quat., C-10a and C-6a), 138.6,
138.6, 138.7 (quat., 3 × ipso-Ph), 144.2, 143.9* (quat., C-8),
152.7, 153.8* (quat., C-5a), 156.9, 157.0* (quat., C-7), 175.4,
175.3* (quat., C-2), 182.8, 182.4*, 184.4, 185.5* (quat., C-6 and
ϩ
149.9, 151.5 (quat., C-2, C-7); m/z (CI) 449 (MH3 , 100%), 447
(MHϩ, 77), 431 (37), 413 (21), 403 (46), 385 (45), 371 (29).
References
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ϩ
C-11); m/z (CI) 732 (MH2 , 24%), 702 (M-CO, 20), 181 (30),
91 (C7H7, 100).
More careful chromatography at Ϫ10 ЊC allowed some
degree of separation of the diastereomers with considerable
loss of material to afford (i) The less polar diastereomer 29 or
30 (8 mg, 19%) as an orange glass; δH (200 MHz; CDCl3) 1.73
(3H, d, Jvic 6.2, CH3), 1.29–1.38 (1H, m, 2Јax-H), 2.40–2.60 (1H,
m, 2Јeq-H), 2.72 (1H, d, Jgem 17.3, 3-HA), 2.90 (1H, dd, Jgem 17.3,
J3B,3a 4.5, 3-HB), 3.46–3.84 (5H, m, 3ЈH, 4Ј-H, 5Ј-H, 6Ј-HA and
6Ј-HB), 3.88 (3H, s, OCH3), 4.30–4.38 (1H, m, 3a-H), 4.55–4.75
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(1H, d, Jgem 10.7, CHPh), 5.27 (1H, br s, 11b-H), 5.38 (1H, dd,
J1Ј,2Јax 10.8, J1Ј,2Јeq 2.9, 1Ј-H), 7.24–7.35 (15H, m, ArH), 7.94 (1H,
apparent s, 9-H), 7.96 (1H, apparent s, 10-H) (ii) The more
polar diastereomer 30 or 29 (10 mg, 24%) as an orange glass;
δH (200 MHz; CDCl3) 1.57 (3H, d, Jvic 6.6, CH3), 1.29–1.38 (1H,
m, 2Јax-H), 2.40–2.60 (1H, m, 2Јeq-H), 2.72 (1H, d, Jgem 17.3,
3-HA), 2.90 (1H, dd, Jgem 17.3, J3B,3a 4.5, 3-HB), 3.46–3.84 (5H,
m, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA and 6Ј-HB), 3.81 (3H, s, OCH3),
4.30–4.38 (1H, m, 3a-H), 4.55–4.75 (5H, m, 5 × CHPh), 4.80
(1H, dq, Jvic 6.6, J5,11b 1.8, 5-H), 4.96 (1H, d, Jgem 10.9, CHPh),
5.27 (1H, br s, 11b-H), 5.38 (1H, dd, J1Ј,2Јax 10.8, J1Ј,2Јeq 2.9,
1Ј-H), 7.24–7.35 (15H, m, ArH), 7.94 (1H, apparent s, 9-H),
7.96 (1H, apparent s, 10-H).
3 T. Okabe, K. Namoto, H. Funabashi, S. Okuda, H. Suzuki and
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[2,1-d]pyran-2,6,11-trione 6 and (11bS,5S,3aS)-8-(2Ј-deoxy-ꢀ-
D-arabino-hexopyranosyl)-7-hydroxy-5-methyl-3,3a,5,11b-
tetrahydro-2H-furo[3,2-b]naphtho[2,1-d]pyran-2,6,11-trione 31
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A solution of boron tribromide in dichloromethane (0.27 mL,
0.27 mmol) was added dropwise to a solution of ethers 29 and
30 (33 mg, 0.045 mmol) (ratio of more polar diastereomer : less
polar diastereoisomer, 3 : 1) in dichloromethane (1 mL) cooled
to Ϫ48 ЊC under an atmosphere of nitrogen. After 5 min,
acetonitrile (1 mL) was added and the reaction mixture was
allowed to warm to room temperature. Stirring was continued
for a further 0.5 h. The reaction mixture was treated with water
(1 mL), stirred for 5 min, and the aqueous layer was extracted
with ethyl acetate (3 × 5 mL). The organic phases were com-
bined, dried, and the solvent was removed at reduced pressure
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1634
J. Chem. Soc., Perkin Trans. 1, 2001, 1624–1634