C-Glycosylation of tri-O-benzyl-2-deoxy-D-glucose: Synthesis of naphthyl-substituted 3,6-dioxabicyclo[3.2.2]nonanes

Article abstract of DOI:10.1039/b102807n

The syntheses of naphthol 7, naphthol 8, naphthol 11 and naphthol 12 are described, starting from juglone 13. C-Glycosylation of naphthol 8 with benzyl-protected glycosyl donor 10 using trimethylsilyl trifluoromethanesulfonate and silver perchlorate or boron trifluoride-diethyl ether affords rearranged product 36 in which the glycosyl donor has undergone an unusual 1,6-hydride shift. Use of the corresponding naphthol 12 as the glycosyl acceptor under the same conditions affords the expected C-glycoside 34. Use of the naphthol 7 and naphthol 11 affords predominantly rearranged products 35 and 37 respectively, albeit in much lower yield than the reactions using the corresponding bromonaphthols. The study described herein establishes that introduction of an acetyl group to C-3, as in C-glycosylnaphthoquinone 4, as required for conversion to analogues of medermycin 1 such as 3, necessitates that the C-glycosylation step be effected before regioselective introduction of the acetyl group.

Full text of DOI:10.1039/b102807n

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C-Glycosylation of tri-O-benzyl-2-deoxy-D-glucose: synthesis of
naphthyl-substituted 3,6-dioxabicyclo[3.2.2]nonanes
Margaret A. Brimble*† and Timothy J. Brenstrum
1
School of Chemistry, F11, University of Sydney, Camperdown, NSW 2006, Australia
Received (in Cambridge, UK) 27th March 2001, Accepted 22nd May 2001
First published as an Advance Article on the web 5th July 2001
The syntheses of naphthol 7, naphthol 8, naphthol 11 and naphthol 12 are described, starting from juglone 13.
C-Glycosylation of naphthol 8 with benzyl-protected glycosyl donor 10 using trimethylsilyl trifluoromethanesulfonate
and silver perchlorate or boron trifluoride–diethyl ether affords rearranged product 36 in which the glycosyl donor
has undergone an unusual 1,6-hydride shift. Use of the corresponding naphthol 12 as the glycosyl acceptor under the
same conditions affords the expected C-glycoside 34. Use of the naphthol 7 and naphthol 11 affords predominantly
rearranged products 35 and 37 respectively, albeit in much lower yield than the reactions using the corresponding
bromonaphthols. The study described herein establishes that introduction of an acetyl group to C-3, as in
C-glycosylnaphthoquinone 4, as required for conversion to analogues of medermycin 1 such as 3, necessitates
that the C-glycosylation step be effected before regioselective introduction of the acetyl group.
Medermycin 1 was isolated from Streptomyces tanashiensis1
and is highly active against gram-positive organisms 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 at a
concentration of 0.03 µg mLϪ1.3 Another property of meder-
mycin 1 is its ability to act as a bioreductive alkylating agent
in vivo via quinone methide intermediates, as postulated
by Moore.4 Medermycin 1 possesses the same pyranonaphtho-
quinone ring skeleton as kalafungin 25 with an additional β
C-glycoside linkage at C-8 to an amino sugar, -angolosamine.
Given the reported improvement in anthelmintic activity
reported for kalafungin 2 in the presence of various natural
sugars,6 an efficient and flexible method for the introduction
of a C-glycoside linkage at C-8 of the kalafungin molecule
was sought, such that a range of C-glycosidic pyranonaphtho-
quinones could be prepared for biological evaluation.
To date only one (lengthy) synthesis of medermycin 1 has
been reported7 in which a pyranonaphthalene skeleton was
assembled by addition of a sulfonylphthalide to an enone. The
sulfonylphthalide was prepared in a seventeen-step sequence in
which C-glycosylation was effected by addition of a substituted
aryllithium species to a bromolactone derived from -rhamnal.
Our synthetic effort to date has focused on the synthesis of a 2-
deoxyglycosyl analogue of medermycin, compound 3,8 using a
furofuran annulation–oxidative rearrangement strategy that we
have successfully used for the synthesis of kalafungin 29 and
related aglycones.10 Initial studies,11 focused on developing
an efficient synthesis of the key benzyl-protected 2-acetyl-2Ј-
deoxyglucosyl-1,4-naphthoquinone 4, unveiled an extensive
rearrangement of the tri-O-benzyl-2-deoxyglucosyl moiety. We
therefore herein report the full details of the formation of naph-
thyl C-glycosides derived from this rearranged tri-O-benzyl-
2-deoxyglucosyl skeleton.
quinone 4 was required in order to realise a synthesis of a 2-
deoxyglucosyl analogue of medermycin, compound 3, based
on the retrosynthesis outlined in Scheme 1. Preliminary studies
hadindicatedthatdirectC-glycosylation12 ofkalafungin2,which
contains a 5-hydroxy-1,4-naphthoquinone (juglone) skeleton,
was not feasible given the low reactivity of this glycosyl
acceptor due to the strong hydrogen bonding between the
hydroxy group and the neighbouring quinone carbonyl group.
Mindful of these limitations13 we decided to focus our attention
on the synthesis of C-glycosylnaphthalenes 5 and 6 which would
serve as suitable precursors to the key C-glycosylnaphtho-
quinone 4. In turn C-glycosylnaphthalenes 5 and 6 were
envisaged to be prepared via C-glycosylation of the acetyl-
naphthol 7 or the bromonaphthol 8.
It transpired that the reactivity of 3-functionalised naphth-
alenes 7 and 8 towards the 2-deoxyglucosyl donors 9 and 10
differed markedly from the reactivity of the corresponding
2-functionalised naphthols 11 and 12. Thus the starting point
for the synthetic work reported herein is the synthesis of
naphthols 7 and 8, together with their regioisomers 11 and 12,
starting from juglone 13 (Scheme 2).
Results and discussion
A
synthesis of the 2-acetyl-7-deoxyglucosyl-1,4-naphtho-
The first step in the synthesis was the bromination of juglone
13.14 Bromination of juglone 13 in chloroform at 0 ЊC followed
by the addition of a trace of glacial acetic acid afforded a 3.6:1
mixture of 14 and 15 in an overall yield of 97%. 3-Bromo-
† Present address: Department of Chemistry, University of Auckland,
Private Bag 92019, Auckland, New Zealand. Fax: ϩ64 9 3737422;
email: m.brimble@auckland.ac.nz
1612
J. Chem. Soc., Perkin Trans. 1, 2001, 1612–1623
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102807n

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juglone 14 was the less polar of the two regioisomers and
melted at 171–172 ЊC, in good agreement with the literature.15
The more polar 2-bromojuglone 15 melted at 135–136 ЊC which
was also in good agreement with the literature value.15
With 3-bromojuglone 14 in hand, attention turned to the
benzylation and reductive methylation steps (Scheme 2). A
solution of 3-bromojuglone 14 in chloroform was treated with
benzyl bromide and silver() oxide. The yellow crystalline
benzyl ether 16 was obtained in 89% yield after work-up and
chromatography. The 2-bromo isomer 15 was subjected to the
same conditions, affording the crystalline benzyl ether 17 in
84% yield.
With the hydroxy group at C-5 protected as a benzyl ether,
reductive methylation of the quinone was next undertaken.
Naphthoquinone 16 was reduced with aq. disodium dithionite
to give an air-sensitive hydroquinone, which underwent methyl-
ation using dimethyl sulfate and potassium carbonate to give the
dimethoxynaphthalene 18 in 76% yield. The 2-bromo isomer
17 reacted under the same conditions to give the dimethyl-
ated product 19 in 79% yield. The final step in the synthesis
of bromonaphthol 8 was the removal of the benzyl protecting
group which was effected in 98% yield by hydrogenolysis over
10% palladium on charcoal in ethyl acetate. Likewise, the
2-bromo isomer 12 was readily afforded by hydrogenolysis of
benzyl ether 19 in 94% yield.
It was hoped that the acetyl group in naphthol 7 could
be installed in one step by reaction of the lithiated anion of
bromide 18 with acetyl chloride; however, treatment of a
solution of 18 in tetrahydrofuran at Ϫ78 ЊC with n-butyllithium
(1.35 equiv.) followed by quenching with freshly distilled acetyl
chloride afforded only protonated material. More success was
realised when using acetaldehyde as the electrophile, taking care
to add the acetaldehyde immediately after generation of the
organolithium reagent. This procedure afforded the benzylic
alcohol 20 in 98% yield. The regioisomeric bromide 19 was
converted to alcohol 21 in 97% yield using these optimum
conditions.
Oxidation of alcohol 20 to ketone 22 was initially attempted
using manganese dioxide; however, no reaction took place even
after stirring for a day. Use of tetra-n-propylammonium per-
ruthenate (TPAP), in combination with N-methylmorpholine
N-oxide (NMO) as the reoxidant, and powdered molecular
sieves (4 Å) in dichloromethane afforded ketone 22 in 80% yield
after flash chromatography.16 The regioisomeric alcohol 21 was
also conveniently oxidised to ketone 23 in 78% yield using these
reagents.
Finally, treatment of a solution of 22 in ethyl acetate with
palladium on charcoal (50 mg mmolϪ1) under an atmosphere of
hydrogen gave acetylnaphthol 7, in 53% yield after purification
by flash chromatography. Similarly, the regioisomeric ketone 23
underwent debenzylation in 58% yield. Formation of more
polar benzylic alcohol by-products accounted for the poor
yields from this reaction. Re-oxidation using TPAP–NMO
allowed recycling of these unwanted by-products to the desired
ketones 7 and 11, thereby increasing the overall yield to
approximately 70%.
Scheme 1
Scheme 2 Reagents, conditions and yields: (i) Br2, AcOH, CHCl3, 70 min: 14 (76%), 15 (21%) (ii) BnBr, Ag2O, CHCl3, 2 h: 16 (89%), 17 (84%) (iii) aq.
n
Na2S2O4, CH2Cl2–Et2O; then Me2SO4, K2CO3, acetone, heat, 48 h: 18 (76%), 19 (79%) (iv) H2, Pd/C, EtOAc, 8 h: 8 (98%), 12 (94%) (v) BuLi,
Ϫ78 ЊC, THF, 0.5 min; then AcH: 20 (98%), 21 (97%) (vi) TPAP, NMO, CH2Cl2, 3 h, 4 Å mol. sieves: 22 (80%), 23 (78%) (vii) H2, Pd/C, EtOAc, 8 h:
7 (53%), 11 (58%). The juglone numbering scheme is presented here, and is used for NMR assignments of all compounds described in the
Experimental section.
J. Chem. Soc., Perkin Trans. 1, 2001, 1612–1623
1613

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was recovered and deacetylation at the anomeric position of the
sugar was observed.
Formation of the β-C-glycoside 29 was established by the 1H
NMR spectrum in which the anomeric proton, 1Ј-H, resonated
at δ 5.12 as a doublet of doublets, with coupling constants J1Ј,2Јax
11.3 and J1Ј,2Јeq 2.0 Hz consistent with β-stereochemistry at
the anomeric position. Doublets of doublets of doublets at
δ 1.78 and 2.52 were assigned to 2Јax-H, with coupling con-
stants, Jgem 12.7, J2Јax,3Ј 11.3 and J2Јax,1Ј 11.3 Hz, and 2Јeq-H, with
coupling constants, Jgem 12.7, J2Јeq,3Ј 4.8 and J2Јeq,1Ј 2.0 Hz,
respectively. The three three-proton singlets at δ 2.02, 2.07
and 2.09 were assigned to the acetate methyl protons of the
glycoside, and the hydroxy proton resonated as a singlet at
δ 9.70. The 1H NMR spectrum of β-C-glycoside 33 was
similarly supportive of the proposed structure. The anomeric
proton, 1Ј-H, resonated at δ 5.12 as a doublet of doublets, with
coupling constants J1Ј,2Јax 11.3 and J1Ј,2Јeq 2.0 Hz, while the
hydroxy proton resonated as a singlet at δ 9.49.
Scheme 3 Reagents, conditions and yields: (i) BnBr, Ag2O, CHCl3, 2 h
(80%) (ii) aq. Na2S2O4, Me2SO4, K2CO3, acetone, heat, 4 h (75%) (iii)
Br2, CCl4, 5 min (99%) (iv) NaH, MeI, DMF, 12 h (74%).
Disappointed by the poor recovery of β-C-glycoside 29 from
attempted C-glycosylation of the bromonaphthol 8 with
acetate-protected glycosyl acetate 9, our attention next turned
to use of the benzyl-protected sugar 10. Accordingly, trimethyl-
silyl triflate (1.5 equiv.) and silver perchlorate (5 mol%) were
added to a solution of bromonaphthol 8 and glycosyl acetate 10
in dry acetonitrile at 0 ЊC. After 1 hour the reaction was
quenched with aqueous sodium bicarbonate and a mixture con-
taining β-C-glycoside 30 and the rearranged product 36 (1 : 6)
was isolated after flash chromatography. Upon attempting to
separate these two products by semi-preparative HPLC (0.375%
iPrOH–hexane; Partisil 10 column, 50 cm × 9.4 mm I.D., flow
rate 4 mL minϪ1), the rearranged product 36 was obtained in
48% yield, while the less stable C-glycoside 30 decomposed and
was not isolated. The use of boron trifluoride–diethyl ether gave
a similar result, affording the rearranged product 36 in a slightly
better yield (59%).
Due to the initial problems encountered with the regio-
selective bromination of juglone 13, an alternative synthesis of
bromide 8 (via benzyl ether 18) was developed (Scheme 3).
Juglone 13 was first converted to benzyl ether 2417 by treatment
with benzyl bromide and silver() oxide. Reductive methylation
of benzyl juglone 24 was then carried out, as for bromide 16,
by reduction to the hydroquinone using aqueous dithionite,
followed by methylation using dimethyl sulfate and potassium
carbonate in acetone under reflux. In this case, the reaction was
worked up before methylation of the second, more hindered,
hydroxy group at C-4 took place, affording methoxynaphthol
25 in 75% yield.
Regioselective bromination of naphthol 25 was then possible
due to the strong ortho-directing effect of the hydroxy group.
Thus, treatment of the naphthol 25 with bromine in tetrachloro-
methane gave the crystalline bromonaphthol 26 in essentially
quantitative yield after purification by flash chromatography.
The hydroxy group of bromonaphthol 26 was then methylated
by treatment with sodium hydride and iodomethane in dimeth-
ylformamide to give methyl ether 18 in 74% yield after chrom-
atography. Methyl ether 18 was identical in all respects to the
material prepared by the original method and was converted to
3-bromonaphthol 8 as described above.
The acetate-protected 2-deoxypyranoside 9 was prepared by
acetylation of 2-deoxyglucose according to the procedure of
Overend et al.,18 affording glycosyl acetate 9 (α : β, 10 : 1) in
73% yield. Alternatively, the procedure of Mioskowski et al.19
required treatment tri-O-acetyl--glucal with triphenylphos-
phine hydrobromide and acetic acid, affording the desired
acetate 9 (α : β, 9 : 1) in 72% yield. The benzyl-protected
2-deoxypyranoside 10 was also prepared from tri-O-benzyl--
glucal according to the procedure of Mioskowski et al.,19
affording glycosyl acetate 10 (α : β, 9 : 1) in 86% yield.
With naphthols 7, 8, 11 and 12 in hand, our initial attention
focused on their C-glycosylation using the acetate-protected
glycosyl donor 9. Trimethylsilyl triflate (TMSOTf ) in com-
bination with silver perchlorate has been used to effect
C-glycosylation of β-naphthol in excellent yield20 and
acetonitrile has been recommended as the solvent of choice for
effecting C-glycosylation of 5,8-dimethoxy-1-naphthol using
BF3ؒEt2O.21 Attempted C-glycosylation of acetylnaphthols 7
and 11 with glycosyl acetate 9 using either BF3ؒEt2O (1.5–2.0
equiv.) in acetonitrile or TMSOTf (1.5 equiv.) and silver
perchlorate (5 mol%) in acetonitrile afforded neither of the
desired C-glycosides 27 and 31 (Table 1). The bromonaphthol
12 proved more reactive than bromonaphthol 8, affording
C-glycoside 33 in 48–57% yield using the same Lewis acids. The
corresponding C-glycoside 29 derived from bromonaphthol
8 was obtained in only 5% yield using TMSOTf and silver per-
chlorate. In all of the above cases much of the starting naphthol
1
In the H NMR spectrum of the rearranged product 36 two
singlets at δ 5.06 and 5.86 were assigned to 7Ј-H and 2Ј-H
respectively. Doublets of doublets of doublets at δ 1.43 and 1.98
corresponded to the geminal protons 8Ј-HA and 8Ј-HB respect-
ively. The doublet of doublets at δ 2.19 was assigned as 1Ј-H
with couplings of J1Ј,8ЈA 4.8 and J1Ј,8ЈB 2.2 Hz, and the resonances
at δ 3.85 and 3.94 corresponded to the two methoxy groups.
4Ј-HA resonated as a doublet at δ 4.08 with coupling constant
Jgem 13.4 Hz, while 4Ј-HB resonated as a doublet of doublets
at δ 4.21 showing an additional coupling constant, J4ЈB,5Ј 5.5
Hz. The 9Ј-H proton resonated as a doublet of doublets at
δ 4.16 with coupling constants J9Ј,8ЈA 9.7 and J9Ј,8ЈB 4.8 Hz. 2-H
resonated as a singlet at δ 6.70, while 8-H and 7-H resonated as
a pair of doublets at δ 7.64 and 8.04 with a coupling constant,
J7,8 8.7 Hz.
The assignment of 36 was aided by comparison with com-
pound 39, which bears essentially the same structure as the
rearranged glycosyl moiety of 36 (Table 2). The literature22
compound 39 has a β-benzyloxy substituent at C-7Ј, whereas in
our rearranged product 36 the lack of coupling with 1Ј-H
suggests that 7Ј-H is exo and the aryl moiety is therefore endo.
This assignment of stereochemistry was confirmed by obtain-
ing an X-ray crystal structure of the acetate derivative of the
rearranged product 36.23
The formation of rearranged C-glycoside 36 can be ration-
alised (Scheme 4) by initial generation of an oxacarbenium ion
followed by a 1,6-hydride shift to regenerate a glycal producing
a benzylic oxacarbenium ion. Attack of the glycal on this latter
ion followed by trapping with the appropriate substituted
naphthol affords the unusual C-glycosides. An analogous
rearrangement has been observed by Steel et al.22 during
investigations of the dimerisation of tri-O-benzyl--glucal
using acetyl perchlorate. These authors also carried out
deuterium-labelling studies which provided evidence for the
critical 1,6-hydride shift.
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J. Chem. Soc., Perkin Trans. 1, 2001, 1612–1623

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Table 1 C-Glycosylation of naphthols 7, 8, 11, 12, with the naphthol moiety given the juglone numbering system
2-Deoxyglycoside
Rearranged product
Yield (%)
Entry
Glycosyl donor
Naphthol
Lewis acid
Yield (%)
1
2
3
4
5
6
7
8
9
9
7
TMSOTf, AgClO4
TMSOTf, AgClO4
TMSOTf, AgClO4
BF3ؒEt2O
TMSOTf, AgClO4
BF3ؒEt2O
TMSOTf, AgClO4
BF3ؒEt2O
BF3ؒEt2O
9
11
8
9
29
5
9
8
9
12
12
8
33
33
30
30
34
28
32
57
48
5a
9a
53
7
9
10
10
10
10
10
36
36
48
59
8
12
7
10
11
BF3ؒEt2O
BF3ؒEt2O
35
37
12
23
11
9
a Not isolated (estimated yield from analysis of 1H NMR spectrum of crude product mixture).
Table 2 1H and 13C NMR shifts for 36 and 39
39
36
δH (ppm)
m
J/Hz
δC (ppm)
δH (ppm)
m
J/Hz
δC (ppm)
1Ј
2Ј
4ЈA
4ЈB
5Ј
2.35
5.47
4.00
4.10
4.35
5.18
1.44
2.38
4.17
m
s
d
dd
d
d
m
m
dd
44.8
76.0
71.4
2.19
5.86
4.08
4.21
4.36
5.06
1.43
1.98
4.16
dd
s
d
dd
d
s
ddd
ddd
dd
4.8, 2.2
13.4
13.4, 5.5
5.5
45.5
76.2
71.1
7.1
13.1, 5.2
5.0
77.4
98.4
25.6
76.6
86.2
22.4
7Ј
4.4
8ЈA
8ЈB
9Ј
14.4, 4.8, 4.8
14.4, 9.7, 2.2
9.7, 4.8
9.2, 4.0
73.0
73.7
By way of contrast, the bromonaphthol 12 coupled smoothly
with glycosyl acetate 10 using boron trifluoride–diethyl ether as
promoter to give β-C-glycoside 34 in 53% yield after flash
chromatography with none of the rearranged C-glycoside 38
6-bromonaphthol 12 exhibited towards the benzyl-protected
glycosyl donor 10 was greater than was displayed by the
7-bromonaphthol 8. The lack of reactivity in the latter case
resulted in the Lewis acid-mediated 1,6-hydride shift rearrange-
ment reaction to afford the unusual bicyclic acetal 36. In light
of these results, it was decided to investigate the C-glycosylation
of acetylnaphthol 7 with the same glycosyl donor 10. It was
hoped that replacement of the bulky bromine atom by an acetyl
group may alter the outcome of the critical C-glycosylation
reaction.
1
being formed. The H NMR spectrum of 34 was consistent
with formation of a β-C-glycoside, featuring doublets of
doublets of doublets at δ 1.63 and 2.59 corresponding to
2Јax-H and 2Јeq-H. 1Ј-H resonated as a doublet of doublets at
δ 4.98 with a coupling constant J1Јax,2Јax10 Hz, establishing the
β-stereochemistry at the anomeric carbon.
As was observed for glycosylation reactions employing
the acetate-protected glycosyl donor 9, the reactivity that the
Boron trifluoride–diethyl ether was added to a solution of
the acetylnaphthol 7 and glycosyl acetate 10 in dry acetonitrile
J. Chem. Soc., Perkin Trans. 1, 2001, 1612–1623
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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-
ations: s = strong, m = medium, w = weak and br = broad.
1H 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 as internal standard and reported
as position (δC), multiplicity (aided by DEPT 135, DEPT 90,
COSY and HETCOR experiments) and assignment. Low-
resolution mass spectra were recorded on a VG70-250S, a
VG70-SD or an 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
appropriate. 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 256 nm and an 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 polari-
meter using a 5 mL cell. Samples were prepared in the solvent
indicated at the concentration specified (measured in g/100
mL). [α]D-Values are given in units of 10Ϫ1 deg cm2 gϪ1.
Scheme 4
at 0 ЊC. After 20 min the reaction was quenched with water and
a mixture of β-C-glycoside 28 and the rearranged product 35
(≈ 1 : 3 from the crude 1H NMR spectrum) was isolated
i
after chromatography. Semi-preparative HPLC (1.5% PrOH–
hexane; Partisil 10 column, 50 cm × 9.4 mm I.D.; flow rate
4 mL minϪ1) allowed isolation of the pure compounds, in yields
of 7 and 12% respectively.
1
The H NMR spectrum of the major product 35 featured
characteristic singlets at δ 5.15 and 5.98, assigned to 7Ј-H and
2Ј-H, respectively. The 1H NMR spectrum of the minor
product 28 featured a characteristic doublets of doublets of
doublets at δ 1.65 and 2.57 assigned to 2Јax-H and 2Јeq-H
respectively. 1Ј-H resonated as a doublet of doublets at δ 5.04
with a large axial–axial coupling constant, J1Јax,2Јax 11.4 Hz,
confirming the β-stereochemistry of the C-glycoside 28.
Use of the regioisomeric acetylnaphthol 11 as the glycosyl
acceptor with glycosyl acetate 10 and boron trifluoride–diethyl
ether in acetonitrile also afforded a mixture of C-glycoside 32
and rearranged product 37 in low yield. Semi-preparative
i
HPLC (1.5% PrOH–hexane; Partisil 10 column, 50 cm × 9.4
mm I.D.; flow rate = 4 mL minϪ1) was required to isolate the
pure components 32 and 37, in yields of 9 and 23% respectively.
A number of trends emerge from the C-glycosylations
described herein. Slightly better results were obtained with the
acetate-protected sugar 9 using the trimethylsilyl triflate–silver
perchlorate system rather than with boron trifluoride–diethyl
ether (Table 1, entries 1–6). The reverse was true for the benzyl-
protected sugar 10, where boron trifluoride–diethyl ether gave
slightly improved results (entries 7, 8). More important, how-
ever, was the reactivity of the naphthols. Using the acetate-
protected sugar 9 poor reactivity was observed with naphthols
7 and 8 (entries 1, 3, 4) and naphthol 11 (entry 2), only forming
C-glycosides in reasonable yield using the bromonaphthol
12 (entries 5, 6). Likewise, using the more reactive benzyl-
protected glycosyl donor 10, poor yields were obtained for
naphthols 7 and 8 (entries 7, 8, 10) with the sugar undergoing
substantial rearrangement to give the rearranged compounds
35 and 36. Again, reasonable yields of C-glycosides were only
obtained using naphthol 12 (entry 9).
The work reported herein provides the first example of the
C-glycosylation of this unusual rearranged tri-O-benzyl--
glucal skeleton. The different reactivity and product profiles
that are observed, depending upon whether the substituent in
the right-hand ring of the naphthalene is at C-2 or C-3, illus-
trate the subtle nature of these C-glycosylations. These differ-
ences may be attributed to the ability of the 3-bromonaphthol
8, compared with the 2-bromonaphthol 12, to better stabilise
the positive charge that develops when C-glycosylation occurs.
For our purposes the results described herein indicate that
in order to synthesise the 3-acetyl-C-glycosylnaphthoquinone
4 required for synthesis of the 2-deoxyglucosyl analogue of
medermycin 3, a naphthol which is unsubstituted at C-3 must
be used in the C-glycosylation step. The required acetyl group
at C-3 must then be introduced regioselectively after the critical
C-glycosylation has been effected. This strategy did result
in a successful synthesis of the 2-deoxyglucosyl analogue of
medermycin 3.24
3-Bromo-5-hydroxy-1,4-naphthoquinone (3-bromojuglone) 14
and 2-bromo-5-hydroxy-1,4-naphthoquinone (2-bromojuglone)
15
A solution of bromine (400 mg, 2.50 mmol) in chloroform
(5 mL) was added to a stirred solution of juglone 1325 (400 mg,
2.30 mmol) and acetic acid (4 drops) in chloroform (5 mL) at
0 ЊC. Stirring was continued for 70 min, after which the solvent
was removed at reduced pressure. Flash chromatography of the
resulting orange solid (juglone dibromide) using toluene–
hexane (4 : 1) as eluent afforded 3-bromojuglone 14 (442 mg,
76%) and the more polar 2-bromojuglone 15 (122 mg, 21%).
Alternatively, the orange solid was redissolved in a mixture of
ethanol (10 mL) and boron trifluoride–diethyl ether (1 mL) and
heated for 15 min on a steam-bath. The reaction mixture was
cooled, diluted with both water (10 mL) and chloroform (30
mL), then filtered and the residue was washed well with chloro-
1616
J. Chem. Soc., Perkin Trans. 1, 2001, 1612–1623

View Article Online
form (15 mL). The phases were separated and the aqueous
phase was extracted with chloroform (2 × 40 mL). The com-
bined organic fractions were washed with water (100 mL), dried
(sodium sulfate), and the solvent was removed at reduced
pressure. Purification of the residue by flash chromatography
using toluene–hexane (4 : 1) as eluent gave 3-bromojuglone 14
(343 mg, 59%) as the sole product, which was recrystallised
from ethanol to give orange needles, mp 171–172 ЊC (lit.,15
the solution was filtered through a Celite pad to remove silver
salts and the solvent was removed at reduced pressure. The
resultant orange oil was purified by flash chromatography
using hexane–ethyl acetate (18 : 1 to 9 : 1) as eluent to afford
5-benzyloxy-2-bromo-1,4-naphthoquinone 17 (2.30 g, 84%),
which was recrystallised from ethanol to give yellow needles,
mp 122–123 ЊC [Found (EI): Mϩ, 343.9875, 341.9893. C17H11-
BrO3 requires M, 343.9871, 341.9892]; νmax/cmϪ1 1676, 1656
(C᎐O, quin.); δ (400 MHz; CDCl3)‡ 5.30 (2H, s, CH2Ph),
172 ЊC); νmax/cmϪ1 3050 (OH), 1656, 1631 (C᎐O, quin.), 1459
᎐
᎐
H
(C-O); δH (200 MHz; CDCl3)‡ 7.31 (1H, dd, J6,7 6.9 and J6,8 2.8,
6-H), 7.50 (1H, s, 2-H), 7.62–7.72 (2H, m, 7-H and 8-H), 11.74
(1H, s, OH); δC (50 MHz; CDCl3)‡ 114.2 (quat., C-4a), 119.8
(CH, C-8), 124.6 (CH, C-6), 131.9 (quat., C-8a), 137.3 (CH,
C-7), 141.5 (CH, C-2), 142.4 (quat., C-3), 162.2 (quat., C-5),
181.7 (quat., C-1), 183.1 (quat., C-4); m/z (EI) 254, 252 (Mϩ,
26%), 173 (M Ϫ Br, 100).
7.33–7.43 (5H, m, 6-H, 3-H, p-Ph, m-Ph), 7.58 (2H, dd, Jo 7.3
and Jm 0.8, o-Ph), 7.66 (1H, dd, J7,8 8.5 and J7,6 8.1, 7-H), 7.73
(1H, dd, J8,7 8.5 and J8,6 1.1, 8-H); δC (100 MHz; CDCl3)‡ 70.9
(CH2, CH2Ph), 119.8 (quat., C-4a), 120.9, 120.1 (CH, C-6,
C-8), 126.7 (CH, o-Ph), 128.1 (CH, p-Ph), 128.7 (CH, m-Ph),
133.1 (quat., C-8a), 135.9 (CH, C-7), 135.7, 136.9 (quat., C-2,
ipso-Ph), 142.3 (CH, C-3), 158.8 (quat., C-5), 178.2, 181.3
(quat., C-1, C-4); m/z (EI) 344, 342 (Mϩ, 90%), 91 (C7H7, 100).
2-Bromojuglone 15 (122 mg, 21%) was recrystallised from
hexane to give orange plates, 135–136 ЊC (lit.,15 136 ЊC); νmax
/
cmϪ1 1675, 1633 (C᎐O, quin.), 1589 (C-O); δ (200 MHz;
5-Benzyloxy-3-bromo-1,4-dimethoxynaphthalene 18
᎐
H
CDCl3)‡ 7.32 (1H, dd, J6,7 8.3 and J6,8 1.4, 6-H), 7.50 (1H, s,
3-H), 7.64 (1H, dd, J7,6 8.3 and J7,8 7.4, 7-H), 7.75 (1H, dd, J8,7
7.4 and J8,6 1.4, 8-H), 11.77 (1H, s, OH); δC (50 MHz; CDCl3)‡
114.6 (quat., C-4a), 121.0 (CH, C-8), 125.1 (CH, C-6), 130.7
(quat., C-8a), 136.4 (CH, C-7), 140.3 (CH, C-3), 140.9 (quat.,
C-2), 161.7 (quat., C-5), 176.0 (quat., C-1), 187.5 (quat., C-4);
m/z (EI) 254, 252 (Mϩ, 25%), 173 (M Ϫ Br, 100).
The intermediate 2,3-dibromo-2,3-dihydro-5-hydroxy-1,4-
naphthoquinone (juglone dibromide) could be isolated by
filtration as an orange solid, mp 104 ЊC (lit.,26 109 ЊC); δH (200
MHz; CDCl3)‡ 4.92, 4.96 (2H, d, J2,3 3.2 Hz, 2-H and 3-H),
7.36 (1H, dd, J6,7 8.0 and J6,8 1.4, 6-H), 7.65 (1H, dd, J8,7 7.4 and
J8,6 1.4, 8-H), 7.74 (1H, dd, J7,6 8.0 and J7,8 7.4, 7-H), 11.42 (1H,
s, OH); δC (50 MHz; CDCl3)‡ 45.4, 45.5 (CH, C-2 and C-3),
113.0 (quat., C-4a), 120.2 (CH, C-8), 125.4 (CH, C-6), 130.2
(quat., C-8a), 138.0 (CH, C-7), 162.6 (quat., C-5), 185.7, 192.7
(quat., C-1 and C-4); m/z (EI) 336, 334, 332 (Mϩ, 20, 40, 20%),
255, 254, 253, 252 (M Ϫ Br, 100), 173 (M Ϫ 2Br, 95), 145 (75),
118 (40), 63 (60).
The naphthoquinone 16 (2.7 g, 7.87 mmol) was dissolved in
dichloromethane–diethyl ether (1 : 3) (200 mL) and shaken with
a freshly prepared solution of sodium dithionite (12 g, 55
mmol) in water (120 mL) for 10 min. The organic layer was
separated, washed with brine (80 mL), and dried (magnesium
sulfate). The solvent was removed under reduced pressure to
give the crude hydroquinone as a pale brown oil. This was dis-
solved in dry acetone (45 mL) and transferred by double-ended
needle to a reaction vessel containing a stirred suspension of
potassium carbonate (13.0 g, 94 mmol) in dry acetone (130
mL). Dimethyl sulfate (5.2 mL, 55 mmol) was added in one
portion and the solution was stirred and 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 redissolved in diethyl ether (100 mL) and stirred with
triethylamine (8.78 mL, 63 mmol). After 20 min the solution
was washed successively with hydrochloric acid (1 M; 2 × 50
mL), water (50 mL) and brine (50 mL). The organic extract
was then dried (sodium sulfate), and concentrated in vacuo to
give an oily residue, which was purified by flash chrom-
atography using hexane–ethyl acetate (6 : 1) as eluent to afford
5-benzyloxy-3-bromo-1,4-dimethoxynaphthalene 18 (2.16 g,
76%) as a brown solid, which was recrystallised from hexane–
ethyl acetate to give tan needles, mp 93.5–94.5 ЊC [Found
(FAB): Mϩ, 372.0363. C19H1779BrO3 requires M, 372.0361);
νmax/cmϪ1 1577, 1508 (C-O); δH (400 MHz; CDCl3)‡ 3.71, 3.95
(each 3H, s, 2 × OCH3), 5.19 (2H, s, CH2Ph), 6.95 (1H, s, 2-H),
7.03 (1H, d, J6,7 7.7, 6-H), 7.30–7.46 (4H, m, 7-H, m-Ph, p-Ph),
7.58 (2H, d, Jo 7.8, o-Ph), 7.85 (1H, dd, J8,7 8.4 and J8,6 0.8,
8-H); δC (100 MHz; CDCl3)‡ 56.6, 62.5 (CH3, 2 × OCH3), 72.4
(CH2, CH2Ph), 109.7 (CH, C-2), 110.1 (CH, C-6), 115.0 (quat.,
C-3), 116.1 (CH, C-7), 122.3 (quat., C-4a), 126.7 (CH, C-8),
128.4–129.2 (CH, Ph), 128.9 (quat., C-8a), 137.6 (quat.,
ipso-Ph), 147.5 (quat., C-5), 152.5, 155.2 (quat., C-1, C-4);
m/z (EI) 374, 372 (Mϩ, 4%), 283, 281 (M Ϫ C7H7, 6), 202
(M Ϫ C7H7 Ϫ Br, 11), 174 (10), 91 (C7H7, 67), 83 (17), 72 (55),
59 (100).
5-Benzyloxy-3-bromo-1,4-naphthoquinone 16
Silver() oxide (5.5 g, 23.7 mmol) was added to a stirred solution
of 3-bromojuglone 14 (1.50 g, 5.93 mmol) and benzyl bromide
(1.41 mL, 11.9 mmol) in chloroform (15 mL). After 2 h the
solution was filtered through a Celite pad to remove silver salts
and the solvent was removed at reduced pressure. The resultant
orange oil was purified by flash chromatography using hexane–
ethyl acetate (18 : 1 to 9 : 1) as eluent to afford 5-benzyloxy-
3-bromo-1,4-naphthoquinone 16 (1.82 g, 89%), which was
recrystallised from ethanol to give yellow needles, mp 107–
108 ЊC [Found (FAB): Mϩ, 343.9875, 341.9893. C17H11BrO3
requires M, 343.9871, 341.9892]; νmax/cmϪ1 1672 (C᎐O, quin.),
᎐
1583 (C-O); δH (400 MHz; CDCl3)‡ 5.30 (2H, s, CH2Ph), 7.34
(1H, d, Jo 7.3, p-Ph), 7.35 (1H, dd, J6,7 8.7 and J6,8 0.7, 6-H),
7.43 (2H, t, Jo 7.3, m-Ph), 7.45 (1H, s, 2-H), 7.58 (2H, d, Jo 7.3,
o-Ph), 7.66 (1H, dd, J7,6 8.1 and J7,8 8.1, 7-H), 7.73 (1H, dd, J8,7
7.8 and J8,6 1.0, 8-H); δC (100 MHz; CDCl3)‡ 70.1 (CH2,
CH2Ph), 119.6, 119.7 (CH, C-6, C-8), 120.1 (quat., C-4a), 126.7
(CH, o-Ph), 128.1 (CH, p-Ph), 128.7 (CH, m-Ph), 133.3 (quat.,
C-8a), 135.4 (CH, C-7), 135.7 (quat., ipso-Ph), 138.3 (CH, C-2),
142.6 (quat., C-3), 159.2 (quat., C-5), 176.0, 182.5 (quat., C-1,
C-4); m/z (EI) 344, 342 (Mϩ, 9%), 253, 251 (M Ϫ C7H7, 12), 91
(C7H7, 100).
5-Benzyloxy-2-bromo-1,4-dimethoxynaphthalene 19
Using the above conditions, the 2-bromonaphthoquinone 17
(1.35 g, 3.94 mmol) was reduced to the hydroquinone and then
methylated. Purification by flash chromatography using
hexane–ethyl acetate (6 : 1) as eluent afforded 5-benzyloxy-2-
bromo-1,4-dimethoxynaphthalene 19 (1.12 g, 79%) as a tan solid,
which was recrystallised from hexane–ethyl acetate to give
colourless needles, mp 90.4–90.9 ЊC [Found (EI): Mϩ, 374.0330,
5-Benzyloxy-2-bromo-1,4-naphthoquinone 17
Silver() oxide (9.25 g, 39.9 mmol) was added to a stirred solu-
tion of 2-bromojuglone 15 (2.02 g, 7.98 mmol) and benzyl
bromide (7.8 mL, 11.2 mmol) in chloroform (15 mL). After 2 h
372.0368. C19H17BrO3 requires M, 374.0341, 372.0361]; νmax
/
cmϪ1 1578 (C-O); δH (400 MHz; CDCl3)‡ 3.91, 3.93 (each 3H, s,
2 × OCH3), 5.20 (2H, s, CH2Ph), 6.91 (1H, s, 3-H), 6.97 (1H, d,
J6,7 7.7, 6-H), 7.33 (1H, t, Jo 7.4, p-Ph), 7.40 (2H, t, Jo 7.4,
‡ Juglone numbering scheme (see Scheme 2).
J. Chem. Soc., Perkin Trans. 1, 2001, 1612–1623
1617

View Article Online
m-Ph), 7.45 (1H, dd, J6,7 7.7 and J7,8 8.4, 7-H), 7.57 (2H, br d,
Jo 7.4, o-Ph), 7.71 (1H, br d, J8,7 8.4, 8-H); δC (400 MHz;
CDCl3)‡ 55.6, 61.2 (CH3, 2 × OCH3), 71.4 (CH2, CH2Ph),
109.2 (CH, C-3), 109.7 (CH, C-6), 115.1 (CH, C-8), 118.1
(quat., C-4a), 126.9 (CH, o-Ph), 127.5, 127.6 (CH, p-Ph, C-7),
128.4 (CH, m-Ph), 131.8 (quat., C-8a), 137.3 (quat., ipso-Ph),
146.6 (quat., C-1), 154.0, 156.5 (quat., C-4, C-5); m/z (EI) 374,
372 (Mϩ, 27%), 283, 281 (M Ϫ C7H7, 10), 174 (15), 91 (C7H7,
100).
using hexane–ethyl acetate (4 : 1 to 2 : 1) as eluent to afford
5-benzyloxy-3-(1-hydroxyethyl)-1,4-dimethoxynaphthalene 20
(266 mg, 98%) as a colourless oil which slowly turned yellow on
storage [Found (FAB): Mϩ, 338.1526. C21H22O4 requires M,
338.1518]; νmax/cmϪ1 3405br (OH), 2968, 2929 (C-H), 1600,
1579, 1510 (C᎐C), 1361, 1262, 1067 (C-O); δ (200 MHz;
᎐
H
CDCl3)‡ 1.57 (3H, d, Jvic 6.4, CH3), 2.30 (1H, br s, OH), 3.68,
3.98 (each 3H, s, 2 × OCH3), 5.20 (2H, s, CH2Ph), 5.50 (1H, q,
Jvic 7.1, CHOH), 6.94 (1H, s, 2-H), 6.99 (1H, dd, J6,7 7.7 and J6,8
0.9, 6-H), 7.30–7.46 (4H, m, m-Ph, p-Ph, 7-H), 7.56 (2H, dd,
Jo 7.6 and Jm 1.5, o-Ph), 7.88 (1H, dd, J8,7 8.4 and J8,6 0.9, 8-H);
δC (50 MHz; CDCl3)‡ 24.4 (CH3, CH3), 55.7 (CH3, OCH3), 63.3
(CH, CHOH), 64.6 (CH3, OCH3), 71.5 (CH2, CH2Ph), 102.0
(CH, C-2), 109.2 (CH, C-6), 115.3 (CH, C-8), 120.7 (quat.,
C-4a), 125.5 (CH, C-7), 127.6 (CH, o-Ph), 127.8 (CH, p-Ph),
128.4 (quat., C-8a), 128.5 (CH, m-Ph), 134.3 (quat., C-3), 137.1
(quat., ipso-Ph), 146.0 (quat., C-4), 151.9, 155.0 (quat., C-1,
C-5); m/z 338 (Mϩ, 100%), 217 (M Ϫ C7H7 Ϫ Me Ϫ Me, 65), 91
(C7H7, 100).
3-Bromo-5-hydroxy-1,4-dimethoxynaphthalene 8
A solution of benzyl ether 18 (1.00 g, 2.68 mmol) in ethyl
acetate (15 mL) was stirred under an atmosphere of hydrogen
gas over palladium on charcoal (10%; 140 mg, 50 mg mmolϪ1).
After 8 h the reaction was complete and the mixture was filtered
through Celite. The solvent was removed at reduced pressure
and the resultant green oil was purified by flash chrom-
atography using hexane–ethyl acetate (4 : 1) as eluent to afford
3-bromo-5-hydroxy-1,4-dimethoxynaphthalene 8 (745 mg, 98%)
as a pale green solid, which was recrystallised from ethanol to
give colourless needles, mp 75.5–76.5 ЊC (Found: C, 51.42; H,
3.71. C12H11BrO3 requires C, 51.07; H, 3.93%); νmax/cmϪ1 3362
5-Benzyloxy-2-(1-hydroxyethyl)-1,4-dimethoxynaphthalene 21
Using the conditions described above for 18, 5-benzyloxy-2-
bromo-1,4-dimethoxynaphthalene 19 (300 mg, 0.804 mmol)
afforded 5-benzyloxy-2-(1-hydroxyethyl)-1,4-dimethoxynaphth-
alene 21 (287 mg, 97%) as a tan oil [Found (EI): Mϩ, 338.1520.
C21H22O4 requires M, 338.1518]; νmax/cmϪ1 3410br (OH), 1583
(C-O), 1511, 1454, 1385; δH (400 MHz; CDCl3)‡ 1.55 (3H, d,
Jvic 6.5, CH3), 2.45 (1H, br s, OH), 3.86, 3.92 (each 3H, s,
2 × OCH3), 5.18 (2H, s, CH2Ph), 2.41 (1H, q, Jvic 6.5, CHOH),
6.92 (1H, s, 3-H), 6.92 (1H, br d, J6,7 7.7, 6-H), 7.30–7.45 (4H,
m, m-Ph, p-Ph, 7-H), 7.58 (2H, br d, Jo 7.5, o-Ph), 7.65 (1H, dd,
J8,7 8.5 and J8,6 0.9, 8-H); δC (100 MHz; CDCl3)‡ 24.2 (CH3,
CH3), 56.5, 62.4 (CH3, 2 × OCH3), 64.7 (CH, CHOH), 71.5
(CH2, CH2Ph), 103.4 (CH, C-3), 108.9 (CH, C-6), 115.2 (CH,
C-8), 118.4 (quat., C-4a), 126.7 (CH, C-7), 126.9 (CH, o-Ph),
127.5 (CH, p-Ph), 128.3 (CH, m-Ph), 131.2 (quat., C-8a), 133.8
(quat., C-2), 137.5 (quat., ipso-Ph), 145.5 (quat., C-1), 154.0,
156.4 (quat., C-4, C-5); m/z 338 (Mϩ, 100%), 217 (65), 91 (C7H7,
100), 43 (12).
br (OH), 1595, 1583 (C᎐C), 1381, 1335 (C-O); δ (400 MHz;
᎐
H
CDCl3)‡ 3.95, 4.01 (each 3H, s, 2 × OCH3), 6.84 (1H, s, 2-H),
6.99 (1H, dd, J6,7 7.7 and J6,8 1.1, 6-H), 7.39 (1H, dd, J7,6 7.7 and
J7,8 8.3, 7-H), 7.70 (1H, dd, J8,7 8.3 and J8,6 1.1, 8-H), 9.39 (1H,
s, OH); δC (100 MHz; CDCl3)‡ 56.6, 63.2 (CH3, 2 × OCH3),
108.9 (CH, C-2), 111.1 (quat., C-3), 113.1, 114.4 (CH, C-6,
C-7), 118.7 (quat., C-4a), 127.5 (quat., C-8a), 128.1 (CH, C-8),
146.8 (quat., C-5), 153.5, 153.6 (quat., C-1, C-4); m/z (EI) 284,
282 (Mϩ, 70%), 269, 267 (M Ϫ CH3, 100), 173 (M Ϫ CH3Br, 30).
2-Bromo-5-hydroxy-1,4-dimethoxynaphthalene 12
A solution of benzyl ether 19 (500 mg, 1.34 mmol) in ethyl
acetate (8 mL) was stirred over palladium on charcoal (10%;
67 mg, 50 mg mmolϪ1) under an atmosphere of hydrogen gas.
After 8 h the reaction was complete and the mixture was filtered
through Celite. The solvent was removed at reduced pressure
and the resultant green oil was purified by flash chrom-
atography using hexane–ethyl acetate (4 : 1) as eluent to afford
2-bromo-5-hydroxy-1,4-dimethoxynaphthalene 12 (356 mg, 94%)
as a pale green solid, which was recrystallised from ethanol
to give colourless needles, mp 140.5–141.5 ЊC [Found (EI):
Mϩ, 283.9874, 281.9884. C12H11BrO3 requires M, 283.9871,
281.9892]; νmax/cmϪ1 3362br (OH); δH (200 MHz; CDCl3)‡ 3.92,
4.05 (each 3H, s, 2 × OCH3), 6.86 (1H, s, 3-H), 6.93 (1H, dd, J6,7
7.7 and J6,8 1.1, 6-H), 7.43 (1H, dd, J7,8 8.3 and J7,6 7.7, 7-H),
7.57 (1H, dd, J8,7 8.3 and J8,6 1.1, 8-H), 9.19 (1H, s, OH); δC (100
MHz; CDCl3)‡ 56.5, 61.1 (CH3, 2 × OCH3), 107.7 (CH, C-3),
111.5 (CH, C-6 and quat., C-2), 113.1 (CH, C-8), 114.9 (quat.,
C-4a), 128.7 (CH, C-7), 131.1 (quat., C-8a), 147.7 (quat., C-1),
152.6, 154.9 (quat., C-4, C-5); m/z (EI) 284, 282 (Mϩ, 70%), 269
(100), 267 (100), 173 (30).
3-Acetyl-5-benzyloxy-1,4-dimethoxynaphthalene 22
Tetrapropylammonium perruthenate (26 mg, 0.074 mmol) was
added to a stirred solution of benzylic alcohol 20 (290 mg,
0.858 mmol), N-methylmorpholine N-oxide (260 mg, 2.22
mmol) and powdered molecular sieves (4 Å, 30 mg) in dry
dichloromethane (3 mL). When the reaction was complete
(2–3 h) the mixture was filtered through a pad of silica using
dichloromethane as eluent. The mixture was evaporated and
the residue was purified by flash chromatography using hexane–
ethyl acetate (4 : 1) as eluent to afford 3-acetyl-5-benzyloxy-1,4-
dimethoxynaphthalene 22 (230 mg, 80%) as a pale yellow oil
[Found (EI): Mϩ, 336.1361. C21H20O4 requires M, 336.1362];
νmax/cmϪ1 2933, 2842 (C-H), 1685 (C᎐O, ketone), 1615, 1573,
᎐
1508, 1410 (C᎐C), 1366, 1265, 1224, 1065 (C-O); δ (200 MHz;
᎐
H
5-Benzyloxy-3-(1-hydroxyethyl)-1,4-dimethoxynaphthalene 20
CDCl3)‡ 2.78 (3H, s, COCH3), 3.71, 3.99 (each 3H, s,
2 × OCH3), 5.25 (2H, s, CH2Ph), 7.06 (1H, dd, J6,7 7.8 and J6,8
0.9, 6-H), 7.07 (1H, s, 2-H), 7.36–7.60 (6H, m, Ph, 7-H), 7.91
(1H, dd, J8,7 8.3 and J8,6 0.9, 8-H); δC (50 MHz; CDCl3)‡ 31.4
(CH3, COCH3), 55.7, 64.1 (CH3, 2 × OCH3), 71.4 (CH2,
CH2Ph), 103.2 (CH, C-2), 109.3 (CH, C-6), 115.2 (CH, C-8),
120.6 (quat., C-4a), 127.6 (CH, o-Ph, p-Ph), 128.0 (CH, C-7),
128.5 (CH, m-Ph), 129.1 (quat., C-3), 131.2 (quat., C-8a), 136.7
(quat., ipso-Ph), 151.3, 152.2, 156.1 (quat., C-1, C-4, C-5), 201.3
(quat., COCH3); m/z (EI) 336 (Mϩ, 65%), 245 (M Ϫ C7H7, 38),
91 (C7H7, 100), 43 (COCH3, 18).
A solution of 5-benzyloxy-3-bromo-1,4-dimethoxynaphthalene
18 (300 mg, 0.804 mmol) in tetrahydrofuran (10 mL) was stirred
at Ϫ78 ЊC under an atmosphere of nitrogen. n-Butyllithium
(1.36 M solution in hexane; 800 µL, 1.09 mmol) was added,
followed immediately by an excess of acetaldehyde (>32 µL)
[any delay before the addition of acetaldehyde resulted in the
formation of considerable amounts of the protonated by-
product, 5-benzyloxy-1,4-dimethoxynaphthalene]. The solution
was allowed to warm to room temperature over a period of 1 h,
then was quenched with saturated aq. ammonium chloride
(5 mL) and extracted with dichloromethane (3 × 20 mL). The
combined organic fractions were washed with water (30 mL)
and dried (sodium sulfate). The solvent was removed at reduced
pressure and the residue was purified by flash chromatography
2-Acetyl-5-benzyloxy-1,4-dimethoxynaphthalene 23
Using the conditions described above for 20, benzylic alcohol
21 (290 mg, 0.858 mmol) was oxidised to afford 2-acetyl-5-
1618
J. Chem. Soc., Perkin Trans. 1, 2001, 1612–1623

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benzyloxy-1,4-dimethoxynaphthalene 23 (224 mg, 78%) as a
yellow solid, which was recrystallised from ethanol to give
colourless needles, mp 109–110 ЊC [Found (EI): Mϩ, 336.1363.
C21H20O4 requires M, 336.1362]; νmax/cmϪ1 2934 (C-H), 1668
s, 3-H), 7.47 (1H, dd, J7,8 8.4 and J7,6 7.7, 7-H), 7.67 (1H, dd, J8,7
8.4 and J8,6 0.6, 8-H), 9.37 (1H, s, OH); δC (100 MHz; CDCl3)‡
30.9 (CH3, COCH3), 56.4, 63.6 (CH3, 2 × OCH3), 102.0 (CH,
C-3), 113.6, 114.6 (CH, C-6, C-8), 117.8 (quat., C-4a), 126.9
(quat., C-2), 128.6 (CH, C-7), 131.1 (quat., C-8a), 152.4, 152.8,
154.9 (quat., C-1, C-4, C-5), 199.3 (quat., COCH3); m/z (EI) 246
(Mϩ, 70%), 231 (M Ϫ CH3, 100), 203 (M Ϫ COCH3, 45), 175
(25), 145 (20), 115 (30), 89 (18), 43 (COCH3, 27).
5-Hydroxy-2-(1-hydroxyethyl)-1,4-dimethoxynaphthalene
(32 mg, 21%), a colourless oil, was identified on the basis of its
1H NMR spectrum; δH (200 MHz; CDCl3) 1.52 (3H, d, Jvic 6.5,
Me), 2.68 (1H, br s, CHOH ), 3.83, 3.93 (3H, s, 2 × OCH3), 5.41
(1H, q, Jvic 6.5, CHOH), 6.77 (1H, s, 3-H), 6.86 (1H, dd, J6,7 7.4
and J6,8 1.2, 6-H), 7.36 (1H, dd, J7,8 8.3 and J7,6 7.4, 7-H), 7.45
(1H, dd, J8,7 8.3 and J8,6 1.2, 8-H), 9.32 (1H, s, OH).
(C᎐O, ketone), 1593 (C᎐C), 1375 (C-O); δ (400 MHz; CDCl )‡
᎐
᎐
H
3
2.79 (3H, s, COCH3), 3.92, 3.97 (each 3H, s, 2 × OCH3), 5.21
(2H, s, CH2Ph), 7.07 (1H, br d, J6,7 7.7, 6-H), 7.10 (1H, s, 3-H),
7.34 (1H, t, Jo 7.4, p-Ph), 7.42 (2H, t, Jo 7.4, m-Ph), 7.47 (1H,
dd, J7,8 8.4 and J7,6 7.7, 7-H), 7.59 (2H, br d, Jo 7.4, o-Ph), 7.82
(1H, dd, J8,7 8.4 and J8,6 0.7, 8-H); δC (100 MHz; CDCl3)‡ 30.9
(CH3, COCH3), 56.3, 63.6 (CH3, 2 × OCH3), 71.6 (CH2,
CH2Ph), 103.9 (CH, C-3), 111.3 (CH, C-6), 116.4 (CH, C-8),
121.2 (quat., C-4a), 126.9 (CH, o-Ph), 126.9 (quat., C-2), 127.3
(CH, C-7), 127.6 (CH, p-Ph), 128.4 (CH, m-Ph), 131.8 (CH,
C-8a), 137.2 (quat., ipso-Ph), 151.2, 153.5, 156.4 (quat., C-1,
C-4, C-5), 199.9 (quat., COCH3); m/z (EI) 336 (Mϩ, 59%), 245
(M Ϫ C7H7, 35), 91 (C7H7, 100), 43 (COCH3, 12).
This diol (32 mg, 0.129 mmol) was oxidized as described
above to give ketone 11 (28 mg, 89%).
3-Acetyl-5-hydroxy-1,4-dimethoxynaphthalene 7
5-Benzyloxy-1,4-naphthoquinone 24
A solution of benzyl ether 22 (223 mg, 0.664 mmol) in ethyl
acetate (5 mL) was stirred under an atmosphere of hydrogen
over palladium on charcoal (10%; 33 mg, 50 mg mmolϪ1). After
8 h the reaction was incomplete, therefore the mixture was
filtered through Celite and the solvent was removed in vacuo.
The residue was redissolved in ethyl acetate and the hydrogen-
ation procedure repeated with the reaction going to completion
almost immediately. The mixture was filtered through Celite
and the solvent was evaporated off at reduced pressure. The oily
green residue was purified by flash chromatography using
hexane–ethyl acetate (4 : 1) as eluent to afford ketone 7 (86 mg,
53%) as a pale yellow oil [Found (FAB): Mϩ, 246.0894. C14H14-
O4 requires M, 246.0892]; νmax/cmϪ1 3357br (OH), 2939, 2843
Silver() oxide (14 g, 62 mmol) was added to a stirred solution
of juglone 13 (2.70 g, 15.5 mmol) and benzyl bromide (5.5 mL,
46.6 mmol) in chloroform (50 mL). After 2 h the solution was
filtered through a Celite pad to remove silver salts and the
solvent was removed at reduced pressure. The oily residue was
purified by flash chromatography using hexane–ethyl acetate
(18 : 1 to 9 : 1) as eluent to afford 5-benzyloxy-1,4-naphtho-
quinone 24 (3.28 g, 80%) as fine orange needles, mp 111–
111.5 ЊC (lit.,17 113 ЊC); νmax/cmϪ1 1659 (C᎐O, quin.); δ (400
MHz; CDCl3)‡ 5.30 (2H, s, CH2Ph), 6.89 (2H, s, 2-H and 3-H),
7.33–7.37 (2H, m, 6-H, p-Ph), 7.42 (2H, t, Jo 7.3, m-Ph), 7.58
(2H, d, Jo 7.3, o-Ph), 7.65 (1H, dd, J6,7 8.0 and J7,8 7.6, 7-H),
7.74 (1H, dd, J8,7 7.6 and J8,6 0.9, 8-H); δC (100 MHz; CDCl3)‡
70.9 (CH2, CH2Ph), 119.5, 119.6 (CH, C-7, C-8), 126.6 (CH,
o-Ph), 128.0 (CH, p-Ph), 128.7 (CH, m-Ph), 130.2, 134.1 (quat.,
C-8a, C-4a), 134.8, 136.2, 140.9 (CH, C-6, C-2, C-3), 136.0
(quat., ipso-Ph), 158.5 (quat., C-5), 184.1, 185.2 (quat., C-1,
C-4); m/z (EI) 264 (Mϩ, 25%), 91 (C7H7, 100).
᎐
H
(C-H), 1672 (C᎐O), 1627, 1598, 1512 (C᎐C), 1367, 1240 (C-O);
᎐
᎐
δH (200 MHz; CDCl3)‡ 2.76 (3H, s, COCH3), 3.94, 4.00 (3H, s,
2 × OCH3), 6.95 (1H, s, 2-H), 7.00 (1H, dd, J6,7 7.8 and J6,8 0.9,
6-H), 7.47 (1H, dd, J7,6 7.8 and J7,8 8.3, 7-H), 7.75 (1H, dd, J8,7
8.3 and J8,6 0.9, 8-H), 9.49 (1H, s, OH); δC (50 MHz; CDCl3)‡
30.3 (CH3, COCH3), 55.7, 65.5 (CH3, 2 × OCH3), 102.4 (CH,
C-2), 112.4, 113.5 (CH, C-6, C-8), 117.1 (quat., C-4a), 126.6
(quat., C-3), 129.3 (CH, C-7), 130.2 (quat., C-8a), 151.3, 152.2,
154.7 (quat., C-1, C-4, C-5), 199.4 (quat., COCH3); m/z (EI) 246
(Mϩ, 70%), 231 (M Ϫ CH3, 100), 203 (M Ϫ COCH3, 45), 175
(25), 145 (20), 115 (30), 89 (18), 43 (COCH3, 27).
5-Hydroxy-3-(1-hydroxyethyl)-1,4-dimethoxynaphthalene
(43 mg, 26%), a colourless oil, although not characterised, was
identified on the basis of its 1H NMR spectrum; δH (200 MHz;
CDCl3)‡ 1.54 (3H, d, Jvic 6.4, CH3), 2.27 (1H, br s, CHOH),
3.86, 4.00 (3H, s, 2 × OCH3), 5.43 (1H, q, Jvic 6.4, CHOH), 6.82
(1H, s, 2-H), 6.88 (1H, dd, J6,7 7.5 and J6,8 1.2, 6-H), 7.38 (1H,
dd, J7,8 8.3 and J7,6 7.5, 7-H), 7.49 (1H, dd, J8,7 8.3 and J8,6 1.2,
8-H), 9.35 (1H, s, OH).
A solution of this diol (43 mg, 0.173 mmol) in dry dichloro-
methane (1 mL) was treated with tetrapropylammonium per-
ruthenate (3 mg, 0.009 mmol), N-methylmorpholine N-oxide
(30 mg, 0.260 mmol) and molecular sieves (4 Å, 10 mg) and
stirred for 2 h. The mixture was filtered through silica and the
solvent was removed at reduced pressure. Purification by flash
chromatography using hexane–ethyl acetate (4 : 1) as eluent
afforded ketone 7 (35 mg, 83%).
5-Benzyloxy-4-hydroxy-1-methoxynaphthalene 25
The naphthoquinone 24 (1.01 g, 3.78 mmol) was dissolved in
dichloromethane–diethyl ether (1 : 3) (60 mL) and shaken with
a freshly prepared solution of sodium dithionite (4.6 g, 26.5
mmol) in water (30 mL) for 10 min. The organic layer was
washed with water (30 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 (50 mL) and transferred by double-ended needle to a
reaction vessel containing a slurry of potassium carbonate
(1.57 g, 11.3 mmol) and dry acetone (20 mL). Dimethyl sulfate
(1.43 mL, 15.0 mmol) was added and the solution was stirred
and then heated at reflux until the reaction was complete
(2–3 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 (100 mL) and stirred with
triethylamine (2.3 mL, 16.6 mmol) for 20 min. The ethereal
solution was washed successively with hydrochloric acid (1 M;
2 × 50 mL), water (50 mL), and brine (50 mL), then dried
(sodium sulfate), and concentrated in vacuo. The oily residue
was purified by flash chromatography using hexane–ethyl
acetate (4 : 1) as eluent to afford 5-benzyloxy-4-hydroxy-1-
methoxynaphthalene 25 (761 mg, 75%) as a brown solid, which
was recrystallised from ethanol to give tan needles, mp 108–
108.5 ЊC (lit.,17 108 ЊC); νmax/cmϪ1 3407br (OH); δH (200 MHz;
CDCl3)‡ 3.91 (3H, s, OCH3), 5.23 (2H, s, CH2Ph), 6.75 (2H, s,
2-H and 3-H), 6.90 (1H, d, J7,6 7.9, 6-H), 7.31 (1H, dd, J7,8 8.1
and J6,7 7.9, 7-H), 7.34–7.50 (5H, m, Ph), 7.86 (1H, dd, J7,8 8.1
and J8,6 0.8, 8-H), 8.98 (1H, s, OH); δC (50 MHz; CDCl3)‡ 56.0
(CH3, OCH3), 71.7 (CH2, CH2Ph), 106.3 (CH, C-2 and C-3),
109.1, 116.2, 125.1 (CH, C-6, C-7, C-8), 115.7 (quat., C-4a),
2-Acetyl-5-hydroxy-1,4-dimethoxynaphthalene 11
A solution of benzyl ether 23 (205 mg, 0.610 mmol) was debenz-
ylated using the conditions described above for 22 to afford
ketone 11 (87 mg, 58%), which was recrystallised from hexane–
ethyl acetate to give colourless needles, mp 96.5–97.5 ЊC [Found
(FAB): Mϩ, 246.0894. C14H14O4 requires M, 246.0892]; νmax
/
cmϪ1 3362br (OH), 1660 (C᎐O, ketone), 1611 (C᎐C), 1375, 1214
᎐
᎐
(C-O); δH (400 MHz; CDCl3)‡ 2.79 (3H, s, COCH3), 3.93, 4.01
(each 3H, s, 2 × OCH3), 7.01 (1H, br d, J6,7 7.7, 6-H), 7.06 (1H,
J. Chem. Soc., Perkin Trans. 1, 2001, 1612–1623
1619

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126.0 (quat., C-8a), 128.0 (CH, o-Ph), 128.8 (CH, p-Ph), 129.0
(CH, m-Ph), 135.3 (quat., ipso-Ph), 147.9 (quat., C-1), 148.1
(quat., C-5), 155.1 (quat., C-4); m/z (EI) 280 (Mϩ, 20%), 189
(M Ϫ C7H7, 100), 91 (C7H7, 40).
(c 1.01, ethanol) {lit.,18 mp 91 ЊC; [α]2D0 ϩ12.3 (c 0.325, ethanol)};
νmax/cmϪ1 1745 (C᎐O), 1376 (C-O); α-anomer: δ (200 MHz;
᎐
H
CDCl3) 1.87 (1H, ddd, Jgem 12.3, J2ax,3 11.3, J2ax,1 10.0, 2ax-H),
2.04, 2.05, 2.09, 2.12 (each 3H, s, 4 × COCH3), 2.36 (1H, ddd,
Jgem 12.3, J2eq,3 4.7, J2eq,1 2.3, 2eq-H), 3.75 (1H, ddd, J5,4 9.4, J5,6B
4.7 and J5,6A 2.3, 5-H), 4.09 (1H, dd, Jgem 12.4, J6A,5 2.3, 6-HA),
4.32 (1H, dd, Jgem 12.4, J6B,5 4.7, 6-HB), 4.97–5.14 (2H, m, 3-H,
4-H), 5.80 (1H, dd, J1,2ax 10.0 and J1,2eq 2.3, 1-H); δC (50 MHz;
CDCl3) 20.6, 20.7, 20.8, 20.9 (CH3, 4 × COCH3), 34.7 (CH2,
C-2), 61.9 (CH2, C-6), 68.2, 70.1, 72.3 (CH, C-3, C-4, C-5), 91.0
(CH, C-1), 168.7, 169.7, 170.0, 170.6 (quat., 4 × COCH3);
β-anomer: δH (200 MHz; CDCl3) 5.78 (1H, dd, J1,2ax 10.5 and
J1,2eq 2.5, 1-H).
5-Benzyloxy-3-bromo-4-hydroxy-1-methoxynaphthalene 26
A solution of bromine (190 mg, 1.18 mmol) in tetrachloro-
methane (1.0 mL) was added dropwise to a solution of the
naphthol 25 (300 mg, 1.07 mmol) in tetrachloromethane (6.0
mL) at 0 ЊC. The reaction mixture was stirred for a further 2
min before being quenched with saturated aq. sodium thio-
sulfate (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 (magnesium sulfate)
and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography using hexane–
ethyl acetate (6 : 1) as eluent to afford 5-benzyloxy-3-bromo-4-
hydroxy-1-methoxynaphthalene 26 (380 mg, 99%), which was
recrystallised from hexane–ethyl acetate to give red needles, mp
132.5–133.5 ЊC [Found (FAB): Mϩ, 358.0207. C18H1579BrO3
requires M, 358.0205]; νmax/cmϪ1 3343br (OH); δH (400 MHz;
CDCl3)‡ 3.86 (3H, s, OCH3), 5.17 (2H, s, CH2Ph), 6.87 (1H, s,
2-H), 6.91 (1H, dd, J7,6 7.8 and J6,8 1.0, 6-H), 7.28 (1H, dd, J6,7
8.9 and J8,7 7.8, 7-H), 7.33–7.43 (5H, m, Ph), 7.77 (1H, dd, J8,7
8.9 and J8,6 1.0, 8-H), 9.58 (1H, s, OH); δC (100 MHz; CDCl3)‡
56.7 (CH3, OCH3), 72.6 (CH2, CH2Ph), 103.6 (quat., C-3),
107.9 (CH, C-2), 110.8, 117.0, 126.2 (CH, C-6, C-7, C-8), 116.4
(quat., C-4a), 128.0 (quat., C-8a), 128.9 (CH, o-Ph), 129.7 (CH,
p-Ph), 129.7 (CH, m-Ph), 135.4 (quat., ipso-Ph), 145.0 (quat.,
C-1), 148.8 (quat., C-5), 155.0 (quat., C-4); m/z (EI) 360, 358
(Mϩ, 15%), 279 (M Ϫ Br, 20), 269, 267 (M Ϫ C7H7, 100), 91
(C7H7, 60).
(ii) Using tri-O-acetyl-D-glucal.19 Distilled glacial acetic acid
(351 mL, 5.51 mol) was added to a stirred solution of tri-
O-acetyl--glucal (1.002 g, 3.67 mmol) and triphenylphosphine
hydrogen bromide27 (63 mg, 0.184 mmol) in anhydrous dichloro-
methane (18 mL). The mixture was stirred for 2 days at room
temperature, then the solvent was removed at reduced pressure.
The resultant oil was purified by flash chromatography using
hexane–ethyl acetate (4 : 1) as eluent to give 1,3,4,6-tetra-O-
acetyl-2-deoxy--arabino-hexopyranoside 9 as a mixture of
anomers (α : β, 9 : 1) (879 mg, 72%). The spectroscopic data
were in agreement with those reported above.
3,4,6-Tri-O-benzyl-2-deoxy-D-arabino-hexopyranosyl acetate 10
Glacial acetic acid (0.432 g, 7.2 mmol) was added to a stirred
solution of tri-O-benzyl--glucal28 (2.0 g, 4.80 mmol) and
triphenylphosphine hydrogen bromide (82 mg, 0.240 mmol) in
dry dichloromethane (35 mL). The mixture was stirred over-
night at room temperature. Removal of the solvent under
reduced pressure and purification of the residue by flash chrom-
atography using hexane–ethyl acetate (4 : 1) as eluent gave
3,4,6-tri-O-benzyl-2-deoxy--arabino-hexopyranosyl acetate 10
(α : β, 9 : 1) (1.97 g, 86%) as a colourless oil, [α]2D0 ϩ71.2 (c 0.876,
CHCl3); the spectroscopic data were in agreement with those
reported in the literature;19 α-anomer: δH (200 MHz; CDCl3)
1.84 (1H, ddd, Jgem 13.6, J2ax,3 11.4, J2ax,1 3.4, 2ax-H), 2.03 (3H, s,
COCH3), 2.28 (1H, ddd, Jgem 13.5, J2eq,3 4.9, J2eq,1 1.7, 2eq-H),
3.53–4.02 (5H, m, 3-H, 4-H, 5-H, 6-HA, 6-HB), 4.47–4.71 (5H,
m, 5 × CHPh), 4.91 (1H, d, Jgem 10.7, CHPh), 6.26 (1H, d, J1,2
1.7, 1-H), 7.16–7.34 (15H, m, Ph); δC (50 MHz; CDCl3) 21.0
(CH3, COCH3), 34.1 (CH2, C-2), 68.3 (CH2, C-6), 71.7 (CH2,
CH2Ph), 73.3 (CH, C-3), 73.4, 75.0 (CH2, 2 × CH2Ph), 76.7
(CH, C-5), 77.4 (CH, C-4), 92.0 (CH, C-1), 127.5–128.5 (CH,
Ph), 138.0, 138.1, 138.2 (quat., 3 × ipso-Ph), 169.1 (quat.,
COCH3).
β-Anomer: δH (200 MHz; CDCl3) 1.77 (1H, m, 2ax-H), 2.09
(3H, s, COCH3), 2.36 (1H, m, 2eq-H), 3.53–4.02 (5H, m, 3-H,
4-H, 5-H, 6-HA, 6-HB), 4.47–4.71 (5H, m, 5 × CHPh), 4.87
(1H, d, Jgem 10.8, CHPH), 5.67 (1H, dd, J1,2ax 10.0 and J1,2eq 2.2,
1-H), 7.16–7.34 (15H, m, Ph-H); δC (50 MHz; CDCl3) 21.1
(CH3, COCH3), 35.4 (CH2, C-2), 68.5 (CH2, C-6), 71.7, 73.5,
75.0 (CH2, 3 × CH2Ph), 75.8 (CH, C-3), 77.3 (CH, C-5), 78.9
(CH, C-4), 92.2 (CH, C-1), 127.5–128.5 (CH, Ph), 138.0, 138.1,
138.2 (quat., 3 × ipso-Ph), 169.1 (quat., COCH3).
5-Benzyloxy-3-bromo-1,4-dimethoxynaphthalene 18 (alternative
preparation)
A slurry of oil-free sodium hydride (259 mg, 10.8 mmol) in dry
dimethylformamide (2 mL) was added dropwise to a stirred
solution of the bromonaphthol 26 (1.94 g, 5.40 mmol) in
dimethylformamide (15 mL) at 0 ЊC. The mixture was stirred
for 15 min at 0 ЊC, then iodomethane (3.36 mL, 54 mmol) was
added and the reaction mixture was allowed to warm to room
temperature overnight before being quenched with water
(1 mL) and extracted with dichloromethane (3 × 50 mL). The
combined organic extracts were washed with water (50 mL),
dried (magnesium sulfate), and the solvent was removed under
reduced pressure. The residue was purified by flash chrom-
atography using hexane–ethyl acetate (4 : 1) as eluent to afford
5-benzyloxy-3-bromo-1,4-dimethoxynaphthalene 18 (1.49 g,
74%), which was recrystallised from hexane–ethyl acetate to
give tan needles, mp 93.5–94 ЊC. The spectroscopic data were
identical to those reported above.
1,3,4,6-Tetra-O-acetyl-2-deoxy-D-arabino-hexopyranoside 9
(i) Using 2-deoxyglucose.18 2-Deoxy--glucose (1.5 g, 9.14
mmol) was suspended in dry pyridine (25 mL) at 0 ЊC and
freshly distilled acetic anhydride (20 mL) was added. The reac-
tion mixture was kept at 0 ЊC for 4 days, at the end of which
time the starting material had completely dissolved. The solu-
tion was diluted with water and then extracted with chloroform.
The combined extracts were washed successively with sulfuric
acid (0.01 M; 3 × 50 mL), dilute aq. sodium bicarbonate
(50 mL) and water (50 mL). After drying (calcium chloride), the
solvent was removed at reduced pressure and the residue was
triturated with ethanol–diethyl ether (3 : 1). The resulting solid
was recrystallised several times from ethanol to give 1,3,4,6-
tetra-O-acetyl-2-deoxy--arabino-hexopyranoside 9 (2.21 g,
73%) (α : β, 10 : 1) as white needles, mp 92–93 ЊC; [α]1D8 ϩ10.9
3-Bromo-5-hydroxy-1,4-dimethoxy-6-(3Ј,4Ј,6Ј-tri-O-acetyl-2Ј-
deoxy-ꢀ-D-arabino-hexopyranosyl)naphthalene 29
Trimethylsilyl trifluoromethanesulfonate (51 µL, 0.266 mmol)
and silver perchlorate (2 mg, 5 mol%) were added to a stirred
solution of 3-bromo-5-hydroxy-1,4-dimethoxynaphthalene 8
(50 mg, 0.177 mmol) and tetra-O-acetyl-2-deoxy--glucoside 9
(100 mg, 210 mmol) in dry acetonitrile (5 mL) at 0 ЊC. The
mixture was stirred for 1 h, then was quenched with aq. sodium
bicarbonate (5 mL). The reaction mixture was extracted with
dichloromethane (3 × 50 mL), washed with water (100 mL) and
dried (magnesium sulfate). The solvent was removed at reduced
1620
J. Chem. Soc., Perkin Trans. 1, 2001, 1612–1623

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pressure and the oily residue was purified by flash chrom-
atography using hexane–ethyl acetate (6 : 1) as eluent to give the
title compound 29 (5 mg, 5%) as a colourless oil [Found (EI):
Mϩ, 554.0785. C24H2779BrO10 requires M, 554.0788]; νmax/cmϪ1
M, 590.1304]; νmax/cmϪ1 3329 (OH), 2934 (C-H), 1591 (C᎐C),
1508, 1453 (C-O); δH (400 MHz; CDCl3)‡ 1.43 (1H, ddd, Jgem
᎐
14.4, J8ЈA,9Ј 4.8 and J8ЈA,1Ј 4.8, 8Ј-HA), 1.98 (1H, ddd, Jgem 14.4,
J8ЈB,9Ј 9.7 and J8ЈB,1Ј 2.2, 8Ј-HB), 2.19 (1H, dd, J1Ј,8ЈA 4.8 and J1Ј,8ЈB
2.2, 1Ј-H), 3.85 (3H, s, 1-OCH3), 3.94 (3H, s, 4-OCH3), 4.08
(1H, d, Jgem 13.4, 4Ј-HA), 4.16 (1H, dd, J9Ј,8ЈB 9.7 and J9Ј,8ЈA 4.8,
9Ј-H), 4.21 (1H, dd, Jgem 13.4 and J4ЈB,5Ј 5.5, 4Ј-HB), 4.36 (1H, d,
J5Ј,4ЈB 5.5, 5Ј-H), 4.48 (1H, d, Jgem 11.9, CHPh), 4.52 (1H, d, Jgem
11.9, CHPH), 5.06 (1H, s, 7Ј-H), 5.86 (1H, s, 2Ј-H), 6.70 (1H, s,
2-H), 7.14 (1H, t, Jo 7.2, p-Ph), 7.24 (2H, t, Jo 7.2, m-Ph), 7.29–
7.35 (7H, m, o-Ph, CH2Ph), 7.64 (1H, d, J7,8 8.7, 8-H), 8.04 (1H,
d, J7,8 8.7, 7-H), 9.68 (1H, s, OH); δC (100 MHz; CDCl3)‡ 22.4
(CH2, C-8Ј), 45.5 (CH, C-1Ј), 55.9 (CH3, 1-OCH3), 62.6 (CH3,
4-OCH3), 70.2 (CH2, CH2Ph), 71.1 (CH2, C-4Ј), 73.7 (CH,
C-9Ј), 76.2 (CH, C-2Ј), 76.6 (CH, C-5Ј), 86.2 (CH, C-7Ј), 107.6
(CH, C-7), 110.3 (quat., C-3), 113.0 (CH, C-8), 117.4 (quat.,
C-8a), 125.5 (CH, Ph), 126.1 (CH, C-2), 126.4, 126.6 (quat.,
C-2, C-4a), 127.0–128.4 (CH, Ph), 138.6 (quat., ipso-Ph), 142.4
(quat., ipso-Ph), 146.0 (quat., C-5), 148.5, 152.8 (quat., C-1,
C-4); m/z (EI) 592, 590 (Mϩ, 27%), 321 (11), 91 (C7H7, 100).
3345 (OH), 1741 (C᎐O), 1631 (C᎐C), 1391 (C-O); δ (200 MHz;
᎐
᎐
H
CDCl3)‡ 1.78 (1H, ddd, Jgem 12.7, J2Јax,1Ј 11.3 and J2Јax,3Ј 11.3,
2Јax-H), 2.02, 2.07, 2.09 (each 3H, s, 3 × COCH3), 2.52 (1H,
ddd, Jgem 12.7, J2Јeq,3Ј 4.8 and J2Јeq,1Ј 2.0, 2Јeq-H), 3.84 (1H, ddd,
J5Ј,4Ј 9.7, J5Ј,6ЈB 4.8 and J5Ј,6ЈA 2.3, 5Ј-H), 3.95, 3.99 (each 3H, s,
2 × OCH3), 4.20 (1H, dd, Jgem 12.2 and J6ЈA,5Ј 2.3, 6Ј-HA), 4.35
(1H, dd, Jgem 12.2 and J6ЈB,5Ј 4.8, 6Ј-HB), 5.12 (1H, dd, J1Ј,2Јax 11.3
and J1Ј,2Јeq 2.0, 1Ј-H), 5.14 (1H, dd, J4Ј,3Ј 9.7 and J4Ј,5Ј 9.7, 4Ј-H),
5.25 (1H, ddd, J3Ј,2Јax 11.3, J3Ј,4Ј 9.7, J3Ј,2Јeq 4.8, 3Ј-H), 6.83 (1H, s,
2-H), 7.57 (1H, d, J8,7 8.8, 8-H), 7.72 (1H, d, J7,8 8.8 Hz, 7-H),
9.70 (1H, s, OH); m/z (EI) 556, 554 (Mϩ, 38%), 43 (100).
2-Bromo-5-hydroxy-1,4-dimethoxy-6-(3Ј,4Ј,6Ј-tri-O-acetyl-2Ј-
deoxy-ꢀ-D-arabino-hexopyranosyl)naphthalene 33
Under the same conditions as described above for the prepar-
ation of 29, 2-bromo-5-hydroxy-1,4-dimethoxynaphthalene 12
(50 mg, 0.177 mmol) and tetra-O-acetyl-2-deoxy--glucoside 9
(100 mg, 210 mmol) reacted to afford 2-bromo-5-hydroxy-1,4-
dimethoxy-6-(3Ј,4Ј,6Ј-tri-O-acetyl-2Ј-deoxy-β--arabino-hexo-
pyranosyl)naphthalene 33 (71 mg, 57%) as a colourless oil; [α]D22
ϩ17.49 (c 0.27, CHCl3) [Found (EI): Mϩ, 556.0774 and
554.0777. C24H27BrO10 requires M, 556.0767 and 554.0788];
νmax/cmϪ1 3346 (OH), 2938 (C-H), 1742 (C᎐O), 1631 (C᎐C),
1
Although not able to be fully characterised, H NMR shifts
for β-C-glycoside 30 were identified from the spectrum of the
mixture; δH (400 MHz; CDCl3)‡ 2.50 (1H, ddd, Jgem 12.7, J2Јeq,3Ј
4.8 and J2Јeq,1Ј 1.8, 2eqЈ-H), 7.59 (1H, d, J8,7 8.0, 8-H), 6.74 (1H, s,
2-H), 7.66 (1H, d, J7,8 8.0, 7-H), 9.60 (1H, s, OH).
Triethylamine (0.50 mL, 3.59 mmol), acetic anhydride (0.25
mL, 2.65 mmol) and a catalytic quantity of 4-(dimethylamino)-
pyridine were added to a solution of 36 (98 mg, 0.166 mmol) in
dichloromethane (2 mL). The solution was stirred overnight,
then the solvent was removed at reduced pressure. The residue
was purified by flash chromatography using hexane–ethyl
acetate (4 : 1) to give the acetate derivative (99 mg, 94%), which
was recrystallised from hexane–ethyl acetate (1:1) to give white
needles, mp 204–205 ЊC (from which a crystal structure was
obtained23); [α]D20 Ϫ192 (c 0.45, CHCl3) [Found (LSIMS): Mϩ,
632.1422. C34H3379BrO7 requires M, 632.1410]; νmax/cmϪ1 2933
᎐
᎐
1391 (C-O); δH (200 MHz; CDCl3)‡ 1.26 (1H, ddd, Jgem 12.7,
J2Јax,1Ј 11.3 and J2Јax,3Ј 11.3, 2Јax-H), 2.02, 2.08, 2.10 (each 3H, s,
3 × COCH3), 2.52 (1H, ddd, Jgem 12.7, J2Јeq,3Ј 4.8 and J2Јeq,1Ј 2.0,
2Јeq-H), 3.84 (1H, ddd, J5Ј,4Ј 9.7, J5Ј,6ЈB 4.8 and J5Ј,6ЈA 2.3, 5Ј-H),
3.91, 4.04 (each 3H, s, 2 × OCH3), 4.20 (1H, dd, Jgem 12.2 and
J6ЈA,5Ј 2.3, 6Ј-HA), 4.35 (1H, dd, Jgem 12.2 and J6ЈB,5Ј 4.8, 6Ј-HB),
5.12 (1H, dd, J1Ј,2Јax 11.3 and J1Ј,2Јeq 2.0, 1Ј-H), 5.14 (1H, dd, J4Ј,3Ј
9.7 and J4Ј,5Ј 9.7, 4Ј-H), 5.25 (1H, ddd, J3Ј,2Јax 11.3, J3Ј,4Ј 9.7, J3Ј,2Јeq
4.8, 3Ј-H), 6.86 (1H, s, 3-H), 7.58 (1H, d, J8,7 8.8, 8-H), 7.64
(1H, d, J7,8, 7-H), 9.49 (1H, s, OH); δC (50 MHz; CDCl3)‡ 20.8,
20.9, 21.0 (CH3, 3 × COCH3), 36.7 (CH2, C-2Ј), 56.7, 61.2
(CH3, 2 × OCH3), 62.9 (CH2, C-6Ј), 69.6 (CH, C-4Ј), 71.7 (CH,
C-1Ј), 72.5 (CH, C-3Ј), 76.2 (CH, C-5Ј), 108.2 (CH, C-3), 113.4
(CH, C-7), 114.5 (quat., C-2), 122.5 (quat., C-4a), 125.9 (CH,
C-8), 130.1 (quat., C-8a), 133.5 (quat., C-6), 147.8, 150.5, 152.7
(quat., C-1, C-4, C-5), 170.0, 170.4, 170.9 (quat., 3 × COCH3);
m/z (EI) 556, 554 (Mϩ, 42%), 321, 319 (48), 43 (COCH3, 100).
(C-H), 1769 (C᎐O, ester), 1587 (C᎐C), 1506, 1453, 1411 (C-O);
᎐
᎐
δH (400 MHz; 360 K; C7D8) 1.63 (1H, ddd, Jgem 14.4, J8ЈB,9Ј 4.6
and J8ЈB,1Ј 4.6, 8Ј-HB), 2.01 (1H, ddd, Jgem 14.4, J8ЈA,9Ј 9.7 and
J8ЈA,1Ј 2.2, 8Ј-HA), 2.14 (3H, s, COCH3), 2.31 (1H, dd, J1Ј,8ЈB 4.6
and J1Ј,8ЈA 2.2, 1Ј-H), 3.37, 3.66 (each 3H, s, 2 × OCH3), 3.91
(1H, d, Jgem 13.4, 4Ј-HA), 3.98 (1H, dd, Jgem 13.4 and J4ЈB,5Ј 5.1,
4Ј-HB), 4.09 (1H, dd, J9Ј,8ЈA 9.7 and J9Ј,8ЈB 4.6, 9Ј-H), 4.24 (1H, d,
J5Ј,4ЈB 5.1, 5Ј-H), 4.34 (1H, d, Jgem 12.2, CHPH), 4.37 (1H, d,
Jgem 12.2, CHPH), 4.92 (1H, s, 7Ј-H), 5.81 (1H, s, 2Ј-H), 6.68
(1H, s, 2-H), 7.03–7.09 (2H, m, p-Ph), 7.15–7.20 (4H, m, m-Ph),
7.30 (2H, d, Jo 7.7, o-Ph), 7.44 (2H, d, Jo 7.7, o-Ph), 8.14 (1H, d,
J7,8 8.9, 8-H), 8.45 (1H, d, J7,8 8.9, 7-H); m/z (CI) 634, 632 (Mϩ,
10%), 91 (C7H7, 100).
(1ЈR,2ЈR,5ЈR,7ЈS,9ЈS)-6-(9Ј-Benzyloxy-2Ј-phenyl-3Ј,6Ј-dioxa-
bicyclo[3.2.2]nonan-7Ј-yl)-3-bromo-5-hydroxy-1,4-dimethoxy-
naphthalene 36
Trimethylsilyl trifluoromethanesulfonate (51 µL, 0.266 mmol)
and silver perchlorate (2 mg, 5 mol%) were added to a stirred
solution of 3-bromo-5-hydroxy-1,4-dimethoxynaphthalene 8
(50 mg, 0.177 mmol) and tri-O-benzyl-2-deoxy--glucosyl
acetate 10 (101 mg, 210 mmol) in dry acetonitrile (5 mL) at
0 ЊC. The mixture was stirred for 1 h, then was quenched with
aq. sodium bicarbonate (5 mL). The reaction mixture was
extracted with dichloromethane (3 × 50 mL), washed with
water (100 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 a mixture of the rearranged compound 36 and
β-C-glycoside 30 (71 mg; 6 : 1). These were subjected to HPLC.
Analytical HPLC established the optimal separation conditions
2-Bromo-5-hydroxy-1,4-dimethoxy-6-(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-
deoxy-ꢀ-D-arabino-hexopyranosyl)naphthalene 34
Boron trifluoride–diethyl ether (43 µL, 0.350 mmol) was added
dropwise to a stirred solution of naphthol 12 (50 mg, 0.177
mmol) and tri-O-benzyl-2-deoxy--glucosyl acetate 10 (100 mg,
210 mmol) in dry acetonitrile (5 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 × 50
mL), washed with water (100 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 (6 : 1) as eluent to give the title compound
34 (65 mg, 53%) as a colourless glass; [α]2D2 ϩ29.3 (c 0.3, CHCl3)
[Found (FAB): Mϩ, 700.1855, 698.1872. C39H39BrO7 requires
M, 700.1859, 698.1879]; νmax/cmϪ1 3384 (OH), 3056 (C-H), 1643
i
(0.375% PrOH–hexane; Partisil 5 column, 25 cm × 4.6 mm
I.D.; flow rate 1.5 mL minϪ1), but on a semi-preparative scale
i
(0.375% PrOH–hexane; Partisil 10 column, 50 cm × 9.4 mm
I.D.; flow rate 4 mL minϪ1) the unstable β-C-glycoside 30
decomposed. The more stable rearranged product 36 (59 mg,
48%) was recovered as a colourless oil; [α]2D2 Ϫ105 (c 0.24,
CHCl3) [Found (LSIMS): Mϩ, 590.1295. C32H3179BrO6 requires
(C᎐C), 1419 (C-O); δ (200 MHz; CDCl )‡ 1.63 (1H, ddd, J
᎐
H
3
gem
12.9, J2Јax,1Ј 11.6 and J2Јax,3Ј 11.6, 2axЈ-H), 2.59 (1H, ddd, Jgem
12.9, J2Јeq,3Ј 5.0 and J2Јeq,1Ј 1.0, 2eqЈ-H), 3.66–4.02 (5H, m, 3Ј-H,
4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 3.90, 3.98 (each 3H, s, 2 × OCH3),
J. Chem. Soc., Perkin Trans. 1, 2001, 1612–1623
1621

View Article Online
4.58–4.74 (5H, m, 5 × CHPh), 4.97 (1H, d, Jgem 10.8, CHPh),
4.98 (1H, dd, J1Ј,2Јax 10.0 and J1Ј,2Јeq 1.0 Hz, 1Ј-H), 6.82 (1H, s,
3-H), 7.21–7.41 (15H, m, Ph), 7.59 (1H, d, J8,7 8.7, 8-H), 7.73
(1H, d, J7,8 8.7, 7-H), 9.47 (1H, s, OH); δC (50 MHz; CDCl3)‡
38.5 (CH2, C-2Ј), 56.5, 61.1 (CH3, 2 × OCH3), 69.6 (CH2, C-6Ј),
71.1 (CH2, CH2Ph), 71.6 (CH, C-1Ј), 73.4, 75.0 (CH2,
2 × CH2Ph), 78.4, 79.4, 81.3 (CH, C-3Ј, C-4Ј, C-5Ј), 108.0 (CH,
C-7), 111.1 (quat., C-2), 113.3 (CH, C-8), 114.5 (quat., C-4a),
124.0 (quat., C-8a), 126.4 (CH, C-3), 127.4–128.3 (CH, Ph),
130.2 (quat., C-6), 138.5, 138.6, 138.6 (quat., 3 × ipso-Ph),
147.8, 150.1, 152.7 (quat., C-1, C-4, C-5); m/z (EI) 700, 698
(Mϩ, 12%), 592, 590 (20), 91 (C7H7, 100).
CDCl3)‡ 30.5 (CH3, COCH3), 37.4 (CH2, C-2Ј), 55.8, 65.6 (CH3,
2 × OCH3), 69.6 (CH2, C-6Ј), 71.3 (CH2, CH2Ph), 71.7 (CH,
C-1Ј), 73.4, 75.1 (CH2, 2 × CH2Ph), 78.5, 79.5, 81.4 (CH, C-3Ј,
C-4Ј, C-5Ј), 102.3 (CH, C-2), 113.7 (CH, C-8), 116.8 (quat.,
C-4a), 124.9, 125.5 (quat., C-3, C-6), 127.1 (CH, C-7), 127.5–
128.3 (CH, Ph), 129.4 (quat., C-8a), 138.5, 138.6, 138.6 (quat.,
3 × ipso-Ph), 150.1, 151.3, 152.3 (quat., C-1, C-8, C-5), 199.7
(quat., COCH3); m/z (EI) 662 (Mϩ, 0.5%), 554 (1), 272 (12), 91
(C7H7, 100).
(1ЈR,2ЈR,5ЈR,7ЈS,9ЈS)-2-Acetyl-6-(9Ј-benzyloxy-2Ј-phenyl-
3Ј,6Ј-dioxabicyclo[3.2.2]nonan-7Ј-yl)-5-hydroxy-1,4-dimethoxy-
naphthalene 37 and 2-acetyl-5-hydroxy-1,4-dimethoxy-6-
(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-ꢀ-D-arabino-hexopyranosyl)-
naphthalene 32
(1ЈR,2ЈR,5ЈR,7ЈS,9ЈS)-3-Acetyl-6-(9Ј-benzyloxy-2Ј-phenyl-
3Ј,6Ј-dioxabicyclo[3.2.2]nonan-7Ј-yl)-5-hydroxy-1,4-dimethoxy-
naphthalene 35 and 3-acetyl-5-hydroxy-1,4-dimethoxy-6-
(3Ј,4Ј,6Ј-tri-O-benzyl-2Ј-deoxy-ꢀ-D-arabino-hexopyranosyl)-
naphthalene 28
Boron trifluoride–diethyl ether (40 µL, 0.325 mmol) was added
dropwise to a stirred solution of tri-O-benzyl-2-deoxy--
glucosyl acetate 10 (93 mg, 0.195 mmol) and 2-acetyl-1,4-
dimethoxy-5-hydroxynaphthalene 11 (40 mg, 0.163 mmol) in
dry acetonitrile (3 mL) at 0 ЊC. The mixture was stirred for 1 h
at 0 ЊC, then was quenched with water (2 mL). The crude reac-
tion mixture was extracted with dichloromethane (3 × 25 mL),
washed with water (50 mL) and dried (magnesium sulfate). The
solvent was removed at reduced pressure and the oily residue
was purified by flash chromatography using hexane–ethyl acet-
ate (4 : 1) as eluent to give the starting naphthol 11 (17 mg,
43% recovery) as well as a (1 : 2) mixture of β-C-glycoside 32
and the rearranged product 37 (60 mg). These were separated by
Boron trifluoride–diethyl ether (40 µL, 0.325 mmol) was added
dropwise to a stirred solution of tri-O-benzyl-2-deoxy--
glucosyl acetate 10 (93 mg, 0.195 mmol) and naphthol 7 (40 mg,
0.163 mmol) in dry acetonitrile (3 mL) at 0 ЊC. The mixture was
stirred for 1 h at 0 ЊC, then was quenched with water (2 mL).
The crude reaction mixture was extracted with dichloro-
methane (3 × 25 mL), washed with water (50 mL) and dried
(magnesium sulfate). The solvent was removed at reduced pres-
sure and the oily residue was purified by flash chromatography
using hexane–ethyl acetate (4 : 1) as eluent to give the starting
naphthol 7 (24 mg, 60% recovery) as well as a (1 : 2) mixture of
the β-C-glycoside 28 and the rearranged product 35 (29 mg).
These products were separated by semipreparative HPLC (1.5%
iPrOH–hexane; Partisil 10 column, 50 cm × 9.4 mm I.D.; flow
rate 4 mL minϪ1) to give title compound 35 (11 mg, 12%) as a
yellow oil; [α]2D2 Ϫ147.5 (c 0.24, CHCl3) [Found (EI): Mϩ,
554.2294. C34H34O7 requires M, 554.2305]; νmax/cmϪ1 3328br
i
HPLC (1.5% PrOH–hexane; Partisil 5 column; rt; 45 min) to
give (1ЈR,2ЈR,5ЈR,7ЈS,9ЈS)-2-acetyl-6-(9Ј-benzyloxy-2Ј-phenyl-
3Ј,6Ј-dioxabicyclo[3.2.2]-nonan-7Ј-yl)-5-hydroxy-1,4-dimeth-
oxynaphthalene 37 (21 mg, 23%) as a colourless oil; [α]2D2 Ϫ201 (c
0.38, CHCl3) [Found (EI): Mϩ, 554.2317. C34H34O7 requires M,
554.2305]; νmax/cmϪ1 3366br (OH), 2938, 2855 (C-H), 1668
(C᎐O), 1608 (C᎐C), 1371 (C-O); δ (400 MHz; CDCl3)‡ 1.52
᎐
᎐
H
(OH), 2956, 2917, 2851 (C-H), 1667 (C᎐O), 1602, 1514 (C᎐C),
(1H, ddd, Jgem 14.3, J8ЈB,9Ј 4.7 and J8ЈB,1Ј 4.6, 8Ј-HB), 2.09 (1H,
ddd, Jgem 14.3, J8ЈA,9Ј 9.6 and J8ЈA,1Ј 2.3, 8Ј-HA), 2.29 (1H, dd,
J1Ј,8ЈB 4.6 and J1Ј,8ЈA 2.3, 1Ј-H), 2.79 (3H, s, COCH3), 3.93, 4.11
(each 3H, s, 2 × OCH3), 4.17 (1H, d, Jgem 13.5, 4Ј-HA), 4.26 (1H,
dd, J9Ј,8ЈA 9.6 and J9Ј,8ЈB 4.7, 9Ј-H), 4.31 (1H, dd, Jgem 13.5 and
J4ЈB,5Ј 5.4, 4Ј-HB), 4.46 (1H, d, J5Ј,4ЈB 5.4, 5Ј-H), 4.61 (2H, s,
CH2Ph), 5.14 (1H, s, 7Ј-H), 5.94 (1H, s, 2Ј-H), 7.08 (1H, s, 3-H),
7.24 (1H, t, Jo 7.4, p-Ph), 7.33 (2H, t, Jo 7.4, m-Ph), 7.35–7.45
(7H, m, Ph), 7.70 (1H, d, J7,8 8.7, 8-H), 8.21 (1H, d, J7,8 8.7,
7-H), 9.72 (1H, s, OH); δC (100 MHz; CDCl3)‡ 23.2 (CH2,
C-8Ј), 31.6 (CH3, COCH3), 45.9 (CH, C-1Ј), 57.1, 64.3 (CH3,
2 × OCH3), 71.0 (CH2, CH2Ph), 71.9 (CH2, C-4Ј), 74.5 (CH,
C-9Ј), 76.9 (CH, C-2Ј), 77.2 (CH, C-5Ј), 86.1 (CH, C-7Ј), 102.7
(CH, C-7), 114.5 (CH, C-8), 118.1 (quat., C-4a), 126.2 (CH,
Ph), 127.0 (quat., C-6), 127.7, 128.0, 128.2, 128.3 (CH, Ph,
C-3), 128.4 (quat., C-8a), 128.7, 129.1 (CH, Ph), 130.8 (quat.,
C-2), 139.3 (quat., ipso-Ph), 143.1 (quat., 3 × ipso-Ph), 151.3,
153.1, 153.8 (quat., C-1, C-5, C-4), 199.8 (quat., COCH3); m/z
(EI) 554 (Mϩ, 3%), 285 (18), 91 (C7H7, 100) and 2-acetyl-
5-hydroxy-1,4-dimethoxy-6-(3Ј,4Ј-Ј,6Ј-tri-O-benzyl-2Ј-deoxy-β-
-arabino-hexopyranosyl)naphthalene 32 (10 mg, 9%) as a
colourless oil; [α]2D2 ϩ45.0 (c 0.16, CHCl3) [Found (EI): Mϩ,
662.2898. C41H42O8 requires M, 662.2880]; νmax/cmϪ1 3359br,
᎐
᎐
1366 (s, C-O); δH (400 MHz; CDCl3)‡ 1.52 (1H, ddd, Jgem 14.5,
J8ЈB,1Ј 4.9 and J8ЈB,9Ј 4.8, 8Ј-HB), 2.09 (1H, ddd, Jgem 14.5, J8ЈA,9Ј
9.7 and J8ЈA,1Ј 2.3, 8Ј-HA), 2.29 (1H, dd, J1Ј,8ЈB 4.9 and J1Ј,8ЈA 2.3,
1Ј-H), 2.76 (3H, s, COCH3), 3.96, 3.99 (each 3H, s, 2 × OCH3),
4.17 (1H, d, Jgem 13.5, 4Ј-HA), 4.25 (1H, dd, J9Ј,8ЈA 9.7 and J9Ј,8ЈB
4.8, 9Ј-H), 4.31 (1H, dd, Jgem 13.5 and J4ЈB,5Ј 5.3, 4Ј-HB), 4.45
(1H, d, J5Ј,4ЈB 5.3, 5Ј-H), 4.58 (1H, d, Jgem 11.9, CHPh), 4.62
(1H, d, Jgem 11.9, CHPh), 5.15 (1H, s, 7Ј-H), 5.98 (1H, s, 2Ј-H),
6.91 (1H, s, 2-H), 7.24 (1H, t, Jo 7.4, p-Ph), 7.33 (2H, t, Jo 7.4,
m-Ph), 7.38–7.46 (7H, m, Ph), 7.78 (1H, d, J7,8 8.7, 8-H), 8.21
(1H, d, J7,8 8.7, 7-H), 9.88 (1H, s, OH); δC (100 MHz; CDCl3)‡
22.4 (CH2, C-8Ј), 30.5 (CH3, COCH3), 45.5 (CH, C-1Ј), 55.8,
65.6 (CH3, 2 × OCH3), 70.2 (CH2, CH2Ph), 71.2 (CH2, C-4Ј),
73.7 (CH, C-9Ј), 76.2 (CH, C-2Ј), 76.6 (CH, C-5Ј), 86.2 (CH,
C-7Ј), 101.9 (CH, C-7), 112.9 (CH, C-8), 116.6 (quat., C-4a),
125.5 (CH, Ph), 126.4, 126.7 (quat., C-6, C-8a), 127.0, 127.5,
127.6, 128.1, 128.2, 128.4 (CH, Ph, C-2), 129.3 (quat., C-3),
138.6 (quat., ipso-Ph), 142.5 (quat., ipso-Ph), 150.4, 151.3, 152.4
(quat., C-1, C-5, C-4), 199.6 (quat., COCH3); m/z (EI) 554 (Mϩ,
4%), 285 (17), 91 (C7H7, 100) and title compound 28 (8 mg, 7%)
as a yellow oil; [α]2D2 ϩ40.0 (c 0.40, CHCl3) [Found (EI): Mϩ,
662.2868. C41H42O8 requires M, 662.2880]; νmax/cmϪ1 3327br
(OH), 2921, 2853 (C-H), 1672 (C᎐O), 1604, 1514, 1453 (C᎐C),
(OH), 2955, 2922, 2863 (C-H), 1668 (C᎐O), 1610 (C᎐C), 1454,
᎐
᎐
᎐ ᎐
1368 (s, C-O); δH (400 MHz; CDCl3)‡ 1.65 (1H, ddd, Jgem 12.7,
J2Јax,3Ј 11.5 and J2Јax,1Ј 11.5, 2Јax-H), 2.57 (1H, ddd, Jgem 12.7,
J2Јeq,3Ј 4.8 and J2Јeq,1Ј 1.8, 2Јeq-H), 2.76 (3H, s, COCH3), 3.65–4.20
(5H, m, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 3.93, 3.99 (each 3H, s,
2 × OCH3), 4.61 (1H, d, Jgem 12.4, CHPh), 4.65 (1H, d, Jgem
11.6, CHPh), 4.66 (1H, d, Jgem 10.9, CHPh), 4.70 (1H, d, Jgem
12.4, CHPh), 4.74 (1H, d, Jgem 11.6, CHPh), 4.97 (1H, d, Jgem
10.9, CHPh), 5.04 (1H, dd, J1Ј,2Јax 11.4 and J1Ј,2Јeq 1.6, 1Ј-H), 6.92
(1H, s, 2-H), 7.20–7.50 (15H, m, Ph), 7.75 (1H, d, J8,7 8.7, 8-H),
7.79 (1H, d, J7,8 8.7, 7-H), 9.78 (1H, s, OH); δC (100 MHz;
1372 (C-O); δH (400 MHz; CDCl3)‡ 1.62 (1H, ddd, Jgem 12.7,
J2Јax,3Ј 11.4 and J2Јax,1Ј 11.4, 2Јax-H), 2.62 (1H, ddd, Jgem 12.7,
J2Јeq,3Ј 4.9 and J2Јeq,1Ј 1.7, 2Јeq-H), 2.79 (3H, s, COCH3), 3.65–3.92
(5H, m, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 3.93, 4.08 (each 3H, s,
2 × OCH3), 4.61 (1H, d, Jgem 12.4, CHPh), 4.65 (1H, d, Jgem 11.6,
CHPh), 4.66 (1H, d, Jgem 10.9, CHPh), 4.71 (1H, d, Jgem 12.4,
CHPh), 4.73 (1H, d, Jgem 11.6, CHPh), 4.97 (1H, d, Jgem 10.9,
CHPh), 5.00 (1H, dd, J1Ј,2Јax 11.4 and J1Ј,2Јeq 1.7, 1Ј-H), 7.08 (1H,
s, 3-H), 7.25–7.40 (15H, m, Ph), 7.71 (1H, d, J8,7 8.7, 8-H), 7.77
(1H, d, J7,8 8.7, 7-H), 9.65 (1H, s, OH); δC (100 MHz; CDCl3)‡
1622
J. Chem. Soc., Perkin Trans. 1, 2001, 1612–1623

View Article Online
9 M. A. Brimble and S. J. Stuart, J. Chem. Soc., Perkin Trans. 1, 1990,
881.
10 M. A. Brimble, S. J. Phythian and H. Prabaharan, J. Chem. Soc.,
Perkin Trans. 1, 1995, 2855.
11 For a preliminary communication on this work see: M. A. Brimble
and T. J. Brenstrum, Tetrahedron Lett., 2000, 41, 1107.
12 For recent reviews on C-glycosylation see: (a) M. H. D. Postema,
Tetrahedron, 1992, 48, 8545; (b) C. Jaramillo and S. Knapp,
Synthesis, 1994, 1; (c) D. E. Levy and C. Tang, The Chemistry of
C-Glycosides, Pergamon Press, Oxford, 1995; (d ) Y. Du and R. J.
Lindhardt, Tetrahedron, 1998, 54, 9913.
30.9 (CH3, COCH3), 37.2 (CH2, C-2Ј), 56.4, 63.6 (CH3, 2 ×
OCH3), 69.7 (CH2, C-6Ј), 71.2 (CH2, CH2Ph), 71.7 (CH, C-1Ј),
73.4, 75.1 (CH2, 2 × CH2Ph), 78.4, 79.5, 81.3 (CH, C-3Ј, C-4Ј,
C-5Ј), 102.4 (CH, C-3), 114.8 (CH, C-8), 117.5 (quat., C-4a),
126.2 (CH, C-7), 126.3, 126.6 (quat., C-2, C-6), 127.5–128.4
(CH, Ph), 130.2 (quat., C-8a), 138.6, 138.6, 138.6 (quat., 3 ×
ipso-Ph), 150.2, 152.5, 152.9 (quat., C-1, C-4, C-5), 199.1 (quat.,
COCH3); m/z (EI) 662 (Mϩ, 0.5%), 554 (0.2), 272 (8), 181 (5),
149 (7), 91 (C7H7, 100).
13 The lack of reactivity of juglone towards C-glycosylation has been
observed previously. See: G. Matsuo, Y. Miki, M. Nakata,
S. Matsumura and K. Toshima, J. Org. Chem., 1999, 64, 7101.
14 H. Rappoport, R. L. Hannan and R. B. Barber, J. Org. Chem., 1979,
44, 2153.
15 R. H. Thompson, J. Org. Chem., 1948, 13, 377.
16 S. V. Ley, W. P. Griffith, J. Norman and S. P. Marsden, Synthesis,
1994, 639.
Acknowledgements
We thank Dr Patrick Steel (University of Durham, UK) for
supplying NMR spectra for compounds related to the
rearranged C-glycosides reported herein.
17 H. Laatsch, Liebigs Ann. Chem., 1980, 1321.
18 W. G. Overend, M. Stacey and J. Stanek, J. Chem. Soc., 1949, 2841.
19 C. Mioskowski, V. Bolitt, S.-G. Lee and J. R. Falck, J. Org. Chem.,
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20 K. Toshima, G. Matsuo and K. Tatsuka, Tetrahedron Lett., 1992, 33,
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21 D. S. Larsen and F. L. Andrews, Tetrahedron Lett., 1994, 35, 8693.
22 P. G. Steel, A. L. J. Byerly, A. M. Kenwright and C. W. Lehman,
J. Org. Chem., 1998, 63, 193.
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