Synthesis of 3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl pyranonaphthoquinone analogues of medermycin.

Article abstract of DOI:10.1039/b301449p

The synthesis of an isomeric mixture of 4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl analogues 6 of the C-glycosylpyranonaphthoquinone antibiotic medermycin is described. The key 3-acetyl-6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino- hexopyranosyl)-5-methoxy-1,4-naphthoquinone 8 was prepared via Stille coupling of 6-(3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl)-3-bromo-1,4- naphthoquinone 17 with (alpha-ethoxyvinyl)tributyl-stannane followed by hydrolysis and oxidation of the resultant hydroquinone 18. Bromonaphthoquinone 17 in turn was afforded by oxidative demethylation of 6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl)-3- bromo-1,4,5-trimethoxynaphthalene 16 formed by regioselective bromination of 6-(4-acetyl-3-azido-2,3,6-trideoxy- beta-D-arabino-hexopyranosyl)-1,4,5-trimethoxynaphthalene 10. This latter naphthalene 10 was prepared via direct C-glycosylation of naphthol 12 with glycosyl donor 11 using BF3.Et2O in acetonitrile. The regioselectivity of the bromination of naphthalene 10 was independently determined by reductive monomethylation of the 6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino- hexopyranosyl)-5-methoxy-1,4-naphthoquinone 22 to naphthol 23 followed by selective ortho bromination to bromide 24 and methylation to 16. Attempts to effect acetylation of 6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino- hexopyranosyl)-3-bromo-1,4,5-trimethoxynaphthalene 16 and 3-bromo-6-(3-dimethylamino-2,3,6-trideoxy-beta-D-arabino- hexopyranosyl)-1,4,5-trimethoxynaphthalene 26 via Stille coupling with (alpha-ethoxyvinyl)tributylstannane were low yielding thereby establishing the necessity to use an azido group as a latent dimethylamino group and a more electrophilic bromonaphthoquinone as the coupling partner for the Stille reaction. Addition of 2-trimethylsilyloxyfuran 9 to 3-acetyl-6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl)- 5-methoxy-1,4-naphthoquinone 8 afforded the furofuran adducts 7 and 19 as an inseparable mixture of diastereomers. Oxidative rearrangement of this diastereomeric mixture using ceric ammonium nitrate afforded the inseparable diastereomeric furonaphthopyrans 6 and 20.

Full text of DOI:10.1039/b301449p

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Synthesis of 3-azido-2,3,6-trideoxy-ꢀ-D-arabino-hexopyranosyl
pyranonaphthoquinone analogues of medermycin
Margaret A. Brimble,*a Roger M. Davey,b Malcolm D. McLeodb and Maureen Murphyb
a Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
b School of Chemistry, F11, University of Sydney, Camperdown, NSW 2006, Australia
Received 5th February 2003, Accepted 31st March 2003
First published as an Advance Article on the web 11th April 2003
The synthesis of an isomeric mixture of 4-O-acetyl-3-azido-2,3,6-trideoxy-β--arabino-hexopyranosyl analogues 6 of
the C-glycosylpyranonaphthoquinone antibiotic medermycin is described. The key 3-acetyl-6-(4-O-acetyl-3-azido-
2,3,6-trideoxy-β--arabino-hexopyranosyl)-5-methoxy-1,4-naphthoquinone 8 was prepared via Stille coupling of
6-(3-azido-2,3,6-trideoxy-β--arabino-hexopyranosyl)-3-bromo-1,4-naphthoquinone 17 with (α-ethoxyvinyl)tributyl-
stannane followed by hydrolysis and oxidation of the resultant hydroquinone 18. Bromonaphthoquinone 17 in turn
was afforded by oxidative demethylation of 6-(4-O-acetyl-3-azido-2,3,6-trideoxy-β--arabino-hexopyranosyl)-3-
bromo-1,4,5-trimethoxynaphthalene 16 formed by regioselective bromination of 6-(4-acetyl-3-azido-2,3,6-trideoxy-
β--arabino-hexopyranosyl)-1,4,5-trimethoxynaphthalene 10. This latter naphthalene 10 was prepared via direct
C-glycosylation of naphthol 12 with glycosyl donor 11 using BF3ؒEt2O in acetonitrile. The regioselectivity of the
bromination of naphthalene 10 was independently determined by reductive monomethylation of the 6-(4-O-acetyl-3-
azido-2,3,6-trideoxy-β--arabino-hexopyranosyl)-5-methoxy-1,4-naphthoquinone 22 to naphthol 23 followed by
selective ortho bromination to bromide 24 and methylation to 16. Attempts to effect acetylation of 6-(4-O-acetyl-3-
azido-2,3,6-trideoxy-β--arabino-hexopyranosyl)-3-bromo-1,4,5-trimethoxynaphthalene 16 and 3-bromo-6-(3-
dimethylamino-2,3,6-trideoxy-β--arabino-hexopyranosyl)-1,4,5-trimethoxynaphthalene 26 via Stille coupling with
(α-ethoxyvinyl)tributylstannane were low yielding thereby establishing the necessity to use an azido group as a latent
dimethylamino group and a more electrophilic bromonaphthoquinone as the coupling partner for the Stille reaction.
Addition of 2-trimethylsilyloxyfuran 9 to 3-acetyl-6-(4-O-acetyl-3-azido-2,3,6-trideoxy-β--arabino-hexopyranosyl)-
5-methoxy-1,4-naphthoquinone 8 afforded the furofuran adducts 7 and 19 as an inseparable mixture of
diastereomers. Oxidative rearrangement of this diastereomeric mixture using ceric ammonium nitrate afforded
the inseparable diastereomeric furonaphthopyrans 6 and 20.
Wyeth researchers11 presented sophisticated NMR evidence in
support of the original structure for medermycin/lactoquino-
mycin A 1.
Introduction
Medermycin is a unique member of the pyranonaphtho-
quinonefamilyofantibiotics1,2 inthatitcontainsaβ-C-glycoside
Our synthetic efforts towards medermycin focused on the
linkage to an aminosugar, -angolosamine. Medermycin was
efficient introduction of a C-glycoside at C-8 on the pyrano-
isolated3 from a strain of Streptomyces K73 and was shown
to exhibit activity against Gram-positive bacteria including
naphthoquinone skeleton and have resulted in the synthesis of a
2-deoxyglucosyl analogue12 and an azido analogue13 of meder-
Staphylococcus aureus. The structure of medermycin 1 was ini-
mycin 1. Given the significant biological activity exhibited by
tially assigned as having the same skeleton as kalafungin 3 with
medermycin 1, and the prevalence of other naphthoquinone
the amino sugar moiety attached to the pyranonaphthoquinone
antibiotics such as the quanoliranes, capomycins, urdamycins,
nucleus at C-8. There was some confusion when Tanaka et al.4,5
reported the isolation and structure of an antitumour agent
lactoquinomycin and suggested that medermycin could be an
amicenomycins, and saquayamicins in which the C-glycoside
linkage is ortho to a phenolic group,14 our synthetic programme
provides access to a range of C-glycosidic pyranonaphtho-
isomer of lactoquinomycin based on apparent differences in
quinones related to medermycin 1 that can be evaluated for
their physicochemical properties and biological activities. This
biological activity.
was resolved, however, when a synthesis of medermycin by
To date only one synthesis of medermycin 2 has been
Tatsuta et al.6 allowed comparison of the synthetic and natural
reported6 in which the pyranonaphthalene skeleton was
samples thereby establishing that all three samples were identi-
assembled by addition of a C-glycosylsulfonylphthalide to an
enone. Substantial functional group manipulation was required
after construction of the C-glycoside linkage in order to access
the required -angolosaminide moiety and the dimethylamino
cal. Lactoquinomycin/medermycin were also shown to inhibit
platelet aggregation.7
The situation recently changed when Morin and co-workers8
provided chemical and spectroscopic evidence that necessitated
the original structure of medermycin be revised to structure 2
wherein the C-glycoside is attached to the kalafungin skeleton
at the C-10 position para to the hydroxyl group. Morin and co-
group on the sugar was introduced in low yield in the final steps
of the synthesis. We herein report the full details13 of our syn-
thesis of an azido analogue of medermycin 1 using a furofuran
annulation – oxidative rearrangement strategy as previously
workers8 also established that Tatsuta et al.6 had in fact in-
used for the synthesis of kalafungin 315 and related aglycones.16
advertantly synthesized medermycin with the revised structure 2
although Tatsuta et al.6 had initially claimed a synthesis of
medermycin with the original structure 1. These recent studies
Results and discussion
In our approach to the synthesis of the original structure of
medermycin 1 we required a flexible strategy for construction of
the C-glycoside moiety ortho to the phenolic group that was
by Morin and co-workers8 also suggested revision of the previ-
ous structures for the related C-glycosyl pyranonaphtho-
quinone antibiotics lactoquinomycin B9 and menoxymycin A10
to structures 4 and 5, respectively. However, more recently
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 9 0 – 1 7 0 0
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Scheme 1
sugar 11 provides C-glycosylnaphthalene 10 that serves as an
appropriate precursor to the key C-glycosyl acetylnaphthoquin-
one 8 required for the furofuran annulation with 2-trimethyl-
silyloxyfuran 9 providing adduct 7 that undergoes oxidative
rearrangement to pyranonaphthoquinone 6.
Preliminary investigations17 established the necessity to use
an azido group as a latent dimethylamino group in the glycosyl
donor 11 due to problems encountered with quaternization of
the dimethylamino group when undertaking further manipu-
lation of the naphthol fragment after the C-glycosylation step.
Furthermore it was also found17 that use of 5-hydroxy-1,4-di-
methoxynaphthalene 12 was essential to ensure good yields in
the C-glycosylation step in that use of naphthols further substi-
tuted at C-3, only afforded low yields of the desired C-glyco-
sides. Our synthetic strategy therefore focused on introduction
of a bromine at C-3 of the initial C-glycoside 10 in preparation
for subsequent introduction of an acetyl group at C-3 in
naphthoquinone 8 which is essential for effective regiocontrol in
the ensuing furofuran annulation step. Whilst direct C-glyco-
sylation of 3-acetyl-5-hydroxy-1,4-dimethoxynaphthalene 13 or
3-bromo-5-hydroxy-1,4-dimethoxynaphthalene 14 with glyco-
syl donor 11 would have provided a more direct approach, the
low yields observed in the C-glycosylation step using these
naphthols precluded this strategy.17
Glycosyl donor 11 was readily prepared17 from di-O-acetyl-
-rhamnal by adaptation of existing methodology for the syn-
thesis of the -isomer reported by Monneret and co-workers.18
After substantial experimentation17 to evaluate the optimum
method for effecting the key C-glycosylation19 step, arylation
of azido C-glycosyl donor 11 with naphthol 1212 was optim-
ally achieved in 60% yield using two equivalents of boron tri-
fluoride (2.0 equiv.) in acetonitrile at 0 ЊC. Treatment of
the resultant C-glycoside 15 with sodium hydride and methyl
iodide in DMF then afforded methyl ether 10 in 82% yield
(Scheme 2).
amenable to the construction of other analogues with varying
C-glycoside moieties. A synthesis of an azido analogue 6 of
medermycin was realized based on the retrosynthesis outlined
(Scheme 1). Direct C-glycosylation of naphthol 12 with azido
The next challenge in the synthesis was the introduction of a
bromine substituent at C-3. It was envisaged that the resulting
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 9 0 – 1 7 0 0
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Scheme 2 Reagents, conditions and yields: (i) BF3ؒEt2O (2.0 equiv.), CH3CN, 0 ЊC (60%); (ii) NaH, DMF, MeI, 0 ЊC (82%); (iii) NBS (1.0 equiv.),
CH2Cl2, 1.5 h (73%); (iv) (NH4)2Ce(NO3)6 (2.5 equiv.), CH3CN, 5 min, (99%); (v) (α-ethoxyvinyl)tributylstannane (1.1. equiv.), Pd(PPh3)4, CuBr, 1,4-
dioxane, 100 ЊC, 50 min, then CH2Cl2, aq. Na2S2O4, then 0.5 M HCl (71%); (vi) Ag2O, Et2O; (vii) 9 (2.0 equiv.), CH3CN, 0 ЊC; then SiO2, MeOH,
room temp., 18 h (40% over 2 steps); (viii) (NH4)2Ce(NO3)6 (2.0 equiv.), CH3CN, 5 min (89%).
3-bromonaphthalene 16 would undergo palladium(0)-mediated
coupling with (α-ethoxyvinyl)tributylstannane followed by
hydrolysis to introduce an acetyl group at C-3. In our synthesis
of a 2-deoxyglucosyl analogue of medermycin12 introduction
of a bromine at C-3 was achieved using a five step procedure via
initial oxidation to a naphthoquinone. A substantial improve-
ment was made in the present work when it was found that
C-glycosylnaphthalene 10 underwent regioselective bromin-
ation at C-3 in a single step.
C-Glycosylnaphthalene 10 has three sites where electrophilic
attack might occur. It was expected that bromination would
predominate at C-3 and C-2 due to the presence of two elec-
tron-donating methoxyl substituents on the right-hand ring.
Furthermore, the C-5 methoxy group is expected to favour C-3
bromination when resonance structures for the cationic inter-
mediates are considered.
In the event, bromination of 10 occurred smoothly using
N-bromosuccinimide in dichloromethane to give the desired
3-bromonaphthalene 16 in 73% yield and 2-bromonaphthalene
21 in 20% yield after column chromatography (Scheme 3). None
of the C-8 brominated product was observed. High resolution
mass spectrometry established the molecular formula C21H24-
N3O6Br for the major regioisomer 16. The mass spectrum
featured two peaks of approximately equal intensity at m/z 493
and m/z 495, consistent with the introduction of a bromine
atom. The 1H NMR spectrum featured a one-proton singlet at
δ 6.94, which was assigned to 2-H. 7-H and 8-H both resonated
as doublets with J7,8 8.8 Hz, at δ 8.05 and δ 7.59 respectively.
Accurate mass determination also established the molecular
formula C21H24N3O6Br for the minor regioisomer 21. A one-
proton singlet observed at δ 6.94 in the 1H NMR spectrum was
assigned to 3-H. 7-H and 8-H resonated as doublets at δ 7.90
and δ 7.64 respectively.
Unambiguous confirmation of the regiochemical assignment
of the major regioisomer was achieved by preparing 3-brom-
onaphthalene 16 via an independent route (Scheme 4). Thus,
oxidative methylation of trimethoxynaphthalene 10 afforded
naphthoquinone 22 which underwent reductive monomethyl-
ation to naphthol 23. Selective ortho-bromination of naphthol
23 then afforded 3-bromonaphthol 24 that upon methylation
1
furnished 3-bromotrimethoxynaphthalene 16 for which the H
NMR spectrum was identical to the major bromide obtained
from the one-step bromination of 10.
It was found that the 2-bromo regioisomer 21 could be
efficiently recycled by performing a lithium–bromine exchange
using 1.0 equivalent of n-butyllithium in tetrahydrofuran
and quenching the resulting aryllithium with water to give
debrominated compound 10 which could then be recycled into
the synthesis. Surprisingly, the acetyl group survived this oper-
ation intact, although it was found that by-products of higher
polarity (and lower yields of 10) were obtained when excess
n-butyllithium was used.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 9 0 – 1 7 0 0
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Scheme 3 Reagents, conditions and yields: (i) NBS (1.0 equiv.), CH2Cl2, 1.5 h, 16 (73%), 21 (20%); (ii) BuLi, Ϫ78 ЊC to 0 ЊC, 1 h, then H2O, 82%.
Scheme 4 Reagents, conditions and yields: (i) (NH4)2Ce(NO3)6, CH3CN, H2O (71%); (ii) NaS2O6, H2O, Et2O; (iii) K2CO3, MeI, acetone; (iv) Br2,
CCl4; (v) NaH, Me2SO4 42% over 4 steps.
Since it was apparent from the reaction with N-bromo-
succinimide that electrophilic attack on naphthalene 10 occurs
preferentially at C-3, an electrophilic acylation strategy was
investigated as a method to introduce an acetyl group at C-3 on
naphthalene 10 which would obviate the need to proceed via
bromide 16. Towards this goal a variety of acetylation pro-
cedures were investigated. Initially attention focused on the
use of an acetic acid–trifluoroacetic anhydride system,20 which
has previously been used successfully to acetylate related poly-
alkoxynaphthalenes.21 Unfortunately, naphthalene 10 proved
totally unreactive towards this system, even at elevated temper-
atures. Friedel–Crafts acetylation using acetyl chloride and
aluminium chloride in dichloromethane also failed, with some
decomposition observed using this system at elevated temper-
atures. Finally, 10 was exposed to the highly reactive mixed
anhydride, acetyl triflate 22 at Ϫ40 ЊC, which disappointingly
only afforded recovered starting material 10. The very poor
reactivity of naphthalene 10 towards acetylation was disappoint-
ing and our attention therefore turned to the palladium(0)-
mediated coupling of bromonaphthalene 10 with (α-ethoxy-
vinyl)tributylstannane23 as a method for introduction of the
required acetyl group.
Despite extensive experimentation, attempts to convert the
bromide in naphthalene 16 to an acetyl group via Stille coupling
with (α-ethoxyvinyl)tributylstannane followed by acidic
hydrolysis of the enol ether intermediate mainly resulted in
recovered starting material. This outcome was disappointing
given that an analogous transformation had been successfully
achieved in the synthesis of a 2-deoxyglucosyl analogue of
medermycin in which the C-glycoside lacked an azide group.
Even when the bidentate ligand 1,1Ј-bis(diphenylphosphino)-
ferrocene (dppf )24 was used, very little reaction had occurred
after 18 h and the starting bromide 16 was recovered in 92%
yield. It was postulated that the phosphine ligands of the
catalyst were undergoing a Staudinger reaction25 with the azide
function at C-3Ј. The Staudinger reaction is commonly used as
a chemoselective method for the reduction of azides to primary
amines. This hypothesis suggested that a superior coupling
method might be achieved if the azide group were converted
into a dimethylamino group prior to the Stille coupling.
Reduction of the azide group in C-glycoside 16 to an amine
with retention of the bromine was achieved via hydrogenation
over platinum() oxide in methanol. The acetate group at C-4Ј
was cleaved under these conditions affording amino-C-glyco-
side 25 in high yield (Scheme 5). Primary amine 25 was then
converted to dimethylamino derivative 26 using sodium boro-
hydride in acetonitrile at room temperature. With bromide
26 in hand, it was then disappointing to find that attempted
Stille coupling–hydrolysis to 3-acetylnaphthalene 27 prior to
oxidation to the desired naphthoquinone 28 was unsuccessful.
Despite the use of many sets of conditions including the use of
copper() co-catalysts26 to effect this reaction only recovered
bromide 26 was obtained.
In Stille reactions the oxidative addition to palladium(0) is
usually the rate determining step and electron rich bromides
such as 16 and 26 provide lower yields of coupled products than
aryl bromides with electron withdrawing substituents.27 Ortho
substituents have also been proposed to coordinate to the
palladium center with a detrimental effect on the rate of cross-
coupling.27 In the present work it was therefore decided that the
best way to improve the Stille reaction was to use a more
reactive bromide coupling partner which prompted the use of
bromoquinones 17 and 29 for this reaction (Schemes 2,6). The
use of simple 2- and 3-bromonaphthoquinones as electrophiles
in palladium()- and copper()-catalyzed Stille couplings with
various aryl, vinyl and alkyl stannanes has been successfully
achieved by Echavarren et al.28
The viability of using C-glycosylnaphthoquinone 29 as coup-
ling partner was first investigated (Scheme 6) in that use of
bromonaphthoquinone 29 would obviate the need to carry out
the reduction of the azide to a dimethylamino group at a later
stage. Bromonaphthalene 26 was therefore oxidized using ceric
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 9 0 – 1 7 0 0
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Scheme 5 Reagents, conditions and yields: (i) PtO2, H2, MeOH, 24 h (99%); (ii) NaCNBH3, H2CO, CH3CN (93%).
analysis of the reaction indicated that complete consumption
of starting material had occurred within 50 min and the reac-
tion mixture was then subjected to a reductive hydrolysis with
sodium dithionite and 0.5 M hydrochloric acid. Care was taken
to ensure extraction of the tertiary amine product by treatment
of the aqueous phase with sodium bicarbonate, however, dis-
appointingly only a 22% yield of acetyl hydroquinone 30 was
obtained.
The high resolution mass spectrum of compound 30 con-
tained a molecular ion at m/z 389.1841, establishing the molecu-
lar formula C21H27NO6. A strong peak at 1625 cmϪ1 in the
infrared spectrum was assigned to the ortho-hydroxy ketone. A
singlet in the 1H NMR spectrum at δ 7.06 was assigned to 2-H
and 7-H and 8-H resonated as mutually coupled doublets, at
δ 7.99 and δ 7.74 respectively. In the 13C NMR spectrum a new
peak at δ 205.0 was consistent with the introduction of a methyl
ketone.
Bromoquinone 29 was poorly soluble in 1,4-dioxane (and
even less soluble in toluene, another reaction solvent commonly
used to effect Stille couplings), suggesting that more efficient
coupling might depend on solubilising 29 in the reaction
medium. To this end, a coupling experiment was attempted
using dimethylsulfoxide as an additive; however, this led to no
improvement in yield. In other experiments attention was paid
to exhaustive extraction of the aqueous phases with a variety of
organic solvents. However, the initial yield of 22% was not
improved. Frustratingly, the success of the reaction even when
using the optimized conditions appeared to be highly variable.
These problems were exacerbated when attempts to oxidize C-
glycosylhydroquinone 30 to the key naphthoquinone 28 using
silver() oxide, manganese() oxide and ceric ammonium
nitrate afforded only complex mixtures.
These latter disappointing results forced us to return to the
use of azido C-glycosylbromonaphthoquinone 17 (Scheme 2)
as the electrophilic coupling partner for the Stille reaction.
Thus, treatment of 3-bromonaphthalene 16 with ceric ammo-
nium nitrate afforded bromonaphthoquinone 17 in high yield.
High resolution mass spectrometry established the molecular
formula C19H18N3O6Br for compound 16 and the infrared spec-
trum revealed a strong band at 1673 cmϪ1, attributed to the
1
quinone carbonyl groups. In the H NMR spectrum a single
Scheme 6 Reagents, conditions and yields: (i) CAN (2.5 equiv.),
CH3CN, 5 min (85%); (ii) (α-ethoxyvinyl)tributylstannane (1.1 equiv.),
Pd(PPh3)4, CuBr, 1,4-dioxane, 100 ЊC, 50 min; then CH2Cl2, aq.
Na2S2O4, then 0.5 M HCl (22%).
methoxy group resonated at δ 3.93, consistent with oxidative
demethylation, while a large downfield shift was observed for
2-H, which resonated at δ 7.50. 7-H and 8-H resonated as an
unresolved multiplet at δ 7.96–7.91. In the 13C NMR spectrum,
two peaks attributed to the quinone carbonyl carbons were
observed at δ 182.6 and δ 177.1. Retention of bromine was
evident in the mass spectrum, which exhibited two molecular
ions of approximately equal intensity at m/z 465 and 463.
ammonium nitrate to give the desired naphthoquinone 29 in
85% yield after chromatography. Coupling of bromoquinone 29
with (α-ethoxyvinyl)tributylstannane was then attempted using
Pd(PPh3)4 and copper() bromide in 1,4-dioxane at 100 ЊC. TLC
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 9 0 – 1 7 0 0
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Stille coupling of bromonaphthoquinone17 with (α-ethoxy-
vinyl)tributylstannane proceeded smoothly and bromo-
naphthoquinone 17 was entirely consumed within 50 min
(Scheme 2). After treatment with aqueous dithionite and
hydrochloric acid the desired acetylhydroquinone 18 was fur-
nished in 71% yield after chromatography. This compound was
somewhat unstable on silica, and it was very important to use as
small a column as possible, in conjunction with a fast eluent
(hexanes–ethyl acetate, 1 : 1) in order to obtain this optimum
yield. The high resolution mass spectrum of compound 18 con-
tained a molecular ion at m/z 429.1549, establishing the molecu-
lar formula C21H23N3O7. A strong peak in the infrared spectrum
at 1626 cmϪ1 was consistent with the presence of the carbonyl
signal at δ 2.34 was assigned to 2eqЈ*-H. 2axЈ-H and 2axЈ*-H
resonated at δ 1.71 and 1.78 respectively, while 1Ј-H and 1Ј*-H
gave rise to doublets of doublets at δ 5.01 and 5.04 respectively.
1
This H NMR data did not allow individual resonances to be
assigned to either 7 or 19.
The 13C NMR spectrum was also complicated by splitting of
peaks due to the presence of two diastereomers although where
chemical shift differences were observed they were small, typi-
cally of the order of 0.1–0.2 ppm. A comparison of key carbon
resonances with those obtained for similar 2-deoxyglucosyl
furonaphthofuran adducts12 was consistent with the proposed
structure.
With the furonaphthofuran adducts 7 and 19 in hand as a
1 : 1 mixture of diastereomers, attention next turned to the
oxidative rearrangement step (Scheme 2). The reaction pro-
ceeded smoothly using ceric ammonium nitrate in aqueous
acetonitrile to give a mixture of the diastereomeric lactols 6 and
20 in 89% yield, and in a 1 : 1 ratio as measured by analysis of
the 1H NMR spectrum. The crude material was of satisfactory
1
group of an ortho hydroxy aromatic ketone. In the H NMR
spectrum, 2-H resonated as a singlet at δ 7.00, while two mutu-
ally coupled doublets at δ 7.94 and δ 7.73 (J7,8 8.7 Hz) were
assigned to 7-H and 8-H respectively. Inspection of the 13C
NMR spectrum revealed the loss of the two quinone carbons
and the appearance of a peak at δ 204.5, which was assigned to
the ketone carbonyl.
1
purity based on inspection of the H NMR spectrum, which
3-Acetylhydroquinone 18 was then oxidized to 3-acetylnaph-
thoquinone 8 using silver() oxide in diethyl ether (Scheme 2),
however, attempts to purify 3-acetylnaphthoquinone 8 were
fruitless and severe decomposition occurred upon attempted
purification by chromatography. Use of flash silica pre-treated
with triethylamine made little or no difference to the outcome.
Quinone 8 also appeared to be somewhat unstable in solution,
and underwent decomposition during storage; the material was
therefore used immediately in crude form for the subsequent
reaction with 2-trimethylsilyloxyfuran 9.
With the key naphthoquinone 8 in hand, albeit in crude
form, attention shifted to the final phase of the synthesis
namely, use of a 2-trimethylsilyloxyfuran addition–oxidative
rearrangement strategy to establish the pyranonaphthoquinone
skeleton present in medermycin 1 (Scheme 2). Towards this end,
2-trimethysilyloxyfuran 9 (2.0 equiv.) was added to a solution
of C-glycosylnaphthoquinone 8 in acetonitrile at 0 ЊC. After an
hour a small amount of methanol and silica were added
and the mixture was left to stir at room temperature overnight.
Subsequent work up and chromatography afforded a mixture
of furonaphthofurans 7 and 19 in 40% yield. The ratio of
diastereomers 7 : 19 was 1 : 1 as determined by 1H NMR analy-
sis. In some experiments this ratio was somewhat less (or more)
than 1 : 1, probably due to discarding of impure early or late
fractions during chromatography. Purification was difficult due
to the instability of adducts 7 and 19 on silica gel.
Accurate mass determination established the molecular
formula C25H25N3O9 for the mixture of adducts 7 and 19. The
infrared spectrum featured a broad band at 3502 cmϪ1, which
was assigned to the hydroxyl group and a strong band at 1775
cmϪ1 was assigned to the newly introduced γ-lactone carbonyl.
The 1H NMR spectrum was complicated by the presence of the
two diastereomers. The bridgehead proton 6b-H resonated as a
doublet at δ 6.45 (J6b,9a 6.3 Hz), while the corresponding signal
for the diastereomeric proton 6b*-H appeared as a doublet at
δ 6.46 (J6b*,9a* 6.3 Hz). The other bridgehead protons H-9a and
H-9a* overlapped to give an unresolved multiplet at δ 5.53–5.50.
The coupling constant J6b,9a 6.3 Hz was consistent with the
proposed formation of a cis-fused 2H-furo[3,2-b]naphtho-
[2,3-d]furan ring system.12,15 An unresolved multiplet at δ 3.15–
3.12 was assigned to 9-H and 9*-H. A singlet at δ 2.81 was
assigned to the methyl ketone protons of both diastereomers. In
one diastereomer 1-H and 2-H resonated as mutually coupled
doublets at δ 7.80 and 7.73 respectively, while in the other
diastereomer 1*-H and 2*-H gave rise to separate resonances at
δ 7.79 and 7.75 respectively. Resonances for certain protons on
the azido sugar moiety also exhibited chemical shift differences
between the two diastereomers, for example a doublet of doub-
lets of doublets at δ 2.38 (J2Јeq,1Ј 1.9 Hz, J2Јeq,3Ј 4.9 Hz and J2Јeq,2Јax
13.2 Hz) was assigned to 2eqЈ-H, whereas a virtually identical
was fortuitous given that attempts to purify lactols 6 and 20 by
conducting chromatography using solvents chilled to Ϫ30 ЊC
were unsuccessful due to severe decomposition of the lactols on
the column. By necessity, therefore, the two diastereomers 6 and
20 were characterized as an inseparable 1 : 1 mixture.
The high resolution mass spectrum of lactols 6 and 20 con-
tained a molecular ion at m/z 527.1526, confirming the molecu-
lar formula C25H25N3O10. The infrared spectrum contained a
broad band at 3417 cmϪ1, which was assigned to the OH
stretch. Strong bands at 1774, 1743 and 1668 cmϪ1 were
assigned to the γ-lactone, acetate and quinone carbonyls
1
respectively. As expected, the H NMR spectrum was compli-
cated by the presence of two diastereomers. The geminal pro-
tons 3A-H and 3B-H gave rise to doublets at δ 2.95 and δ 2.74
respectively, with coupling constant, J3A,3B 20.2 Hz. The analo-
gous protons 3A*-H and 3B*-H in the alternative diastereomer
gave rise to separate signals slightly further upfield. Doublets at
δ 5.27 and δ 5.28 were assigned to the bridgehead protons 11b-H
and 11b*-H respectively. The resonances for 3a-H and 3a*-H
overlapped and appeared as an unresolved multiplet at δ 4.91–
4.85. The coupling constant observed for J11b,3a was 2.8 Hz
in both diastereomers, which is consistent with the presence
of a cis-fused 2H-furo[3,2-b]naphtho[2,3-d]pyran system.12,15
A distinct separation of the methoxy resonances for the two
diastereomers was observed with the appearance of two singlets
at δ 3.94 (OMe) and 3.88 (OMe*), while the methyl ketone
groups for the two diastereomers were coincident resonating as
a singlet at δ 1.80. Differences between the two diastereomers
were also observed in the chemical shifts of certain protons on
the azido sugar moiety, although 1Ј-H and 1Ј*-H together gave
rise to a broad multiplet at δ 5.13–5.07. 2Јeq-H and 2Јeq*-H
resonated at δ 2.38 and δ 2.43 respectively, while the axial
protons 2Јax-H and 2Јax*-H gave rise to overlapping signals at
δ 1.66–1.54.
The 13C NMR spectrum was likewise complicated by the
doubling up of many signals due to the presence of the two
diastereomers and was consistent with that reported for related
compounds.12,15 Only two diastereomers were evident in the 1H
and 13C NMR spectra, indicating that only one relative con-
figuration at the lactol carbon was present. The assignment
made in the present case places the hydroxyl group axial, where
additional stability is gained from the anomeric effect.29 This
1
assignment was supported by the comparison of the H NMR
chemical shifts for the bridgehead proton 3a-H and the 5-Me
group, with those observed for 2-deoxyglucosyl analogues.12
With lactols 6 and 20 in hand, it was hoped that subsequent
reduction with triethylsilane and trifluoracetic acid would
afford the diastereomeric ethers 31 and 32 (Scheme 7) in
which axial delivery of hydride takes place as reported by
Kraus et al.30 Despite carrying out this reaction at Ϫ10 ЊC over
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 9 0 – 1 7 0 0
1695

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Scheme 7 Reagents, conditions and yields: (i) CF3CO2H, Et3SiH, CH2Cl2, Ϫ10 ЊC, 72 h; (ii) H2, Pd-C, MeOH then H2CO, NaBH3CN–ZnCl2, MeOH
then CH2N2.
three days using a similar procedure developed for the capri-
cious reduction of similar 2-deoxyglucosyl lactols,12 it was dis-
appointing to only observe substantial decomposition to base-
line materials in this case.
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 spectro-
meter operating with an ionisation potential of 70eV (EI, DEI,
CI and DCI). High resolution mass spectra were recorded at
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 ionis-
ation 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. Thin layer chromatography (TLC) was per-
formed using 0.2 mm thick pre-coated silica gel plates (Merck
Kieselgel 60 F254 or Riedel-de Haen Kieselgel S F254). Com-
pounds were visualised by ultraviolet fluorescence or by stain-
ing with iodine or vanillin in methanolic sulfuric acid. Optical
rotations were recorded on an Optical Activity POLAAR 2001
polarimeter using a 5 dmϪ3 cell. Samples were prepared in the
solvent indicated at the concentration specified (measured in g
100 cmϪ3).
A second approach to the reduction of lactols 6 and 20, made
use of catalytic hydrogenation as successfully used for the syn-
thesis of deoxyfrenolicin.31 It was envisaged that catalytic
hydrogenation of lactols 6 and 20 would effect reduction of
the azide group to an amino group and hydrogenolysis of
the γ-lactone to a carboxylic acid that would undergo esterifi-
cation with diazomethane to afford esters 33 and 34 after
‘in situ’ reductive methylation of the resultant amino function-
ality. With these ideas in mind, lactols 6 and 20 were sub-
jected to catalytic hydrogenation over palladium on charcoal
in methanol for three hours. After filtration to remove the
catalyst, aqueous formaldehyde and zinc-modified cyano-
borohydride in methanol were added to effect reductive methyl-
ation. Finally after 6 h, the reaction mixture was treated with
excess diazomethane, however, this procedure resulted in
substantial loss of material and the formation of several prod-
ucts presumably due to the competitive formation of quinone
methide intermediates upon reduction of the quinone to a
hydroquinone.
In summary, an efficient synthesis of azido C-glycosylpyrano-
naphthoquinones 6 and 20 has been achieved providing
analogues of the naturally occurring antibiotic medermycin 1
for biological evaluation. In light of the difficulties experienced
with the final reduction of the azide and lactol groups in 6 and
20, the work reported herein has necessitated a change in
direction for our synthesis of medermycin 1.
6-(4Ј-O-Acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-hexo-
pyranosyl)-1,4,5-trimethoxynaphthalene 10
To a cooled (0 ЊC) solution of C-glycosylnaphthol 1517 (1.52 g,
3.79 mmol) in N,N-dimethylformamide (50 mL) was added
sodium hydride (228 mg of a 60% dispersion in oil, 5.75 mmol).
The mixture was stirred at 0 ЊC under an atmosphere of nitro-
gen for 5 min then methyl iodide (1.22 mL, 37.9 mmol) was
added dropwise. The mixture was stirred for a further 2 h then
quenched with water (100 mL) and extracted with dichloro-
methane (3 × 100 mL). The combined organic phases were
washed with water (3 × 100 mL), dried over anhydrous sodium
sulfate and concentrated in vacuo. Purification by flash col-
umn chromatography (hexanes–ethyl acetate, 3 : 1 as eluent)
gave 6-(4Ј-O-acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-β--arabino-hex-
opyranosyl)-1,4,5-trimethoxynaphthalene 10 (1.25 g, 82%) as a
pale foam (Found: C, 60.9; H, 5.9; N, 9.8%; Mϩ, 415.1740.
C21H25N3O6 requires: C, 60.7, H, 6.1, N, 10.1%; M, 415.1743);
[α]2D2 ϩ16.9 (c 0.5 in CH2Cl2); νmax(film)/cmϪ1 2935, 2835, 2096
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 an 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 tem-
perature with complete proton decoupling. When NMR data
(N ), 1746 (C᎐O), 1602, 1584, 1414, 1351 and 1260; δ (400
᎐
3
H
MHz; CDCl3) 1.28 (3 H, d, J6Ј,5Ј 6.2, 6Ј-H), 1.83 (1 H, ddd,
J2Јax,1Ј = J2Јax,3Ј 11.2 and J2Јax,2Јeq 13.2, 2Јax-H), 2.16 (3 H, s, OAc),
2.35 (1 H, ddd, J2Јeq,1Ј 1.6, J2Јeq,2Јax 13.2 and J2Јeq,3Ј 4.8, 2Јeq-H),
3.60–3.66 (2 H, m, 3Ј-H and 5Ј-H), 3.85 (3 H, s, OMe), 3.94
(3 H, s, OMe), 3.96 (3 H, s, OMe), 4.80 (1 H, dd, J4Ј,3Ј = J4Ј,5Ј 9.6,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 9 0 – 1 7 0 0
1696

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4Ј-H), 5.06 (1 H, dd, J1Ј,2Јax 11.2 and J1Ј,2Јeq 1.6, 1Ј-H), 6.73 (1 H,
d, J3,2 8.5, 3-H), 6.79 (1 H, d, J2,3 8.5, 2-H), 7.58 (1 H, d, J8,7 8.8,
8-H) and 8.07 (1 H, d, J7,8 8.8, 7-H); δC(100 MHz; CDCl3) 18.7,
21.6, 38.6, 56.6, 57.4, 62.4, 63.7, 73.0, 75.6, 76.2, 104.8, 107.0,
119.6, 121.1, 124.5, 129.3, 131.6, 150.4, 150.5, 153.2 and 170.9;
m/z (EI) 415 (Mϩ, 2%), 401 (2), 388 (52), 387 (100), 300 (12),
284 (17), 255 (19), 247 (17), 246 (51), 244 (71), 231 (45), 229
(49), 215 (23) and 201 (25).
sodium hydrogen carbonate solution (5 mL). The mixture was
extracted with diethyl ether (2 × 10 mL), and the combined
ethereal phases were washed with water (10 mL), dried over
anhydrous sodium sulfate and concentrated in vacuo. The resi-
due was purified by flash column chromatography (hexanes–
ethyl acetate 4 : 1) to give 6-(4Ј-O-acetyl-3Ј-azido-2Ј,3Ј,6Ј-tride-
oxy-β--arabino-hexopyranosyl)-1,4,5-trimethoxynaphthalene
10 (34 mg, 82%) as a pale foam. The 1H NMR data was identi-
cal to that reported above.
6-(4Ј-O-Acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-hexo-
pyranosyl)-3-bromo-1,4,5-trimethoxynaphthalene 16 and 6-(4Ј-
O-acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-hexopyranosyl)-
2-bromo-1,4,5-trimethoxynaphthalene 21
6-(3Ј-Amino-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-hexopyranosyl)-3-
bromo-1,4,5-trimethoxynaphthalene 25
To a solution of C-glycosyl-3-bromonaphthalene 16 (318 mg,
0.644 mmol) in methanol (20 mL) was added platinum()
oxide hydrate (32 mg). The reaction vessel was placed under
vacuum using a water aspirator, and the atmosphere was
replaced with hydrogen by means of a balloon. This purging
process was repeated two times. The reaction mixture was
stirred under an atmosphere of hydrogen for 24 h before being
filtered through Celite and concentrated in vacuo. Purification
by flash column chromatography (dichloromethane–methanol,
4 : 1 as eluent) gave 6-(3Ј-amino-2Ј,3Ј,6Ј-trideoxy-β--arabino-
hexopyranosyl)-3-bromo-1,4,5-trimethoxynaphthalene 25 (280
mg, 99%) as a pale foam (Found: Mϩ, 425.0837 and 427.0825.
C19H24NO5Br requires M, 425.0838 and 427.0817); [α]2D2 ϩ27.2
(c 0.4 in CH3OH); νmax (film)/cmϪ1 3354 (NH, OH), 2932, 1588
and 1328; δH(400 MHz; CD3OD) 1.34 (3 H, d, J6Ј,5Ј 6.1, 6Ј-H);
1.66 (1 H, ddd, J2Јax,1Ј = J2Јax,3Ј 11.3 and J2Јax,2Јeq 13.2, 2Јax-H), 2.15
(1 H, ddd, J2Јeq,1Ј 1.8, J2Јeq,3Ј 4.1 and J2Јeq,2Јax 13.2, 2Јeq-H), 2.98–
2.95 (1 H, m, 3-HЈ), 2.99 (1 H, dd, J4Ј,3Ј = J4Ј,5Ј 9.2, 4Ј-H), 3.51–
3.47 (1 H, m, 5Ј-H), 3.80 (3 H, s, OMe), 3.83 (3 H, s, OMe), 3.96
(3 H, s, OMe), 5.10 (1 H, dd, J1Ј,2Јax 11.3 and J1Ј,2Јeq 1.8, 1Ј-H),
7.04 (1 H, s, 2-H), 7.61 (1 H, d, J8,7 8.9, 8-H) and 8.02 (1 H, d,
J7,8 8.9, 7-H); δC(100 MHz; CD3OD) 17.2, 39.7, 54.0, 55.1, 60.7,
62.3, 72.1, 76.9, 77.4, 108.2, 114.6, 118.5, 122.8, 124.2, 127.5,
133.5, 145.4, 151.1 and 152.1; m/z (EI) 427/425 (Mϩ, 26%), 396/
To a solution of naphthalene 10 (379 mg, 0.912 mmol) in
dichloromethane (15 mL) was added N-bromosuccinimide
(163 mg, 0.916 mmol) in a single portion. The mixture was
stirred for 90 min, then quenched with saturated sodium sulfite
solution (10 mL) and stirred for an additional 5 min. The
phases were separated, and the aqueous phase was extracted
with dichloromethane (5 mL). The combined organic phases
were then washed with water (10 mL), dried over anhydrous
sodium sulfate and concentrated in vacuo. Purification by
flash column chromatography (hexanes–ethyl acetate, 85 : 15)
afforded the following:
(i) 6-(4Ј-O-Acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-
hexopyranosyl)-3-bromo-1,4,5- trimethoxynaphthalene 16. (328
mg, 73%) as a pale yellow foam (Found (EI): Mϩ, 493.0850 and
495.0837. C21H24N3O6Br requires M, 493.0848 and 495.08280);
[α]2D2 ϩ23.9 (c 0.4 in CH2Cl2); νmax (film)/cmϪ1 2923, 2850,
2098 (N ), 1744 (C᎐O), 1588, 1458, 1329 and 1226; δ (400
᎐
3
H
MHz; CDCl3) 1.28 (3 H, d, J6Ј,5Ј 6.2, 6Ј-H), 1.84 (1 H, ddd,
J2Јax,1Ј = J2Јax,3Ј 11.4 and J2Јax,2Јeq 13.2, 2Јax-H), 2.17 (3 H, s, OAc),
2.32 (1 H, ddd, J2Јeq,1Ј 2.0, J2Јeq,2Јax 13.2 and J2Јeq,3Ј 4.9, 2Јeq-H),
3.81–3.65 (2 H, m, 3Ј-H and 5Ј-H), 3.83 (3 H, s, OMe), 3.86
(3 H, s, OMe), 3.96 (3 H, s, OMe), 4.82 (1 H, dd, J4Ј,3Ј = J4Ј,5Ј 9.6,
4Ј-H), 5.08 (1 H, dd, J1Ј,2Јax 11.4 and J1Ј,2Јeq 2.0, 1Ј-H), 6.94 (1 H,
s, 2-H), 7.59 (1 H, d, J8,7 8.8, 8-H) and 8.05 (d, 1H, J7,8 8.8,
H-7); δC(100 MHz; CDCl3) 18.0, 20.9, 38.0, 56.0, 61.7, 61.8,
63.4, 72.0, 75.0, 75.4, 108.8, 115.1, 119.5, 123.0, 124.0, 127.9,
132.2, 145.6, 151.2, 152.2 and 170.1; m/z (EI) 495/493 (Mϩ,
49%), 467/465 (M Ϫ N2, 7), 324 (14), 309 (12), 178 (18) and 43
(100).
394 (M᎐OMe, 100), 352/350 (24), 338/336 (43), 322/320 (91),
᎐
311/309 (30) and 213 (29).
3-Bromo-6-(3Ј-dimethylamino-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-
hexopyranosyl)-1,4,5-trimethoxynaphthalene 26
To a solution of C-glycosyl-3-bromonaphthalene 25 (280 mg,
0.657 mmol) in acetonitrile (5 mL) was added aqueous form-
aldehyde (36%, 1.02 mL, 13.2 mmol), followed by sodium
cyanoborohydride (132 mg, 2.10 mmol). After 15 min the solu-
tion was found to be alkaline (tested using red Litmus paper)
and acetic acid was added dropwise until the solution was
nearly neutral. The mixture was stirred for a further 2 h, adjust-
ing the pH with acetic acid as necessary. The reaction mixture
was then diluted with dichloromethane (50 mL) and washed
with saturated sodium hydrogen carbonate solution (2 × 20
mL). The organic phase was then dried over anhydrous sodium
sulfate and concentrated in vacuo. Purification of the residue by
flash column chromatography (ethyl acetate-hexanes, 4:1) gave
3-bromo-6-(3Ј-dimethylamino-2Ј,3Ј,6Ј-trideoxy-β--arabino-
hexopyranosyl)-1,4,5-trimethoxynaphthalene 26 (270 mg, 93%)
(ii) 6-(4Ј-O-Acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-
hexopyranosyl)-2-bromo-1,4,5- trimethoxynaphthalene 21. (91
mg, 20%) as a yellow oil (Found (EI): Mϩ, 493.0847 and
495.0821. C21H24N3O6Br requires M, 493.0848 and 495.0828);
[α]2D2 ϩ16.4 (c 0.3, CH2Cl2); νmax (film)/cmϪ1 2934, 2840,
2098 (N ), 1746 (C᎐O), 1574, 1447, 1374 and 1227; δ (400
᎐
3
H
MHz; CDCl3) 1.28 (3 H, d, J6Ј,5Ј 6.2, 6Ј-H), 1.82 (1 H, ddd,
J2Јax,1Ј = J2Јax,3Ј 11.3 and J2Јax,2Јeq 13.2, 2Јax-H), 2.17 (3 H, s, OAc),
2.34 (1 H, ddd, J2Јeq,1Ј 1.9, J2Јeq,2Јax 13.2 and J2Јeq,3Ј 4.8, 2Јeq-H),
3.80–3.65 (2 H, m, 3Ј-H and 5Ј-H), 3.83 (3 H, s, OMe), 3.91
(3 H, s, OMe), 3.99 (3 H, s, OMe), 4.80 (1 H, dd, J4Ј,3Ј = J4Ј,5Ј 9.6,
4Ј-H), 5.04 (1 H, dd, J1Ј,2Јax 11.3 and J1Ј,2Јeq 1.9, 1Ј-H), 6.94 (1 H,
s, 6-H), 7.64 (1 H, d, J8,7 8.8, 8-H) and 7.90 (1 H, d, J7,8 8.8,
7-H); δC (100 MHz; CDCl3) 18.7, 21.6, 38.5, 57.2, 62.1, 62.3,
63.9, 72.8, 75.6, 76.1, 110.7, 113.1, 119.7, 120.5, 126.2, 131.8,
132.1, 147.7, 153.3, 153.9 and 170.9; m/z (EI) 495/493 (Mϩ,
100%), 457 (31), 415 (11), 324 (30), 309 (45) and 281 (14).
as
a
pale foam (Found: Mϩ, 453.1156 and 455.1137;
C21H28NO5Br requires M, 453.1154 and 455.1130); [α]2D2 ϩ16.1
(c 1.0 in CH2Cl2); νmax (film)/cmϪ1 3458 (OH), 2932, 2833, 1587
and 1504; δH(400 MHz; CDCl3) 1.43 (3 H, d, J6Ј,5Ј 6.1, 6Ј-H),
1.63 (1 H, ddd, J2Јax,1Ј = J2Јax,3Ј 11.0 and J2Јax,2Јeq 12.7, 2Јax-H), 1.98
(1 H, ddd, J2Јeq,1Ј 2.0, J2Јeq,3Ј 3.6 and J2Јeq,2Јax 12.7, 2Јeq-H), 2.32 (6
H, s, NMe2), 2.77–2.71 (1 H, m, 3Ј-H), 3.23 (1 H, dd, J4Ј,3Ј = J4Ј,5Ј
9.7, 4Ј-H), 3.61–3.56 (1 H, m, 5Ј-H), 3.85 (3 H, s, OMe), 3.86 (1
H, br s, OH ), 3.87 (3 H, s, OMe), 3.96 (3H, s, OMe), 5.07 (1 H,
dd, J1Ј,2Јeq 2.0 and J1Ј,2Јax 11.0, 1Ј-H), 6.93 (1 H, s, 2-H), 7.63 (1 H,
d, J8,7 8.8, 8-H) and 8.04 (1 H, d, J7,8 8.8, 7-H); δC (100 MHz;
CDCl3) 19.5, 29.6, 41.0, 56.7, 62.5, 64.1, 68.2, 72.4, 73.6, 78.4,
109.3, 115.6, 120.0, 123.9, 125.2, 128.4, 134.6, 146.4, 151.8,
Recycling of 2-bromonaphthalene 21
To a cooled (Ϫ78 ЊC) solution of 2-bromonaphthalene 21 (50
mg, 0.101 mmol) in tetrahydrofuran (1 mL) stirring under an
atmosphere of nitrogen was added n-BuLi as a solution in hex-
anes (1.50 M, 71 µL, 0.106 mmol). The mixture was allowed to
warm gradually to 0 ЊC over 1 h, then quenched with saturated
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 9 0 – 1 7 0 0
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152.9; m/z (EI) 453/455 (Mϩ, 9%), 396/394 (11), 326/324 (27),
6-(4Ј-O-Acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-hexo-
311/309 (9) and 71 (100).
pyranosyl)-3-bromo-5-methoxy-1,4-naphthoquinone 17
To a solution of 3-bromonaphthalene 16 (100 mg, 0.202 mmol)
in acetonitrile (10 mL) was added a solution of ceric ammo-
nium nitrate (276 mg, 0.503 mmol) in water (2 mL). After stir-
ring for 5 min, the mixture was diluted with dichloromethane
(50 mL) and washed with water (2 × 50 mL). The organic phase
was dried over anhydrous sodium sulfate and concentrated
in vacuo. Purification by passage through a small plug of flash
silica gel (hexanes–ethyl acetate, 1 : 1 as eluent) afforded 6-(4Ј-
O-acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-β--arabino-hexopyrano-
syl)-3-bromo-5-methoxy-1,4-naphthoquinone 17 (93 mg, 99%)
3-Bromo-6-(3Ј-dimethylamino-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-
hexopyranosyl)-5-methoxy-1,4-naphthoquinone 29
To a solution of bromonaphthalene 26 (306 mg, 0.692 mmol) in
acetonitrile (8 mL) was added a solution of ceric ammonium
nitrate (948 mg, 1.72 mmol) in water (4 mL). After 5 min satur-
ated sodium hydrogen carbonate solution (5 mL) was added,
and the mixture extracted with dichloromethane (2 × 25 mL).
The combined organic phases were washed with a saturated
solution of sodium hydrogen carbonate (20 mL), dried over
anhydrous sodium sulfate and concentrated in vacuo. Purifi-
cation by flash column chromatography (ethyl acetate–hexanes,
4 : 1, short column) afforded 3-bromo-6-(3Ј-dimethylamino-
2Ј,3Ј,6Ј-trideoxy-β--arabino-hexopyranosyl)-5-methoxy-1,4-
naphthoquinone 29 (242 mg, 85%) as a red–brown foam (Found:
Mϩ, 423.0691 and 425.0662. C19H22NO5Br requires M,
423.0681 and 425.0661); [α]2D2 ϩ19.3 (c 0.3 in CH2Cl2); νmax
as
a
bright orange foam (Found (EI): Mϩ, 463.0382.
C19H18N3O679Br requires M, 463.0379); [α]2D2 Ϫ5.9 (c 0.05 in
CH2Cl2); νmax (film)/cmϪ1 2936, 2099 (N ), 1745 (ester C᎐O),
᎐
3
1673 (quinone C᎐O), 1599, 1574 and 1226; δ (400 MHz;
᎐
H
CDCl3) 1.28 (3 H, d, J6Ј,5Ј 6.2, 6Ј-H), 1.60 (1 H, ddd,
J2Јax,1Ј = J2Јax,3Ј 11.3 and J2Јax,2Јeq 13.2, 2Јax-H), 2.41 (1 H, ddd,
J2Јeq,1Ј 2.0, J2Јeq,2Јax 13.2 and J2Јeq,3Ј 4.9, 2Јeq-H), 2.17 (3 H, s, OAc),
3.68–3.64 (1 H, m, 5Ј-H), 3.79–3.73 (1 H, m, 3Ј-H), 3.93 (3 H, s,
OMe), 4.78 (1 H, dd, J4Ј,5Ј = J4Ј,3Ј 9.6, 4Ј-H), 4.89 (1 H, dd, J1Ј,2Јeq
2.0 and J1Ј,2Јax 11.3, 1Ј-H), 7.50 (1 H, s, 2-H) and 7.96–7.91 (2 H,
m, 7-H and 8-H); δC(100 MHz; CDCl3) 18.6, 21.6, 38.2, 62.0,
63.4, 72.6, 75.7, 75.8, 123.2, 124.3, 133.7, 133.9, 139.6, 142.4,
143.4, 158.2, 170.8, 177.1 and 182.6; m/z (EI) 465/463 (Mϩ,
12%), 363/361 (21), 319 (13), 295/293 (59) and 43 (100).
(film)/cmϪ1 3307 (OH), 2937, 2869, 1673 (quinone C᎐O), 1599,
᎐
1574, 1282 and 1082; δH(400 MHz; CDCl3) 1.38 (3 H, d,
J6Ј,5Ј 6.0, 6Ј-H), 1.51 (1 H, ddd, J2Јax,2Јeq 12.1 and J2Јax,1Ј = J2Јax,3Ј
10.6, 2Јax-H), 2.38 (1 H, ddd, J2Јeq,1Ј 1.9, J2Јeq,3Ј 3.9 and J2Јeq,2Јax
12.1, 2Јeq-H), 2.79 (6 H, s, NMe2), 2.81 (1 H, s, OH ), 2.87–2.76
(1 H, m, 3Ј-H), 3.41 (1 H, dd, J4Ј,5Ј = J4Ј,3Ј 9.4, 4Ј-H), 3.61–3.54
(1 H, m, 5Ј-H), 3.88 (3 H, s, OMe), 4.85 (1 H, dd, J1Ј,2Јax 10.6
and J1Ј,2Јeq 1.9, 1Ј-H), 7.87 (2 H, m, 7-H and 8-H) and 7.45 (1 H,
s, 2-H); δC (100 MHz; CDCl3): 17.8, 30.8, 40.0, 62.7, 67.4, 70.0,
71.7, 76.7, 122.5, 123.5, 133.0, 133.2, 138.9, 141.6, 142.4, 157.4,
176.4 and 181.9; m/z (EI) 427/425 (Mϩ, 1%), 394/392 (1), 218 (7)
and 130 (100).
3-Acetyl-6-(4Ј-O-acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-
hexopyranosyl)-1,4-dihydroxy-5-methoxynaphthalene 18
To a solution of bromoquinone 17 (96 mg, 0.207 mmol) in
dioxane (2 mL) was added copper() bromide (1.6 mg, 0.011
mmol), tetrakis(triphenylphosphine)palladium() (12.7 mg,
0.011 mmol) and (α-ethoxyvinyl)tributylstannane32 (80 mg,
0.222 mmol). The reaction was stirred at 100–105 ЊC under an
atmosphere of nitrogen for 50 min, then concentrated in vacuo.
The dark brown oil was dissolved in dichloromethane (10 mL)
and shaken in a separating funnel with a solution of sodium
dithionite (2.1 g) in water (10 mL) for 2 min. The phases were
separated, and the organic phase was washed with hydrochloric
acid (0.5 M, 10 mL) and water (10 mL). The organic phase was
then dried over sodium sulfate, filtered, and concentrated
in vacuo. Purification by flash column chromatography (ethyl
acetate–hexanes, 3 : 2, base-treated silica) gave 3-acetyl-6-(4Ј-
O-acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-β--arabino-hexopyrano-
syl)-1,4-dihydroxy-5-methoxynaphthalene 18 (62 mg, 71%) as a
fluorescent yellow–tinted brown oil (Found (EI): Mϩ, 429.1549.
C21H23N3O7 requires M, 429.1536); [α]2D2 Ϫ7 (c 0.02 in CH2Cl2);
νmax (film)/cmϪ1 3386 (OH), 2956, 2099 (N ), 1745 (ester C᎐O)
3-Acetyl-6-(3Ј-dimethylamino-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-
hexopyranosyl)-1,4-dihydroxy-5-methoxynaphthalene 30
To a solution of bromoquinone 29 (30 mg, 0.070 mmol) in
dioxane (1 mL) was added copper() bromide (0.5 mg, 0.003
mmol), tetrakis(triphenylphosphine)palladium() (4.3 mg,
0.004 mmol) and (α-ethoxyvinyl)tributylstannane32 (26 mg,
0.072 mmol). The reaction was stirred at 100–110 ЊC under an
atmosphere of nitrogen for 105 min, then allowed to cool to
room temperature. The mixture was then diluted with di-
chloromethane–ether (2 : 1, 10 mL) and shaken in a separating
funnel with a solution of sodium dithionite (0.8 g) in water
(5 mL) for 2 min. The phases were separated, and the aqueous
phase was adjusted to pH 8 using saturated sodium hydrogen
carbonate solution. The aqueous phase was then extracted with
dichloromethane (2 × 5 mL) and the combined dichloro-
methane phases were subsequently washed with saturated
sodium hydrogen carbonate solution (2 × 5 mL) and dried over
sodium sulfate, filtered, and concentrated in vacuo. Purification
by flash column chromatography (dichloromethane–methanol,
9 : 1, short column) afforded 3-acetyl-6-(3Ј-dimethylamino-
2Ј,3Ј,6Ј-trideoxy-β--arabino-hexopyranosyl)-1,4-dihydroxy-5-
methoxynaphthalene 30 (6 mg, 22%) as a fluorescent yellow oil
(Found (EI): Mϩ, 389.1841. C21H27NO6 requires M, 389.1838);
[α]2D2 ϩ4 (c 0.01 in CH2Cl2); υmax (film)/cmϪ1 3242 (OH), 2934,
1625 (o-hydroxyacetophenone), 1386, 1244 and 1080; δH(200
MHz; CDCl3 and CD3OD) 1.44 (3 H, d, J6Ј,5Ј 5.9, 6Ј-H), 1.55
(1 H, ddd, J2Јax,1Ј = J2Јax,3Ј 10.1 and J2Јax,2Јeq 13.1, 2Јax-H), 2.30–
2.20 (1 H, m, 2Јeq-H), 2.62 (6 H, s, NMe2), 2.65 (3 H, s, COMe),
3.35–3.20 (1 H, m, 3Ј-H), 3.41 (1 H, dd, J4Ј,3Ј = J4Ј,5Ј 8.9, 4Ј-H),
3.65–3.57 (1 H, m, 5Ј-H), 3.91 (3 H, s, OMe), 4.97 (1 H, br d,
J1Ј,2Јax 10.1, 1Ј-H), 7.06 (1 H, s, 2-H), 7.74 (1 H, d, J8,7 8.7, 8-H)
and 7.99 (1 H, d, J7,8 8.7, 7-H); δC (50 MHz; CDCl3 and
CD3OD) 18.6, 28.1, 31.7, 38.5, 43.0, 64.0, 68.9, 70.8, 72.6,
105.4, 107.2, 114.0, 115.6, 119.8, 128.1, 131.9, 144.8, 155.3,
159.2 and 205.0; m/z (EI) 389 (Mϩ, 6%), 356 (23), 330 (13), 312
(33) and 71 (100).
᎐
3
and 1626 (o-hydroxyacetophenone); δH (400 MHz; CDCl3) 1.29
(3 H, d, J6Ј,5Ј 6.1, 6Ј-H), 1.79 (1 H, ddd, J2Јax,1Ј = J2Јax,3Ј 11.4 and
J2Јax,2Јeq 13.2, 2Јax-H), 2.17 (3 H, s, OAc), 2.35 (1 H, ddd, J2Јeq,1Ј
1.9, J2Јeq,3Ј 4.9 and J2Јeq,2Јax 13.2, 2Јeq-H), 2.61 (3 H, s, COMe),
3.81–3.66 (2 H, m, 3Ј-H and 5Ј-H), 3.92 (3 H, s, OMe), 4.81
(1 H, dd, J4Ј,3Ј = J4Ј,5Ј 9.6, 4Ј-H), 5.06 (1 H, dd, J1Ј,2Јax 11.4 and
J1Ј,2Јeq 1.9, 1Ј-H), 5.85 (1 H, br s, OH ), 7.00 (1 H, s, 2-H), 7.73 (1
H, d, J8,7 8.7, 8-H), 7.94 (1 H, d, J7,8 8.7, 7-H) and 12.92 (1 H, s,
OH ); δC (100 MHz; CDCl3) 18.2, 18.6, 21.6, 28.0, 38.5, 62.2,
64.1, 72.6, 76.2, 107.8, 113.6, 119.4, 120.5, 128.9, 132.4, 132.5,
143.6, 156.3, 158.6, 171.1 and 204.5; m/z (EI) 429 (Mϩ, 25%),
325 (10), 257 (31) and 43 (100, CH3CO).
(6bR, 9aR)-6-Acetyl-3-(4Ј-O-acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-
ꢀ-D-arabino-hexopyranosyl)-6b,9a-dihydro-5-hydroxy-4-
methoxyfuro[3,2-b]naphtho[2,1-d]furan-8(9H)-one 7 and (6bS,
9aS )-6-acetyl-3-(4Ј-O-acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-
arabino-hexopyranosyl)-6b,9a-dihydro-5-hydroxy-4-methoxy-
furo[3,2-b]naphtho[2,1-d]furan-8(9H)-one 19
To a solution of hydroquinone 18 (96 mg, 0.225 mmol) in
diethyl ether (5 mL) was added silver() oxide (104 mg, 0.449
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 9 0 – 1 7 0 0
1698

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mmol). The mixture was stirred vigorously for 3 h, then filtered
through Celite and the filtrate concentrated in vacuo. The result-
ing red oil was dissolved in dry acetonitrile (3 mL) and cooled
to 0 ЊC. 2-(Trimethylsilyloxy)furan (74 µL, 0.51 mmol) was
added dropwise as a solution in acetonitrile (0.5 mL), and the
mixture was stirred for 1 h. Silica gel (25 mg) and methanol
(0.25 mL) were subsequently added, and the mixture left to stir
at room temperature overnight. The mixture was then diluted
with dichloromethane (20 mL), washed with water, dried over
anhydrous sodium sulfate and concentrated in vacuo. Purifi-
cation by flash column chromatography (hexanes–ethyl acetate,
3 : 2, short column) gave the title compounds 7 and 19 (46 mg,
40%; 1 : 1 mixture by 1H NMR)†‡ as a yellow oil (Found (EI):
Mϩ, 511.1590. C25H25N3O9 requires M, 511.1591); υmax (film)/
cmϪ1 3502 (OH), 2936, 2100 (N ), 1775 (γ-lactone C᎐O) and
J2Јeq,2Јax 13.2, 2Јeq*-H), 2.73 (1 H, apparent d, J3B,3A 20.3, 3B-H),
2.74 (1 H, apparent d, J3B,3A 20.3, 3B*-H), 2.94 (1 H, dd, J3A,3a
5.2 and J3A,3B 20.3, 3A-H), 2.95 (1 H, dd, J3A,3a 4.7 and J3A,3B
20.2, 3A*-H), 3.79–3.61 (4 H, m, 3Ј-H/3Ј*-H and 5Ј-H/5*-H),
3.88 (3 H, s, OMe*), 3.94 (3 H, s, OMe), 4.76 (1 H, dd,
J4Ј,3Ј = J4Ј,5Ј 9.6, 4Ј*-H), 4.77 (1 H, dd, J4Ј,3Ј = J4Ј,5Ј 9.6, 4Ј-H), 4.91–
4.85 (2 H, m, 3a-H/3a*-H), 5.13–5.07 (2 H, br m, 1Ј-H/1Ј*-H),
5.27 (1 H, d, J11b,3a 2.8, 11b-H), 5.28 (1 H, d, J11b,3a 2.8, 11b*-H),
7.92 (1 H, d, J10,9 8.0, 10*-H), 7.93 (1 H, d, J10,9 8.0, 10-H), 7.96
(1 H, d, J9.10 8.0, 9*-H) and 7.97 (1 H, d, J9,10 8.0, 9-H)¶; δC(100
MHz; CDCl3) 18.6, 21.5/21.3*, 28.2/28.1*, 37.2, 38.2/38.1*,
61.9, 63.7/63.5*, 67.8/67.8*, 69.3/69.2*, 72.6*/72.5, 75.7,
75.8, 93.9/93.8*, 123.9, 124.1, 127.6/127.0*, 131.1/130.2*,
133.7/133.5*, 143.5/143.3*, 148.2, 157.6*/157.5, 170.3, 174.9,
183.0/182.6* and 185.3*/184.6; m/z (EI) 527 (Mϩ, 1%), 467
(M–CH3CO2H, 23), 439 (8), 311 (9), 295 (9) and 44 (CH3-
CHOϩ, 100).
᎐
3
1743 (ester C᎐O); δH (400 MHz; CDCl3) 1.26 (3 H, d, J6Ј,5Ј 6.1,
᎐
6Ј*-H), 1.28 (3 H, d, J6Ј,5Ј 6.1, 6Ј-H), 1.71 (1 H, ddd, J2Јax,1Ј
J1Јax,3Ј 11.4 and J2Јax,2Јeq 13.2, 2Јax-H), 1.78 (1 H, ddd, J2Јax,1Ј
=
=
6-(4Ј-O-Acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-hexo-
pyranosyl)-5-methoxy-1,4-naphthoquinone 22
J2Јax,3Ј 12.3 and J2Јax,2Јeq 13.2, 2Јax*-H), 2.16 (6 H, s, OAc/OAc*),
2.34 (1 H, ddd, J2Јeq,1Ј 2.0, J2Јeq,3Ј 5.2 and J2Јeq,2Јax 13.2, 2Јeq*-H),
2.38 (1 H, ddd, J2Јeq,1Ј 1.9, J2Јeq,3Ј 4.9 and J2Јeq,2Јax 13.2, 2Јeq-H),
2.81 (6 H, s, COMe/COMe*), 3.15–3.12 (4 H, m, 9-H/9*-H),
3.81–3.64 (4 H, m, 3Ј-H/3Ј*-H and 5Ј-H/5Ј*-H), 3.92 (3 H, s,
OMe*), 3.93 (3 H, s, OMe), 4.76 (1 H, dd, J4Ј,3Ј = J4Ј,5Ј 9.6, 4Ј-H),
4.79 (1 H, dd, J4Ј,3Ј = J4Ј,5Ј 9.6, 4Ј*-H), 5.01 (1 H, dd, J1Ј,2Јax 11.4
and J1Ј,2Јeq 1.9, 1Ј-H), 5.04 (1 H, dd, J1Ј,2Јax 12.3 and J1Ј,2Јeq 2.0,
1Ј*-H), 5.53–5.50 (2 H, m, 9a-H/9a*-H), 6.45 (1 H, d, J6b,9a 6.3,
6b-H), 6.46 (d, 1 H, J6b,9a 6.3, 6b*-H), 7.73 (1 H, d, J1,2 8.6,
1-H), 7.75 (1 H, d, J1,2 8.6, 1*-H), 7.79 (1 H, d, J2,1 8.6, 2*-H)
and 7.80 (1 H, d, J2,1 8.6, 2-H)§; δC(100 MHz; CDCl3) 18.6,
21.6, 31.4, 36.2, 38.5*/38.5, 62.2, 64.3*/64.2, 72.6/72.4*, 75.7*/
75.6, 76.0, 81.5/81.5*, 86.5, 111.8*/111.7, 113.3*/113.1, 119.9*/
119.8, 121.6, 126.8, 129.9*/129.9, 134.4/134.3*, 151.0/150.9*,
156.4*/156.3, 160.6/160.5*, 170.8, 174.8/174.7* and 203.2; m/z
(EI) 511 (Mϩ, 1%), 495 (1), 493 (1), 467 (1), 368 (1), 314 (1), 256
(1) and 149 (100).
A solution of ceric ammonium nitrate (766 mg, 1.4 mmol) in
water (0.7 mL) was added dropwise to a stirred solution of
C-glycosyltrimethoxynaphthalene 10 (290 mg, 0.7 mmol) in
acetonitrile (5 mL) at 0 ЊC. The reaction mixture briefly turned
blue then turned yellow. Water (10 mL) was added and the
reaction mixture diluted with dichloromethane (10 mL) then
washed with water (10 mL). The combined organic extracts
were dried over magnesium sulfate and the solvent removed at
reduced pressure. Careful purification of the residue by flash
chromatography (hexanes–ethyl acetate, 2 : 1 as eluent) gave
6-(4Ј-O-acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-β--arabino-hexo-
pyranosyl)-5-methoxy-1,4-naphthoquinone 22 (190 mg, 71%)
as a glassy foaming yellow solid; mp 72–74 ЊC (Found: C, 58.9;
H, 5.0; N, 10.6%. C19H19N3O6 requires C, 59.2; H, 5.0; N,
10.9%); [α]2D2 = Ϫ65.6 (c 0.25 in CH2Cl2); υmax (film)/cmϪ1 2982,
2938 (CH), 2099 (N ), 1744, 1666 (C᎐O) and 1228 (C᎐O);
᎐
᎐
3
δH(200 MHz; CDCl3) 1.26 (3 H, d, J6Ј,5Ј 6.2, 6Ј-H), 1.55–1.66
(1 H, m, 2Јax-H), 2.14 (3 H, s, CH3CO), 2.34–2.43 (1 H, m, 2Јeq-
H), 3.59–3.88 (2 H, m, 3Ј-H and 5Ј-H), 3.90 (3 H, s, OMe), 4.74
(1 H, dd, J4Ј,3Ј 9.6 and J4Ј,5Ј 9.6, 4Ј-H), 4.87 (1 H, dd, J1Ј,2Јax 11.3
and J1Ј,2Јeq 1.9, 1Ј-H), 6.88 (1 H, d, J 10.3, 2-H or 3-H), 6.92
(1 H, d, J 10.3, 3-H or 2-H), 7.89 (1 H, d, J 8.0, 7-H or 8-H) and
7.93 (1 H, d, J 8.0, 8-H or 7-H); δC (200 MHz; CDCl3) 17.8,
20.8, 37.5, 61.2, 62.4, 71.8, 74.8, 75.1, 123.2, 123.4, 132.2, 133.3,
136.8, 140.3, 142.2, 156.6, 170.0, 184.16 and 184.18; m/z (EI) 385
(Mϩ, 3%), 283 (5), 215 (15), 83 (30), 43 (CH3CO, 88), 28 (100).
(3aR, 5S, 11bR)-3,3a,5,11b-Tetrahydro-8-(4Ј-O-acetyl-3Ј-azido-
2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-hexopyranosyl)-5-hydroxy-7-
methoxy-5-methyl-2H-furo[3,2-b]naphtho[2,3-d]pyran-2,6,11-
trione 6 and (3aS, 5R, 11bS )-3,3a,5,11b-tetrahydro-8-(4Ј-O-
acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-hexopyranosyl)-5-
hydroxy-7-methoxy-5-methyl-2H-furo[3,2-b]naphtho[2,3-d]-
pyran-2,6,11-trione 20
To a solution of adducts 7 and 19 (27 mg, 0.052 mmol) in
acetonitrile (5 mL) was added a solution of ceric ammonium
nitrate (58 mg, 0.106 mmol) in water (0.5 mL), and the mixture
was stirred for 5 min. The mixture was then diluted with di-
chloromethane (25 mL), washed with water (2 × 25 mL), dried
over anhydrous sodium sulfate and concentrated in vacuo to
afford the title compounds 6 and 20 (22 mg, 89%; ca. 3 : 2
6-(4Ј-O-Acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-hexo-
pyranosyl)-4-hydroxy-1,5-dimethoxynaphthalene 23
A solution of the above quinone 22 (50 mg, 0.13 mmol) in
dichloromethane (10 mL) was shaken with saturated aqueous
sodium dithionite (5 mL) until the yellow colour disappeared
(5 min). The organic extract was dried by filtration through a
short column of magnesium sulfate and the solvent removed at
reduced pressure to give the crude hydroquinone (46 mg) as an
unstable pale brown oil; δH (200 MHz; CDCl3) 1.27 (3 H, d, J6Ј,5Ј
6.2, 6Ј-H), 1.89–2.08 (1 H, m, 2Јax-H), 2.18 (3 H, s, CH3CO),
2.18–2.29 (1 H, m, 2Јeq-H), 3.62–3.85 (2 H, m, 3Ј-H and 5Ј-H),
3.91 (3 H, s, OCH3), 4.84 (1 H, dd, J4Ј,3Ј 9.5 and J4Ј,5Ј 9.6, 4Ј-H),
4.95 (1 H, dd, J1Ј,2Јax 11.3 and J1Ј,2Јeq 2.0, 1Ј-H), 6.75 (2 H, s, 2-H
and 3-H), 7.50 (1 H, d, J8,7 8.9, 8-H), 8.00 (1 H, d, J7,8 8.9, 7-H)
and 8.82 (1 H, br s, OH).
1
mixture of diastereomers by H NMR) as a yellow oil (Found
(EI): Mϩ, 527.1526. C25H25N3O10 requires M, 527.1540); νmax
(film)/cmϪ1 3417 (OH), 2982, 2939, 1774 (γ-lactone C᎐O), 1743
᎐
(ester C᎐O) and 1668 (quinone C᎐O); δ (400 MHz; CDCl )
᎐
᎐
H
3
1.28 (3 H, d, J6Ј,5Ј 6.2, 6Ј*-H), 1.29 (3 H, d, J6Ј,5Ј 6.2, 6Ј-H), 1.66–
1.54 (2 H, m, 2Јax-H/2Јax*-H), 1.80 (6 H, s, 5-Me/5-Me*), 2.16
(6 H, s, OAc/OAc*), 2.38 (1 H, ddd, J2Јeq,1Ј 2.0, J2Јeq,3Ј 4.9 and
J2Јeq,2Јax 13.2, 2Јeq-H), 2.43 (1 H, ddd, J2Јeq,1Ј 2.0, J2Јeq,3Ј 4.8 and
† In a separate experiment, a non-1 : 1 ratio of diastereomers was
obtained, allowing signals to be grouped according to diastereomer
based on the difference in integration between the two diastereomers.
Signals belonging to the different diastereomers are distinguished by
the presence or absence of an asterisk (*). For the 13C NMR data,
signals which were coincidental for both diastereomers are reported as a
single value. Assignment of an individual set of resonances to a specific
diastereomer was not made.
A two-neck flask containing this crude dihydroquinone
(46 mg) was evacuated for 1 hour and dry degassed acetone
(3 mL) was added by syringe under nitrogen. Potassium carb-
onate (83 mg, 0.6 mmol) was added and the reaction mixture
darkened. Dimethyl sulfate (37 µL, 0.36 mmol) was added and a
‡ 1H and 13C NMR spectra were complicated by the presence of resid-
ual butenolide obtained from hydrolysis of 2-trimethylsilyloxyfuran 9.
§ Resonances due to the phenolic OH were not observed.
¶ Resonances due to the phenolic OH were not observed.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 9 0 – 1 7 0 0
1699

View Article Online
2 For a review on the synthesis of pyranonaphthoquinone antibiotics
see: M. A. Brimble, M. R. Nairn and H. Prabaharan, Tetrahedron,
2000, 56, 1937.
3 S. Takano, K. Hasuda, A. Ito, Y. Koide, F. Ishii, I. Haneda,
S. Chihara and Y. Koyama, J. Antibiot., 1976, 29, 765.
4 N. Tanaka, T. Okabe, F. Isono, M. Kashowagi, K. Nomoto,
M. Takahashi, A. Shimazu and T. Nishimura, J. Antibiot., 1985, 38,
1327.
5 T. Okabe, K. Namoto, H. Funabashi, S. Okuda, H. Suzuki and
N. Tanaka, J. Antibiot., 1985, 38, 1333.
6 K. Tatsuta, H. Ozeki, M. Yamaguchi, M. Tanaka and T. Okui,
Tetrahedron Lett., 1990, 31, 5495.
lightening of the reaction mixture was then observed. The reac-
tion mixture was heated at reflux for 25 min then cooled and
filtered through a plug of Celite. The solvent was evaporated
at reduced pressure to afford crude 6-(4Ј-O-acetyl-3Ј-azido-
2Ј,3Ј,6Ј-trideoxy-β--arabino-hexopyranosyl)-4-hydroxy-1,5-
dimethoxynaphthalene 23 (42 mg) as an unstable red oil;
δH (200 MHz; CDCl3) 1.27 (3 H, d, J6Ј,5Ј 6.1, 6Ј-H), 1.95–2.07
(1 H, m, 2Јax-H), 2.22 (3 H, s, CH3CO), 2.20–2.28 (1 H, m, 2Јeq-
H), 3.64–3.95 (2 H, m, 3Ј-H and 5Ј-H), 3.93 (3 H, s, OCH3),
3.95 (3 H, s, OCH3), 4.83 (1 H, dd, J4Ј,3Ј 9.5 and J4Ј,5Ј 9.6, 4Ј-H),
4.97 (1 H, dd, J1Ј,2Јax11.3 and J1Ј,2Јeq 2.0, 1Ј-H), 6.75 (1H, d, J 8.2,
2-H or 3-H), 6.83 (1H, d, J 8.2, 3-H or 2-H), 7.50 (1 H, d, J8,7
8.9, 8-H), 8.07 (1 H, d, J7,8 8.9, 7-H) and 8.83 (1 H, br s, OH).
7 S. Omura, A. Nakagawa, N. Fukamachi, K. Yamaki, M. Hayashi,
S. Ohishi and B. Kobayashi, J. Antibiot., 1987, 40, 1075.
8 P.-M. Leo, C. Morin and C. Philouze, Org. Lett., 2002, 4,
2711.
9 N. Tanaka, T. Okabe and K. Nomoto, J. Antibiot., 1986,
39, 1.
10 Y. Hayakawa, K. Ishigami, K. Shin-Ya and H. Seto, J. Antibiot.,
1994, 47, 1344.
11 R. T. Williamson, L. A. McDonald, L. R. Barbieri and G. T. Carter,
Org. Lett., 2002, 4, 4659.
6-(4Ј-O-Acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-hexo-
pyranosyl)-3-bromo-1,4,5-trimethoxynaphthalene 16 from
6-(4Ј-O-acetyl-3Ј-azido-2Ј,3Ј,6Ј-trideoxy-ꢀ-D-arabino-hexo-
pyranosyl)-3-bromo-4-hydroxy-1,5-dimethoxynaphthalene 24
A solution of bromine (23 mg, 0.144 mmol) in carbon tetra-
chloride (0.5 mL) was carefully added dropwise to a stirred
solution of crude naphthol 23 (42 mg) in carbon tetrachloride
(1 mL) at 0 ЊC under nitrogen. The reaction mixture was stirred
for 5 min then quenched with saturated aqueous sodium thio-
sulfate (5 mL) and diluted with dichloromethane (10 mL). The
organic layer was washed with water (10 mL) and the aqueous
layer extracted with dichloromethane (2 × 5 mL). The combi-
ned organic extracts were dried over magnesium sulfate and
evaporated to give crude 6-(4Ј-O-acetyl-3Ј-azido-2Ј,3Ј,6Ј-tri-
deoxy-β--arabino-hexopyranosyl)-3-bromo-4-hydroxy-1,5-di-
methoxynaphthalene 24 (45 mg) as an unstable tan oil that
rapidly darkened on standing; δH (200 MHz, CDCl3) 1.24–1.28
(3 H, d, 6Ј-H), 1.70–1.92 (1 H, m, 2Јax-H), 2.16 (3 H, s, CH3CO),
2.25-2.35 (1 H, m, 2Јeq-H), 3.65–3.90 (2 H, m, 3Ј-H and 5Ј-H),
3.81 (3 H, s, OCH3), 3.84 (3 H, s, OCH3), 4.80 (1 H, dd, J4Ј,3Ј 9.6
and J4Ј,5Ј 9.6, 4Ј-H), 5.05 (1 H, dd, J1Ј,2Јax 9.5 and J1Ј,2Јeq 1.9,
1Ј-H), 6.92 (1H, s, 2-H), 7.57 (1 H, d, J8,7 8.8, 8-H) and 8.04
(1 H, d, J7,8 8.8, 7-H).
12 M. A. Brimble and T. J. Brenstrum, J. Chem. Soc., Perkin Trans. 1,
2001, 1624.
13 For a preliminary communication of this work see: M. A. Brimble,
R. M. Davey and M. D. McLeod, Synlett, 2002, 1318.
14 For a recent example see: F. M. Hauser and X. Hu, Org. Lett., 2002,
4, 977.
15 M. A. Brimble and S. J. Stuart, J. Chem. Soc., Perkin Trans. 1, 1990,
881.
16 M. A. Brimble, S. J. Phythian and H. Prabaharan, J. Chem. Soc.,
Perkin Trans. 1, 1995, 2855.
17 M. A. Brimble, R. M. Davey and M. D. McLeod, Aust. J. Chem.,
in press.
18 (a) J.-C. Florent and C. Monneret, J. Chem. Soc., Chem. Commun.,
1987, 1171; (b) B. Abbaci, J.-C. Florent and C. Monneret, Bull. Soc.
Chim. Fr., 1989, 5.
19 For reviews on C-glycosylation see: (a) M. H. D. Postema,
Tetrahedron, 1992, 40, 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.
20 E. J. Borne, M. Stacey, J. C. Tatlow and J. M. Tedder, J. Chem. Soc.,
1951, 718.
To a slurry of sodium hydride (10 mg, 60% dispersion in oil,
0.24 mmol) in dry DMF (1 mL) at 0 ЊC was added dropwise a
solution of this crude naphthol 24 (45 mg) in dry DMF (1 mL).
The reaction mixture turned a deep brown colour. Dimethyl
sulfate (25 µl, 0.24 mmol) was then added and the reaction
mixture stirred for 5 min at 0 ЊC then quenched with water (1
mL). The reaction mixture was extracted with dichloromethane
(10 mL), washed with water (3 × 10 mL), dried over magnesium
sulfate and concentrated under reduced pressure. The resultant
residue was purified by flash chromatography (hexanes–ethyl
acetate, 4 : 1 as eluent) to give 6-(4Ј-O-acetyl-3Ј-azido-2Ј,3Ј,6Ј-
trideoxy-β--arabino-hexopyranosyl)-3-bromo-1,4,5-trimeth-
oxynaphthalene 16 (30 mg, 42% from 22) as a pale yellow oil for
21 T. A. Chorn, R. G. F. Giles, I. R. Green, V. I. Hugo, P. R. K.
Mitchell and S. C. Yorke, J. Chem. Soc., Perkin Trans. 1, 1984,
1339.
22 F. Effenberger, E. Sohn and G. Epple, Chem. Ber., 1983, 116,
1195.
23 M. Kosugi, T. Sumiya, Y. Obara, M. Suzuki, H. Sano and T. Migita,
Bull. Chem. Soc. Jpn., 1987, 60, 767.
24 W. J. Thompson, J. H. Jones, P. A. Lyle and J. E. Thies, J. Org.
Chem., 1988, 53, 2052.
25 H. Staudinger and J. Meyer, Helv. Chim. Acta, 1919, 2, 635.
26 L. S. Liebeskind and S. W. Reisinger, J. Org. Chem., 1993, 58,
408.
27 N. Kato and N. Miyaura, Tetrahedron, 1996, 52, 13347.
28 (a) O. Frutos, C. Atienza and A. M. Echavarren, Eur. J. Org. Chem.,
2001, 163; A. M. Echavarren, N. Tamayo and D. J. Cardenas,
Tetrahedron, 1997, 53, 16835.
1
which the H NMR, IR and MS data were in agreement with
that reported above.
29 P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry,
Pergamon Press, Oxford, 1983.
30 G. A. Kraus, M. T. Molina and J. A. Walling, J. Org. Chem., 1987,
52, 1273.
31 M. A. Brimble and S. M. Lynds, J. Chem. Soc., Perkin Trans 1, 1994,
493.
32 M. Kosugi, T. Sumiya, Y. Obara, M. Suzuki, H. Sano and T. Migita,
Bull. Chem. Soc. Jpn, 1987, 60, 767.
References
1 For a review on the isolation and structure of pyranonaphtho-
quinone antibiotics see: M. A. Brimble, L. J. Duncalf and
M. R. Nairn, Nat. Prod. Rev., 1999, 16, 267.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 9 0 – 1 7 0 0
1700