Studies related to carba-pyranoses: A strategy for the synthesis of β-1,3-glycosidically linked aminomonocarba-disaccharides

Article abstract of DOI:10.1039/b105374b

The reaction of (E)-1-(2′-3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosy loxy)-3-(trimethylsiloxy)buta-1,3-diene 1 and maleic anhydride gives cycloadduct 10 and ketone 12. Reduction of ketone 13, formed by acidic hydrolysis of silyl enol ether 10, with sodium cyanoborohydride in acetic acid gives an 83: 17 mixture of the γ- and δ-lactone 14 and 15. γ-Lactone 14 is transformed into the aminomonocarba-disaccharide, 4-acetamido-2,4-dideoxy-3-O-(β-D-glucopyranosyl)-5a-carba-β-L-lyxo-hex opyranose 7, using a five-step procedure involving the Curtius rearrangement of acyl azide 16. A similar sequence using γ-lactone 21, prepared from ketone 12, gives the protected aminomonocarbadisaccharide, 4-acetamido-1,6-di-O-acetyl-2,4-dideoxy-3-O-(2′,3′,4′,6′ -tetra-O-acetyl-β-D-glucopyranosyl)-5a-carba- β-D-lyxo-hexopyranose 8. Reaction of cycloadduct 10 with dimethyldioxirane gives acyloin 26. Acetylation under acidic conditions followed by reduction with sodium cyanoborohydride in acetic acid gives a 75: 25 mixture of the γ- and δ-lactone 28 and 29. Using a sequence similar to that employed for the preparation of compounds 7 and 8, γ-lactone 28 is converted into the fully substituted aminomonocarba-disaccharide, 4-acetamido-1,2,6-tri-O-acetyl-4-deoxy-3-O-(2′,3′,4′,6′- tetra-O-acetyl-β-D-glucopyranosyl)-5a-carba-β-L-galactopyranose 9.

Full text of DOI:10.1039/b105374b

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Studies related to carba-pyranoses: a strategy for the synthesis of
ꢀ-1,3-glycosidically linked aminomonocarba-disaccharides1
David S. Larsen,*a Roger J. Lins,a Richard J. Stoodleyb and Nicholas S. Trottera
1
a Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand
b Department of Chemistry, UMIST, PO Box 88, Manchester, UK M60 1QD
Received (in Cambridge, UK) 19th June 2001, Accepted 19th July 2001
First published as an Advance Article on the web 23rd August 2001
The reaction of (E)-1-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-β--glucopyranosyloxy)-3-(trimethylsiloxy)buta-1,3-diene 1 and
maleic anhydride gives cycloadduct 10 and ketone 12. Reduction of ketone 13, formed by acidic hydrolysis of silyl
enol ether 10, with sodium cyanoborohydride in acetic acid gives an 83 : 17 mixture of the γ- and δ-lactone 14 and 15.
γ-Lactone 14 is transformed into the aminomonocarba-disaccharide, 4-acetamido-2,4-dideoxy-3-O-(β--gluco-
pyranosyl)-5a-carba-β--lyxo-hexopyranose 7, using a five-step procedure involving the Curtius rearrangement of
acyl azide 16. A similar sequence using γ-lactone 21, prepared from ketone 12, gives the protected aminomonocarba-
disaccharide, 4-acetamido-1,6-di-O-acetyl-2,4-dideoxy-3-O-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-β--glucopyranosyl)-5a-carba-
β--lyxo-hexopyranose 8.
Reaction of cycloadduct 10 with dimethyldioxirane gives acyloin 26. Acetylation under acidic conditions followed
by reduction with sodium cyanoborohydride in acetic acid gives a 75 : 25 mixture of the γ- and δ-lactone 28 and 29.
Using a sequence similar to that employed for the preparation of compounds 7 and 8, γ-lactone 28 is converted into
the fully substituted aminomonocarba-disaccharide, 4-acetamido-1,2,6-tri-O-acetyl-4-deoxy-3-O-(2Ј,3Ј,4Ј,6Ј-tetra-O-
acetyl-β--glucopyranosyl)-5a-carba-β--galactopyranose 9.
a fully substituted monocarba-disaccharide, i.e. 4-acetamido-
1,2,6-tri-O-acetyl-4-deoxy-3-O-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-β--
glucopyranosyl)-5a-carba-β--galactopyranose 9.
Introduction
Over the past few years, we have shown that anomerically
linked glycopyranose units can confer a useful degree of facial
reactivity on 1-oxybuta-1,3-dienes in cycloaddition reactions.2–9
For example, the diene 1 displays good Re-face reactivity and
Results and discussion
undergoes highly endo-selective Diels–Alder reactions2,3,5 with
cyclic dienophiles of type 2 to give predominantly cycloadducts
of type 3. As well as endeavouring to understand the basis
of the stereoinduction, we have sought to employ such cyclo-
additions in the assembly of compounds of biological
relevance. Within the latter context, asymmetric syntheses of
anthracyclinones,2,5 bostrycins,6 dehydropiperazic acids7,8 and
5-arylpentopyranoses9 have been effected.
The strategy employed for the synthesis of (1 3)-linked
monocarba-disaccharides would require that C-5 of cyclo-
adducts, typified by 10, would become the pseudo-anomeric
centre of the carba-pyranose ring. This necessitates that the
anhydride carbonyl function at C-1 be selectively reduced to a
hydroxymethyl group and that that at C-2 be replaced with
heteroatom functionality. With respect to the latter issue, it was
envisaged that amino functionality could be introduced with
retention of stereochemistry using the Curtius rearrangement
of a derived acyl azide. Oxidation of the silyl enol ether group
and reduction of the resulting α-hydroxy ketone would serve to
install the 1- and 2-hydroxy groups.
In this study, conducted on a ≈50 mmol scale, diene 1 reacted
with maleic anhydride in benzene3 to give a 3 : 1 mixture of the
two cycloadducts 10 and 11. Trituration of the crude product
with diethyl ether afforded cycloadduct 10 in 59% yield. Careful
crystallisation of the residue obtained from the filtrate gave the
previously unreported ketone 12, formed by adventitious
hydrolysis of cycloadduct 11, in 15% yield.
We felt that the critical step in the strategy would be the
differentiation of the carbonyl groups of the anhydride. Thus,
our initial study employed ketone 13 prepared by the acidic
hydrolysis of silyl enol ether 10.3 It was inferred from models
that reduction of the ketone would produce an intermediary
alcohol that could react with the C-1 and/or C-2 anhydride
carbonyl group. Gratifyingly, treatment of a solution of ketone
13 in glacial acetic acid with sodium cyanoborohydride resulted
in a regioselective opening of the anhydride to afford an 83 : 17
mixture of the γ- and δ-lactone acids 14 and 15 which were
isolated in yields of 72 and 7%, respectively. The structures of
In the aforementioned syntheses, the glycopyranose moiety
served a ‘chiral auxiliary’ role, being removed from the pre-
target structures by mild acidic hydrolysis. Mindful of the
emerging importance of saccharides in medicinal chemistry,10,11
we have also sought to prepare oligosaccharide-like compounds
that retain the glycopyranose unit. Within this framework,
monocarba-disaccharides that feature a pyranose entity glyco-
sidically linked to a carba-pyranose moiety have attracted our
attention. Such assemblies, which are found in some amino-
glycoside antibiotics, e.g. validamycin A 4,12 have been the
subject of relatively few synthetic endeavours.
We planned to use Diels–Alder reactions to construct such
monocarba-disaccharides and initially decided to employ the
readily available diene 1.2,3 In consequence, any targets would
feature a β--glucopyranosyl unit. Noting that few acetal-
linked (1 3)-monocarba-disaccharides had been synthesised13
(examples include compounds 5 and 614), we decided to
prepare further representatives of this group. Earlier,1 we
communicated our initial findings where we synthesised 4-
acetamido-2,4-dideoxy-3-O-(β--glucopyranosyl)-5a-carba-β-
-lyxo-hexopyranose 7. This paper describes those findings
in full and extensions to that work which culminated in the
syntheses of a relative with the -lyxo configuration, i.e. 8, and
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J. Chem. Soc., Perkin Trans. 1, 2001, 2204–2212
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b105374b

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Scheme 1 Reagents and conditons: i, (COCl)2, DMF, CH2Cl2; then
NaN3, THF (90%); ii, C6H6, ∆ (98%); iii, NEt3, aq. THF (35%); iv,
LiAlH4, THF, v, Ac2O, pyr (81% over two steps); vi, IRA-400 (OHϪ),
MeOH (73%); vii, BnOH, C6H6, ∆ (94%); viii, 10% Pd–C, EtOH (84%).
Fig. 1 NOE enhancement for 17.
Fig. 2 Solution conformation of carba-pyranoses 9 and 20.
amine 19 in 35% yield. The sequence was continued with
the lithium aluminium hydride reduction of lactone 19 which
gave, after subsequent treatment with acetic anhydride and
pyridine, the peracetylated 4-amino-2,4-dideoxy-monocarba-
disaccharide 20 in 81% yield. The structure and lyxo-
stereochemistry of the carbocyclic ring of compound 20 was
apparent from an analysis of the 1H NMR spectrum. The
pseudo-anomeric proton, 1-H, resonated as an apparent triplet
of triplets with coupling constants J1,5a-ax (11 Hz) and J1,2ax
(12 Hz) confirming its axial orientation. Similarly, axial orient-
ations of 3-H and 5-H were apparent from the coupling con-
stants J2ax,3 (12 Hz) and J5,5a-ax (13 Hz). The coupling constants
J3,4 and J4,5, both of 4 Hz, indicated the equatorial disposition
of 4-H, thus confirming that the Curtius rearrangement of acyl
azide 16 had indeed proceeded with retention of configuration.
The analysis of coupling-constant data was also consistent with
the carbocyclic ring adopting a 1C4 chair-like conformation
(Fig. 2). The final step in the sequence involved deacetylation of
compound 20 using IRA-400 (OHϪ) resin in methanol; after
the last-cited compounds were deduced from their analytical
and spectroscopic data, with the γ-lactonic acid 14 exhibiting
a peak at 1769 cmϪ1 in the IR spectrum attributable to the
γ-lactone carbonyl group.
Acyl azide 16 was prepared from the acid 14 under standard
conditions in a 90% yield (Scheme 1). A near-quantitative con-
version of acyl azide 16 into isocyanate 17 was achieved by
heating at reflux in benzene. The retention of stereochemistry at
C-2 for the rearrangement was apparent from the strong (5%)
NOE enhancement between 2-H and 8-Hβ (Fig. 1). Hydrolysis
of the isocyanate 17 to the amine 19 proved to be problematic.
To avoid urea formation, the hydrolysis was best effected under
basic conditions using triethylamine in aq. THF to give the
J. Chem. Soc., Perkin Trans. 1, 2001, 2204–2212
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purification by reversed-phase HPLC, the pseudo-disaccharide
7 was isolated in 73% yield. Although the spectral data were
consistent with the proposed structure, microanalysis suggested
that compound 7 existed as a hydrate. Reacetylation of com-
pound 7 under standard conditions confirmed the structural
assignment by furnishing 20 in 81% yield.
The low-yielding step in the 14
7 sequence was the
hydrolysis of the isocyanate 17. We believed that this was due
to competing hydrolyses of the lactone and ester functions of
compound 17 and that the resulting by-products could also
be converted into monocarba-disaccharide 7. Indeed, when the
crude reaction product from the hydrolysis was subjected to
the reduction, acetylation and deprotection sequence, the
monocarba-disaccharide 7 was isolated in an improved overall
yield of 56% (cf. 21% overall yield for the earlier sequence).
An alternative method for the preparation of amine 19 was
also pursued. Treatment of isocyanate 17 with benzyl alcohol
gave carbamate 18 in 94% yield, catalytic hydrogenolysis of
which furnished an 84% yield of amine 19.
Scheme 3 Reagents and conditions: i, DMDO in Me2CO (85%); ii,
Ac2O, cat HClO4 (84%); iii, NaBH3CN, AcOH (52% for 28).
A similar sequence using isomeric ketone 12 allowed the
synthesis of a carba-sugar with the opposite stereochemistry at
the carbocyclic ring. Sodium cyanoborohydride reduction of
ketone 12 gave a 75 : 25 mixture of the lactonic acids 21 and 22.
achieved by treatment of cycloadduct 10 with an acetone solu-
tion of dimethyldioxirane (DMDO)15 (Scheme 3). The acyloin
26 was obtained in 85% yield after crystallisation. The con-
figuration at C-4 could not be determined from NMR data;
however, it is reasonable to assume that the oxidant reacted
preferentially from the least-hindered face of the enol ether to
give the C-4 β-alcohol. The next step in the sequence involved
reduction of ketone 26 with sodium cyanoborohydride.
Unfortunately, it did not result in the desired lactonisation but
instead gave diol 30 (56% yield). This problem was overcome by
acetylation of the hydroxy group of 26 under acidic conditions.
Sodium cyanoborohydride reduction of the resultant acetoxy
ketone 27 gave a 75 : 25 mixture of the lactonic acids 28 and
29 which were isolated in 52 and 9% yield, respectively.
Problems were encountered with the formation of the
corresponding acyl azide derived from the acid 28. Using the
protocol developed for the formation of compound 16, the acid
28 gave the unsaturated acyl azide 31 via β-elimination of the
Crystallisation of the mixture gave the major lactonic acid 21
in 58% yield. Treatment of the acid chloride derived from
acid 21 with sodium azide gave acyl azide 23 which, on heating
in a mixture of benzyl alcohol and benzene, gave the carbamate
24 (Scheme 2). The yield for the two steps was 88%. Hydro-
tetra-O-acetyl--glucopyranose moiety. This was overcome
using a two-step procedure involving initial isolation of
acid chloride 32 (Scheme 4) and its subsequent treatment, in
Scheme 2 Reagents and conditons: i, (COCl)2, DMF, CH2Cl2; then
NaN3, THF (99%); ii, C6H6, BnOH, ∆ (89%); iii, 10% Pd–C, EtOH
(57%); iv, LiAlH4, THF; v, Ac2O, pyr (63% over two steps).
genolysis of benzyl carbamate 24 gave amine 25 (57%), which
was then reduced with lithium aluminium hydride and
acetylated to give the protected monocarba-disaccharide 8
(63%).
Our attention then focused on hydroxylation at C-4 of the
carbocycle to give a fully substituted carba-sugar. This was
Scheme 4 Reagents and conditons: i, (COCl)2, DMF, CH2Cl2 (82%): ii,
NaN3, CH2Cl2 (92%); iii, C6H6, BnOH, ∆ (85%); iv, 10% Pd–C, EtOH
(55%); v, LiAlH4, THF; vi, Ac2O, pyr (61% over two steps).
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J. Chem. Soc., Perkin Trans. 1, 2001, 2204–2212

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dichloromethane, with sodium azide. The desired acyl azide 33
was isolated in 92% yield. Conversion into the carbamate 34,
hydrogenolysis to the amine 35, lithium aluminium hydride
reduction and acetylation gave the target monocarba-
disaccharide 9 in 29% overall yield. Once again, the spectral
data were consistent with the structure, and analysis of
coupling data showed equatorial orientations of the C-1, -3, -4,
and -5 substituents. Although the 2-H resonance was partly
obscured by other signals, it could be observed as an apparent
triplet at δ 5.09 using resolution-enhancement techniques, with
coupling constants J2,3 and J1,2 of 9.5 Hz, confirming the axial
orientation of 2-H. Collectively, analysis of the coupling-
constant data indicates that the carbocyclic ring of compound 9
adopts a 1C4-like conformation as depicted in Fig. 2.
In conclusion, we have demonstrated that the asymmetric
Diels–Alder reaction of dienyl glucoside 1 can provide a
method for accessing 1,3-glycosidically linked aminomono-
carba-disaccharides. Further work is underway to establish
methods for the introduction of other heteroatom functionality
at C-4 in these systems and also for modifying the synthetic
procedures to provide 1,1- and 1,4-glycosidically linked mono-
carba-disaccharides.
(1S,2S,3R)-5-oxo-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-β--glucopyrano-
syloxy)cyclohexane-1,2-dicarboxylic anhydride 12 (4.2 g, 15%)
as a slightly impure solid. Recrystallisation from dichloro-
methane–diethyl ether yielded compound 12 as analytically
pure colourless crystals (1.8 g, 6%); mp 176–179 ЊC (Found:
C, 51.6; H, 5.3. C22H26O14 requires C, 51.4; H, 5.1%) [α]D ϩ30
(c 0.3 in CH2Cl2); νmax (KBr)/cmϪ1 1784 (anhydride C᎐O), 1750
᎐
(ester C᎐O) and 1722 (ketone C᎐O); δ (300 MHz; CDCl3)
᎐
᎐
H
1.99, 2.01 and 2.11 (6, 3 and 3 H, each s, 4 × OAc), 2.36 (1 H,
dd, J 18 and 2, 4-H), 2.78 (1 H, dd, J 18 and 4, 4-H), 2.79 (1 H,
dd, J 18 and 10, 6-H), 2.88 (1 H, dd, J 18 and 8, 6-H), 3.37
(1 H, dd, J 10.5 and 3, 2-H), 3.58 (1 H, dt, J 8 and 10, 1-H),
3.67 (1 H, dt, J 9.5 and 3.5, 5Ј-H), 4.18 (2 H, d, separation
3.5, 6Ј-H2), 4.55 (1 H, d, J 8, 1Ј-H), 4.82 (1 H, q, J 3.5, 3-H),
4.89 (1 H, dd, J 9 and 8, 2Ј-H), 5.07 (1 H, t, J 9.5, 4Ј-H)
and 5.16 (1 H, t, J 9, 3Ј-H); δC (75 MHz; d6-DMSO) 20.2,
20.4, 20.5, 20.7, 35.6, 36.2, 44.7, 61.9, 68.3, 70.5, 70.9, 72.0,
72.3, 96.0, 169.0, 169.4, 169.7, 170.2, 170.7, 174.2 and 209.0
(5-CO); m/z (FAB) 515 (MHϩ, 13%), 331 (C14H19O9ϩ, 56) and
154 (100).
Sodium cyanoborohydride reduction of ketone 13
Sodium cyanoborohydride (6.70 g, 107 mmol) was added to a
solution of ketone 133 (11.2 g, 21.7 mmol) in glacial acetic acid
(120 cm3). After stirring of the mixture for 15 h, the solvent was
removed in vacuo and the residue was partitioned between
dichloromethane and hydrochloric acid (1 mol dmϪ3). The
aqueous layer was extracted with dichloromethane (3 × 40 cm3)
and the combined organic extracts were washed with aq.
sodium hydrogen carbonate (2 × 100 cm3). The combined basic
aqueous layers were acidified with conc. hydrochloric acid
and then extracted with dichloromethane (2 × 100 cm3). The
organic layer was dried (MgSO4) and the solvent was removed
in vacuo to give a white foam, shown to be an 83 : 17 mixture of
the lactonic acids 14 and 15 on the basis of 200 MHz 1H NMR
analysis. Crystallisation of the residue from dichloromethane–
diethyl ether gave (1R,2R,3S,5S)-7-oxo-3-(2Ј,3Ј,4Ј,6Ј-tetra-
O-acetyl-β--glucopyranosyloxy)-6-oxabicyclo[3.2.1]octane-2-
carboxylic acid 14 (8.10 g, 72%) as colourless crystals; mp
193–195 ЊC (Found: C, 51.5; H, 5.5. C22H28O14 requires C,
51.2; H, 5.5%) [α]D Ϫ13 (c 0.03 in CH2Cl2) [α]D Ϫ34 (c 0.2 in
Experimental
Mps were measured on a Gallenkamp capillary melting-point
apparatus and are uncorrected. Specific optical rotations [α]D,
given in 10Ϫ1 deg cm2 gϪ1, were measured at ≈22 ЊC using either
a JASCO DIP-370 or DIP-1000 polarimeter with a cell of path
length 1.0 dm. Varian Gemini 200 and VXR300 spectrometers
were used to obtain H (200 and 300 MHz) and 13C (50 and
1
75 MHz) NMR spectra. Chemical shifts are reported as parts
per million (ppm) using the δ-scale. Coupling constants (J)
and separations are reported to the nearest 0.5 Hz. IR spectra
were recorded on a Perkin-Elmer 1600 series FTIR spectro-
photometer. HPLC separations were carried out with an
Activon ODS column (25 × 1 cm) employing a JASCO PU-980
pump and JASCO UV-975 UV/vis detector. FAB mass spectra
were recorded on a Kratos MSORF mass spectrometer; m-
nitrobenzyl alcohol was used as the matrix and xenon as the
ionising gas.
Elemental analyses were carried out by Dr R. G. Cunning-
hame and associates at the Campbell Microanalytical Labora-
tory, University of Otago, Dunedin, New Zealand. Thin-layer
chromatography (TLC) was performed on Merck silica gel
DC Alurolle Kieselgel 60F254 plates and plates were visualised
under a UV lamp and/or with a spray consisting of 5% w/v
dodecamolybdophosphoric acid in ethanol with subsequent
heating. Flash column chromatography was carried out using
Merck Kieselgel 60 (230–400 mesh). All chromatography
solvents were reagent grade. THF was distilled from sodium/
potassium–benzophenone ketyl under nitrogen, and dichloro-
methane was distilled from phosphorus pentaoxide. All other
solvents and reagents were purified using the methods described
by Perrin et al.16
Me2CO); νmax (KBr)/cmϪ1 3000br (O–H), 1769 (lactone C᎐O)
᎐
and 1743 (acid and ester C᎐O); δ (300 MHz; CDCl ) 1.77 (1 H,
᎐
H
3
d, J 11.5, 8-Hβ), 1.95 (1 H, dd, J 15.5 and 4.5, 4-Hβ), 1.99,
2.02, 2.07 and 2.10 (each 3 H, s, 4 × OAc), 2.55–2.67 (2 H, m,
4- and 8-Hα), 3.00 (1 H, dd, J 4.5 and 2, 2-H), 3.06 (1 H, br d,
J 5, 1-H), 3.68 (1 H, br dt, J 10 and 4, 5Ј-H), 4.18–4.21 (2 H, m,
6Ј-H2), 4.56 (1 H, br t, J 4.5, 3-H), 4.70 (1 H, d, J 8, 1Ј-H),
4.85 (1 H, br t, J 5, 5-H), 4.93 (1 H, dd, J 9.5 and 8, 2Ј-H), 5.06
(1 H, t, J 9, 4Ј-H) and 5.15 (1 H, t, J 9, 3Ј-H); δC (75 MHz;
d6-DMSO) 20.3, 20.4, 20.5, 34.7, 36.1, 36.9, 48.9, 61.6, 68.1,
70.3, 70.6, 72.2, 75.1, 75.7, 102.0, 168.8, 169.3, 169.6, 170.0,
170.4 and 175.5; m/z (FAB) 517 (MHϩ, 2%), 331 (C14H19O9ϩ, 7)
and 154 (100).
Removal of the solvent from the filtrate gave a foam
which was found to be the slightly impure lactonic acid 15
(1.67 g). Slow crystallisation from dichloromethane–diethyl
ether–hexanes gave (1R,2R,4S,7S)-6-oxo-7-(2Ј,3Ј,4Ј,6Ј-tetra-
O-acetyl-β--glucopyranosyloxy)-5-oxabicyclo[2.2.2]octane-2-
carboxylic acid† 15 (0.730 g, 7%) as clear crystals; mp 91–93 ЊC
(Found: C, 51.2; H, 5.8. C22H28O14 requires C, 51.2; H, 5.5%)
[α]D Ϫ65 (c 0.5 in Me2CO); νmax (KBr)/cmϪ1 3300 (O–H)
Diels–Alder cycloaddition of diene 1 and maleic anhydride
A solution of freshly sublimed maleic anhydride (5.5 g,
56 mmol) and diene 1 (27.0 g, 55 mmol) in dry benzene
(150 cm3) was stirred for 24 h under an atmosphere of nitrogen.
Evaporation of the mixture left a residue that comprised
1
mainly a 75 : 25 mixture of the cycloadducts 10 and 11 by H
and 1755 (acid, lactone and ester C᎐O); δH (300 MHz; CDCl3)
᎐
NMR spectroscopy. Addition of diethyl ether to the residue
and filtration of the crystalline material gave (1R,2R,3S)-3-
(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-β--glucopyranosyloxy)-5-(trimethyl-
siloxy)cyclohex-4-ene-1,2-dicarboxylic anhydride 10 as white
crystals (19.0 g, 59%); mp 214–215 ЊC (lit.,3 212–213 ЊC).
Removal of the solvent from the filtrate and slow crystallisation
of the residue from dichloromethane–diethyl ether gave
1.89–2.12 (2 H, m, 3- and 8-H) overlapping with 2.00, 2.03, 2.08
and 2.10 (each 3 H, s, 4 × OAc), 2.17 (1 H, dd, J 14 and 9, 8-H),
2.32 (1 H, ddt, J 13.5, 6.5 and 3.5, 3-H), 2.83 (1 H, ddd, J 10.5,
7 and 1.5, 2-H), 3.00–3.45 (1 H, br s, COOH), 3.35 (1 H, br dd,
† Non-systematic numbering for the bicyclic ring.
J. Chem. Soc., Perkin Trans. 1, 2001, 2204–2212
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J 3 and 1.5, 1-H), 3.75 (1 H, ddd, J 9.5, 4 and 2.5, 5Ј-H), 4.17
(1 H, dd, J 12.5 and 2.5, 6Ј-H), 4.27 (1 H, dd, J 12.5 and 4,
6Ј-H), 4.39 (1 H, dt, J 9 and 3, 7-H), 4.76 (1 H, d, J 8, 1Ј-H),
4.76–4.81 (1 H, m, 4-H), 4.95 (1 H, dd, J 9.5 and 8, 2Ј-H), 5.09
(1 H, t, J 9.5, 4Ј-H) and 5.23 (1 H, t, J 9.5, 3Ј-H); m/z (FAB) 539
(MNaϩ, 7%), 517 (MHϩ, 23), 331 (C14H19O9ϩ, 45), 169 (90) and
136 (100).
hydrogen carbonate and extracted with dichloromethane
(2 × 100 cm3). The organic extracts were washed with water,
dried (MgSO4) and evaporated to leave a residue (0.240
g), which was crystallised from dichloromethane–diethyl ether
to give the title compound 19 (0.168 g, 35%) as fine colourless
needles; mp 191–194 ЊC (Found: C, 51.5; H, 6.0; N, 2.7.
C21H29NO12 requires C, 51.7; H, 6.0; N, 2.9%) [α]D Ϫ38 (c 0.5 in
CH2Cl2); νmax (KBr)/cmϪ1 3378 (N–H), 1751 (lactone C᎐O) and
᎐
1733 (ester C᎐O); δH (300 MHz; CDCl3) 1.65–1.75 (3 H, br m,
᎐
(1R,2R,3S,5S)-7-Oxo-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-ꢀ-D-gluco-
pyranosyloxy)-6-oxabicyclo[3.2.1]octane-2-carbonyl azide 16
NH2 and 8-Hβ), 1.89 (1 H, dd, J 15 and 5.5, 4-Hβ), 1.99, 2.01,
2.09 and 2.12 (each 3 H, s, 4 × OAc), 2.38–2.43 (1 H, m, 1-H),
2.44–2.56 (2 H, m, 4- and 8-Hα), 3.14–3.20 (1 H, m, 2-H), 3.64
(1 H, dt, J 9.5 and 3.5, 5Ј-H), 4.18 and 4.21 [3 H, overlapping d
(separation 4) and t (J 4.5), 6Ј-H2 and 3-H, respectively], 4.77
(1H, br t, J 4.5, 5-H), 4.82 (1 H, d, J 8, 1Ј-H), 5.03 (1 H, dd,
J 9.5 and 8, 2Ј-H), 5.08 (1 H, t, J 9.5, 4Ј-H) and 5.16 (1 H, t, J 9,
3Ј-H); δC (50 MHz; CDCl3) 20.6, 20.7, 35.8, 37.2, 46.2, 55.5,
61.9, 68.5, 71.3, 71.8, 73.0, 75.9, 76.0, 101.7, 169.0, 169.3, 170.4,
Oxalyl dichloride (1.20 cm3, 13.8 mmol) was added to a solu-
tion of lactonic acid 14 (4.50 g, 8.71 mmol) and dry DMF (6
drops) in dry dichloromethane (360 cm3) at room temperature.
Stirring was continued until the evolution of bubbles ceased
(30 min). After removal of solvent under reduced pressure
(<30 ЊC), the residue was dissolved in dry THF (100 cm3) and
sodium azide (4.5 g, 69 mmol) was added. The resulting mixture
was stirred at 0 ЊC for 1 h, poured into water (200 cm3) and
extracted with dichloromethane (2 × 100 cm3). The combined
organic extracts were washed with water (100 cm3), dried
(MgSO4) and the solvent removed. Crystallisation of the
residue from dichloromethane–diethyl ether gave the title
compound 16 (4.24 g, 90%) as white crystals; mp 218–230 ЊC
(decomp.) (Found: C, 48.8; H, 4.9; N, 7.4. C22H27N3O13 requires
C, 48.8; H, 5.0; N, 7.8%) [α]D Ϫ25 (c 1.1 in CH2Cl2); νmax (KBr)/
cmϪ1 2137 (N ), 1775 (lactone C᎐O) and 1726 (ester and acyl
ϩ
,
170.6 and 176.4; m/z (FAB) 488 (MHϩ, 83%), 331 (C14H19O9
27), 307 (42), 289 (30) and 136 (100).
4-Acetamido-1,6-di-O-acetyl-2,4-dideoxy-3-O-(2Ј,3Ј,4Ј,6Ј-
tetra-O-acetyl-ꢀ-D-glucopyranosyl)-5a-carba-ꢀ-L-lyxo-hexo-
pyranose 20
Lithium aluminium hydride (0.400 g, 10.5 mmol) was added
carefully to a solution of amine 19 (0.529 g, 1.09 mmol) in dry
THF (50 cm3) and the resulting mixture was heated under reflux
for 24 h. The reaction was quenched by successive additions
of ‘wet’ diethyl ether (10 cm3), water (1 cm3) and aq. sodium
hydroxide (15% w/v; 0.7 cm3). Evaporation of the mixture gave
a residue, which was dissolved in a mixture of acetic anhydride
(10 cm3) and pyridine (10 cm3) and the solution was stirred
for 48 h. Water was added and, after a further 3 h of stirring,
᎐
3
azide C᎐O); δ (300 MHz; CDCl3) 1.71 (1 H, d, J 11.5, 8-Hβ),
᎐
H
1.89 (1 H, dd, J 16 and 5, 4-Hβ), 1.98, 2.01, 2.06 and 2.10 (each
3 H, s, 4 × OAc), 2.50–2.70 (2 H, m, 4- and 8-Hα), 2.89 (1 H, dd,
J 4.5 and 2, 2-H), 3.04–3.10 (1 H, m, 1-H), 3.68 (1 H, dt, J 9 and
3.5, 5Ј-H), 4.19 (2 H, d, separation 3.5, 6Ј-H2), 4.47 (1 H, br t,
J 4, 3-H), 4.71 (1 H, d, J 8, 1Ј-H), 4.80 (1 H, br t, J 4.5, 5-H),
4.94 (1 H, dd, J 9.5 and 8, 2Ј-H), 5.05 (1 H, t, J 9.5, 4Ј-H) and
5.17 (1 H, t, J 9, 3Ј-H); m/z (FAB) 542 (MHϩ, 33%) and 331
(C14H19O9ϩ, 100).
the mixture was poured into hydrochloric acid (1 mol dmϪ3
;
200 cm3) then extracted with dichloromethane. The organic
layer was washed successively with hydrochloric acid (1 mol
dmϪ3) and water, dried (MgSO4) and the solvent was removed.
The residue was purified by silica gel column chromatography
[EtOAc–hexanes (9 : 1) as eluent] giving the title compound 20
(0.547 g, 81%) as a colourless foam; Rf 0.6 (EtOAc) (Found: C,
52.2; H, 6.4; N, 2.2; MHϩ, 618.2399. C27H39NO15 requires C,
52.5; H, 6.4; N, 2.3%; MHϩ, 618.2398) [α]D Ϫ23 (c 0.2 in
CH2Cl2); νmax (KBr)/cmϪ1 3387br (N–H), 2946, 1738 (ester
(1R,2R,3S,5S)-2-Isocyanato-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-ꢀ-D-
glucopyranosyloxy)-6-oxabicyclo[3.2.1]octan-7-one 17
A suspension of acyl azide 16 (0.200 g, 0.369 mmol) in dry
benzene (30 cm3) was heated under reflux for 2 h. Removal of
the solvent in vacuo and crystallisation of the residue from
dichloromethane–diethyl ether gave the title compound 17 as
colourless crystals (0.185 g, 98%); mp 230–232 ЊC (Found: C,
51.4; H, 5.4; N, 2.8. C22H27NO13 requires C, 51.5; H, 5.3; N,
2.7%) [α]D Ϫ45 (c 0.9 in CH2Cl2); νmax (KBr)/cmϪ1 2287 (NCO),
C᎐O) and 1672 (amide C᎐O); δH (300 MHz; CDCl3) 1.12 (1 H,
᎐
᎐
br q, J 13, 5a-Hax), 1.53 (1 H, q, J 12, 2-Hax), 1.80–1.95 (2 H, m,
5-H and 5a-Heq), 1.97, 1.98, 2.01, 2.03, 2.04, 2.05 and 2.08 (each
3 H, s, 6 × OAc and NAc), 2.22–2.33 (1 H, m, 2-Heq), 3.70 (1 H,
ddd, J 10, 5 and 2.5, 5Ј-H), 3.74–3.87 (2 H, m, 3- and 6-H),
4.06–4.16 (2 H, m, 6Ј- and 6-H), 4.26 (1 H, dd, J 12 and 5,
6Ј-H), 4.55 (1 H, br dt, J 10 and 4, 4-H), 4.62 (1 H, d, J 8, 1Ј-H),
4.76 (1 H, br tt, J 12 and 4, 1-H), 4.91 (1 H, dd, J 10 and 8,
2Ј-H), 5.02 (1 H, t, J 10, 4Ј-H), 5.17 (1 H, t, J 10, 3Ј-H) and 5.40
(1 H, br d, J 10, NH); δC (75 MHz; CDCl3) 20.6, 20.7, 20.9 and
21.1 (6 × OCOCH3), 23.2 (NCOCH3), 28.6 (5a-CH2), 34.0
(2-CH2), 35.8 (5-CH), 46.0 (4-CH), 62.0 (6Ј-CH2), 64.5 (6-CH2),
68.4 (4Ј-CH), 68.6 (1-CH), 71.0 (2Ј-CH), 71.7 (5Ј-CH), 72.6
(3Ј-CH), 75.0 (3-CH), 99.8 (1Ј-CH) and 169.5, 169.6, 170.1,
170.5, 170.7 and 171.0 (7 × CO); m/z (FAB) 618 (MHϩ, 25%),
558 (MHϩ Ϫ CH3CO2H, 6), 331 (C14H19O9ϩ, 90) and 307 (100).
1768 (lactone C᎐O) and 1750 (ester C᎐O); δ (300 MHz;
᎐
᎐
H
CDCl3) 1.75 (1 H, d, J 12, 8-Hβ), 1.88 (1 H, dd, J 15.5 and 5,
4-Hβ), 1.99, 2.01, 2.08 and 2.11 (each 3 H, s, 4 × OAc), 2.49–
2.59 (2 H, m, 4- and 8-Hα), 2.68–2.75 (1 H, m, 1-H), 3.67 and
3.71 [2 H, overlapping dt (J 10 and 3.5) and dd (J 4 and 2.5),
5Ј- and 2-H, respectively], 4.18 and 4.22 [3 H, overlapping d
(separation 3.5) and t (J 4.5), 6Ј-H2 and 3-H, respectively], 4.75
and 4.79 [2 H, overlapping d (J 8) and t (J 5), 1Ј- and 5-H,
respectively], 5.02–5.12 (2 H, m, 2Ј- and 4Ј-H) and 5.19 (1 H, t,
J 9.5, 3Ј-H); δC (75 MHz; CDCl3) 20.6, 20.7 (2×), 20.8, 35.0,
37.2, 43.7, 56.6, 61.8, 68.6, 70.8, 71.9, 72.8, 72.9, 75.5, 101.1,
125.3, 169.5, 169.7, 170.4, 170.7 and 174.6; m/z (FAB) 514
(MHϩ, 25%), 331 (C14H19O9ϩ, 94) and 169 (100).
(1R,2R,3S,5S)-2-Amino-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-ꢀ-D-
glucopyranosyloxy)-6-oxabicyclo[3.2.1]octan-7-one 19
4-Acetamido-2,4-dideoxy-3-O-(ꢀ-D-glucopyranosyl)-5a-carba-ꢀ-
L-lyxo-hexopyranose 7
Triethylamine (0.120 cm3, 0.861 mmol) was added to a stirred
solution of isocyanate 17 (0.500 g, 0.974 mmol) in a mixture
of THF (25 cm3) and water (25 cm3). After 10 min at room
temperature, the solution was acidified with hydrochloric acid
(1 mol dmϪ3), poured into dichloromethane (100 cm3) and
extracted with hydrochloric acid (1 mol dmϪ3; 3 × 60 cm3). The
combined aqueous extracts were basified using solid sodium
IRA-400 (OHϪ) Resin (1 g) was added to a solution of com-
pound 20 (0.212 g, 0.343 mmol) in absolute methanol (43 cm3)
and the mixture was stirred at ambient temperature until the
presence of starting material could not be detected by TLC
(12 h). The mixture was filtered, the resin was washed with
water (30 cm3), and the combined filtrate and washings were
2208
J. Chem. Soc., Perkin Trans. 1, 2001, 2204–2212

View Article Online
evaporated in vacuo. Purification of the glassy residue by
semi-preparative reversed-phase HPLC [water–MeOH (7 : 3) as
eluent; λ = 220 nm] gave the title compound 7 (0.092 g, 73%) as a
glass (Found: C, 46.6; H, 7.6; N, 3.5. C15H27NO9ؒH2O requires
C, 47.1; H, 7.4; N, 3.7%) [α]D Ϫ24 (c 0.1 in water); δH (300 MHz;
D2O) 1.10 (1 H, br dt, J 11 and 14, 5a-Hax), 1.56 (1 H, q, J 12,
2-Hax), 1.75–1.89 (2 H, m, 5-H and 5a-Heq), 2.07 (3 H, s, NAc),
2.16–2.27 (1 H, m, 2-Heq), 3.19 (1 H, dd, J 9 and 8, 2Ј-H), 3.31–
3.52 (5 H, m, 3Ј-, 4Ј- and 5Ј-H and 6-H2), 3.70 (1 H, dd, J 12
and 6, 6Ј-H), 3.79 (1 H, br tt, J 11 and 4, 1-H), 3.91 (1 H, dd,
J 12 and 2, 6Ј-H), 4.06 (1 H, dt, J 13 and 4, 3-H) and 4.53 and
4.56 [2 H, overlapping t (J 4) and d (J 8), 4- and 1Ј-H, respec-
tively]; δC (75 MHz; D2O) 23.3 (NCOCH3), 31.9 (5a-CH2), 37.4
(2-CH2), 39.1 (5-CH), 47.4 (4-CH), 62.0 (6Ј-CH2), 63.5 (6-CH2),
68.1 (1-CH), 71.0, 74.3 (2Ј-CH), 76.7, 76.8, 77.3, 101.8 (1Ј-CH)
and 176.7 (CO); m/z (FAB) 366 (MHϩ, 2%), 307 (12), 289 (10),
204 (10) and 154 (100).
Sodium cyanoborohydride reduction of ketone 12
Using the method for the preparation of lactones 14 and 15,
sodium cyanoborohydride (4.74 g, 75.5 mmol) was added to
a solution of ketone 12 (7.75 g, 15.1 mmol) in glacial acetic
acid (100 cm3) and the mixture was stirred under a drying tube
(CaCl2) overnight. Work-up gave a foam which comprised
a 75 : 25 mixture of the acids 21 and 22.‡ Crystallisation
of the mixture from dichloromethane–diethyl ether gave
(1S,2S,3R,5R)-7-oxo-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-β--gluco-
pyranosyloxy)-6-oxabicyclo[3.2.1]octane-2-carboxylic acid 21
as colourless crystals (4.50 g, 58%); mp 192–194 ЊC (Found:
C, 51.0; H, 5.2. C22H28O14 requires C, 51.2; H, 5.5%); [α]D Ϫ25
(c 1.0 in CH2Cl2); νmax (KBr)/cmϪ1 3431 (O–H), 1755 (lactone
C᎐O) and 1740 (ester and acid C᎐O); δ (300 MHz; CDCl3)
᎐
᎐
H
1.78 (1 H, dd, J 16 and 4, 4-Hβ), 1.81 (1 H, d, J 12, 8-Hβ), 2.01,
2.03, 2.10 and 2.12 (each 3 H, s, 4 × OAc), 2.20–2.75 (1 H, br s,
COOH), 2.45 (1 H, br d, J 15, 4-Hα), 2.57 (1 H, ddt, J 12, 2 and
6, 8-Hα), 3.00 (1 H, dd, J 4.5 and 1.5, 2-H), 3.04 (1 H, br d, J 5.5,
1-H), 3.67 (1 H, ddd, J 10, 4 and 2.5, 5Ј-H), 4.11 (1 H, dd, J 12.5
and 4, 6Ј-H), 4.35 (1 H, dd, J 12.5 and 2.5, 6Ј-H), 4.68–4.72
(1 H, m, 3-H), 4.70 (1 H, d, J 7.5, 1Ј-H), 4.79 (1 H, br t, J 5,
5-H), 4.87 (1 H, dd, J 9 and 7.5, 2Ј-H) and 5.09–5.21 (2 H, m,
4Ј- and 3Ј-H); δC (75 MHz; CDCl3) 20.7 (2×), 20.8, 20.9, 30.5,
36.5, 38.0, 49.8, 61.8, 68.6, 71.1, 71.6, 71.9, 72.8, 75.1, 96.5,
160.9, 169.4, 169.6, 170.5, 171.4 and 175.2; m/z (FAB) 1055
(M2Naϩ, 1%), 1033 (M2Hϩ, 2), 539 (MNaϩ, 13), 517 (MHϩ, 23),
331 (C14H19O9ϩ, 72) and 154 (100).
Preparation of pseudo-disaccharide 7 from isocyanate 17
Triethylamine (1.00 cm3, 7.17 mmol) was added to a solution of
isocyanate 17 (0.25 g, 0.501 mmol) in a 1 : 1 mixture of THF–
water (25 cm3) and the mixture was stirred for 15 min. After
removal of the solvent under reduced pressure, the residue was
dissolved in dry THF (50 cm3), and lithium aluminium hydride
(0.227 g, 5.98 mmol) was carefully added; the resulting mixture
was heated under reflux for 24 h. The reaction mixture was
quenched by successive additions of ‘wet’ diethyl ether (10 cm3),
water (1 cm3) and aq. sodium hydroxide (15% w/v; 0.7 cm3).
Evaporation of the mixture gave a colourless residue which was
dissolved in a mixture of acetic anhydride (10 cm3) and pyridine
(10 cm3) and this mixture was stirred for 48 h. Water (100 cm3)
was added and, after a further 3 h of stirring, the mixture was
poured into hydrochloric acid (1 mol dmϪ3; 200 cm3) then
extracted with dichloromethane (2 × 100 cm3). The combined
organic layers were washed successively with hydrochloric acid
(1 mol dmϪ3; 200 cm3) and water (200 cm3), dried (MgSO4) and
concentrated in vacuo. IRA-400 (OHϪ) Resin (1 g) was added
to a stirred solution of the crude residue in absolute methanol
(50 cm3). When the presence of compound 20 could not be
detected by TLC (12 h), the mixture was filtered, the resin was
washed with water (30 cm3) and the combined filtrate and
washings were evaporated in vacuo. Purification of the glassy
residue by semi-preparative reversed-phase HPLC [water–
MeOH (7 : 3) as eluent; λ = 220 nm] gave the title compound 7
(0.103 g, 56% based on isocyanate 17).
The mother liquors were concentrated under reduced
pressure to give (1S,2S,4R,7R)-6-oxo-7-(2Ј,3Ј,4Ј,6Ј-tetra-O-
acetyl-β--glucopyranosyloxy)-5-oxabicyclo[2.2.2]octane-2-carb-
oxylic acid† 22 as a slightly impure colourless foam (0.930 g,
12%); νmax (KBr)/cmϪ1 3429 (O–H), 1762 (lactone and ester
C᎐O) and 1712 (acid C᎐O); δ (300 MHz; CDCl3) inter alia
᎐
᎐
H
1.82–1.98 (2 H, m, 3- and 8-H), 2.00, 2.03 (2×) and 2.11 (each
3 H, s, 4 × OAc), 2.05–2.17 (1 H, m, 8-H), 2.35 (1 H, br ddt,
J 14.5, 6.5 and 3.5, 3-H), 2.87 (1 H, br ddd, J 10.5, 6.5 and 1.5,
2-H), 3.36 (1 H, br dd, J 3 and 1.5, 1-H), 3.72 (1 H, dt, J 9.5 and
3.5, 5Ј-H), 4.19 (1 H, dd, J 12 and 2.5, 6Ј-H), 4.23 (1 H, dd,
J 12.5 and 4.5, 6Ј-H), 4.30 (1H, dt, J 9 and 3, 7-H), 4.65 (1 H, d,
J 8, 1Ј-H), 4.75–4.80 (1 H, m, 5-H), 4.95 (1 H, dd, J 9.5 and 8,
2Ј-H), 5.08 (1 H, t, J 9.5, 4Ј-H) and 5.20 (1 H, t, J 9.5, 3Ј-H);
δC (75 MHz; CDCl3) 20.7, 20.8, 28.4, 33.5, 37.3, 44.4, 62.1, 68.4,
71.1, 72.0, 72.7, 73.1, 99.5, 169.2, 169.4, 170.5, 171.1 and 174.9.
(1S,2S,3R,5R)-7-Oxo-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-ꢀ-D-gluco-
pyranosyloxy)-6-oxabicyclo[3.2.1]octane-2-carbonyl azide 23
Benzyl (1R,2R,3S,5S)-7-oxo-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-ꢀ-D-
glucopyranosyloxy)-6-oxabicyclo[3.2.1]octane-2-carbamate 18
Using the procedure described for the preparation of acyl azide
16, lactonic acid 21 (0.500 g, 0.97 mmol) gave a colourless solid,
which was crystallised from dichloromethane–diethyl ether to
give the title compound 23 (0.520 g, 99%) as colourless crystals;
mp 205–215 ЊC (Found: C, 48.0; H, 5.1; N, 7.5. C22H27N3O13
requires C, 48.8; H, 5.0; N, 7.8%) [α]D ϩ15 (c 0.5 in CH2Cl2);
νmax (KBr)/cmϪ1 2143 (N ), 1778 (lactone C᎐O), 1762 (ester
A mixture of dry benzyl alcohol (0.380 g, 3.67 mmol) and iso-
cyanate 17 (0.310 g, 0.604 mmol) in dry benzene (30 cm3) was
heated under reflux for 20 h. Evaporation of the mixture in
vacuo and crystallisation of the residue from dichloromethane–
diethyl ether gave the title compound 18 as colourless crystals
(0.351 g, 94%); mp 221–223 ЊC (Found: C, 55.7; H, 5.6; N, 2.2.
C29H35NO14 requires C, 56.0; H, 5.7; N, 2.25%) [α]D Ϫ18 (c 0.5
in CH2Cl2); νmax (KBr)/cmϪ1 3414 (N–H), 2930, 1753 (lactone
᎐
3
C᎐O) and 1716 (acyl azide C᎐O); δ (300 MHz; CDCl3) 1.70–
᎐
᎐
H
1.81 (2 H, m, 4- and 8-Hβ), 2.00, 2.02, 2.08 and 2.11 (each 3 H,
s, 4 × OAc), 2.46 (1 H, br d, J 15, 4-Hα), 2.57 (1 H, ddt, J 12, 2
and 6, 8-Hα), 2.89 (1 H, dd, J 4.5 and 2, 2-H), 3.05 (1H, br d,
J 5, 1-H), 3.67 (1 H, ddd, J 10, 4.5 and 2.5, 5Ј-H), 4.15 (1 H, dd,
J 12.5 and 2.5, 6Ј-H), 4.22 (1 H, dd, J 12.5 and 4.5, 6Ј-H), 4.66
(1 H, br t, J 5, 3-H), 4.69 (1 H, d, J 8, 1Ј-H), 4.78 (1 H, br t,
J 5, 5-H), 4.86 (1 H, dd, J 9.5 and 8, 2Ј-H), 5.09 (1 H, t, J 9.5,
4Ј-H) and 5.21 (1 H, t, J 9.5, 3Ј-H); δC (75 MHz; CDCl3) 20.7
(3×), 20.8, 30.5, 36.0, 37.8, 51.5, 61.9, 68.4, 71.0, 71.3, 72.0,
72.7, 74.6, 96.6, 169.2, 169.3, 170.4, 170.7, 174.1 and 175.8; m/z
(FAB) 564 (MNaϩ, 15%), 542 (MHϩ, 3), 536 (33), 331
(C14H19O9ϩ, 45) and (100).
C᎐O), 1746 (ester C᎐O) and 1736 (carbamate C᎐O); δ (300
᎐
᎐
᎐
H
MHz; CDCl3) 1.82 (1 H, d, J 11.5, 8-Hβ), 1.91 (1 H, dd, J 15
and 5, 4-Hβ), 1.98, 1.99, 2.02 and 2.08 (each 3 H, s, 4 × OAc),
2.46–2.63 (3 H, m, 1-H and 4- and 8-Hα), 3.52 (1 H, dt, J 9 and
3.5, 5Ј-H), 4.07–4.20 (4 H, m, 2- and 3-H and 6Ј-H2), 4.47 (1 H,
d, J 8, 1Ј-H), 4.78 (1 H, br t, J 5, 5-H), 4.94–5.19 (5 H, m,
2Ј-, 3Ј- and 4Ј-H and OCH2Ph), 5.68 (1 H, br d, J 9.5, NH)
and 7.28–7.41 (5 H, m, C6H5); δC (50 MHz; CDCl3) 20.4,
20.6 (2×), 20.8, 35.3, 36.9, 42.1, 53.1, 61.7, 67.3, 68.2, 71.5,
72.0, 72.9, 75.6, 75.8, 102.1, 128.3, 128.7, 136.1, 155.6, 168.8,
169.2, 170.4, 170.6 and 176.0; m/z (FAB) 622 (MHϩ, 45%), 604
(8), 562 (MHϩ Ϫ CH3CO2H, 4), 331 (C14H19O9ϩ, 86) and 169
(100).
‡ The ratio was determined on the methyl esters obtained from the acids
21 and 22 by the action of ethereal diazomethane.
J. Chem. Soc., Perkin Trans. 1, 2001, 2204–2212
2209

View Article Online
(FAB) 564 (MNaϩ, 15%), 542 (MHϩ, 3), 536 (33), 331
(C14H19O9ϩ, 45) and (100).
m, 5a-Hax), 1.57 (1 H, br dt, J 13.5 and 10, 2-Hax), 1.76–1.91
(1 H, m, 5a-Heq), 1.92–2.15 (2 H, m, 2-Heq and 5-H), 1.98, 2.00,
2.03, 2.04, 2.05 and 2.08 (6, 3, 3, 3, 3 and 3 H, each s, 6 × OAc
and NAc), 3.67 (1 H, ddd, J 9.5, 4 and 2.5, 5Ј-H), 3.81 (1 H, dt,
J 10 and 4.5, 3-H), 3.93 (1 H, dd, J 11 and 8, 6-H), 4.14 (1 H,
dd, J 12.5 and 2.5, 6Ј-H), 4.19 (1 H, dd, J 11 and 6, 6-H), 4.26
(1 H, dd, J 12.5 and 4, 6Ј-H), 4.43 (1 H, dt, J 8.5 and 4, 4-H),
4.56 (1 H, d, J 8, 1Ј-H), 4.78 (1 H, tt, J 10 and 5, 1-H), 4.94 (1 H,
dd, J 9.5 and 8, 2Ј-H), 5.06 (1 H, t, J 9.5, 4Ј-H), 5.16 (1 H, t,
J 9.5, 3Ј-H) and 5.60 (1 H, br d, J 8.5, NH); δC(75 MHz; CDCl3)
20.6, 20.7, 20.8, 21.0, 21.2, 23.4, 28.8, 33.1, 36.2, 48.4, 61.5,
64.9, 67.9, 68.2, 71.5, 72.1, 72.7, 76.0, 99.9, 169.3, 169.4, 170.3,
170.4, 170.7 and 171.0; m/z (FAB) 1235 (M2Hϩ, 3%), 640
(MNaϩ, 4), 618 (MHϩ, 39), 331 (C14H19O9ϩ, 79) and 169 (100).
Benzyl (1S,2S,3R,5R)-7-oxo-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-ꢀ-D-
glucopyranosyloxy)-6-oxabicyclo[3.2.1]octane-2-carbamate 24
A mixture of acyl azide 23 (400 mg, 0.74 mmol) and dry benzyl
alcohol (0.80 cm3, 7.7 mmol) in dry benzene (15 cm3) was
heated to reflux under a drying tube (CaCl2) for 24 h. The solu-
tion was concentrated under reduced pressure and the residue
was dried in vacuo to a gel. Crystallisation from dichloro-
methane–diethyl ether–hexanes gave the title compound 24
(0.410 g, 89%) as colourless crystals; mp 197–199 ЊC (Found: C,
56.1; H, 5.7; N, 2.2. C29H35NO14 requires C, 56.0; H, 5.7; N,
2.3%) [α]D Ϫ34 (c 1.0 in CH2Cl2); νmax (KBr)/cmϪ1 3434 (N-H),
1770 (lactone C᎐O), 1755 (ester C᎐O) and 1716 (carbamate C᎐
᎐
᎐
᎐
(1R,2R,3R,4S)-4-Hydroxy-5-oxo-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-
O); δH (300 MHz; CDCl3) 1.76 (1 H, dd, J 15.5 and 5, 4-Hβ),
1.88 (1 H, d, J 12, 8-Hβ), 1.99, 2.00, 2.01 and 2.11 (each 3 H, s,
4 × OAc), 2.39 (1 H, br d, J 15.5, 4-Hα), 2.53 (1 H, ddt, J 11.5, 2
and 6, 8-Hα), 2.72 (1 H, br d, J 5.5, 1-H), 3.64 (1 H, ddd, J 10,
4.5 and 2.5, 5Ј-H), 4.07 (1 H, dd, J 12.5 and 2.5, 6Ј-H), 4.08–
4.13 (1 H, m, 2-H), 4.19 (1 H, dd, J 12.5 and 4.5, 6Ј-H), 4.29
(1 H, br t, J 4.5, 3-H), 4.61 (1 H, d, J 8, 1Ј-H), 4.76 (1 H, br t,
J 4.5, 5-H), 4.96 (1 H, dd, J 9.5 and 8, 2Ј-H), 5.07 (1 H, t, J 9.5,
4Ј-H), 5.09 and 5.12 (each 1 H, d, J 11.5, OCH2Ph), 5.22 (1 H,
t, J 9.5, 3Ј-H), 5.95 (1 H, d, J 9.5, NH) and 7.28–7.42 (5 H, m,
C6H5); δC (75 MHz; CDCl3) 20.6 (3×), 20.8, 30.2, 37.2, 41.8,
52.9, 61.7, 67.0, 68.3, 70.8, 72.1, 72.4, 72.8, 75.1, 97.4, 128.1
(3×), 128.5 (2×), 136.3, 155.9, 169.3, 169.4, 170.3, 170.6 and
175.5; m/z (FAB) 644 (MNaϩ, 1%), 622 (MHϩ, 5), 578 (1), 331
(C14H19O9ϩ, 13), 169 (53) and 154 (100).
ꢀ-D-glucopyranosyloxy)cyclohexane-1,2-dicarboxylic anhydride
26
Cycloadduct 10 (3.512 g, 5.99 mmol) was added to an excess of
a freshly prepared solution of DMDO in dry acetone (90 cm3)
and the resulting yellow solution was stirred at ambient
temperature for 1 h. The solution was filtered and the filtrate
was concentrated in vacuo. The residual solid was crystallised
from acetone–diethyl ether to give the title compound 26 as
colourless crystals (2.704 g, 85%); mp 168–170 ЊC (Found: C,
49.9; H, 4.85. C22H26O15 requires C, 49.8; H, 4.9%) [α]D Ϫ91
(c 0.2 in CH2Cl2); νmax (KBr)/cmϪ1 3477br (O-H), 1866 and 1780
(anhydride C᎐O) and 1747 (ester and ketone C᎐O); δ (300
᎐
᎐
H
MHz; CDCl3) 1.99, 2.03, 2.09 and 2.12 (each 3 H, s, 4 × OAc),
2.85–2.97 (1 H, m, 6-H), 3.02–3.14 (1 H, m, 6-H), 3.43–3.56
(2 H, m, 1- and 2-H), 3.72 (1 H, ddd, J 10, 5 and 2.5, 5Ј-H), 4.15
(1 H, dd, J 12.5 and 2.5, 6Ј-H), 4.22 and 4.26 [2 H, overlapping
d (J 2.5) and dd (J 12.5 and 2.5), 4- and 6Ј-H, respectively], 4.53
(1 H, t, J 3, 3-H), 4.64 (1 H, d, J 8, 1Ј-H), 4.95 (1 H, dd, J 10 and
8, 2Ј-H), 5.02 (1 H, t, J 10, 4Ј-H) and 5.19 (1 H, t, J 9.5, 3Ј-H);
δC (50 MHz; d6-DMSO) 20.2, 20.4, 20.5, 33.6 (6-CH2), 36.0,
41.5, 61.6 (6Ј-CH2), 68.1, 70.3 (2×), 70.6, 71.5, 79.3, 100.5,
168.8, 169.2, 169.5, 170.0, 171.5, 173.3 and 204.7 (5-CO);
m/z (FAB) 531 (MHϩ, 1%), 471 (MHϩ Ϫ CH3CO2H, 1), 331
(C14H19O9ϩ, 19), 205 (7), 169 (29) and 154 (100).
(1S,2S,3R,5R)-2-Amino-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-ꢀ-D-
glucopyranosyloxy)-6-oxabicyclo[3.2.1]octan-7-one 25
A mixture of the benzyl carbamate 24 (400 mg, 0.64 mmol) and
10% palladium–carbon (50 mg) in ethanol (50 cm3) was stirred
under a hydrogen atmosphere overnight. The mixture was fil-
tered through Celite® and the filtrate was concentrated under
reduced pressure. The residue was dried in vacuo to a solid,
which was crystallised from dichloromethane–diethyl ether to
give the title compound 25 (0.180 g, 57%) as colourless crystals;
mp 225–227 ЊC (Found: C, 51.5; H, 5.8; N, 2.9. C21H29NO12
requires C, 51.7; H, 6.0; N, 2.9%) [α]D Ϫ59 (c 0.5 in CH2Cl2);
(1R,2R,3R,4R,5S)-4,5-Dihydroxy-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-
ꢀ-D-glucopyranosyloxy)cyclohexane-1,2-dicarboxylic anhydride
30
νmax (KBr)/cmϪ1 3380 (N-H), 1764 (lactone C᎐O) and 1752
᎐
(ester C᎐O); δ (300 MHz; CDCl ) 1.66–1.82 (2 H, m, 4- and 8-
᎐
H
3
Hβ), 2.01, 2.02, 2.08 and 2.12 (each 3 H, s, 4 × OAc), 2.36–2.56
(3 H, m, 1-H and 4- and 8-Hα), 3.22 (1 H, br d, J 4, 2-H), 3.67
(1 H, ddd, J 10, 4 and 2.5, 5Ј-H), 4.16 (1 H, dd, J 12.5 and 2.5,
6Ј-H), 4.21 (1 H, dd, J 12.5 and 4.5, 6Ј-H), 4.28 (1 H, br t, J 4.5,
3-H), 4.67 (1 H, d, J 8, 1Ј-H), 4.74 (1 H, br t, J 4.5, 5-H), 4.99
(1 H, dd, J 9.5 and 8, 2Ј-H), 5.08 (1 H, t, J 9.5, 4Ј-H) and 5.23
(1 H, t, J 9.5, 3Ј-H); δC(75 MHz; CDCl3) 20.7 (2×), 20.8 (2×),
30.9, 37.6, 45.2, 54.7, 61.8, 68.5, 70.8, 72.0, 72.7, 73.6, 75.4,
96.9, 169.3, 169.5, 170.4, 170.7 and 176.1; m/z (FAB) 510
(MNaϩ, 4%), 488 (MHϩ, 50), 331 (C14H19O9ϩ, 10) and 169
(100).
A solution of acyloin 26 (1.022 g, 1.93 mmol) in glacial acetic
acid (30 cm3) was treated with sodium cyanoborohydride
(0.613 g, 9.75 mmol) and stirred overnight (15 h) at room tem-
perature. The solvent was removed in vacuo and the residue was
partitioned between dichloromethane (50 cm3) and hydro-
chloric acid (≈1 mol dmϪ3; 100 cm3). The aqueous layer was
extracted with dichloromethane (2 × 40 cm3) and the combined
organic layers were washed with water (200 cm3) and dried
(MgSO4). Removal of the solvent gave a residue, which was
crystallised from dichloromethane–diethyl ether to yield the
title compound 30 (0.578 g, 56%) as colourless crystals; mp 187–
190 ЊC (Found: C, 49.5; H, 5.3. C22H28O15 requires C, 49.6; H,
5.3%) [α]D ϩ16 (c 0.2 in CH2Cl2); νmax (KBr)/cm–1 3522 and
4-Acetamido-1,6-di-O-acetyl-2,4-dideoxy-3-O-(2Ј,3Ј,4Ј,6Ј-tetra-
O-acetyl-ꢀ-D-glucopyranosyl)-5a-carba-ꢀ-D-lyxo-hexopyranose
8
3490br (O-H), 1852 and 1780 (anhydride C᎐O) and 1749 and
᎐
1721 (ester C᎐O); δ (300 MHz; CDCl3) 1.92–2.04 (1 H, m,
᎐
H
6-H) overlapping with 1.99, 2.04, 2.11 and 2.14 (each 3 H, s,
4 × OAc), 2.18 (1 H, dt, J 14 and 4.5, 6-H), 2.69 (1 H, br d,
J 2.5, 4-OH), 2.81 (1 H, br d, J 2.5, 5-OH), 3.29 (1 H, dt, J 3.5
and 9, 1-H), 3.45 (1 H, dd, J 9.5 and 4.5, 2-H), 3.64 (1 H, ddd,
J 10, 4 and 2.5, 5Ј-H), 4.02–4.15 (3 H, m, 4-, 5- and 6Ј-H), 4.24
(1 H, t, J 4, 3-H), 4.50 and 4.52 [2 H, overlapping dd (J 12.5 and
2) and d (J 8), 6Ј- and 1Ј-H, respectively], 4.89 (1 H, dd, J 9.5
and 8, 2Ј-H), 5.03 (1 H, t, J 9.5, 4Ј-H) and 5.14 (1 H, t, J 9.5,
3Ј-H); m/z (FAB) 555 (MNaϩ, 2%), 331 (C14H19O9ϩ, 13), 176 (8)
and 136 (100).
Treatment of compound 25 (80 mg, 0.16 mmol) with lithium
aluminium hydride (100 mg, 2.6 mmol) in dry THF (10 cm3)
and subsequent acetylation as described for the preparation of
compound 20 gave, after purification by flash chromatography
[EtOAc–hexanes (4 : 1) as eluent], the title compound 8 (0.060 g,
63%) as a colourless foam (Found: C, 52.4; H, 6.5; N, 2.3.
C27H39NO15 requires C, 52.5; H, 6.4; N, 2.3%) [α]D ϩ2.7 (c 1.0 in
CH2Cl2); νmax (KBr)/cmϪ1 3431 (N-H), 2977, 1756 (ester C᎐O)
᎐
and 1679 (amide C᎐O); δ (300 MHz; CDCl3) 1.33–1.47 (1 H,
᎐
H
2210
J. Chem. Soc., Perkin Trans. 1, 2001, 2204–2212

View Article Online
(1R,2R,3R,4S)-4-Acetoxy-5-oxo-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-ꢀ-
D-glucopyranosyloxy)cyclohexane-1,2-dicarboxylic anhydride 27
(1R,2R,3R,4R,5S)-4-Acetoxy-7-oxo-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-
acetyl-ꢀ-D-glucopyranosyloxy)-6-oxabicyclo[3.2.1]octane-2-
carbonyl chloride 32
Acyloin 26 (1.060 g, 2.00 mmol) was added to a stirred solution
of acetic anhydride (5 cm3) and a catalytic amount of perchloric
acid (70% v/v; 2 drops) cooled in an ice-bath. After 10 min, the
mixture was poured into water (60 cm3) and extracted with
dichloromethane (2 × 50 cm3). The organic extracts were dried
(MgSO4), and concentrated in vacuo (<40 ЊC). Crystallisation
of the residue from dichloromethane–diethyl ether gave the
title compound 27 (0.958 g, 84%) as colourless crystals; mp 172–
175 ЊC (Found: C, 50.6; H, 4.7. C24H28O16 requires C, 50.4;
H, 4.9%) [α]D Ϫ106 (c 0.3 in CH2Cl2); νmax (KBr)/cmϪ1 1864
To a solution of lactonic acid 28 (1.119 g, 1.95 mmol) in
dry dichloromethane (50 cm3) were added oxalyl dichloride
(0.50 cm3, 5.73 mmol) and a catalytic amount of dry DMF
(2 drops). Stirring was continued until the evolution of bubbles
ceased (30 min). The mixture was poured into water (100 cm3),
extracted with dichloromethane (2 × 30 cm3) and the combined
extracts were washed with water (200 cm3), dried (MgSO4)
and the solvent was removed in vacuo (<30 ЊC). Crystallisation
of the residue from dichloromethane–diethyl ether gave the title
compound 32 as colourless crystals (0.950 g, 82%); mp 160–
167 ЊC (decomp.) (Found: C, 48.4; H, 4.8; Cl, 5.9. C24H29ClO15
requires C, 48.6; H, 4.9; Cl, 6.0%); νmax (KBr)/cmϪ1 1818 (acyl
and 1782 (anhydride C᎐O), 1752 (ester C᎐O) and 1734 (ketone
᎐
᎐
C᎐O); δ (300 MHz; CDCl3) 1.99, 2.02, 2.08, 2.10 and 2.13
᎐
H
(each 3 H, s, 5 × OAc), 2.95 (1 H, dd, J 15.5 and 8.5, 6-H), 3.06
(1 H, dd, J 15.5 and 10, 6-H), 3.48 (1 H, dd, J 10.5 and 3.5,
2-H), 3.58 (1 H, dt, J 8.5 and 10, 1-H), 3.76 (1 H, ddd, J 10, 5
and 2.5, 5Ј-H), 4.13 (1 H, dd, J 12.5 and 2.5, 6Ј-H), 4.23 (1 H,
dd, J 12.5 and 5.5, 6Ј-H), 4.51 (1 H, dd, J 3.5 and 2.5, 3-H), 4.65
(1 H, d, J 8, 1Ј-H), 4.95 (1 H, dd, J 10 and 8, 2Ј-H), 5.01 (1 H,
t, J 10, 4Ј-H), 5.19 (1 H, t, J 9.5, 3Ј-H) and 5.34 (1 H, d, J 2.5,
4-H); m/z (FAB) 573 (MHϩ, 2%), 513 (MHϩ Ϫ CH3CO2H, 3),
331 (C14H19O9ϩ, 62), 169 (94) and 136 (100).
chloride C᎐O), 1790 (lactone C᎐O) and 1758br (ester C᎐O);
᎐
᎐
᎐
δH (300 MHz; CDCl3) 1.98, 2.01, 2.05, 2.09 and 2.14 (each 3 H,
s, 5 × OAc), 1.98–2.14 (1 H, m, 8-Hβ), 2.40–2.50 (1 H, m, 8-Hα),
3.05 (1 H, br d, J 5, 1-H), 3.44 (1 H, dd, J 4.5 and 2, 2-H), 3.74
(1 H, ddd, J 9.5, 4 and 2.5, 5Ј-H), 4.21 (1 H, dd, J 12.5 and 4,
6Ј-H), 4.28 (1 H, dd, J 12.5 and 3, 6Ј-H), 4.46 (1 H, br d, J 4,
3-H), 4.71 and 4.75 [2 H, overlapping d (J 8) and t (J 4.5),
1Ј- and 5-H, respectively], 4.99 (1 H, dd, J 9.5 and 8, 2Ј-H), 5.08
(1 H, t, J 9.5, 4Ј-H), 5.17 (1 H, t, J 9.5, 3Ј-H) and 5.66 (1 H, br d,
J 4.5, 4-H); m/z (FAB) 595 and 593 (each MHϩ, 0.5 and 2%),
331 (C14H19O9ϩ, 32), 169 (67) and 154 (100).
Sodium cyanoborohydride reduction of ketone 27
A solution of ketone 27 (2.57 g, 4.48 mmol) in glacial acetic
acid (40 cm3) was treated with sodium cyanoborohydride
(1.55 g, 24.7 mmol) and stirred overnight. Work-up, as
employed for the preparation of lactone 14, gave a 75 : 25
mixture of lactonic acids 28 and 29 (1.97 g). Slow crystallisation
of the residue from dichloromethane–diethyl ether gave (1R,
2R,3R,4R,5S)-4-acetoxy-7-oxo-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-β-
-glucopyranosyloxy)-6-oxabicyclo[3.2.1]octane-2-carboxylic
acid 28 as colourless crystals (1.33 g, 52%); mp 111–120 ЊC
(Found: C, 50.2; H, 5.3. C24H30O16 requires C, 50.2; H, 5.3%)
[α]D Ϫ29 (c 0.3 in CH2Cl2); νmax (KBr)/cmϪ1 3600–2700br
(1R,4S,5S)-4-Acetoxy-7-oxo-6-oxabicyclo[3.2.1]oct-2-ene-2-
carbonyl azide 31
Sodium azide (0.338 g, 5.20 mmol) was added to a stirred solu-
tion of acid chloride 32 (0.383 g, 0.646 mmol) in THF (30 cm3)
and the resulting reaction was monitored by TLC until com-
plete (≈4 h). The reaction mixture was then poured into water
(100 cm3) and extracted with dichloromethane (2 × 50 cm3),
and the combined extracts were washed with water (200 cm3),
dried (MgSO4) and the solvent was removed in vacuo. The
residue was purified by silica gel column chromatography
(O-H), 1788 (lactone C᎐O) and 1743 (ester and acid C᎐O);
᎐
᎐
δH (300 MHz; CDCl3) 1.99, 2.01, 2.05, 2.09 and 2.11 (each 3 H,
s, 5 × OAc), 2.16 (1 H, d, J 12.5, 8-Hβ), 2.44 (1 H, dt, J 12 and 6,
8-Hα), 3.06 (1 H, br d, J 5.5, 1-H), 3.12 (1 H, dd, J 4.5 and 1.5,
2-H), 3.72 (1 H, dt, J 9.5 and 3.5, 5Ј-H), 4.23 (2 H, d, J 3.5,
6Ј-H2), 4.33 (1 H, br d, J 4.5, 3-H), 4.72 (1 H, d, J 8, 1Ј-H), 4.76
(1 H, t, J 4.5, 5-H), 4.94 (1 H, dd, J 9.5 and 8, 2Ј-H), 5.08 (1 H,
t, J 9.5, 4Ј-H), 5.16 (1 H, t, J 9.5 Hz, 3Ј-H) and 5.46 (1 H, br d,
J 4.5, 4-H); δC (50 MHz; CDCl3) 20.5, 20.6, 20.7 (2×), 20.9,
32.6 (8-CH2), 35.7, 47.2, 61.8 (6Ј-CH2), 68.5, 68.9, 70.9, 71.9,
72.8, 74.7, 76.9, 102.0, 168.7, 169.4, 169.6, 170.8, 170.9, 171.3
and 175.1; m/z (FAB) 597 (MNaϩ, 3%), 575 (MHϩ, 3), 515
(MHϩ Ϫ CH3CO2H, 1), 331 (C14H19O9ϩ, 30), 169 (63) and 136
(100).
[gradient elution; EtOAc–hexanes (1 : 1
fractions.
The first fraction was the title compound 31 (0.115 g, 71%) as
a colourless solid; mp 90–91 ЊC (from CH2Cl2–Et2O) (Found:
C, 47.8; H, 3.5; N, 17.0. C10H9N3O5 requires C, 47.8; H, 3.6; N,
16.7%) [α]D ϩ271 (c 0.2 in CH2Cl2); νmax (KBr)/cmϪ1 2142 (N3),
7 : 3)] to give two
1782 (lactone C᎐O), 1732 (ester C᎐O) and 1680 (unsaturated
᎐
᎐
acyl azide C᎐O); δ (300 MHz; CDCl ) 2.04 (1 H, d, J 12, 8-Hβ),
᎐
H
3
2.13 (3 H, s, OAc), 2.49 (1 H, dt, J 12 and 5, 8-Hα), 3.76 (1 H,
d, J 4.5, 1-H), 4.74–4.80 (1 H, m, 5-H), 5.40 (1 H, t, J 3, 4-H)
and 6.87 (1 H, ddd, J 3.5, 1.5 and 1, 3-H); δC (75 MHz; CDCl3)
20.8, 30.7, 36.6, 65.7, 75.2, 135.2, 135.8, 169.2, 169.6 and 174.0;
m/z (FAB) 252 (MHϩ, 17%), 167 (10) and 136 (100).
Slow crystallisation of the mother liquor from dichloro-
methane–diethyl ether–hexanes gave (1R,2R,4S,7R,8S)-8-
acetoxy-6-oxo-7-(2Ј,3Ј,4Ј,6Ј-tetra-O-acetyl-β--glucopyranosyl-
oxy)-5-oxabicyclo[2.2.2]octane-2-carboxylic acid† 29 as colour-
less crystals (0.237 g, 9%); mp 203–204 ЊC (Found: C, 49.9; H,
5.5. C24H30O16 requires C, 50.2; H, 5.3%) [α]D Ϫ59 (c 0.3 in
CH2Cl2); νmax (KBr)/cmϪ1 3378br (O-H) and 1750 (lactone,
The second fraction was a mixture of the α- and β-anomer of
tetra-O-acetyl--glucopyranose (0.219 g, 97%) as a clear syrup.
(1R,2R,3R,4R,5S)-4-Acetoxy-7-oxo-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-
acetyl-ꢀ-D-glucopyranosyloxy)-6-oxabicyclo[3.2.1]octane-2-
carbonyl azide 33
ester and acid C᎐O); δ (300 MHz; CDCl ) 2.00, 2.03, 2.06, 2.11
Sodium azide (0.544 g, 8.37 mmol) was added to a solution
of acid chloride 32 (0.528 g, 0.891 mmol) in dichloromethane
(50 cm3) and the resulting mixture was stirred until starting
material could not be detected by TLC (≈2 h). Water (100 cm3)
was added and the mixture was extracted with dichloromethane
(2 × 50 cm3). The combined extracts were washed with water
(200 cm3), dried (MgSO4) and concentrated. Crystallisation of
the residue from dichloromethane–diethyl ether gave the title
compound 33 (0.493 g, 92%) as colourless crystals; mp 160–
209 ЊC (decomp.) [α]D Ϫ41 (c 0.3 in CH2Cl2); νmax (KBr)/cmϪ1
2154 (N ), 1789 (lactone C᎐O) and 1755 (ester and azide C᎐O);
᎐
H
3
and 2.13 (each 3 H, s, 5 × OAc), 2.00–2.35 (2 H, m, 3-H2), 2.96
(1 H, ddd, J 10.5, 7 and 1.5, 2-H), 3.30–3.34 (1 H, m, 1-H), 3.74
(1 H, dt, J 10 and 3.5, 5Ј-H), 4.13 (1 H, br t, J 2.5, 7-H), 4.20
(1 H, dd, J 12.5 and 2.5, 6Ј-H), 4.26 (1 H, dd, J 12.5 and 3.5,
6Ј-H), 4.74 (1 H, d, J 8, 1Ј-H), 4.77–4.83 (1 H, m, 4-H), 4.97
(1 H, dd, J 9.5 and 8, 2Ј-H), 5.05–5.13 (2 H, m, 8- and 4Ј-H) and
5.22 (1 H, t, J 9.5, 3Ј-H); δC (75 MHz; CDCl3) 20.6, 20.7, 20.8,
23.5, 36.8, 42.1, 61.6, 68.2, 70.7, 72.0, 72.7, 77.4, 97.9, 169.0,
169.3, 169.5, 169.7, 170.5, 170.9 and 174.8; m/z (FAB) 597
(MNaϩ, 4%), 575 (MHϩ, 6), 515 (MHϩ Ϫ CH3CO2H, 1), 331
(C14H19O9ϩ, 49), 169 (78) and 136 (100).
᎐
᎐
3
δH (300 MHz; CDCl3) 1.99, 2.01, 2.05 and 2.09 (each 3 H, s,
J. Chem. Soc., Perkin Trans. 1, 2001, 2204–2212 2211

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4 × OAc), 2.11 and 2.13 [4 H, overlapping s and d (J 12.5), OAc
and 8-Hβ, respectively], 2.38–2.50 (1 H, m, 8-Hα), 3.01–3.08
(2 H, m, 1- and 2-H), 3.72 (1 H, ddd, J 10, 4 and 3, 5Ј-H), 4.18–
4.29 (3 H, m, 6Ј-H2 and 3-H), 4.69 (1 H, d, J 8, 1Ј-H), 4.74 (1 H,
t, J 5, 5-H), 4.96 (1 H, dd, J 9.5 and 8, 2Ј-H), 5.08 (1 H, t, J 9.5,
4Ј-H), 5.17 (1 H, t, J 9.5, 3Ј-H) and 5.48 (1 H, br d, J 4.5, 4-H);
m/z (FAB) 600 (MHϩ, 7%), 594 (2), 331 (C14H19O9ϩ, 52), 169
(64) and 139 (100).
2%), 568 (MNaϩ, 5), 546 (MHϩ, 26), 331 (C14H19O9ϩ, 7) and
154 (100).
4-Acetamido-1,2,6-tri-O-acetyl-4-deoxy-3-O-(2Ј,3Ј,4Ј,6Ј-tetra-
O-acetyl-ꢀ-D-glucopyranosyl)-5a-carba-ꢀ-L-galactopyranose 9
Lithium aluminium hydride (0.152 g, 4.01 mmol) was carefully
added to a solution of amine 35 (0.078 g, 0.143 mmol) in dry
THF (30 cm3) and the resulting mixture was heated under reflux
for 36 h. The work-up procedure and subsequent acetylation
protocol was that used for the preparation of compound 16.
Purification of the residue obtained by silica gel column
chromatography [EtOAc–hexanes (9 : 1) as eluent] gave the
title compound 9 as a colourless syrup (0.059 g, 61%); Rf 0.6
(EtOAc) (Found: MHϩ, 676.2455. C29H42NO17 requires MHϩ,
676.2453) [α]D Ϫ20 (c 0.3 in CH2Cl2); νmax (film)/cmϪ1 3450 (N-
Benzyl (1R,2R,3R,4R,5S)-4-acetoxy-7-oxo-3-(2Ј,3Ј,4Ј,6Ј-tetra-
O-acetyl-ꢀ-D-glucopyranosyloxy)-6-oxabicyclo[3.2.1]octane-2-
carbamate 34
A mixture of dry benzyl alcohol (0.19 cm3, 1.84 mmol) and acyl
azide 33 (0.087 g, 0.145 mmol) in dry benzene (30 cm3) was
heated under reflux for 48 h. Evaporation of the mixture in
vacuo and purification of the residue by silica gel column
chromatography [gradient elution; EtOAc–hexanes (2 : 3 4 : 1)]
gave the title compound 34 (0.084 g, 85%) as a clear oil (Found:
MHϩ, 680.2178. C31H38NO16 requires MHϩ, 680.2191);
[α]D Ϫ30 (c 0.3 in CH2Cl2); νmax (Nujol)/cmϪ1 3402 (N-H), 1785
H), 1744 (ester C᎐O) and 1688 and 1671 (amide C᎐O); δH (300
᎐
᎐
MHz; CDCl3) 1.36 (1 H, br q, J 12.5, 5a-Hax), 1.98, 2.01, 2.03,
2.06 and 2.08 (3, 6, 6, 6 and 3 H, each s, 7 × OAc and NAc)
overlapping with 2.01–2.08 (2 H, m, 5-H and 5a-Heq), 3.72 (1 H,
ddd, J 10, 4.5 and 2.5, 5Ј-H), 3.78–3.87 (2 H, m, 3- and 6-H),
4.06 (1 H, dd, J 12.5 and 2, 6Ј-H), 4.16 (1 H, dd, J 11.5 and 7,
6-H), 4.35 (1 H, dd, J 12.5 and 4.5, 6Ј-H), 4.61 and 4.60–4.67
[2 H, overlapping d (J 7.5) and m, 1Ј- and 4-H, respectively],
4.79–4.91 (2 H, m, 1- and 2Ј-H), 5.06, 5.09 and 5.16 [3 H, over-
lapping t (J 10), t (J 9.5) and t (J 9), 4Ј-, 2- and 3Ј-H, respec-
tively] and 5.60 (1 H, br d, J 9.5, NH); δC (75 MHz; CDCl3)
20.6, 20.7, 20.8, 21.0, 23.4, 27.5, 35.5, 46.8, 61.8, 64.2, 68.1,
70.7, 71.0, 71.6, 71.8, 73.0, 98.9, 169.5 (2×), 170.1 (2×), 170.3,
170.5 (2×) and 170.8; m/z (FAB) 698 (MNaϩ, 1%), 676 (MHϩ,
10), 616 (MHϩ Ϫ CH3CO2H, 6), 331 (C14H19O9ϩ, 50), 169 (95)
and 136 (100).
(lactone C᎐O), 1754 (ester C᎐O) and 1723 and 1707 (carbamate
᎐
᎐
C᎐O); δ (300 MHz; CDCl3) 1.88, 1.97, 2.01, 2.08 and 2.10
᎐
H
(each 3 H, s, 5 × OAc), 2.27 (1 H, d, J 12.5, 8-Hβ), 2.42 (1 H, br
dt, J 12 and 6, 8-Hα), 2.62 (1 H, dd, J 5.5 and 2.5, 1-H), 3.65
(1 H, dt, J 9.5 and 3.5, 5Ј-H), 3.95 (1 H, br d, J 4.5, 3-H), 4.20
and 4.24 [3 H, overlapping d (separation 3.5) and ddd (J 10, 5
and 2.5), 6Ј-H2 and 2-H, respectively], 4.55 (1 H, d, J 8, 1Ј-H),
4.73 (1 H, t, J 5, 5-H), 4.97 (1 H, br t, J 8.5, 2Ј-H), 5.03–5.19
(4 H, m, OCH2Ph, 3Ј- and 4Ј-H), 5.50 (1 H, br d, J 4.5, 4-H),
5.58 (1 H, br d, J 10, NH) and 7.32–7.38 (5 H, m, C6H5); δC (75
MHz; CDCl3) 20.4, 20.7, 20.8, 20.9, 31.8, 41.4, 51.0, 61.7, 67.5,
68.2, 69.2, 71.7, 72.2, 72.9, 74.9, 78.9, 102.7, 128.5, 128.7, 135.9,
155.6, 168.9, 169.2, 169.3, 170.4, 170.8 and 175.2; m/z (FAB)
702 (MNaϩ, 1%), 680 (MHϩ, 4), 331 (C14H19O9ϩ, 13), 169 (27)
and 91 (100).
References
1 Preliminary communication: D. S. Larsen, N. S. Trotter and
R. J. Stoodley, Tetrahedron Lett., 1993, 34, 8151.
2 R. C. Gupta, P. A. Harland and R. J. Stoodley, Tetrahedron, 1984,
40, 4657.
(1R,2R,3R,4R,5S)-4-Acetoxy-2-amino-3-(2Ј,3Ј,4Ј,6Ј-tetra-O-
acetyl-ꢀ-D-glucopyranosyloxy)-6-oxabicyclo[3.2.1]octan-7-one
35
3 R. C. Gupta, C. M. Raynor, R. J. Stoodley, A. M. Z. Slawin and
D. J. Williams, J. Chem. Soc., Perkin Trans. 1, 1988, 1773.
4 R. C. Gupta, D. S. Larsen, R. J. Stoodley, A. M. Z. Slawin and
D. J. Williams, J. Chem. Soc., Perkin Trans. 1, 1989, 739; D. S. Larsen
and R. J. Stoodley, J. Chem. Soc., Perkin Trans. 1, 1989, 1841;
D. S. Larsen and R. J. Stoodley, J. Chem. Soc., Perkin Trans. 1, 1990,
1339; B. Beagley, D. S. Larsen, R. G. Pritchard and R. J. Stoodley,
J. Chem. Soc., Perkin Trans. 1, 1990, 3113.
5 W. D. Edwards, R. C. Gupta, C. M. Raynor and R. J. Stoodley,
J. Chem. Soc., Perkin Trans. 1, 1991, 1913.
6 D. S. Larsen and R. J. Stoodley, Tetrahedron, 1990, 46, 4711.
7 I. H. Aspinall, P. M. Cowley, G. Mitchell and R. J. Stoodley,
J. Chem. Soc., Chem. Commun., 1993, 1179; I. H. Aspinall,
P. M. Cowley, G. Mitchell, C. M. Raynor and R. J. Stoodley,
J. Chem. Soc., Perkin Trans. 1, 1999, 2591.
8 I. H. Aspinall, P. M. Cowley, R. J. Stoodley and G. Mitchell,
Tetrahedron Lett., 1994, 35, 3397; P. M. Cowley, R. J. Stoodley and
G. Mitchell, Tetrahedron Lett., 1994, 35, 7853.
9 M. Helliwell, I. M. Phillips, R. G. Pritchard and R. J. Stoodley,
Tetrahedron Lett., 1999, 40, 8651.
10 J. H. Musser, Annu. Rep. Med. Chem., 1992, 27, 301.
11 Carbohydrates—Synthetic Methods and Applications in Medicinal
Chemistry, ed. H. Ogura, A. Hasegawa and T. Suami, Kodansha,
Tokyo and VCH, Weinheim, 1992.
12 Dictionary of Antibiotics and Related Substances, ed. B. W. Bycroft,
Chapman and Hall, London and New York, 1988, p. 722.
13 T. Suami, Pure Appl. Chem., 1987, 59, 1509; T. Suami and S. Ogawa,
Adv. Carbohydr. Chem. Biochem., 1990, 48, 21; T. Suami, Top. Curr.
Chem., 1990, 154, 257; T. Suami, ref. 11, p. 136.
A mixture of the benzyl carbamate 34 (0.075 g, 0.110 mmol)
and 10% palladium–carbon (0.033 g, 0.45 mass equiv.) in
ethanol (25 cm3) was stirred under an atmosphere of hydrogen
for 21 h. The mixture was filtered through a Celite® pad, which
was then washed with dichloromethane (50 cm3). The combined
filtrate and washings were concentrated in vacuo. The residue
was dissolved in dichloromethane (20 cm3) and the solution was
extracted with hydrochloric acid (≈1 mol dmϪ3; 3 × 30 cm3).
The combined aqueous layers were basified using solid sodium
hydrogen carbonate and extracted with dichloromethane
(2 × 80 cm3). The organic extracts were washed with water (200
cm3), dried (MgSO4) and the solvent was removed. Crystallisa-
tion of the residue from dichloromethane–diethyl ether gave the
title compound 35 (0.033 g, 55%) as colourless crystals; mp 195–
205 ЊC (Found: C, 50.6; H, 5.5; N, 2.5. C23H31NO14 requires C,
50.6; H, 5.7; N, 2.6%) [α]D Ϫ42 (c 0.2 in CH2Cl2); νmax (KBr)/
cmϪ1 3419 (N-H), 1775 (lactone C᎐O) and 1746 (ester C᎐O);
᎐
᎐
δH (300 MHz; CDCl3) 1.99, 2.01, 2.07, 2.08 and 2.09 (each 3 H,
s, 5 × OAc), 2.14 (1 H, d, J 11.5, 8-Hβ), 2.28–2.43 (2 H, m, 8-Hα
and 1-H), 3.28 (1 H, dd, J 5 and 2, 2-H), 3.69 (1 H, ddd, J 9.5,
4.5 and 3, 5Ј-H), 4.00 (1 H, br d, J 5, 3-H), 4.19 and 4.24 [2 H,
overlapping dd (J 12 and 3) and dd (J 12 and 4.5), 6Ј-H2], 4.72
and 4.76 [2 H, overlapping br t (J 5.5) and d (J 8), 5- and 1Ј-H,
respectively], 5.03 (1 H, dd, J 9.5 and 8, 2Ј-H), 5.09 (1 H, t,
J 9.5, 4Ј-H), 5.17 (1 H, t, J 9.5, 3Ј-H) and 5.40 (1 H, dt, J 4.5
and 1.5, 4-H); δC (75 MHz; CDCl3) 20.6, 20.7, 20.8, 31.9, 45.2,
52.9, 61.8, 68.4, 69.9, 71.4, 72.0, 72.9, 75.0, 79.1, 102.2, 168.8,
169.0, 169.3, 170.3, 170.7 and 175.7; m/z (FAB) 1091 (M2Hϩ,
14 S. Ogawa, Y. Shibata, N. Chida and T. Suami, Bull. Chem. Soc. Jpn.,
1983, 56, 494.
15 W. Adam, J. Bialas and L. Hadjiarapoglou, Chem. Ber., 1991, 124,
2377.
16 D. D. Perrin, W. L. F. Armarego and D. R. Perrin, Purification of
Laboratory Chemicals, Pergamon Press, UK, 2nd edn., 1980.
2212
J. Chem. Soc., Perkin Trans. 1, 2001, 2204–2212