Synthesis of 4-deoxy-4-nitrosialic acid

Article abstract of DOI:10.1039/b605218e

The synthesis of 4-deoxy-4-nitrosialic acid (3,4,5-trideoxy-4-nitro-d- glycero-β-d-galacto-non-2-ulopyranosonic acid, 5), was completed in seven steps starting from d-arabinose. Coupling of the 6-carbon fragment, 2-acetamido-1,2-dideoxy-1-nitro-d-mannitol (6) with ethyl α-(bromomethyl) acrylate afforded a 2: 1 mixture of ethyl 5-acetamido-2,3,4,5-tetradeoxy-2- methylene-4-nitro-d-glycero-d-galacto-nononate (9a-S) and ethyl 5-acetamido-2,3,4,5-tetradeoxy-2-methylene-4-nitro-d-glycero-d-talo-nononate (9a-R). This mixture of enones was subjected to ozonolysis, and following reduction of the ozonide, the resultant products cyclised to the pyranosides. The target compound, ethyl 4-deoxy-4-nitrosialate (11a) was isolated by fractional crystallisation. Hydrolysis of the ethyl ester proved problematic; thus, the synthesis was modified by using tert-butyl α-(bromomethyl) acrylate. Following ozonolysis of the corresponding tert-butyl enoate esters and diastereomer separation, the tert-butyl ester of 4-nitrosialic acid (11b) could be deprotected under acidic conditions to afford 5. The target compound is a useful intermediate for synthesis of a variety of C-4 substituted sialic acid derivatives, and it is synthesised by a modular route. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b605218e

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of 4-deoxy-4-nitrosialic acid
Ivan Hemeon and Andrew J. Bennet*
Received (in Pittsburgh, PA, USA) 11th April 2006, Accepted 16th June 2006
First published as an Advance Article on the web 5th July 2006
DOI: 10.1039/b605218e
The synthesis of 4-deoxy-4-nitrosialic acid (3,4,5-trideoxy-4-nitro-D-glycero-b-D-galacto-non-2-
ulopyranosonic acid, 5), was completed in seven steps starting from D-arabinose. Coupling of the
6-carbon fragment, 2-acetamido-1,2-dideoxy-1-nitro-D-mannitol (6) with ethyl
a-(bromomethyl)acrylate afforded a 2 : 1 mixture of ethyl 5-acetamido-2,3,4,5-tetradeoxy-2-
methylene-4-nitro-D-glycero-D-galacto-nononate (9a-S) and ethyl 5-acetamido-2,3,4,5-
tetradeoxy-2-methylene-4-nitro-D-glycero-D-talo-nononate (9a-R). This mixture of enones was
subjected to ozonolysis, and following reduction of the ozonide, the resultant products cyclised to the
pyranosides. The target compound, ethyl 4-deoxy-4-nitrosialate (11a) was isolated by fractional
crystallisation. Hydrolysis of the ethyl ester proved problematic; thus, the synthesis was modified by
using tert-butyl a-(bromomethyl)acrylate. Following ozonolysis of the corresponding tert-butyl enoate
esters and diastereomer separation, the tert-butyl ester of 4-nitrosialic acid (11b) could be deprotected
under acidic conditions to afford 5. The target compound is a useful intermediate for synthesis of a
variety of C-4 substituted sialic acid derivatives, and it is synthesised by a modular route.
Introduction
Sialic acid (N-acetylneuraminic acid, Neu5Ac, 1) is a 9-carbon
sugar often found a-ketosidically linked within many biolog-
ically important glycoconjugates.1 Indeed, it is often present
on the termini of the oligosaccharide chain components of
these biomolecules and as such plays many important roles in
biological function, including cell recognition, cell ageing, tumour
formation, and many other immunological events.1 Sialic acid also
plays a role in influenza infection, as it has been shown that the
influenza virus particles recognise and bind to these residues that
are present on the surface of host cells, an event that initiates
infection.2 Upon budding from the infected cell, the progeny
Scheme 1 Sialic acid aldolase-catalyzed synthesis of sialic acid from
virus particles clump together, as they are coated in cellular sialic
acid residues. At this juncture, the viral sialidase (neuraminidase,
EC 3.2.1.18) hydrolyses the glycosidic linkage between sialic acid
residues and the glycoconjugates, a process that allows virus
proliferation. Inhibition of this viral sialidase therefore provides
an attractive target for developing anti-influenza therapeutics.3
Considerable effort has been made toward synthesising numer-
ous derivatives of sialic acid substituted at various positions within
the 9-carbon framework, for purposes that include being potential
therapeutics for influenza infection. A common synthetic route to
sialic acid derivatives uses the enzyme sialic acid aldolase (N-
acylneuraminate pyruvate lyase, EC 4.1.3.3) to couple pyruvate
with an appropriate aldose, N-acetylmannosamine in the case of
sialic acid synthesis (Scheme 1). This enzyme has been shown to
accept a wide assortment of aldoses, allowing the synthesis of
a variety of derivatives.4,5 However, since the reaction proceeds
by nucleophilic attack of pyruvate’s C-3 atom on the aldehyde
carbon (C-1) of the aldose, an OH-group is necessarily gener-
ated at C-4 of the product. Chemical syntheses of sialic acid
derivatives commonly use a similar strategy. For example, the
N-acetyl-D-mannosamine and pyruvate.
indium-mediated coupling of ethyl a-(bromomethyl)acrylate6 or a-
(bromomethyl)acrylic acid7 with an aldose followed by ozonolysis
of the resulting enone installs the a-ketoacid moiety. Strategies
such as this also result in the generation of an OH-group on C-4
of the product.
Due to the prevalence of these synthetic strategies, there are
few general routes leading to variously C-4 substituted sialic
acid derivatives. An azido group has been introduced at C-
4 by treatment of the peracetylated methyl ester of the glycal
of sialic acid (2-deoxy-2,3-didehydro-N-acetylneuraminic acid,
DANA) with BF3·OEt2, resulting in the formation of oxazoline
2, which was opened with azide ion.8 Further functionalisation
of the azido group led to 4-amino derivatives that could also be
functionalised. Among other derivatives, this synthetic route was
used to make zanamavir (3, sold as RelenzaTM), which became one
of the first sialidase inhibitors on the market as an anti-influenza
therapeutic.3 Oxazoline 2 has also been opened with chloride ion
to generate a 4-chlorosialic acid derivative,9 a compound that was
used in palladium(0)-mediated coupling reactions with various
organotin reagents to install unsaturated functional groups at
Department of Chemistry, Simon Fraser University, 8888 University Drive,
Burnaby, V5A 1S6, British Columbia, Canada. E-mail: bennet@sfu.ca
2986 | Org. Biomol. Chem., 2006, 4, 2986–2992
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
C-4.10 Various ether derivatives have been made at C-4 by reacting
the free hydroxyl group with bromoacetonitrile and then further
functionalisation of the nitrile group.11 Zbiral and co-workers have
synthesised derivatives of sialic acid modified at various positions,
and have performed several functional group manipulations
involving the C-4 hydroxyl group, including oxidation to a ketone,
replacement of the ketone oxygen with a methylene group, and
reduction of the methylene group to give a 4-deoxy-4-methyl sialic
acid derivative.12 They have also synthesised 2-deoxy versions of
these derivatives13 and several 4-substituted sialic acid glycals.14
In addition, the 4-deoxy-4-methylene derivative was treated with
MCPBA to give spiro-epoxide 4, which could be opened with a
nucleophile to install an OH and a new substituent on C-4.15 The
oxygen of the epoxide was delivered exclusively from the top face
of the molecule to generate the 4S-diastereomer (the D-glycero-D-
talo isomer, 4), and nucleophilic ring opening by azide, methoxide,
cyanide, and chloride all occurred with exclusive attack on the
less-hindered exocyclic CH2.
Scheme
2
Base-promoted nitroaldopyranose addition to tert-butyl
a-(bromomethyl)acrylate followed by hydrolysis of the nitroketal leading
to an intermediate in Vasella’s sialic acid synthesis. Reagents and conditions:
(a) 2 eq. DBU, THF, 0 ◦C, 24 h; (b) urea, phosphate buffer pH 6.6, RT,
3 days.18
instance, it can be reduced to several different nitrogen-containing
functionalities (including oximes, hydroxylamines, or amines),
hydrolysed to a ketone, alkylated via its nitronate anion, and made
to undergo various radical-mediated processes.21
Results and discussion
Starting from D-arabinose, the method of Sowden et al.17 was
used to synthesise D-arabino-tetraacetoxy-1-nitro-1-hexene (7) in
three steps (Scheme 3). This sequence began with a base-promoted
Henry reaction between D-arabinose and nitromethane, after
which peracetylation of the diastereomeric nitromannitol and
nitroglucitol products followed by elimination of HOAc gave
nitrohexene 7. Of note, the crude products from the first two
reaction steps could be used without purification, thus allowing the
routine formation of multi-gram quantities of the nitroalkene (7),
which could be recrystallised from ethanol to give a light yellow
powder in 54% yield over three steps.
Although several different types of functional groups have been
installed at C-4, there are still few general and/or modular routes
to C-4 substituted sialic acid derivatives. Given that the effects of a
nitro group at C-4 have never been explored, a synthetic route was
devised to give 4-deoxy-4-nitrosialic acid (5). The chosen synthetic
route involves the synthesis of a 6-carbon fragment, 2-acetamido-
1,2-dideoxy-1-nitro-D-mannitol (6), by known methods,16,17 fol-
lowed by a key coupling step involving deprotonation of this
nitroalditol and reaction of the resultant nitronate anion with an
appropriate 3-carbon electrophile to afford the 9-carbon backbone
of 4-nitrosialic acid. A conceptually similar synthetic route to sialic
acid derivatives has been reported by the group of Vasella, and
involves the deprotonation of a nitroaldopyranose followed by
reaction with a 3-carbon electrophile (Scheme 2).18,19 Notably, in
these syntheses alkylation of the nitro group gives a nitroketal
functionality that was hydrolysed, presumably via a glycosyl
oxacarbenium ion intermediate, to give a hemiketal (Scheme 2).
This material was then further modified to yield sialic acid, 4-epi-
sialic acid and 4-deoxysialic acid.18,19 A limitation to this synthetic
protocol is that glycosidic nitroketal groups are less synthetically
versatile than acyclic nitroalkanes, however, Vasella’s group have
reported an ingenious synthesis of [6-2H]-sialic acid by a radical-
initiated reduction of a glycosidic nitroketal precursor.20
Subsequently, the Michael addition of NH3 to the double
bond of 7 (Scheme 3) was first attempted by bubbling ammonia
Our proposed route is modular, as many different nitroalditols
could be used in the coupling reaction to generate 4-nitrosialic
acid derivatives. It is also general in that the secondary nitroalkyl
group is a flexible unit for functional group interconversions; for
Scheme 3 Synthesis of 2-acetamido-1,2-dideoxy-1-nitro-D-mannitol 6.
Reagents and conditions: (a) CH3NO2, NaOMe/MeOH, 18 h; (b) Amber-
lite H+; (c) Ac2O, cat. H2SO4, 80 ◦C, 1 h; (d) NaHCO3 (s), benzene, reflux,
3 h; (e) sat. NH3/MeOH, 0 ◦C to RT, 16 h.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2986–2992 | 2987
©

View Article Online
through a methanol suspension of the nitroalkene for 15 h
according to Sowden’s procedure. This reaction accomplished the
installation of the desired amine on C-2 while also deacetylating
and causing migration of an acetyl group onto the amine, forming
acetamidonitromannitol 6. Although this procedure worked, it
never afforded greater than a 43% yield of the mannitol isomer
after purification by recrystallisation from ethanol, a procedure
that separated the mannitol isomer from the glucitol isomer
and other impurities (Sowden obtained 51%). A higher-yielding
procedure was developed by O’Neill, in which the nitroalkene was
slowly added portionwise to a saturated solution of ammonia in
methanol at 0 ◦C.16 This procedure afforded a modestly improved
56% yield of 6 (O’Neill reported 82%).
Slight difficulties were encountered while attempting to couple
the acetamidonitromannitol 6 with an appropriate 3-carbon
fragment to complete the synthesis of the necessary 9-carbon
backbone. This involved deprotonation of the nitrosugar and using
it as a nucleophile to attack a 3-carbon electrophile. Initially,
ethyl bromopyruvate was used as an electrophile in a methanol
solution of acetamidonitromannitol and NaOMe, but after 22 h
no product was isolated. Addition of AgBF4 to increase the
electrophilicity of the alkyl bromide did not afford any product
after 2 days. The electrophile was changed to allyl bromide, whose
reaction product could be dihydroxylated and carefully oxidised
to the a-ketoester moiety. This should then cyclise to give the
desired sialic acid derivative. Although this reaction gave some
coupled product after 24 h using NaOMe/MeOH, the majority
of the crude product mixture was starting material. To rule
out the possibility that the hydroxyl groups were reducing the
reactivity of the acetamidonitromannitol, they were protected as
isopropylidene ketals using acetone, CuSO4, and catalytic H2SO4
(Scheme 4), a procedure that is a slight variation from that
reported in the literature.22 Coupling of the diisopropylidene 8
with ethyl bromopyruvate was attempted using a variety of bases
(0.5 M NaOH (aq.), EtNiPr2, DBU, LDA) in THF, but in all
cases only starting material was isolated. Coupling with allyl
bromide was also attempted using NaOMe/MeOH and 0.5 M
aqueous NaOH/THF, but very little coupled product was iso-
lated. As a result, the electrophile ethyl a-(bromomethyl)acrylate
was tested, with which nucleophilic attack could proceed via a
Michael addition instead of an SN2-type displacement.23 The
coupled product could then undergo ozonolysis to remove the
methylene carbon, thus installing the desired a-ketoacid moiety.
Ethyl a-(bromomethyl)acrylate, when stirred with unprotected
acetamidonitromannitol 6 in NaOMe/MeOH solution, gave the
coupled enoate ester 9a-(R,S) (Scheme 5) as a 2 : 1 (S : R)
diastereomeric mixture in 72% yield on a 1 g scale. A lower yield
(55%) was obtained on a larger scale (13 g), but the balance
of unreacted acetamidonitromannitol (45%) was recovered and
reused. Attempts to purify enoate ester 9a-(R,S) by crystallisation
from EtOH–Et2O and EtOH–hexanes failed. Thus, column chro-
matography was used to purify the crude material, affording the
diastereomeric mixture of enoate esters as a light yellow foam. The
diisopropylidene-protected nitromannitol 8 was also coupled with
ethyl a-(bromomethyl)acrylate using aqueous sodium hydroxide
in THF to afford the enoate ester product 10-(R,S) in 81%
yield as a 1.9 : 1.0 (S : R) diastereomeric mixture. However,
since the coupling could be performed with the unprotected
nitromannitol 6, the diisopropylidene 8 was not used in this syn-
thesis, as this avoided two unnecessary protection/deprotection
steps.
The diastereomeric mixture of enoate esters 9a-(R,S) was
subjected to ozonolysis followed by reductive workup to cleave
the terminal vinylic CH2 and replace it with an oxygen to install
the necessary a-ketoester (Scheme 5). The ozonised product
spontaneously cyclised to the pyranoside, and the desired 4S-
isomer precipitated out of solution while the 4R-isomer remained
in the CH2Cl2–MeOH solution. After filtration, a second crop
of the 4S-isomer was obtained by concentrating the filtrate and
crystallising it from MeOH to give a 55% yield of ethyl 4-deoxy-4-
nitrosialate (11a). The stereochemistry at C-4 was assigned after
analysis of the H-3/H-4 and H-4/H-5 coupling constants, where
the large values indicated trans-diaxial coupling (J3ax,4 = J4,5
=
11.2 Hz versus J3eq,4 = 5.0 Hz) and that H-4 was axial, possessing
the S configuration. After concentration of the filtrate, the 4R-
isomer was separated from most of the contaminating DMSO
by column chromatography in 33% yield. The small values of
all coupling constants to H-4 indicated its equatorial orientation
(J3eq,4 = 3.2 Hz, J3ax,4 = 5.0 Hz, J4,5 = 4.0 Hz) allowing assignment
of the minor product as the 4R-isomer. From the product ratio of
Scheme 4 Isopropylidene protection of acetamidonitromannitol 6 and
coupling with ethyl a-(bromomethyl)acrylate. Reagents and conditions: (a)
acetone, CuSO4, cat. H2SO4, 24 h; (b) ethyla-(bromomethyl)acrylate, 0.5 M
NaOH (aq.), THF, 2 days.
Scheme 5 Synthesis of ethyl 4-deoxy-4-nitrosialate (11a) and tert-butyl 4-deoxy-4-nitrosialate (11b) from acetamidonitromannitol 6. Reagents and
conditions: (a) NaOMe/MeOH, 18 h; (b) O3, CH2Cl2–MeOH, −78 ◦C, 1 h; (c) DMS, −78 ◦C to RT, 16 h, fractional crystallisation.
2988 | Org. Biomol. Chem., 2006, 4, 2986–2992
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
the ozonolysis reaction it can be reasoned that the major isomer
of enone 9a possesses the 4S-configuration and the minor isomer
is the 4R-isomer.
Hydrolysis of the ethyl ester proved to be problematic. The
presence of an acidic proton a- to the nitro group on C-4 is the
likely cause for complicating the normally straightforward basic
hydrolysis of an ethyl ester. When compound 11a was treated
with lithium hydroxide in THF–water at 0 ◦C, the major product
lacked the ethyl ester but did not have the expected spectral
characteristics. The signals for the protons on C-3 in the 1H NMR
spectrum were shifted downfield to 2.7 and 2.9 ppm from their
normal positions at 2.4–2.5 ppm and their respective coupling
constants to H-4 had decreased to 4.4 and 8.3 Hz, showing a lack
of trans-diaxial coupling. In the 13C NMR spectrum a peak for the
C-2 hemiketal carbon was not observed at its normal frequency
at around 94 ppm, but an HMBC spectrum showed correlations
between the H-3 protons and a carbon at 200 ppm, indicating
that C-2 was a ketone; in addition, the IR spectrum showed a
peak for a ketone carbonyl stretch at 1712 cm−1. This, along with
the lack of trans-diaxial coupling, seemed to indicate that the
reaction product was acyclic. Also of note, the frequency for the H-
4 resonance had shifted upfield from a chemical shift of 5.00 ppm
to one of 4.04 ppm, and the IR spectrum showed no NO2 stretching
bands. As a consequence, it was apparent that the nitro group on
C-4 had undergone a reaction. After a variety of nucleophilic
de-esterification conditions failed to afford the desired material,
the synthetic route was modified to use a tert-butyl ester, which
can be removed under acidic conditions, in place of the ethyl
ester.
Thus, acetamidonitromannitol 6 was stirred with tert-butyl
a-(bromomethyl)acrylate in NaOMe/MeOH solution for 16 h
to afford the enoate tert-butyl ester product 9b-(R,S) after
chromatography in 79% yield as a tan foam. The 1.4 : 1.0 (S :
R) diastereomeric mixture of these products was subjected to
ozonolysis and reductive workup, after which the desired 4S-
diastereomer precipitated out of solution, while a mixture of
4R- and 4S-diastereomers remained in solution. The precipitate
was isolated by filtration, affording the 4S-isomer of tert-butyl
4-deoxy-4-nitrosialate 11b in 33% yield, while a further 25%
was isolated from the filtrate after chromatography. As with
the ethyl ester, the stereochemistry at C-4 was assigned based
on the large trans-diaxial coupling between H-4/H-3ax and H-
4/H-5 (J3ax,4 = 12.9 Hz, J4,5 = 10.6 Hz versus J3eq,4 = 4.6 Hz)
for the major product isomer, as compared to the smaller
coupling constants for the minor product isomer (J3,4 = 3.2,
5.0 Hz). Using this information, the enoate ester precursors
can be assigned as 4S (major diastereomer) and 4R (minor di-
astereomer).
Scheme
6
Hydrolysis of tert-butyl ester 11b to afford 4-de-
oxy-4-nitrosialic acid 5. Reagents and conditions: (a) CF3COOH, H2O,
RT, 18 h.
Conclusions
A synthetic route has been developed that gives access to gram
quantities of 4-deoxy-4-nitrosialic acid esters, compounds that
when used as synthetic intermediates open up potential pathways
to previously inaccessible 4-substituted sialic acid analogues. The
key synthetic step in this route was the carbon backbone extension
from the coupling of the 6-carbon acetamidonitromannitol 6 with
an alkyl a-(bromomethyl)acrylate. The products of this reaction
could then be ozonised to give the sialic acid pyranose structure,
the tert-butyl ester of which could be hydrolysed under acidic
conditions. This synthetic route is modular in that many different
nitroalditols could potentially be used to generate a number of
a-ketoacid sugar analogues, and the products of these reactions
are synthetically versatile due to the large variety of reaction types
that the nitro group can undergo. Currently, the syntheses of a
number of 4-modified sialic acid analogues from the compounds
reported here are being pursued, in order to test these materials as
substrates and/or inhibitors of various sialidase enzymes.
Experimental
Thin-layer chromatography (TLC) was performed on aluminum-
backed TLC plates pre-coated with Merck silica gel 60 F254
.
Compounds were visualised with UV light and/or staining with
phosphomolybdic acid (5% solution in EtOH). Flash chromatog-
raphy was performed using Avanco silica gel 60 (230–400 mesh).
Melting points were recorded on a Gallenkamp melting point
apparatus and are uncorrected. Solvents used for anhydrous
reactions were dried and distilled immediately prior to use.
Methanol was dried and distilled over magnesium methoxide.
Dichloromethane was dried and distilled over calcium hydride.
Glassware for anhydrous reactions was flame-dried and cooled
under a nitrogen atmosphere immediately prior to use. NMR
spectra were recorded on a Varian Unity 500 MHz spectrometer.
Chemical shifts (d) are listed in ppm downfield from TMS using
the residual solvent peak as an internal reference. 1H and 13C NMR
Hydrolysis of the tert-butyl ester 11b proceeded smoothly by
stirring overnight in aqueous trifluoroacetic acid (Scheme 6).
After the solvent was evaporated, 4-deoxy-4-nitrosialic acid 5
was obtained as an off-white powder in 90% yield. Attempts
to improve the purity of this compound through recrystalli-
sation or column chromatography were fruitless, as the com-
pound partially decomposed during these attempts. These at-
tempts were unnecessary, however, because the compound, when
isolated directly from the deprotection medium, was analyti-
cally pure as determined by NMR spectroscopy and elemental
analysis.
peak assignments are made based on H–1H COSY and H–13C
HMQC experiments. IR spectra were recorded on a Bomem IR
spectrometer and samples were prepared as cast evaporative films
1
1
This journal is The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2986–2992 | 2989
©

View Article Online
on NaCl plates from CH2Cl2. Optical rotations were measured
using a Perkin–Elmer 341 polarimeter and are reported in units
of deg cm2 g−1 (concentrations reported in units of g per
100 cm3). 2-Acetamido-1,2-dideoxy-1-nitro-D-mannitol (6) was
prepared from D-arabinose according to literature procedures,16,17
as was ethyl a-(bromomethyl)acrylate from diethyl malonate and
formaldehyde;24 the spectral characteristics of these molecules
matched those reported in the literature.
3.9 Hz, H-3a), 2.96 (dd, 1H, J3a,3b = 14.9 Hz, J3b,4 = 10.6 Hz,
H-3b), 3.47 (d, 1H, J7,8 = 9.3 Hz, H-7), 3.61 (dd, 1H, J8,9a
6.3 Hz, J9a,9b = 11.8 Hz, H-9a), 3.70 (ddd, 1H, J7,8 = 9.0 Hz, J8,9a
6.2 Hz, J8,9b = 2.7 Hz, H-8), 3.82 (dd, 1H, J8,9b = 2.7 Hz, J9a,9b
=
=
=
11.8 Hz, H-9b), 3.97 (d, 1H, J5,6 = 10.4 Hz, H-6), 4.19–4.28 (m,
2H, CH3CH2O), 4.84 (dd, 1H, J4,5 = 4.8 Hz, J5,6 = 10.4 Hz, H-
5), 5.23 (ddd, 1H, J3a,4 = 4.4 Hz, J3b,4 = 10.4 Hz, J4,5 = 4.4 Hz,
H-4), 5.78 (s, 1H, C CHaHb), 6.30 (s, 1H, C CHaHb). 13C NMR
(D2O) 4S isomer: d: 13.4 (CH3CH2O), 22.0 (NHCOCH3), 33.1
(C-3), 51.2 (C-5), 62.4 (CH3CH2O), 63.28 (C-9), 68.4 (C-6), 69.2
=
=
2-Acetamido-1,2-dideoxy-3,4:5,6-di-O-isopropylidene-1-nitro-D-
mannitol (8)
=
=
(C-7), 70.61 (C-8), 86.3 (C-4), 130.6 (C CH2), 134.5 (C CH2),
=
=
168.1 (C O), 174.5 (C O); 4R isomer: d: 13.4 (CH3CH2O), 21.9
(NHCOCH3), 30.4 (C-3), 52.4 (C-5), 62.4 (CH3CH2O), 63.30 (C-
9), 69.08 (C-6/7), 69.11 (C-6/7), 70.57 (C-8), 87.2 (C-4), 130.3
2-Acetamido-1,2-dideoxy-1-nitro-D-mannitol (6, 15.2 g, 60.3 mmol)
was dissolved in reagent-grade acetone (500 cm3). Anhydrous
CuSO4 (9.7 g, 60.8 mmol) was added along with 1 cm3 of
concentrated H2SO4, and the light blue suspension was vigorously
stirred for 24 h. The reaction was filtered through a Celite pad
(3 cm) and the Celite was washed with acetone (100 cm3). The
resultant filtrate was diluted with CHCl3 (400 cm3) and washed
with brine (3 × 500 cm3); the aqueous layer was neutral after the
second wash. The organic layer was dried (MgSO4), filtered, and
concentrated under reduced pressure to give the diisopropylidene
product 8 as a white solid (14.9 g, 44.8 mmol, 74%). The material
exhibited identical NMR spectral data to that reported in the
literature.22 The purity was deemed adequate for further use (mp
131–133 ◦C) but this could be improved by recrystallisation from
CH2Cl2–hexanes (1 : 4) (mp 134.0–134.5 ◦C).
=
=
=
=
(C CH2), 134.6 (C CH2), 168.2 (C O), 174.4 (C O). Anal.
calcd. for C14H24N2O9: C 46.15, H 6.64, N 7.69; found: C 46.51, H
6.96, N 7.47.
Ethyl 5-acetamido-2,3,4,5-tetradeoxy-6,7:8,9-di-O-isopropylidene-
2-methylene-4-nitro-D-glycero-D-galacto-nononate, ethyl
5-acetamido-2,3,4,5-tetradeoxy-6,7:8,9-di-O-isopropylidene-2-
methylene-4-nitro-D-glycero-D-talo-nononate (10-(R,S))
2-Acetamido-1,2-dideoxy-3,4:5,6-di-O-isopropylidene-1-nitro-D-
mannitol (8, 14.9 g, 44.8 mmol) was dissolved in THF (500 cm3)
along with ethyl a-(bromomethyl)acrylate (11.2 g, 58.0 mmol).
An aqueous solution of NaOH (0.5 M; 116 cm3, 58 mmol) was
added dropwise via an addition funnel over 30 min and the turbid
yellow solution was stirred at room temperature. After 2 days,
the reaction was diluted with 400 cm3 water and extracted with
CH2Cl2 (3 × 300 cm3). The organic layer was dried (MgSO4),
filtered, and concentrated under reduced pressure to a dark yellow
oil. This was purified by flash chromatography (CH2Cl2–methanol
gradient solvent system from pure CH2Cl2 to 20 : 1 v/v) to afford
the product 10 as a light yellow syrup (16.2 g, 36.4 mmol, 81%)
Ethyl 5-acetamido-2,3,4,5-tetradeoxy-2-methylene-4-nitro-D-
glycero-D-galacto-nononate, ethyl 5-acetamido-2,3,4,5-tetradeoxy-
2-methylene-4-nitro-D-glycero-D-talo-nononate (9a-(R,S))
2-Acetamido-1,2-dideoxy-1-D-nitromannitol (6, 13.0 g, 51.5 mmol)
was suspended in dry methanol (150 cm3). To this suspension
was added a solution of sodium methoxide in methanol that had
been prepared by adding sodium metal (1.3 g, 56.6 mmol) to dry
methanol (75 cm3). The resulting clear light brown solution was
stirred for 10 min, after which time ethyl a-(bromomethyl)acrylate
(10.9 g, 56.6 mmol) was added. After 18 h, the solution was
concentrated under reduced pressure to give a yellow foam
which was purified by column chromatography (hexanes–EtOAc
gradient solvent system from 5 : 1 v/v to 3 : 1 v/v), to afford the
acrylate-coupled enone product 9a as a light yellow foam (10.3 g,
28.3 mmol, 55%) in a 2 : 1 4S : 4R diastereomeric mixture. In
addition, a quantity of unreacted nitromannitol (5.8 g, 23 mmol,
45%) was also isolated and could be re-used. IR (cm−1): 1374
in a 1.9 : 1 diastereomeric mixture. 4S isomer: [a]2D0 −29.4 (c
−1
=
1.14, CHCl3). IR (cm ): 1372 (NO2), 1553 (NO2), 1634 (C C),
=
=
1666 (amide C O), 1714 (unsaturated ester C O), 3295 (amide
1
NH). H NMR (CDCl3) 4S-isomer: d: 1.31 (t, 3H, J = 7.1 Hz,
CH3CH2O), 1.34 (s, 6H, CMe2), 1.38 (s, 3H, CMe2), 1.39 (s, 3H,
CMe2), 2.07 (s, 3H, NHCOCH3), 2.88–2.90 (m, 2H, H-3ax, H-3eq),
3.828 (dd, 1H, J9a,9b = 8.8 Hz, J8,9a = 12.2 Hz, H-9a), 3.829 (d,
1H, J7,8 = 8.8 Hz, H-7), 3.93–3.98 (m, 2H, H-6, H-8), 4.13 (dd,
1H, J9a,9b = 8.8 Hz, J8,9b = 6.3 Hz, H-9b), 4.23 (q, 2H, J = 7.1 Hz,
CH3CH2O), 4.56 (dt, 1H, J4,5 = 2.9 Hz, J5,6 = J5,NH = 9.8 Hz, H-5),
5.26 (ddd, 1H, J3a,4 = 5.9 Hz, J3b,4 = 8.8 Hz, J4,5 = 2.9 Hz, H-4),
=
=
(NO2), 1549 (NO2), 1666 (amide C O), 1711 (unsaturated ester
5.71 (s, 1H, C CHaHb), 6.15 (d, 1H, J5,NH = 9.8 Hz, NHCOCH3),
1
=
=
C O), 3369 (OH). H NMR (D2O) 4S isomer: d: 1.29 (t, 3H,
6.30 (s, 1H, C CHaHb); 4R-isomer: d: 1.32 (t, 3H, J = 7.1 Hz,
J = 7.1 Hz, CH3CH2O), 2.07 (s, 3H, NHCOCH3), 2.90 (dd, 1H,
CH3CH2O), 1.37 (s, 6H, CMe2), 1.41 (s, 3H CMe2), 1.42 (s, 3H,
CMe2), 2.01 (s, 3H, NHCOCH3), 2.94 (dd, 1H, J3a,3b = 14.9 Hz,
J3a,4 = 3.7 Hz, H-3a), 3.02 (dd, 1H, J3a,3b = 14.9 Hz, J3b,4 = 10.5 Hz,
H-3b), 3.80–3.84 (m, 2H, H-7, H-9a), 3.95–4.01 (m, 1H, H-8), 4.10
J3a,3b = 14.8 Hz, J3a,4 = 4.9 Hz, H-3a), 2.98 (dd, 1H, J3a,3b
=
14.8 Hz, J3b,4 = 9.8 Hz, H-3b), 3.45 (d, 1H, J7,8 = 9.2 Hz, H-7),
3.60 (dd, 1H, J8,9a = 6.3 Hz, J9a,9b = 11.9 Hz, H-9a), 3.69 (ddd, 1H,
J7,8 = 9.0 Hz, J8,9a = 6.2 Hz, J8,9b = 2.7 Hz, H-8), 3.81 (dd, 1H,
J8,9b = 2.7 Hz, J9a,9b = 11.7 Hz, H-9b), 3.86 (d, 1H, J5,6 = 10.3 Hz,
(dd, 1H, J5,6 = 9.5 Hz, J6,7 = 5.8 Hz, H-6), 4.18 (dd, 1H, J9a,9b
+
J8,9b = 14.9 Hz, H-9b), 4.24 (q, 2H, J = 7.1 Hz, CH3CH2O),
4.66 (dt, 1H, J4,5 = 4.9 Hz, J5,6 = J5,NH = 8.8 Hz, H-5), 5.10
(dt, 1H, J3b,4 = 10.7 Hz, J3a,4 + J4,5 = 8.5 Hz, H-4), 5.71 (s, 1H,
H-6), 4.24 (q, 2H, J = 7.2 Hz, CH3CH2O), 4.55 (dd, 1H, J4,5
3.3 Hz, J5,6 = 10.3 Hz, H-5), 5.35 (ddd, 1H, J3a,4 = 5.0 Hz, J3b,4
=
=
=
=
9.6 Hz, J4,5 = 3.4 Hz, H-4), 5.79 (s, 1H, C CHaHb), 6.32 (s, 1H,
C CHaHb), 6.11 (d, 1H, J5,NH = 8.3 Hz, NHCOCH3), 6.28 (s, 1H,
C CHaHb); 4R isomer: d: 1.29 (t, 3H, J = 7.1 Hz, CH3CH2O),
C CHaHb). 13C NMR (CDCl3) 4S isomer: d: 13.9 (CH3CH2O),
=
=
2.02 (s, 3H, NHCOCH3), 2.91 (dd, 1H, J3a,3b = 15.0 Hz, J3a,4
2990 | Org. Biomol. Chem., 2006, 4, 2986–2992
=
23.2 (NHCOCH3), 25.1, 26.4, 27.0, 27.4 (C(CH3)2 × 2), 34.0
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
(C-3), 51.9 (C-5), 61.0 (CH3CH2O), 67.6 (C-9), 76.7 (C-8), 79.2
(C-6), 80.5 (C-7), 85.4 (C-4), 109.6, 110.7 (C(CH3)2 × 2), 129.7
tert-Butyl 5-acetamido-2,3,4,5-tetradeoxy-2-methylene-4-nitro-D-
glycero-D-galacto-nononate, tert-butyl 5-acetamido 2,3,4,5-
tetradeoxy-2-methylene-4-nitro-D-glycero-D-talo-nononate
(9b-(R,S))
=
=
=
=
(C CH2), 134.0 (C CH2), 165.5 (C O), 170.2 (C O); 4R isomer:
d: 13.9 (CH3CH2O), 23.0 (NHCOCH3), 25.1, 26.4, 26.5, 27.2
(C(CH3)2 × 2), 31.8 (C-3), 53.7 (C-5), 61.0 (CH3CH2O), 67.9
(C-9), 77.0 (C-8), 79.3 (C-6), 80.5 (C-7), 87.1 (C-4), 109.8, 110.9
2-Acetamido-1,2-dideoxy-4-nitro-D-mannitol (6, 12.0 g, 47.6 mmol)
was suspended in dry methanol (150 cm3). A solution of sodium
methoxide, prepared by reacting sodium metal (1.5 g, 65 mmol)
with dry methanol (75 cm3), was then added. The resulting clear,
brown solution was stirred for 10 min, after which time tert-
butyl a-(bromomethyl)acrylate (12.6 g, 39.2 mmol) was added. The
solution was stirred under nitrogen for 20 h and was concentrated
under reduced pressure to a dark brown foamy syrup. This
was purified by flash chromatography (CH2Cl2–MeOH gradient
solvent system from 5 : 1 v/v to 3 : 1 v/v) to afford the product
9b as a tan foam (12.2 g, 31.1 mmol, 79%) in a 1.4 : 1.0 4S :
4R diastereomeric ratio. IR (cm−1): 1152 (C–O–C), 1370 (NO2),
=
=
=
(C(CH3)2 × 2), 128.9 (C CH2), 134.5 (C CH2), 165.8 (C O),
:
=
170.2 (C O). Anal. calcd. for C20H32N2O9 C 54.04, H 7.26, N
6.30; found: C 54.01, H 7.21, N 6.31.
Ethyl 5-acetamido-3,4,5-trideoxy-4-nitro-D-glycero-b-D-galacto-
non-2-ulopyranosonate (11a)
Ozone was bubbled through a cooled (−78 ◦C) solution of enoate
ester 9a (10.0 g, 27.4 mmol, ∼2 : 1 diastereomeric mixture) in a 1 :
1 v/v mixture of dry CH2Cl2 and dry methanol (300 cm3) for 1 h,
after which time the reaction became light blue in colour. Addition
of dimethyl sulfide (5 cm3) caused the product to precipitate. The
resulting mixture was allowed to warm to room temperature over
16 h with stirring, after which time the cloudy white suspension
was cooled in ice and vacuum-filtered. The white flocculent solid
was washed with CH2Cl2 (100 cm3) and dried under vacuum to
give the sialoside 11a (4.8 g, 13.1 mmol, 48%). A second crop was
obtained by concentrating the filtrate under reduced pressure to
give a yellow syrup, adding methanol (20 cm3), and isolating the
resultant white flocculent solid as above to g◦ive a further 0.68 g of
sialoside 11a (1.9 mmol, 7%), mp 175–177 C (dec.). [a]2D0 −28.9
=
=
1552 (NO2), 1659 (amide C O), 1707 (unsaturated ester C O),
3316 (OH). 1H NMR (D2O) 4S-isomer: d: 1.49 (s, 9H, C(CH3)3),
2.07 (s, 3H, NHCOCH3), 2.86 (dd, 1H, J3a,3b = 14.5 Hz, J3a,4
=
4.8 Hz, H-3a), 2.94 (dd, 1H, J3a,3b = 14.6 Hz, J3b,4 = 9.9 Hz, H-3b),
3.44 (d, 1H, J7,8 = 9.2 Hz, H-7), 3.60 (dd, 1H, J9a,9b = 11.8 Hz,
J8,9b = 6.2 Hz, H-9a), 3.67–3.71 (m, 1H, H-8), 3.81 (dd, 1H, J9a,9b
11.8 Hz, J8,9b = 2.8 Hz, H-9b), 4.53 (dd, 1H, J4,5 = 3.3 Hz, J5,6
10.2 Hz, H-5), 5.36 (ddd, 1H, J3a,4 = 4.8 Hz, J3b,4 = 9.8 Hz, J4,5
=
=
=
=
=
3.5 Hz, H-4), 5.71 (s, 1H, C CHaHb), 6.22 (s, 1H, C CHaHb);
4R-isomer: d: 1.49 (s, 9H, C(CH3)3), 2.02 (s, 3H, NHCOCH3),
2.84–2.94 (m, 2H, H-3a, H-3b), 3.48 (d, 1H, J7,8 = 9.2 Hz, H-7),
3.61 (dd, 1H, J9a,9b = 11.7 Hz, J8,9b = 6.22 Hz, H-9a), 3.67–3.71
(m, 1H, H-8), 3.82 (dd, 1H, J9a,9b = 11.8 Hz, J8,9b = 2.8 Hz, H-9b),
(c 0.63, DMSO). IR (cm−1): 1373 (NO2), 1544 (NO2), 1658 (amide
1
=
=
C O), 1735 (ester C O), 3330 (OH). H NMR (D2O) d: 1.15 (t,
3H, J = 7.1 Hz, CH3CH2O), 1.84 (s, 3H, NHCOCH3), 2.40–2.50
(m, 2H, H-3ax, H-3eq), 3.44 (d, 1H, J7,8 = 9.3 Hz, H-7), 3.46 (dd,
3.97 (d, 1H, J5,6 = 10.4 Hz, H-6), 4.83 (dd, 1H, J4,5 = 5.0 Hz, J5,6
=
10.5 Hz, H-5), 5.21 (dt, 1H, J3a,4 + J3b,4 + J4,5 = 19.8 Hz, H-4), 5.71
1H, J9a,9b = 11.7 Hz, J9a,8 = 6.1 Hz, H-9a), 3.59 (ddd, 1H, J7,8
9.2 Hz, J8,9a = 6.2 Hz, J8,9b = 2.7 Hz, H-8), 3.68 (dd, 1H, J9a,9b
=
=
(s, 1H, C CHaHb), 6.21 (s, 1H, C CHaHb). 13C NMR (D2O) 4S
isomer: d: 22.0 (NHCOCH3), 27.3 (C(CH3)3), 33.4 (C-3), 51.2 (C-
5), 63.3 (C-9), 68.4 (C-6), 69.2 (C-7), 70.6 (C-8), 83.6 (C(CH3)3),
=
=
11.9 Hz, J8,9b = 2.7 Hz, H-9b), 4.11 (d, 1H, J5,6 = 10.5 Hz, H-6),
4.10–4.21 (m, 2H, CH3CH2O), 4.44 (t, 1H, J4,5 = J5,6 = 10.7 Hz,
H-5), 5.00 (dt, 1H, J3eq,4 = 5.0 Hz, J3ax,4 = J4,5 = 11.2 Hz, H-4).
13C NMR (CD3OD) d: 13.1 (CH3CH2O), 21.3 (NHCOCH3), 35.9
(C-3), 49.0 (C-5), 62.1 (CH3CH2O), 63.5 (C-9), 68.6 (C-7), 70.1 (C-
=
=
=
86.5 (C-4), 129.8 (C CH2), 136.0 (C CH2), 167.3 (C O), 174.4
=
(C O); 4R isomer: d: 21.9 (NHCOCH3), 27.3 (C(CH3)3), 30.7
(C-3), 52.3 (C-5), 63.3 (C-9), 69.10 (C-6), 69.14 (C-7), 70.6 (C-
=
=
8), 83.6 (C(CH3)3), 87.5 (C-4), 129.5 (C CH2), 136.1 (C CH2),
=
=
6), 70.4 (C-8), 83.3 (C-4), 94.3 (C-2), 169.1 (C O), 172.8 (C O).
Anal. calcd. for C13H22N2O10: C 42.62, H 6.05, N 7.65; found: C
42.77, H 6.12, N 7.51.
=
=
167.5 (C O), 174.5 (C O). Anal. calcd. for C16H28N2O9: C 48.97,
H 7.19, N 7.14; found: C 49.04, H 6.97, N 7.06.
tert-Butyl a-(bromomethyl)acrylate
tert-Butyl 5-acetamido-3,4,5-trideoxy-4-nitro-D-glycero-b-D-
galacto-non-2-ulopyranosonate (11b)
2-Methylpropene (25.6 g, 0.456 mol) was condensed in a
Schlenk tube at −78 ◦C. To this was added a solution of a-
(bromomethyl)acrylic acid (26.2 g, 0.159 mol, prepared according
to ref. 19) in dry CH2Cl2 (120 cm3), along with 0.5 cm3 conc. H2SO4.
The Schlenk tube was sealed, and the reaction mixture was allowed
to warm to room temperature. Some a-(bromomethyl)acrylic acid
that had precipitated at −78 ◦C re-dissolved upon reaching room
temperature, and the solution was stirred overnight. The solution
was then concentrated to half its volume under reduced pressure
to remove excess 2-methylpropene and was diluted with CH2Cl2
(300 cm3) and washed with sat. NaHCO3 (2 × 400 cm3). The
organic layer was dried (MgSO4), filtered, and concentrated under
reduced pressure to afford the product as a light yellow oil (27.6 g,
0.125 mmol, 79%). The material exhibited identical spectra data
to those reported in the literature.25
A solution of tert-butyl enoate ester 9b-(R,S) (10.7 g, 27.3 mmol,
1.4 : 1.0 diastereomeric mixture) was prepared in a 1 : 1 v/v
mixture of dry CH2Cl2 and dry methanol (300 cm3), which was
cooled to −78 ◦C. Ozone was bubbled through the cold solution
for 1 h 45 min, after which time the colour was light green. The
ozonides were reduced with dimethyl sulfide (5 cm3), which caused
the product to precipitate. The reaction was stirred overnight and
allowed to warm to room temperature, and was then cooled in ice
and filtered. The white solid was washed with CH2Cl2 (75 cm3)
and dried to afford the product 11b as a white solid (3.58 g,
9.08 mmol, 33%). The filtrate, which contained a mixture of
DMSO, 11b and its C-4 epimer, was concentrated and purified by
flash chromatography (CH2Cl2–methanol gradient solvent system
from 10 : 1 v/v to 3 : 1 v/v) to afford a further 2.70 g of sialoside
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2986–2992 | 2991
©

View Article Online
11b (6.8 mmol, 25%) as a white foamy solid, mp 147–149 ◦C (dec.).
University for financial support of this work. IH thanks the
Michael Smith Foundation for Health Research for a Trainee
Scholarship. Finally, we thank an anonymous referee for their
thorough critical review of this manuscript and for their helpful
comments.
[a]2D0 −25.9 (c 0.695, DMSO). IR (cm−1): 1371 (NO2), 1556 (NO2),
1
=
=
1652 (amide C O), 1724 (ester C O), 3358 (OH). H NMR (D2O)
d: 1.50 (s, 9H, C(CH3)3), 1.98 (s, 3H, NHCOCH3), 2.52 (dd, 1H,
J3ax,3eq = J3ax,4 = 12.9 Hz, H-3ax), 2.61 (dd, 1H, J3ax,3eq = 13.0 Hz,
J3eq,4 = 4.6 Hz, H-3eq), 3.59 (d, 1H, J7,8 = 8.2 Hz, H-7), 3.63 (dd, 1H,
J9a,9b = 11.8 Hz, J8,9a = 6.3 Hz, H-9a), 3.75 (ddd, 1H, J7,8 = 8.9 Hz,
J8,9a = 6.2 Hz, J8,9b = 2.6 Hz, H-8), 3.83 (dd, 1H, J9a,9b = 11.8 Hz,
J8,9b = 2.7 Hz, H-9b), 4.23 (d, 1H, J5,6 = 10.5 Hz, H-6), 4.57 (dd,
1H, J4,5 = J5,6 = 10.6 Hz, H-5), 5.13 (dt, 1H, J3eq,4 = 4.6 Hz,
J3ax,4 + J4,5 = 23.1 Hz). 13C NMR (CD3OD) d: 22.6 (NHCOCH3),
28.1 (C(CH3)3), 50.3 (C-5), 64.8 (C-9), 70.0 (C-7), 71.4 (C-6), 71.8
(C-8), 84.3 (C(CH3)3), 84.6 (C-4), 95.6 (C-2), 169.6 (C-1), 174.1
(NHCOCH3). Anal. calcd. for C15H26N2O10: C 45.68, H 6.65, N
7.10; found: C 45.81, H 6.71, N 7.09.
References
1 R. Schauer, S. Kelm, G. Reuter and P. Roggentin, in Biology of the
Sialic Acids, ed. A. Rosenberg, Plenum Press, New York, 1995, pp.
7–67.
2 J. J. Skehel and D. C. Wiley, Annu. Rev. Biochem., 2000, 69, 531–569.
3 R. Thomson and M. von Itzstein, in Carbohydrate-Based Drug
Discovery, ed. C.-H. Wong, Wiley-VCH, Weinheim, 2003, vol. 2, pp.
831–862.
4 M. J. Kim, W. J. Hennen, H. M. Sweers and C. H. Wong, J. Am. Chem.
Soc., 1988, 110, 6481–6486.
5 W. Fitz, J.-R. Schwark and C.-H. Wong, J. Org. Chem., 1995, 60, 3663–
3670.
3,4,5-Trideoxy-4-nitro-D-glycero-b-D-galacto-non-2-
ulopyranosonic acid (5)
6 D. M. Gordon and G. M. Whitesides, J. Org. Chem., 1993, 58, 7937–
7938.
7 T.-H. Chan and M.-C. Lee, J. Org. Chem., 1995, 60, 4228–4232.
8 M. von Itzstein, B. Jin, W. Y. Wu and M. Chandler, Carbohydr. Res.,
1993, 244, 181–185.
Trifluoroacetic acid (6.0 cm3) was added to a suspension of tert-
butyl ester 11b (148 mg, 0.375 mmol) in water (12 cm3). The clear,
colourless solution was stirred at room temperature for 16 h, after
which time the solution took on a light pink tinge. The solution
was concentrated under reduced pressure to afford the de-esterified
product 5 as an off-white powder (114 mg, 0.338 mmol, 90%), mp
9 G. B. Kok, A. D. Norton and M. von Itzstein, Synthesis, 1997, 1185–
1188.
10 G. B. Kok and M. von Itzstein, J. Chem. Soc., Perkin Trans. 1, 1998,
905–908.
11 K. Ikeda, K. Sano, M. Ito, M. Saito, K. Hidari, T. Suzuki, Y. Suzuki
and K. Tanaka, Carbohydr. Res., 2001, 330, 31–41.
12 M. Hartmann, R. Christian and E. Zbiral, Monatsh. Chem., 1991, 122,
111–125.
13 M. Hartmann and E. Zbiral, Liebigs Ann. Chem., 1991, 795–801.
14 E. Schreiner, E. Zbiral, R. G. Kleineidam and R. Schauer, Liebigs Ann.
Chem., 1991, 129–134.
15 D. R. Groves and M. von Itzstein, J. Chem. Soc., Perkin Trans. 1, 1996,
2817–2821.
◦
175–177 C (dec.). [a]D20 −23 (c 0.21, DMSO). IR (cm−1): 1372
=
=
(NO2), 1557 (NO2), 1664 (amide C O), 1721 (acid C O), 3338
(OH/NH). 1H NMR (D2O) d: 1.98 (s, 3H, NHCOCH3), 2.50 (dd,
1H, J3ax,3eq = J3ax,4 = 12.8 Hz, H-3ax), 2.58 (dd, 1H, J3ax,3eq = 12.9 Hz,
J3eq,4 = 4.6 Hz, H-3eq), 3.56 (d, 1H, J7,8 = 9.4 Hz, H-7), 3.60 (dd,
1H, J9a,9b = 11.8 Hz, J8,9a = 6.3 Hz, H-9a), 3.75 (ddd, 1H, J7,8
9.2 Hz, J8,9a = 6.3 Hz, J8,9b = 2.6 Hz, H-8), 3.83 (dd, 1H, J8,9b
=
=
16 A. N. O’Neill, Can. J. Chem., 1959, 37, 1747–1753.
17 J. C. Sowden and M. Offdahl, Methods Carbohydr. Chem., 1962, 1,
235–237.
2.6 Hz, J9a,9b = 11.8 Hz, H-9b), 4.21 (d, 1H, J5,6 = 10.3 Hz, H-6),
4.56 (dd, 1H, J4,5 = J5,6 = 10.5 Hz, H-5), 5.13 (dt, 1H, J3ax,4
+
18 F. Baumberger and A. Vasella, Helv. Chim. Acta, 1986, 69, 1205–
J4,5 = 23.1 Hz, J3eq,4 = 4.6 Hz). 13C NMR (DMSO-d6) d: 22.5
1215.
19 F. Baumberger and A. Vasella, Helv. Chim. Acta, 1986, 69, 1535–
1541.
(NHCOCH3), 35.4 (C-3), 48.5 (C-5), 63.3 (C-9), 68.4 (C-7), 69.3
=
(C-6), 69.9 (C-8), 83.7 (C-4), 93.5 (C-2), 170.06 (C O), 170.13
20 R. Julina, I. Mu¨ller, A. Vasella and R. Wyler, Carbohydr. Res., 1987,
=
(C O). Anal. calcd. for C11H18N2O10: C 39.06, H 5.36, N 8.28;
164, 415–432.
21 N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, New York,
2001.
found: C 39.32, H 5.24, N 8.36.
22 H. Mack and R. Brossmer, Tetrahedron, 1998, 54, 4539–4560.
23 R. Ballini and G. Bosica, Eur. J. Org. Chem., 1998, 355–357.
24 K. Ramarajan, K. Ramalingam, D. J. O’Donnell and K. D. Berlin, Org.
Synth., 1983, 61, 56–59.
25 R. K. Haynes, A. Katsifis and S. C. Vonwiller, Aust. J. Chem., 1984, 37,
1571–1578.
Acknowledgements
The authors gratefully acknowledge the Natural Sciences and
Engineering Research Council of Canada and Simon Fraser
2992 | Org. Biomol. Chem., 2006, 4, 2986–2992
This journal is
The Royal Society of Chemistry 2006
©