Synthesis of polyhydroxylated α-nitrocyclohexane carboxylic acids derived from D-glucose: A striking case of racemization

Article abstract of DOI:10.1016/S0957-4166(03)00274-X

The first total synthesis of polyhydroxylated α-nitrocyclohexane carboxylic acids from sugars is reported. A salient aspect of the synthesis is an unexpected Henry-mediated racemization of this new class of highly functionalized cyclohexanes.

Full text of DOI:10.1016/S0957-4166(03)00274-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1653–1658
Synthesis of polyhydroxylated a-nitrocyclohexane carboxylic
acids derived from -glucose: a striking case of racemization
D
Raquel G. Soengas,a Juan C. Este´vez,a Ramo´n J. Este´veza,* and Miguel A. Maestrob
aDepartamento de Qu´ımica Orga´nica, Universidade de Santiago, 15782 Santiago de Compostela, Spain
bServicios Xerais de Apoio a´ Investigacio´n, Universidade de A Corun˜a, 15071 A Corun˜a, Spain
Received 24 February 2003; accepted 20 March 2003
Abstract—The first total synthesis of polyhydroxylated a-nitrocyclohexane carboxylic acids from sugars is reported. A salient
aspect of the synthesis is an unexpected Henry-mediated racemization of this new class of highly functionalized cyclohexanes.
© 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The classical nitroaldol condensation (the Henry reac-
tion) involves reaction between a carbonyl compound and
an alkylnitro compound bearing a-hydrogens. This reac-
tion results in the formation of a carbonꢀcarbon bond
with concomitant generation of a b-nitroalcohol, from
which a wide variety of other organic compounds can be
derived by functional transformations of the hydroxy and
the nitro functional groups.1 The intramolecular Henry
reaction has also proven to be a powerful method for the
preparation of nitro cycloalkanes, and representative
examples include synthetic intermediates recently used in
the preparation of the natural compound perhydrohis-
tionicotoxin,2 the lycoricidine alkaloid pancratistatin3
and the antineoplastic agent taxol.4 Furthermore, this
reaction is of appreciable interest for the synthesis of
nitro-containing sugars (nitro sugars), recognized both as
novel compounds and as valuable synthetic intermediates
for the transformation of sugars into cyclohexane and
cyclopentane derivatives5 such as 16 and 2,7 which can
also be prepared by reaction of nitromethane with
dialdehydes derived from sugars (Fig. 1).
Nitroacetic acid and its esters often show a similar
reactivity to alkylnitro compounds and they are there-
fore convenient starting materials for the synthesis of
2-nitroalkanoic acids, which in turn are valuable syn-
thetic intermediates for the synthesis of nitro alcohols,
nitro amines, halonitro compounds, nitroacrylates,
amino acids, amino alcohols, etc.8 In fact, methyl
nitroacetate has been shown to be a versatile glycine
synthetic equivalent in the preparation of non-natural
a-amino acids,9 including cyclic amino acids from
dialdehydes,10 but its chemistry with sugars has received
much less attention than the corresponding nitro alka-
nes. Indeed, despite the fact that a few examples have
been reported of intramolecular reactions of methyl
nitroacetate with dialdehydes derived from sugars to
give 3-nitropyranose derivatives,11 the nitroacetic acid-
mediated transformation of sugars into cycloalkanes
has not been carried out.
The work described in this paper concerns preliminary
results from a project aimed at the synthesis of sugar-
derived cycloalkane a-nitro acid esters, illustrated by
the preparation of a-nitro acid esters 10 and 11
(Scheme 1), which were obtained by a synthetic
sequence involving two consecutive Henry reactions.
The first Henry reaction was performed between ethyl
nitroacetate and
D
-glucose derivative 3, a process that
Figure 1.
gave a mixture of epimeric compounds 5. The second
step was an intramolecular Henry reaction of epimeric
mixture 6. Alternatively, compounds 5 were trans
* Corresponding author. Tel.: +34-981-563100; fax: +34-981-591014;
e-mail: qorjec@usc.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00274-X

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R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 1653–1658
Scheme 1.
formed into the epimeric mixture of compounds 14+15
via compounds 12 and 13 (Scheme 2).
steps, [h]2D0 0.0). The stereochemistry of these two com-
pounds was firmly established by an X-ray crystallo-
graphic study of the mixture 10+11.14
In the first experiment, condensation of aldehyde 312
with ethyl nitroacetate under typical Henry reaction
conditions gave a 70% yield of a 3:2 mixture of epimers
513 (Scheme 1), which decompose on standing. Subse-
quent removal of the acetonide protecting group by
treatment of 5 with a 1:1 trifluoroacetic acid/water
mixture gave an unstable mixture of compounds 6,
which was immediately treated with 2% aqueous
sodium bicarbonate solution to give, surprisingly, the
racemic mixture of ethyl a-nitrocyclohexane carboxyl-
ates 8 and 9 ([h]2D0 0.0). The racemic mixture 8+9 was
subsequently reacted with acetic anhydride and p-tolue-
nesulphonic acid to give the corresponding racemic
mixture 10+11 (64% overall yield for the three last
The crystallographic study also indicated that the
favored chair conformations are, respectively, those
represented in Figure 2—both of which have an equato-
rial disposition of the hydrogen at C2 and axial disposi-
tions of hydrogens at C3, C4, C5 and C6. These
conformations are also the ones favored in solution, a
1
fact easily established from the H NMR spectrum of
the mixture 10+11, which includes two doublets at 6.03
and 6.15 ppm due to the highly deshielded protons at
C6 and C2. The doublet at 6.03 ppm was assigned to the
proton at C6 on the basis of its coupling constant
(J=10.0 Hz), which indicates a diaxial disposition for
both protons at C6 and at C5. The coupling constant
Scheme 2.

R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 1653–1658
1655
mixture of cyclohexane nitroesters 14 (46% yield, [h]D17
−6.45) and 15 (24% yield, [h]1D7 −11.0) resulted from this
procedure and both compounds were formed from the
expected intramolecular Henry reaction. The stereo-
chemistry of each compound was established from their
spectroscopic data.
Compound 14 shows an NOE between the ethyl chain
(methyl group) and the hydroxy groups at C3 (2.4%),
C5 (5.2%) and C6 (0.7%). Therefore, the relative stereo-
chemistry is that corresponding to a cyclohexane chain
conformation where the ethoxy carbonyl substituent is
axial, the hydroxy groups at C3 and C5 are axial and
the hydroxy group at C6 is equatorial. Additionally, the
intense NOE (22%) between protons H5 and H6 pro-
vides further evidence for the equatorial and the axial
disposition proposed for both protons. Moreover, the
presence of two singlets at l=5.02 ppm (J=10.9 Hz)
and l=5.06 (J=11.3 Hz), due to protons H6 and H2,
clearly indicates an axial disposition of the two protons
(Fig. 3).
Figure 2. Chair conformation of compounds 10 and 11, and
ORTEP diagram corresponding to an X-ray molecular struc-
ture of compound 10.
for the doublet at 6.15 ppm (J=3.2 Hz) allowed us to
establish the equatorial disposition of the proton at C2
and the axial disposition of the proton at C3.
Similar 1H NMR experiments for compound 15
allowed us to establish it to be a C1 epimer of com-
pound 14. Compound 15 showed an intense NOE
(19.1%) between protons H5 and H6, a situation consis-
tent with an axial–equatorial disposition or a diequato-
rial disposition of the two protons. However, the
coupling constant values for the signals of both protons
H6 (d, l=4.85 ppm, J=10.4 Hz, 1H) and H2 (d,
l=5.02, J=11.5 Hz, 1H) correspond to an axial–equa-
torial disposition.
These results may be explained on the assumption that
the intramolecular Henry reaction of compounds 6
gives diastereomers 7 and 8, and that 8 is a stable
compound, but 7 isomerizes to the more stable com-
pound 9 through a retro-Henry reaction followed by a
stereoselective intramolecular Henry reaction.15 The
equimolar amounts of enantiomers 8 and 9 resulting
from this process may be explained in terms of equili-
bration based on the reversibility of the Henry reaction.
In summary, we describe here the first transformation
of a sugar ( -glucose) into polyhydroxylated a-nitrocy-
D
clohexane carboxylic acids. A salient aspect of this
synthesis was that we unexpectedly obtained the
racemic mixture 8+9, as a consequence of the regiospe-
cific b-epimerization of compound 7 to compound 9
(the enantiomer of compound 8) by a Henry reaction
and the subsequent equilibration of compounds 8 an 9
We next decided to explore the possibility of modifying
the process leading to the racemic mixture 8+9 by
protecting (as the benzyloxy derivative) the strategic
hydroxy group at C5 in compounds 5, which is implied
in the transformation of 7 into 9. Accordingly, the
mixture of nitroesters
5
was reacted with
benzyltrichloroacetimidate16 and the resulting mixture
of epimers 12 was then subjected to the same reaction
sequence as compounds 5. This sequence again
involved removal of the acetonide group of 12 with
trifluoroacetic acid and water, followed by treatment of
the resulting mixture of compounds 13 with 2%
aqueous sodium bicarbonate solution (Scheme 2). A 2:1
through compounds
6 and 7. Racemization was
efficiently avoided by appropriate protection of the C5
OH group of compound 6.
This new chemistry could be used for the transforma-
tion of dialdehydes—including sugar-derived dialde-
hydes—into
polyhydroxylated
a-nitrocycloalkane
Figure 3.

1656
R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 1653–1658
carboxylic acids, that could in turn be converted into
polyhydroxylated cycloalkane a-amino acids, a class of
compounds that have not been studied to any great
extent.17 Future efforts will focus on the application of
the new method to the synthesis of this amino acids
with a view to their incorporation into peptides.
137.12, 163.11, 163.39; MS (EI) m/z 354 (M+−1, 0.1%),
217 (0.3%), 127 (1.2%), 91 (100%).
3.2. Ethyl 3-O-benzyl-6-deoxy-6-nitro-D,L-glycero-a-D-
glucoheptofuronate 6
A solution of compounds 5 (0.23 g, 0.57 mmol) in a 1:1
mixture of trifluoroacetic acid/water (4 ml) was stirred
at rt for 9 h. The solvent was evaporated in vacuo and
the residue was coevaporated with toluene (3×1 ml) to
remove traces of trifluoroacetic acid. The product was
used in the next step without further purification.
3. Experimental
Melting points were determined using a Kofler Ther-
mogerate apparatus and are uncorrected. Specific rota-
tions were recorded on a JASCO DIP-370 optical
polarimeter. Infrared spectra were recorded on a
MIDAC FTIR spectrophotometer. Nuclear magnetic
resonance spectra were recorded on a Bruker WM-300
apparatus or a Bruker AMX-500, using deuterochloro-
form solutions containing tetramethylsilane as internal
standard. Mass spectra were obtained on a Kratos MS
50 TC mass spectrometer. Elemental analyses were
obtained from the Elemental Analysis Service at the
University of Santiago de Compostela. Thin-layer chro-
matography (TLC) was performed using Merck GF-
254 type 60 silica gel and ethyl acetate/hexane mixtures
as eluants; the TLC spots were visualized with Hane-
sian mixture. Column chromatography was carried out
using Merck type 9385 silica gel. Solvents were purified
as per Ref. 18. Solutions of extracts in organic solvents
were dried with anhydrous sodium sulfate.
3.3. (1R,2R,3R,4R,5S,6R)-4-O-Benzyl-1-ethoxycar-
bonyl-2,3,5,6-tetrahydroxy-1-nitrocyclohexane 8 and
(1S,2S,3R,4S,5S,6S)-4-O-benzyl-1-ethoxycarbonyl-
2,3,5,6-tetrahydroxy-1-nitrocyclohexane 9
A 2% aqueous solution of sodium bicarbonate (6 ml)
was added to a solution of compound 6 (0.2 g, 0.54
mmol) in methanol (17 ml) and the mixture was stirred
at rt for 14 h. The reaction mixture was then acidified
with a resin (DOWEX 50W), filtered and the solvent
evaporated in vacuo. The residue was submitted to
flash column chromatography (eluant: 2:3 ethyl acetate/
hexane) and the racemic mixture 8+9 (100 mg, 50%
yield) was isolated as an unstable white solid: [h]2D0 0.0
(c 1.08 in CHCl3); IR (NaCl, cm−1) 3364–3468 (–OH),
1678 (–CꢁO), 1562 (–NO2), 1380 (–NO2); 1H NMR
(300 MHz, CDCl3) l 1.42 (t, 3H, J=7.3 Hz, –CH3),
3.73–3.85 (m, 2H), 4.33–4.58 (m, 4H), 4.67 (d, J5,6=9.3
Hz, 1H), 5.06 (d, J2,3=2.8 Hz, 1H), 7.40–7.62 (m, 5H,
H–Ph); 13C NMR (75.3 MHz, CDCl3) l 12.8, 62.66,
70.76, 71.11, 72.99, 73.40, 74.71, 81.01, 98.81, 127.09,
127.78, 139.17, 164.61; MS (EI) m/z 280 (M+−91,
0.2%), 157 (3%), 145 (5%), 107 (12%), 91 (100%).
3.1. Ethyl 3-O-benzyl-6-deoxy-6-nitro-1,2-O-isopropyl-
D,L-glycero-a-D-glucoheptofuronate 5
Ethyl nitroacetate (0.91 g, 6.87 mmol), a solution of
compound 3 (1.27 g, 4.58 mmol) in THF (5 ml),
triethylamine (0.47 g, 4.58 mmol) and a solution of
tert-butyldimethylsilyl chloride (1.04 g, 6.87 mmol) in
THF (7 ml) were sequentially added to a solution of
tetrabutylammonium fluoride (0.55 g, 1.74 mmol) in
THF (6 ml) at 0°C. The reaction mixture was stirred at
rt for 15 min and then filtered. The solvent was evapo-
rated in vacuo and the solid residue was dissolved in
dichloromethane (125 ml). The resulting solution was
washed with water (3×100 ml) and the organic layer
was dried with anhydrous sodium sulphate, filtered and
evaporated in vacuo. The residue was submitted to
flash column chromatography (eluant: 2:7 ethyl acetate/
hexane) to yield ethyl 3-O-benzyl-6-deoxy-6-nitro-
3.4. (1R,2R,3R,4S,5S,6R)-2,3,5,6-Tetraacetoxy-4-O-
benzyl-1-ethoxycarbonyl-1-nitrocyclohexane 10 and
(1S,2S,3R,4R,5S,6S)-2,3,5,6-tetraacetoxy-4-O-benzyl-1-
ethoxycarbonyl-1-nitrocyclohexane 11
p-Toluenesulphonic acid (10 mg, 0.05 mmol) was added
to a solution of the racemic mixture 8+9 (41 mg, 0.11
mmol) in acetic anhydride (6 ml) and the mixture was
stirred at rt for 12 h. The reaction mixture was then
evaporated in vacuo and coevaporated with toluene
(3×1 ml) to remove traces of acetic acid. The residue
was submitted to flash column chromatography (eluant:
2:7 ethyl acetate/hexane) to give the racemic mixture
10+11 (12.2 mg, 84%). Spectroscopic data for the
racemic mixture: mp 115–118°C (EtOH); [h]2D0 0.0 (c 1
in CHCl3); IR (NaCl, cm−1) 2925 (–CH–), 1754
1,2-O-isopropyl-
D
,
L
-glycero-a-D-glucoheptofuronate 5
(1.31 g, 70%) as a 3:2 mixture of epimers: IR (NaCl,
cm−1) 3390 (–OH), 1694 (CꢁO), 1567 (–NO2), 1381
1
(–NO2); H NMR (500 MHz, CDCl3) l 1.32 (s, 3H,
–CH3), 1.33 (s, 3H, –CH3), 1.45 (s, 3H, –CH3), 1.48 (s,
3H, –CH3), 1.32 (t, 6H, J=7.2 Hz, 2×–OCH2CH3), 3.26
(d, 1H, J=6.3 Hz, 1×–OH), 3.27 (d, 1H, 8.8 Hz,
1×–OH), 4.12–4.19 (m, 2H), 4.19–4.21 (m, 1H), 4.30–
4.35 (m, 5H), 4.58–4.72 (m, 7H), 4.78–4.81 (m, 1H),
5.46 (d, 1H, J=3.4 Hz, H6), 5.50 (d, 1H, J=1.6 Hz,
H6), 5.88 (d, 1H, J=3.2 Hz, H1), 5.89 (d, 1H, J=3.2
Hz, H1), 7.30–7.38 (m, 10H, 10×H-Ph); 13C NMR (75.3
MHz, CDCl3) l 13.86, 13.92, 26.45, 26.95, 63.20, 63.39,
68.13, 68.36, 72.65, 79.19, 80.68, 80.99, 82.31, 82.36,
88.40, 88.56, 105.17, 105.32, 127.92, 128.25, 128.67,
1
(–CO2Et, –OAc), 1574 (–NO2), 1374 (–NO2); H NMR
(300 MHz, CDCl3) l 1.37 (t, J=7.23 Hz, 3H, –CH3),
1.96, 1.97, 2.04, 2.07 (4×s, 12H, –COCH3), 3.95–4.02
(m, 1H), 4.36–4.72 (m, 4H), 5.43–5.49 (m, 1H), 5.77
(dd, 1H, J=3.2 Hz, J=10.4 Hz), 6.03 (d, 1H, J5,6=10
Hz), 6.15 (d, 1H, J2,3=3.2 Hz), 7.23–7.38 (m, 5H,
H-Ph); 13C NMR (75.3 MHz, CDCl3) l 13.92, 20.41,
20.49, 20.61, 64.70, 69.38, 70.82, 72.05, 76.61, 77.46,
93.28, 127.42, 127.95, 128.46, 137.60, 161.64, 168.08,
168.66, 169.53, 169.56; MS (CI, NH3) m/z 540 (M++1,

R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 1653–1658
1657
1
12%), 432 (12%), 390 (18%), 91 (100%). Anal. calcd for
C24H29NO13: C, 53.43; H, 5.42; N, 2.60. Found C,
53.45; H, 5.40; N, 2.65.
(–OH), 1748 (–CꢁO), 1554 (–NO2), 1370 (–NO2); H
NMR (300 MHz, CDCl3) l 1.26 (t, 3H, J=7.3 Hz,
–OCH2CH3), 2.45 (bs, 1H, –OH), 2.83 (bs, 1H, –OH),
3.38 (bs, 1H, –OH), 3.74–3.77 and 3.83–3.87 (m, 2H,
–OCH2Ph), 4.11–4.18 and 4.30–4.37 (m, 2H,
–OCH2CH3), 4.47–4.54 (m, 4H), 4.75 (d, 1H, J=11.3
Hz), 5.02 (d, 1H, J=10.9 Hz), 5.06 (d, J=11.3 Hz, 1H),
7.16–7.41 (m, 10H, H-Ph); 13C NMR (75.3 MHz,
CDCl2) l 13.72, 64.48, 71.39, 71.61, 72.60, 75.04, 77.05,
77.84, 80.27, 95.68, 127.22, 127.90, 128.01, 128.21,
128.42, 128.64, 137.41, 138.35, 164.36; MS (EI) m/z 460
(M+−1, 0.03%), 370 (1.6%), 264 (3%), 181 (5%), 107
(10%), 91 (100%), 65 (10%). HRMS calcd for:
C23H26NO9 (M+−1) 460.1607. Found 460.1608. Data
for compound 15: [h]D17 −11.0 (c, 1.60 in CHCl3); IR
(NaCl, cm−1) 3549–3453 (2×–OH), 1741 (–CꢁO), 1564
3.5. Ethyl 3,5-di-O-benzyl-6-deoxy-6-nitro-1,2-O-isopro-
pyl-D,L-glycero-a-D-glucoheptofuronate 12
A mixture of benzyl-2,2,2-trichloroacetimidate (1.5 ml,
8.04 mmol) and trifluoromethanesulphonic acid (0.009
ml) in dry cyclohexane (32 ml) was added to a solution
of 5 (1.65 g, 4.02 mmol) in dry dichloromethane (16
ml). The mixture was stirred at rt for 16 h under argon,
filtered and the filtrate washed with saturated aqueous
sodium bicarbonate solution (1×60 ml) and water (1×60
ml). The organic layers were dried, filtered and the
solvent evaporated in vacuo. The residue was submitted
to flash column chromatography (eluant: 1:6 ethyl ace-
tate/hexane) to give ethyl 3,5-di-O-benzyl-6-deoxy-6-
1
(–NO2), 1371 (–NO2); H NMR (300 MHz, CDCl3) l
1.29 (t, J=7.1 Hz, 3H, –OCH2CH3), 2.32 (d, 1H,
–OH), 2.76 (bs, J=3.0 Hz, 1H, –OH), 3.26 (d, J=3.4
Hz, 1H, –OH), 3.75–3.84 (m, 2H, –OCH2Ph), 4.30 (q,
2H, –OCH2CH3), 4.45–4.49 (m, 2H), 4.57–4.60 (m,
2H), 4.76 (d, J=11.5 Hz, 1H), 4.85 (d, J=10.4 Hz,
1H), 5.02 (d, J=11.5 Hz, 1H), 7.17–7.40 (m, 10H,
H-Ph); 13C NMR (75.3 MHz, CDCl3) l 13.85, 63.75,
71.63, 71.95, 73.05, 74.86, 76.59, 79.62, 79.91, 97.43,
128.00, 128.03, 128.21, 128.37, 128.65, 137.22, 138.38,
163.33; MS (EI) m/z 460 (M+−1, 0.13), 370 (6), 264 (4),
181 (4), 107 (10), 91 (100). HRMS calcd for:
C23H26NO9 (M+−1) 460.1607. Found 461.1603.
nitro-1,2-O-isopropyl-
D
,L
-glycero-a-D-glucoheptofurona
te (12) (1.14 g, 56% yield) as a yellow oil: IR (NaCl,
cm−1) 1754 (–CꢁO), 1565 (–NO2), 1375 (–NO2); 1H
NMR (300 MHz, CDCl3) l 1.24–1.35 (m, 12H, 2×–
CO2CH2CH3), 1.52, 1.57 (2×s, 6H, 2×–CH3), 4.12–4.93
(m, 16H), 5.59 (d, 1H, J5,6=4.2 Hz, H-6), 5.63 (s, 1H,
H-6), 5.90, 5.91 (2×d, 2H, J1,2=3.8 Hz, J1,2=4.2 Hz,
2×H1), 7.11–7.37 (m, 20H, H–Ph); 13C NMR (75.3
MHz, CDCl3) l 13.78, 13.93, 26.52, 26.94, 62.89, 63.07,
71.70, 71.86, 74.21, 78.96, 79.04, 80.91, 81.17, 82.54,
81.74, 89.11, 89.29, 104.89, 127.38, 127.72, 127.79,
128.17, 128.30, 128.35, 128.45, 128.56, 128.65, 136.92,
137.51, 137.69, 162.74, 163.13; MS (CI, NH3) m/z 501
(M+, 0.1), 500 [(M+H)+, 0.25], 271 (2), 181 (22), 129
(14), 91 (100). HRMS: calcd for C26H31NO9 (M+)
501.1954. Found 501.1948.
Acknowledgements
Special thanks are due to Professor G. W. J. Fleet for
helpful discussions on this chemistry. We also acknowl-
edge the ‘Xunta de Galicia’ and the Spanish Ministry of
Science and Technology for financial support and the
later for a grant to Raquel G. Soengas.
3.6. Ethyl 3,5-di-O-benzyl-6-deoxy-6-nitro-
D,L-glycero-
a- -glucoheptofuronate 13
D
A solution of compounds 12 (0.51 g, 1.03 mmol) in a
1:1 mixture of trifluoroacetic acid/water (18 ml) was
stirred at rt for 21 h. The solvent was evaporated in
vacuo, coevaporated with toluene (3×10 ml) in order to
remove traces of trifluoroacetic acid, and the solid
residue was used in the next step without further
purification.
References
1. (a) Henry, L. C.R. Acad. Sci. Paris 1895, 120, 1265; (b)
Luzzio, F. A. Tetrahedron 2001, 57, 915; (c) Noboru, O.
In The Nitro Group in Organic Synthesis; Feuer, H., Ed.
Organic Nitro Chemistry Series; Wiley-VCH, 2001;
Chapter 2.
2. Luzzio, F. A.; Fitch, R. W. J. Org. Chem. 1999, 64, 5485.
3. McNulty, J.; Mo, R. Chem. Commun. 1998, 933.
4. Magnus, P.; Booth, J.; Diorazio, L.; Donohoe, T.; Lynch,
V.; Magnus, N.; Mendoza, J.; Pye, P.; Tarrant, J. Tetra-
hedron 1996, 52, 14103.
3.7. (1S,2R,3R,4R,5S,6S)-2,4-Di-O-benzyl-1-ethoxycar-
bonyl-3,5,6-trihydroxy-1-nitrocyclohexane 14 and
(1R,2R,3R,4R,5S,6S)-4-di-O-benzyl-1-ethoxycarbonyl-
3,5,6-trihydroxy-1-nitrocyclohexane 15
A 2% aqueous solution of sodium bicarbonate (12 ml)
was added to a solution of 13 (0.46 g, 9.98 mmol) in
methanol (36 ml) and the mixture was stirred at rt for
14 h. The reaction mixture was then acidified with a
resin (DOWEX 50W), filtered and the solvent evapo-
rated in vacuo. The residue was submitted to flash
column chromatography (eluant: 4:9 ethyl acetate/hex-
ane) to give compound 14 (0.22 g, 46% over the last
two steps) and compound 15 (0.10 g, 24% over the last
two steps) as yellow oils. Data for compound 14: [h]D17
−6.45 (c, 1.10 in CH2Cl2); IR (NaCl, cm−1) 3539–3472
5. Ferrier, J. F.; Middleton, S. Chem. Rev. 1993, 93, 2779.
6. Yoshikawa, M.; Cha, B. C.; Nakae, T.; Kitagawa, I.
Chem. Pharm. Bull. 1988, 36, 3714.
7. Yoshikawa, M.; Cha, B. C.; Nakae, T.; Kitagawa, I.
Chem. Pharm. Bull. 1988, 36, 3718.
8. For reviews, see: (a) Schipchandler, M. T. Synthesis 1979,
666; (b) Shvekhgeimer, M. G. A. Russ. Chem. Rev. 1998,
67, 35; (c) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller,
T. Chimia 1979, 33, 1; (d) Rosini, G.; Ballini, R. Synthesis
1988, 833.

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R. G. Soengas et al. / Tetrahedron: Asymmetry 14 (2003) 1653–1658
9. (a) Nouguier, R.; Be´raud, V.; Vanelle, P.; Crozet, M. P.
at a final R1=0.0489 [for I>2|(I)], wR2=0.01588 [for all
data], 434 parameters, with allowance for the thermal
anisotropy for all non-hydrogen atoms. The weighting
Tetrahedron Lett. 1999, 40, 5013; (b) Fornicola, R. S.;
Montgomery, J. Tetrahedron Lett. 1999, 40, 8337 and
references cited therein.
scheme employed was w=[|2(F0 +(0.0812P)2+(0.4066P)]
2
2
2
and P=(ꢀF0ꢀ +2ꢀFcꢀ )/3 and the goodness-of-fit on F2 was
1.008 for all observed reflections. Crystallographic data
(excluding structure factors) for the structure reported in
this paper have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publications
no. CCDC 205855 (10+11). Copies of the data can be
obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: (+44)1223-
336-033; e-mail: deposit@ccdc.cam.ac.uk). Crystallo-
graphic data for (10+11): C24H29NO13, M=539.48.
Monoclinic, space group P2(1)/c with a=13.444(1), b=
10. Zen, S.; Takeda, Y.; Yasuda, A. Bull. Chem. Soc. Jpn.
1967, 40, 431.
11. (a) Lichtenthaler, F. W.; Bambach, G. J. Org. Chem.
1972, 37, 1621; (b) Rosenthal, A.; Cliff, B. J. Carbohydr.
Nucleosides Nucleotides 1975, 2, 263; (c) Butcher, M. E.;
Lee, J. B. Tetrahedron Lett. 1974, 15, 2663.
12. Fleet, G. W. F.; Witty, D. W. Tetrahedron: Asymmetry
1990, 1, 119.
13. Paulsen, H.; Brieden, M.; Sinwell, V. Liebigs Ann. Chem.
1985, 113.
14. Crystal structure determination: A suitable crystal of the
racemic mixture (10+11) (block, colorless, dimensions
0.45×0.40×0.35 mm3) was used for the structure determi-
,
14.710(1), c=14.261(1) A, h=90°, i=101.440(2)°, k=
3
g .
cm−3
,
90°, V=2764.2(4) A , Dcalcd (Z=4)=1.296
F(000)=1136. Absorption coefficient=0.0107 cm−1
15. Kovar, J.; Baer, H. H. Carbohydr. Res. 1975, 39, 19.
nation. X-Ray data were collected using
a Bruker
.
SMART CCD area detector single-crystal diffractometer
with graphite-monochromatized Mo-Ka radiation (u=
16. Protection of OH at C5 in compounds 5 was performed
in an acidic medium with benzyltrichloroacetididate
owing to the instability of 5 in basic media, see: Kokotos,
G.; Chiou, A. Synthesis 1997, 168.
17. Fairbanks, A. J.; Hui, A.; Skead, B. M.; de, Q.; Lilley, P.
M.; Lamont, R. B.; Storer, R.; Saunders, J.; Watkin, D.
J.; Fleet, G. W. J. Tetrahedron Lett. 1994, 35, 8891.
18. Perrin, D. D.; Armarego, W. L. F. Purification of Labo-
ratory Chemicals; Pergamon Press: New York, 1988.
19. SADABS. Sheldrick, G. M., University of Go¨ttingen,
Germany, 1996. Program for absorption corrections
using Bruker CCD data.
20. Bruker SHLXTL-PC. Sheldrick, G. M., University of
Go¨ttingen, Germany, 1997.
21. SHLXTL-PC. Sheldrick, G. M., Program for Crystal
Structure Solution; University of Go¨ttingen: Go¨ttingen,
Germany, 1997.
,
0.71073 A) by the phi-omega scan method at 298(2) K. A
total of 1271 frames of intensity data were collected for
each compound. The first 50 frames were recollected at
the end of data collection to monitor for decay. The
crystal used for the diffraction study showed slight
decomposition during data collection (0.1%). The integra-
tion process yielded a total of 16807 reflections, of which
5648 [R(int)=0.0192] were independent. Absorption cor-
rections were applied using the SADABS19 program
(maximum and minimum transmission coefficients,
0.9637 and 0.9536). The structure was solved using the
Bruker SHLXTL-PC20,21 software by direct methods and
refined by full-matrix least-squares methods on F2.
Hydrogen atoms were located on residual density maps
except those of the methyl groups that were included in
calculated positions, then fixed their positions and refined
in the riding mode. For 10+11 convergence was reached