Synthesis of five and six membered aminocyclitols: stereoselective Michael and Henry reaction approach with d-glucose derived α,β-unsaturated ester

Article abstract of DOI:10.1016/j.tet.2008.07.049

The stereoselective intermolecular Michael addition of nitromethane to d-glucose derived α,β-unsaturated ester 7 afforded l-ido-configurated nitroester 8 as the only product that on reduction of the ester functionality, cleavage of 1,2-acetonide and the i

Full text of DOI:10.1016/j.tet.2008.07.049

Tetrahedron 64 (2008) 9574–9580
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of five and six membered aminocyclitols: stereoselective Michael
and Henry reaction approach with
D-glucose derived
a,
b-unsaturated ester
,
Chaitali Chakraborty a, Vinod P. Vyavahare a, Vedavati G. Puranik b, Dilip D. Dhavale a
*
a Department of Chemistry, Garware Research Centre, University of Pune, Pune 411 007, India
b Centre for Material Characterization, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective intermolecular Michael addition of nitromethane to
D-glucose derived a,b-un-
Received 21 April 2008
Received in revised form 14 July 2008
Accepted 15 July 2008
saturated ester 7 afforded L-ido-configurated nitroester 8 as the only product that on reduction of the
ester functionality, cleavage of 1,2-acetonide and the intramolecular Henry reaction afforded exclusively
muco-nitroinositol 9. While reduction of the ester functionality in 8, deprotection of 1,2-acetonide,
oxidative cleavage with NaIO4 and the intramolecular Henry reaction afforded nitrocyclopentitol 13.
Nitrocyclitols 9 and 13 were converted to the hydroxyethyl substituted aminocyclohexitol 5 and
aminocyclopentitol 6, respectively.
Available online 18 July 2008
Keywords:
Aminocyclitols
Carbohydrates
Henry reaction
Michael addition
Nitroinositol
Ó 2008 Elsevier Ltd. All rights reserved.
10
1. Introduction
area of aminocyclitols,
we are now reporting the synthesis of
hitherto unknown aminocyclohexitol 5 and aminocyclopentitol 6
Among the C–C bond formation reactions, the Henry reaction of
with hydroxyethyl substituent.11
a carbonyl compound and a nitroalkane bearing
a
-hydrogen,
During the past two decades, the design of synthetic analogues
of aminocyclitols with improved biological profile using asym-
metric, enzymatic as well as chiron approaches has received
leading to the formation of either -nitroalcohol (with two newly
b
generated stereocentres) or nitroolefin, is one of the well known
classical named reactions.1 The mild reaction conditions coupled
with the new chiral catalyst or chiral substrate make both intra-
and/or intermolecular Henry approaches more versatile in the
synthesis of optically pure amino alcohols and natural products.2 In
particular, the nitrocyclitols obtained by an intramolecular Henry
reaction constitute a key intermediate in the synthesis of amino-
cyclitols. This type of compounds, particularly five and six mem-
bered aminocyclitols, e.g., mannostatin A 1,3 allozamizoline 24 and
validamine 35 (Fig. 1), are potent glycosidase inhibitors owing to
their sugar-mimetic structures. In addition, aminocyclitol ring
skeleton constitutes a structural subunit of complex natural prod-
ucts such as pancratistatin 4 and validamycins.5,6 In the naturally
occurring aminocyclitols, the presence of hydroxymethyl side chain
is common and characteristic making them to be designated as
C7N-aminocyclitols.7
SMe
OH
HOH2C
HO
H2N
HO
NMe2
N
OH
HO
1
2
OH
O
NH2
O
HO
HO
NH
OH
OH
O
OH
OH
HO
OH
3
4
HO
NH2
HO
NH2
These C7N-aminocyclitols containing natural products such as
pyralomicins8 and cetoniacytone A9 are antibacterial and anti-
tumour agents, respectively. As a part of our ongoing interest in the
OH
OH
OH
HO
OH
OH
HO
5
6
* Corresponding author. Tel./fax: þ91 20 25691728.
Figure 1. Structure of aminocyclitols.
E-mail address: ddd@chem.unipune.ernet.in (D.D. Dhavale).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.049

C. Chakraborty et al. / Tetrahedron 64 (2008) 9574–9580
9575
considerable attention.7 In general, carbohydrates have been
exploited as substrates utilizing aldol condensations,12 rearrange-
ment reactions (Ferrier and Claisen),13 radical cyclizations,14 cy-
cloadditions,15 ring closing metathesis and chemo enzymatic
pathway.7,16 However, the intramolecular Henry reaction approach
to aminocyclitols using sugars is more appealing due to the easy
access to introduce nitroalkane substituent in the polyhydroxylated
carbon framework with aldehyde functionality. The literature sur-
vey indicates that the introduction of required nitroalkane moiety
in the sugar substrate is achieved either by the intermolecular
Henry reaction with other free aldehyde group2,17 or by displace-
ment of –OR (leaving group) in aldoses18 in the synthesis of
nitroinositol/aminocyclitols.
reported earlier by us.18 Having both the 7a (E) and 7b (Z) isomers
in hand, the conjugate addition reaction with nitromethane was
studied with different bases. The Michael addition of nitromethane
(2.2 equiv) with 7a at reflux for 5 h, using potassium carbonate as
a base in ethanol, led to a reaction mixture from which the L-ido
configured nitrosugar 8 was isolated in 87% yield (Scheme 2).21 Our
efforts to alter the stereochemistry at the prochiral C-5 centre
under various reaction conditions (e.g., change of solvent, tem-
perature, bases and stoichiometry) had no effect on the stereo-
selectivity. To understand the effect of the double bond geometry
on the stereoselectivity, the reactions were also performed with
7b (Z-isomer). Under identical reaction conditions as above, no
change was observed in the stereoselectivity, but the reactions with
E-isomer were found to be sluggish as compared to the Z-isomer.
These findings led us to make use of the geometric mixture of
Recently, we reported the intermolecular Michael addition of
benzyl amine to
C-5 epimeric
D-glucose derived a,b-unsaturated ester 7 to get
b
-aminoesters I that were exploited in the synthesis
a,b-unsaturated ester 7 for further studies.
of mono- and bicyclic iminosuagars (Scheme 1).19 Inspired with this
observation, we thought of intermolecular Michael addition of ni-
NO2
O
CH3NO2,
tromethane to a,b-unsaturated ester 7 to get the nitrosugar II with
O
K2CO3, EtOH
the required nitroalkane moiety suitably placed at C-5 of hexulose
for the Henry reaction (Scheme 1). Thus, reduction of the ester and
cleavage of 1,2-acetonide functionality in nitrosugar II followed by
an intramolecular Henry reaction will afford nitrocyclohexitol ring
skeleton III that could be elaborated to the hydroxyethyl
substituted aminocyclohexitol IV. On the contrary, reduction and
cleavage of 1,2-acetonide functionality in II followed by oxidative
cleavage would lead to nitroaldose V, with one carbon atom less,
that on intramolecular Henry reaction would lead to the formation
of nitropentitol VIdan immediate precursor to aminocyclopentitol
EtO
7
OBn
87%
H
O
8
O
TFA-H2O
NO2
NO2
EtO2C
OH
O
H
OH
OBn
OBn
O
CO2Et
OH
OH
DABCO,
benzene
80%
5
OR
8
O
VII. Although the conjugate addition of nitroalkane with
saturated carbonyl compounds has been widely studied,20 the
Michael addition of nitromethane with -unsaturated ester 7 and
a,b-un-
7
5
EtO
a,b
RO
4
NO2
OR
HO
4
NO2
LAH, THF
30%
6
6
subsequent Henry approach to aminocyclitols, to the best of our
knowledge is not known. The Michael and the Henry reactions are
expected to give eight stereoisomers of each IV and VI, however;
our efforts in the exclusive and stereoselective synthesis of
aminocyclitols 5 and 6 are discussed herein.
3
2
3
1
1
BnO
BnO
OH
2
OR
OH
9
Ac2O, PTSA
70%
10: R = H
11: R = Ac
Scheme 2. Synthesis of nitroinositol 10.
Iminosugars
D-glucose
The stereochemistry at the newly generated stereocentre C-5
could not be assigned from the 1H NMR data. Fortunately, the
nitrosugar 8 was obtained as a white crystalline solid and the single
crystal X-ray analysis established the 5R absolute configuration
(Fig. 2).22,27
NHBn
O
EtO2C
O
EtO2C
OP
OP
H
O
O
O
In the next step, cleavage of 1,2-acetonide group in 8 with TFA/
H2O afforded a mixture of hemiacetals (as evident from the 1H NMR
spectrum of the column purified product), which was immediately
subjected to the intramolecular Henry reaction. In general, the
bases of choice for promoting nitroaldol reaction in sugars are
alkoxides or hydroxides.23 Therefore, the reaction of hemiacetal
was performed using sodium ethoxide in ethanol, which under
different reaction conditions (solvent and temperature) afforded
a complex mixture of products. The use of triethylamine as well as
diisopropylethyl amine in alcoholic solvents, at different reaction
temperatures, also led to the complex mixture of products. How-
ever, the best results were obtained on treatment of hemiacetal
with DABCO24 (3.0 equiv) using benzene as a solvent at reflux for
1 h that afforded nitrocyclitol 9 as a single diastereomer in 80%
yield.25 The structure and the absolute configuration at the newly
generated C-1 and C-6 stereocentres in 9 were assigned on the basis
of 1H NMR studies, wherein the assignment of the signals to the
respective protons and the coupling constant information were
obtained by COSY and decoupling experiments. In the formation of
O
O
O
7
I
Reduction
Michael
O2N
HO
R
OH
OH
Henry
O
HO
OP
HO
OH
II
III: R = NO2
IV: R = NH2
HO
Cleavage of
C1-C2
R
O2N
OH
OH
Henry
OCHO
OP
HOH2C
CHO
HO
V
VI: R = NO2
VII: R = NH2
P = Protecting group
Scheme 1. Synthetic strategy.
2. Results and discussion
9, the hydroxylated carbons C2, C3 and C4 are derived from the D-
Our synthetic route starts with
as a mixture of E and Z-isomers in the ratio 3:1 from
a
,
b
-unsaturated ester 7 obtained
glucose and the stereochemistry at C5 was established in the Mi-
chael addition product. Assuming that the same stereochemistry is
D-glucose as

9576
C. Chakraborty et al. / Tetrahedron 64 (2008) 9574–9580
Figure 2. ORTEP drawing of compound 8.
retained in the product 9, the stereochemical outcome at C1 and C6
could be derived from the 1H NMR splitting pattern of H-1 and H-6.
Amongst the different cyclohexane ring protons, the most di-
agnostic and downfield proton was found to be the H-6 methine
proton (deshielded due to strong ꢀI effect of the nitro group),
Figure 3. ORTEP drawing of compound 11.
The low yield in the reduction of 9 to get alcohol 10 prompted us
to find other method. Thus, as an alternative pathway (Scheme 3),
the Michael adduct 8 was first subjected to reduction by LAH in THF
at 0 ꢁC to afford a primary alcohol 12 in 60% yield, with the nitro-
functionality intact.26 In the subsequent step, cleavage of 1,2-ace-
tonide group in 12 with TFA/H2O afforded a mixture of hemiacetals,
which was directly subjected to the intramolecular Henry reaction
with DABCO in benzene under refluxcondition to get nitroalcohol 10
as the only product in 75% yield. The melting point, analytical and
spectral datawere found to be identical with the product obtained in
the previous reaction sequence (9 to 10). The formation of the same
inositol 10 in both the sequences indicated that the ester group in
compound 9 is not having any significant role in the transition state
for the stereoselective formation of the Henry product.
which appeared at
d 4.69 as a triplet. The large coupling constant
(J6,1¼J6,5¼10.4 Hz) indicated that H-6/H-1 and H-6/H-5 are trans-
diaxially oriented. While H-1 appeared at 4.35 as doublet of
d
doublet, wherein the large coupling constant J1,6¼10.4 Hz is
agreeing with trans-orientation of H-1/H-6, the small coupling
constant J1,2¼3.3 Hz showed axial–equatorial relationship between
H-1 and H-2. This established the absolute configurations at new
stereocentres as 1S and 6R.
In the next step, reaction of 9 with LAH in THF at 0 ꢁC led to the
formation of primary alcohol 10 as a solid in only 30% yield with
nitro-functionality intact.26 Our attempts to increase the yield un-
der various reaction conditions were unsuccessful. In order to
confirm the absolute configurations, the nitroinositol 10 was first
acetylated with acetic anhydride and pyridine in the presence of
catalytic amount of DMAP, however; the reaction resulted into
a complex mixture of products probably due to epimerization, at
NO2
O
a
-carbon to the nitro group, and elimination under basic condition.
LAH, THF
60%
HO
OBn
As an alternative, we thought of acetylation under mild acidic
condition. Thus, the reaction of 10 with acetic anhydride in the
presence of catalytic amount of PTSA afforded the corresponding
tetra-acetylated derivative 11 as a white crystalline solid. The
conformational and configurational assignments in 11 were made
on the basis of coupling constant data, obtained by decoupling
experiments. In the 1H NMR spectrum, H-6 showed a triplet with
large coupling constant (J6,5¼J6,1¼10.8 Hz) while H-1 appeared as a
doublet of doublet (J1,6¼10.8; J1,2¼3.3 Hz). The large coupling con-
stant between H-6 and H-1 indicated the trans-diaxial relationship
of these protons, whereas the small coupling constant between H-1
and H-2 showed an axial-equatorial relationship. This observation
was attributed to the conformational structure muco-nitroinositol
11 with absolute configurations as 1S and 6R. The structure 11 was
further confirmed by single crystal X-ray analysis (Fig. 3).27
8
H
O
O
12
i) TFA-H2O
ii) DABCO,
benzene
75%
OH
NH2
HCOONH4,
OBn
H
H
10% Pd-C,
MeOH
OH
OH
OH
NO2
72%
OR
H
OR
OR
HO
OH
5
HCl,
10: R = H
11: R = Ac
Ac2O,
PTSA
MeOH
5a = 5.HCl
Scheme 3. Synthesis of aminocyclohexitol 5.

C. Chakraborty et al. / Tetrahedron 64 (2008) 9574–9580
9577
In the final step, treatment of 10 with 10% Pd/C and ammonium
formate in refluxing methanol afforded aminocyclohexitol 5 as
a brown liquid, which was further converted to its hydrochloride
salt 5a. The spectral and analytical data were found to be in con-
sonance with the assigned structure.
and C4 are derived from the substrate 12 and we presume that the
same stereochemistry is retained in the product. In order to es-
tablish the configurations at C1 and C5, the splitting pattern of H-5
is decisive. In compounds 6 and 6a, the H-5 appeared at d 2.81 and
3.26 as a triplet with coupling constants J5,1¼9.1 and 9.0 Hz, re-
spectively. The large coupling constant indicates cis-relative ste-
reochemistry of H-5/H-1 and H-5/H-4, and established the absolute
configurations as 1S and 5S.
While targeting the synthesis of five membered aminocyclitol 6,
the nitroalcohol 12 was considered to be the key intermediate.
Thus, as shown in Scheme 4, treatment of nitroalcohol 12 with TFA/
H2O followed by oxidative cleavage of C1–C2 bond with NaIO4 in
acetone/water (5:1) afforded nitroaldehyde V that on reaction with
DABCO in benzene under reflux afforded nitrocyclopentitol 13 as
the only stereoisomer in 80% yield. The assignment of the absolute
configurations at the newly formed stereocentres was difficult on
the basis of the 1H NMR data of compound 13. Therefore, com-
pound 13 was acetylated using Ac2O in the presence of PTSA (cat.)
that afforded diacetylated nitroalkene 14. The formation of 14 un-
der mild acidic condition was surprising. This sequence probably
involves first acetylation of 13 to give the tri-acetylated derivative
that undergoes facile deacetylation to give di-acylated nitroolefin
14. The efficient deacetylation in tri-acetylated derivative 13 in-
dicated the cis-relative stereochemistry of H-1/H-5 in which the
facile anti-elimination gives 14. Based on this observation, the ab-
solute configuration at the new stereocentres was tentatively
assigned as 1S and 5S. It is worth to mention that in the six
membered nitrocyclitol 10, we have isolated the tetra-acetyl de-
rivative in which trans-relative stereochemistry of protons at C6
and C1 precludes the syn-elimination leading to the formation of
nitroolefin adduct.25
2.1. Explanation for the observed stereoselectivity in the
Henry reaction
We believe that DABCO being a tertiary base abstracts the pro-
ton from the a-carbon to the nitro functionality in nitroalkane and
the carbanion thus formed is more stabilized in the nitronate form
under thermodynamically controlled condition. With this as-
sumption, the observed stereoselectivity in the intramolecular
Henry reaction to get 9/10 could be explained in terms of six
membered cyclic transition states TS 1 and TS 2 in which the bulky
–CH2CO2Et/–CH2CH2OH and –NO2 substituents are placed equato-
rially oriented (Fig. 4). Among the two transition states, the tran-
sition state TS 1, that assumes product-like geometry, is stabilized
by the
p-orbital overlap of C]O and C]N of the nitronate due to
their parallel alignment, wherein the attack of the nitronate anion
to the Si-face of the C]O group afforded 9/10. However, the per-
pendicular orientation of C]O and C]N precludes the
p-orbital
overlap and disfavours the TS 2 in which failure to attack from the
Re-face of carbonyl group did not afford other stereomer.
The stereoselective formation of the nitrocyclopentitol 13 could
also be explained on the basis of transition states for the in-
termediate V. We assumed, the two transition states TS 3 and TS 4,
in which C]O and C]N are parallelly oriented and allows overlap
NO2
i) TFA-H2O
ii) NaIO4,
Acetone-H2O
OCHO
12
HO
OBn
of
p-orbitals. We believe that TS 4 is stabilized due to the intra-
CHO
V
molecular hydrogen bonding between the carbonyl group and the
quasi-axial C-3 hydroxyl group, wherein Si-face attack to the car-
bonyl group affords 13, which is further stabilized by the intra-
molecular hydrogen bonding between the two quasi-axial hydroxyl
groups.
DABCO,
benzene
80%
HO
7
NO2
1
7
HO
NH2
1
HCOONH4,
10% Pd-C,
MeOH
5
5
6
OH
6
OH
4
4
3. Conclusion
2
2
OH
70%
3
3
OBn
HO
HO
In conclusion, intermolecular Michael addition of nitromethane
to a,b-unsaturated ester 7 afforded 8 as the only isomer. Reduction
13
6
HCl, MeOH,
70%
6a = 6.HCl
Ac2O,
PTSA
of the ester and the cleavage of 1,2-acetonide functionality in 8 and
intramolecular Henry reaction afforded nitrocyclitol 9 that was
converted to the aminocyclohexitol 5. While reduction, cleavage of
1,2-acetonide functionality in 8 and NaIO4 mediated oxidative
cleavage gave nitroaldose that on the intramolecular Henry re-
action afforded nitropentitol 13dan immediate precursor to ami-
nocyclopentitol 6. Both the Michael and the Henry reactions were
highly stereoselective leading to the exclusive formation of ther-
modynamically stable products. It is worth to note that the struc-
ture and the stereochemistry of aminocyclohexitol 5 were found to
be identical with that of the inositol ring C of the pancratistatin 4.
The readily available starting material, high yielding and stereo-
selective steps make our synthetic route more practicable and ef-
ficient for the synthesis of new analogues of aminocyclitols.
OAc
OAc
NO2
H
NO2
O
On silica gel
82%
C
O
CH3
H
OBn
AcO
OBn
AcO
14
Scheme 4. Synthesis of aminocyclopentitol 6.
In the final step, treatment of 13 with 10% Pd/C and ammonium
formate in refluxing methanol afforded aminocyclopentitol 6 as
a semisolid, which was reacted with methanol/HCl to give the
corresponding hydrochloride salt 6a. The stereochemical assign-
ment in 6 and 6a was established from the 1H NMR spectrum and
decoupling experiments and the coupling constant values are given
in Table 1. In compound 6a, the absolute configurations at C2, C3
4. Experimental
4.1. General methods
Table 1
Coupling constant data for aminocyclopentitol 6 and its hydrochloride salt 6a
Melting points were recorded with Thomas Hoover Capillary
melting point apparatus and are uncorrected. IR spectra were
recorded with an FTIR as a thin film or in Nujol mull or using KBr
pellets and are expressed in cmꢀ1. 1H (300 MHz) and 13C (75 MHz)
Compound
J1,2 (Hz)
J2,3 (Hz)
J3,4 (Hz)
J4,5 (Hz)
J6,1 (Hz)
6
6a
9.1
9.1
d
d
4.2
4.5
7.2
7.2
9.1
9.0

9578
C. Chakraborty et al. / Tetrahedron 64 (2008) 9574–9580
O
N
H
O
O
OH
NO2
O
O
NO
OBn
BnO
BnO
2
OBn
N
O
R
OH
R
R
R
R
X
H
OH
OH
9/10
OH
OH
R
O
O
H
H
OH
OH
TS 2
R = CH2COOEt
R = CH2CH2OH
A
TS 1
O
O
O
OBn
NO2
OH
NO2
OBn
OBn
R
OBn
N
N
R
H
O
O
X
O
O
O
O
OH
H
13
H
TS 3
H
OH
H
TS4
B
R = CH2CH2OH
Figure 4. Explanation for observed stereoselectivity.
NMR spectra were recorded using CDCl3 or D2O as a solvent.
Chemical shifts were reported in units (parts per million) with
On cooling, Amberlite IR-120 (acidic resin, 1.0 g) was added, stirred
for 1 h and solvent was evaporated under reduced pressure. Col-
umn chromatography and elution with n-hexane/ethyl acetate
d
reference to TMS as an internal standard and J values are given in
hertz. Elemental analyses were carried out with a Thermo electron
corporation flash EA 1112 series CHNS-analyzer at the Department
of Chemistry, University of Pune as well as at the analytical division,
National Chemical Laboratory, Pune. Optical rotations were mea-
sured using a Jasco P-1020 polarimeter at 25 ꢁC. Thin layer chro-
matography was performed on pre-coated plates (0.25 mm, silica
gel 80 F254). Column chromatography was carried out with silica gel
(100–200 mesh). The reactions were carried out in oven-dried
glassware under dry N2. Methanol, benzene and THF were purified
and dried before use. Distilled n-hexane and ethyl acetate were
used for column chromatography. Pd/C (10%) and DABCO were
purchased from Aldrich and/or Fluka and ammonium formate from
Merck. After quenching of the reaction with water, the work-up
involves washing of combined organic layers with water, brine,
drying over anhydrous sodium sulfate and evaporation of the sol-
vent at reduced pressure.
(2/1) afforded compound 9 as a yellow liquid (0.81 g, 80%): Rf 0.53
25
(n-hexane/ethyl acetate¼1/1); [
a]
ꢀ171.2 (c 0.12, CHCl3); IR
D
(neat): 3300–3450, 2929, 1728, 1554 cmꢀ1
CDCl3/D2O)
;
1H NMR (300 MHz,
d
1.19 (t, J¼8.9 Hz, 3H), 2.23 (dd, J¼16.2, 3.3 Hz,1H), 2.70
(dd, J¼16.2, 9.6 Hz, 1H), 2.83–2.98 (m, 1H), 3.83 (t, J¼3.0 Hz, 1H),
3.98–4.18 (m, 4H), 4.35 (dd, J¼10.4, 3.3 Hz, 1H), 4.48 (ABq,
J¼11.7 Hz, 2H), 4.69 (t, J¼10.4 Hz, 1H), 7.21–7.32 (m, 5H); 13C NMR
(75 MHz, CDCl3/D2O)
d 14.1, 32.3, 37.2, 61.3, 69.8, 70.5, 72.1, 72.2,
75.3, 88.3,127.5, 127.7,127.9,128.4,128.5,137.0,171.7. Anal. Calcd for
17H23NO8: C, 55.28; H, 8.28. Found: C, 55.44; H, 8.32.
C
4.1.3. (1S,2S,3S,4R,5R,6R)-3-(Benzyloxy)-5-(2-hydroxyethyl)-
6-nitrocyclohexane-1,2,4-triol (10)
To an ice cooled suspension of LAH (0.3 g, 7.59 mmol) in dry THF
(5 mL) was added a solution of 9 (0.4 g, 1.08 mmol) in dry THF
(5 mL) over a period of 10 min. The reaction mixture was warmed
to room temperature and stirred for 1 h. On cooling to 0 ꢁC, ethyl
acetate (10 mL) was added, stirred for 10 min and quenched with
saturated solution of Na2SO4 (2 mL). The solution was filtered, the
residue washed with ethyl acetate (3ꢂ3 mL), and the organic layer
evaporated and purified by column chromatography (n-hexane/
4.1.1. Ethyl 1,2-O-isopropylidene-3-O-benzyl-5-nitromethyl-5,8-
dideoxy-b-L-ido-heptofuranuronate (8)
A solution of 7 (11.0 g, 31.81 mmol), nitromethane (3.78 mL,
89.54 mmol) and K2CO3 (9.28 g, 87.01 mmol) in ethanol (100 mL)
was refluxed for 5 h. The solvent was evaporated under reduced
pressure to get thick oil. Column chromatography and elution with
n-hexane/ethyl acetate¼9/1 afforded nitrosugar 8 (10.24 g, 87%) as
ethyl acetate¼4/8) to give 10 (0.27 g, 30%) as a white solid: mp¼98–
25
100 ꢁC; Rf 0.53 (ethyl acetate); [
a]
ꢀ18.92 (c 0.22, CH3OH);
D
IR(Nujol): 2932–3383, 1554 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
a white crystalline solid: mp¼82–84 ꢁC; Rf 0.49 (n-hexane/ethyl
d
1.24–1.41 (m, 1H), 1.75–1.80 (m, 1H), 2.45–2.53 (m, 1H), 3.25 (br s,
25
acetate¼4/1);
[
a]
ꢀ58.1 (c 0.13, CHCl3); IR (Nujol): 1728,
1H), 3.47–3.54 (m, 1H), 3.78 (t, J¼3.3 Hz, 1H), 4.00 (br d, J¼18.2 Hz,
2H), 4.20 (dd, J¼10.8, 3.3 Hz, 1H), 4.57 (s, 2H), 4.84 (t, J¼10.8 Hz,
D
1558 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
1.23 (t, J¼7.2 Hz, 3H), 1.31
(s, 3H), 1.48 (s, 3H), 2.27–2.30 (m, 2H), 3.05–3.07 (m, 1H), 3.89 (d,
J¼2.1 Hz, 1H), 4.10 (q, J¼7.2 Hz, 2H), 4.19 (dd, J¼7.8, 1.8 Hz, 1H), 4.44
(d, J¼11.7 Hz, 1H), 4.80–4.87 (m, 3H), 4.79 (dd, J¼13.2, 4.2 Hz, 1H),
5.87 (d, J¼3.8 Hz, 1H), 7.24–7.31 (m, 5H); 13C NMR (75 MHz, CDCl3)
1H), 7.23–7.32 (m, 5H); 13C NMR (75 MHz, CDCl3)
d 30.0, 38.0, 58.2,
69.4, 70.7, 71.7, 71.9, 75.9, 89.2, 127.2 (s), 127.5, 128.1 (s), 137.3. Anal.
Calcd for C15H21NO7: C, 55.04; H, 8.47. Found: C, 55.23; H, 8.29. The
1H NMR spectrum was not very clear due to poor solubility of the
compound in CDCl3. Addition of DMSO-d6 to the solution leads to
broadening of the signals.
d
14.8, 28.7, 27.1, 33.1, 33.3, 33.7, 72.1, 75.8, 79.2, 81.3, 82.0, 104.9,
112.1, 128.3, 128.5, 128.8, 138.9, 171.0. Anal. Calcd for C20H27NO8: C,
58.87; H, 8.85. Found: C, 58.88; H, 8.50.
4.1.4. (1S,2S,3S,4R,5R,6R)-5-(2-Acetoxyethyl)-3-(benzyloxy)-
nitrocyclohexane-1,2,4-triyl triacetate (11)
4.1.2. (1S,2S,3S,4R,5R,6R)-3-(Benzyloxy)-5-(2-carbethoxymethyl)-
6-nitrocyclohexane-1,2,4-triol (9)
To a solution of 10 (0.09 g, 0.27 mmol) in acetic anhydride
(0.83 mL, 8.84 mmol) was added catalytic amount of PTSA (0.002 g,
0.01 mol) at 0 ꢁC. The solution was warmed to room temperature
and stirred for 18 h. The reaction mixture was concentrated under
reduced pressure. Column chromatography and elution (n-hexane/
ethyl acetate¼4/1) afforded tetra-acetate 12 (0.09 g, 70%) as a white
A solution of compound 8 (1.0 g, 2.44 mmol) in TFA/water (8:4,
10 mL) was stirred at 0 ꢁC for 20 min and allowed to attain room
temperature. The solution was stirred for 2 h and concentrated
under reduced pressure. Column chromatography and elution with
n-hexane/ethyl acetate (4/1) afforded a mixture of hemiacetal as
a white solid (0.85 g, 94%). The 1H NMR spectrum suggested
crystalline solid: mp¼110–112 ꢁC; Rf 0.89 (n-hexane/ethyl
25
a mixture of two anomers (
the hemiacetal (0.78 g, 2.05 mmol) in benzene was added DABCO
(0.89 g, 8.18 mmol) and the reaction mixture was refluxed for 1 h.
a
/
b
¼7:3). To a well-stirred solution of
acetate¼3/2); [
1558 cmꢀ1
1.92 (m, 1H), 1.97 (s, 3H), 1.98 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.73–
a
]
þ2.88 (c 1.8, CHCl3); IR (Nujol): 1740 (br),
D
; d 1.45–1.82 (m, 1H), 1.75–
1H NMR (300 MHz, CDCl3)

C. Chakraborty et al. / Tetrahedron 64 (2008) 9574–9580
9579
2.81 (m, 1H), 3.83 (br s, 1H), 3.97 (br m, 2H), 4.88 (ABq, J¼11.7 Hz,
2H), 4.91 (t, J¼11.4 Hz, 1H), 5.09 (br s, 1H), 5.52 (br s, 1H), 5.84 (dd,
J¼11.4, 3.3 Hz, 1H), 7.25–7.35 (m, 5H); 13C NMR (75 MHz, CDCl3)
(0.05 g, 80% yield) as a semisolid: Rf 0.12 (CH3OH) (elongated trail
25
observed on TLC plate); [
a
]
þ1.29 (c 3.0, CH3OH); IR (neat):
D
2888–3381 (br) cmꢀ1 1H NMR (300 MHz, D2O)
;
d 1.52–1.75 (m,
d
20.4, 20.7, 20.8, 25.8, 38.7, 60.8, 68.2, 69.1, 69.8, 72.7, 73.1, 85.5,
2H), 1.93–2.74 (m, 1H), 3.22 (t, J¼10.5 Hz, 1H), 3.55–3.85 (m, 2H),
127.4, 127.8 (s), 128.1, 128.4, 138.4, 188.7, 189.0, 189.3, 170.4. Anal.
Calcd for C23H29NO11: C, 55.75; H, 5.90. Found: C, 55.80; H, 6.13.
3.87–3.80 (m, 2H), 3.87 (br s, 1H), 3.92 (br d, J¼3.0 Hz, 1H); 13C
NMR (75 MHz, D2O)
d 38.1, 51.7, 58.8, 82.7, 88.9, 70.3, 70.4, 72.4.
Anal. Calcd for C8H18ClNO5: C, 39.43; H, 7.45. Found: C, 39.73; H,
7.70.
4.1.5. 1,2-O-Isopropylidene-3-O-benzyl-5,6-dideoxy-5-nitromethyl-
b
-L
-ido-hepto-1,4-furanose (12)
The reaction of (2.0 g, 4.89 mmol) with LAH (0.37 g,
8
4.1.9. (1S,2S,3R,4R,5S)-2-(Benzyloxy)-4-(2-hydroxymethyl)-5-
nitrocyclopentane-1,3-diol (13)
9.78 mmol) in dry THF (10 mL) followed by work-up as described
for compound 10 and purification by column chromatography (n-
To a cooled solution of hemiacetal (0.30 g, 0.92 mmol), obtained
from 12, in acetone/water (3:2, 10 mL) was added sodium meta-
periodate (0.39 g, 1.83 mmol). After stirring for 1 h at 0 ꢁC, the ex-
cess of sodium metaperiodate was decomposed using ethylene
glycol (0.20 mL). The reaction mixture was filtered through Celite,
residue washed with acetone and the combined solvent was
evaporated under reduced pressure to afford a crude product. The
crude product thus obtained was subjected to further reaction. To
a well-stirred solution of aldehyde (0.25 g, 0.84 mmol) in benzene
(10 mL), DABCO (0.34 g, 3.04 mmol) was added and the reaction
mixture was refluxed for 1 h. On cooling, the acidic resin (Amberlite
IR-120, 0.40 g) was added to the reaction mixture and stirred for
30 min. Filtration, removal of the solvent and purification by col-
umn chromatography with n-hexane/ethyl acetate (8/4) afforded
hexane/ethyl acetate¼4/1) afforded 12 as a pale yellow liquid
25
(1.08 g, 60%): Rf 0.28 (n-hexane/ethyl acetate¼3/2); [
a]
ꢀ52.04 (c
D
1.35, CHCl3); IR (neat): 2932–3383, 1554 cmꢀ1; 1H NMR (300 MHz,
CDCl3) 1.31(s, 3H), 1.47 (s, 3H), 1.51–1.58 (m, 2H), 2.39 (br s, ex-
d
changes with D2O, 1H), 2.79–2.85 (m, 1H), 3.81 (t, J¼8.3 Hz, 2H),
3.92 (d, J¼3.3 Hz, 1H), 4.18 (dd, J¼8.4, 3.3 Hz, 1H), 4.51 (d, J¼11.7 Hz,
1H), 4.55 (dd, J¼13.2, 8.8 Hz, 1H), 4.82 (d, J¼3.9 Hz, 1H), 4.87 (d,
J¼11.7 Hz, 1H), 4.75 (dd, J¼12.9, 4.2 Hz, 1H), 5.88 (d, J¼3.9 Hz, 1H),
7.25–7.38 (m, 5H); 13C NMR (75 MHz, CDCl3)
d 28.2, 28.8, 31.1, 33.8,
59.4, 71.8, 78.0, 78.8, 79.7, 81.3, 81.5, 104.3, 111.8, 127.8, 127.9, 128.2,
128.3, 138.8. Anal. Calcd for C18H25NO7: C, 58.84; H, 5.88. Found: C,
58.99; H, 5.71.
4.1.6. (1S,2S,3S,4R,5R,6R)-3-(Benzyloxy)-5-(2-hydroxymethyl)-6-
nitrocyclohexane-1,2,4-triol (10) from 12
a thick oil 13 (0.20 g, 80%): Rf 0.45 (n-hexane/ethyl acetate¼1/1);
þ7.70 (c 1.3, CHCl3); IR (neat): 3338–3500 (br), 1580 cmꢀ1; 1H
25
[a
]
D
Compound 12 (1.0 g, 2.94 mmol) was dissolved in TFA/water
(8:4, 10 mL), stirred at 0 ꢁC for 20 min and allowed to warm up to
room temperature. The solution was stirred for 2 h at room tem-
perature and concentrated under reduced pressure. Column chro-
matography on silica gel (n-hexane/ethyl acetate¼2/1) afforded the
hemiacetal as a white solid (0.73 g, 82%).
To an ice cooled suspension of LAH (0.3 g, 7.59 mmol) in dry THF
(5 mL) was added a solution of hemiacetal (0.20 g, 0.81 mmol) in
dry THF (5 mL) over a period of 10 min. The reaction mixture was
warmed to room temperature and stirred for 1 h. On cooling to 0 ꢁC,
ethyl acetate (10 mL) was added, stirred for 10 min and quenched
with saturated solution of Na2SO4 (2 mL). The solution was filtered,
the residue washed with ethyl acetate (3ꢂ5 mL), and the organic
layer evaporated and purified by column chromatography (n-hex-
ane/ethyl acetate¼2/1) to give 10 (0.15 g, 75%) as a white solid. The
spectral and analytical data of the compound match that of com-
pound 10 synthesized earlier in Section 4.1.3.
NMR (300 MHz, CDCl3) d 1.82–1.72 (m, 1H), 1.78–1.95 (m, 1H), 2.80–
2.80 (m, 1H), 3.00–3.40 (br, 1H, exchanges with D2O), 3.42–3.80 (m,
1H), 3.80–3.70 (m, 1H), 3.73 (d, J¼2.1 Hz, 1H), 4.17 (d, J¼5.4 Hz, 1H),
4.00–4.35 (br, 2H, exchanges with D2O), 4.40–4.85 (m, 4H), 7.21–
7.28 (m, 5H); 13C NMR (75 MHz, CHCl3)
d 28.4, 45.0, 60.5, 71.8, 74.4,
79.7, 88.4, 94.1, 127.7, 127.8, 128.4, 137.2. Anal. Calcd for C14H19NO8:
C, 58.58; H, 8.44. Found: C, 58.39; H, 8.83.
4.1.10. (1R,2R,5R)-5-(2-Acetoxyethyl)-2-(benzyloxy)-4-
nitrocyclopent-3-enyl acetate (14)
To a solution of 13 (0.10 g, 0.34 mmol) in acetic anhydride
(0.80 mL, 8.4 mmol), catalytic amount of PTSA (0.005 g, 0.03 mmol)
was added at 0 ꢁC. The solution was warmed to room temperature
and stirred for 18 h. Column chromatography (n-hexane/ethyl
acetate¼4/1) on silica gel afforded compound 14 (0.1 g, 82%) as
25
a thick liquid: Rf 0.5 (n-hexane/ethyl acetate¼4/1); [
a
]
D
ꢀ114.45 (c
1.3, CHCl3); IR (neat): 2872–3488 (br), 1743, 1525 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) 1.72–1.81 (m, 1H), 1.95 (s, 3H), 2.00–2.09 (m,
d
4.1.7. (1S,2S,3S,4R,5R,6R)-6-Amino-5-(2-hydroxyethyl)-
cyclohexane-1,2,3,4-tetraol (5)
1H), 2.13 (s, 3H), 3.71–3.72 (m,1H), 3.92–3.99 (m,1H), 4.04–4.12 (m,
1H), 4.85 (s, 2H), 4.78 (d, J¼5.4 Hz, 1H), 5.38 (dd, J¼7.8, 8.3 Hz, 1H),
To a well-stirred solution of compound 10 (0.11 g, 0.33 mmol) in
dry methanol (10 mL) were added 5% Pd/C (0.1 g) and ammonium
formate (0.15 g, 2.35 mmol). The reaction mixture was refluxed for
45 min and on cooling was filtered through Celite. Evaporation of
solvent and purification by column chromatography (chloroform/
6.84 (s, 1H), 7.25–7.35 (m, 5H); 13C NMR (75 MHz, CHCl3)
d 20.8,
20.9, 28.1, 40.9, 61.9, 72.8, 79.1, 83.4, 127.7, 128.1, 128.5, 132.9, 138.9,
153.4, 189.7, 170.8. Anal. Calcd for C18H21NO7: C, 59.50; H, 5.83.
Found: C, 59.87; H, 5.73.
methanol¼1/9) afforded 5 (0.05 g, 72%) as a brown liquid: Rf 0.17
4.1.11. (1S,2S,3R,4R,5S)-5-Amino-4-(2-hydroxyethyl)cyclo-
pentane-1,2,3-triol (6)
25
(CH3OH); [
a
]
þ27.82 (c 0.34, CH3OH); IR (neat): 2809–3381 cmꢀ1
;
D
1H NMR (300 MHz, D2O)
d
1.72–1.87 (m, 2H), 2.10–2.22 (m, 1H),
To a well-stirred solution of compound 13 (0.12 g, 0.33 mmol) in
dry methanol (10 mL) were added 5% Pd/C (0.1 g) and ammonium
formate (0.1 g, 1.82 mmol). The reaction mixture was refluxed for
45 min and on cooling was filtered through Celite. Evaporation of
solvent and purification by column chromatography (chloroform/
3.38 (t, J¼9.8 Hz, 1H), 3.58–3.88 (m, 1H), 3.70–3.82 (m, 1H), 3.84–
3.94 (m, 2H), 3.98–4.04 (m, 1H), 4.07 (t, J¼3.8 Hz, 1H); 13C NMR
(75 MHz, D2O)
d 34.0, 40.9, 58.5, 63.8, 73.8, 75.2, 75.3, 77.3. Anal.
Calcd for C8H17NO5: C, 48.37; H, 8.27. Found: C, 48.49; H, 8.48.
methanol¼1/9) afforded 6 (0.05 g, 70%) as a semisolid: Rf 0.12
25
4.1.8. (1S,2S,3S,4R,5R,6R)-6-Amino-5-(2-hydroxyethyl)-
cyclohexane-1,2,3,4-tetraol hydrochloride (5a)
(CH3OH); [
a
]
þ27.45 (c 3.0, MeOH); IR (neat): 2800–3390
D
(br) cmꢀ1 1H NMR (300 MHz, D2O)
; d 1.80–1.72 (m, 1H), 1.74–1.98
A solution of 5 (0.05 g, 0.24 mmol) in methanol/HCl (10 mL,
0.5 M) was stirred at room temperature for 24 h. The solvent was
evaporated under reduced pressure and the residue was washed
with ethyl acetate, dry ether and dried in vacuum to get 5a
(m, 2H), 2.81 (t, J¼9.1 Hz, 1H), 3.52 (dd, J¼8.1, 7.2 Hz, 1H), 3.55–3.72
(m, 3H), 3.94 (dd, J¼7.2, 4.2 Hz, 1H); 13C NMR (75 MHz, D2O)
d 29.5,
43.1, 59.0, 60.5, 74.7, 81.8, 82.4. Anal. Calcd for C7H13NO8: C, 40.58;
H, 8.32. Found: C, 40.81; H, 8.87.

9580
C. Chakraborty et al. / Tetrahedron 64 (2008) 9574–9580
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11. For hydroxyethyl substituted aminocyclopentitols, see: (a) Bojstrup, M.; Lundt,
I. Org. Biomol. Chem. 2005, 3, 1738–1745; (b) Bojstrup, M.; Fanefjord, M.; Lundt,
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4.1.12. (1S,2S,3R,4R,5S)-5-Amino-4-(2-hydroxyethyl)cyclopentane-
1,2,3-triol hydrochloride (6a)
Compound 6 (0.05 g, 0.28 mmol) was converted to its hydro-
chloride salt following the same procedure as 5a to obtain
25
a semisolid 6a (0.05 g, 70%): Rf 0.20 (CH3OH); [
MeOH); IR (neat): 2878–3390 (br) cmꢀ1
1.81–1.78 (m, 1H), 1.84–2.02 (m, 1H), 2.20–2.40 (m, 1H), 3.28 (t,
a
]
þ7.41 (c 3.0,
D
;
1H NMR (300 MHz, D2O)
d
J¼9.0 Hz, 1H), 3.58–3.72 (m, 1H), 3.75–3.98 (m, 3H), 4.05 (dd,
J¼7.2, 4.5 Hz, 1H); 13C NMR (75 MHz, D2O)
d 29.3, 40.8, 59.4, 60.3,
74.3, 78.0, 81.4. Anal. Calcd for C7H18ClNO4: C, 39.35; H, 7.55.
Found: 39.78, H, 8.00.
12. (a) Grosheintz, J. M.; Fischer, H. O. L. J. Am. Chem. Soc. 1948, 70, 1476–1479; (b)
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Acknowledgements
We are grateful to Prof. M. S. Wadia for helpful discussions and
to Department of Science and Technology, New Delhi for the
financial support (SR/S1/OC-21/2005). C. C. is thankful to the
University of Pune for the stipend.
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Supplementary data
Supplementary data of the NMR spectra associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2008.07.049.
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L
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D
-gluco¼92:08.
a,b
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25. The reaction mixture was heated for a prolonged period of 8 h. Compound 9
was the only product, which could be isolated while no formation of nitro-
alkene or any other stereoisomer was detected in the reaction mixture. The 1
H
and 13C NMR spectra of crude reaction mixture showed additional signals <05%
probably due to the side product.
26. Our observation was found to be analogous to that reported wherein –NO2
functionality is compatible under LAH condition see Ref. 1.
27. The crystallographic data have been deposited with the Cambridge Crystallo-
graphic Data Centre as deposition nos. CCDC-685631 (8) and CCDC-685632
(11). Copies of the data can be obtained, free of charge, on application to the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: þ44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk].