Intra-molecular nitrone-olefin cycloaddition of d-glucose derived allylic alcohol: synthesis of new aminocyclohexitols

Article abstract of DOI:10.1016/j.tet.2007.09.011

Diastereo- and regioselelective intra-molecular nitrone-olefin cycloaddition reaction of in situ generated N-benzylnitrones, obtained from d-glucose derived precursors 5a/5b furnished dihydroxy functionalized isoxazolidines. The N-O bond reductive cleavag

Full text of DOI:10.1016/j.tet.2007.09.011

Tetrahedron 63 (2007) 11984–11990
Intra-molecular nitrone–olefin cycloaddition of D-glucose
derived allylic alcohol: synthesis of new aminocyclohexitols
*
Chaitali Chakraborty, Vinod P. Vyavahare and Dilip D. Dhavale
Department of Chemistry, Garware Research Centre, University of Pune, Pune 411007, Maharashtra, India
Received 21 June 2007; revised 28 August 2007; accepted 6 September 2007
Available online 9 September 2007
Abstract—Diastereo- and regioselelective intra-molecular nitrone–olefin cycloaddition reaction of in situ generated N-benzylnitrones,
obtained from D-glucose derived precursors 5a/5b furnished dihydroxy functionalized isoxazolidines. The N–O bond reductive cleavage
and removal of N/O-benzyl groups led to the formation of stereochemically well defined aminocyclohexitols.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
attention as compared to the five membered aminocyclopen-
titols. In general, carbohydrates have been exploited as sub-
strates for the synthesis of the aminocyclitols utilizing ring
closing metathesis, metal catalyzed reactions and free radi-
cal cyclizations1d,4 as the key steps. Apart from these meth-
odologies, an intra-molecular nitrone–olefin cycloaddition
(INOC) reaction, especially with the nitrones derived from
sugars, has received more attention.5,6 The sugar substituted
isoxazolidines thus obtained are amenable to the construc-
tion of five/six/seven membered aminocyclitols, depending
on the formation of bicyclic fused/bridged isoxazolidine
ring systems wherein the regio/stereo-chemical outcome of
the reaction is controlled by the geometric constraints, steric
and electronic factors.5h,7 We have recently reported the
INOC reaction of an in situ generated D-glucose derived
nitrone for the synthesis of aminocyclopentitol.8 As a part
of our continuing interest in the area of nitrones,9 we have
now investigated the INOC reaction of an in situ generated
nitrone, obtained from the cleavage of the 1,2-acetonide
functionality in 3,5-di-O-benzyl-6,7-dideoxy-1,2-O-iso-
propylidene-hept-6-ene-furanose 5 followed by treatment
with N-benzylhydroxylamine hydrochloride. The reaction
resulted in the formation of a fused bicyclic isoxazolidine
ring skeleton, which on N–O bond reductive cleavage
afforded three new aminocyclohexitols 2a–c. Our results
in this direction are presented herein.
Amongst polyhydroxylated carbocycles,1 the amino
substituted polyhydroxylated carbocycles, commonly known
as aminocyclitols, constitute the key structural fragments for
amino-glycoside antibiotics and are potential glycosidase
inhibitors as well as antiviral agents.2 Advances in the eluci-
dation of biological processes have proved the importance of
the six membered aminocyclitols owing to their sugar-
mimetic structure. For example, validamine 1 (Fig. 1), a
natural aminocyclohexitol, and its unnatural derivatives are
at the forefront of the bio-organic research field because of
their ability to serve as potent glycosidase inhibitors. This
has consequently made them valuable therapeutic agents.3
These compounds, however, receive limited synthetic
HO
HO
HO
HO
HO
HO
NH2
OH
NH2
OH
OH
1
2a
HO
HO
HO
HO
NH2
OH
HO
HO
NH2
OH
OH
OH
2. Results and discussion
2b
2c
As shown in Scheme 1, the Grignard reaction of vinylmag-
nesium bromide with 3-O-benzyl-1,2-O-isopropylidene-a-
D-xylo-pentodialdose 3,10 in THF at 0 ꢀC gave D-gluco- and
L-ido-configurated allylic alcohols 4a and 4b, respectively,
in the ratio of 2:3 as reported earlier by us and others.11
Figure 1. Validamine and its analogues.
Keywords: Cyclitols; Nitrones; Isoxazolidines; Carbohydrates.
* Corresponding author. E-mail: ddd@chem.unipune.ernet.in
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.011

C. Chakraborty et al. / Tetrahedron 63 (2007) 11984–11990
11985
Treatment of 4a and 4b individually with benzyl bromide
and NaH in THF afforded the corresponding benzyl pro-
tected compounds 5a and 5b. Removal of the 1,2-acetonide
group in 5a with TFA/H2O afforded a hemiacetaly that was
directly reacted with N-benzylhydroxylamine hydrochloride
and NaHCO3 in ethanol/water (8:2) under reflux to give
fused bicyclic isoxazolidine 6a as a single diastereomer in
88% yield. The formation of the isoxazolidine 6a plausibly
involves in situ formation of N-benzyl nitrone at the C-1
that concomitantly undergoes regio- and stereoselective
INOC reaction to give 6a.12 In the next step, treatment of
6a with 10% Pd/C and ammonium formate in refluxing
methanol afforded aminocyclohexitol 2a as a semisolid
wherein reductive cleavage of the N–O bond and removal
of the N- and O-benzyl protections were achieved in one
pot. Reaction of 2a with methanolic-HCl (0.5 M) at room
temperature afforded corresponding hydrochloride salt 8a.
Similarly, treatment of 5b with TFA/H2O followed by treat-
ment with N-benzylhydroxylamine hydrochloride and
NaHCO3 in ethanol/water under reflux afforded a diastereo-
meric mixture of fused bicyclic isoxazolidines 6b and 6c in
the ratio 4:1.12 The individual reaction of 6b and 6c with
10% Pd/C and ammonium formate in refluxing methanol
afforded corresponding aminocyclohexitols 2b and 2c that
on treatment with methanolic-HCl gave hydrochloride salts
8b and 8c, respectively.
hydroxyl (or protected hydroxyl) substituents in the sugar
ring skeleton.13 We observed that the relative stereochemis-
try at C1 and C6 in aminocyclitols 2a–c is determined by the
configuration of the C5–OBn group found in compound 5.
For the stereochemical elucidation, isoxazolidines 6a–c
were individually acetylated with acetic anhydride in pyr-
idine/DMAP to afford corresponding diacetylated derivatives
7a–c. The conformational and configurational assignments
were made on the basis of coupling constant data (Table 1),
obtained by decoupling experiments, and 1D NOESY
studies.
1
In the H NMR spectrum of isoxazolidine 7a, H1 showed
a triplet with large coupling constant (J¼9.0 Hz). This indi-
cated the trans boat-diaxial relationship of H1 and H2 and an
eclipsed conformational arrangement between H1 and H6.
In the precursor 5a, the relative stereochemistry at H2–H3
and H3–H4 is trans while that at H4–H5 is cis and the
same stereochemistry is retained in the isoxazolidine 6a
and its diacetylated derivative 7a as evident from the cou-
pling constant values. This observation was attributed to
the cis-fused isoxazolidine 7a with a boat conformation in
which the C2 acetyl and C5–OBn groups are projecting out-
wards. This fact was supported by 1D NOESY experiments
in which irradiation at H1 showed NOE at H6 and H3 while
irradiation at H5 showed NOE at H2 and H7. Further evi-
dence for the cis-fused isoxazolidine 7a was derived from
the coupling constant values in the corresponding amino-
cyclitol 2a in which J4,5 was found to be 10.8 Hz indicating
a trans diaxial orientation, while J5,6 was found to be 5.4 Hz
and J1,6 to be 2.4 Hz. This indicated the 5R and 6R absolute
configurations with the axial orientation of –CH2OH
functionality at C6 and equatorial position of the amino
functionality.
R1
R2
O
Vinylmagnesium
bromide
O
O
H
OBn
OBn
H
H
81%
O
O
O
O
4a: R1 = OH; R2 = H
3
4b: R1 = H; R2 = OH
NaH, BnBr
96%
5a: R1 = OBn; R2 = H
5b: R1 = H; R2 = OBn
O
NBn
NH2
In case of isoxazolidine 7b, H1 appeared as a doublet of dou-
OH
OH
OH
10% Pd-C,
HO
HO
blet (d 3.5) with small coupling constants (J1,2¼4.5; J1,6
¼
HCOONH4
84%
i) TFA-H2O (3:2)
BnO
5a
OBn
6.3 Hz), while H5 appeared as a triplet with J¼8.0 Hz.
This showed an axial–axial relationship between H5 and
H6. This observation was attributed to the cis-fused isoxazo-
lidine 7b with the chair conformation as shown in Figure 2.
This fact was further supported by the 1H NMR data of 2b in
which H1 appeared as a triplet with J¼3.6 Hz, and H5 as
a triplet with J¼10.8 Hz accounting to equatorial and axial
orientation of the hydroxy methyl group at C6 and the amino
group at C5, respectively, with the 5S and 6S absolute con-
figuration. In the case of isoxazolidine 7c, an analogous
observation as in the case of 7a was noticed except for the
orientation of C5–OBn. Therefore, the cis-fused isoxazolidine
ii) NHBn(OH).HCl,
NaHCO3, 88%
OH
6a
OH
2a
0.5M MeOH-HCl
90%
8a = 2a.HCl
NBn
O
O
NBn
OH
OH
+
i) TFA-H2O (3:2)
BnO
OBn
BnO
5b
OBn
ii) NHBn(OH).HCl,
NaHCO3, 83%
(4:1)
OH
6c
OH
6b
85%
80%
HCOONH4, 10% Pd-C
NH2
NH2
OH
OH
OH
HO
HO
HO
HO
OH
OH
Table 1. Coupling constant values in hertz for compounds 2a–c, 7a–c and
8a–c
OH
2c
2b
8b = 2b.HCl
0.5 M MeOH-HCl
90%
0.5 M MeOH-HCl
90%
8c = 2c.HCl
Compound
J1,2
9.0
2.4
3.3
4.5
10.8
9.3
J2,3
J3,4
J4,5
3.0
10.8
—
8.0
3.6
—
8.7
11.1
11.7
J5,6
J1,6
9.0
2.4
3.0
7aa
2a
8.4
—
2.8
7.2
—
9.0
9.3
9.3
8.7
9.1
9.0
8.4
5.4
—
8.0
3.6
—
6.0
4.5
4.5
Scheme 1. Syntheses of aminocyclohexitols.
8a
9.9
9.0
9.3
9.3
9.3
9.1
9.0
7ba
2b
8b
7ca
2c
6.3
2.1. Conformational assignment
10.8
11.4
8.0
5.5
5.1
It is known that the stereochemical outcome of INOC of
sugar-derived nitrones is dictated by the orientation of the
9.3
10.0
9.9
8c
y
The INOC of the hemiacetals did not go to completion even after
prolonged reflux for 20 h.
a
For 7a–c, the proton numberings are as in Figure 2.

11986
C. Chakraborty et al. / Tetrahedron 63 (2007) 11984–11990
nOe
OBn
H
H
H
OBn
H
O
H
H
H
6
O
5
7
4
HO
BnO
H
H
O
OR
RO
H
BnO
N
OH
NBn
N
BnO
2
3
1
Bn
Bn
HO
H
H
BnO
HO
H
6a: R = H
7a: R = Ac
TS 1'
TS 1
HO
BnO
H
no reaction
O
OBn
HO
HO
HO
N
TS 2
Bn
H
OBn
4
OBn
6
HO
BnO
RO
7
2
5
H
6b: R = H
7b: R = Ac
BnO
O
1
TS 3
3
N
O
N
RO
N
Bn
H
Bn
BnO
H
BnO
OBn
H
6
4
O
H
H
5
HO
BnO
7
H
O
H
OH
O
OR
H
N
BnO
N
2
Bn
BnO
3
1
RO
Bn
H
H
Bn
HO
6c: R = H
7c: R = Ac
TS 4'
TS 4
nOe
Figure 2. Transition states for INOC.
with the boat conformation having a 1S and 6R configuration
was assigned to 7c based on coupling constant and 1D
NOESY data. Formation of isoxazolidines 6a–c could be ex-
plained based on the six membered transition states (TS) 1–4
in which we propose that the orientation of the C5–OBn
functionality dictates the geometry of the in situ generated
nitrone (Z or E) and in turn decides the stereochemical out-
come of the INOC. Thus, in case of the D-gluco-configured
nitrone substrate derived from 5a, we believe that TS1
with a Z-nitrone prevails over TS2 having an E-nitrone geom-
etry13 due to the 1,3-diaxial interactions between C5–OBn
and the C1–C]N. In the chair-like TS1, the olefin C]C
and C]N of the nitrone are orthogonal, therefore the TS1
changes to the boat conformation (TS10) wherein the parallel
orientation of olefin and nitrone achieves the maximum
orbital overlap (with the relief of the 1,3-diaxial interaction)
leading to exclusive formation of the isoxazolidine 6a.
dictated by the orientation of the C5–OBn functionality.
The isoxazolidines thus obtained were elaborated to the
new analogues of aminohexitols, 2a–c.
3. Experimental
3.1. General methods
Melting points were recorded with Thomas Hoover Capil-
lary melting point apparatus and are uncorrected. IR spectra
were recorded with a FTIR as a thin film or in Nujol mull or
using KBr pellets and are expressed in cmꢁ1. 1H (300 MHz)
and 13C (75 MHz) NMR spectra were recorded using CDCl3
or D2O as a solvent. Chemical shifts were reported in d units
(ppm) with reference to TMS as an internal standard, and J
values are given in hertz. Elemental analyses were carried
out with a C, H-analyzer. Optical rotations were measured
using a Jasco P-1020 polarimeter at 25 ꢀC. Thin layer chro-
matography was performed on pre-coated plates (0.25 mm,
silica gel 60 F254). Column chromatography was carried
out with silica gel (100–200 mesh). The reactions were car-
ried out in oven-dried glassware under dry N2. Methanol and
THF were purified and dried before use. Distilled n-hexane
and ethyl acetate were used for column chromatography.
Pd/C (10%) was 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 solvent at
reduced pressure.
In case of the L-ido-configurated nitrone (derived from 5b),
the TS3 with the E-nitrone geometry having the pseudo-
axial orientation of C]N is preferred over the Z-nitrone,
which on subsequent INOC reaction led to the preferred
chair conformation of the major isomer 6b, while the
INOC of the Z-nitrone via the TS4 gave the minor isomer
6c with preferable boat conformation. In both cases we pre-
sume that the stability of the product conformation dictates
the preferential formation of the TS.
In conclusion, we have demonstrated that the in situ generated
nitrones from D-gluco- and L-ido-configured 3,5-di-O-benzyl-
6,7-dideoxy-1,2-O-isoropylidene-heptulo-6-en-1,4-furanoses
5a and 5b, respectively, undergo INOC reaction to give
isoxazolidines 6 in which the stereochemical outcome is
3.1.1. 3,5-Di-O-benzyl-6,7-dideoxy-1,2-O-isopropyl-
idene-a-D-gluco-hepta-6-en-1,4-furanose (5a). Sodium

C. Chakraborty et al. / Tetrahedron 63 (2007) 11984–11990
11987
hydride (0.67 g, 16.81 mmol) was washed with dry hexane
(10 mL). Compound 4a (3.43 g, 11.21 mmol) was dissolved
in dry THF (30 mL) and added dropwise to the reaction mix-
ture at 0 ꢀC. After stirring the reaction mixture for 30 min,
benzyl bromide (1.47 mL, 12.33 mmol) was added dropwise
followed by the addition of tetrabutylammonium iodide
(0.2 g, 0.56 mmol). The whole mixture was stirred at room
temperature for 6 h. The mixture was then poured into ice
water (10 mL) and the THF was evaporated under reduced
pressure. The residual aqueous layer was extracted with
ether (25 mLꢂ3) and purified by column chromatography
(n-hexane/ethyl acetate¼98:2) to give 5a as a white crystal-
line solid (1.24 g, 96%). Mp¼54–56 ꢀC; Rf¼0.6 (n-hexane/
ethyl acetate¼4:1); [a]2D5 ꢁ37.3 (c 0.75, CHCl3); IR
136.5, 137.3, 138.0. Anal. Calcd for C28H31NO5: C, 72.86;
H, 6.77. Found: C, 73.05; H, 6.94.
3.2.2. (3aS,4S,5R,6R,7S,7aS)-1-Benzyl-4,6-bis(benzyl-
oxy)-octahydrobenzo[c]isoxazole-5,7-diol (6b). Chroma-
tography on silica gel (hexane/ethyl acetate¼9:1) yielded
compound 6b (0.3 g, 66%) as a colourlss oil. Rf¼0.37 (hex-
ane/ethyl acetate¼7:3); [a]2D5 ꢁ22.2 (c 0.45, CHCl3); IR
(neat)¼3411.8, 1074.3 cmꢁ1; 1H NMR (300 MHz, CDCl3+
D2O) d 2.71–2.73 (m, 1H, H-3a), 3.39 (dd, J¼5.1, 2.7 Hz,
1H, H-7a), 3.77–3.85 (m, 5H), 4.03–4.10 (m, 3H), 4.62
(dd, J¼11.7, 4.2 Hz, 1H, H-3), 4.79 (ABq, J¼12.0 Hz, 2H,
O–CH2Ph), 7.23–7.31 (m, 15H, Ar–H); 13C NMR
(75 MHz, CDCl3) d 47.0, 62.3, 65.4, 69.4, 69.5, 69.6, 73.1,
73.7, 76.2, 80.8, 81.8, 127.5, 127.7, 128.4, 128.9, 136.7,
138.1. Anal. Calcd for C28H31NO5: C, 72.86; H, 6.77.
Found: C, 72.74; H, 6.62.
1
(Nujol)¼1602 cmꢁ1; H NMR (300 MHz, CDCl3) d 1.31
(s, 3H, CH3), 1.54 (s, 3H, CH3), 4.18 (dd, J¼13.8, 3.0 Hz,
1H, H-4), 4.21 (d, J¼11.2 Hz, 1H, O–CH2Ph), 4.23 (dd,
J¼13.8, 9.0 Hz, 1H, H-5), 4.34 (d, J¼11.2 Hz, 1H, O–
CH2Ph), 4.55 (d, J¼3.0 Hz, 1H, H-3), 4.57 (d, J¼11.7 Hz,
1H, O–CH2Ph), 4.63 (d, J¼3.6 Hz, 1H, H-2), 4.68 (d,
J¼11.7 Hz, 1H, O–CH2Ph), 5.43 (dt, J¼10.2, 1.8 Hz, 1H,
H-7a), 5.47 (dt, J¼14.7, 1.8 Hz, 1H, H-7b), 5.95 (ddd,
J¼13.8, 10.2, 7.2 Hz, 1H, H-6), 5.98 (d, J¼3.6 Hz, 1H, H-
1), 7.21–7.45 (10H, m, Ar–H); 13C NMR (75 MHz,
CDCl3) d 26.2, 26.7, 70.3, 72.2, 81.5, 81.7, 82.0, 105.0,
111.7, 119.1, 127.5, 127.7, 127.8, 128.3, 128.4, 128.8,
129.0, 137.6, 138.2, 136.1. Anal. Calcd for C24H28O5: C,
72.2; H, 7.12. Found: C, 72.12; H, 7.21.
3.2.3. (3aR,4S,5R,6R,7S,7aR)-1-Benzyl-4,6-bis(benzyl-
oxy)-octahydrobenzo[c]isoxazole-5,7-diol (6c). Chroma-
tography on silica gel (hexane/ethyl acetate¼9:1) yielded
6c (0.1 g, 17%) as a colourless oil. Rf¼0.25 (hexane/ethyl
acetate¼7:3); [a]2D5 +14.8 (c 0.27, CHCl3); IR (neat)¼3435,
1
1080 cmꢁ1; H NMR (300 MHz, CDCl3+D2O) d 3.04 (dd,
J¼9.3 Hz, 1H, H-7a), 3.18 (t, J¼9.3 Hz, 1H, H-3), 3.32–
3.38 (m, 1H, H-3a), 3.68 (t, J¼9.3 Hz, 1H, H-7), 3.71 (dd,
J¼10.8, 4.8 Hz, 1H, H-4), 3.75 (d, J¼13.5 Hz, 2H, N–
CH2Ph), 3.78 (t, J¼9.3 Hz, 1H, H-5), 3.84 (t, J¼8.7 Hz,
1H, H-30), 4.07 (d, J¼12.6 Hz, 1H, O–CH2Ph), 4.63 (m,
3H, O–CH2Ph), 4.91 (d, J¼11.2 Hz, 1H, O–CH2Ph), 7.21–
7.41 (m, 15H, Ar–H); 13C NMR (75 MHz, CDCl3) d 41.7,
60.6, 67.4, 67.8, 72.0, 72.2, 72.6, 74.7, 78.0 81.3, 127.6,
127.7, 128.0, 128.1, 128.2, 128.4, 128.4, 128.5, 129.0,
137.9, 138.3. Anal. Calcd for C28H31NO5: C, 72.86; H,
6.77. Found: C, 73.09; H, 7.07.
3.2. General procedure for nitrone–olefin cycloaddition
Compound 5 (1.0 g, 2.52 mmol) was dissolved in TFA/water
(6:4, 10 mL) and 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 chroma-
tography on silica gel (hexane/ethyl acetate¼4:1) afforded
1
the hemiacetal as a thick oil (0.73 g, 82%). The H NMR
3.3. General procedure for the conversion of 6 to 7
spectrum suggested a mixture of two anomers (a/b¼7:3).
To a well-stirred solution of the hemiacetal (0.57 g,
1.60 mmol) in ethanol/water (3:1, 10 mL) was added N-benz-
ylhydroxylamine hydrochloride (0.49 g, 3.07 mmol) fol-
lowed by sodium bicarbonate (0.35 g, 4.1 mmol) and the
solution was heated at reflux for 4 h. Ethanol was removed
under reduced pressure and the residue was extracted with
CHCl3 (10 mLꢂ3). Usual work-up and column chromato-
graphy purification afforded isoxazolidine 6.
To an ice cold solution of 6 (0.1 g, 0.20 mmol) in dry pyr-
idine (0.3 mL, 3.82 mmol) were added acetic anhydride
(0.6 mL, 6.43 mmol) and DMAP (0.0019 g, 0.015 mmol)
and the mixture was stirred for 12 h at room temperature.
The reaction mixture was treated with cold water (2 mL)
and extracted with chloroform (3ꢂ5 mL).
3.3.1. (3aR,4R,5R,6R,7S,7aR)-1-Benzyl-4,6-bis(benzyl-
oxy)-octahydrobenzo[c]isoxazole-5,7-diyl diacetate (7a).
By column chromatography (n-hexane/ethyl acetate¼9:1),
compound 7a was obtained as a yellow liquid (0.1 g,
88%). Rf¼0.40 (hexane/ethyl acetate¼7:3); [a]2D5 +19.6 (c
3.2.1. (3aR,4R,5R,6R,7S,7aR)-1-Benzyl-4,6-bis(benzyl-
oxy)-octahydrobenzo[c]isoxazole-5,7-diol (6a). Chroma-
tography on silica gel (n-hexane/ethyl acetate¼9:1)
yielded compound 6a (0.9 g, 88%) as a pale yellow oil.
Rf¼0.31 (hexane/ethyl acetate¼7:3); [a]2D5 +40.6 (c 0.69,
0.61, CHCl3); IR (neat)¼1100, 1700 cmꢁ1
;
1H NMR
(300 MHz, CDCl3) d 1.84 (s, 3H, CH3), 2.09 (s, 3H, CH3),
3.14–3.16 (m, 1H, H-3a), 3.32 (t, J¼9.0 Hz, 1H, H-7a),
3.57 (dd, J¼8.4, 2.8 Hz, 1H, H-6), 3.80 (dd, J¼8.7,
5.1 Hz, 1H, H-3), 3.86 (d, J¼12.9 Hz, 1H, N–CH2Ph),
3.92 (dd, J¼8.4, 2.8 Hz, 1H, H-4), 4.07 (d, J¼12.9 Hz,
1H, N–CH2Ph), 4.29 (t, J¼8.7 Hz, 1H, H-30), 4.48 (d,
J¼11.7 Hz, 1H, O–CH2Ph), 4.58 (d, J¼12.0 Hz, 1H, O–
CH2Ph), 4.68 (d, J¼11.7 Hz, 1H, O–CH2Ph), 4.74 (d,
J¼12.0 Hz, 1H, O–CH2Ph), 5.18 (dd, J¼9.9, 8.4 Hz, 1H,
H-7), 5.39 (t, J¼2.8 Hz, 1H, H-5), 7.21–7.45 (m, 15H, Ar–
H). 13C NMR (75 MHz, CDCl3) d 21.0, 21.1, 43.5, 60.3,
64.7, 69.5, 71.2, 71.9, 71.9, 74.9, 78.6, 127.5, 127.7,
CHCl3); IR (neat)¼3433 cmꢁ1
;
1H NMR (300 MHz,
CDCl3+D2O) d 3.04–3.14 (m, 1H, H-3a), 3.25 (t,
J¼9.0 Hz, 1H, H-7a), 3.63 (dd, J¼9.0, 4.2 Hz, 1H, H-6),
3.68 (t, J¼8.5 Hz, 1H, H-3), 3.75 (t, J¼9.0 Hz, 1H, H-7),
3.86 (dd, J¼7.8, 3.0 Hz, 1H, H-4), 3.99 (ABq, J¼13.5 Hz,
2H, N–CH2Ph), 4.07 (dd, J¼4.2, 3.0 Hz, 1H, H-5), 4.27
(t, J¼8.5 Hz, 1H, H-30), 4.63 (ABq, J¼11.5 Hz, 2H,
O–CH2Ph), 4.80 (br s, 2H, O–CH2Ph), 7.21–7.45 (m, 15H,
Ar–H); 13C NMR (75 MHz, CDCl3) d 42.7, 60.4, 68.0,
69.0, 70.7, 71.1, 71.9, 72.7, 77.0, 82.0, 127.3, 127.5,
127.5, 127.6, 127.8, 128.0, 128.1, 128.2, 128.3, 128.8,

11988
C. Chakraborty et al. / Tetrahedron 63 (2007) 11984–11990
127.9, 128.0, 128.1, 128.3, 128.6, 129.0, 136.7, 137.4, 137.7,
169.5, 170.0. Anal. Calcd for C32H35NO7: C, 70.44; H, 6.47.
Found: C, 70.27; H, 6.62.
4.14 (t, J¼2.4 Hz, 1H, H-1); 13C NMR (75 MHz, D2O)
d 45.6, 50.8, 58.2, 70.0, 71.1, 73.4, 73.8. Anal. Calcd for
C7H15NO5: C, 43.52; H, 7.83. Found: C, 43.80; H, 8.10.
3.3.2. (3aS,4S,5R,6R,7S,7aS)-1-Benzyl-4,6-bis(benzyl-
oxy)-octahydrobenzo[c]isoxazole-5,7-diyl diacetate (7b).
After column chromatography (n-hexane/ethyl acetate¼
4:1), compound 7b was obtained as a white crystalline solid
(0.09 g, 77%). Mp¼136–137 ꢀC; Rf¼0.38 (hexane/ethyl
acetate¼7:3); [a]2D5 ꢁ35.4 (c 0.62, CHCl3); IR (Nujol)¼
3.4.2. (1S,2R,3R,4S,5S,6S)-5-Amino-6-(hydroxymethyl)-
cyclohexane-1,2,3,4-tetraol (2b). Column chromatography
(chloroform/methanol¼1:9) afforded compound 2b as a
semisolid (0.03 g, 85%). [a]2D5 ꢁ86.9 (c 0.07, MeOH); IR
(neat)¼3350, 1417–1454 cmꢁ1; 1H NMR (300 MHz, D2O)
d 1.78–1.90 (m, 1H, H-6), 3.31 (t, J¼9.3 Hz, 1H, H-3),
3.51 (t, J¼3.6 Hz, 1H, H-5), 3.52–3.62 (m, 2H, H-2, H-1)
3.64 (dd, J¼9.3, 3.6 Hz, 1H, H-4), 3.78 (dd, J¼10.8,
7.5 Hz, 1H, H-7a), 3.90 (dd, J¼11.4, 4.2 Hz, 1H, H-7b);
13C NMR (75 MHz, D2O) d 43.2, 51.4, 59.8, 69.2, 72.2,
72.5, 77.32. Anal. Calcd for C7H15NO5: C, 43.52; H, 7.83.
Found: C, 43.86; H, 8.03.
1
1074, 1730 cmꢁ1; H NMR (300 MHz, CDCl3) d 1.90 (s,
3H, CH3), 1.99 (s, 3H, CH3), 2.73 (m, 1H, H-3a), 3.51 (dd,
J¼6.3, 4.5 Hz, 1H, H-7a), 3.75 (dd, J¼8.4, 1.8 Hz, 1H, H-
3), 3.87 (d, J¼13.8 Hz, 1H, N–CH2Ph), 3.91 (t, J¼9.3 Hz,
1H, H-6), 3.94 (dd, J¼8.4, 3.4 Hz, 1H, H-30), 3.99 (d,
J¼13.8 Hz, 1H, N–CH2Ph), 4.02 (t, J¼8.0 Hz, 1H, H-4),
4.55 (d, J¼11.4 Hz, 1H, O–CH2Ph), 4.67 (br s, 3H, O–
CH2Ph), 5.23 (dd, J¼9.0, 8.0 Hz, 1H, H-5), 5.24 (dd,
J¼9.0, 4.5 Hz, 1H, H-7), 7.22–7.36 (m, 15H, Ar–H);
13C NMR (75 MHz, CDCl3) d 18.6 (s), 45.4, 61.0,
61.6, 66.1, 66.9, 71.8, 72.2, 74.1, 74.3, 75.1, 124.8, 125.3,
125.7, 126.0, 126.6, 134.9, 135.6, 167.4 (s). Anal.
Calcd for C32H35NO7: C, 70.44; H, 6.47. Found: C, 70.59;
H, 6.25.
3.4.3. (1S,2S,3R,4S,5R,6R)-5-Amino-6-(hydroxymethyl)-
cyclohexane-1,2,3,4-tetraol (2c). Column chromatography
(chloroform/methanol¼1:9) afforded compound 2c as
a semisolid (0.03 g, 80%). [a]2D5 ꢁ30.7 (c 0.13, MeOH);
IR (neat)¼3352, 1421–1452 cmꢁ1
;
1H NMR (300 MHz,
D2O) d 2.49–2.56 (m, 1H, H-6), 3.20 (dd, J¼11.1 Hz,
4.5 Hz, 1H, H-5), 3.29 (t, J¼9.1 Hz, 1H, H-3), 3.52 (dd,
J¼10.0, 9.1 Hz, 1H, H-2), 3.74 (dd, J¼10.0, 5.5 Hz, 1H,
H-1), 3.77 (dd, J¼11.1, 9.1 Hz, 1H, H-4), 3.86 (dd,
J¼11.8, 7.8 Hz, 1H, H-7a), 3.96 (dd, J¼11.8, 4.2 Hz, 1H,
H-7b); 13C NMR (75 MHz, D2O) d 46.8, 54.8, 59.1, 73.9,
75.7, 75.9, 78.3. Anal. Calcd for C7H15NO5: C, 43.52;
H, 7.83. Found: C, 43.75; H, 7.95.
3.3.3. (3aR,4S,5R,6R,7S,7aR)-1-Benzyl-4,6-bis(benzyl-
oxy)-octahydrobenzo[c]isoxazole-5,7-diyl diacetate (7c).
After column chromatography (n-hexane/ethyl acetate¼
4:1), compound 7c was obtained as a white crystalline solid
(0.09 g, 78%). Mp¼131–133 ꢀC; Rf¼0.25 (hexane/ethyl
acetate¼7:3); [a]2D5 +10.6 (c 0.75, CHCl3); IR (Nujol)¼
1
1070, 1700 cmꢁ1; H NMR (300 MHz, CDCl3) d 1.90 (s,
3.5. General procedure for the conversion of 2 to 8
3H, CH3), 1.99 (s, 3H, CH3), 3.12 (br dd, J¼9.3, 8.0 Hz,
1H, H-7a), 3.29–3.38 (m, 1H, H-3a), 3.43 (t, J¼9.3 Hz, 1H,
H-6), 3.73 (d, J¼14.1 Hz, 1H, N–CH2Ph), 3.75 (dd, J¼8.7,
6.0 Hz, 1H, H-4), 4.08 (t, J¼8.7 Hz, 1H, H-3), 4.14 (d,
J¼14.1 Hz, 1H, N–CH2Ph), 4.22 (t, J¼8.7 Hz, 1H, H-30),
4.58 (ABq, J¼11.7 Hz, 2H, O–CH2Ph), 4.65 (br s, 2H, O–
CH2Ph), 5.30 (t, J¼9.3 Hz, 1H, H-7), 5.40 (t, J¼8.7 Hz,
1H, H-5), 7.22–7.43 (m, 15H, Ar–H); 13C NMR (75 MHz,
CDCl3) d 20.8 (s), 41.7, 60.5, 64.2, 67.4, 72.2 (s), 72.4,
73.5, 75.2, 78.8, 127.5, 127.7, 127.8, 128.2, 128.3, 128.8,
136.5, 137.6, 137.8, 169.2, 169.5. Anal. Calcd for
C32H35NO7: C, 70.44; H, 6.47. Found: C, 70.28; 6.33.
A solution of compound 2 (0.02 g, 0.09 mmol) in 0.5 M HCl
(1 mL) in methanol was stirred at room temperature for 20 h.
The solvent was evaporated under reduced pressure and res-
idue was dried in vacuo. The residue was washed with dry
ether and ethyl acetate.
3.5.1. (1R,2R,3R,4S,5R,6R)-5-Amino-6-(hydroxymethyl)-
cyclohexane-1,2,3,4-tetraol hydrochloride (8a). Com-
pound was dried in vacuo to afford the hydrochloride salt
8a (0.02 g, 0.09 mmol) as a semisolid. [a]2D5 ꢁ100.0
1
(c 0.12, MeOH); IR (neat)¼3440, 1454 cmꢁ1; H NMR
(300 MHz, D2O) d 2.53–2.57 (m, 1H, H-6), 3.58 (dd,
J¼9.9, 3.3 Hz, 1H, H-2), 3.61–3.85 (m, 5H, H-5, H-4, H-
3, H-7a, H-7b), 4.12 (t, J¼3.0 Hz, 1H, H-1); 13C NMR
(75 MHz, D2O) d 43.7, 51.9, 58.7, 69.8, 70.4, 71.0, 73.7.
Anal. Calcd for C7H16ClNO5: C, 36.61; H, 7.02. Found: C,
36.52; H, 7.19.
3.4. General procedure for the conversion of 6 to 2
To a well-stirred solution of compound 6 (0.1 g, 0.20 mmol)
in dry methanol (5 mL) were added 10% Pd/C (0.1 g) and
ammonium formate (0.9 g, 1.41 mmol). The reaction was
heated at reflux for 45 min. The reaction mixture was filtered
through Celite and solvent was evaporated to give a sticky
solid. The residue was washed with dry ether and ethyl
acetate.
3.5.2. (1S,2R,3R,4S,5S,6S)-5-Amino-6-(hydroxymethyl)-
cyclohexane-1,2,3,4-tetraol hydrochloride (8b). Com-
pound was dried in vacuo to afford the hydrochloride salt
8b (0.02 g, 0.09 mmol) as a semisolid. [a]2D5 ꢁ42.8
1
3.4.1. (1R,2R,3R,4S,5R,6R)-5-Amino-6-(hydroxymethyl)-
cyclohexane-1,2,3,4-tetraol (2a). Column chromatography
(chloroform/methanol¼1:9) afforded 2a as a semisolid
(0.03 g, 84%). [a]2D5 ꢁ114.2 (c 0.04, MeOH); IR (neat)¼
(c 0.07, MeOH); IR (neat)¼3330, 1456 cmꢁ1; H NMR
(300 MHz, D2O) d 1.96–2.21 (m, 1H, H-6), 3.38 (t,
J¼9.3 Hz, 1H, H-2), 3.49 (t, J¼9.3 Hz, 1H, H-3), 3.69 (dd,
J¼11.4, 9.3 Hz, 1H, H-1), 3.81–3.86 (m, H-1, 2H, H-4),
3.89 (dd, J¼11.7, 3.0 Hz, 1H, H-7a), 3.98 (dd, J¼11.7,
5.4 Hz, 1H, H-7b); 13C NMR (75 MHz, D2O) d 40.6, 54.0,
58.9, 67.4, 69.6, 72.0, 76.4. Anal. Calcd for C7H16ClNO5:
C, 36.61; H, 7.02. Found: C, 36.45; H, 6.91.
1
3433, 1417 cmꢁ1; H NMR (300 MHz, D2O) d 2.32–2.36
(m, 1H, H-6), 3.26 (dd, J¼10.8, 5.4 Hz, 1H, H-5),
3.48 (dd, J¼10.8, 7.2 Hz, 1H, H-4), 3.55–3.62 (m, 3H,
H-3, H-2, H-7a), 3.82 (dd, J¼11.4, 6.0 Hz, 1H, H-7b),

C. Chakraborty et al. / Tetrahedron 63 (2007) 11984–11990
11989
2. (a) Umezawa, W. Adv. Carbohydr. Chem. Biochem. 1974, 30,
111; (b) Rinehart, K. L.; Stroshane, R. M. J. Antibiot. 1976,
29, 319; (c) Daniels, P. J. L. Kirk-Othmer Encycl. Chem.
Technol. 1978, 2, 819; (d) Rinehart, K. L.; Suami, T.
Aminocyclitol Antibiotics. ACS Symposium Series 125;
American Chemical Society: Washington, DC, 1980.
3. (a) Paul, B. J.; Willis, J.; Martinot, T. A.; Ghiviriga, I.; Abboud,
K. A.; Hudlicky, T. J. Am. Chem. Soc. 2002, 124, 10416; (b)
Hans, P.; Burkhard, M.; Wolfgang, D. Liebigs Ann. Chem.
1987, 5, 439; (c) Trost, B. M.; Dudash, J., Jr.; Hembre, E. J.
Chem.—Eur. J. 2001, 7, 1619.
4. (a) Szolcsanyi, P.; Gracza, T. Tetrahedron 2006, 62, 8498; (b)
Xin, C.; Liao, Q. J.; Yao, Z. J. J. Org. Chem. 2004, 69, 5314;
(c) Sellier, O.; Van De weghe, P.; Le Nouen, D.; Strehler, C.;
Eustache, J. Tetrahedron Lett. 1999, 40, 853; (d) Ogawa, S.;
Shibata, Y. Carbohydr. Res. 1986, 148, 257.
3.5.3. (1S,2S,3R,4S,5R,6R)-5-Amino-6-(hydroxymethyl)-
cyclohexane-1,2,3,4-tetraol hydrochloride (8c). Com-
pound was dried in vacuo to afford the hydrochloride salt
8c (0.02 g, 0.09 mmol) as a semisolid. [a]2D5 ꢁ10.5 (c 0.19,
MeOH); IR (neat)¼3346, 1417–1450 cmꢁ1
;
1H NMR
(300 MHz, D2O) d 2.58–2.68 (m, 1H, H-6), 3.31 (t,
J¼9.0 Hz, 1H, H-3), 3.36 (dd, J¼11.7, 4.5 Hz, 1H, H-5),
3.49 (t, J¼9.9 Hz, 1H, H-2), 3.74 (dd, J¼9.9, 5.1 Hz, 1H,
H-1), 3.82–3.93 (m, H-4, 2H, H-7a), 4.01 (dd, J¼11.4,
3.3 Hz, 1H, H-7b); 13C NMR (75 MHz, D2O) d 44.3, 55.3,
58.9, 72.1, 72.6, 75.2, 77.9. Anal. Calcd for C7H16ClNO5:
C, 36.61; H, 7.02. Found: C, 36.79; H, 7.13.
Acknowledgements
5. (a) Tufariello, J. J. 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; John Wiley and Sons: New York, NY, 1984;
Vol. 2, Chapter 9, pp 83–168; (b) Torsell, K. B. G. Nitrile
oxides, Nitrones and Nitronates in Organic Synthesis; VCH:
New York, NY, 1988; (c) Confalone, P. N.; Huie, E. M. Org.
React. 1988, 36, 1; (d) Annunziata, R.; Cinquini, M.; Cozzi,
F.; Raimondi, L. Gazz. Chim. Ital. 1989, 119, 253; (e) Wade,
P. A. Comprehensive Organic Chemistry; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 1111–
1168; (f) Breuer, E. Nitrones, Nitronates and Nitroxides;
Breuer, E., Aurich, H. G., Nielsen, A., Eds.; John Wiley and
Sons: Chichester, UK, 1989; Chapters 2 and 3, pp 139–244
and 245–312; (g) Fisera, L.; Al-Timari, U. A. R.; Ertl, P.
Cycloadditions in Carbohydrate Chemistry. ACS Monograph;
American Chemical Society: Washington, DC, 1992; 158; (h)
Balasubramanian, N. Org. Prep. Proced. Int. 1985, 17, 23; (i)
1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-
Interscience: New York, NY, 1984; Chapter 9, p 277; (j)
Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863
and references therein.
6. (a) RajanBabu, T. V. Preparative Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, NY, 1997;
p 545; (b) Huryn, D.; Okabe, M. Chem. Rev. 1992, 92,
1745; (c) Ferrero, M.; Gotor, V. Chem. Rev. 2000, 100,
4319; (d) Roy, B. G.; Maity, J. K.; Drew, M. G. B.;
Achari, B.; Mandal, S. B. Tetrahedron Lett. 2006, 47, 8821;
(e) Roy, A.; Chakrabarty, K.; Dutta, P. K.; Bar, N. C.;
Basu, N.; Achari, B.; Mandal, S. B. J. Org. Chem. 1999,
64, 2304.
We are grateful to Professor M. S. Wadia for helpful discus-
sions. We are thankful to DST, New Delhi (SR/S1/OC-21/
2005) for the financial support.
References and notes
1. (a) Blidi, L. El.; Ahbala, M.; Bolte, J.; Lemaire, M.
Tetrahedron: Asymmetry 2006, 17, 2684; (b) Nasi, R.;
Pinto, B. M. Carbohydr. Res. 2006, 341, 2305; (c) Chen,
Y. L.; Leguijt, R.; Redlich, H. Synthesis 2006, 13, 2242; (d)
Alegret, C.; Benet-Buchholz, J.; Riera, A. Org. Lett. 2006,
8, 3069; (e) Feng, X.; Duesler, E. N.; Mariano, P. S. J. Org.
Chem. 2005, 70, 5618; (f) Hu, G.; Vasella, A. Helv. Chim.
Acta 2004, 87, 2434 and references cited therein; (g)
Akiyama, M.; Awamura, T.; Kimura, K.; Hosomi, Y.;
Kobayashi, A.; Tsuji, K.; Kuboki, A.; Ohira, S. Tetrahedron
Lett. 2004, 45, 7133; (h) Ogawa, S.; Sakata, Y.; Ito, N.;
Watanabe, M.; Kabayama, K.; Itoh, M.; Korenaga, T.
Bioorg. Med. Chem. 2004, 12, 995 and references cited
therein; (i) Mahmud, T. Nat. Prod. Rep. 2003, 20, 137; (j)
Gravier-Pelletier, C.; Maton, W.; Dintinger, T.; Tellier, C.;
Le Merrer, Y. Tetrahedron 2003, 59, 8705; (k) Soengas, R.;
Estevez, G. J. C.; Estevez, R. J. Org. Lett. 2003, 5, 1423;
(l) Mehta, G.; Lakshminath, S.; Talukdar, P. Tetrahedron
Lett. 2002, 43, 335 and references cited therein; (m)
Tanaka, K. S.; Winters, G. C.; Batchelor, R. J.; Einstein,
F. W.; Bennet, A. J. J. Am. Chem. Soc. 2001, 123, 998; (n)
Kleban, M.; Hilgers, P.; Greul, J. N.; Kugler, R. D.;
Picasso, S.; Vogel, P.; Jager, V. Chem. Bio. Chem. 2001, 2,
365; (o) Boss, O.; Leroy, E.; Blaser, A.; Reymond, J. L.
Org. Lett. 2000, 2, 151; (p) Dransfield, P. J.; Moutel, S.;
Shipman, M.; Sik, V. J. Chem. Soc., Perkin Trans. 1 1999,
3349; (q) Martinez-Grau, A.; Marco-Contelles, M. Chem.
Soc. Rev. 1998, 27, 155; (r) Jiang, S.; McCullough, K. J.;
Mekki, B.; Singh, G.; Wightman, R. H. J. Chem. Soc.,
Perkin Trans. 1 1997, 1805; (s) Collins, P.; Ferrier, R. R.
Monosaccharides; Wiley and Sons: Chichester, UK, 1995;
(t) Peet, N.; Huber, E. W.; Farr, R. A. Tetrahedron 1991,
47, 7537; (u) Shing, T. K. M.; Elsey, D. A.; Gillhouley,
J. G. J. Chem. Soc., Chem. Commun. 1989, 1285; (v)
Nakata, M.; Akazawa, S.; Kitamura, S.; Tatsuta, K.
Tetrahedron Lett. 1991, 32, 5363 and references cited therein;
(w) Bar, N. C.; Roy, A.; Patra, R.; Achari, B.; Mandal, S. B.
7. (a) Houk, K. N.; Sims, J.; Watts, C. R.; Luslus, L. J. J. Am.
Chem. Soc. 1973, 95, 7301; (b) Houk, K. N.; Yamaguchi, K.
1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, NY, 1984; Vol. 2, p 407; (c) Sustmann, R.
Tetrahedron Lett. 1971, 2717; (d) Sustmann, R. Pure Appl.
Chem. 1974, 40, 569.
8. Jachak, S. M.; Karche, N. P.; Dhavale, D. D. Tetrahedron Lett.
2001, 42, 4925.
9. (a) Saha, N. N.; Desai, V. N.; Dhavale, D. D. Tetrahedron 2001,
57, 39; (b) Karanjule, N. S.; Markad, S. D.; Sharma, T.;
Sabharwal, S. G.; Puranik, V. G.; Dhavale, D. D. J. Org.
Chem. 2005, 70, 1356; (c) Karanjule, N. S.; Markad, S. D.;
Dhavale, D. D. J. Org. Chem. 2006, 71, 6273; (d) Karanjule,
N. S.; Markad, S. D.; Shinde, V. S.; Dhavale, D. D. J. Org.
Chem. 2006, 71, 4667 and references cited therein.
ꢀ
Indian J. Chem. 1997, 36B, 275; (x) Duclos, O.; Dureault, A.;
Depezay, J. C. Tetrahedron Lett. 1992, 33, 1059 and refer-
ences therein.
10. Wolfrom, M. L.; Hanessian, S. J. Org. Chem. 1962, 27, 1800.
11. (a) Markad, S. D.; Karanjule, N. S.; Sharma, T.; Sabharwal, S.;
Puranik, V. G.; Dhavale, D. D. Org. Biomol. Chem. 2006, 4,

11990
C. Chakraborty et al. / Tetrahedron 63 (2007) 11984–11990
2549; (b) Lubineau, A.; Gavard, O.; Alias, J.; Bonaffe, D.
13. Inter conversion of (Z)- and (E)-nitrones under the
reaction conditions is known, see: (a) Vasella, A. Helv.
Chim. Acta 1977, 60, 426 and 1273; (b) Bjorgo, J.; Boyd,
D. R.; Neil, D. C. J. Chem. Soc., Chem. Commun. 1975,
478; (c) Inoue, Y.; Hara, J.; Kakisawa, H. Chem. Lett. 1980,
1407.
Tetrahedron Lett. 2000, 41, 307; (c) Nishikawa, A.; Saito, S.;
Hashimoto, Y.; Koga, K.; Shirai, R. Tetrahedron Lett. 2001,
42, 9195 and references cited therein.
12. Shing, T. K. M.; Zhong, Y. L.; Mak, T. C. W.; Wang, R.; Xue, F.
J. Org. Chem. 1998, 63, 414.