Synthesis of (+)-isofagomine

Article abstract of DOI:10.1016/j.tetasy.2012.08.012

The synthesis of (+)-isofagomine 1 using 4-pentenol 3 as a chiral precursor is described herein.

Full text of DOI:10.1016/j.tetasy.2012.08.012

Tetrahedron: Asymmetry 23 (2012) 1234–1237
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Tetrahedron: Asymmetry
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Synthesis of (+)-isofagomine
⇑
Mukund G. Kulkarni , Yunnus B. Shaikh, Deekshaputra R. Birhade, Ajit S. Borhade, Sanjay W. Chavhan,
Attrimuni P. Dhondge, Dnyaneshwar D. Gaikwad, Nagorao R. Dhatrak
Department of Chemistry, University of Pune, Pune 411007, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of (+)-isofagomine 1 using 4-pentenol 3 as a chiral precursor is described herein.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 31 May 2012
Accepted 14 August 2012
Available online 12 September 2012
1. Introduction
increased interest towards the development of general and flexi-
ble methodologies for the synthesis of such polyhydroxylated
Isofagomine 1 (Fig. 1), a non-natural product designed and
synthesized by Bols et al. in 1994,1 has turned out to be a very
effective member of the azasugar family, which inhibits diverse
enzymes.2 Due to its structural features, the stable protonated
form of isofagomine 1a (Fig. 1) shows obvious stereoelectronic
similarity to the oxocarbenium ion 2 (Fig. 1). This carbonium
ion is developed in the transition state during the enzymatic
hydrolysis of a glucoside and is stabilized by the enzyme.3
Therefore, isofagomine is one of the most potent inhibitors of
frameworks. Some synthetic approaches deliver the racemic form
of isofagomine10 and require multiple steps to establish the rela-
tive stereochemistry. Other synthetic approaches have described
the asymmetric synthesis11 from a racemic or prochiral precursor
but in most cases, however, enantiomer or diastereomer separa-
tion is cumbersome. Synthetic approaches starting from chiral
pool compounds1,12 have the advantage of a defined stereochem-
istry to give an enantiomerically pure product, but the disadvan-
tages are that these syntheses are rather lengthy, require a
complex protecting group strategy and are also both material
and time consuming. Therefore there is enough scope to develop
a new efficient synthetic approach for the synthesis of isofago-
mine. Herein we report our efforts towards the synthesis of isof-
agomine from enantiopure 4-pentenol 3 (Fig. 1).
b-glucosidase (Ki = 0.11
phosphorylase (Ki = 0.7
and glucagon stimulated glycogen degradation in cultured hepa-
tocytes (Ki = 2–3
M).5 It is an active-site inhibitor and increases
l
M, sweet almonds)1,12a and glycogen
M).4 Moreover, it is able to prevent basal
l
l
GlcCerase activity by 3.0 0.6-fold in N370S fibroblasts by several
mechanisms.6 As a result, isofagomine and its analogues have re-
ceived greater attention because they are new therapeutic candi-
dates for the treatment of Gaucher’s disease,6,9 type-II diabetes7
and cardiovascular diseases.8 The tartrate salt of isofagomine
was designed as a drug for the treatment of Gaucher’s disease,
which failed phase III clinical trials.9 Due to the aforementioned
importance and selective inhibition activities, there has been an
2. Results and discussions
Over the course of our ongoing programme aimed at the
asymmetric synthesis of bioactive molecules, we gained access
to high value-added and enantioenriched 4-pentenol 3 accessible
from inexpensive and readily available 2,3-O-cyclohexylidene-D-
OH
OH
OH
O
O
O
NH
NH2
HO
HO
HO
OH
OH
OH
OH
OH
1
1a
3
2
Figure 1.
⇑
Corresponding author. Tel.: +91 20 25601394; fax: +91 20 25691728.
E-mail address: mgkulkarni@chem.unipune.ac.in (M.G. Kulkarni).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.08.012

M. G. Kulkarni et al. / Tetrahedron: Asymmetry 23 (2012) 1234–1237
1235
OH
O
O
O
f
b
e
O
O
O
N3
R
OH
BnO
OR
OBn
8
5 R = OAc
6, R = OH
7, R = N3
3, R = H
4, R = Bn
a
c
d
OH
OH
OH
O
O
H
O
O
H
HO
OH
OH
O
O
O
O
HO
g
h
i
N
H
N
H
N
BnO
N3
H
11
1
9
10
Scheme 1. Reagents and conditions: (a) BnBr, NaH, THF, 0 °C to rt, 7 h, 94%; (b) Pd(OAc)2, BQ, 1:1 DMSO/AcOH, 4 Å MS, 40 °C, 48 h, 65%; (c) NaOH, MeOH, rt, 0.5 h, 97%; (d) (i)
MsCl, TEA, CH2Cl2, 0 °C to rt, 0.5 h; (ii) NaN3, DMF, 100 °C, 4 h, 84% over two steps; (e) AD mix-b, 1:1 tBuOH/H2O, 0 °C, 12 h; (f) cyclohexanone, HC(OEt)3, pTSA, rt, 1.5 h, 85%
over two steps; (g) (i) H2, 10% Pd/C, MeOH, rt, 24 h; (ii) DIAD, PPh3, rt, 18 h, 52% over two steps; (h) Conc. HCl, MeOH, rt, 6 h then NH4OH, 90%; (i) NaIO4, 3:1 MeOH/H2O, 0 °C,
1 h then NaBH4, rt, 0.5 h then conc. HCl reflux 3 h then NH4OH, 76%.
glyceraldehyde through Wittig olefination-Claisen rearrange-
ment protocol. This has proven to be a versatile and useful
intermediate.13
4. Experimental
4.1. General
As depicted in Scheme 1, our synthesis commenced with the
protection of 4-pentenol 3 as benzyl ether 4. Compound 4 was
subjected to Pd(II) catalysed allylic oxidation along with olefin
isomerization.14 For this, the olefin was heated with 10 mol %
Pd(OAc)2 and benzoquinone in 1:1 DMSO/AcOH at 40 °C to give
E-allyl acetate 5 in 65% yield. Allyl acetate 5 was hydrolysed with
NaOH in aq. MeOH to give allyl alcohol 6. Alcohol 6 was con-
verted into the corresponding methylate, which was heated at
100 °C with sodium azide in DMF to give azide 7 in 84% yield.
Exposing 7 to a dihydroxylation reaction with 2.5 mol % K2OsO4/
aq NMO in THF at 0 °C afforded an inseparable diastereomeric
mixture of the corresponding azido diol (dr = ꢀ1:1, from 1H
NMR). In order to overcome this problem, compound 7 was sub-
jected to a Sharpless asymmetric dihydroxylation reaction with
AD mix-b15 to afford the corresponding azido diol 8, which as
such on treatment with cyclohexanone, HC(OEt)3 and cat. pTSA
gave dicyclohexylidene derivative 9 as the sole enantiomerically
pure diastereomer in 85% yield. Compound 9 was transformed
into the corresponding amino alcohol via hydrogenolysis using
10% Pd/C. The crude product was subjected to cyclization with
an intramolecular Mitsunobu reaction16 to give piperidene
derivative 10 in 52% yield. Compound 10 was treated with conc.
HCl in MeOH to give novel azasugar 11. The terminal diols of 11
were subjected to oxidative cleavage with NaIO4 followed by
in situ NaBH4 reduction of the resulting aldehyde to afford isofag-
All solvents were distilled before use. All liquid reagents were
distilled and stored under anhydrous conditions. Dry THF was ob-
tained by distillation from a dark-blue solution of sodium benzo-
phenone radical anion under a nitrogen atmosphere. Dry CH2Cl2
was prepared by distillation over calcium hydride and stored over
molecular sieves (4 Å). Petroleum ether was of the 60–80 °C boiling
point range. All anhydrous reactions were carried out under a
nitrogen atmosphere. Silica gel (100–200-mesh) was used for col-
umn chromatography. IR spectra were recorded on a Shimadzu
FTIR-8400 series instrument. 1H NMR spectra [ppm, TMS_internal
standard in CDCl3] were recorded on a VARIAN Mercury 300 MHz
instrument. 13C NMR spectra were recorded on a Varian Mercury
75 MHz instrument. Optical rotations were measured on a JAS-
CO-181 digital polarimeter. Elemental analyses were obtained on
a HOSLI semiautomatic C, H analyser.
4.2. (S)-2-((R)-1-(Benzyloxy)pent-4-en-2-yl)-1,4-diox-
aspiro[4.5]decane 4
To a suspension of sodium hydride (60% in mineral oil, 1.09 g,
27.17 mmol) in dry THF (30 mL) at 0 °C, a solution of alcohol 3
(5.12 g, 22.64 mmol) in dry THF (30 mL) was added over 15 min
and stirred for another 10 min. To this mixture, benzyl bromide
(2.96 mL, 24.90 mmol) was added dropwise after which the reac-
tion mixture was allowed to return to room temperature and stir-
red for 7 h. After completion of reaction (TLC), the mixture was
cooled in an ice bath and the reaction was quenched with water.
The layers were separated and the aqueous layer was extracted
with ethyl acetate (3 ꢂ 40 mL). The combined organic layer was
washed with brine, dried over anhydrous sodium sulfate and con-
centrated under reduced pressure. The crude residue was purified
by silica gel column chromatography using ethyl acetate/pet ether
(5:95) mobile phase to give benzyl ether 4 as a colourless thick li-
omine
1
in 76% yield,
½
a 2D1
ꢁ
¼ þ17:8 (c 0.13, EtOH), {Lit.12e
½
a 2D0
ꢁ
¼ þ16:25 (c 0.32, EtOH)}. The inhibitory activity of azasugar
11 was tested against four glycosidases at a millimolar concentra-
tion.17 However, compound 11 showed no inhibition activity
against any of the glycosidases tested.
3. Conclusion
quid (6.74 g, 94% yield). ½a D21
ꢁ
¼ ꢃ1:5 (c 1.53, CHCl3); IR (film):
In conclusion, an efficient synthesis of (+)-isofagomine 1 was
achieved in 15% overall yield starting from chiral 4-pentenol 3 in
an effective manner. Furthermore this synthetic route also gave ac-
cess to novel azasugar 11.
2933, 2858, 1641, 1448, 1103, 912 cmꢃ1
;
1H NMR (300 MHz,
CDCl3): d 1.39–1.67 (m, 10H), 1.84–1.94 (m, 1H), 2.12–2.22 (m,
1H), 2.36–2.44 (m, 1H), 3.37 (dd, 1H, J = 9.4 and 6.7 Hz), 3.45 (dd,

1236
M. G. Kulkarni et al. / Tetrahedron: Asymmetry 23 (2012) 1234–1237
1H, J = 9.5 and 4.6 Hz), 3.66–3.72 (m, 1H), 4.00–4.11 (m, 2H), 4.45
(s, 2H), 5.01 (d, 1H, J = 8.2 Hz), 5.04 (d, 1H, J = 15.4 Hz), 5.74–5.88
(m, 1H), 7.25–7.36 (m, 5H); 13C NMR (75 MHz, CDCl3): d 23.9,
24.0, 25.2, 32.7, 35.2, 36.3, 42.0, 67.9, 70.1, 73.2, 76.7, 108.6,
116.4, 127.4, 127.5, 128.3, 136.5, 138.3; Anal. Calcd for C20H28O3:
C, 75.91; H, 8.92. Found: C, 75.80; H, 8.98.
der reduced pressure to give a crude mesylate. The crude mesylate
was dissolved in DMF (20 mL). To this solution sodium azide
(600 mg, 9.22 mmol) was added and reaction mixture was heated
at 100 °C for 4 h. After completion of reaction, the mixture was
cooled to room temperature, diluted with EtOAc (100 mL) and then
washed with water (80 mL). The aqueous layer was washed with
EtOAc (3 ꢂ 50 mL) and the combined organic layer was dried over
anhydrous sodium sulfate and concentrated under reduced pres-
sure. The crude residue was purified by column chromatography
to give the desired azide 7 as a colourless oil (1.38 g, 84% yield).
4.3. (R,E)-5-(Benzyloxy)-4-((S)-1,4-dioxaspiro[4.5]decan-2-yl)
pent-2-enyl acetate 5
To a stirred solution of olefin 4 (3.50 g, 11.06 mmol) in 1:1
½
a 2D8
ꢁ
¼ ꢃ8:5 (c 1.80, CHCl3); IR (film): 2932, 2854, 2099, 1450,
DMSO/AcOH (50 mL) in
a
glass vial were added Pd(OAc)2
1363, 1101, 931 cmꢃ1 1H NMR (300 MHz, CDCl3): d 1.37–1.57 (m,
;
(249 mg, 1.11 mmol, 10 mol%), benzoquinone (2.39 g, 22.12 mmol)
and 4 Å molecular sieves (2.39 g). The vial was capped and the
reaction mixture was stirred at 40 °C for 48 h. After completion
of the reaction (TLC), the mixture was quenched with saturated
aqueous NH4Cl (80 mL) and extracted with CH2Cl2 (3 ꢂ 250 mL).
The combined organic layer was washed with water, dried over
anhydrous Na2SO4 and concentrated under reduced pressure to
give a crude brown oil. Purification of the crude residue by silica
gel column chromatography using ethyl acetate/pet ether (5:95)
mobile phase afforded E-allyl acetate 5 (2.70 g, 65% yield) as a col-
10H), 2.50–2.57 (m, 1H), 3.47 (dd, 1H, J = 9.4 and 6.1 Hz), 3.53 (dd,
1H, J = 9.4 and 7.1 Hz), 3.66 (t, 1H, J = 7.9 Hz), 3.73 (d, 2H,
J = 6.2 Hz), 4.00 (dd, 1H, J = 8.2 and 6.1 Hz), 4.17–4.24 (m, 1H), 4.49
(s, 2H), 5.64 (dt, 1H, J = 15.5 and 6.2 Hz), 5.76 (dd, 1H, J = 15.6 and
8.3 Hz), 7.24–7.36 (m, 5H); 13C NMR (CDCl3, 75 MHz): d 23.8, 23.9,
25.1, 34.9, 35.9, 45.7, 52.7, 67.2, 71.0, 73.2, 75.2, 109.2, 126.2,
127.5, 127.6, 128.3, 133.1, 138.0; Anal. Calcd for C20H27N3O3: C,
67.20; H, 7.61; N, 11.76. Found: C, 67.38; H, 7.56; N, 11.93.
4.6. ((S)-2-((R)-1-((2R,3R)-3-(Azidomethyl)-1,4-dioxaspiro[4.5]
decan-2-yl)-2-(benzyloxy) ethyl)-1,4-dioxaspiro[4.5]decane 9
ourless viscous liquid. ½a D21
ꢁ
¼ ꢃ0:4 (c 0.93, CHCl3); IR (film): 2930,
2853, 1740, 1664, 1452, 1232, 1099, 929 cmꢃ1; 1H NMR (300 MHz,
CDCl3): d 1.32–1.63 (m, 10H), 2.06 (s, 3H), 2.47–2.56 (m, 1H), 3.49
(dd, 1H, J = 9.4 and 5.8 Hz), 3.55 (dd, 1H, J = 9.4 and 7.4 Hz), 3.67 (t,
1H, J = 7.8 Hz), 4.00 (dd, 1H, J = 8.0 and 6.2 Hz), 4.19–4.26 (m, 1H),
4.50 (s, 2H), 4.55 (d, 2H, J = 5.0 Hz), 5.64–5.81 (m, 2H), 7.26–7.36
(m, 5H); 13C NMR (75 MHz, CDCl3): d 20.9, 23.8, 23.9, 25.2, 35.0,
35.9, 45.5, 64.9, 67.2, 70.9, 73.2, 75.3, 109.2, 127.3, 127.5, 127.6,
128.3, 132.1, 138.1, 170.2; Anal. Calcd for C22H30O5: C, 70.56; H,
8.07. Found: C, 70.75; H, 7.89.
To 1:1 tBuOH/H2O (30 mL) was added AD mix-b (3.23 g) and the
resulting mixture was stirred at room temperature for approxi-
mately 15 min and then cooled to 0 °C. To this solution was added
allyl azide 7 (827 mg, 2.31 mmol) and the reaction was stirred vig-
orously at 0 °C overnight. The reaction was quenched with solid so-
dium sulfite (3.5 g) at room temperature. Ethyl acetate (30 mL)
was added to the reaction mixture and, after separation of the lay-
ers, the aqueous phase was further extracted with the organic sol-
vent (2 ꢂ 20 mL). The combined organic layers were washed with
brine, dried over anhydrous sodium sulfate and concentrated un-
der reduced pressure to give 816 mg of azido diol 8.
4.4. (R,E)-5-(Benzyloxy)-4-((S)-1,4-dioxaspiro[4.5]decan-2-yl)
pent-2-en-1-ol 6
To a stirred solution of crude diol 8, cyclohexanone (0.32 mL,
3.13 mmol) and triethyl orthoformate (0.35 mL, 2.09 mmol) in
dry CH2Cl2 (10 mL) was added p-TSA (40 mg, 10 mol %). The reac-
tion mixture was allowed to stir at room temperature for 1.5 h.
After completion of the reaction, the mixture was quenched by
adding a 10% aqueous NaHCO3 solution (10 mL). The layers were
separated and aqueous layer was extracted with CH2Cl2
(3 ꢂ 15 mL). The combined organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The
crude residue was purified by silica gel column chromatography
using ethyl acetate/pet ether (5:95) as the mobile phase to give
dicyclohexylidene 9 as a colourless sticky liquid (927 mg, 85%
To a stirred solution of allyl acetate 5 (2.56 g, 6.84 mmol) in 10%
aqueous methanol (25 mL), sodium hydroxide (410 mg,
10.25 mmol) was added and reaction mixture was stirred at ambi-
ent temperature for 30 min. After completion of reaction, the mix-
ture was concentrated under reduced pressure. The crude residue
was partitioned between ethyl acetate and brine. The layers were
separated and the aqueous layer was extracted with ethyl acetate
(3 ꢂ 20 mL). The combined organic layer was dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude resi-
due was purified by silica gel column chromatography using ethyl
acetate/pet ether (10:90) mobile phase to give allyl alcohol 6 as a
colourless viscous liquid (2.20 g, 97% yield). ½a D20
ꢁ
¼ ꢃ11:2 (c 0.67,
yield). ½a 2D7
ꢁ
¼ þ40:1 (c 1.33, MeOH); IR (film): 2934, 2858, 2098,
CHCl3); IR (film): 3381, 2928, 2854, 1670, 1452, 1099, 931 cmꢃ1
;
1448, 1280, 1109, 933 cmꢃ1 1H NMR (300 MHz, CDCl3): d 1.25–
;
1H NMR (300 MHz, CDCl3): d 1.30–1.65 (m, 10H), 1.94–2.06 (br s,
1H, exchangeable with D2O), 2.46–2.55 (m, 1H), 3.43–3.59 (m,
2H), 3.69 (t, 1H, J = 7.8 Hz), 4.01 (t, 1H, J = 7.4 Hz), 4.12 (d, 2H,
J = 5.0 Hz), 4.18–4.27 (m, 1H), 4.50 (s, 2H,), 5.67 (dd, 1H, J = 15.8
and 8.0 Hz), 5.79 (dt, 1H, J = 15.8 and 5.0 Hz), 7.23–7.37 (m, 5H);
13C NMR (75 MHz, CDCl3): d 23.8, 23.9, 25.4, 34.9, 35.9, 45.7,
63.5, 67.2, 71.1, 73.2, 75.5, 109.2, 127.6, 128.4, 128.9, 132.6,
138.1; Anal. Calcd for C20H28O4: C, 72.26; H, 8.49. Found: C,
72.41; H, 8.32.
1.67 (m, 20H), 2.16–2.20 (m, 1H), 3.27 (dd, 1H, J = 13.3 and
5.7 Hz), 3.50 (dd, 1H, J = 13.3 and 3.3 Hz), 3.54-3.57 (m, 2H), 3.72
(t, 1H, J = 8.1 Hz), 4.02 (dd, 1H, J = 8.1 and 5.7 Hz), 4.10 (dd, 1H,
J = 8.5 and 4.7 Hz), 4.19–4.26 (m, 1H), 4.29–4.35 (m, 1H), 4.45 (s,
2H), 7.26–7.37 (m, 5H); 13C NMR (CDCl3, 75 MHz): d 23.9, 25.1,
25.2, 35.1, 36.2, 36.4, 36.6, 43.3, 52.4, 67.5, 73.3, 73.9, 76.5, 77.2,
108.9, 109.5, 127.6, 127.7, 128.4, 137.8; Anal. Calcd for
C26H37N3O5: C, 66.22; H, 7.91; N, 8.91. Found: C, 65.99; H, 7.87;
N, 9.03.
4.5. (S)-2-((R,E)-5-Azido-1-(benzyloxy)pent-3-en-2-yl)-1,4-diox
4.7. (3aR,7R,7aR)-7-((S)-1,4-Dioxaspiro[4.5]decan-2-yl)hexahyd-
aspiro[4.5]decane 7
rospiro[[1,3]di-oxolo [4,5-c]pyridine-2,1’-cyclohexane] 10
A solution of alcohol 6 (1.53 g, 4.61 mmol), and Et3N (1.92 mL,
13.83 mmol) in CH2Cl2 (25 mL) at 0 °C was treated with MsCl
(0.38 mL, 4.84 mmol) and the mixture was stirred for 30 min at rt.
After completion of the reaction, the mixture was concentrated un-
A mixture of dicyclohexylidene 9 (714 mg, 1.52 mmol) and 10%
Pd/C (36 mg, 5 wt %) in methanol (10 mL) was hydrogenated at
room temperature under 40 psi pressure for 24 h. After completion
of the reaction, the mixture was filtered through short bed of Celite

M. G. Kulkarni et al. / Tetrahedron: Asymmetry 23 (2012) 1234–1237
1237
and concentrated under reduced pressure to give a crude amino
alcohol.
The crude residue was dissolved in dry THF (10 mL) and then
Acknowledgments
Authors Y.B.S., D.R.B., A.S.B., S.W.C., A.P.D. and D.D.G thank the
CSIR, New Delhi for research fellowship.
PPh3 (794 mg, 3.03 mmol) was added. The solution was cooled at
0 °C, and then DIAD (0.60 mL, 3.03 mmol) was added slowly. The
mixture was stirred for 18 h at rt, and then the solvent was removed
under reduced pressure after which the crude residue was purified
by flash column chromatography using chloroform/methanol
(97:3) mobile phase, yielding piperidene 10 as a colourless viscous
liquid (266 mg, 52% yield). IR (film): 3339, 2924, 2852, 1458, 1149,
1109 cmꢃ1; 1H NMR (300 MHz, CDCl3): d 1.17–1.60 (m, 20H), 1.87–
1.90 (m, 1H), 2.10–2.14 (m, 2H), 2.55–2.59 (m, 2H), 3.01 (dd, 1H,
J = 13.6 and 4.0 Hz), 3.25–3.40 (m, 2H), 3.90 (dd, 1H, J = 5.8 and
4.1 Hz), 3.96–4.10 (m, 2H); 13C NMR (75 MHz, CDCl3): d 23.7,
23.8, 23.9, 24.0, 25.1, 25.2, 35.5, 35.7, 35.9, 36.6, 47.3, 48.0, 66.5,
75.1, 78.0, 109.4, 109.7; Anal. Calcd for C19H31NO4: C, 67.63; H,
9.26; N, 4.15. Found: C, 67.75; H, 9.15; N, 4.09.
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To a stirred solution of piperidine 10 (117 mg, 0.35 mmol) in
MeOH (3 mL) was added conc. HCl (0.1 mL). The reaction mixture
was then allowed to stir at room temperature for 6 h. After comple-
tion of the reaction, the mixture was basified with 25% aq. ammo-
nia. The solvent was evaporated under reduced pressure and the
crude residue was purified by silica gel column chromatography
using methanol/chloroform/25% aq ammonia (20:70:10) mobile
phase to give azasugar 11 as white amorphous solid (55 mg, 90%
9. (a) Dulsat, C.; Mealy, N. Drug Future 2009, 34, 23–25; (b) Horne, G.; Wilson, F.
X.; Tinsley, J.; Williams, D. H.; Store, R. Drug Discovery Today 2011, 16, 107–118.
10. (a) Hansen, S. U.; Bols, M. J. Chem. Soc., Perkin Trans 2000, 1, 911–915; (b)
Imahori, T.; Ojima, H.; Tateyama, H.; Mihara, Y.; Takahata, H. Tetrahedron Lett.
2008, 49, 265–268.
11. (a) Zhao, G.; Deo, U. C.; Ganem, B. Org. Lett. 2001, 3, 201–203; (b) Jakobsen, P.;
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Chem. 2001, 9, 733–744; (c) Guanti, G.; Riva, R. Tetrahedron Lett. 2003, 44, 357–
360; (d) Ouchi, H.; Mihara, Y.; Watanabe, H.; Takahata, H. Tetrahedron Lett.
2004, 45, 7053–7056; (e) Ouchi, H.; Mihara, Y.; Takahata, H. J. Org. Chem. 2005,
70, 5207–5214; (f) Espeel, P. E. R.; Piens, K.; Callewaert, N.; Eyeken, J. V. Synlett
2008, 2321–2325; (g) Malik, G.; Guinchard, X.; Crich, D. Org. Lett. 2012, 14,
596–599.
12. (a) Jespersen, T. M.; Dong, W.; Sierks, M. R.; Skrydstrup, T.; Lundt, I.; Bols, M.
Angew. Chem., Int. Ed. 1994, 33, 1778–1779; (b) Ichikawa, Y.; Igarashi, Y.;
Ichikawa, M.; Suhara, Y. J. Am. Chem. Soc. 1998, 120, 3007–3018; (c) JKim, Y.;
Ichikawa, M.; Ichikawa, Y. J. Org. Chem. 2000, 65, 2599–2602; (d) Mehta, G.;
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2001, 7, 3744–3747; (g) Best, W. M.; Macdonald, J. M.; Skelton, B. W.; Stick, R.
V.; Tilbrook, D. M. G.; White, A. H. Can. J. Chem. 2002, 80, 857–865; (h) Zhu, X.;
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yield). ½a 2D1
ꢁ
¼ ꢃ11:5 (c 0.53, MeOH); IR (KBr): 3421, 3327, 2929,
1437, 1207 cmꢃ1
;
1H NMR (300 MHz, D2O): d 1.89–1.98 (m, 1H),
2.71 (td, 1H, J = 11.8 & 2.8 Hz), 2.87 (td, 1H, J = 12.9 and 2.9 Hz),
3.30–3.38 (m, 2H), 3.45–3.64 (m, 4H), 3.81–3.84 (m, 1H); 13C
NMR (75 MHz, D2O): d 44.4, 46.7, 48.9, 65.7, 71.3, 73.2, 73.8; Anal.
Calcd for C7H15NO4: C, 47.45; H, 8.53; N, 7.90. Found: C, 47.31; H,
8.66; N, 8.13.
4.9. (3R,4R,5R)-5-(Hydroxymethyl)piperidine-3,4-diol
(isofagomine) 1
To a stirred solution of azasugar 11 (40 mg, 0.23 mmol) in 3:1
methanol/ water (1 mL) was added NaIO4 (51 mg, 0.24 mmol) at
0 °C. Reaction mixture was allowed to stir at 0 °C for 1 h. After
completion of reaction NaBH4 (10 mg, 0.27 mmol) was added to
it and reaction mixture was stirred at room temperature for
30 min. After that conc. HCl (0.1 mL) was added and reaction mix-
ture was set to reflux for 3 h. The reaction was allowed to cool at
room temperature and the mixture was basified by adding 25%
aq ammonia. Solvents were evaporated under reduced pressure
and crude residue obtained was purified by flash column chroma-
tography using methanol/chloroform/25% aq ammonia (20:70:10)
mobile phase to get isofagomine (1) as colourless gum (25 mg,
13. (a) Kulkarni, M. G.; Shaikh, Y. B.; Borhade, A. S.; Dhondge, A. P.; Chavhan, S. W.;
Desai, M. P.; Birhade, D. R.; Dhatrak, N. R.; Gannimani, R. Tetrahedron:
Asymmetry 2010, 21, 2394–2398; (b) Kulkarni, M. G.; Borhade, A. S.; Shaikh,
Y. B.; Dhondge, A. P.; Birhade, D. R.; Dhatrak, N. R. Tetrahedron Lett. 2011, 52,
5559–5562.
14. Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346–1347.
15. (a) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7570–
7571; (b) Heinrich, B.; Marcos, S. A.; Sharpless, K. B. Tetrahedron 1995, 51,
1345–1376.
76% yield). ½a 2D1
ꢁ
¼ þ17:8 (c 0.13, EtOH); IR (KBr): 3380, 3190,
2938, 2535, 1426, 1346, 862 cmꢃ1
;
1H NMR of HCl salt (300 MHz,
16. Ferla, B. L.; Bugada, P.; Nicotra, F. J. J. Carbohydr. Chem. 2006, 25, 151–162.
17. The glycosidases used in tested were b-galactosidase and b-glucosidase
D2O) d: 1.76–1.82 (m, 1H), 2.71 (t, 1H, J = 11.9 Hz), 2.80 (t, 1H,
J = 12.9 Hz), 3.32–3.38 (m, 3H), 3.54–3.60 (m, 2H), 3.66 (dd, 1H,
J = 11.9 and 3.3 Hz); 13C NMR of HCl salt (75 MHz, D2O) d: 43.8,
47.6, 49.4, 61.8, 71.3, 73.9; Anal. Calcd for C6H14ClNO3: C, 39.24;
H, 7.68; N, 7.63. Found: C, 39.13; H, 7.59; N, 7.81.
(sweet almonds) and
a-glucosidase (yeast cells and rice) adopting a known
protocol.18
18. (a) Dey, P. M.; Pridham, J. B. Adv. Enzymol. Relat. Area Mol. Biol. 1972, 36, 91; (b)
Li, Y.-T.; Li, S.-C. Methods Enzymol. 1972, 28, 702–713.