An efficient synthesis of aldohexose-derived piperidine nitrones: Precursors of piperidine iminosugars

Article abstract of DOI:10.3390/molecules18056021

D-Glucopyranose-derived and L-idopyranose-derived piperidine nitrones were synthesized in good overall yields through six-step reaction sequence starting from readily available 2,3,4,6-tetra-O-benzyl-D-glucopyranose. The method is efficient and could be general for the synthesis of aldohexose-derived piperidine nitrones which are precursors of piperidine iminosugars.

Full text of DOI:10.3390/molecules18056021

Molecules 2013, 18, 6021-6034; doi:10.3390/molecules18056021
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
An Efficient Synthesis of Aldohexose-Derived Piperidine Nitrones:
Precursors of Piperidine Iminosugars
Hui Zhao, Wen-Bo Zhao, Jian-She Zhu, Yue-Mei Jia and Chu-Yi Yu *
Beijing National Laboratory for Molecular Science, CAS Key Laboratory of Molecular Recoganition
and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
* Author to whom correspondence should be addressed; E-Mail: yucy@iccas.ac.cn;
Tel./Fax: +86-010-6261-2893.
Received: 7 May 2013; in revised form: 15 May 2013 / Accepted: 17 May 2013 /
Published: 21 May 2013
Abstract: D-Glucopyranose-derived and L-idopyranose-derived piperidine nitrones were
synthesized in good overall yields through six-step reaction sequence starting from readily
available 2,3,4,6-tetra-O-benzyl-D-glucopyranose. The method is efficient and could be
general for the synthesis of aldohexose-derived piperidine nitrones which are precursors of
piperidine iminosugars.
Keywords: aldohexose-derived cyclic nitrones; synthesis; piperidine iminosugars
1. Introduction
Because of their remarkable biological activities [1–3], iminosugars, the ‘nitrogen-in-the-ring’
analogues of pyranoses and furanoses, have attracted considerable attention from synthetic organic
chemists [4–7]. Over the last 40 years, a very large number of azapyranose sugars, i.e., piperidine
iminosugars, have been isolated from various plants and animal sources (Figure 1). Nearly all these
naturally-occurring iminosugars, as well as the majority of synthetic azapyranose sugars, elicit some
sort of biological response [6]. Although great efforts have been made and numerous synthetic
procedures have been developed for the synthesis of iminosugars [8–22], efficient methods for the
rapid generation of azapyranoses with the structural diversity necessary for in-depth structure-activity
studies are still lacking. Due to the versatile reactivities of the nitrone functionality, synthetic methods
based on sugar-derived cyclic nitrones have emerged as a potentially powerful strategy for the
diversity-oriented synthesis of iminosugars among the existing approaches [23–33].

Molecules 2013, 18
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Figure 1. Some naturally occurring azapyranose alkaloids.
As a result of their capability of undergoing a variety of synthetically useful reactions, such as
1,3-dipolar cycloadditions [34–40], nucleophilic additions [39,41–48], and pinacol-type coupling
reactions [49–56], etc., nitrones [57,58] have been shown to be powerful synthetic intermediates for
the construction of structurally complex molecules [59–61]. Polyhydroxylated cyclic nitrones or sugar-
derived cyclic nitrones, which have been widely used in the synthesis of various natural and
biologically active nitrogen-containing compounds [27,28,32,33,62–65], are especially valuable in
organic synthesis. The piperidine nitrones, may serve as the powerful synthons or precursors for the
synthesis of naturally-occurring piperidine iminosugars, especially for the diversity-oriented synthesis.
Although, methods for the synthesis of cyclic nitrones have been well documented [66], including
oxidation of hydroxylamine [67–69], amines [70–73], and imines [74,75], condensation of ketones
with hydroxylamines [76,77], and N-alkylation of oximes [78–80], efficient synthetic methods for the
preparation of pyranose-derived nitrones are still lacking. Several syntheses of pentopyranose-derived
piperidine nitrones have been reported before [81–83], however, to the best of our knowledge, the only
synthesis of a hexopyranose-derived piperidine nitrone so far has been reported in 1996 by van den
Broek and co-workers [84] who described the preparation of pyranose-derived nitrones by oxidation of
2,3,4,6-O-benzyl-DNJ 6 employing 2,2-dimethydioxirane (DMDO) as oxidizing agent (Scheme 1).
This method, however, has obvious drawbacks in that the regioselectivity of the oxidation was poor
and the oxidation of the piperidine resulted in the formation of an inseparable mixture of two
regio-isomers, i.e., the aldo and keto nitrones 7 and 8.
Scheme 1. van den Broek’s synthesis of pyranose-derived nitrone.
In the context of our ongoing projects on the synthesis and application of sugar-derived cyclic
nitrones [80], herein we report an efficient synthesis of D-glucopyranose- and L-idopyranose-derived
piperidine nitrones. We intend to develop a general and efficient method for the synthesis of
aldohexose-derived piperidine nitrones, which could be powerful synthons for the synthesis of
iminosugars containing a piperidine moiety in the molecules.

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2. Results and Discussion
2.1. The Unsuccessful N-alkylation Strategy
Intramolecular N-alkylation, the most widely used strategy in cyclic nitrone synthesis, was not
applicable here. Oxime 10, prepared from D-glucose-derived aldehyde 9, failed under various conditions to
undergo the predicted intramolecular N-alkylation to give the desired hexopyranose-derived piperidine
nitrone 11 (Scheme 2). It seems that intramolecular nucleophilic substitution to form hexopyranose-type
piperidine rings is less favorable than for furanose- or pentopyranose rings, possibly due to the
relatively poor reactivity of the leaving group at C5 of the hexopyranose.
Scheme 2. Unsuccessful intramolecular N-alkylation strategy.
In order to avoid the low regioselectivity and ring formation problems of the method of oxidation
and intramolecular N-alkylation, we turned to a less employed strategy in sugar-derived cyclic nitrone
synthesis—the intramolecular condensation of aldehydes with hydroxylamines [76,77,85,86]—which has
been successfully applied in the synthesis of aldohexose-derived azepane nitrones.
2.2. The Preparation of Diethyl Dithioacetal
The readily available 2,3,4,6-tetra-O-benzyl-D-glucopyranose (12) was chosen as the starting
material for our investigation on the synthesis of aldohexose-derived piperidine nitrones, which is expected
to give two nitrones, i.e., a D-glucopyranose-derived nitrone and an L-idopyranose-derived nitrone.
Table 1. Screening of conditions of preparing diethyl dithioacetal.
Entry Additives
Eq.
0.2
0.2
0.2
Solvent Tem. (°C) Yield a (%)
1
2
3
5
6
7
8
9
TMSCl
BF3⋅Et2O
AcCl
CHCl3
CHCl3
CH2Cl2
RT
RT
-
-
RT
-
conc. HCl excess MeOH
HCl (g) excess Dioxane
RT
-
RT
56
trace
trace
84 b
BDMS
BDMS
BDMS
0.2
0.2
0.2
CH3CN
CH2Cl2
EtSH
0- RT
0- RT
RT
a Isolated yield. b Reference [82].

Molecules 2013, 18
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First of all, in order to find the optimal reaction conditions for the synthesis of the key intermediate,
the alcohol 13, through the pyranose hemiacetal ring opening by ethanethiol, various reagents
and reaction conditions has been screened (Table 1). It turned out that the method using
bromodimethylsulfonium bromide (BDMS), reported by Khan’s group [87], gave the best result.
2.3. Completion of the Synthesis
Oxidation of the resulting alcohol 13 using tetrapropylammonium perruthenate (TPAP) [88] gave
the corresponding ketone 14 in 81% yield (Scheme 3). Other methods of oxidation, such as the Swern
oxidation, Corey-Suggs oxidation (PCC), and Dess-Martin oxidation (DMP), all failed to oxidize 13
into the desired ketone 14. To transform the diethyl dithiolacetal protecting group of 14 into more
acid-labile dimethyl acetal protecting group, the ketone 14 was treated with mercury salts in the
presence of methanol to form the dimethyl acetal protected ketone 15 in 81% yield.
Scheme 3. Completion of the synthesis of D-glucopyranose-derived and
L-idopyranose-derived piperidine nitrones.
Then, condensation of ketone 15 with NH2OH, followed by reduction of the resulting oxime with
sodium cyanoborohydride gave the hydroxylamine 16 as an inseparable mixture of two C5 isomers in
73% yield. A pure analytical sample of the major C5 isomer of 16 was obtained by flash column
chromatography and its structure was determined by NMR (see Supporting Information). Finally,
acidic hydrolysis of the dimethyl acetal 16 by CH3CN/6 N HCl and subsequent intramolecular
condensation of the hydroxylamine and aldehyde produced a mixture of two products, the D-gluco-
pyranose-derived piperidine nitrone 7 and L-idopyranose-derived piperidine nitrone 17, in 81% total
yield, which are easily separated by column chromatography on silica gel with a ratio of 2:1. The
structures of the two nitrones have been determined undoubtedly by NMR and NOESY experiments
(see Supplementary Materials). It is worth noting that the D-glucopyranose-derived piperidine nitrone
7 was found to be quite stable, even at room temperature, rather than unstable as has been reported
before [84], while the L-idopyranose-derived piperidine nitrone 17 is less stable, and gradually
decomposed at room temperature, although it was stable at low temperature when stored in a fridge.

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3. Experimental
3.1. General Methods
All reagents were used as received from commercial sources without further purification or
prepared as described in the literature. Reactions were stirred using Teflon-coated magnetic stirring
bars. Analytical TLC was performed with 0.20 mm silica gel 60F plates with 254 nm fluorescent
indicator. TLC plates were visualized by ultraviolet light or by treatment with a spray of Pancaldi
reagent [(NH4)6MoO4, Ce(SO4)2, H2SO4, H2O]. Chromatographic purification of products was carried
out by flash column chromatography on silica gel (200–300 mesh). Infrared spectra were recorded on a
JASCO FT/IR-480 plus Fourier transform spectrometer. NMR spectra were measured in CDCl3 (with
13
TMS as internal standard) on a Bruker AV300 (1H at 300 MHz, C at 75 MHz) magnetic resonance
spectrometer. Chemical shifts (δ) are reported in ppm, and coupling constants (J) are in Hz. The
following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet. High-resolution mass spectra (HRMS) were recorded on a Thermo
Scientific LTQ/FT mass spectrometer or a GCT mass spectrometer. Polarimetry was carried out using
an Optical Activity AA-10R polarimeter and the measurements were made at the sodium D-line with a
0.5 dm pathlength cell. Concentrations (c) are given in gram per 100 mL.
3.2. Synthesis
(2R,3R,4S,5R)-1,3,4,5-Tetrakis(benzyloxy)-6,6-bis(ethylthio)hexan-2-ol (13). A catalytic amount (7 mg,
0.03 mmol) of bromodimethylsulfonium bromide (BDMS) was added to a stirred mixture of 2,3,4,6-
tetra-O-benzyl-D-glucopyranose (12, 500 mg, 1 mmol) and ethanethiol (5 mL) at room temperature.
The mixture was stirred for 2 h, and the mixture gradually became clear. TLC indicated the
disappearance of starting material, then the excess ethanethiol was removed in vacuo. The residual
products were dissolved in ethyl acetate, and washed with aq. NaHCO3 (3 × 10 mL). Removal of the
solvent in vacuo after dried over MgSO4, the crude product was purified by column chromatography on
silica gel (petroleum ether-ethyl acetate = 40:1–20:1) to give compound 13 (552 mg, 84%) as a colourless
oil. 1H-NMR (CDCl3) δ 7.48–7.25 (m, 20H), 4.95 (d, J = 11.1 Hz, 1H), 4.86 (d, J = 11.2 Hz, 1H), 4.85
(d, J = 11.2 Hz, 1H), 4.73 (d, J = 11.2 Hz, 1H), 4.64–4.54 (m, 4H), 4.33 (dd, J = 6.6, 3.6 Hz, 1H), 4.20
(dd, J = 6.6, 3.7 Hz, 1H), 4.13 (dt, J = 10.1, 4.9 Hz, 1H), 3.98 (d, J = 3.7 Hz, 1H), 3.77 (dd, J = 7.0, 3.6 Hz,
1H), 3.71 (d, J = 3.8 Hz, 1H), 3.69 (d, J = 5.5 Hz, 1H), 3.15 (d, J = 4.7 Hz, 1H), 2.72 (q, J = 7.4 Hz,
2H), 2.67–2.53 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.6 Hz, 3H). 13C-NMR (CDCl3) δ 138.5,
138.1, 137.9, 128.5, 128.4, 128.4, 128.3, 128.2, 127.9, 127.9, 127.78, 127.75, 127.5, 82.7, 80.0, 75.3,
1
74.9, 73.5, 72.8, 71.4, 70.9, 53.8, 25.5, 25.3, 14.5. [lit. [82] H-NMR (400 MHz; CDCl3) δ 7.38–7.23
(m, 20H), 4.89 (d, J = 11.2 Hz, 1H), 4.80 (d, J = 11.2, 1H), 4.79 (d, , J = 11.6, 1H), 4.67 (d, J = 11.6 Hz,
1H), 4.59–4.49 (m, 4H), 4.27 (dd, J = 6.8, 3.6 Hz, 1H), 4.14 (dd, J = 6.8, 4.0 Hz, 1H), 4.15–4.03 (m,
1H), 3.93 (d, J = 4.0 Hz, 1H), 3.71 (dd, J = 6.8, 3.6 Hz, 1H), 3.66 (dd, J = 10.0, 4.0 Hz, 1H), 3.61 (dd,
J = 10.0, 5.6 Hz, 1H), 3.08 (d, J = 5.2 Hz, 1H), 2.66 (q, J = 7.6 Hz, 2H), 2.60–2.50 (m, 2H), 1.18 (t,
13
J = 7.2 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3H); C-NMR (100 MHz; CDCl3) δ 138.7, 138.4, 138.1, 128.6,
128.4, 128.3, 128.2, 128.03, 128.0, 127.96, 127.9, 127.6, 82.9, 80.3, 77.5, 75.5, 75.1, 73.7, 73.0, 71.6,
71.1, 54.0, 25.7, 25.5, 14.6.]

Molecules 2013, 18
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(3S,4S,5R)-1,3,4,5-Tetrakis(benzyloxy)-6,6-bis(ethylthio)hexan-2-one (14). Solid TPAP (68 mg,
0.19 mmol) was added portionwise to a stirred mixture of dithioacetal 13 (2.49 g, 3.85 mmol),
4-methylmorpholine N-oxide (NMO) (676 mg, 5.77 mmol) and powdered 4 Å molecular sieves (2 g)
in dry CH2Cl2 (8 mL) at 0 °C under nitrogen. The mixture was stirred for 45 min at room temperature,
filtered through a short pad of silica and eluted with ethyl acetate. The filtrate was concentrated
in vacuo to give a yellow oil. Column chromatography (petroleum ether-ethyl acetate = 6:1) provided
ketone 14 (2.07 g, 81%) as a colourless oil. 1H-NMR (CDCl3) δ 7.43–7.13 (m, 20H), 4.81 (d, J = 10.9 Hz,
1H), 4.73 (d, J = 11.2 Hz, 1H), 4.70 (s, 1H), 4.66 (s, 1H), 4.51 (d, J = 11.2 Hz, 1H), 4.41–4.32 (m,
4H), 4.23 (d, J = 17.5 Hz, 1H), 4.16 (d, J = 4.2 Hz, 1H), 4.11 (d, J = 17.6 Hz, 1H), 4.03 (dd, J = 5.8,
4.6 Hz, 1H), 3.75 (d, J = 4.4 Hz, 1H), 2.69–2.60 (m, 2H), 2.55 (dd, J = 14.9, 7.8 Hz, 2H), 1.18 (t,
13
J = 7.2 Hz, 3H,), 1.17 (t, J = 7.6 Hz, 3H). C-NMR (CDCl3) δ 206.5, 138.3, 137.8, 137.4, 136.9,
128.6, 128.43, 128.38, 128.35, 128.24, 128.21, 128.0, 127.9, 127.8, 127.5, 81.7, 81.4, 80.8, 75.2, 75.1,
74.4, 73.4, 73.3, 53.4, 25.3, 14.4. [lit. [89] 1H-NMR (300 MHz; CDCl3) δ 7.43–7.18 (20H, m), 4.82 (d,
J = 11.0 Hz, 1H), 4.74 (d, J = 11.0 Hz, 1H), 4.70 (d, J = 11.0 Hz, 1H), 4.69 (d, J = 11.0 Hz, 1H), 4.52
(d, J = 11.0 Hz, 1H), 4.41–4.33 (m, 4H), 4.24 (d, J = 18.0 Hz, 1H), 4.16 (d, J = 4.0 Hz, 1H), 4.12 (d,
J = 18.0 Hz, 1H), 4.04 (dd, J = 6.0, 4.5 Hz, 1H), 3.75 (d, J = 4.5 Hz, 1H), 2.64 (m, 2H), 2.56 (m, 2H),
13
1.19 (t, J = 7.5 Hz, 3H), 1.18 (t, J = 7.5 Hz, 3H); C-NMR (75 MHz; CDCl3) δ 206.5, 138.3, 137.7,
137.3, 136.8, 128.6, 128.46, 128.43, 128.38, 128.35, 128.25, 128.21, 127.9, 127.87, 127.85, 127.5,
81.6, 81.4, 80.7, 75.2, 75.1, 74.3, 73.34, 73.31, 53.3, 25.2, 14.4].
(3S,4R,5R)-1,3,4,5-Tetrakis(benzyloxy)-6,6-dimethoxyhexan-2-one (15). Mercuric oxide (HgO;
yellow) (1.06 g, 4.90 mmol) was added to a solution of ketone 14 (790 mg, 1.22 mmol) in boiling
MeOH (33 mL). The hot solution was stirred vigorously while a solution of HgCl2 (1.00 g, 3.67 mmol)
in dry MeOH (4 mL) was added over a period of 1 min, and stirring was continued while the
suspension was refluxed for 15 min. The hot solution was filtered, the solid matter washed with
MeOH, and the combined solutions concentrated in vacuo to give a syrup, which was dissolved in
CH2Cl2 (25 mL). A white solid was filtered off and the filtrate washed successively with water, 10%
aqueous KI (2 × 10 mL) and water (3 × 10 mL). The solution was dried over MgSO4 and the solvent
was removed in vacuo to give a colorless oil. Column chromatography (petroleum ether-ethyl acetate
= 5:1) provided ketone 15 (577 mg, 81%) as a colourless oil. 1H-NMR (CDCl3) δ 7.32–7.07 (m, 20H),
4.64 (d, J = 10.8 Hz, 1H), 4.56 (d, J = 11.8 Hz, 1H), 4.54 (d, J = 11.3 Hz, 1H), 4.49–4.42 (m, 2H), 4.35
(d, J = 5.9 Hz, 1H), 4.28 (d, J = 11.9 Hz, 1H), 4.22 (d, J = 11.9 Hz, 1H), 4.12 (s, 2H), 4.07 (d, J = 4.9 Hz,
13
1H), 3.93 (t, J = 4.5 Hz, 1H), 3.65 (dd, J = 5.9, 4.3 Hz, 1H), 3.31 (s, 3H), 3.22 (s, 3H). C-NMR
(CDCl3) δ 206.3, 138.5, 137.8, 137.7, 137.4, 128.5, 128.5, 128.43, 128.41, 128.38, 128.2, 128.0, 127.9,
127.8, 127.5, 105.5, 80.9, 80.0, 77.7, 74.8, 74.3, 74.3, 73.3, 73.2, 56.0, 54.7. [lit. [89] 1H-NMR (300 MHz;
CDCl3) δ 7.50–7.15 (m, 20H), 4.72 (d, J = 11.0 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 11.0 Hz,
1H), 4.53 (m, 2H), 4.46 (d, J = 12.0 Hz, 1H), 4.43 (d, J = 6.3 Hz, 1H), 4.37 (d, J = 12.0 Hz, 1H), 4.31
(d, J = 12.0 Hz, 1H), 4.21 (s, 2H), 4.15 (d, J = 4.7 Hz, 1H), 4.00 (dd, J = 4.5, 4.7 Hz, 1H), 3.73 (dd,
13
J = 4.5, 6.3 Hz, 1H), 3.40 (s, 3H), 3.31 (s, 3H); C-NMR (75 MHz; CDCl3) δ 206.3, 138.4, 137.7,
137.6, 137.3, 128.5, 128.45, 128.43, 128.39, 128.36, 128.2, 128.0, 127.8, 127.7, 127.5, 105.4, 80.8,
79.9, 77.6, 74.7, 74.3, 74.2, 73.3, 73.2, 56.0, 54.7].

Molecules 2013, 18
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N-((3R,4S,5R)-1,3,4,5-Tetrakis(benzyloxy)-6,6-dimethoxyhexan-2-yl)hydroxylamine (16). A stirred
solution of ketone 15 (592 mg, 1.01 mmol), hydroxylamine hydrochloride (211 mg, 3.03 mmol),
pyridine (327 mL, 4.05 mmol) and EtOH (2.5 mL) was heated at 60 °C for 20 min. The solvent was
removed in vacuo and the residue taken up in Et2O and washed with water. The organic layer was
dried over MgSO4, filtered and the solvent was removed in vacuo. Column chromatography
(petroleum ether-ethyl acetate = 3:1 containing 1% Et3N) provided oxime (546 mg, 90%) as a
colourless oil and as a 1:1 mixture of Z and E isomers. The oxime (200 mg, 0.33 mmol) was
redissolved in methanol (10 mL) and sodium cyanoborohydride (42 mg, 0.66 mmol) was added. 4
drops of methyl orange was added as the indicator. The resulting solution was carefully treated at room
temperature with concentrated HCl/methanol (v/v = 1/10) to maintain the pH value between 3 and 4.
After the completion of the reaction, the resulting solution was concentrated in vacuo. The residue was
dissolved in CH2Cl2 (10 mL) and washed with 1 N NaOH (1 × 10 mL) and then brine (2 × 10 mL).
After dried (MgSO4) and condensed under reduced pressure, the crude product was purified by column
chromatography on silica gel (petroleum ether-ethyl acetate = 3:1 to 1:1) to afford isomers of
1
hydroxylamine 16 (181 mg, 73% for 2 steps) as a colorless oil. H-NMR (CDCl3) δ 7.49–7.12
(m, 20H), 5.14 (br, 1H), 4.87 (d, J = 10.7 Hz, 2H), 4.83–4.71 (m, 3H), 4.64 (d, J = 10.5 Hz, 3H), 4.59
(s, 2H), 4.50 (d, J = 11.0 Hz, 2H), 4.38 (s, 3H), 4.08 (s, 1H), 3.99 (s, 1H), 3.70 (s, 2H), 3.64–3.52
(m, 2H), 3.46 (s, 3H), 3.36 (s, 2H), 3.25 (s, 3H), 3.20 (d, J = 7.0 Hz, 2H). 13C-NMR (CDCl3) δ 138.8,
138.5, 138.1, 128.4, 128.3, 128.1, 127.8, 127.6, 127.4, 105.4, 79.5, 78.3, 78.2, 75.0, 74.8, 73.9, 73.3,
68.4, 62.0, 56.0, 54.1. ESI-MS: m/z 602.96 [M+H]+
(2R,3R,4S,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-2,3,4,5-Tetrahydropyridine
1-oxide
(D-Glucopyranose-Derived Piperidine Nitrone (7) and (2S,3R,4S,5S)-3,4,5-tris(benzyloxy)-2-
((benzyloxy)methyl)-2,3,4,5-Tetrahydropyridine 1-oxide (L-Idopyranose-Derived Piperidine Nitrone (17).
To a solution of hydroxylamine 16 (180 mg, 0.3 mmol) in CH3CN (6 mL) was added concentrated HCl
(2 mL) and the resulting solution was stirred at room temperature for 2 h. The solution was diluted
with EtOAc (10 mL) and then washed with H2O (2 × 20 mL) and saturated NaHCO3 solution (1 × 10 mL).
The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1 to ethyl acetate)
to afford D-glucopyranose-type nitrone 7 (87 mg, 54%) and L-idopyranose-type nitrone 17 (44 mg,
27%) as yellow oils.
14
D-Glucopyranose-derived piperidine nitrone (7). [α]D = +33.33° (c 1.2, CH2Cl2). IR (KBr, cm−1):
3031, 2870, 1454. 1H-NMR (CDCl3) δ 7.41–7.22 (m, 17H), 7.17 (d, J = 3.5 Hz, 2H), 7.16 (s, 1H), 7.06
(s, 1H), 4.86 (d, J = 4.1 Hz, 2H), 4.81 (s, 1H), 4.68 (s, 2H), 4.56 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 11.0 Hz,
1H), 4.38 (s, 1H), 4.35 (d, J = 4.1 Hz, 1H), 4.26 (dd, J = 5.5, 2.2 Hz, 1H), 4.17–4.08 (m, 1H), 3.85 (dd,
13
J = 9.5, 7.9 Hz, 1H), 3.76 (d, J = 8.3 Hz, 1H), 3.63 (d, J = 10.0 Hz, 1H). C-NMR (CDCl3) δ 137.9,
137.8, 137.6 137.0, 135.3, 128.7, 128.5, 128.4, 128.3, 128.1, 128.0, 128.0, 127.8, 81.0, 76.1, 75.1,
73.8, 73.3, 73.2, 72.4, 64.6. HRMS-ESI (m/z): calcd for C34H36NO5 [M+H]+ 538.25880, found
538.25879.

Molecules 2013, 18
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14
L-Idopyranose-derived Piperidine Nitrone (17). [α]D = −0.1° (c 1.0, CH2Cl2). IR (KBr, cm−1): 3031,
2825, 1454. 1H-NMR (CDCl3) δ 7.40–7.33 (m, 12H), 7.32–7.28 (m, 6H), 7.26 (d, J = 6.9 Hz, 2H), 7.10 (d,
J = 2.7 Hz, 1H), 4.89 (d, J = 11.3 Hz, 1H), 4.80 (t, J = 12.4 Hz, 2H), 4.67 (d, J = 11.6 Hz, 2H), 4.60 (t,
J = 10.4 Hz, 2H), 4.53 (d, J = 12.0 Hz, 1H), 4.51–4.48 (m, 1H), 4.30 (s, 1H), 4.17 (dd, J = 9.9, 3.4 Hz,
13
1H), 4.14 (d, J = 8.6 Hz, 1H), 4.02 (s, 1H), 4.01–3.97 (m, 1H). C-NMR (CDCl3) δ 138.1, 137.8,
137.43, 135.6, 128.6, 128.5, 128.5, 128.3, 128.1, 128.0, 127.9, 127.8, 127.6, 77.0, 76.4, 75.1, 74.4,
73.7, 73.6, 71.7, 70.0, 65.2. HRMS-ESI (m/z): calcd for C34H36NO5 [M+H]+ 538.25880, found 538.25879.
4. Conclusions
In summary, D-glucopyranose- and L-idopyranose-derived piperidine nitrones have been
synthesized in good overall yields through six-step reaction sequence starting from the readily
available 2,3,4,6-tetra-O-benzyl-D-glucopyranose . The method is efficient and could be general for the
synthesis of aldohexose-derived piperidine nitrones which are precursors of piperidine iminosugars.
Based on this procedure, many other hexopyranose-derived cyclic nitrones can be prepared, therefore
this method should prove significant for future work on the design, synthesis and discovery of
glycosidase inhibitors with better selectivity and potency.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/5/6021/s1.
Acknowledgments
Financial support from National Basic Research Program of China (No. 2012CB822101 and
2011CB808603), and The Natural Science Foundation of China (No. 21272240 and 21102149) is
gratefully acknowledged.
Conflict of Interest
The authors declare no conflict of interest.
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