Synthesis and glycosidase inhibition study of 2-C-hydroxymethyl- and 6-C-hydroxymethyl-branched piperidines from D-glucose using ene-yne metathesis as a key step

Article abstract of DOI:10.1002/ejoc.201402142

Two polyhydroxylated piperidine-based 2-C-hydroxymethyl-branched analogues of L-1-deoxyallonojirimycin (L-allo-DNJ) were synthesized from readily available 1,2:5,6-di-O-isopropylidene-α-glucofuranose through an ene-yne metathesis as the key step. The glycosidase inhibition activity of these compounds against some commercially available enzymes was examined, and the analogues were found to be very selective glycosidase inhibitors at concentrations in the range of 21-44 μM. Piperidine-based 2-C-hydroxymethyl-branched analogues of L-1-deoxyallonojirimycin (L-allo-DNJ) were synthesized from readily available D-glucose by using an ene-yne metathesis as the key step; PG = protecting group. The glycosidase inhibition activity of these compounds was studied and found to be active and very selective. Copyright

Full text of DOI:10.1002/ejoc.201402142

FULL PAPER
DOI: 10.1002/ejoc.201402142
Synthesis and Glycosidase Inhibition Study of 2-C-Hydroxymethyl- and 6-C-
Hydroxymethyl-Branched Piperidines from -Glucose Using Ene-Yne
D
Metathesis as a Key Step
Asadulla Mallick[a] and Yashwant D. Vankar*[a]
Keywords: Carbohydrates / Azasugars / Metathesis / Inhibitors
Two polyhydroxylated piperidine-based 2-C-hydroxymethyl-
branched analogues of -1-deoxyallonojirimycin ( -allo-DNJ)
were synthesized from readily available 1,2:5,6-di-O-iso-
propylidene-α-glucofuranose through an ene-yne metathesis
as the key step. The glycosidase inhibition activity of these
compounds against some commercially available enzymes
was examined, and the analogues were found to be very se-
lective glycosidase inhibitors at concentrations in the range
L
L
of 21–44 μM.
the synthesis of natural and unnatural azasugar/imino-
sugars from carbohydrate building blocks,[13] we are inter-
ested in the preparation of new molecules with combined
structural features as mentioned above, that is, molecules
that have a quaternary carbon atom with dihydroxyethyl
Introduction
Polyhydroxylated piperidine systems have received con-
siderable attention in recent years, as some of these mo-
lecules exhibit important biological activities such as the
inhibition of glycosidase and glycosyl transferase.[1,2] These
systems are recognized as having significant therapeutic po-
tential for the treatment of various diseases such as diabe-
tes,[3] cancer,[4] lysosomal storage disorders[5] and viral in-
fection such as HIV-AIDS.[6] For example, 1-deoxynojiri-
mycin [DNJ (1), see Figure 1] is a very good α-glucosidase
inhibitor,[7] and its derivative miglitol (1b) is used against
type II diabetes.[8] Similarly, miglustat (1a) is a drug used
to treat Gaucher’s disease.[8] Because of these and other
similar applications, much synthetic effort has been made
to prepare these molecules and their derivatives,[9] as
changes to the piperidine ring are very effective in relation
to enzyme inhibition. Thus, the incorporation of features
such as those that result from 1,2-dihydroxyethylation (i.e.,
2a and 2b),[10] 2-C-hydroxymethylation (i.e., 3a and
3b),[10c,11] and α-geminal dihydroxymethylation (i.e., 4a and
4b)[12] has proved to be beneficial. Similarly, potent α-gluco-
sidase inhibitors such as valiolamine (5a) and voglibose (5b,
a drug against type II diabetes) have a quaternary carbon
atom that is bonded to a hydroxyl and hydroxymethyl
group as their key features. In the recent past, we have in-
troduced these typical functional groups into pyrrolidine as
well as piperidine-based imino sugars, and they turned out
to be promising glycosidase inhibitors.[10c,11c] Thus, in view
of these literature precedents and our continued interest in
[a] Department of Chemistry, Indian Institute of Technology,
Kanpur 208016, India
E-mail: vankar@iitk.ac.in
http://home.iitk.ac.in/~vankar/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402142.
Figure 1. Derivatives of 1-deoxysugars containing C-hydroxy-
methyl branch.
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A. Mallick, Y. D. Vankar
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1
and hydroxymethyl side chains. To determine the effect of of compound 7 was confirmed by H NMR spectroscopic
additional hydroxymethyl groups in l-allo-DNJ (6a), its 2- analysis with the disappearance of the acetylenic proton sig-
C- and 6-C-hydroxymethyl-branched piperidine 6c and 2-C- nal at δ = 2.19 ppm and the appearance of the exocyclic
hydroxymethyl-branched piperidine 6d were prepared and vinyl proton signal as a doublet of doublets at δ =
examined for inhibition activity against various glycosid- 6.30 ppm.
ases.
Attempts to dihydroxylate the terminal double bond of
compound 7 by treatment with OsO4-NMO or OsO4-
NMO-CH3SO2NH2 or to cleave the double bond by treat-
ment with OsO4-NMO-NaIO4 (NMO = N-methylmorph-
oline N-oxide) failed, perhaps, because of steric factors.
This matter was resolved by removing the 1,2-O-isoprop-
ylidene group to allow the dihydroxylation to take place.
Thus, the 1,2-O-isopropylidene moiety was hydrolyzed by
treatment with 4% H2SO4 in CH3CN/H2O at room tem-
perature to give the corresponding hemiacetal, which upon
reduction with NaBH4 in MeOH followed by acetylation
with Ac2O and Et3N led to the formation of the expected
triacetate 11 (59% yield, over three steps; see Scheme 3).
The structure of acetate 11 was confirmed by spectral
analyses (see Exp. Sect.). The selective dihydroxylation of
the terminal alkene was successfully executed by treatment
with OsO4-NMO in acetone/water (1:1) at room tempera-
ture for 4 h to afford compound 12 in 84% yield. Diol 12
was oxidatively cleaved with NaIO4 followed by a reduction
with NaBH4 to furnish the corresponding primary alcohol.
Under these conditions, the acetate groups, however, were
partially hydrolyzed, and thus the crude product was fur-
ther acetylated to give tetraacetate 13 in 61% yield (over
three steps). Unfortunately, the dihydroxylation of com-
pound 13 again by using either OsO4-NMO or the AD-
Results and Discussion
Our retrosynthetic analysis illustrates that target mol-
ecules 6c and 6d could be obtained from diene intermediate
7, which could be prepared from 8 through an ene-yne me-
tathesis reaction (see Scheme 1). Compound 8 could then
be easily synthesized from d-glucose. Thus, the synthesis
proceeded from olefin 10 (see Scheme 2), which was ob-
tained from d-glucose in six steps by following literature
procedures.[14,15] The N-propargylation of compound 10
was achieved by treatment with NaH and propargyl brom-
ide in N,N-dimethylformamide (DMF) at 0 °C to afford the
desired product 8 in 93% yield. The crucial ene-yne metath-
esis reaction to form diene 7 was unsuccessful under an
inert atmosphere with Grubbs first and second generation
catalysts as well as with Hoveyda–Grubbs first-generation
catalyst. However, the use of either Grubbs first or Grubbs
second-generation catalyst under an ethylene atmosphere[16]
successfully gave the desired diene 7. The reaction reached
completion in 4 d with Grubbs first generation catalyst,
whereas that with Grubbs second generation catalyst pro-
ceeded at room temperature in only 10–12 h. The formation
Scheme 1. Retosynthetic analysis for compounds 6c and 6d (Cbz =
benzyloxycarbonyl).
Scheme 3. Reagents and conditions: (i) (a) 4% H2SO4 in CH3CN/
H2O (3:1), room temp., 6 h; (b) NaBH4, MeOH, 0 °C to room
temp., 2 h; (c) Ac2O, Et3N, 4-(dimethylamino)pyridine (DMAP),
DCM, room temp., 12 h, 59% (over three steps); (ii) OsO4-NMO,
acetone/water (1:1), room temp., 4 h, 84%; (iii) (a) NaIO4, MeOH/
H2O (1:1), 0 °C, 15 min; (b) NaBH4 MeOH, 0 °C to room temp.,
2 h; (c) Ac2O, Et3N, DMAP, DCM, room temp., 12 h, 61% (over
three steps); (iv) (a) RuCl3·(H2O)3, NaIO4, EtOAc/H2O (1:1), 0 °C
to room temp., 30 min; (b) Ac2O, Et3N, DMAP, DCM, room
temp., 12 h, 67% (over two steps); (v) (a) NaOMe, MeOH, room
temp., 2 h; (b) Amberlite IR 120 (acidic resin); (c) H2, Pd(OH)2/C,
MeOH, 2 h, 96% (over two steps).
Scheme 2. Reagents and conditions: (i) propargyl bromide, NaH,
DMF, 0 °C, 30 min, 93%; (ii) Grubbs second generation catalyst,
dichloromethane (DCM), ethylene, room temp., overnight, 82%.
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Synthesis and Glycosidase Inhibition Study
mix-α and AD-mix-β reagent systems did not give any of
the desired dihydroxylated product. On the other hand, the
[17]
use of the RuCl3·(H2O)3-NaIO4 reagent system gave the
expected diol as a single isomer, which was isolated as hexa-
acetate 14 after acetylation of the resulting diol. Treatment
of 14 with NaOMe followed by hydrogenation under a pres-
sure of 1 atm furnished the final polyhydroxylated piperi-
dine 6c in good yield.
For the synthesis of compound 6d (see Scheme 4), inter-
mediate 7 was converted into the corresponding triol
through the same sequence of reactions, that is, the removal
of the acetonide followed by reduction with NaBH4. The
oxidative cleavage of the 1,2-diol unit of the resulting triol
was then carried out by treatment with NaIO4 to give the
corresponding aldehyde. The aldehyde was then further re-
duced to the corresponding primary alcohol by using
NaBH4 to give eventually a diol, which underwent acetyl-
ation to give 15 in 53% yield (see Scheme 4). Compound
15 was converted into the final compound 6d by following
the same reaction sequence that was employed for the syn-
thesis of 6c. The stereochemical outcome of the Ru-cata-
lyzed dihydroxylation was confirmed by the spectral analy-
sis (1H NMR, COSY, and NOE experiments) of n-butyl
analogue 19 (see Scheme 5). In the NOE experiment, the
irradiation of the H-4 resonance at δ = 5.17 ppm clearly
resulted in a 3.6% enhancement of the signal for the
branched –CH2– group at δ = 4.60 ppm, and no NOE en-
hancement of the H-3 resonance was observed when the
signal for H-5 was irradiated.
Scheme 5. Reagents and conditions: (i) (a) butyraldehyde, H2,
Pd(OH)2/C, MeOH, room temp., 6 h; (b) Ac2O, Et3N, DMAP,
CH2Cl2, room temp., 12 h, 40% (over two steps).
The biological activity of compounds 6c and 6d was
tested against a few commercially available glycosidases[18]
(see Table 1). Compound 6c was very active and selective
against α-galactosidase (coffee beans) at a concentration of
32 μm, whereas compound 6d was active against β-gluco-
sidase (almonds) and α-galactosidase (coffee beans) at con-
centrations of 21 and 44 μm, respectively. It is clear that the
introduction of an additional hydroxy group in the side
chain provides additional binding to the active site of the
enzyme to lead to better and more selective inhibition as is
observed with compounds 6c and 6d against α-galactosid-
ase (coffee beans). It is noteworthy that in compound 6c
the combination of a hydroxy group in the β-orientation
and a hydroxymethyl group in the α-orientation at C-2 and
a hydroxymethyl group in the side chain at C-6 led to good
and very selective inhibition compared to its parent com-
pound 6a.[9c] Furthermore, compound 6d with
a
hydroxymethyl group at C-2 showed much better inhibition
than compound 6a, which was active against α-mannosid-
ase (jack beans) and α-galactosidase (coffee beans) at con-
centrations of 30 and 290 μm, respectively.[9c] Likewise, sim-
ilar structural features in compound 6d with the hydroxy
group in the β-orientation and the hydroxymethyl group in
the α-orientation at C-2 led to a more effective enzyme in-
hibitor compared to compound 6b, in which the hydroxy
group is in the α-orientation and the hydroxymethyl group
Table 1. IC50 (μm) values for synthesized polyhydroxylated com-
pounds 6c and 6d.[a]
Scheme 4. Reagents and conditions: (i) (a) 4% H2SO4 in CH3CN/
H2O (3:1), room temp., 6 h; (b) NaBH4, MeOH, 0 °C to room
temp., 2 h; (c) NaIO4, MeOH/H2O (1:1), 0 °C, 15 min; (d) NaBH4,
MeOH, 0 °C to room temp., 2 h; (e) Ac2O, Et3N, DMAP, CH2Cl2,
room temp., 12 h, 53% (over five steps); (ii) OsO4-NMO, acetone/
water (1:1), room temp., 4 h, 81%; (iii) (a) NaIO4, MeOH/H2O
(1:1), 0 °C, 15 min; (b) NaBH4 MeOH, 0 °C to room temp., 2 h;
(c) Ac2O, Et3N, DMAP, CH2Cl2, room temp., 12 h, 64% (over
three steps); (iv) (a) RuCl3·(H2O)3, NaIO4, EtOAc/H2O (1:1), 0 °C
to room temp., 30 min; (b) Ac2O, Et3N, DMAP, CH2Cl2, room
temp., 12 h, 66% (over two steps); (v) (a) NaOMe, MeOH, room
Enzyme
6c
6d
α-Glucosidase (yeast)
β-Glucosidase (almonds)
n.i.
n.i.
32
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
21
44
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
α-Galactosidase (coffee beans)
β-Galactosidase (bovine liver)
α-Mannosidase (jack beans)
α-Glucosidase (rice)
β-Mannosidase (Helix pomatia)
β-Galactosidase (Aspergillus niger)
α-l-Fucosidase (bovine liver)
temp., 2 h; (b) Amberlite IR 120 (acidic resin); (c) H2, Pd(OH)2/C, [a] n.i.: no inhibition at concentration of 3 mm. Enzyme inhibition
MeOH, 2 h, 89% (over two steps).
was carried out at the optimal pH of the enzyme at 37 °C.
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A. Mallick, Y. D. Vankar
FULL PAPER
is in the β-orientation at C-2.[11c] Compound 6b is reported
to exhibit poor inhibition against α-galactosidase (coffee
beans), β-galactosidase (bovine liver), and α-glucosidase
(rice) at concentrations of 29.00, 0.76, and 1.00 mm, respec-
tively. Thus, the glycosidase inhibition activity of 6d against
α-galactosidase (coffee beans) has improved by more than
650 fold over that of compound 6b. Clearly, there is a
change both in terms of specificity as well as inhibition con-
stant values as a result of the incorporation of the extra
of compound 10 (5.500 g, 17.234 mmol) in dry DMF (40 mL) was
added NaH (50–60% NaH in mineral oil, 1.654 g, 34.468 mmol)
portionwise followed by the dropwise addition of propargyl brom-
ide (2.0 mL, 26.410 mmol), and the reaction was stirred at room
temperature for 30 min. The reaction mixture was poured into ice
cold water, and the resulting solution was extracted with EtOAc
(3ϫ 20 mL). The combined organic layers were washed with brine
and dried with Na2SO4. The organic layer was evaporated under
reduced pressure to give crude 8. Chromatographic purification on
a silica gel column gave pure 8 (5.706 g, 93% yield) as a yellow oil;
hydroxymethyl groups at the C-2 and C-6 atoms, which was Rf = 0.5 (hexane/ethyl acetate, 8:2). [α]2D5 = +49.2 (c = 0.6, CH2Cl2).
IR (neat): ν
= 3286, 2987, 1704, 1238, 1022 cm–1. 1H NMR
˜
the goal of the present study.
max
(500 MHz, CDCl3): δ = 7.37–7.31 (m, 5 H), 5.89 (br. s, 1 H), 5.79
(br. s, 1 H), 5.49 (d, J = 17.1 Hz, 1 H), 5.29–5.24 (m, 1 H), 5.19 (s,
2 H), 4.76–4.68 (m, 2 H), 4.42–4.37 (m, 3 H), 2.19 (s, 1 H), 1.59 (s,
3 H), 1.31 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 156.2,
136.2, 134.0, 128.5, 128.1, 127.7, 119.5, 112.9, 103.8, 79.9, 76.0,
71.4, 68.0, 61.5, 34.7, 26.7, 26.2 ppm. HRMS: calcd. for
C20H23NNaO5 [M + Na]+ 380.1474; found 380.1471.
Conclusions
In summary, we have described the synthesis of 2-C-
hydroxymethyl-branched analogues (i.e., 6c and 6d) of l-1-
deoxyallonojirimycin (l-allo-DNJ, 6a) from readily avail-
able starting materials. We also used inhibition studies to
determine that compound 6d with a 2-C-hydroxymethyl
group is a much better inhibitor of α-galactosidase (coffee
beans) than its parent compound 6a,[9c] which has no 2-C-
hydroxymethyl group. Also, the incorporation of the extra
hydroxymethyl group at the side chain of 6c provided good
and highly selective inhibition of α-galactosidase (coffee
beans).
(3R)-Benzylcarboxylamino-3,8-dideoxy-5,6-dihydro-6-vinyl-2-O-
isopropylidine-α-D-glucose (7): To a solution of compound 8
(1.450 g, 4.057 mmol) in dry CH2Cl2 (120 mL) was added Grubbs
second generation catalyst (172 mg, 5 mol-%), and the mixture was
stirred at room temperature for 10–12 h under an ethylene atmo-
sphere (1 atm.). Upon completion of the reaction, the solvent was
evaporated, and the crude product was purified by column
chromatography to give 7 (1.196 g, 82% yield) as a white solid;
m.p. 66–68 °C. Rf = 0.5 (hexane/ethyl acetate, 8:2). [α]2D5 = +68.2 (c
= 0.8, CH Cl ). IR (neat): νmax = 2984, 1705, 1214 cm–1. 1H NMR
˜
2
2
(500 MHz, CDCl3): δ = 7.43–7.32 (m, 5 H), 6.30 (dd, J = 11.0,
17.7 Hz, 1 H), 6.21 (br. s, 1 H), 5.81 (br. s, 1 H), 5.31–5.09 (m, 5
H), 4.57 (d, J = 9.7 Hz, 1 H), 4.38 (d, J = 16.2 Hz, 1 H), 4.02 (d,
J = 16.2 Hz, 1 H), 2.87 (dd, J = 3.3, 9.4 Hz, 1 H), 1.58 (s, 3 H),
1.54 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 155.9, 136.3,
135.1, 133.4, 128.8, 128.5, 128.2, 128.1, 127.9, 127.4, 113.9, 112.6,
105.9, 78.9, 73.6, 67.9, 61.4, 45.0, 26.3, 26.2 ppm. HRMS: calcd.
for C20H23NNaO5 [M + Na]+ 380.1474; found 380.1472.
Experimental Section
General Methods: All solvents and common reagents were purified
by established procedures. All reactions were performed under
nitrogen. FTIR spectra were recorded as thin films or KBr pellets,
and the data are reported in cm–1. The H (400 or 500 MHz) and
1
13C (100 and 125 MHz) NMR spectroscopic data were recorded
with JEOL JNM-LA 400 or 500 spectrometers. CDCl3 or D2O
were used at the solvents with tetramethylsilane as the internal
standard. The mass spectra were recorded with a Waters HAB 213
Q-Tof Premier Micromass spectrometer. Optical rotations were re-
corded with an Autopol II automatic polarimeter using the sodium
d-line (589 nm) as the wavelength at 25 °C. A Perkin–Elmer
Lamda-20 UV/Visual spectrophotometer was used for the enzyme
assay. Column chromatography was performed on silica gel (100–
200 mesh), and thin layer chromatography was performed on silica
gel plates made by grade-G silica gel that was obtained from s.d.
fine-chem Ltd., Mumbai or on Merck silica gel precoated plates.
(R)-1-[(2R,3R)-3-Acetoxy-1-(benzyloxycarbonyl)-5-vinyl-1,2,3,6-
tetrahydropyridin-2-yl]ethane-1,2-diyl Diacetate (11): Compound 7
(1.00 g, 2.801 mmol) was dissolved in a solution of 4% H2SO4 in
CH3CN/H2O (3:1; 17 mL) at room temperature, and the resulting
solution was stirred for 6 h. The mixture was then cooled to 0 °C,
and the excess amount of acid was neutralized by the addition of
an aqueous solution of NaHCO3. The biphasic mixture was sepa-
rated, and the aqueous layer was washed with EtOAc (3ϫ 10 mL).
The combined organic layers were dried with Na2SO4 and concen-
trated under reduced pressure to give the crude hemiacetal, which
was further dissolved in MeOH (20 mL). To this solution was
added NaBH4 (423 mg, 11.204 mmol) portionwise at 0 °C. The re-
action mixture was stirred at room temperature for 2 h, and then
water (10 mL) was added. The mixture was extracted with EtOAc
(3ϫ 10 mL), and the combined organic extracts were washed with
brine, dried with Na2SO4, and concentrated in vacuo to give the
corresponding triol. To a stirred solution of this triol in dry CH2Cl2
(5 mL) were added acetic anhydride (1.32 mL, 14.005 mmol), tri-
ethylamine (2.34 mL, 16.806 mmol), and a catalytic amount of
DMAP (68 mg, 0.560 mmol). The reaction mixture was stirred at
room temperature for 12 h and was then quenched by the addition
of water (10 mL). The aqueous layer was extracted with CH2Cl2
(3ϫ 10 mL), and the combined organic layers were washed with
water and brine and then dried with Na2SO4. Concentration in
vacuo followed by chromatographic purification over silica gel gave
pure 11 (736 mg, 59% yield) as a colorless oil; Rf = 0.5 (hexane/
General Procedure for Enzyme Inhibition: The inhibition studies of
azasugars 6c and 6d were carried out by measuring the residual
hydrolytic activity of the glycosidase.[19] The substrate concentra-
tion (3 mm) was prepared in its respective buffer solution, and test
compounds were preincubated with the enzymes at 37 °C for 1 h.
To this mixture was added an equal amount of the specific sub-
strate (100 μL of solution), which was prepared in a specific buffer
solution for the corresponding enzyme, and again incubated for
10 min. The reaction was terminated by the addition of sodium
borate (0.05 m solution), and the activity of the compound was
determined by comparing the absorption of the control and test
reaction at a wavelength of 405 nm using a UV/Vis spectrophoto-
meter. From the absorption difference, the percentage inhibition
and IC50 values were determined.
Benzyl
(3aR,5R,6R,6aR)-2,2-Dimethyl-5-vinyltetrahydrofuro[2,3-
d][1,3]dioxol-6-yl(prop-2-ynyl)carbamate (8): To an ice cold solution
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Synthesis and Glycosidase Inhibition Study
ethyl acetate, 7:3). [α]2D5 = –97.9 (c = 0.5, CH Cl ). IR (neat): ν
˜
max
and brine and then dried with Na2SO4. Concentration in vacuo
= 2961, 1743, 1704, 1228 cm–1. H NMR (500 MHz, CDCl3, 1.2:1 and purification by silica gel chromatography gave pure 13 (247 mg,
mixture of rotamers): δ = 7.37–7.31 (m, 10 H, both rotamers), 6.33– 61% yield) as a colorless oil; Rf = 0.5 (hexane/ethyl acetate, 6:4).
2
2
1
6.27 (m, 2 H, both rotamers), 5.87 (d, J = 6.0 Hz, 1 H, minor [α]2D5 = –59.2 (c = 1.3, CH Cl ). IR (neat): νmax = 2925, 1747, 1709,
˜
2
2
1
rotamer), 5.83 (d, J = 6.0 Hz, 1 H, major rotamer), 5.34–5.17 (m,
8 H, both rotamers), 5.08–5.00 (m, 4 H, both rotamers), 4.84–4.75
(m, 2 H, both rotamers), 4.67–4.61 (m, 2 H, both rotamers), 4.33
1234 cm–1. H NMR (500 MHz, CDCl3, 1:1 mixture of rotamers):
δ = 7.34–7.30 (m, 10 H, both rotamers), 5.92–5.89 (m, 2 H, both
rotamers), 5.74–5.72 (m, 1 H, single rotamer), 5.51–4.90 (m, 10 H,
(dd, J = 3.0, 12.1 Hz, 1 H, major rotamer), 4.25 (dd, J = 3.0, both rotamers), 4.76–4.52 (m, 4 H, both rotamers), 4.42–4.22 (m,
12.1 Hz, 1 H, minor rotamer), 4.11–4.07 (m, 1 H, minor rotamer), 3 H, both rotamers), 4.07–3.92 (m, 2 H, both rotamers), 3.67–3.53
3.98–3.95 (m, 1 H, major rotamer), 3.77 (m, 1 H, minor rotamer),
3.67 (m, 1 H, major rotamer), 2.09 (s, 3 H, minor rotamer), 2.07
(m, 2 H, both rotamers), 2.08–1.90 (m, 24 H, both rotamers) ppm.
13C NMR (125 MHz, CDCl3): δ = 170.8, 170.4, 170.3, 170.2, 170.0,
(s, 3 H, major rotamer), 2.01 (s, 6 H, both rotamers), 1.91 (s, 3 155.5, 155.2, 137.3, 136.5, 136.2, 128.7, 128.6, 128.4, 128.3, 128.1,
H, major rotamer), 1.89 (s, 3 H, minor rotamer) ppm. 13C NMR
127.9, 119.2, 118.6, 69.1, 68.4, 67.9, 67.8, 64.7, 64.7, 64.4, 63.1,
(125 MHz, CDCl3): δ = 170.8, 170.5, 170.0, 155.7, 155.4, 138.3, 62.9, 53.2, 52.7, 41.4, 41.1, 21.1, 21.0, 20.9, 20.8, 20.6 ppm.
138.1, 135.4, 135.3, 128.7, 128.3, 128.0, 127.9, 120.9, 120.2, 116.0,
HRMS: calcd. for C24H29NNaO10 [M + Na]+ 514.1689; found
115.6, 69.2, 68.5, 67.9, 65.4, 65.2, 63.3, 62.8, 53.3, 52.8, 40.2, 39.9, 514.1689.
21.1, 21.0, 20.9, 20.8, 20.6 ppm. HRMS: calcd. for C23H27NNaO8
(2S,3S,4S,5S)-5-(Acetoxymethyl)-1-(benzyloxycarbonyl)-2-[(R)-
1,2-bis(acetoxyethyl)]piperidine-3,4,5-triyl Triacetate (14): A mix-
[M + Na]+ 468.1634; found 468.1635.
(R)-1-[(2R,3R)-3-Acetoxy-1-(benzyloxycarbonyl)-5-(1,2-dihydroxy- ture of NaIO4 (35 mg, 0.168 mmol) and RuCl3·(H2O)3 (1.5 mg,
ethyl)-1,2,3,6-tetrahydropyridin-2-yl]ethane-1,2-diyl Diacetate (12): 0.005 mmol) in H2O (1 mL) was stirred at room temperature for
Compound 11 (530 mg, 1.185 mmol) was dissolved in acetone/
10 min, and a transparent bright yellow solution resulted. The reac-
water (1:1, 5 mL), and to the solution was added NMO (208 mg, tion mixture was then cooled to 0 °C, and a solution of alkene 13
1.777 mmol) followed by a catalytic amount of OsO4 (25 mgmL–1
in tBuOH, 0.05 mL, 0.005 mmol). After stirring at room tempera-
ture for 4 h, the reaction was quenched by the addition of a satu-
rated solution of Na2S2O5 (5 mL). The resulting mixture was ex-
tracted with EtOAc (3ϫ 10 mL), and the combined organic layers
were washed with water and brine and then dried with Na2SO4.
Concentration under reduced pressure and purification by
chromatography on a silica gel column led to pure diol 12 (443 mg,
(55 mg, 0.112 mmol) in EtOAc (1 mL) was added, which resulted
in a dark brown, heterogeneous mixture. This mixture was stirred
at 0 °C for 30 min, and then saturated Na2S2O5 (2 mL) was added.
The mixture was diluted with H2O (10 mL), and the resulting solu-
tion was extracted with EtOAc (3ϫ 5 mL). The combined organic
layers were washed with water and brine, dried with Na2SO4, and
concentrated under vacuum. The inorganic impurity was removed
on a short silica gel column, and the crude product was used for
84% yield) as a colorless oil; Rf = 0.5 (hexane/ethyl acetate, 2:8). the acetylation. To a solution of the resulting diol (15 mg,
[α]2D5 = –27.9 (c = 0.5, CH Cl ). IR (neat): νmax = 3450, 2956, 1742,
0.028 mmol) in dry CH2Cl2 (2 mL) were added Et3N (0.02 mL,
0.14 mmol), acetic anhydride (0. 01 mL, 0.011 mmol), and a cata-
lytic amount of DMAP. The resulting mixture was stirred at room
temperature for 10–12 h and was then quenched by the addition of
water (5 mL). The aqueous layer was extracted with CH2Cl2 (3ϫ
10 mL), and the combined organic layers were washed with water
and brine, dried with Na2SO4, and concentrated in vacuo. The
crude acetate product was purified by silica gel chromatography to
give pure 14 (24 mg, 60% yield) as a colorless oil; Rf = 0.6 (hexane/
˜
2
2
1704, 1234 cm–1. H NMR (500 MHz, CDCl3, mixture of rota-
mers): δ = 7.35–7.30 (m, 10 H), 5.96–5.86 (m, 2 H), 5.86–5.69 (m,
1 H), 5.49–5.40 (m, 1 H), 5.29–5.04 (m, 7 H), 4.71–4.54 (m, 2 H),
4.31–4.20 (m, 5 H), 4.02–3.90 (m, 2 H), 3.79–3.60 (m, 6 H), 2.12–
1.85 (m, 18 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.1,
170.9, 170.8, 170.7, 170.5, 170.4, 155.8, 155.7, 155.4, 155.3, 142.5,
142.1, 141.5, 136.3, 128.7, 128.4, 128.3, 128.1, 128.0, 127.8, 117.2,
116.9, 116.7, 116.5, 73.5, 73.4, 73.0, 68.9, 68.4, 68.3, 68.1, 67.9,
65.6, 64.9, 64.8, 64.7, 63.7, 63.3, 53.2, 52.6, 41.1, 40.8, 40.5, 21.1,
20.9, 20.8, 20.6 ppm. HRMS: calcd. for C23H29NNaO10 [M +
Na]+ 502.1689; found 502.1686.
1
ethyl acetate, 7:3). [α]2D5 = –11.1 (c = 0.9, CH Cl ). IR (neat): ν
˜
2
2
max
1
= 2960, 1748, 1707, 1228 cm–1. H NMR (500 MHz, CDCl3, mix-
ture of rotamers): δ = 7.36–7.34 (m, 5 H), 5.61–5.54 (m, 1 H), 5.42–
4.96 (m, 5 H), 4.73–4.59 (m, 2 H), 4.44–4.23 (m, 2 H), 4.11–4.02
(m, 1 H), 3.28–3.20 (m, 1 H), 2.17–1.98 (m, 18 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 170.6, 170.4, 170.1, 169.9, 169.5, 155.8,
155.3, 136.0, 135.8, 128.5, 128.4, 128.3, 127.9, 80.5, 80.3, 68.5, 68.3,
68.2, 67.5, 67.4, 66.4, 66.1, 63.4, 62.4, 61.0, 60.6, 51.4, 51.2, 43.2,
42.7, 42.7, 42.6, 21.2, 21.1, 20.7, 20.6, 20.4 ppm. HRMS: calcd. for
C28H35NNaO14 [M + Na]+ 632.1955; found 632.1956.
(R)-1-[(2R,3R)-3-Acetoxy-5-(acetoxymethyl)-1-(benzyloxycarbon-
yl)-1,2,3,6-tetrahydropyridin-2-yl]ethane-1,2-diyl Diacetate (13):
Diol 12 (393 mg, 0.820 mmol) was dissolved in MeOH/H2O (1:1,
5 mL), and NaIO4 (211 mg, 0.984 mmol) was added at 0 °C over
15–20 min. The reaction mixture was stirred at this temperature for
an additional 40 min and then extracted with EtOAc (3ϫ 10 mL).
The combined organic layers were washed with brine, dried with
Na2SO4, and concentrated in vacuo to give the crude product. To
a stirred solution of this crude product in MeOH (2 mL) at 0 °C
was added NaBH4 (124 mg, 3.280 mmol) portionwise, and the stir-
ring was continued at room temperature for 2 h. The reaction was
then quenched by the addition of a few drops of glacial acetic acid,
and the MeOH/H2O was removed under reduced pressure. The re-
maining trace amount of water was removed by coevaporation with
toluene (3ϫ). The crude solid mixture was dried under vacuum for
several hours. To the crude sample were added dry Et3N (2 mL)
and acetic anhydride (1 mL). The resulting mixture was stirred at
room temperature for 10–12 h was then quenched by the addition
of water (10 mL). The aqueous layer was extracted with CH2Cl2
(3ϫ 10 mL). The combined organic layers were washed with water
1,5-Dideoxy-6-hydroxy-2-hydroxymethyl-1,5-imino-α-D-glycero-L-
allo-heptitol (6c): To a solution of compound 14 (37 mg,
0.070 mmol) in dry MeOH (1 mL) at 0 °C was added a catalytic
amount of NaOMe (1 mg), and the mixture was stirred at room
temperature for 2 h. The excess amount of base was quenched by
passing the reaction mixture through acidic resin Amberlite IR 120,
and the evaporation of the solvent gave the polyhydroxylated com-
pound. The hydroxylated compound was dissolved in MeOH
(2 mL), and 20% Pd(OH)2/C (5 mg) was added. The reaction mix-
ture was then stirred under H2 pressure (1 atm.) at room tempera-
ture for 2 h. The catalyst was removed by filtration through Celite,
and the filtrate was concentrated under reduced pressure to give
6c. (15 mg, 96 % yield); Rf = 0.4 (ethyl acetate/methanol, 1:1).
Eur. J. Org. Chem. 2014, 4155–4161
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4159

A. Mallick, Y. D. Vankar
3442, 2927, 1740, 1703, 1424, 1368, 1231, 1036 cm–1 1H NMR
(500 MHz, CDCl3, mixture of rotamers): δ = 7.39–7.31 (m, 5 H),
5.68–5.52 (m, 1 H), 5.26–4.90 (m, 4 H), 4.46–4.00 (m, 4 H), 3.73–
3.57 (m, 3 H), 2.12–1.19 (m, 6 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 170.7, 170.6, 170.1, 155.6, 136.4, 136.3, 128.6, 128.3,
128.0, 127.9, 120.9, 120.3, 120.0, 73.2, 72.8, 67.6, 67.4, 67.0, 65.6,
65.5, 59.6, 59.4, 49.7, 40.3, 40.2, 21.1, 20.9, 20.6 ppm. HRMS:
calcd. for C20H25NNaO8 [M + Na]+ 430.1478; found 430.1479.
FULL PAPER
[α]2D5 = –12.0 (c = 0.7, MeOH). IR (neat): νmax = 3366, 2926, 1595,
.
˜
1
1454, 1067 cm–1. H NMR (500 MHz, D2O): δ = 4.17 (br. s, 1 H),
3.97 (br. s, 1 H), 3.80–3.54 (m, 5 H), 3.32–3.22 (m, 2 H), 3.03 (d,
J = 13.7 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 70.5,
68.9, 68.6, 67.3, 63.3, 62.9, 55.0, 44.5 ppm. HRMS: calcd. for
C8H18NO6 [M + H]+ 224.1134; found 224.1135.
Benzyl (5R,6S)-5-Acetoxy-6-(acetoxymethyl)-3-vinyl-5,6-dihydro-
pyridine-1(2H)-carboxylate (15): Compound 7 (1.30 g, 3.341 mmol)
was dissolved in a solution of 4% H2SO4 in CH3CN/H2O (3:1,
20 mL) at room temperature, and the resulting solution was stirred
for 6 h. The mixture was then cooled to 0 °C, and the excess
amount of acid was neutralized by the addition of aqueous
NaHCO3. The biphasic mixture was separated, and the aqueous
layer was washed with EtOAc (3ϫ 10 mL). The combined organic
layers were dried with Na2SO4 and concentrated under reduced
pressure to give the crude hemiacetal, which was further dissolved
in MeOH (20 mL). To this solution was added NaBH4 (550 mg,
14.538 mmol) portionwise at 0 °C. The reaction mixture was stirred
at room temperature for 2 h, and then water (10 mL) was added.
The mixture was extracted with EtOAc (3ϫ 10 mL), and the com-
bined organic layers were washed with brine and dried with
Na2SO4. Concentration of the organic layer in vacuo led to the
corresponding triol. To a stirred solution of this triol in MeOH/
H2O (1:1, 15 mL) was added NaIO4 (1.43 g, 6.694 mmol) at 0 °C,
and the stirring was continued at the same temperature for 40 min.
The methanol was removed under reduced pressure, and the mix-
ture was extracted with CH2Cl2 (3ϫ 10 mL). The combined or-
ganic layers were washed with brine, dried with Na2SO4, and con-
centrated under reduced pressure to give the cleavage product,
which was dissolved in MeOH (20 mL). To this solution was added
NaBH4 (189 mg, 5.011 mmol) at 0 °C, and the resulting mixture
was stirred at room temperature for 2 h. Water (10 mL) was added,
and the mixture was extracted with EtOAc (3ϫ 10 mL). The com-
bined organic layers were washed with brine, dried with Na2SO4,
and concentrated in vacuo to give the corresponding diol. To a
stirred solution of this diol in dry CH2Cl2 (5 mL) were added acetic
anhydride (1.363 mL, 13.364 mmol), triethylamine (2.34 mL,
16.806 mmol), and a catalytic amount of DMAP (68 mg,
0.560 mmol). The reaction mixture was stirred at room temperature
for 12 h and was then quenched by the addition of water (10 mL).
The aqueous layer was extracted with CH2Cl2 (3ϫ 10 mL). The
combined organic layers were washed with water and brine and
then dried with Na2SO4. Concentration in vacuo and purification
by silica gel chromatography gave pure compound 15 (719 mg, 53%
Benzyl (5R,6S)-5-Acetoxy-3,6-bis(acetoxymethyl)-5,6-dihydropyr-
idine-1(2H)-carboxylate (17): A procedure similar to that described
for the synthesis of 13 was followed by using 16 to give 17 (64%
yield); Rf = 0.6 (hexane/ethyl acetate, 7.5:2.5). [α]2D5 = –9.7 (c = 0.6,
CH Cl ). IR (neat): ν = 2925, 1745, 1707, 1424, 1369, 1229,
˜
max
2
2
1044 cm–1 1H NMR (500 MHz, CDCl3, 1.1:1 mixture of rota-
.
mers): δ = 7.36–7.30 (m, 10 H, both rotamers), 5.66 (br. s, 2 H,
both rotamers), 5.52 (br. s, 2 H, both rotamers), 5.28–4.92 (m, 6
H, both rotamers), 4.55 (s, 4 H, both rotamers), 4.36 (br. s, 1 H,
minor rotamer), 4.32 (br. s, 1 H, major rotamer), 4.20–4.19 (m, 2
H, both rotamers), 4.12–4.03 (m, 2 H, both rotamers), 3.65–3.60
(m, 1 H, minor rotamer), 3.57–3.53 (m, 1 H, major rotamer), 2.12–
2.03 (m, 18 H, both rotamers) ppm. 13C NMR (125 MHz, CDCl3):
δ = 170.8, 170.5, 170.4, 155.4, 136.4, 136.3, 133.3, 128.6, 128.3,
128.1, 127.9, 123.2, 123.5, 67.6, 66.7, 66.4, 64.8, 64.6, 59.6, 59.4,
49.5, 49.1, 41.1, 40.8, 21.0, 20.8, 20.7, 20.5 ppm. HRMS: calcd. for
C21H25NNaO8 [M + Na]+ 442.1478; found 442.1481.
(2S,3S,4S,5S)-2,5-Bis(acetoxymethyl)-1-(benzyloxycarbonyl)piper-
idine-3,4,5-triyl Triacetate (18): A procedure similar to that de-
scribed for the synthesis of 14 was followed by using 17 to give 18
(66% yield); Rf = 0.5 (hexane/ethyl acetate, 7:3). [α]2D5 = –23.0 (c =
0.6, CH Cl ). IR (neat): νmax = 2928, 1748, 1707, 1427, 1369, 1228,
˜
2
2
1
1045 cm–1. H NMR (500 MHz, CDCl3, 1:1 mixture of rotamers):
δ = 7.35–7.33 (m, 10 H, both rotamers), 5.54–5.46 (m, 2 H, both
rotamers), 5.34–5.27 (m, 2 H, both rotamers), 5.19–4.95 (m, 9 H,
both rotamers), 4.73–4.59 (m, 2 H, both rotamers), 4.53–4.37 (m,
3 H, both rotamers), 4.22–4.15 (m, 2 H, both rotamers), 3.37 (d, J
= 15.0 Hz, 1 H, single rotamer), 3.24 (d, J = 15.0 Hz, 1 H, single
rotamer), 2.17–1.98 (m, 30 H, both rotamers) ppm. 13C NMR
(125 MHz, CDCl3): δ = 170.4, 169.8, 169.5, 155.5, 136.3, 135.9,
128.6, 128.5, 128.4, 128.1, 80.5, 68.7, 68.3, 68.0, 67.5, 61.4, 61.2,
60.6, 60.0, 51.6, 51.3, 42.7, 42.2, 21.5, 21.3, 20.8, 20.7, 20.6 ppm.
HRMS: calcd. for C25H31NNaO12 [M + Na]+ 560.1744; found
560.1747.
1,5-Dideoxy-2-(hydroxymethyl)-1,5-imino-L-allitol (6d): A pro-
cedure similar to that described for the synthesis of 6c was followed
by using 18 to give 6d (89% yield); Rf = 0.4 (ethyl acetate/methanol,
yield) as a colorless oil; Rf = 0.5 (hexane/ethyl acetate, 7:3). [α]2D5
–17.1 (c = 0.6, CH Cl ). IR (neat): ν = 2962, 1744, 1703, 1420,
=
˜
max
2
2
1:1). [α]2D5 = –20.0 (c = 0.2, MeOH). IR (neat): ν
= 3430, 1633,
1226 cm–1 1H NMR (500 MHz, CDCl3, 1.3:1 mixture of rota-
.
˜
max
1384, 1069 cm–1. H NMR (500 MHz, D2O): δ = 3.98–3.94 (m, 1
H), 3.80–3.77 (m, 1 H), 3.68–3.65 (m, 1 H), 3.56–3.53 (m, 3 H),
3.42 (d, J = 11.9 Hz, 1 H), 3.11 (d, J = 13.4 Hz, 1 H), 2.96 (d, J =
13.4 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 71.9, 68.3,
66.6, 62.9, 56.6, 54.9, 43.8 ppm. HRMS: calcd. for C7H15NO5 [M
+ H]+ 194.1028; found 194.1021.
1
mers): δ = 7.38–7.29 (m, 10 H, both rotamers), 6.26 (m, 2 H, both
rotamers), 5.59 (br. s, 4 H, both rotamers), 5.30–4.94 (m, 10 H,
both rotamers), 4.54 (d, J = 17.8 Hz, 1 H, major rotamer), 4.42 (d,
J = 17.8 Hz, 1 H, minor rotamer), 4.24–4.21 (m, 2 H, both rota-
mers), 4.11–4.02 (m, 2 H, both rotamers), 3.78 (d, J = 17.8 Hz, 1
H, minor rotamer), 3.69 (d, J = 17.8 Hz, 1 H, major rotamer),
2.29–1.92 (m, 12 H, both rotamers) ppm. 13C NMR (125 MHz,
CDCl3): δ = 170.8, 170.0, 155.6, 135.2, 134.9, 128.6, 128.2, 128.1,
123.9, 114.85, 67.6, 67.4, 59.8, 59.6, 49.8, 39.6, 21.0, 20.8,
20.5 ppm. HRMS: calcd. for C20H23NNaO6 [M + Na]+ 396.1423;
found 396.1417.
6-Acetoxy-2-(acetoxymethyl)-2,3,4,7-tetra-O-acetyl-N-butyl-1,5-
dideoxy-1,5-imino-α-D-glycero-L-allo-heptitol (19): To a stirred solu-
tion of polyhydroxylated compound 6c (15 mg, 0.067 mmol) in dry
MeOH (1 mL) were added butyraldehyde (9 μL, 0.100 mmol) and
Pd(OH)2/C (2 mg), and the stirring was continued under H2 (1 atm)
for 6 h. The catalyst was removed by filtration through Celite, and
the filtrate was concentrated under reduced pressure to give the
crude butylated product. The polar crude product was dissolved in
Et3N (1 mL) and Ac2O (0.05 mL). A catalytic amount of DMAP
was added. The reaction mixture was stirred at room temperature
Benzyl (5R,6S)-5-Acetoxy-6-(acetoxymethyl)-3-(1,2-dihydroxy-
ethyl)-5,6-dihydropyridine-1(2H)-carboxylate (16): A procedure
similar to that described for the synthesis of 12 was followed by
using compound 15 to give 16 (81% yield); Rf = 0.4 (hexane/ethyl
acetate, 2:8). [α]2D5 = –15.6 (c = 0.5, CH Cl ). IR (neat): ν
=
˜
max
2
2
4160
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4155–4161

Synthesis and Glycosidase Inhibition Study
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for 12 h and then was quenched by the addition of water (5 mL).
The aqueous layer was extracted with CH2Cl2 (3ϫ 10 mL). The
combined organic layers were washed with water and brine and
then dried with Na2SO4. Concentration in vacuo followed by silica
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1
(neat): ν
= 2923, 2853, 1746, 1371, 1226, 1044 cm–1. H NMR
˜
max
(500 MHz, CDCl3): δ = 5.45 (d, J = 5.8 Hz, 1 H, 3-H), 5.40–5.18
(m, 1 H, 6-H), 5. 17 (br. s, 1 H, 4-H), 4.60 (s, 2 H, -CH2OAc), 4.34
(dd, J = 3.0, 11.8 Hz, 1 H, 7-H), 4.10 (dd, J = 7.3, 11.8 Hz, 1 H,
7Ј-H), 3.24–3.22 (m, 2 H, 1-H, 1Ј-H), 3.07–3.01 (m, 1 H, 5-H),
2.88–2.82 (m, 1 H, NCH2-), 2.67–2.63 (m, 1 H, NCH2), 2.11 (s, 3
H, -COCH3), 2.08 (s, 3 H, -COCH3), 2.07 (s, 3 H, -COCH3), 2.05
(s, 3 H, -COCH3), 2.03 (s, 3 H, -COCH3), 2.01 (s, 3 H, -COCH3),
1.42–1.36 (m, 2 H, NCH2CH2-), 1.31–1.24 (m, 2 H, CH3CH2-),
0.90 (t, J = 7.3 Hz, 3 H, -CH3) ppm. 13C NMR (125 MHz, CDCl3):
δ = 170.4, 170.1, 169.8, 79.2, 67.7, 67.6, 63.8, 61.8, 60.0, 54.4, 21.9,
21.0, 20.9, 20.8, 20.7, 20.2, 14.0 ppm. HRMS: calcd. for
C24H38NO12 [M + H]+ 532.2394; found 532.2394.
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Acknowledgments
The authors thank the Department of Science and Technology
(DST), New Delhi for a J. C. Bose National Fellowship to Y. D. V.
(JCB/SR/S2/JCB-26/2010) and the Council of Scientific and Indus-
trial Research (CSIR), New Delhi for the financial support [grant
number: 02(0124)/13/EMR-II, grant to Y. D. V.]. A. M. thanks
CSIR for a senior research fellowship.
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Published Online: May 19, 2014
Eur. J. Org. Chem. 2014, 4155–4161
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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