Synthesis of new nitrogen analogues of salacinol and deoxynojirimycin and their evaluation as glycosidase inhibitors

Article abstract of DOI:10.1021/jo0517388

The synthesis of two enantiomerically pure iminosugars, analogues of 1-L-deoxynojirimycin (L-DNJ) and 1-D-deoxymannojirimycin (DMJ), was achieved using cyclic sulfate substituted isoxazoline derivatives. The piperidine ring was formed via the reduction of

Full text of DOI:10.1021/jo0517388

Synthesis of New Nitrogen Analogues of Salacinol and
Deoxynojirimycin and Their Evaluation as Glycosidase Inhibitors
Estelle Gallienne, Thierry Gefflaut, Jean Bolte, and Marielle Lemaire*
Laboratoire SEESIB, UMR 6504 CNRS, UniVersite´ Blaise Pascal, 24 aVenue des Landais,
63177 Aubie`re Cedex, France
marielle.lemaire@uniV-bpclermont.fr
ReceiVed August 17, 2005
The synthesis of two enantiomerically pure iminosugars, analogues of 1-L-deoxynojirimycin (L-DNJ)
and 1-D-deoxymannojirimycin (DMJ), was achieved using cyclic sulfate substituted isoxazoline derivatives.
The piperidine ring was formed via the reduction of an isoxazoline into an amine which underwent a
spontaneous intramolecular cyclization by reaction with the cyclic sulfate moiety. The nucleophilic attack
of these two trisubstituted piperidines and morpholine on L- and D-erythritol-1,3-cyclic sulfates gave six
new nitrogen analogues of salacinol. The inhibitory properties of the synthesized salacinol analogues
were evaluated on several commercial glycosidases.
Introduction
The design and synthesis of glycosidase inhibitors are mainly
focused on mimicking the transition state (TS) that occurs in
enzymatic glycoside hydrolysis.8 A partial positive charge
develops at the anomeric carbon atom and the endocyclic oxygen
atom (Figure 1). Natural and synthetic alkaloid sugar mimics
with a nitrogen in the ring (iminosugars), such as 1-deoxynojiri-
mycin (DNJ, 1) and 1-deoxymannojirimycin (DMJ, 2) (Figure
1), are of particular interest in inhibitor design.8,9 They are
supposed to be partially protonated in the active site at
physiological pH, mimicking the TS where the positive charge
is located at the endocyclic oxygen atom. As a consequence, a
wide range of synthetic approaches including both chemical and
enzymatic methods have been used to develop this class of
compounds, employing a wide range of starting materials from
sugars to aromatic compounds.10
Glycosidases are widely distributed in microorganisms, plants,
and animals. They selectively hydrolyze glycosidic bonds and
play important roles in crucial biological pathways, including
polysaccharide and glycoconjugate anabolism and catabolism,1
cellular recognition,2 and eukaryotic glycoprotein processing.3
Glycosidases are also involved in a variety of metabolic
disorders and diseases such as diabetes, viral or bacterial
infection, and cancer formation. Therefore, glycosidase inhibitors
have many potential applications4 as antidiabetic,5 antiviral
(HIV, influenza),6 or anticancer7 drugs.
* To whom correspondence should be addressed. Tel: 33 4 73 40 75 84.
Fax: 33 4 73 40 77 17.
(1) (a) Kobata, A. Anal. Biochem. 1979, 100, 1. (b) Lehmann, J.
Carbohydrates: Structure and Biology; Thieme, G. Verlag: New York,
1998. (c) Melendez-Hevia, E.; Waddell, T. G.; Shelton, E. D. Biochem. J.
1993, 295, 477.
Salacinol 3 (Figure 1) has recently been attracting a great
deal of attention, due to the fact that the sulfonium cation ensures
(2) (a) Sharon, N.; Lis, H. Sci. Am. 1993, 268, 82. (b) Sharon, N.; Lis,
H. Science 1989, 246, 227.
(7) (a) Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer
Res. 1995, 1, 935. (b) Nishimura, Y.; Satoh, T.; Adachi, H.; Kondo, S.;
Takeuchi, T.; Azetaka, M.; Fukuyasu, H.; Lizuka, Y. J. Med. Chem. 1997,
40, 2626.
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102, 515.
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T.; Banba, Y.; Ouchi, H.; Takahata, H.; Asano, N. J. Med. Chem. 2005,
48, 2036 and references therein.
(3) (a) Kornfeld, R.; Kornfeld, S. Annu. ReV. Biochem. 1976, 45, 217.
(b) Kang, M. S.; Liu, P. S.; Bernotas, R. C.; Harry, B. S.; Sunkara, P. S.
Glycobiology 1995, 5, 147. (c) Varki, A., Cummings, R., Esko, J., Freeze,
H., Hart, G., Marth, J., Eds., 1999 Cold Spring Harbor Laboratory Press:
Woodbury, New York. (d) Herscovics, A. Biochim. Biophys. Acta 1999,
1473, 96.
(4) For a review, see: Asano N. Glycobiology 2003, 13, 93R.
(5) Scheen, A. J. Drugs 2003, 63, 933.
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(b) Mehta, A.; Rudd, P. M.; Block T. M.; Dwek, R. A. Biochem. Soc. Trans.
1997, 25, 1188.
(10) (a) Pearson, M. S. M.; Mathe´-Allainmat, M.; Fargeas, V.; Lebreton,
J. Eur. J. Org. Chem. 2005, 2159. (b) Martin, R.; Murruzzu, C.; Pericas,
M. A.; Riera, A. J. Org. Chem. 2005, 70, 2325 and refs 8-11 cited therein.
10.1021/jo0517388 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/07/2006
894
J. Org. Chem. 2006, 71, 894-902

Synthesis of New Nitrogen Analogues of Salacinol and Deoxynojirimycin
FIGURE 1. Transition-state model, DNJ and DMJ, salacinol, and its nitrogen analogues.
it a permanent positive charge. Salacinol is a naturally occurring
R-glucosidase inhibitor found in Salacia reticulata.11 The
aqueous extracts of this plant are used in India and Sri Lanka
in traditional medicine for the treatment of diabetes. This
compound has a unique zwitterionic structure: a sulfonium
cation stabilized by a sulfate anion. As for iminosugars, it was
proposed that salacinol mimics the oxocarbenium-ion intermedi-
ate with the positive charge located on the endocyclic oxygen
atom.8 Salacinol can also be considered as a disaccharide-like
substrate, with the acyclic part mimicking a second carbohydrate
unit, and where the role of the sulfate group is not fully
established. Several syntheses of salacinol12 and analogues have
been described including nitrogen (compounds 4-8, Figure 1),13
sulfur,13c,d,14 and selenium analogues.13d,15 Yuasa et al.12a
initiated the major strategy employed for preparing such
zwitterionic compounds, which is based on the nucleophilic
attack of the heteroatom of a protected or unprotected polyhy-
droxylated heterocycle such as compound B at the least-hindered
carbon atom of a protected L- or D-erythritol cyclic sulfate C,
as illustrated in Scheme 1. Several nitrogen analogues of
salacinol were synthesized, including 4 and several stereo-
isomers.13a-c Piperidine analogues 5-8 were also prepared, and
5 and 7 can be also considered as DNJ derivatives.13d Muraoka
et al.13b showed that compound 4 inhibited intestinal R-glucosi-
dases including maltase, sucrase, and isomaltase with IC50 values
of 306, 44, and 136 µM, respectively. Almond â-glucosidase
is not inhibited by 4. Ghavami et al.13a,c showed that compound
4 and two other stereoisomers are not active against Aspergillus
niger glucoamylase G2, barley R-amylase, and porcine pancre-
atic R-amylase. Compounds 5-8 are inactive against glucoamy-
lase G2.13d
SCHEME 1. Synthesis and Alkylation of the Piperidines
SCHEME 2. Morpholine Alkylation
DMJ, via a stereocontrolled reduction of an isoxazoline A by
hydrogenolysis (Scheme 1).16 ∆-2-Isoxazolines A are usually
obtained by 1,3-dipolar cycloaddition reaction of nitrile oxides
(generated in situ from primary nitro derivatives) with alkenes
(Scheme 1). The key step of our isoxazoline route is the one-
pot reduction of the isoxazoline moiety into an amine which
attacks the sulfate ester in a highly stereoselective and regio-
selective intramolecular cyclization.
As part of a search for novel glycosidase inhibitors, we report
here the synthesis of enantiomerically pure L-DNJ and D-DMJ
analogues. Since the effect of substituting a sulfur atom of
salacinol analogues by nitrogen has not been completely
clarified, we also present the further transformation of mor-
pholine and these iminosugars into their substituted ammonium
derivatives (Schemes 1 and 2). To examine the influence of a
side chain with different stereocenters, and of the permanent
positive charge of the ammonium ion associated to the sulfate,
we studied the activity of our zwitterionic piperidines B (where
R ) SO3-, X ) NH2+) and alkylated zwitterionic piperidines
D toward several glycosidases. We also studied compounds E,
where the polyhydroxylated piperidine was replaced by mor-
pholine.
In a preliminary report, we described the synthesis of racemic
trihydroxylated piperidines, which are analogues of DNJ and
(11) (a) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.;
Yamahara, J.; Tanabe, G.; Muraoka, O. Tetrahedron Lett. 1997, 38, 8367.
(b) Yoshikawa, M.; Murakami, T.; Yashiro, K.; Matsuda, H. Chem. Pharm.
Bull. 1998, 46, 1339. (c) Yoshikawa, M.; Morikawa, T.; Matsuda, H.;
Tanabe, G.; Muraoka, O. Bioorg. Med. Chem. 2002, 10, 1547. (d) Matsuda,
H.; Murakami, T.; Yashiro, K.; Yamahara, J.; Yoshikawa, M. Chem. Pharm.
Bull. 1999, 47, 1725.
(12) (a) Yuasa, H.; Takada, J.; Hashimoto, H. Tetrahedron Lett. 2000,
41, 6615. (b) Ghavami, A.; Johnston, B. D.; Pinto, B. M. J. Org. Chem.
2001, 66, 2312. (c) Ghavami, A.; Sadalapure, K. S.; Johnston, B. D.; Lobera,
M.; Snider, B. B.; Pinto, B. M. Synlett 2003, 1259.
(13) (a) Ghavami, A.; Johnston, B. D.; Jensen, M. T.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2001, 123, 6268. (b) Muraoka, O.; Ying, S.;
Yoshikai, K.; Matsuura, Y.; Yamada, E.; Minematsu, T.; Tanabe, G.;
Matsuda, H.; Yoshikawa, M. Chem. Pharm. Bull. 2001, 49, 1503. (c)
Ghavami, A.; Johnston, B. D.; Maddess, M. D.; Chinapoo, S. M.; Jensen,
M. T.; Svensson, B.; Pinto, B. M. Can. J. Chem. 2002, 80, 937. (d)
Szczepina, M. G.; Johnston, B. D.; Yuan, Y.; Svensson, B.; Pinto, B. M. J.
Am. Chem. Soc. 2004, 126, 12458.
(14) (a) Ghavami, A.; Chgen, J. J.-W.; Pinto, B. M. Carbohydr. Res.
2004, 339, 401. (b) Gallienne, E.; Benazza, M.; Demailly, G.; Bolte, J.;
Lemaire, M. Tetrahedron 2005, 61, 4557.
(15) (a) Johnston, B. D.; Ghavami, A.; Jensen, M. T.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2002, 124, 8245. (b) Liu, H.; Pinto, B. M. J. Org.
Chem. 2005, 70, 753.
Results and Discussion
1. Preparation of the Polyhydroxylated Piperidines. The
first step of our synthesis (Scheme 3) starts with the 1,3-dipolar
cycloaddition reaction of the nitrile oxide generated in situ from
nitro compound 1017 with the optically pure alkene 9 prepared
(16) Lemaire, M.; Veny, N.; Gefflaut, T.; Gallienne, E.; Cheˆnevert, R.;
Bolte, J. Synlett 2002, 1359.
(17) Gefflaut, T.; Martin, C.; Delor, S.; Besse, P.; Veschambre, H.; Bolte,
J. J. Org. Chem. 2001, 66, 2296.
J. Org. Chem, Vol. 71, No. 3, 2006 895

Gallienne et al.
SCHEME 3. Synthesis of the Piperidines D-21 and L-22 via the Isoxazoline Sulfates 17 and 18
SCHEME 4. Synthesis of Alkylated Morpholine (-)-28 and
(+)-28
from D-mannitol.18 The improved Mukaiyama procedure19 was
applied to afford the new isoxazolines anti-11 and syn-12 in
52% and 18% yield, respectively. The two diastereoisomers
obtained in a 3:1 ratio were separated on silica gel. Removal
of the cyclohexylidene moiety was performed in acetic acid and
water,20 and the diols 13 and 14 were isolated in 92% and 89%
yield, respectively. During preparation of the cyclic sulfates 17
and 18 from cyclic sulfites 15 and 16, we had previously
observed a difference of the reactivity between the anti and syn
stereoisomers.16 Therefore, two different methods were needed
to oxidize the sulfite group. Following a typical procedure,21
cyclic sulfite anti-15 was obtained in 81% yield. To prevent
the partial oxidation of the benzyl ether into benzoate observed
with RuCl3,16 the sulfite was then oxidized with catalytic RuO2
in the presence of NaIO4 in CH3CN/H2O. The cyclic sulfate
anti-17 was isolated in 82% yield. In the case of the syn
configuration, the cyclic sulfite 16 was used without chromato-
graphic purification and was oxidized with catalytic RuCl3 in
the presence of NaIO4 in CH3CN/H2O. The cyclic sulfate 18
was thus isolated in 61% yield (two steps). The reduction of
the isoxazolines 17 and 18 was performed by hydrogenolysis
over 10% Pd/C in anhydrous methanol in the presence of sodium
carbonate (Scheme 4). Anhydrous conditions were used to
prevent competitive hydrolysis of the imine intermediate into
ketone. Furthermore, without carbonate, strong acidification was
observed due to sulfate decomposition resulting in the formation
of byproducts. In basic conditions, the reduction of the isox-
azoline was followed by the intermediate amine opening the
cyclic sulfate ring, and the zwitterionic piperidines 19 and 20
were obtained in 77% and 34% yield, respectively, after
purification by cation exchange chromatography (Dowex 50WX8,
H+ form). Compound 20 was analyzed in basic medium for
solubility reasons. In both cases, the reaction was highly
regioselective, giving only piperidine rings. From the isoxazoline
anti-17, the reaction was also highly stereoselective, as only
one compound was formed with high purity as evidenced by
NMR analyses of the crude reaction mixture. In the case of the
syn isomer 18, the lower yield was due to the formation of
several byproducts, which could not be clearly identified. In
both cases, the benzyl group was not cleaved due to the basicity
of the reaction medium. This was an advantage for the next
steps. Indeed, this protective group may prevent the possible
nucleophilicity-induced side reactions of a primary alcohol
toward cyclic sulfates, and also simplify the purifications.
(18) Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1999, 64, 2852.
(19) (a) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339.
(b) Kantorowski, E. J.; Brown, S. P.; Kurth, M. J. J. Org. Chem. 1998, 63,
5272.
(20) Gravestock, M. B.; Paton, R. M.; Todd, C. J. Tetrahedron:
Asymmetry 1995, 6, 2723.
(21) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655.
896 J. Org. Chem., Vol. 71, No. 3, 2006

Synthesis of New Nitrogen Analogues of Salacinol and Deoxynojirimycin
SCHEME 5. Synthesis of Alkylated Piperidines 33-36
The sulfate group of 19 and 20 was removed using concen-
trated H2SO4 and water in dioxane.22 The new piperidines D-21
and L-22 were isolated in 93% and 86% yield, respectively, after
purification by cation exchange chromatography (Dowex 50WX8,
H+ form). Compound D-21 with D-manno configuration is a
1,4-D-dideoxymannojirimycin analogue, and L-22 with L-gluco
configuration is a 1,4-L-dideoxynojirimycin analogue.
solid. The acetonide protective group of 27 was hydrolyzed in
the presence of acidic Dowex 50WX8 resin. Compound (+)-
28 was isolated in 97% yield as an amorphous solid.
In the case of the piperidines 21 and 22, dichloromethane
had to be replaced by another solvent. After several attempts
with various more polar solvents (acetone, MeOH, etc.),
anhydrous THF was found to be the best. In the presence of
sodium carbonate and after several hours under reflux with either
cyclic sulfate 24 or 25, compounds 29 and 30 were isolated
from piperidine D-manno 21 in 90% and 87% yield, respectively.
Under the same conditions, the L-gluco stereoisomer 22 was
reacted with D-erythro cyclic sulfate 24 and L-erythro 25.
Zwitterionic compounds 31 and 32 were isolated in 74% and
71% yield, respectively.
2. Preparation of the Salacinol Analogues. Preparation of
the zwitterionic compounds required the synthesis of the cyclic
sulfates D-erythro 24 and L-erythro 25. Both sulfates were
obtained from D-glucose as previously described.14b Morpholine,
first chosen as a model, was reacted with the two cyclic sulfates
24 and 25 in anhydrous dichloromethane in the presence of
sodium carbonate at room temperature (Scheme 4). The
protected zwitterionic compounds 26 and 27 were isolated in
quantitative and 82% yield, respectively. This difference in the
reactivity of these two cyclic sulfates was also observed with
thio heterocycles. We suggested that the axial methyl group of
the acetonide protection creates steric hindrances in the nucleo-
phile approach.14b Nevertheless, the yields were excellent, and
we have shown that such coupling reactions do not always
require polar solvents such as DMF, methanol, acetone, or
hexafluoro-2-propanol (HFIP).12-15 Removal of the benzylidene
protective group of 26 was performed by hydrogenolysis
catalyzed by 10% Pd/C in aqueous acetic acid. The alkylated
morpholine (-)-28 was obtained in 88% yield as an amorphous
Benzyl ether and benzylidene protective groups were cleaved
by hydrogenolysis over 10% Pd/C in aqueous acetic acid. From
29 and 31, 33 and 35 were prepared in 86% and 78% yield,
respectively. The acetonide protective group was cleaved during
the hydrogenolysis by HCl-catalyzed hydrolysis. Zwitterions 34
and 36 were isolated in 73% and 59% nonoptimized yield,
respectively (Scheme 5).
As observed by Pinto et al. with their compounds,13d the
zwitterionic salts 27 to 36 gave dramatically broadened 1H NMR
spectra and nonobservable 13C signals mainly for the heterocycle
moiety at neutral pH. These observations were attributed to the
equilibrium taking place at NMR time scale, between the R and
S configurations of the conjugate acids through the free amines
with their nitrogen inversion.13d The addition of sodium carbon-
(22) Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.;
Zanirato, V. Tetrahedron 1999, 55, 5923.
J. Org. Chem, Vol. 71, No. 3, 2006 897

Gallienne et al.
FIGURE 2. Conformation of 33 and 36 in basic medium.
ate to the NMR samples gave the deprotonated amine form and
the sulfate with sodium as a counterion, with which standard
signals were then observed. As a result, the carbonate neutral-
izing the ammonium, the NMR spectra of compounds 27 to 36
are described as amine and sodium sulfate salts. Compound 26
was an exception and could be studied in its zwitterionic form.
sulfate association carried a negative effect. Somehow, this was
surprising, since N,N-dimethyl-1-DNJ and N-methyl-1-DNJ -N-
oxide, having a permanent positive charge (ammonium), have
been previously described as inhibitors of R- and â-glucosi-
dases.25
In conclusion, we have developed an original asymmetric
synthesis of two polysubstituted piperidines with D-manno and
L-gluco configurations. The one-pot reduction-cyclization key
step on isoxazoline sulfate compounds was highly regio- and
stereoselective for the D-manno series. Coupling the two
piperidines and morpholine with two cyclic 1,3-sulfates allowed
us to isolate new zwitterionic analogues of salacinol, in very
high yields. The evaluation of inhibitory properties revealed that
the zwitterionic compounds showed no activity against the tested
enzymes. The association of an ammonium and a sulfate anion
has an apparently negative effect on inhibition.
As determined by NMR analyses, the major conformation
6′
adopted by the piperidine rings was
C
(1C4 as usually
3′
employed if those compounds are considered as carbohydrates
analogues and using carbohydrate numbering) for D-manno
3′
configuration 33 and 34 and
C
for L-gluco 35 and 36 (4C1
6′
using carbohydrate numbering) (Figure 2). In every case, the
amines were present in one major configuration at the nitrogen
center. Determination of this configuration was performed on
the sodium salt forms of 33 and 36 with a NOESY experiment.
Correlations were found between the two H4 with H2′, H6′b, and
H6′a. The bond N-C4 is in the equatorial position, and the linear
chain is trans relative to the hydroxymethyl (Figure 2). Such a
conformation and configuration were also observed on other
analogous compounds.13c,d By extension and based on NMR
results for 34 and 35, we can propose the same trans config-
uration between the hydroxymethyl and the side chain bonded
to the nitrogen.
3. Glycosidase Inhibition Studies. The zwitterionic pip-
eridines 19 and 20 and the alkylated heterocycles (-)-28, (+)-
28 and 33-36 were evaluated as inhibitors of six commercial
glycosidases: baker’s yeast R-glucosidase, rice R-glucosidase,
almond â-glucosidase, green coffee bean R-galactosidase,
Aspergillus oryzae â-galactosidase, and jack bean R-mannosi-
dase. p-Nitro- or o-nitrophenylglycopyranosides were used as
the corresponding substrates following a previously described
procedure.14b
To our surprise, all of the zwitterionic compounds 19, 20,
(-)-28, (+)-28, and 33-36 showed no activity against the tested
glycosidases. Pinto et al. also found no activity toward glu-
coamylase with zwitterionic DNJ analogues 5-8 (Figure 1).13d
Only (+)-28 (morpholine with salacinol side chain) induced a
slight inhibition (Ki ≈ 2 mM, noncompetitive) of green coffee
bean R-galactosidase. A few years ago, morpholines bearing
an alkyl hydroxylated chain (CH2CH2OH, CH2CHOHCH2OH,
CH(CH2OH)2) were shown to inhibit almond â-glucosidase (Ki
620, 640, and 730 µM, respectively).23 The zwitterionic mor-
pholine derivatives (+)- and (-)-28 possessing both sulfate and
permanent ammonium groups had lost their inhibitory potential.
Regarding the zwitterionic piperidines 19 and 20, it should
be noted that the interaction with the C(2)OH group in the active
site has been proven to be fundamental to good inhibition.24
As a result, the bulkier and negatively charged sulfate group in
this position may have induced the loss of inhibition. Concerning
all of the other zwitterionic compounds 33-36, this ammonium
Experimental Section
(5S)-3-Benzyloxymethyl-5-[(1R)-1,2-O-cyclohexylidene-1,2-di-
hydroxyethyl]-2-isoxazoline 11 and (5R)-3-Benzyloxymethyl-5-
[(1R)-1,2-O-cyclohexylidene-1,2-dihydroxyethyl]-2-isoxazoline 12.
To a solution of benzyloxynitroethane 10 (3.87 g, 21.3 mmol, 1.2
equiv) in anhydrous toluene (160 mL) were added under argon (2S)-
1,2-O-cyclohexylidenebut-3-ene-1,2-diol 9 (2.93 g, 17.4 mmol), 1,4-
phenylenediisocyanate (10.43 g, 64.4 mmol, 3.7 equiv), and NEt3
(320 µL, 2.3 mmol, 0.1 equiv). The mixture was refluxed for 42 h.
Water (35 mL) was then added, and the mixture was refluxed for
6 h. The precipitate thus formed was filtered and washed with
cyclohexane. The organic phase was dried over MgSO4 and
concentrated under vacuum. The crude product was purified by
flash chromatography (cyclohexane/ether, 8:2 then 6:4) to give 11
(2.99 g, 52%) and 12 (1.03 g, 18%) as slightly yellow oils.
11: Rf 0.18 (cyclohexane/ether, 7:3); [R]D +60 (c 1.3, CHCl3);
1
IR (film) ν 3030, 1626, 1099 cm-1; H NMR (CDCl3) δ 7.38-
7.28 (m, 5H, Harom), 4.58-4.49 (m, 1H, H3), 4.53 (s, 2H, H7), 4.29
(s, 2H, H6), 4.10 (dd, 1H, H1a, J1a-2 ) 6.2, J1a-1b ) 8.5 Hz), 4.04-
3.99 (m, 1H, H2), 3.87 (dd, 1H, H1b, J1b-2 ) 4.8, J1b-1a ) 8.5 Hz),
3.15 (dd, 1H, H4a, J4a-3 ) 9.8, J4a-4b ) 17.5 Hz), 3.09 (dd, 1H,
H4b, J4b-3 ) 7.0, J4b-4a ) 17.5 Hz), 1.63-1.52 (m, 10H, 5CH2);
13C NMR (CDCl3) δ 156.5 (C5), 137.2, 128.4, 127.8, 127.7 (Carom),
110.1 (C8), 80.8 (C3), 75.5 (C2), 72.5 (C7), 66.6 (C1), 64.3 (C6),
37.8 (C4), 36.3, 34.5, 25.0, 23.8, 23.6 (5CH2); MS (CI) m/z 332
[(M + H)+]. Anal. Calcd for C19H25NO4: C, 68.86; H, 7.60; N,
4.23. Found: C, 68.80; H, 7.50; N, 4.35.
12: Rf 0.11 (cyclohexane/ether, 7:3); [R]D -85 (c 1.3, CHCl3);
1
IR (film) ν 3030, 1626, 1071 cm-1; H NMR (CDCl3) δ 7.39-
7.30 (m, 5H, Harom), 4.66 (ddd, 1H, H3, J3-2 ) 4.4, J3-4b ) 7.9,
J3-4a ) 10.9 Hz), 4.55 (dAB, 1H, H7a, JAB ) 11.7 Hz), 4.50 (dAB
,
1H, H7b, JAB ) 11.7 Hz), 4.30 (s, 2H, H6), 4.21 (td, 1H, H2, J2-3
) 4.4, J2-1b ) J2-1a ) 6.5 Hz), 4.04 (dd, 1H, H1a, J1a-2 ) 6.5,
J1a-1b ) 8.4 Hz), 3.84 (dd, 1H, H1b, J1b-2 ) 6.5, J1b-1a ) 8.4 Hz),
3.10 (dd, 1H, H4a, J4a-3 ) 10.9, J4a-4b ) 17.4 Hz), 3.00 (dd, 1H,
H4b, J4b-3 ) 7.9, J4b-4a ) 17.4 Hz), 1.67-1.44 (m, 10H, 5CH2);
(23) El Ashry, E. S. H.; Abdel-Rahman, A. A.-H.; El Kilany, Y.; Schmidt,
R. R. Tetrahedron 1999, 55, 2381.
(24) Vasella, A.; Davies, G. J.; Bo¨hm, M. Curr. Opin. Chem. Biol. 2002,
6, 619.
(25) Ekhart, C. W.; Fechter, M. H.; Hadwiger, P.; Mlaker, E.; Stu¨tz, A.
E.; Tauss, A.; Wrodnigg, T. M. In Iminosugars as Glycosidase Inhibitors;
Stu¨tz, A. E., Ed.; Wiley-VCH: New York, 1999; p 253.
898 J. Org. Chem., Vol. 71, No. 3, 2006

Synthesis of New Nitrogen Analogues of Salacinol and Deoxynojirimycin
13C NMR (CDCl3) δ 156.2 (C5), 137.2, 128.3, 127.8 (Carom), 110.3
(C8), 79.7 (C3), 76.1 (C2), 72.3 (C7), 64.8 (C1), 64.2 (C6), 37.0 (C4),
35.7, 34.7, 25.0, 23.8, 23.6 (5CH2); MS (CI) m/z 332 [(M + H)+].
Anal. Calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23. Found:
C, 69.01; H, 7.70; N, 4.25.
(5S)-3-Benzyloxymethyl-5-[(1R)-1,2-dihydroxyethyl]-2-isox-
azoline 13. Following the procedure described by Gravestock et
al.,20 diol 13 (3.24 g, 12.3 mmol) was obtained in 92% yield after
purification on silica gel (cyclohexane/ether, 6:4).
equiv) was added a solution of NaIO4 (3.93 g, 17.5 mmol, 2 equiv)
in water (20 mL). The mixture was stirred at room temperature for
32 h and then extracted with CH2Cl2 (3 × 30 mL). Organic phases
were washed with brine (50 mL), dried over MgSO4, and
concentrated under vacuum. The crude product was purified by
flash chromatography (cyclohexane/AcOEt, 6:4) to give 17 (2.24
g, 82%) as a slightly yellow oil: Rf 0.40 (cyclohexane/AcOEt, 5:5);
1
[R]D +49 (c 1.1, CHCl3); IR (film) ν 1389, 1210, 1093 cm-1; H
NMR (CDCl3) δ 7.40-7.30 (m, 5H, Harom), 4.82 (ddd, 1H, H3,
J3-4b ) 5.5, J3-2 ) 8.1, J3-4a ) 10.5 Hz), 4.77 (dd, 1H, H1a, J )
3.0, J ) 8.1 Hz), 4.64-4.57 (m, 2H, H2 and H1b), 4.57 (dAB, 1H,
H7a, JAB ) 11.9 Hz), 4.53 (dAB, 1H, H7b, JAB ) 11.9 Hz), 4.32
(dAB, 1H, H6a, JAB ) 12.8 Hz), 4.28 (dAB, 1H, H6b, JAB ) 12.8
Hz), 3.29 (dd, 1H, H4a, J4a-3 ) 10.5, J4a-4b ) 17.9 Hz), 3.09 (dd,
1H, H4b, J4b-3 ) 5.5, J4b-4a ) 17.9 Hz); 13C NMR (CDCl3) δ 157.1
(C5), 137.0, 128.6, 128.2, 128.0 (Carom), 79.3 (C2), 77.6 (C3), 73.3
(C7), 70.4 (C1), 64.0 (C6), 38.7 (C4); MS (EI) m/z 314 [(M + H)+].
Anal. Calcd for C13H15NO6S: C, 49.83; H, 4.83; N, 4.47; S, 10.23.
Found: C, 48.72; H, 5.05; N, 4.33; S, 10.07.
The spectral data are consistent with the data from the literature.17
(5R)-3-Benzyloxymethyl-5-[(1R)-1,2-dihydroxyethyl]-2-isox-
azoline 14. Following the procedure described by Gravestock et
al.,20 diol 14 (693 mg, 2.76 mmol) was obtained in 89% yield after
purification on silica gel (cyclohexane/ether, 6:4).
The spectral data are consistent with the data from the literature.17
(5S)-3-Benzyloxymethyl-5-[(4R)-2-oxo-1,3,2-dioxathiolan-4-
yl]-2-isoxazoline 15. To a solution of diol 13 (3.05 g, 12.1 mmol)
and anhydrous pyridine (3 mL, 36.8 mmol, 3 equiv) in anhydrous
CH2Cl2 (110 mL) was added dropwise at 0 °C and under argon a
solution of SOCl2 (1 mL, 13.7 mmol, 1.1 equiv) in anhydrous CH2-
Cl2 (25 mL). Stirring was continued at room temperature for 2 h.
The mixture was washed with water (2 × 40 mL) and then with
brine (60 mL). The organic phase was dried over MgSO4 and
concentrated under vacuum. The crude product was purified by
flash chromatography (cyclohexane/AcOEt, 6:4) to give a slightly
yellow oil (2.94 g, 81%) as a mixture of two diastereoisomers (67:
33): Rf 0.36 (cyclohexane/AcOEt, 6:4); [R]D +44 (c 1.4, CHCl3);
IR (film) ν 1628, 1209, 1093 cm-1. Major isomer: 1H NMR
(5R)-3-Benzyloxymethyl-5-[(4R)-2,2-dioxo-1,3,2-dioxathiolan-
4-yl]-2-isoxazoline 18. To a solution of crude sulfite 16 (0.539 g,
1.8 mmol) in acetonitrile (20 mL) containing RuCl3 (37 mg, 0.18
mmol, 0.1 equiv) was added a solution of NaIO4 (0.582 g, 2.7 mmol,
1.5 equiv) in water (4.5 mL). The mixture was stirred at room
temperature for 50 min and then extracted with CH2Cl2 (3 × 20
mL). Organic phases were washed with brine (20 mL), dried over
MgSO4, and concentrated under vacuum. The crude product was
purified by flash chromatography (cyclohexane/AcOEt, 6:4) to give
18 (0.34 g, 61%, two steps) as a white solid: Rf 0.26 (cyclohexane/
AcOEt, 5:5); [R]D -129 (c 1.1, CHCl3); mp 93 °C; IR (KBr) ν
(CDCl3) δ 7.40-7.30 (m, 5H, Harom), 4.78 (dd, 1H, H1a, J1a-2
)
6.2, J1a-1b ) 9.0 Hz), 4.69 (ddd, 1H, H2, J2-1b ) 3.8, J2-1a ) 6.2,
J2-3 ) 8.4 Hz), 4.55 (s, 2H, H7), 4.51 (ddd, 1H, H3, J3-4b ) 5.8,
J3-2 ) 8.4, J3-4a ) 10.4 Hz), 4.47 (dd, 1H, H1b, J1b-2 ) 3.8, J1b-1a
) 9.0 Hz), 4.30 (s, 2H, H6), 3.32-3.19 (m, 1H, H4a), 3.06 (dd,
1H, H4b, J4b-3 ) 5.8, J4b-4a ) 17.8 Hz); 13C NMR (CDCl3) δ 157.1
(C5), 137.0, 128.6, 127.9 (Carom), 80.2 (C2), 77.1 (C3), 73.0 (C7),
69.1 (C1), 64.2 (C6), 38.6 (C4). Minor isomer: 1H NMR (CDCl3) δ
7.40-7.30 (m, 5H, Harom), 4.88 (ddd, 1H, H2, J ) 6.6, J2-3 ) 7.5,
J ) 9.9 Hz), 4.65-4.57 (m, 2H, H1a and H1b), 4.55 (s, 2H, H7),
4.41 (td, 1H, H3, J ) 7.5 Hz), 4.30 (s, 2H, H6), 3.32-3.19 (m, 2H,
1
1389, 1210, 1093 cm-1; H NMR (CDCl3) δ 7.39-7.30 (m, 5H,
Harom), 4.98 (td, 1H, H2, J2-3 ) 3.3, J2-1b ) J2-1a ) 7.0 Hz), 4.83
(ddd, 1H, H3, J3-2 ) 3.3, J3-4b ) 6.9, J3-4a ) 11.4 Hz), 4.73-
4.65 (m, 2H, H1), 4.57 (dAB, 1H, H7a, JAB ) 11.9 Hz), 4.53 (dAB
1H, H7b, JAB ) 11.9 Hz), 4.31 (s, 2H, H6), 3.29 (dd, 1H, H4a, J4a-3
,
) 11.4, J4a-4b ) 17.8 Hz), 3.12 (dd, 1H, H4b, J4b-3 ) 6.9, J4b-4a
)
17.8 Hz); 13C NMR (CDCl3) δ 156.7 (C5), 137.1, 128.8, 128.3,
128.2 (Carom), 80.6 (C2), 76.6 (C3), 73.1 (C7), 68.8 (C1), 64.0 (C6),
37.3 (C4); MS (IC) m/z 314 [(M + H)+]. Anal. Calcd for C13H15-
NO6S: C, 49.83; H, 4.83; N, 4.47; S,10.23. Found: C, 49.72; H,
4.89; N, 4.45; S, 10.13.
H
4b and H4a); 13C NMR (CDCl3) δ 157.2 (C5), 137.1, 128.6, 127.9
(Carom), 81.6 (C2), 77.5 (C3), 73.0 (C7), 70.1 (C1), 64.1 (C6), 38.7
(C4); MS (CI) m/z 298 [(M + H)+]. Anal. Calcd for C13H15NO5S:
C, 52.52; H, 5.08; N, 4.71; S, 10.78. Found: C, 52.68; H, 5.13; N,
4.74; S, 10.76.
(2S,4S,5R)-2-Benzyloxymethyl-4-hydroxypiperidinium 5-Sul-
fate 19. A solution of sulfate 17 (1.43 g, 4.6 mmol) in anhydrous
MeOH (82 mL) containing 10% Pd/C (786 mg) and anhydrous
Na2CO3 (536 mg, 5.0 mmol, 1.1 equiv) was stirred at room
temperature under an H2 atmosphere for 5 h. The catalyst was
filtered and washed with MeOH. The filtrate was concentrated under
vacuum, and the crude product was purified by cation-exchange
chromatography (Dowex 50WX8, 200-400 mesh, H+ form) eluted
with distilled water. A white solid was isolated (1.12 g, 77%): Rf
0.27 (CH2Cl2/MeOH, 85:15); [R]D -11 (c 1.0, H2O); mp 182 °C;
(5R)-3-Benzyloxymethyl-5-[(4R)-2-oxo-1,3,2-dioxathiolan-4-
yl]-2-isoxazoline 16. Sulfite 16 was prepared as described above
for compound 15 without the flash chromatography purification
step. It was characterized as a slightly yellow oil obtained in 85%
yield (1.81 g, 6 mmol) after flash chromatography (cyclohexane/
AcOEt, 6:4). Mixture of two diastereoisomers (64:36): Rf 0.26
(cyclohexane/AcOEt, 6:4); [R]D -158 (c 1.2, CHCl3); IR (film) ν
1628, 1209, 1093 cm-1. Major isomer: 1H NMR (CDCl3) δ 7.39-
7.30 (m, 5H, Harom), 5.03-4.94 (m, 1H, H2), 4.79-4.73 (m, 2H,
H3 and H1a), 4.58-4.48 (m, 2H, H7), 4.40 (dd, 1H, H1b, J ) 5.7,
J ) 8.6 Hz), 4.30 (s, 2H, H6), 3.29-3.12 (m, 1H, H4a), 3.07 (dd,
H, H4b, J ) 7.1, J ) 17.6 Hz); 13C NMR (CDCl3) δ 156.6 (C5),
128.6, 128.0 (Carom), 79.9 (C2), 77.6 (C3), 72.8 (C7), 68.5 (C1), 64.1
(C6), 37.5 (C4). Minor isomer: 1H NMR (CDCl3) δ 7.39-7.30 (m,
5H, Harom), 5.03-4.94 (m, 1H, H2), 4.65-4.60 (m, 1H, H3), 4.58-
4.48 (m, 4H, 2H7, H1b and H1a), 4.30 (s, 2H, H6), 3.29-3.12 (m,
2H, H4b and H4a); 13C NMR (CDCl3) δ 128.1, 128.0 (Carom), 82.5
(C2), 77.7 (C3), 72.9 (C7), 67.0 (C1), 64.1 (C6), 37.7 (C4); MS (CI)
m/z 298 [(M + H)+]. Anal. Calcd for C13H15NO5S: C, 52.52; H,
5.08; N, 4.71; S, 10.78. Found: C, 52.36; H, 5.29; N, 4.68; S, 10.73.
Note: absent δ for some carbons means that the signals were
not detected.
1
IR (KBr) ν 3410, 2538, 1622, 1270, 1228, 1078, 1048 cm-1; H
NMR (D2O) δ 7.48-7.39 (m, 5H, Harom), 4.77 (br s, 1H, H5), 4.63
(s, 2H, H8), 4.05 (ddd, 1H, H4, J4-3a ) 3.4, J4-5 ) 4.8, J4-3b
)
12.6 Hz), 3.84 (dd, 1H, H6a, J6a-5 ) 3.0, J6a-6b ) 14.1 Hz), 3.74
(dd, 1H, H7a, J7a-2 ) 3.7, J7a-7b ) 11.1 Hz), 3.65 (dd, 1H, H7b,
J7b-2 ) 8.3, J7b-7a ) 11.1 Hz), 3.59-3.51 (m, 1H, H2), 3.27 (dd,
1H, H6b, J6b-5 ) 1.3, J6b-6a ) 14.1 Hz), 1.99 (td, 1H, H3a, J3a-4
)
J3a-2 ) 3.4, J3a-3b ) 12.6 Hz), 1.82 (td, 1H, H3b, J ) 12.6 Hz);
13C NMR (D2O) δ 136.9, 128.8, 128.5 (Carom), 73.1 (C8), 72.8 (C5),
68.8 (C7), 65.6 (C4), 55.0 (C2), 45.7 (C6), 27.4 (C3); HRMS
(LSIMS+) calcd for C13H20NO6S [(M + H)+] 318.1011, found
318.1014.
(2R,4R,5R)-2-Benzyloxymethyl-4-hydroxypiperidinium 5-Sul-
fate 20. Sulfate 18 (714 mg, 2.3 mmol) was reacted as described
above for compound 17. Compound 20 was isolated as a white
solid (248 mg, 34%): Rf 0.38 (CH2Cl2/MeOH, 85:15); [R]D -34
(c 1.0, NH4OH 0.1 N); mp 241 °C; IR (KBr) ν 3315, 2547, 1640,
1263, 1216, 1104, 1040 cm-1; 1H NMR (D2O + Na2CO3) δ 7.46-
(5S)-3-Benzyloxymethyl-5-[(4R)-2,2-dioxo-1,3,2-dioxathiolan-
4-yl]-2-isoxazoline 17. To a solution of sulfite 15 (2.59 g, 8.7 mmol)
in acetonitrile (95 mL) containing RuO2 (170 mg, 1.27 mmol, 0.15
J. Org. Chem, Vol. 71, No. 3, 2006 899

Gallienne et al.
7.36 (m, 5H, Harom), 4.57 (s, 2H, H8), 4.06 (ddd, 1H, H5, J5-6a
)
Cl2/MeOH, 85:15); [R]D +33 (c 1.1, MeOH); mp 190 °C; IR (KBr)
ν 2785, 1622, 1279, 1207, 1066, 1010 cm-1; 1H NMR (CD3OD +
D2O + Na2CO3) δ 4.11 (dd, 1H, H1a, J1a-2 ) 4.3, J1a-1b ) 11.4
5.2, J5-4 ) 9.1, J5-6b ) 10.8 Hz), 3.68 (ddd, 1H, H4, J4-3a ) 5.1,
J4-5 ) 9.1, J4-3b ) 12.1 Hz), 3.54 (dd, 1H, H7a, J7a-2 ) 4.4, J7a-7b
) 10.3 Hz), 3.43 (dd, 1H, H7b, J7b-2 ) 7.4, J7b-7a ) 10.3 Hz),
3.41 (dd, 1H, H6a, J6a-5 ) 5.2, J6a-6b ) 12.2 Hz), 2.92-2.85 (m,
1H, H2), 2.53 (dd, 1H, H6b, J6b-5 ) 10.8, J6b-6a ) 12.2 Hz), 2.01
(ddd, 1H, H3a, J3a-2 ) 2.6, J3a-4 ) 5.1, J3a-3b ) 12.1 Hz), 1.23
(td, 1H, H3b, J ) 12.1 Hz); 13C NMR (D2O + Na2CO3) δ 137.3,
128.7, 128.4, 128.3 (Carom), 80.1 (C5), 73.0 (C8), 72.7 (C7), 70.3
(C4), 53.2 (C2), 46.9 (C6), 34.7 (C3); HRMS (LSIMS+) calcd for
C13H20NO6S [(M + H)+] 318.1011, found 318.1012.
Hz), 4.09-4.01 (m, 2H, H3 and H2), 3.89 (dd, 1H, H1b, J1b-2
)
6.4, J1b-1a ) 11.4 Hz), 3.76-3.68 (m, 4H, 4H2′), 2.90 (br d, 1H,
H4a, J4a-4b ) 13.9 Hz), 2.63-2.55 (m, 4H, 4H3′), 2.48 (dd, 1H,
H4b, J4b-3 ) 8.1, J4b-4a ) 13.9 Hz), 1.51 (s, 3H, CH3), 1.36 (s, 3H,
CH3); 13C NMR (CD3OD + D2O + Na2CO3) δ 100.9 (C5), 72.6
(C2), 70.8 (C3), 67.3 (2C2′), 63.6 (C1), 60.6 (C4), 54.7 (2C3′), 27.8
(CH3), 20.4 (CH3); HRMS (ESI+) calcd for C11H22NO7S [(M +
H)+] 312.1117, found 312.1132.
(2S,4S,5R)-2-Benzyloxymethyl-4,5-dihydroxypiperidine 21. A
solution of 19 (999 mg, 3.1 mmol) in 1,4-dioxane (50 mL) was
heated at 50 °C with water (500 µL) and concentrated H2SO4 (600
µL) for 36 h. The mixture was neutralized by NH4OH (1 N) and
concentrated under vacuum. The crude product was purified by
cation-exchange chromatography (Dowex 50WX8, 200-400 mesh,
H+ form) eluted with distilled water and then 0.5 N NH4OH to
give 21 (697 mg, 93%) as a slightly yellow solid: Rf 0.21 (CH2-
Cl2/MeOH/H2O, 55:40:5); [R]D -22 (c 1.0, H2O); mp 88 °C; IR
(2R,3S)-1,3-Dihydroxy-4-(morpholin-4-ium-4-yl)butane-2-
sulfate (-)-28. The zwitterion 26 (256 mg, 0.712 mmol) was
dissolved in a mixture of acetic acid and water 4:1 (20 mL). Pd/C
10% (117 mg) was added, and the mixture was stirred at room
temperature under an H2 atmosphere for 24 h. Catalyst was removed
by filtration and washed with methanol. The mixture was concen-
trated under vacuum and the crude product was then purified by
cation-exchange chromatography (Dowex 50WX8, 200-400 mesh,
H+ form) eluted with distilled water to give (-)-28 (169 mg, 88%)
as an amorphous solid: Rf 0.55 (CH2Cl2/MeOH/H2O, 70:30:1); [R]D
-14 (c 1.95, H2O); IR (KBr) ν 3430, 2750, 1636, 1255, 1234, 1060,
1016 cm-1; 1H NMR (CD3OD + D2O + Na2CO3) δ 4.25 (td, 1H,
1
(KBr) ν 3384, 3237, 1141, 1049 cm-1; H NMR (D2O) δ 7.46-
7.37 (m, 5H, Harom), 4.58 (s, 2H, H8), 3.83 (br s, 1H, H5), 3.75
(ddd, 1H, H4, J4-3a ) 3.1, J3-5 ) 4.8, J4-3b ) 12.0 Hz), 3.56-
3.48 (m, 2H, H7), 3.02 (dd, 1H, H6a, J6a-5 ) 2.9, J6a-6b ) 14.1
Hz), 2.83-2.76 (m, 1H, H2), 2.68 (dd, 1H, H6b, J6b-5 ) 1.5, J6b-6a
H2, J2-1b ) J2-1a ) J2-3 ) 4.6 Hz), 4.12 (ddd, 1H, H3, J3-4a
)
3.2, J3-2 ) 4.6, J3-4b ) 8.4 Hz), 3.89 (dd, 1H, H1a, J1a-2 ) 4.6,
J1a-1b ) 12.4 Hz), 3.81 (dd, 1H, H1b, J1b-2 ) 4.6, J1b-1a ) 12.4
Hz), 3.78-3.71 (m, 4H, 4H2′), 2.74 (dd, 1H, H4a, J4a-3 ) 3.2, J4a-4b
) 14.1 Hz), 1.69 (ddd, 1H, H3a, J3a-4 ) 3.1, J3a-2 ) 4.0, J3a-3b
)
12.0 Hz), 1.45 (td, 1H, H3b, J ) 12.0 Hz); 13C NMR (D2O) δ 137.4,
128.7, 128.4, 128.3 (Carom), 73.0 (C8), 72.9 (C7), 69.2 (C4), 67.1
(C5), 53.5 (C2), 48.6 (C6), 30.3 (C3); HRMS (LSIMS+) calcd for
C13H20NO3 [(M + H)+] 238.1443, found 238.1442.
) 13.4 Hz), 2.67-2.58 (m, 4H, 4H3′), 2.50 (dd, 1H, H4b, J4b-3
)
8.4, J4b-4a ) 13.4 Hz); 13C NMR (CD3OD + D2O + Na2CO3) δ
82.2 (C2), 68.4 (C3), 67.3 (2C2′), 61.6 (C4 or C1), 61.1 (C4 or C1),
54.4 (2C3′); HRMS (ESI+) calcd for C8H17NNaO7S [(M + Na)+]
294.0623, found 294.0615.
(2R,4R,5R)-2-Benzyloxymethyl-4,5-dihydroxypiperidine 22.
Compound 20 (147 mg, 0.46 mmol) was reacted as described above
for 19. Compound 22 was isolated as a slightly yellow solid (94.4
mg, 86%): Rf 0.43 (CH2Cl2/MeOH/H2O, 55:40:5); [R]D -29 (c
1.0, H2O); mp 102 °C; IR (KBr) ν 3420, 3320, 1175, 1155, 1049
cm-1; 1H NMR (D2O) δ 7.46-7.37 (m, 5H, Harom), 4.58 (dAB, 1H,
H8a, JAB ) 11.9 Hz), 4.55 (dAB, 1H, H8b, JAB ) 11.9 Hz), 3.54 (dd,
1H, H7a, J ) 4.3, J ) 10.4 Hz), 3.51-3.46 (m, 1H, H4), 3.44-
(2S,3R)-1,3-Dihydroxy-4-(morpholin-4-ium-4-yl)butane-2-
sulfate (+)-28. The zwitterion 27 (187 mg, 0.601 mmol) was
dissolved in distilled water (18 mL). Then, 357 mg of cation-
exchange resin (Dowex 50WX8, 16-40 mesh, H+ form) were
added and the mixture was stirred at room temperature for 5 days.
The resin was removed by filtration and washed with methanol.
The filtrate was concentrated under vacuum to give (+)-28 (158
mg, 97%) as an amorphous solid: [R]D +15 (c 2.8, H2O).
The spectral data are consistent with the data from its enantiomer
(-)-28.
General Procedure for the Piperidine Coupling Reaction. The
piperidine 21 or 22 (1.0 mmol) and the cyclic sulfate 24 or 25 (1.2
mmol) were dissolved in anhydrous THF (3 mL) in the presence
of anhydrous Na2CO3 (0.5 mmol) under argon. The mixture was
refluxed for several hours.
(2R,3S)-1,3-O-Benzylidene-1,3-dihydroxy-4-[(2S,4S,5R)-2-ben-
zyloxymethyl-4,5-dihydroxypiperidinium-1-yl]butane-2-sul-
fate 29. Compound 29 was isolated as a white solid after 20 h of
refluxing and by filtration without further purification (283 mg,
90%): Rf 0.30 (CH2Cl2/MeOH, 85:15); [R]D -53 (c 1.0, MeOH);
mp 129 °C; IR (KBr) ν 3432, 2872, 1636, 1263, 1234, 1088, 1013
cm-1; 1H NMR (CD3OD + D2O + Na2CO3) δ 7.46-7.43 (m, 2H,
3.37 (m, 2H, H7b and H5), 3.11 (dd, 1H, H6a, J6a-5 ) 5.1, J6a-6b
11.9 Hz), 2.91-2.84 (m, 1H, H2), 2.41 (dd, 1H, H6b, J6b-5 ) 10.6,
)
J6b-6a ) 11.9 Hz), 1.94 (ddd, 1H, H3a, J ) 2.5, J ) 4.8, J3a-3b
)
12.1 Hz), 1.14 (td, 1H, H3b, J ) 12.1 Hz); 13C NMR (D2O) δ 137.3,
128.7, 128.4, 128.3 (Carom) 73.0 (C8), 72.9 (C7), 72.7 (C4), 72.2
(C5), 53.5 (C2), 49.1 (C6), 34.8 (C3); HRMS (LSIMS+) calcd for
C13H20NO3 [(M + H)+] 238.1443, found 238.1441.
General Procedure for Morpholine Coupling Reaction. The
cyclic sulfate 24 or 25 (1.2 mmol) was dissolved in anhydrous CH2-
Cl2 (5 mL) in the presence of anhydrous Na2CO3 (0.5 mmol) under
argon. Morpholine 23 (1.0 mmol) was added, and the mixture was
stirred at room temperature for several days and then concentrated
under vacuum. The crude product was purified by flash chroma-
tography (CH2Cl2/MeOH, 85:15) to give 26 or 27.
(2R,3S)-1,3-O-Benzylidene-1,3-dihydroxy-4-(morpholin-4-
ium-4-yl)butane-2-sulfate 26. Compound 26 was obtained as a
white solid after 2 days of stirring (34.7 mg, quantitative): Rf 0.28
(CH2Cl2/MeOH, 85:15); [R]D -37 (c 1.0, MeOH); mp 143 °C; IR
(KBr) ν 2765, 1619, 1243, 1012 cm-1; 1H NMR (CD3OD) δ 7.49-
7.46 (m, 2H, Harom), 7.37-7.33 (m, 3H, Harom), 5.63 (s, 1H, H5),
4.55 (dd, 1H, H1a, J1a-2 ) 5.3, J1a-1b ) 10.9 Hz), 4.25 (td, 1H, H2,
J2-1a ) 5.3, J ) 9.8, J ) 9.8 Hz), 4.16 (td, 1H, H3, J ) 1.2, J )
8.2, J ) 8.2 Hz), 3.84-3.74 (m, 5H, 4H2′ and H1b), 3.38 (br d, 1H,
H4a, J ) 13.8 Hz), 3.06-2.96 (m, 5H, 4H3′ and H4b); 13C NMR
(CD3OD) δ 138.9, 130.1, 129.2, 127.5 (Carom), 102.3 (C5), 77.7
(C3), 70.3 (C1), 69.2 (C2), 66.3 (2C2′), 59.8 (C4), 54.8 (2C3′); HRMS
(ESI+) calcd for C15H21NO7NaS [(M + Na)+] 382.0936, found
382.0917.
H
arom), 7.38-7.27 (m, 8H, Harom), 5.57 (s, 1H, H5), 4.56 (dAB, 1H,
H
8′a, JAB ) 11.6 Hz), 4.56-4.53 (m, 1H, H1a), 4.47 (dAB, 1H, H8′b
,
JAB ) 11.6 Hz), 4.14 (td, 1H, H2, J ) 5.2, J ) 10.4, J2-1b ) 10.4
Hz), 4.01-3.96 (m, 1H, H3), 3.80 (dd, 1H, H1b, J1b-1a ) J1b-2 )10.4
Hz), 3.71 (br s, 1H, H5′), 3.65 (dd, 1H, H7′a, J7′a-2′ ) 4.2, J7′a-7′b
)
10.2 Hz), 3.62-3.57 (m, 1H, H4′), 3.57 (dd, 1H, H7′b, J7′b-2′ ) 3.7,
J7′b-7′a ) 10.2 Hz), 3.23 (br d, 1H, H4a, J4a-4b ) 15.1 Hz), 3.09
(dd, 1H, H6′a, J ) 3.8, J ) 13.0 Hz), 2.98 (dd, 1H, H4b, J4b-3
)
8.2, J4b-4a ) 15.1 Hz), 2.64-2.61 (m, 2H, H2′ and H6′b), 1.80-
1.71 (m, 2H, H3′b and H3′a); 13C NMR (CD3OD + D2O + Na2-
CO3) δ 139.0, 138.8, 130.1, 129.5, 129.3, 128.9, 127.3 (Carom), 102.1
(C5), 77.9 (C3), 74.2 (C8′), 72.8 (C7′), 70.7 (C4′), 70.3 (C1), 69.7
(C2), 69.3 (C5′), 58.8 (C2′), 58.4 (C6′), 54.8 (C4), 33.1 (C3′); HRMS
(ESI+) calcd for C24H32NO9S [(M + H)+] 510.1798, found
510.1815.
(2S,3R)-1,3-Dihydroxy-1,3-O-isopropylidene-4-(morpholin-4-
ium-4-yl)butane-2-sulfate 27. Compound 27 was obtained as a
white solid after 4 days of stirring (295 mg, 82%): Rf 0.22 (CH2-
900 J. Org. Chem., Vol. 71, No. 3, 2006

Synthesis of New Nitrogen Analogues of Salacinol and Deoxynojirimycin
(2S,3R)-1,3-Dihydroxy-1,3-O-isopropylidene-4-[(2S,4S,5R)-2-
benzyloxymethyl-4,5-dihydroxypiperidinium-1-yl]butane-2-sul-
fate 30. Compound 30 was isolated as a white solid after 14 h of
refluxing and purification by flash chromatography (CH2Cl2/MeOH,
85:15) (255 mg, 87%): Rf 0.21 (CH2Cl2/MeOH, 85:15); [R]D -1.7
(c 1.0, MeOH); mp 132 °C; IR (KBr) ν 3430, 2882, 1658, 1265,
an H2 atmosphere for several hours. Catalyst was removed by
filtration and washed with water. The mixture was concentrated
under vacuum, and the crude product was purified by cation-
exchange chromatography (Dowex 50WX8, 200-400 mesh, H+
form) eluted with distilled water to give 33 or 35.
(2R,3S)-1,3-Dihydroxy-4-[(2S,4S,5R)-4,5-dihydroxy-2-hy-
droxymethylpiperidinium-1-yl]butane-2-sulfate 33. Compound
33 was isolated as a white solid after 24 h of stirring (78.6 mg,
86%): Rf 0.28 (CH2Cl2/MeOH/H2O, 55:40:5); [R]D -42 (c 1.0,
1
1226, 1078, 1010 cm-1; H NMR (CD3OD + D2O + Na2CO3) δ
7.42-7.29 (m, 5H, Harom), 4.54 (s, 2H, 2H8′), 4.07 (dd, 1H, H1a,
J1a-2 ) 4.3, J1a-1b ) 11.6 Hz), 4.00-3.95 (m, 2H, H3 and H2),
3.86 (dd, 1H, H1b, J1b-2 ) 6.7, J1b-1a ) 11.6 Hz), 3.76-3.71 (m,
2H, H7′a and H5′), 3.62-3.55 (m, 2H, H4′ and H7′b), 3.17 (br d, 1H,
H4a, J ) 14.6 Hz), 3.04 (dd, 1H, H6′a, J ) 4.0, J ) 12.6 Hz), 2.62-
2.52 (m, 3H, H6′b, H2′ and H4b), 1.84-1.70 (m, 2H, H3′b and H3′a),
1.44 (s, 3H, CH3), 1.30 (s, 3H, CH3); 13C NMR (CD3OD + D2O
+ Na2CO3) δ 138.9, 129.5, 129.0 (Carom), 100.7 (C5), 74.3 (C8′),
72.9 (C2), 72.2 (C7′), 71.0 (C4′ or C3), 70.7 (C4′ or C3), 69.3 (C5′),
63.7 (C1), 59.7 (C2′), 57.7 (C6′), 54.9 (C4), 33.1 (C3′), 27.7 (CH3),
20.5 (CH3); HRMS (ESI+) calcd for C20H32NO7S [(M + H)+]
462.1798, found 462.1802.
H2O); mp 166 °C; IR (KBr) ν 3405, 1636, 1271, 1234, 1064, 1004
1
cm-1; H NMR (D2O + Na2CO3) δ 4.26 (ddd, 1H, H2, J2-1a
)
3.6, J2-1b ) 4.5, J2-3 ) 5.8 Hz), 4.14 (ddd, 1H, H3, J3-4b ) 2.5,
J3-2 ) 5.8, J3-4a ) 9.4 Hz), 3.91 (dd, 1H, H1a, J1a-2 ) 3.6, J1a-1b
) 12.6 Hz), 3.91-3.87 (m, 1H, H5′), 3.84 (dd, 1H, H1b, J1b-2
4.5, J1b-1a ) 12.6 Hz), 3.80 (ddd, 1H, H4′, J4′-3′a ) 3.5, J4′-5′
)
)
,
5.1, J4′-3′b ) 11.3 Hz), 3.73-3.66 (m, 2H, H7′), 3.10 (dd, 1H, H6′a
J6′a-5′ ) 4.0, J6′a-6′b ) 13.0 Hz), 2.89 (dd, 1H, H4a, J4a-3 ) 9.4,
J4a-4b ) 14.2 Hz), 2.68 (dd, 1H, H4b, J4b-3 ) 2.5, J4b-4a ) 14.2
Hz), 2.55 (dd, 1H, H6′b, J6′b-5′ ) 1.6, J6′b-6′a ) 13.0 Hz), 2.56-
2.51 (m, 1H, H2′), 1.82 (td, 1H, H3′a, J3′a-2′ ) 3.5, J3′a-4′ ) 3.5,
J3′a-3′b ) 12.6 Hz), 1.73 (td, 1H, H3′b, J3′b-2′ ) 11.3, J3′b-4′ ) 11.3,
J3′b-3′a ) 12.6 Hz); 13C NMR (D2O + Na2CO3) δ 81.4 (C2), 69.0
(C4′), 67.5 (C5′), 66.6 (C3), 62.7 (C7′), 59.8 (C1), 59.4 (C2′), 55.6
(C6′), 54.6 (C4), 30.6 (C3′); HRMS (ESI+) calcd for C10H21NNaO9S
[(M + Na)+] 354.0835, found 354.0835.
(2R,3S)-1,3-O-Benzylidene-1,3-dihydroxy-4-[(2R,4R,5R)-2-
benzyloxymethyl-4,5-dihydroxypiperidinium-1-yl]butane-2-sul-
fate 31. Compound 31 was isolated as a white solid after 24 h of
refluxing by filtration without further purification (120 mg, 74%):
Rf 0.23 (CH2Cl2/MeOH, 85:15); [R]D -33 (c 0.48, MeOH); mp
208 °C; IR (KBr) ν 3456, 2872, 1636, 1255, 1213, 1090, 1068,
1
1005 cm-1; H NMR (CD3OD + D2O + Na2CO3) δ 7.43-7.40
(2R,3S)-1,3-Dihydroxy-4-[(2R,4R,5R)-4,5-dihydroxy-2-hy-
droxymethylpiperidinium-1-yl]butane-2-sulfate 35. Compound
35 was isolated as an amorphous solid after 23 h of stirring (35.3
mg, 78%): Rf 0.18 (CH2Cl2/MeOH/H2O, 55:40:5); [R]D -16 (c
(m, 2H, Harom), 7.35-7.25 (m, 8H, Harom), 5.57 (s, 1H, H5), 4.54
(dd, 1H, H1a, J1a-2 ) 4.4, J1a-1b ) 10.6 Hz), 4.41 (dAB, 1H, H8′a
,
JAB ) 11.9 Hz), 4.34 (dAB, 1H, H8′b, JAB ) 11.9 Hz), 4.13-4.06
(m, 2H, H3 and H2), 3.80 (dd, 1H, H1b, J1b-1a ) J1b-2 ) 10.6 Hz),
3.64 (dd, 1H, H7′a, J7′a-2′ ) 3.2, J7′a-7′b ) 9.7 Hz), 3.56 (dd, 1H,
1
1.0, H2O); IR (KBr) ν 3403, 1636, 1251, 1163, 1074 cm-1; H
NMR (D2O + Na2CO3) δ 4.25 (ddd, 1H, H2, J2-1a ) 3.4, J2-1b
)
H7′b, J7′b-2′ ) 5.9, J7′b-7′a ) 9.7 Hz), 3.52-3.48 (m, 1H, H5′), 3.39-
4.4, J2-3 ) 5.8 Hz), 4.15 (ddd, 1H, H3, J3-4a ) 2.9, J3-2 ) 5.8,
J3-4b ) 8.4 Hz), 3.90 (dd, 1H, H1a, J1a-2 ) 3.4, J1a-1b ) 12.6 Hz),
3.83 (dd, 1H, H1b, J1b-2 ) 4.4, J1b-1a ) 12.6 Hz), 3.74 (dd, 1H,
3.32 (m, 1H, H4′), 3.28 (br d, 1H, H4a, J4a-4b ) 15.5 Hz), 3.06 (dd,
1H, H6′a, J6′a-5′ ) 4.8, J6′a-6′b ) 11.2 Hz), 2.88 (dd, 1H, H4b, J4b-3
) 7.2, J4b-4a ) 15.5 Hz), 2.75-2.70 (m, 1H, H2′), 2.40 (dd, 1H,
H7′a, J7′a-2′ ) 4.3, J7′a-7′b ) 11.9 Hz), 3.64 (dd, 1H, H7′b, J7′b-2′ )
H
6′b, J6′b-6′a ) J6′b-5′ ) 11.2 Hz), 2.01 (ddd, 1H, H3′a, J ) 2.4, J )
5.3, J7′b-7′a ) 11.9 Hz), 3.57-3.47 (m, 2H, H4′ and H5′), 3.14 (dd,
1H, H6′a, J6′a-5′ ) 4.2, J6′a-6′b ) 11.7 Hz), 3.08 (dd, 1H, H4a, J4a-3
) 2.9, J4a-4b ) 14.6 Hz), 2.69-2.63 (m, 1H, H2′), 2.59 (dd, 1H,
4.8, J3′a-3′b ) 12.5 Hz), 1.45 (td, 1H, H3′b, J3′b-3′a ) 12.5 Hz); 13
C
NMR (CD3OD + D2O + Na2CO3) δ 139.0, 138.4, 129.9, 129.2,
129.1, 128.9, 128.6, 127.0 (Carom), 101.8 (C5), 77.4 (C3), 74.1 (C4′),
74.0 (C8′), 72.4 (C5′), 71.7 (C7′), 70.1 (C1), 69.2 (C2), 59.2 (C2′),
58.5 (C6′), 53.8 (C4), 36.8 (C3′); HRMS (ESI+) calcd for C24H32-
NO9S [(M + H)+] 510.1798, found 510.1791.
H4b, J4b-3 ) 8.4, J4b-4a ) 14.6 Hz), 2.32 (dd, 1H, H6′b, J6′b-5′
)
10.2, J6′b-6′a ) 11.7 Hz), 2.01 (ddd, 1H, H3′a, J ) 2.6, J ) 4.5,
J3′a-3′b ) 12.5 Hz), 1.38 (td, 1H, H3′b, J3′b-3′a ) 12.5 Hz); 13C NMR
(D2O + Na2CO3) δ 81.4 (C2), 72.6 (C5′ or C4′), 70.7 (C5′ or C4′),
68.0 (C3), 62.3 (C7′), 60.6 (C2′), 59.7 (C1), 57.0 (C6′), 53.7 (C4),
34.3 (C3′); HRMS (ESI+) calcd for C10H21NNaO9S [(M + Na)+]
354.0835, found 354.0846.
(2S,3R)-1,3-Dihydroxy-1,3-O-isopropylidene-4-[(2R,4R,5R)-2-
benzyloxymethyl-4,5-dihydroxypiperidinium-1-yl]butane-2-sul-
fate 32. Compound 32 was isolated as a white solid after 24 h of
refluxing and purification by flash chromatography (CH2Cl2/MeOH,
85:15) (115 mg, 71%): Rf 0.16 (CH2Cl2/MeOH, 85:15); [R]D +11
(c 1.1, MeOH); mp 112 °C; IR (KBr) ν 3429, 2863, 1636, 1269,
(2S,3R)-1,3-Dihydroxy-4-[(2S,4S,5R)-4,5-dihydroxy-2-hy-
droxymethylpiperidinium-1-yl]butane-2-sulfate 34. The zwit-
terion 30 (129 mg, 0.280 mmol) was dissolved in 0.01 N HCl (21
mL). Pd/C 10% (98 mg) was added, and the mixture was stirred at
room temperature under an H2 atmosphere for 7 days. Catalyst was
removed by filtration and washed with water. The mixture was
neutralized by 1 N NH4OH and concentrated under vacuum, and
the crude product was purified by cation exchange chromatography
(Dowex 50WX8, 200-400 mesh, H+ form) eluted with distilled
water to give 34 (67.4 mg, 73%) as an amorphous solid: Rf 0.23
(CH2Cl2/MeOH/H2O, 55:40:5); [R]D -4.9 (c 1.1, H2O); IR (KBr)
1
1226, 1082, 1011 cm-1; H NMR (CD3OD + D2O + Na2CO3) δ
7.42-7.31 (m, 5H, Harom), 4.59 (dAB, 1H, H8′a, JAB ) 11.9 Hz),
4.51 (dAB, 1H, H8′b, JAB ) 11.9 Hz), 4.10 (dd, 1H, H1a, J1a-2
)
4.0, J1a-1b ) 11.6 Hz), 4.04-3.98 (m, 2H, H3 and H2), 3.88 (dd,
1H, H1b, J1b-2 ) 6.5, J1b-1a ) 11.6 Hz), 3.62 (dd, 1H, H7′a, J7′a-2′
) 4.1, J7′a-7′b ) 10.3 Hz), 3.52 (dd, 1H, H7′b, J7′b-2′ ) 5.2, J7′b-7′a
) 10.3 Hz), 3.45-3.34 (m, 2H, H4′ and H5′), 3.06 (br d, 1H, H6′a
,
J6′a-6′b ) 11.6 Hz), 3.04 (br d, 1H, H4a, J4a-4b ) 14.7 Hz), 2.76
(dd, 1H, H4b, J4b-3 ) 8.0, J4b-4a ) 14.7 Hz), 2.62-2.59 (m, 1H,
H2′), 2.31 (dd, 1H, H6′b, J6′b-5′ ) 10.6, J6′b-6′a ) 11.6 Hz), 1.98
(ddd, 1H, H3′a, J ) 2.5, J ) 4.4, J3′a-3′b ) 12.5 Hz), 1.48 (s, 3H,
1
ν 3402, 1636, 1251, 1165, 1061, 1013 cm-1; H NMR (D2O +
Na2CO3) δ 4.29 (td, 1H, H2, J2-1a ) 3.6, J2-1b ) J2-3 ) 5.0 Hz),
4.13 (ddd, 1H, H3, J3-4a ) 3.9, J3-2 ) 5.0, J3-4b ) 8.0 Hz), 3.91
(dd, 1H, H1a, J1a-2 ) 3.6, J1a-1b ) 12.7 Hz), 3.89-3.87 (m, 1H,
H5′), 3.82 (dd, 1H, H1b, J1b-2 ) 5.0, J1b-1a ) 12.7 Hz), 3.82-3.78
(m, 1H, H4′), 3.77 (dd, 1H, H7′a, J7′a-2′ ) 4.2, J7′a-7′b ) 11.6 Hz),
3.68 (dd, 1H, H7′b, J7′b-2′ ) 4.9, J7′b-7′a ) 11.6 Hz), 3.10 (dd, 1H,
CH3), 1.45 (td, 1H, H3′b, J3′b-3′a ) 12.5 Hz), 1.36 (s, 3H, CH3); 13
C
NMR (CD3OD + D2O + Na2CO3) δ 139.4, 129.5, 128.9 (Carom),
(C5), 74.4 (C2), 74.2 (C8′), 72.7 (C4′ or C3), 72.5 (C4′ or C3), 72.1
(C7′), 69.3 (C5′), 63.7 (C1), 59.3 (C2′), 59.2 (C6′), 54.6 (C4), 36.6
(C3′), 27.8 (CH3), 20.4 (CH3); HRMS (ESI+) calcd for C20H31-
NO7NaS [(M + Na)+] 484.1617, Found 484.1595.
H4a, J4a-3 ) 3.9, J4a-4b ) 14.6 Hz), 3.08 (dd, 1H, H6′a, J6′a-5′
4.5, J6′a-6′b ) 13.0 Hz), 2.58 (dd, 1H, H6′b, J6′b-5′ ) 1.8, J6′b-6′a
)
)
General Procedure for Benzylidene Protective Group Re-
moval. The zwitterion 29 or 31 (1.0 mmol) was dissolved in a
mixture of acetic acid and water 4:1 (18 mL). Pd/C 10% (350 mg)
was added, and the mixture was stirred at room temperature under
13.0 Hz), 2.59-2.56 (m, 1H, H2′), 2.54 (dd, 1H, H4b, J4b-3 ) 8.0,
J4b-4a ) 14.6 Hz), 1.81 (td, 1H, H3′a, J ) 3.5, J ) 3.5, J3′a-3′b
)
12.9 Hz), 1.69 (td, 1H, H3′b, J ) 10.8, J ) 10.8, J3′b-3′a ) 12.9
Hz); 13C NMR (D2O + Na2CO3) δ 81.4 (C2), 68.9 (C4′), 68.3 (C5′),
J. Org. Chem, Vol. 71, No. 3, 2006 901

Gallienne et al.
67.6 (C3), 62.9 (C7′), 60.3 (C2′), 59.7 (C1), 56.1 (C6′), 54.8 (C4),
30.4 (C3′); HRMS (ESI+) calcd for C10H20NNa2O9S [(M - H +
2Na)+] 376.0654, found 376.0648.
(m, 1H, H3), 3.89 (dd, 1H, H1a, J1a-2 ) 3.3, J1a-1b ) 12.6 Hz),
3.83 (dd, 1H, H1b, J1b-2 ) 4.4, J1b-1a ) 12.6 Hz), 3.68 (dd, 1H,
H7′a, J7′a-2′ ) 3.8, J7′a-7′b ) 12.0 Hz), 3.62 (dd, 1H, H7′b, J7′b-2′ )
(2S,3R)-1,3-Dihydroxy-4-[(2R,4R,5R)-4,5-dihydroxy-2-hy-
droxymethylpiperidinium-1-yl]butane-2-sulfate 36. The zwit-
terion 32 (28.0 mg, 0.061 mmol) was dissolved in 0.01 N HCl
(2.6 mL). Pd/C 10% (21 mg) was added, and the mixture was stirred
at room temperature under an H2 atmosphere for 20 h. Catalyst
was removed by filtration and washed with water. The mixture was
neutralized by 1 N NH4OH before concentration under vacuum.
As the reaction was not completed, the crude product was dissolved
in distilled water (2 mL) containing 75 mg of a cation-exchange
resin (Dowex 50WX8, 16-40 mesh, H+ form). The mixture was
stirred at room temperature for 3 days. The resin was removed by
filtration and washed with water. The filtrate was concentrated under
vacuum, and the crude product was purified by flash chromatog-
raphy (CH2Cl2/MeOH/H2O, 55:44:1) to give 36 (12.0 mg, 59%)
as an amorphous solid: Rf 0.30 (CH2Cl2/MeOH/H2O, 55:40:5); [R]D
5.0, J7′b-7′a ) 12.0 Hz), 3.54-3.45 (m, 2H, H4′ and H5′), 3.13 (dd,
1H, H6′a, J6′a-5′ ) 3.9, J6′a-6′b ) 11.5 Hz), 2.85-2.77 (m, 2H, H4b
and H4a), 2.61-2.55 (m, 1H, H2′), 2.38 (dd, 1H, H6′b, J6′b-5′ ) 10.3,
J6′b-6′a ) 11.5 Hz), 2.04 (ddd, 1H, H3′a, J ) 2.8, J ) 4.1, J3′a-3′b
)
13.0 Hz), 1.44 (td, 1H, H3′b, J ) 13.0 Hz); 13C NMR (D2O + Na2-
CO3) δ 81.4 (C2), 72.6 (C5′ or C4′), 71.1 (C5′ or C4′), 66.6 (C3),
62.1 (C7′), 59.7 (C1), 59.6 (C2′), 57.3 (C6′), 54.3 (C4), 34.5 (C3′);
HRMS (ESI+) calcd for C10H21NNaO9S [(M + Na)+] 354.0835,
found 354.0839.
Supporting Information Available: General experimental
1
information and H and 13C NMR spectra of compounds 19-22,
28, and 33-36. This material is available free of charge via the
Internet at http://pubs.acs.org.
+20 (c 0.9, H2O); IR (KBr) ν 3405, 1636, 1250, 1069, 1008 cm-1
1H NMR (D2O + Na2CO3) δ 4.24-4.20 (m, 1H, H2), 4.20-4.15
.
JO0517388
902 J. Org. Chem., Vol. 71, No. 3, 2006