Improved synthesis of 1,4-dideoxy-1,4-imino-D-galactitol, an inhibitor of E. coli K12 UDP-Gal mutase and mycobacterial galactan biosynthesis

Article abstract of DOI:10.1016/j.tet.2003.09.058

The E. Coli K12 UDP-Gal mutase inhibitor 1 was prepared from D-glucose in 5 steps (42% overall yield). The 4-azido galactose derivative 11, leading to 1, was formed by treatment of galactose dithioacetal 7 with mercuric oxide and mercuric chloride in acet

Full text of DOI:10.1016/j.tet.2003.09.058

Tetrahedron 59 (2003) 9413–9417
Improved synthesis of 1,4-dideoxy-1,4-imino-D-galactitol,
an inhibitor of E. coli K12 UDP-Gal mutase and
mycobacterial galactan biosynthesis
ˇc
Duy-Phong Pham-Huu,a Yonas Gizaw,a,b James N. BeMillera and Ladislav Petrus
,
*
aThe Whistler Center for Carbohydrate Research, Purdue University, West Lafayette, IN 47907-2009, USA
bMiami Valley Laboratories, Procter and Gamble Company, Cincinnati, OH 45253, USA
cInstitute of Chemistry, Slovak Academy of Sciences, SK 84238 Bratislava, Slovakia
Received 14 March 2003; revised 17 September 2003; accepted 17 September 2003
Abstract—The E. Coli K12 UDP-Gal mutase inhibitor 1 was prepared from D-glucose in 5 steps (42% overall yield). The 4-azido galactose
derivative 11, leading to 1, was formed by treatment of galactose dithioacetal 7 with mercuric oxide and mercuric chloride in acetone. To
obtain 7, acetal 3 was tosylated or triflated and treated with NaN3.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
zation of azide 9, providing the desired pyrrolidine 1
(Scheme 1). The dithioacetal precursor 2 was easily
prepared in 90% yield by treatment of D-glucose with 1,3-
propanedithiol in the presence of concentrated hydrochloric
acid.6 Isopropylidenation of 2 with an excess of 2,2-
dimethoxypropane and a catalytic amount of toluene-4-
sulfonic acid in 1,2-dimethoxyethane under anhydrous
conditions7 gave a mixture of 2,3:5,6-di-O-isopropylidene-
D-glucose propane-1,3-diyl dithioacetal (3) and 3,4:5,6-di-
O-isopropylidene-D-glucose propane-1,3-diyl dithioacetal
(4), which were separated by column chromatography to
give yields of 66 and 25%, respectively. All attempts to
increase the ratio of 3 to 4 by using acetone or
2-methoxypropene instead of 2,2-dimethoxypropane and/
or a change of catalyst (ZnCl2) were unsuccessful.
However, in some cases, 2,4:5,6-di-O-isopropylidene-D-
glucose propane-1,3-diyl dithioacetal (5) was also isolated.8
Polyhydroxylated pyrrolidines and piperidines (often
referred to as azasugars) are known as specific and
competitive inhibitors of glycosidases or glycosyl trans-
ferases.1 These classes of compounds are useful for probing
the details of enzyme catalytic mechanisms and have a
potential for therapeutic applications, including treatment of
diseases such as diabetes, cancer, inflammation, and viral
and bacterial infections.2 1,4-Dideoxy-1,4-imino-D-galacti-
tol (1) is the first known inhibitor of E. coli K12 UDP-Gal
mutase and mycobacterial galactan biosynthesis.3 Its
inhibitory activities are highly specific and may represent
a novel therapeutic strategy for the treatment of mycobac-
terial infections such as leprosy and tuberculosis. In
previous syntheses,3,4 compound 1 was made through
complex methods requiring many steps and/or giving low
overall yields, which impacted its evaluation for potential
use. In this paper, we report a simple synthesis of compound
1 from D-glucose propane-1,3-diyl dithioacetal (2) which,
we believe, is more than competitive with previous
synthetic approaches.5
Esterification of the free hydroxyl group at position 4 of 3
with tosyl chloride in pyridine at room temperature resulted
in almost complete formation of the expected fully
substituted dithioacetal 6, which without purification, was
subsequently transformed into 4-azido-4-deoxy-2,3:5,6-di-
O-isopropylidene-D-galactose propane-1,3-diyl dithioacetal
(7) in 54% overall yield by treatment with sodium azide in
DMF at 958C (Scheme 1). Isolation of the azide 7 indicated
that the conversion of tosylated dithioacetal 6 with azido ion
proceeded by a single SN22 type displacement at C-4. A by-
product of the azido replacement was 4-deoxy-2,3:5,6-di-O-
2. Results and discussion
Our synthetic plan relies on the successful Pd-catalyzed
reductive amination and concomitant intramolecular cycli-
isopropylidene-D-xylo-hex-3-enose propane-1,3-diyl
dithioacetal (8), which was formed by elimination of
toluene-4-sulfonic acid. Neither replacement of NaN3 by
Keywords: azasugars; pyrrolidines; Pd-catalyzed reductive amination.
*
Corresponding author. Tel.: þ1-765-494-5684; fax: þ1-765-494-7953;
e-mail: bemiller@purdue.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.058

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D.-P. Pham-Huu et al. / Tetrahedron 59 (2003) 9413–9417
LiN3 or a change of solvent (DMSO) improved the yields of
7. However, some changes increased formation of the
unsaturated product 8. A higher yield (70%) of 7 was
obtained when small amounts of urea and tetra-n-butyl-
amonium bromide were added. When dithioacetal 3 was
submitted to mesylation under standard conditions, the
reaction gave the desired mesylate derivative quantitatively.
However, the substitution reaction of mesylate with sodium
azide gave azido derivative 7 in poor yield. The most
satisfactory displacement (82%) was achieved, when
compound 3 was converted to the corresponding trifluoro-
methanesulfonate derivative, which was subsequently
treated with sodium azide at room temperature
When azido dithioacetal 7 was treated with mercuric
chloride and mercuric oxide in aqueous acetone, 4-azido-
4-deoxy-2,3:5,6-di-O-isopropylidene-D-galactose (11) was
1
isolated as a colorless syrup in 90% yield. Both H NMR
(9.80 ppm, singlet, 1H, CHO) and 13C NMR spectra
(200.3 ppm, CHO) of a freshly prepared sample of 11
indicated that the desired aldehyde had been formed in a
non-hydrated form; however, the compound proved to be
unstable upon storage. Attempts to convert 11 into
pyrrolidine 12 by Pd-catalyzed reductive amination10 in
ethanol were unsuccessful; rather a mixture of unidentified
products was obtained. No ring closure via intramolecular
attack of the amino group on the aldehydo group was
observed, probably because the two reactive centers were
too widely separated from each other due to steric restriction
effected by the 2,3-O-isopropylidene group. Presumably,
the amino group formed by hydrogenation of the azido
group in 11 reacted with the free aldehydo group affording
polymeric materials. In order to overcome this steric
restriction, azido derivative 11 was treated with 6 M HCl
solution to give the corresponding unprotected azido sugar,
whose catalytic hydrogenation and concomitant intramole-
cular reductive amination provided pyrrolidine 1 (identical
with that prepared by the previous route) (Scheme 2).
Deprotection of the dithioacetal moiety of 7, using mercuric
chloride and mercuric oxide in boiling methanol, gave
4-azido-4-deoxy-2,3:5,6-di-O-isopropylidene-D-galactose
dimethylacetal (9) in 94% yield.9 Hydrogenation of the
azido group of 9 in the presence of 10% palladium on
carbon in ethanol at room temperature afforded an almost
quantitative yield of 4-amino-4-deoxy-2,3:5,6-di-O-isopro-
pylidene-D-galactose dimethylacetal (10). A route to
pyrrolidine 1 from compound 10 was straightforward and
simple to manipulate (Scheme 1). Thus, acid-catalyzed
removal of the acetal protecting groups of 10 and
subsequent ring closure via attack of the nitrogen upon
C-1, followed by hydrogenation of the resulting product in the
presence of palladium black gave 1,4-dideoxy-1,4-imino-D-
galactitol (1) in 90% yield. Pyrrolidine 1 was also prepared
by a one-pot synthesis from azido dimethylacetal 9 in 91%
overall yield. The identity of compound 1 prepared in this
way was confirmed by comparison of its spectroscopic data
(1H NMR and 13C NMR) with that in the literature.4d
3. Conclusion
In summary, we have described a new simple synthesis of E.
coli K12 UDP-Gal mutase inhibitor 1 from readily available
D-glucose propane-1,3-diyl dithioacetal. This five-step
approach produces pyrrolidine 1 in 42% overall yield
Scheme 1. (i) HS(CH2)3SH, HCl; (ii) Me2C(OMe)2, TsOH, DME; (iii) TsCl, pyridine, rt; (iv) NaN3, DMF, 958C; (v) Tf2O, pyridine, 08C; then NaN3, DMF, rt;
(vi) HgCl2, HgO, MeOH; (vii) 10% Pd/C, H2, EtOH; (viii) AcOH, H2O, 508C; then 10% Pd/C, H2.

D.-P. Pham-Huu et al. / Tetrahedron 59 (2003) 9413–9417
9415
the same temperature, the reaction mixture was neutralized
with NaHCO3 (3 g) and filtered. The solids were washed
with ethyl acetate (3£10 ml). Concentration of the filtrates
afforded a residue, which was subjected to column
chromatography with hexanes–ethyl acetate (3:1, v/v) as
the eluent to give compounds 3 (5.13 g, 66%) and 4 (1.94 g,
25% yield).
1
Compound 3. H NMR (CDCl3, 300 MHz) d 4.37 (1H, dd,
J1,2¼6.7 Hz, J2,3¼7.5 Hz, H-2); 4.25 (1H, dd, J3,4¼1.9 Hz,
H-3); 4.05–3.96 (4H, m, H-1, H-4, H-6a, H-6b); 3.68 (1H,
m, H-5); 3.00–2.62 (4H, m, CH2–CH2–CH2); 2.08–1.92
(2H, m, CH2–CH2–CH2); 1.43, 1.41, 1.40, 1.32 (4£3H, s,
4£Me). 13C NMR d 110.1, 109.3 (2£CMe2); 78.7, 78.0,
76.6, 70.9 (C-2, C-3, C-4, C-5); 66.7 (C-6); 47.6 (C-1); 28.4,
28.2 (CH2–CH2–CH2); 25.5 (CH2–CH2–CH2); 27.1, 26.8,
25.2, 23.6 (4£Me). Anal. calcd for C15H26O5S2: C, 51.40;
H, 7.48; S, 18.30. Found: C, 51.21; H, 7.52; S, 18.42.
Scheme 2. (i) HgCl2, HgO, acetone; (ii) Pd/C, H2, EtOH; (iii) 6 M HCl,
458C, EtOH; then Pd/C, H2.
from D-glucose and compares favorably with the previous
synthetic routes.
1
Compound 4. H NMR (CDCl3, 300 MHz) d 4.41 (1H, dd,
J2,3¼1.6 Hz, J3,4¼7.2 Hz, H-3); 4.13–4.02 (m, 3H, H-2, H-
6a, H-6b); 3.94–3.72 (m, 3H, H-1, H-4, H-5); 2.98–2.75
(m, 4H, CH2–CH2–CH2); 2.06–1.92 (m, 2H, CH2–CH2–
CH2); 1.39, 1.37, 1.34, 1.30 (4£3H, s, 4£Me). 13C NMR d
110.1, 110.0 (2£CMe2); 79.9, 78.1, 78.0, 70.9 (C-2, C-3, C-4,
C-5); 68.1 (C-6); 49.5 (C-1); 27.6, 27.1 (CH2–CH2–CH2);
25.6 (CH2–CH2–CH2); 28.5, 28.0, 27.0, 26.5 (4£Me).
4. Experimental
4.1. General methods
1H and 13C NMR spectra were recorded using a Bruker
Spectrometer (300 MHz and 75 MHz, respectively). Chemi-
cal shifts are reported in d values ppm relative to an internal
reference of tetramethylsilane (TMS) in CDCl3, except
where noted. All reactions were done in oven-dried
glassware under an atmosphere of nitrogen unless otherwise
indicated. Ascending thin-layer chromatography was per-
formed on plates precoated with silica gel 60 F254 (Merck).
Detection was effected by spraying the chromatograms with
10% ethanolic sulfuric acid and charring them on a hot
plate. Flash chromatography was carried out using silica gel
(Merck 60, 0.04–0.063). All reagents were commercially
available and were used without further purification.
4.1.3. 2,3:5,6-Di-O-isopropylidene-4-O-(toluene-4-sulfo-
nyl)-D-glucose propane-1,3-diyl dithioacetal (6). Dithioa-
cetal 3 (3.50 g, 10 mmol) was dissolved in pyridine (60 ml)
at 08C and p-toluenesulfonyl chloride (3.81 g, 20 mmol)
was added. After stirring the mixture overnight at room
temperature, the mixture was cooled to 08C and water
(10 ml) was added dropwise. After 15 min, the reaction
mixture was poured into aqueous 1 M HCl solution
(150 ml), which was extracted with dichloromethane
(3£50 ml). The combined organic extracts were washed
with 1 M HCl solution (2£50 ml), a saturated solution of
NaHCO3 (50 ml) and water (2£100 ml). The organic phase
was dried (Na2SO4), filtered and concentrated to give the
expected fully substituted dithioacetal 6 (5.06 g, 100%),
which was used in the next step without purification.
4.1.1. D-Glucose propane-1,3-diyl dithioacetal (2). D-
Glucose (10 g, 56 mmol) was dissolved at room temperature
in concentrated HCl (10 ml). 1,3-Propanedithiol was slowly
added, and the solution was stirred vigorously at room
temperature overnight. Ethanol (30 ml) was added and the
product crystallized from the reaction mixture. Crystals
were collected by filtration and washed with cold 85%
aqueous ethanol (4£10 ml) to give dithioacetal 2 (14 g,
93%). Compound 2: 1H NMR (D2O, 300 MHz) d 4.22 (1H,
d, J1,2¼3.5 Hz, H-1); 4.04 (1H, dd, J2,3¼5.2 Hz,
J3,4¼2.1 Hz, H-3); 3.89 (1H, dd, H-2); 3.75 (1H, dd,
J5,6a¼2.3 Hz, J6a,6b¼10.8 Hz, H-6a); 3.73–3.64 (2H, H-4,
H-5); 3.56 (1H, dd, J5,6b¼4.9 Hz, H-6b); 2.89–2.81 (4H, m,
CH2–CH2–CH2); 2.02 (1H, m, CH2–CH2–CH2); 1.76 (1H,
m, CH2–CH2–CH2). 13C NMR d 73.7, 71.8, 71.3, 69.6
(C-2, C-3, C-4, C-5); 63.0 (C-6); 49.4 (C-1); 29.2, 28.5
(CH2–CH2–CH2); 25.5 (CH2–CH2–CH2).
1
Compound 6. H NMR (CDCl3, 300 MHz) d 7.75 (2H, d,
J¼8.5 Hz, H-20, H-60); 7.26 (2H, d, H-30, H-40); 4.91 (1H,
dd, J3,4¼1.5 Hz, J4,5¼6.7 Hz, H-4); 4.41 (1H, t,
J1,2¼J2,3¼7.0 Hz, H-2); 4.30 (1H, dd, H-3); 4.19 (1H, m,
H-5); 3.93 (1H, dd, J5,6a¼5.4 Hz, J6a,6b¼9.1 Hz, H-6a); 3.92
(1H, dd, J5,6b¼6.2 Hz, H-6b); 3.82 (1H, d, H-1); 3.09–2.90
(2H, m, CH2–CH2–CH2); 2.67–2.56 (2H, m, CH2–CH2–
CH2); 2.36 (3H, s, Me of Ts); 1.98–1.93 (2H, m, CH2–
CH2–CH2); 1.32, 1.26, 1.24, 1.20 (4£3H, s, 4£Me). 13C
NMR d 145.0 (C-10); 133.8 (C-40); 129.7 (C-20, C-60); 127.7
(C-30, C-50); 110.6, 109.5 (2£CMe2); 79.1, 78.6, 77.6, 74.7
(C-2, C-3, C-4, C-5); 66.0 (C-6); 46.7 (C-1); 27.5, 26.6,
26.4, 25.2 (4£Me); 27.3, 27.1 (CH2–CH2–CH2); 25.3
(CH2–CH2–CH2); 21.6 (Me of Ts).
4.1.2. 2,3:5,6-Di-O-isopropylidene-D-glucose propane-
1,3-diyl dithioacetal (3) and 3,4:5,6-di-O-isopropyli-
dene-D-glucose propane-1,3-diyl dithioacetal (4). A
mixture of D-glucose dithioacetal 2 (6 g, 22 mmol),
TsOH.H2O (300 mg) and Drierite (5 g) in DME (100 ml)
was stirred at room temperature for 15 min, then 2,2-
dimethoxypropane (10 ml) was added. After 24 h stirring at
4.1.4. 4-Azido-4-deoxy-2,3:5,6-di-O-isopropylidene-D-
galactose propane-1,3-diyl dithioacetal (7) and 4-deoxy-
2,3:5,6-di-O-isopropylidene-D-xylo-hex-3-enose pro-
pane-1,3-diyl dithioacetal (8). From the dithioacetal 6.

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D.-P. Pham-Huu et al. / Tetrahedron 59 (2003) 9413–9417
To a solution of dithioacetal 6 (5.05 g, 10 mmol) in DMF
(30 ml) was added sodium azide (2.6 g, 40 mmol), urea
(100 mg), tetra-n-butylamonium bromide (200 mg) and
water (2 ml). The resulting mixture was stirred at 908C for
3 days. After cooling to room temperature, the reaction
mixture was poured into 1 M HCl solution (150 ml), which
was extracted with chloroform (3£50 ml). The combined
organic extracts were washed with water (3£50 ml), dried
(Na2SO4) and filtered. The solvent was removed at reduced
pressure, and the residue was purified by flash chromatog-
raphy to afford 7 (2.62 g, 70%) and 8 (465 mg, 14%)
methanol (3£20 ml). The combined filtrate and washings
were concentrated in the presence of mercuric oxide. The
residue was extracted with chloroform (3£50 ml), and the
chloroform portions were washed with aqueous 10% KI
solution (2£50 ml) and then with water (3£50 ml). The
organic phase was dried (Na2SO4), filtered and concentrated
to give a syrup, which was purified by passing through a
short column of silica gel with a mixture of hexanes and
ethyl acetate (3:1, v/v) to give 9 (975 mg, 92%).
1
Compound 9. H NMR (CDCl3, 300 MHz) d 4.39 (1H, d,
J1,2¼5.2 Hz, H-1); 4.27 (1H, q, H-5); 4.17 (1H, dd,
J2,3¼5.8 Hz, H-2); 4.08 (1H, dd, J3,4¼6.4 Hz, H-3); 4.05
(1H, dd, J5,6a¼6.6 Hz, J6a,6b¼8.3 Hz, H-6a); 3.85 (1H, dd,
J5,6b¼6.6 Hz, H-6b); 3.36 (1H, t, J4,5¼6.4 Hz, H-4); 3.48,
3.46 (2£3H, s, 2£OMe); 1.49, 1.44, 1.42, 1.38 (4£3H, s,
4£Me). 13C NMR d 110.6, 109.5 (2£CMe2); 104.4 (C-1);
78.3, 76.7, 76.0 (C-2, C-3, C-5); 66.5 (C-6); 65.1 (C-4);
56.4, 54.2 (2£OMe); 27.4, 27.2, 26.3, 25.2 (4£Me).
1
Compound 7. H NMR (CDCl3, 300 MHz) d 4.30 (1H, dd,
J1,2¼3.5 Hz, J2,3¼6.3 Hz, H-2); 4.27 (1H, q, H-5); 4.19 (1H,
d, H-1); 4.09 (1H, dd, J5,6a¼6.4 Hz, J6a,6b¼8.8 Hz, H-6a);
4.06 (1H, dd, J3,4¼8.3 Hz, H-3); 3.90 (1H, dd, J5,6b¼6.7 Hz,
H-6b); 3.29 (1H, dd, J4,5¼6.3 Hz, H-4); 3.03–2.95 (2H, m,
CH2–CH2–CH2); 2.87–2.68 (2H, m, CH2–CH2–CH2);
2.12–1.93 (2H, m, CH2–CH2–CH2); 1.44, 1.43, 1.38, 1.35
(4£3H, s, 4£Me). 13C NMR d 111.2, 109.8 (2£CMe2); 83.9,
77.5, 77.4 (C-2, C-3, C-5); 67.1 (C-6); 65.4 (C-4); 48.1
(C-1); 30.0, 29.4 (CH2–CH2–CH2); 27.5, 26.5, 26.0, 23.9
(4£Me); 25.6 (CH2 –CH2 –CH2). Anal. calcd for
C15H25N3O4S2: C, 47.98; H, 6.71; N, 11.19; S, 17.08.
Found: C, 47.77; H, 6.68; N, 11.32; S, 17.12.
4.1.6. 4-Amino-4-deoxy-2,3:5,6-di-O-isopropylidene-D-
galactose dimethylacetal (10). To a solution of azido
dimethylacetal 9 (163 mg, 0.49 mmol) in EtOH (20 ml) was
added palladium on carbon (40 mg). A hydrogen stream was
introduced into the mixture until no starting material could
be detected on TLC (hexanes–ethyl acetate 3:1, v/v). The
catalyst was removed by filtration and the filtrate was
concentrated to a syrup of amino dimethylacetal 10
(150 mg, 100%).
1
Compound 8. H NMR (CDCl3, 300 MHz) d 4.96 (1H, dt,
H-5); 4.83 (1H, d, J1,2¼3.4 Hz, H-2); 4.61 (1H, d,
J4,5¼7.8 Hz, H-4); 4.13 (1H, d, H-1); 4.09 (1H, dd,
J5,6a¼6.3 Hz, J6a,6b¼7.9 Hz, H-6a); 3.52 (1H, t,
J5,6b¼7.9 Hz, H-6b); 3.01–2.96 (2H, m, CH2–CH2–CH2);
2.89–2.70 (2H, m, CH2–CH2–CH2); 2.12–1.91 (2H, m,
CH2–CH2–CH2); 1.60, 1.43, 1.40, 1.39 (4£3H, s, 4£Me).
13C NMR d 152.6 (C-3); 112.3, 108.6 (2£CMe2); 95.2
(C-4); 80.5, 71.5 (C-2, C-5); 69.4 (C-6); 49.2 (C-1); 29.4,
29.2 (CH2–CH2–CH2); 26.8, 26.0, 25.8, 25.4 (4£Me); 25.3
(CH2–CH2–CH2).
1
Compound 10. H NMR (CDCl3, 300 MHz) d 4.42 (1H, d,
J1,2¼5.3 Hz, H-1); 4.27 (1H, m; H-5); 4.12–3.80 (6H, m,
NH2, H-2, H-3, H-6a, H-6b); 2.99 (1H, t, J3,4¼J4,5¼6.6 Hz,
H-4); 3.50, 3.48 (2£3H, s, 2£OMe); 1.45, 1.40, 1.37, 1.35
(4£3H, s, 4£Me). 13C NMR d 109.6, 108.6 (2£CMe2);
104.4 (C-1); 79.0, 78.0, 75.8 (C-2, C-3, C-5); 66.8 (C-6);
56.5, 55.9 (2£OMe); 54.0 (C-4); 27.0, 26.7, 26.3, 25.0
(4£Me). Anal. calcd for C14H25O6N3: C, 50.74; H, 7.60; N,
12.68. Found: C, 50.59; H, 7.48; N, 12.78
From the dithioacetal 3. Dithioacetal 3 (1.75 g, 5 mmol)
was dissolved in dry dichloromethane (30 ml) at 08C and
treated with pyridine (4 ml) and triflic anhydride (0.92 ml,
5.5 mmol). After stirring the mixture for 1 h at 08C, the
reaction was quenched with buffer solution (pH 7) then
diluted with dichloromethane and washed with aqueous 1 M
HCl solution (50 ml) and water (100 ml). The organic phase
was dried (Na2SO4), filtered and concentrated. The crude
triflate was dissolved in DMF (20 ml) and treated with
sodium azide (1.3 g, 20 mmol). After 5 h at room tempera-
ture, the reaction mixture was poured into 1 M HCl solution
(50 ml), which was extracted with chloroform (3£50 ml).
The combined organic extracts were washed with water
(3£50 ml), dried (Na2SO4) and filtered. The solvent was
removed at reduced pressure, and the residue was purified
by flash chromatography to afford 7 (1.54 g, 82%).
4.1.7. 4-Azido-4-deoxy-2,3:5,6-di-O-isopropylidene-D-
galactose (11). A mixture of azido dithioacetal 7 (939 mg,
2.5 mmol), mercuric oxide (2.70 g, 12.5 mmol) and mercu-
ric chloride (2.71 g, 10 mmol) in aqueous acetone (100 ml,
acetone–H2O 4:1, v/v) was refluxed for 10 h. After cooling
to room temperature, the solids were removed by filtration
and washed with acetone (2£50 ml). The combined filtrate
and washings were concentrated in the presence of HgO.
The residue was extracted with chloroform (3£50 ml) and
the chloroform solution was washed with aqueous 10% KI
solution (2£50 ml), and then with water (3£50 ml). The
organic phase was dried (Na2SO4), filtered and concentrated
to give a syrup, which was purified by passing through a
short column of silica gel with a mixture of hexanes and
ethyl acetate (2:1, v/v), yielding 11 as a colorless syrup
(642 mg, 90%).
4.1.5. 4-Azido-4-deoxy-2,3:5,6-di-O-isopropylidene-D-
galactose dimethylacetal (9). To a stirred mixture of
azido dithioacetal 7 (1.20 g, 3.2 mmol) and mercuric oxide
(3.46 g, 16 mmol) in absolute methanol (100 ml) at
refluxing temperature was added dropwise a methanolic
solution of mercuric chloride (2.60 g, 9.6 mmol). After
refluxing for 10 h and cooling to room temperature, the
solids were removed by filtration and washed with abs.
1
Compound 11. H NMR (CDCl3, 300 MHz) d 9.80 (1H, s,
H-1); 4.55 (1H, d, J2,3¼6.0 Hz, H-2); 4.22 (1H, dd,
J3,4¼5.5 Hz, H-3); 4.18 (1H, m, H-5); 4.13 (1H, dd,
J5,6a¼6.7 Hz, J6a,6b¼8.0 Hz, H-6a); 3.91 (1H, dd,
J5,6b¼6.3 Hz, H-6b); 3.58 (1H, t, J4,5¼5.5 Hz, H-4); 1.54,
1.44, 1.36, 1.35 (4£3H, s, 4£Me). 13C NMR d 200.3 (C-1);

D.-P. Pham-Huu et al. / Tetrahedron 59 (2003) 9413–9417
9417
111.5, 109.8 (2£CMe2); 81.8, 76.7, 75.6 (C-2, C-3, C-5);
66.3 (C-6); 64.1 (C-4); 26.3, 26.1, 25.7, 25.1 (4£Me). Anal.
calcd for C12H19O5N3: C, 50.52; H, 6.71; N, 14.73. Found:
C, 50.59; H, 6.81; N, 14.58.
salt of pyrrolidine 1. Free base 1 (76 mg; 90%) was obtained
by passing an aqueous solution of the hydrochloride salt
through a column of Amberlite IRA-400 (OH2).
4.1.8. 1,4-Dideoxy-1,4-imino-D-galactitol (1). From the
azido dimethylacetal 9. To a solution of azido dimethyla-
cetal 9 (163 mg, 0.49 mmol) in EtOH (20 ml) was added
palladium on carbon (40 mg). A hydrogen stream was
introduced into the mixture until no starting material could
be detected on TLC (hexanes–ethyl acetate 3:1, v/v). Then
6 M HCl solution (10 ml) was added, and the resulting
mixture was heated at 458C for 6 h. After cooling to room
temperature, another portion of palladium on carbon
(40 mg) was added. A hydrogen stream was introduced
into the mixture for 5 h. The catalyst was removed by
filtration through Celite and washed with ethanol. The
filtrate was concentrated to a syrup, to which ethanol
(20 ml) was added and again evaporated. Evaporation of an
ethanol solution was repeated twice more to give the
hydrochloride salt of pyrrolidine 1. Free base 1 (73 mg,
91%) was obtained by passing an aqueous solution of the
hydrochloride salt through a column of Amberlite IRA-400
(OH2). The 1H NMR and 13C NMR data of compound 1 are
in good agreement with those reported in the literature.
[a]2D0¼þ2.9 (c¼2.0, H2O); lit.:4d [a]2D0¼þ3.0 (c¼2.4,
H2O); MS (ESI) m/z 186 (MþNaþ), 164 (MþHþ).
References
1. (a) Wong, C.-H.; Halcomb, R. L.; Ichikawa, Y.; Kajimoto, T.
Angew. Chem., Int. Ed. Engl. 1995, 34, 521. (b) Butters, D. T.;
van den Broek, A. G. M. L.; Fleet, W. J. G.; Krulle, M. T.;
Wormald, R. M.; Dwek, A. R.; Platt, M. F. Tetrahedron:
Asymmetry 2000, 11, 113. (c) Legler, G. Adv. Carbohydr.
Chem. Biochem. 1990, 48, 319. (d) de Raadt, A.; Ekhart, W. C.;
Ebner, M.; Stu¨tz, E. A. Top. Curr. Chem. 1997, 187, 158.
2. (a) Asano, N.; Oseki, K.; Kizu, H.; Matsui, K. J. Med. Chem.
1994, 37, 3701. (b) Vlietinck, A. J.; DeBruyne, T.; Apers, S.;
Pieters, L. A. Planta Med. 1998, 64, 97. (c) Fleet, W. J. G.;
Karpas, A.; Dwek, A. R.; Fellows, E. L.; Tyms, S. A.;
Petursson, S.; Namgoong, K. S.; Ramsden, G. N.; Smith, W. P.;
Son, C. J.; Wilson, F.; Witty, R. D.; Jacob, S. G.; Rademacher,
W. T. FEBS Lett. 1988, 237, 128.
3. Lee, E. R.; Smith, D. M.; Nash, J. R.; Griffiths, C. R.; McNeil,
M.; Grewal, K. R.; Yan, W.; Besra, S. G.; Brennan, J. P.; Fleet,
W. J. G. Tetrahedron Lett. 1997, 38, 6733.
4. (a) Bernotas, C. R. Tetrahedron Lett. 1990, 31, 469. (b) Lundt,
I.; Madsen, R. Synthesis 1993, 720. (c) Paulsen, H.; Steinert,
K.; Heyns, K. Chem. Ber. 1970, 103, 1599. (d) Lombardo, M.;
Fabbroni, S.; Trombini, C. J. Org. Chem. 2001, 66, 1264.
From the amino dimethylacetal 10. A solution of 10
(120 mg, 0.39 mmol) in a mixture of acetic acid (10 ml)
and water (1 ml) was heated at 508C for 3 h. After cooling to
room temperature, palladium on carbon (40 mg) was added
and a hydrogen stream was introduced into the mixture for
5 h. The catalyst was removed by filtration through Celite
and washed with ethanol (2£10 ml). The filtrate and
washings were concentrated to a syrup, which was purified
by passing through a short column of Amberlite IRA-400
(OH2) to give free base 1 (59 mg, 92%).
ˇ
5. Pham-Huu, D.-P.; Gizaw, Y.; BeMiller, J. N.; Petrus, L.
Tetrahedron Lett. 2002, 43, 383.
6. Wolfrom, M. L.; Thompson, A. Methods Carbohydr Chem.
1963, 2, 427.
ˇ ´
7. Pham-Huu, D.-P.; Petrusova, M.; BeMiller, J. N.; Koll, P.;
¨
ˇ
Kopf, J.; Petrus, L. Carbohydr. Res. 1998, 306, 45.
8. Compound 5: 1H NMR (CDCl3, 300 MHz) d 4.29 (1H, d,
J1,2¼9.6 Hz, H-1); 4.15 (1H, m, H-5); 3.96 (1H, dd,
J5,6a¼6.3 Hz, J6a,6b¼8.6 Hz, H-6a); 3.82 (1H, dd,
J2,3¼1.1 Hz, H-2); 3.78 (1H, t, H-3); 3.74 (1H, dd,
J5,6b¼5.0 Hz, H-6b); 3.54 (1H, dd, J3,4¼1.2 Hz, J4,5¼8.1 Hz,
H-4); 2.79–2.70 (4H, m, CH2–CH2–CH2); 2.04–1.73 (2H,
m, CH2–CH2–CH2); 1.36, 1.34, 1.30, 1.24 (4£3H, s, 4£Me).
13C NMR d 109.0, 99.9 (2£CMe2); 74.1, 73.8, 73.1, 66.7 (C-2,
C-3, C-4, C-5); 62.2 (C-6); 46.3 (C-1); 28.9, 28.7 (CH2–CH2–
CH2); 25.7 (CH2–CH2–CH2); 29.1, 26.6, 24.9, 18.8 (4£Me).
9. In Paulsen’s work,4c azido sugar 9 was prepared in 10% yield
by treatment of 2,3:5,6-di-O-isopropylidene-4-O-(toluene-4-
sulfonyl)-D-glucose dimethylacetal with sodium azide.
10. Kajimoto, T.; Chen, L.; Liu, K.-C. K.; Wong, C. H. J. Am.
Chem. Soc. 1991, 113, 6678.
From the azido aldehyde 11. To a solution of azido aldehyde
11 (149 mg, 0.52 mmol) in EtOH (20 ml) was added
aqueous 6 M HCl solution (10 ml). The resulting mixture
was heated at 458C for 6 h. After cooling to room
temperature, palladium on carbon (50 mg) was added. A
hydrogen stream was introduced into the mixture for 6 h.
The catalyst was removed by filtration through Celite and
washed with ethanol. The filtrate and washings were
concentrated to a syrup, to which ethanol (20 ml) was
added and again evaporated. Evaporation of an ethanol
solution was repeated twice more to give the hydrochloride