New synthesis of 1,4-dideoxy-1,4-imino-D-galactitol from D-glucose propane-1,3-diyl dithioacetal

Article abstract of DOI:10.1016/S0040-4039(01)02167-0

The treatment of 4-azido-4-deoxy-2,3:5,6-di-O-isopropylidene-D-galactose propane-1,3-diyl dithioacetal (derived from D-glucose) with mercuric chloride and mercuric oxide in aqueous acetone afforded 4-azido-4-deoxy-2,3:5,6-di-O-isopropylidene-D-galactose.

Full text of DOI:10.1016/S0040-4039(01)02167-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 383–385
New synthesis of 1,4-dideoxy-1,4-imino- -galactitol from
D
D-glucose propane-1,3-diyl dithioacetal
a
a,b
a,
c
Duy-Phong Pham-Huu, Yonas Gizaw, James N. BeMiller * and Ladislav Petrusˇ
a
The Whistler Center for Carbohydrate Research, Purdue University, West Lafayette, IN 47907-1160, USA
b
Miami Valley Laboratories, Procter and Gamble Company, Cincinnati, OH 45253, USA
c
Institute of Chemistry, Slovak Academy of Sciences, 84238 Bratislava, Slovakia
Received 4 October 2001; revised 6 November 2001; accepted 13 November 2001
Abstract—The treatment of 4-azido-4-deoxy-2,3:5,6-di-O-isopropylidene-
-glucose) with mercuric chloride and mercuric oxide in aqueous acetone afforded 4-azido-4-deoxy-2,3:5,6-di-O-isopropylidene-
galactose. Acid-catalyzed deprotection of the azido derivative, followed by catalytic hydrogenation and concomitant intramolec-
ular reductive amination in the presence of 10% palladium on carbon, gave 1,4-dideoxy-1,4-imino- -galactitol in good yield.
2002 Published by Elsevier Science Ltd.
D-galactose propane-1,3-diyl dithioacetal (derived from
D
D-
D
©
An important group of tight-binding glycosidase and
glycotransferase inhibitors includes both natural and
unnatural polyhydroxylated pyrrolidines and piperidi-
acid in 6 1,2-dimethoxyethane under anhydrous
conditions gave a mixture of 2,3:5,6-di-O-isopropyli-
dene-
D
-glucose propane-1,3-diyl dithioacetal (3) and
1
nes (azasugars). Many azasugars that inhibit glycosi-
3,4:5,6-di-O-isopropylidene-
D
-glucose propane-1,3-diyl
dases or glycotransferases have been found to be
potential chemotherapeutic agents for treatment of dis-
eases such as diabetes and cancer, inflammation and
dithioacetal, which was separated by column chro-
matography in yields of 66 and 25%, respectively.
Esterification of the free hydroxyl group at the 4-posi-
tion of 3 with tosyl chloride in pyridine at room
temperature resulted in almost complete formation of
the expected fully substituted dithioacetal, which was
subsequently transformed into 4-azido-4-deoxy-2,3:5,6-
2
viral infections, including HIV. 1,4-Dideoxy-1,4-imino-
D
-galactitol (1) is the first known inhibitor of E. coli
K12 UDP-Gal mutase and mycobacterial galactan
biosynthesis. Its inhibitory activities are highly specific
3
and may represent a novel therapeutic strategy for the
treatment of mycobacterial infections such as leprosy
di-O-isopropylidene-
D
-galactose
propane-1,3-diyl
dithioacetal (4) by treatment with sodium azide in
DMF at 95°C (Scheme 1). A higher yield (70%) was
obtained when small amounts of urea and tetra-n-butyl-
amonium bromide were added. A by-product of the
azido replacement was 4-deoxy-2,3:5,6-di-O-isopropyli-
3,4
and tuberculosis. In previous synthesis, 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 pro-
dene-
which was separated by column chromatography in
4% overall yield.
D-xylo-hex-3-enose propane-1,3-diyl dithioacetal,
pane-1,3-diyl dithioacetal (2) which, we believe, is more
than competitive with the previous synthetic
approaches.
1
Deprotection of the dithioacetal moiety in 4, using
mercuric chloride and mercuric oxide in boiling
methanol, gave 4-azido-4-deoxy-2,3:5,6-di-O-isopropyl-
The dithioacetal precursor 2 was easily prepared in 90%
yield by treatment of -glucose with 1,3-propanedithio5l
D
in the presence of concentrated hydrochloric acid.
Acetonation of 2 with an excess of 2,2-dimethoxy-
propane and a catalytic amount of toluene-4-sulfonic
7
,8
idene- -galactose dimethylacetal (5) in 94% yield.
D
Hydrogenation of the azido group of 5 in the presence
of 10% palladium on carbon in ethanol at room tem-
perature afforded an almost quantitative yield of 4-
amino-4-deoxy-2,3:5,6-di-O-isopropylidene-D-galactose
dimethylacetal (6). Acid-catalyzed removal of the acetal
Keywords: dithioacetals; amino sugars; azasugars; pyrrolidines; Pd-
catalyzed hydrogenations.
*
Corresponding author. Tel.: 765-494-6171; fax: 765-494-7953;
e-mail: bemiller@purdue.edu
protecting groups in 6 and subsequent ring closure via
0
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(01)02167-0

3
84
D.-P. Pham-Huu et al. / Tetrahedron Letters 43 (2002) 383–385
S
S
S
S
S
S
MeO
OMe
O
MeO
OMe
O
CHO
OH
OH
O
O
(i)
(ii)
(iii)
(iv)
(v)
HO
HO
O
O
O
O
OH
OH
OH
OH
OH
OH
OH
O
N3
N3
H2N
O
O
O
O
O
O
O
2
3
4
5
6
(vii)
(vi)
CHO
H
N
O
H
N
HO
O
(v)
(vi)
HO
O
O
N3
HO
OH
O
O
O
O
1
8
Scheme 1. (i) HS(CH ) SH, HCl; (ii) Me C(OMe) , TsOH, DME; (iii) TsCl, pyridine, rt, 2 days; then NaN , DMF, 95°C; (iv)
2
3
2
2
3
HgCl , HgO, MeOH; (v) 10% Pd/C, H , EtOH; (vi) 6 M HCl, EtOH, 45°C; then 10% Pd/C, H ; (vii) HgCl , HgO, acetone.
2
2
2
2
attack of the nitrogen upon C-1, followed by hydro-
genation of the resulting product in the presence of
This five-step approach produces pyrrolidine 1 in 36%
overall yield from -glucose and compares favorably
with the previous synthetic routes.
D
palladium black gave 1,4-dideoxy-1,4-imino-
D
-galacti-
tol in 90% yield. Pyrrolidine 1 was also prepared by a
one-pot synthesis from azido dimethylacetal 5 in 91%
9
1
13
References
overall yield. The H and C NMR data of compound
prepared in this way are in good agreement with
1
1
2
. (a) Wong, C.-H.; Halcomb, R. L.; Ichikawa, Y.; Kaji-
moto, T. Angew. Chem., Int. Ed. Engl. 1995, 34, 521; (b)
Butters, D. T.; van den Broek, A. G. M. L.; Fleet, W. J.
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G. N.; Smith, W. P.; Son, C. J.; Wilson, F.; Witty, R. D.;
Jacob, S. G.; Rademacher, W. T. FEBS Lett. 1988, 237,
those reported in the literature.
When azido dithioacetal 4 was treated with mercuric
chloride and mercuric oxide in aqueous acetone, 4-
azido-4-deoxy-2,3:5,6-di-O-isopropylidene-
D-galactose
1
(
7) was isolated as a colorless syrup in 90% yield. H
1
3
NMR (9.80 ppm, singlet, 1H, CHO) and C NMR
spectra (200.3 ppm, CHO) of freshly prepared sample
of 7 all indicated that the desired aldehyde had been
1
0
formed in non-hydrated form; however the compound
proved to be unstable upon storage. An attempt to
convert 7 into pyrrolidine 8 by Pd-catalyzed reductive
1
1
amination in ethanol was unsuccessful, but a mixture
of unidentified products was obtained. Presumably, the
amino group formed by hydrogenation of the azido
group in 7 immediately reacted with the free aldehydo
group affording polymeric materials. No ring closure
via intramolecular attack of the amino group on the
aldehydo group was observed, probably because the
two reactive centers are too widely separated from each
other due to steric restriction effected by the 2,3-O-iso-
propylidene group. In order to overcome this steric
restriction, azido derivative 7 was treated with 6 M HCl
solution to give the corresponding free aldehyde, whose
catalytic hydrogenation and concomitant intramolecu-
lar reductive amination provided pyrrolidine 1 (identi-
cal with that prepared by the previous route).
1
28.
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.
5. Wolfrom, M. L.; Thompson, A. Method Carbohydr.
Chem. 1963, 2, 427.
6. Pham-Huu, D.-P.; Petru sˇ ov a´ , M.; BeMiller, J. N.; K o¨ ll,
(
P.; Kopf, J.; Petru sˇ , L. Carbohydr. Res. 1998, 306, 45.
7. In Paulsen’s work, azido sugar 5 was prepared in 10%
yield by treatment of 2,3:5,6-di-O-isopropylidene-4-O-
4c
In summary, we have described a new simple synthesis
of E. coli K12 UDP-Gal mutase inhibitor 1 from read-
ily available
D
-glucose propane-1,3-diyl dithioacetal.
tosyl-D-glucose dimethylacetal with sodium azide.

D.-P. Pham-Huu et al. / Tetrahedron Letters 43 (2002) 383–385
385
1
8
. Compound 5: H NMR (CDCl , 300 MHz): l 4.39 (1H,
ture for 5 h. The catalyst was removed by filtration, and
the filtrate was concentrated to give a syrup, to which
ethanol (20 ml) was added and again evaporated. This
was repeated twice more with ethanol to give pyrrolidine
hydrochloride of 1. Free base 1 (73 mg; 91%) was
obtained by passing an aqueous solution of the hydro-
chloride salt of 1 through a column of Amberlite IRA-
3
d, J1,2=5.2 Hz, H-1); 4.27 (1H, q, H-5); 4.17 (1H, dd,
J2,3=5.8 Hz, H-2); 4.08 (1H, dd, J3,4=6.4 Hz, H-3); 4.05
1H, dd, J5,6a=6.6 Hz, J6a,6b=8.3 Hz, H-6a); 3.85 (1H,
dd, J5,6b=6.6 Hz, H-6b); 3.36 (1H, t, J4,5=6.4 Hz, H-4);
(
3
3
.48, 3.46 (2×3H, s, 2×OMe); 1.49, 1.44, 1.42, 1.38 (4×
1
3
H, s, 4×Me). C NMR l 110.6, 109.5 (2×CMe ); 104.4
2
−
(
(
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).
400 (OH ).
10. Compound 7: H NMR (CDCl
1
, 300 MHz): l 9.80 (1H,
3
9
. To a solution of azido dimethylacetal 5 (163 mg, 0.49
mmol) in EtOH (20 ml) was added palladium on carbon
s, H-1); 4.55 (1H, d, J2,3=6.0 Hz, H-2); 4.22 (1H, dd,
3,4=5.5 Hz, H-3); 4.18 (1H, m, H-5); 4.13 (1H, dd,
5,6a=6.7 Hz, J6a,6b=8.0 Hz, H-6a); 3.91 (1H, dd, J5,6b
6.3 Hz, H-6b); 3.58 (1H, t, J4,5=5.5 Hz, H-4); 1.54, 1.44,
J
(40 mg). A hydrogen stream was introduced into the
=
mixture until no starting material could be detected on
TLC (hexanes/ethyl acetate 3:1). Then 6 M HCl solution
13
1.36, 1.35 (4×3H, s, 4×Me). C NMR l 200.3 (C-1);
111.5, 109.8 (2×CMe ); 81.8, 76.7, 75.6 (C-2, C-3, C-5);
(10 ml) was added, and the resulting mixture was heated
2
at 45°C 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 mix-
66.3 (C-6); 64.1 (C-4); 26.3, 26.1, 25.7, 25.1 (4×Me).
11. Kajimoto, T.; Chen, L.; Liu, K.-C. K.; Wong, C. H. J.
Am. Chem. Soc. 1991, 113, 6678.