1,5-Anhydro-D-fructose as chiral building block: A novel approach to 1-deoxymannojirimycin

Article abstract of DOI:10.1055/s-2006-926343

A novel six-step synthesis of 1-deoxymannojirimycin from 1,5-anhydro-D-fructose in 35% overall yield is reported. The key steps are nucleophilic piperidine ring formation and subsequent Lewis acid induced pyran ether cleavage. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926343

PAPER
827
1,5-Anhydro-D-fructose as Chiral Building Block: A Novel Approach to
1-Deoxymannojirimycin
D
eoxymannoj
e
f
ro
t
m
1,5-
e
Anhydro-
D
r
-fructose Maier, Søren Møller Andersen, Inge Lundt*
Department of Chemistry, Technical University of Denmark, Building 201, 2800 Lyngby, Denmark
Fax +4545933968; E-mail: il@kemi.dtu.dk
Received 2 August 2005; revised 6 October 2005
Dedicated to the memory of Professor Christian Pedersen, the excellent Danish carbohydrate chemist
derivatives are known to be potent inhibitors of a-L-fu-
cosidase and a-D-mannosidase10 and have potential thera-
peutic value.11 As a result much effort has been
undertaken in developing methodologies for the synthesis
of 2.12
Abstract: A novel six-step synthesis of 1-deoxymannojirimycin
from 1,5-anhydro-D-fructose in 35% overall yield is reported. The
key steps are nucleophilic piperidine ring formation and subsequent
Lewis acid induced pyran ether cleavage.
Key words: chiral pool, azasugars, glycosidase inhibitors, ring
opening
The synthesis of the bicyclic iminosugar 3 is shown in
Scheme 1. Thus, treatment of 1,5-anhydro-D-fructose (1)
with O-benyzlhydroxylamine gave the crystalline oxime
in excellent yield. Subsequent regioselective tosylation
afforded the 6-O-tosylated oxime 4 in 77% yield after pu-
rification by column chromatography. Hydrogenation of
4, in the presence of hydrochloric acid, afforded stereose-
lectively amine 5 as the crystalline hydrochloride (5·HCl).
The Pd-catalysed hydrogenation thus followed the gener-
al trend to give selectively manno-configured product as
we have shown for similar hydrogenations of AF-deriva-
tives and their oximes.2b Deprotonation of 5·HCl with
triethylamine induced intramolecular nucleophilic dis-
placement of the tosyloxy group by the amine giving 2,6-
anhydro-1-deoxymannojirimycin (3). This procedure pro-
vided 3 in four steps from 1,5-anhydro-D-fructose (1) with
an overall yield of 57%. Conducting the reduction of 4 in
the absence of acid resulted in direct formation of the bi-
cyclic iminosugar 3, which was obtained together with
uncyclised 2-amino intermediate 5. A complete ring clo-
sure was achieved by treating the crude product with py-
ridine. The latter procedure seems, although lower
yielding (43% from 1), more suitable for larger scale prep-
arations since 3 could simply be crystallised as toluene-
sulfonic acid salt without preceding column
chromatographic purification. A synthesis of 2,6-anhy-
dro-1,5-dideoxy-1,5-imino-D-mannitol (3) has been de-
scribed as a nine-step procedure in an overall yield of 11%
from 1,5-anhydro-D-glucitol.13
As part of our ongoing interest for using 1,5-anhydro-D-
fructose (1, AF) as a chiral building block,1,2 we present
here the synthesis of the important glycosidase inhibitor
1-deoxymannojirimycin (2) from 1 through an efficient
and highly stereoselective route via the bicyclic 2,6-anhy-
dro-1-deoxymannojirimycin (3) (Figure 1). 1,5-Anhydro-
D-fructose (1), which was first synthesized by a multistep
synthesis from D-glucose in low yield,3 is now available in
larger amounts by enzymatic degradation of starch by a-
1,4-glucan lyase.4 AF (1) has already proven to be a valu-
able chiral building block, since it was used in the synthe-
sis of the natural products polythazin5 and bissetone.6
Likewise, we previously reported the highly stereoselec-
tive formation of 2-amino-1,5-anhydro-2-deoxy-D-man-
nitol by Pd-catalysed hydrogenation of 1,5-anhydro-D-
fructose oximes2b as well as the stereoselective reduction
of the carbonyl group to give either 1,5-anhydro-D-gluci-
tol or 1,5-anhydro-D-mannitol.2b
HO
HO
HO
HO
O
NH
NH
O
HO
HO
HN
O
=
HO
HO
HO
OH
HO
O
1
2
3
3
Figure 1 Compounds 1–3
In order to prepare 1-deoxymannojirimycin (2) from the
2,6-anhydro derivative 3 the pyran ether bond in 3 needed
to be cleaved. Many reagents are capable of cleaving
ethers as discussed in several earlier reviews.14 We were
especially inspired by some more recently published ex-
amples,15 reporting the use of boron trifluoride and boron
tribromide. Therefore our initial attempts were carried out
using these boron containing Lewis acids and the acetyl
protected derivative of 3, but no ether cleavage was ob-
served under these conditions. Vogel et al., who investi-
gated the BBr3-promoted ether cleavage of 7-
oxabicyclo[2.2.1]heptane derivatives,16 reported that a
The naturally occurring 1-deoxymannojirimycin (1,5-
dideoxy-1,5-imino-D-mannitol) represents a class of imi-
nosugars that have attracted considerable attention in re-
cent years. These compounds are among the most
effective inhibitors of glycosidases7 and glycosyl-
transferases8 due to their ability to mimic charge and con-
formation of the cationic intermediates generated in the
enzymatic process.9 1-Deoxymannojirimycin (2) and its
SYNTHESIS 2006, No. 5, pp 0827–0830
x
x
.
x
x
.2
0
0
6
Advanced online publication: 08.02.2006
DOI: 10.1055/s-2006-926343; Art ID: T10405SS
© Georg Thieme Verlag Stuttgart · New York

828
P. Maier et al.
PAPER
HO
HO
TsO
HO
TsO
HO
HO
HO
NH2OTs
NPiv
O
O
O
NH
a,b
c
b,c
a
HO
PivO
PivO
O
O
HO
HO
O
HO
NOBn
HO
NH3Cl
HO
OH
1
3⋅HOTs
4
6
2
5⋅HCl
Scheme 2 Reagents and conditions: a) PivCl, DMAP, pyridine, r.t.,
93%; b) BBr3 (1.5 equiv), CHCl3, then MeOH, r.t.; c) NaOMe, Me-
OH, r.t., 67% (2 steps).
e
d
NH2OTs
O
NH
O
HO
HO
HO
=
O
HN
Bu4NBr did not effect the reaction either. The observation
that the products shared the fact, that the N-pivaloyl group
in all cases was cleaved and a C-6-O-pivaloyl group was
introduced, could be interpreted in terms of a neighbour-
ing group participation of the N-acyl group in the mecha-
nism of the ether cleavage between C-6 and the oxygen
(Scheme 3). This is further supported by the fact that no
gluco-isomer has been formed as a result of ether cleavage
between C-2 and the oxygen. It should be mentioned that
acyloxonium ions as intermediates in similar BBr3 in-
duced ether cleavages have been suggested.16 Also in this
case no external nucleophile could be introduced in the
end product as a proof for such an intermediate species.
HO
HO
HO
3⋅HOTs
3
Scheme 1 Reagents and conditions: a) NH2OBn·HCl, KOH, r.t.,
EtOH, 91%; b) TsCl (1.2 equiv), pyridine, –20 °C, 77%; c) H2, Pd/C,
MeOH/HCl, 30 bar, r.t., 81%; d) Et3N, DMF, r.t., quant; e) H2, Pd/C,
MeOH, 30 bar, r.t., then pyridine, r.t., 62%.
successful ether cleavage was only achieved when the
pivaloylated ether derivative was applied. The corre-
sponding acetylated compound showed no reactivity.
They assumed that this lack of reactivity was due to the
favoured BBr3 coordination of the acetyl group, whereas
coordination of the bulky pivaloyl groups is sterically hin-
dered, thus not preventing the formation of an intermedi-
ary Lewis acid ether complex. Encouraged by this report
compound 3 was pivaloylated to give 6. Reaction of 6
with BBr3 followed by quenching with either H2O/
NaHCO3 or with MeOH and neutralisation with ion-ex-
change resin, gave a mixture of differently pivaloylated
derivatives of 1-deoxymannojirimycin (2), of which the
4,6-di-O-pivalate was the main compound. This crude
mixture was then treated with NaOMe in MeOH to give 2
as sole reaction product. Purification by column chroma-
tography afforded the desired crystalline iminosugar 2 in
a yield of 67% (Scheme 2).
In summary the very potent glycosidase inhibitor 1-
deoxymannojirimycin (2) was synthesized from 1,5-an-
hydro-D-fructose (1) via nucleophilic piperidine ring for-
mation and BBr3-induced pyran ether cleavage in a highly
stereoselective manner and with an overall yield of 35%
(7 steps) or 27% (6 steps), respectively.
The bicyclic iminosugar intermediate 2,6-anhydro-1-
deoxymannojirimycin (3) was also assayed for inhibition
of a selection of glycosidases. Bennet et al.13 showed that
the hydrochloride of 3 was inactive (Ki >1 mM) against a-
and b-D-glucosidases and a-D-mannosidase. We have
shown17 that 3 was a weak inhibitor of a-L-fucosidase
from bovine kidney (Ki 520 mM), while other tested gly-
cosidases were not inhibited to any extent. Since 2,6-an-
hydro-1-deoxymannojirimycin (3) is a conformationally
restricted azasugar, it is forced to adopt a boat-like confor-
mation (2,5B). This conformation is different from the con-
formation of the natural substrates and thus also from their
intermediates in the active site of the glycosidases.
The remarkable result of this BBr3 induced pyran ether
cleavage led to further investigations of the reaction. Con-
cerning the mechanism, it appears interesting to mention
that the ether cleavage occurred, independently whether
MeOH or H2O/NaHCO3 was used to hydrolyse the reac-
tion mixture and that the presence of a large excess of
O
C(CH3)3
+
NPiv
NPiv
N
+ O
δ
PivO
Br3B
PivO
PivO
O
–
δ
–
PivO
PivO OBBr3
PivO
B
A
3
OPiv
NH
PivO
HO
HO
NH
NH
H2O
NaOMe
MeOH
PivO
PivOδ
PivO
+
Oδ
+
HO
OH
HO
OH
-
2
BBr3
main primary product
C
Scheme 3 Suggested reaction mechanism for the BBr3-induced ether cleavage in 3
Synthesis 2006, No. 5, 827–830 © Thieme Stuttgart · New York

PAPER
Deoxymannojirimycin from 1,5-Anhydro-D-fructose
829
3
2
1H and 13C NMR spectra were recorded on a Varian Mercury 300
instrument. Chemical shifts were measured in deuterated solvents;
the solvent peak was used as reference (CDCl3: d = 7.26 for H,
4.32 (dd, J = 1.0 Hz, J = 11.0 Hz, 1 H, H-6b), 7.39–7.46, 7.73–
7.82 (m, 4 H, CHarom).
1
13C NMR (75 MHz, CD3OD): d = 21.7 (ArCH3), 53.8 (C-2), 67.3
(C-1), 68.4 (C-4), 71.0 (C-6), 71.7 (C-3), 80.2 (C-5), 129.2, 131.2
(CHarom), 134.2, 146.7 (Carom).
77.20 for 13C; MeOH-d4: d = 4.87 for 1H, 49.10 for 13C). NMR data
were assigned using HH- and CH-correlated spectra. Melting points
are uncorrected. Specific rotations were measured on a Perkin-
Elmer 241 polarimeter. Elemental analyses were performed by the
Institute of Physical Chemistry, Vienna. HR-MS was performed by
Bio Centrum, DTU. TLC was performed on Merck 60 F254 pre-
coated silica plates and spots were generally detected by spraying
with a solution of 1.5% NH4Mo2O2, 1% Ce(IV)SO4 and 10% H2SO4
or conc. HCl/MeOH (3:1) and 4-N,N-dimethylaminobenzaldehyde
(10 g/L), followed by charring. Flash chromatography was per-
formed on silica gel 60 (Merck, 40–63 mm). The solvents were con-
centrated on a rotary evaporator at a temperature below 45 °C. The
solvents were dried according to standard procedures and distilled
prior to use. Additions of chemicals were performed by using dis-
posable plastic syringes. Celite refers to Filter Aid from Celite Cor-
poration.
Anal. Calcd for C13H20ClNO6S: C, 44.13; H, 5.70; N, 3.96; Cl,
10.02. Found: C, 44.26; H, 5.75; N, 3.96; Cl, 9.92.
2,6-Anhydro-1,5-dideoxy-1,5-imino-D-mannitol (3)
Method a, from 5: The tosylated amine 5·HCl (165 mg, 0.47 mmol)
was dissolved in DMF (2 mL) and Et3N (0.07 mL, 0.50 mmol) was
added. The mixture was stirred for 16 h at r.t. and concentrated to
give a crude residue. Purification by flash chromatography [SiO2,
CH2Cl2–MeOH (5% NH3), 3:1] afforded 3 as a syrup (73 mg,
quant), which upon addition of a small amount of EtOH crystal-
lised; yield: 40 mg (59%); Rf 0.13 [CH2Cl2–MeOH (5% NH3), 2:1];
mp 176–184 °C; [a]D20 –64.3 (c 1.2, MeOH).
1H NMR (300 MHz, CD3OD): d = 3.02 (m, 1 H, H-5), 3.07 (dd,
3J = 1.5 Hz, 2J = 12.5 Hz, 1 H, H-1a), 3.33 (dd, 3J = 3.5 Hz,
2J = 12.5 Hz, 1 H, H-1b), 3.65 (dd, 3J = 1.5, 3.0 Hz, 1 H, H-3), 3.72
(ddd, 3J = 1.5, 1.5, 3.5 Hz, 1 H, H-2), 3.83 (m, 1 H, H-4), 3.90 (dd,
3J = 1.5 Hz, 2J = 10.0 Hz, 1 H, H-6a), 4.10 (dd, 3J = 2.5 Hz,
2J = 10.0 Hz, 1 H, H-6b).
1,5-Anhydro-6-O-tosyl-D-fructose O-benzyloxime (4)
O-Benzylhydroxylamine hydrochloride (5.7 g, 35.9 mmol) and
KOH pellets (85%, 2.35 g, 35.6 mmol) in EtOH (80 mL) were
stirred for 1 h at r.t. and filtered. The filtrate was cooled to 0 °C and
1,5-anhydro-D-fructose (1; 5.8 g, 35.9 mmol) was added as a solid
under argon. The mixture was stirred at r.t. overnight. Concentra-
tion gave 1,5-anhydro-D-fructose O-benzyloxime as a crude resi-
due, which crystallised on addition of Et2O (8.7 g, 91%).2b The
obtained 1,5-anhydro-D-fructose O-benzyloxime (7.0 g, 26.2
mmol) was dissolved in pyridine (130 mL) and cooled to –20 °C.
TsCl (4.5 g, 23.6 mmol) was added as a solid and the mixture was
stirred under argon at this temperature. Further portions of TsCl
(each 0.5 g, 2.6 mmol) were added after a reaction time of 17, 24
and 43 h. After 48 h, the reaction was quenched by addition of 6 M
HCl (80 mL) at –20 °C, EtOAc (200 mL) was added and the organic
layer was separated. The aqueous phase was extracted with EtOAc
(3 × 200 mL). The combined organic extracts were washed with sat.
aq NaHCO3 (40 mL), dried (MgSO4), filtered and concentrated in
vacuo. Purification by flash chromatography (SiO2, heptane–
EtOAc, 2:1) afforded 4 as a syrup; yield: 8.5 g (77%); Rf 0.45
(EtOAc); [a]D20 +2.7 (c 1.6, MeOH).
1H NMR (300 MHz, CD3OD): d = 2.42 (s, 3 H, ArCH3), 3.38 (dd,
3J = 7.6, 8.8 Hz, 1 H, H-4), 3.45 (ddd, 3J = 1.7, 6.2, 8.8 Hz, 1 H, H-
5), 3.77 (d, 2J = 15.0 Hz, 1 H, H-1a), 4.09 (d, 3J = 7.6 Hz, 1 H, H-
3), 4.13 (dd, 3J = 6.2 Hz, 2J = 10.9 Hz, 1 H, H-6a), 4.28 (dd, 3J = 1.7
Hz, 2J = 10.9 Hz, 1 H, H-6a), 4.89 (d, 2J = 15.0 Hz, 1 H, H-1b), 5.09
(s, 2 H, PhCH2Bn), 7.24–7.47, 7.74–7.82 (m, 9 H, CHarom).
13C NMR (75 MHz, CD3OD): d = 21.7 (ArCH3Ts), 62.3 (C-1), 71.0
(C-6), 73.2 (C-4), 74.4 (C-3), 77.4 (PhCH2), 78.9 (C-5), 129.0,
129.2, 129.3, 129.5, 131.1 (CHarom), 134.3, 139.0, 146.6 (Carom),
156.3 (C-2).
13C NMR (75 MHz, CD3OD): d = 45.6 (C-1), 51.9 (C-5), 66.3 (C-
6), 70.6 (C-2), 75.7 (C-4), 77.3 (C-3).
HRMS: m/z calcd for C6H11NO3: 145.0739 (M+); found: 145.0739.
Method b, from 4: The tosylated oxime 4 (2.1 g, 5.1 mmol) was dis-
solved in MeOH (120 mL) and a suspension of 10% Pd/C (255 mg)
in MeOH (40 mL) was added. The mixture was hydrogenated at 30
bar for 27 h. Filtration through Celite and concentration in vacuo
gave a crude residue, which was dissolved in pyridine and stirred at
r.t. overnight. The mixture was then concentrated in vacuo and co-
concentrated three times in vacuo with toluene to give a solid resi-
due, which upon addition of MeOH crystallised to give 3 as tolue-
nesulfonic acid salt; yield: yield: 1.0 g (62%). Purification of the
mother liquor by flash chromatography [SiO2, CH2Cl2–MeOH (5%
NH3), 4:1] afforded an additional amount of 3 (amine) as a syrup;
yield: 82 mg (11%).
3·TsOH
Mp 210–212 °C; [a]D20 –32.0 (c 1.2, MeOH).
1H NMR (300 MHz, CD3OD): d = 2.32 (s, 3 H, ArCH3), 3.19 (br d,
2J = 12.5 Hz, 1 H, H-1a), 3.26 (m, 1 H, H-5), 3.51 (dd, 3J = 3.8 Hz,
2J = 12.8 Hz, 1 H, H-1b), 3.53, 3.65, 3.86 (m, 3 H, H-2,3,4), 3.87 (br
d, 2J = 11.2 Hz, 1 H, H-6a), 4.08 (dd, 3J = 2.8 Hz, 2J = 11.2 Hz, 1 H,
H-6b) 7.18–7.21, 7.65–7.67 (m, 4 H, CHarom).
13C NMR (75 MHz, CD3OD): d = 21.4 (ArCH3), 44.5 (C-1), 51.9
(C-5), 62.5 (C-6), 68.1 (C-2), 72.5 (C-4), 75.8 (C-3), 127.0, 129.9
(CHarom), 141.9, 143.5 (Carom).
HRMS: m/z calcd for C20H24NO7S: 422.1273 (M + H+); found:
422.1290.
Anal. Calcd for C13H19NO6S: C, 49.20; H, 6.03; N, 4.41. Found: C,
48.97; H, 5.95; N, 4.27.
2-Amino-1,5-anhydro-2-deoxy-6-O-tosyl-D-mannitol (5·HCl)
Compound 4 (740 mg, 1.8 mmol) was dissolved in MeOH (40 mL)
and a suspension of 5% Pd/C (76 mg) and AcCl (0.25 mL, 3.5
mmol) in MeOH (10 mL) was added. The mixture was hydrogenat-
ed at 30 bar for 30 h. Filtration and concentration gave a foam,
which upon addition of Et2O crystallised to give 5 as its hydro-
chloride; yield: 507 mg (82%); mp 156–158 °C; [a]D20 –11.6 (c 1.2,
MeOH).
3,4-Di-O-pivaloyl-N-pivaloyl-2,6-anhydro-1,5-dideoxy-1,5-
imino-D-mannitol (6)
The toluenesulfonic acid salt of 3 (1.1 g, 3.5 mmol) was neutralised
with Amberlite IRA 400 (OH–) ion-exchange resin, the resin was
filtered off and the filtrate was concentrated in vacuo. The crystal-
line residue was dissolved in pyridine (20 mL), and DMAP (27 mg,
cat.) and pivaloyl chloride (5.0 mL, 40.6 mmol) were added. The
mixture was stirred at r.t. under argon overnight. The reaction was
quenched by the addition of ice, CH2Cl2 (100 mL) was added and
the organic layer was separated. The aqueous phase was extracted
with CH2Cl2 (3 × 100 mL). The combined organic extracts were
washed with sat. aq NaHCO3 (20 mL), dried (MgSO4), filtered,
1H NMR (300 MHz, CD3OD): d = 2.43 (s, 3 H, ArCH3), 3.32–3.50
(m, 3 H, H-2, H-4, H-5), 3.66 (dd, 3J = 1.5 Hz, 2J = 13.3 Hz, 1 H, H-
3
3
1a), 3.72 (dd, J = 4.8, 8.8 Hz, 1 H, H-3), 3.92 (dd, J = 1.5 Hz,
2J = 13.3 Hz, 1 H, H-1b), 4.09 (dd, J = 6.6, 11.0 Hz, 1 H, H-6a),
3
Synthesis 2006, No. 5, 827–830 © Thieme Stuttgart · New York

830
P. Maier et al.
PAPER
evaporated in vacuo and co-evaporated three times in vacuo with
References
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20
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1-Deoxymannojirimycin (2, 1,5-Dideoxy-1,5-imino-D-mannitol)
Compound 6 (364 mg, 0.915 mmol) was dissolved in anhyd CHCl3
(13 mL) and BBr3 (0.15 mL, 1.59 mmol) was added at r.t. under ar-
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3.01 (dd, 3J = 2.8 Hz, 2J = 14.2 Hz, 1 H, H-1b), 3.59 (dd, 3J = 3.0,
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(d) Fuhrmann, U.; Bause, E.; Legler, G.; Ploegh, H. Nature
1984, 307, 755.
(11) (a) Hamagashi, N.; Oku, H.; Mega, T.; Hase, S. J. Biochem.
(Tokyo) 1996, 119, 998. (b) Schweden, J.; Legler, G.;
Bause, E. Eur. J. Biochem. 1986, 157, 563.
3
2J = 11.8 Hz, 1 H, H-6a), 4.15 (dd, J = 3.4 Hz, 2J = 11.8 Hz, 1 H,
H-6b), 5.13 (dd, 3J = 9.7, 10.0 Hz, 1 H, H-4).
13C NMR (75 MHz, CD3OD): d = 27.6, 27.7 [C(CH3)3], 38.8, 39.9,
40.1 [C(CH3)3], 50.4 (C-1), 58.7 (C-5), 63.7 (C-6), 70.9, 71.0 (C-2,
C-3), 74.5 (C-4), 179.3, 179.5 (C=O).
HRMS: m/z calcd for C16H29NO6: 332.207 (M + H+); found:
332.2050.
(12) For some recent syntheses of 1, see: (a) Spreitz, J.; Stütz, A.
E.; Wrodnigg, T. M. Carbohydr. Res. 2002, 337, 183.
(b) Singh, O. V.; Han, H. Tetrahedron Lett. 2003, 44, 2387.
(c) Banwell, M. G.; Ma, X.; Asano, N.; Ikeda, K.; Lambert,
J. N. Org. Biomol. Chem. 2003, 1, 2035. (d) McDonnell,
C.; Cronin, L.; O’Brien, J. L.; Murphy, P. V. J. Org. Chem.
2004, 69, 3565.
(13) Bennet, A. J.; Tanaka, K. S. E. Can J. Chem. 1998, 76, 431.
(14) (a) Burwell, R. I. Jr. Chem. Rev. 1954, 54, 615. (b) Kropf,
H.; Thiem, J.; Nimz, H. In Houben-Weyl, 4th ed., Vol. 6/1a;
Kropf, H., Ed.; Thieme: Stuttgart, 1979, 309. (c) Bhatt, M.
V.; Kulkarni, S. U. Synthesis 1983, 249.
(15) (a) Mehta, G.; Ramesh, S. S. Tetrahedron Lett. 2003, 44,
3105. (b) Baran, A.; Kazaz, C.; Secen, H.; Sütbeyaz, Y.
Tetrahedron 2003, 59, 3643.
(16) Vogel, P.; Jotterand, N. Helv. Chim. Acta 1999, 82, 821.
(17) Andersen, S. M. Ph.D. Thesis; Technical University of
Denmark: Lyngby, 1999.
The residue was dissolved in MeOH (4 mL) and a solution of Na (42
mg, 1.83 mmol) in MeOH (2 mL) was added. The mixture was
stirred at r.t. overnight. It was then loaded on a column of Amberlite
IRA 120 (H+) ion-exchange resin. The column was first eluted with
MeOH and then with 24% aq NH3. The alkaline phase was evapo-
rated in vacuo and co-evaporated three times in vacuo with toluene
to give 1-deoxymannojirimycin (2) as the sole reaction product. Pu-
rification by flash chromatography [SiO2, CH2Cl2–MeOH (5%
NH3), 3:1] afforded 2 as a white foam (100 mg, 67%), which was
crystallised from MeOH–Et2O; mp 181–183 °C (Lit. mp 183–
185 °C;18 mp 185–187 °C19). The NMR data agreed with those re-
ported previously.20
Acknowledgment
This work was partially supported by the European Union under the
Cell Factory of 5th Framework Program, QLK3-2001-02400.
(18) Takahashi, S.; Kuzuhara, H. J. Carbohydr. Chem. 1998, 17,
117.
(19) Zou, W.; Szarek, W. A. Carbohydr. Res. 1994, 254, 25.
(20) Takahata, H.; Banba, Y.; Sasatani, M.; Nemoto, H.; Kato,
A.; Adachi, I. Tetrahedron 2004, 60, 8199.
Synthesis 2006, No. 5, 827–830 © Thieme Stuttgart · New York