A short and simple synthesis of 1-deoxynojirimycin derivatives from D-glucose

Article abstract of DOI:10.1055/s-2006-926369

Insertion of an amino functionality at C-5 of D-glucose with inversion of configuration, followed by imine formation with the latent aldehyde at C-1 and concomitant reduction furnished the 1-deoxynojirimycin skeleton. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926369

PAPER
1035
A Short and Simple Synthesis of 1-Deoxynojirimycin Derivatives from
D-Glucose
S
ynthesis of 1-Deo
s
xynojirim
h
ycin
D
erivat
i
ives m Roy, Basudeb Achari, Sukhendu B. Mandal*
Division of Medicinal Chemistry, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India
Fax +91(33)24735197; E-mail: sbmandal@iicb.res.in
Received 20 September 2005
and subsequent reductive ring expansion,8d (iii) opening
Abstract: Insertion of an amino functionality at C-5 of D-glucose
of the diepoxide formed at C-1/C-2 and C-5/C-6 by ben-
with inversion of configuration, followed by imine formation with
the latent aldehyde at C-1 and concomitant reduction furnished the
zyl amine,8e,8f or (iv) asymmetric dihydroxylation of an
a,b-unsaturated ester followed by the introduction of an
amino group through cyclic sulfite formation, nucleo-
philic opening of the ring by azide, and reduction to amino
function for reaction with the aldehyde group.8g Non-car-
bohydrate precursors such as myo-inositol,9a diethyl L-tar-
trate,9b pyrogutamic acid,9c and furan9d have also been
used to synthesize 1b. Besides, many asymmetric
synthesis10 and chemo-enzymatic synthesis11 are known
for 1b in the literature. However, we believe that the de-
velopment of shorter and efficient synthetic routes to nov-
el classes of enantiomerically pure polyhydroxylated
piperidines is still an important task. As a part of our pro-
gram directed towards the synthesis of polyhydroxylated
piperidines and pyrrolidines from D-glucose based sub-
strates, we report herein the synthesis of 1b (as its N,O-
protected derivatives 9–11) in optically pure form.
Scheme 1 retrosynthetically summarizes our envisioned
approach.
1-deoxynojirimycin skeleton.
Key words: 1-deoxynojirimycin, D-glucose, hydrogenolysis, cy-
clization
Naturally occurring or unnatural polyhydroxypiperidines
have been attractive synthetic targets for the last two de-
cades because such sugar mimics have shown significant
biological activity including glycosidase inhibition,1 tu-
mor growth inhibition,2 and anti-HIV effect.3 Among the
representative naturally occurring members which show
promising activity of medicinal interest are nojirimycin
(1a), 1-deoxynojirimycin (1b), 1-deoxymannojirimycin
(1c), and fagomine (1d) (Figure 1).
OH
OH
HO
HO
OH
HO
OH
N
H
N
H
OH
OH
OH
OR
1a
1b
NHCbz
H
RO
OR
OH
O
OH
O
H
OH
HO
OH
N
R
O
BnO
OR
2
N
N
H
H
OH
OH
O
1c
1d
O
H
Figure 1 Naturally occurring polyhydroxypiperidines 1a–d
O
O
1-Deoxynojirimycin (1b), isolated first from plants of ge-
nus Morus4 and later from strains of Bacillus5 and from
O
HO
3
mulberry tree,6 shows antiviral as well as antidiabetic ac- Scheme 1 Retrosynthetic analysis for 1b
tivity.7 Thus, intense research activity targeting the syn-
thesis of 1b has been going on, culminating in a large
Our strategy is based on the reductive cyclization of an
number of syntheses based on carbohydrate8 and non-car-
bohydrate precursors.9 The carbohydrate-derived strate-
gies mostly involved (i) judiciously placing an amino
group and an aldehyde (latent) or a suitable leaving group
at proper positions8a–c for ring closure and reduction if
necessary, (ii) radical cyclization of an appropriate oxime
amino functionality generated at C-5 of the glucose back-
bone with the latent aldehyde at C-1. Stereochemical con-
siderations necessitated an inversion of stereochemistry at
C-5 to produce the desired amine. Compound 2 was,
therefore, considered as a key intermediate for cycliza-
tion. This could be prepared from 1,2:5,6-di-O-isopro-
pylidene-a-D-glucofuranose (3) through a sequence of
reactions. Thus, benzylation of 3-OH of 3 with benzyl
bromide and 50% NaOH under phase-transfer condition
followed by selective deprotection of the 5,6 ketal with
SYNTHESIS 2006, No. 6, pp 1035–1039
x
x
.
x
x
.2
0
0
6
Advanced online publication: 10.03.2006
DOI: 10.1055/s-2006-926369; Art ID: P15005SS
© Georg Thieme Verlag Stuttgart · New York

1036
A. Roy et al.
PAPER
80% AcOH (Scheme 2) and preferential protection of the do molecular ion peaks at m/z 444 (M + H)+ and m/z 466
primary hydroxyl at C-6 with TBDMS-Cl at 0 °C fur- (M + Na)+ in the mass spectrum confirmed the structure of
nished 4. Mesylation of the C-5 hydroxyl group with the key intermediate 2.
MsCl and triethylamine afforded the mesylated derivative
5. Nucleophilic displacement of the mesyl group using
NaN3 in DMF failed to produce the azido compound 6
Removal of 1,2 protection from 2 (Scheme 3) created the
latent aldehyde 8, which was then subjected to catalytic
hydrogenation with the hope that the deprotected amino
when the reaction was carried out at 90 °C, but it delivered
group would undergo spontaneous intramolecular cy-
the desired product with the required stereochemistry at
clization with concomitant benzyl group deprotection to
generate the desired product 1b. To our surprise the O-
benzyl group remained intact in the product 9. Deprotec-
tion however, could ultimately be brought about by hy-
C-5 when carried out at 120 °C. Subsequent removal of
the TBDMS group from 6 using TBAF in THF afforded
the azido alcohol 7, which was then converted to an amino
alcohol by PPh3 in moist THF. The amino alcohol thus
drogenolysis using Pd(OH)2/C instead of Pd/C as catalyst.
produced was treated with benzyl chloroformate in pres-
Although the product gave the correct molecular ion in the
ence of NaHCO3 in MeOH to produce the key intermedi-
mass spectrum, the 1H NMR spectrum was not satisfacto-
ate 2. The structures of these compounds were
ry, pointing to the presence of an inseparable impurity.
unequivocally determined from spectral analysis. The ap-
We then acetylated this product as well as 9 to get the re-
pearance of two upfield signals at d = 0.07 and 0.91 in the
1
spective derivatives 10 and 11. The H NMR and 13C
1H NMR and at d = –5.5 and 25.8 in the 13C NMR spectra
NMR spectra of both 10 and 11 showed two sets of signals
confirmed the presence of TBDMS group in 4. Similarly,
for most of the protons and carbons indicating the pres-
1
disappearance of signals at d = 0.07 and 0.91 in the H
ence of the amide bond, which can exist as geometrical
NMR spectrum and presence of characteristic absorptions
isomers. The mass spectral analysis of 9, 10 and 11 was in
good agreement with the adopted structures as indicated.
at 2103 and 3462 cm–1 in the IR spectrum of 7 indicated
its azido alcohol structure. Regarding the structure of the
The stereochemistry at C-2, C-3, and C-4 in 9 should be
key intermediate 2, presence of the extra aromatic proton
1
the same as the corresponding carbons in D-glucose, as
these were not disturbed during the reaction sequence.
The b-orientation of the C-5 hydroxymethyl group in 9
was deduced from mechanistic consideration, i.e. nucleo-
philic displacement of mesyl group in 5 by NaN3 should
be accompanied by inversion of configuration to give the
product 6.
signals in the H NMR spectrum, and appearance of an
oxycarbonyl signal at d = 157.3 in addition to three meth-
ylene carbon signals in the 13C NMR indicated the inclu-
sion of the benzyloxycarbonyl functionality in the
structure of 2. Finally, the peak at 1709 cm–1 due to car-
bamate carbonyl in the IR spectrum and presence of pseu-
OTBDMS
OH
H
HO
NHCbz
H
O
O
a–c
O
H
OH
OH
a
H
3
2
O
BnO
BnO
4
8
d
b
OTBDMS
N3
OTBDMS
H
OBn
OBn
H
H
AcO
OAc
MsO
HO
OH
d
O
O
O
O
e
H
N
N
H
O
OAc
O
BnO
Ac
OH
BnO
6
5
11
9
c, d
f
OH
N3
OAc
AcO
OAc
H
H
O
O
g,h
2
N
OAc
O
Ac
BnO
10
7
Scheme 2 Reagents and conditions: (a) BnBr, CH2Cl2, 50% NaOH,
Bu4NBr, 12 h, r.t.; (b) 80% AcOH, r.t., 12 h; (c) TBDMS-Cl, imid-
azole, CH2Cl2, 0 °C, 1.5 h; (d) MsCl, Et3N, CH2Cl2, 0 °C; (e) NaN3,
DMF, 120 °C; (f) Bu4NF, THF, r.t.; (g) PPh3, moist THF, r.t., 24 h;
(h) Cbz-Cl, NaHCO3, MeOH.
Scheme 3 Reagents and conditions: (a) TFA–H2O (3:2), r.t., 3 h; (b)
H2, Pd/C (10%), MeOH; (c) H2, Pd(OH)2/C, MeOH; (d) Ac2O, Py, 12
h.
Synthesis 2006, No. 6, 1035–1039 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Deoxynojirimycin Derivatives
1037
1H and 13C NMR spectra were recorded on a Bruker AM 300 L
spectrometer using either CDCl3 or D2O as solvent and TMS as in-
ternal standard. Mass spectra were obtained using Micromass Q-
Tof MicroTM spectrometer. IR spectra were measured on a JASCO
700 spectrophotometer. Elemental analyses were carried out with a
C,H,N-analyzer. Specific rotations were measured at 589 nm on a
JASCO P-1020 polarimeter. TLC was performed on pre-coated
plates (0.25 nm, silica gel, 60 F254). Petroleum ether (PE) used refers
to the fraction boiling in the range 60–80 °C.
[2-Azido-2-(6-benzyloxy-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl)ethoxy]-tert-butyl dimethylsilane (6)
A mixture of 5 (4.8 g, 9.5 mmol) and NaN3 (6.2 g) in anhyd DMF
(15 mL) was heated at 120 °C for 20 h. The mixture was cooled to
r.t. and the solvent was evaporated under reduced pressure. The
mixture was extracted with CHCl3 (3 × 30 mL), the combined ex-
tracts were washed with H2O (3 × 30 mL), dried (Na2SO4) and
evaporated. The crude product was purified by chromatography on
a silica gel column using CHCl3–PE (1:1) as eluent to afford 6 as a
thick liquid (2.8 g, 55%); [a]D25 –38.2 (c 0.22, CHCl3).
1-(6-Benzyloxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-
5-yl)-2-(tert-butyldimethylsilyloxy)ethanol (4)
IR (neat): 2101, 1466, 1377, 1256, 1121, 1078, 1023, 837 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.02 (s, 3 H), 0.05 (s, 3 H), 0.89
(s, 9 H), 1.33 (s, 3 H), 1.51 (s, 3 H), 3.55 (dd, 1 H, J = 11.2 Hz),
3.69–3.74 (m, 2 H), 3.90 (d, 1 H, J = 3.1 Hz), 4.30 (dd, 1 H, J = 3.2,
8.3 Hz), 4.46 (d, 1 H, J = 11.8 Hz), 4.68 (d, 1 H, J = 3.7 Hz), 4.74
(d, 1 H, J = 11.8 Hz), 6.00 (d, 1 H, J = 3.6 Hz), 7.28–7.37 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = –5.24 (CH3), –5.17 (CH3), 18.5
(C), 26.2 (3 × CH3), 26.8 (CH3), 27.2 (CH3), 62.4 (CH), 63.6 (CH2),
72.0 (CH2), 79.3 (CH), 81.9 (CH), 82.3 (CH), 105.2 (CH), 112.3
(C), 128.4 (2 × CH), 128.6 (CH), 129.0 (2 × CH), 137.3 (C).
A solution of 3 (5.0 g, 19.2 mmol) in CH2Cl2 (30 mL) was treated
with benzyl bromide (3.4 mL, 28.8 mmol), 50% NaOH (20 mL) and
Bu4NBr (0.62 g, 1.92 mmol) and the mixture was stirred at r.t. for
12 h. The organic layer was washed repeatedly with H2O (4 × 30
mL), dried (Na2SO4), and evaporated to furnish a sticky material
which was then subjected to column chromatography over silica gel
(60–120 mesh). Elution with CHCl3–PE (3:7) afforded 3-O-benzyl
1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (5.25 g, 78%). The
material was dissolved in 80% AcOH (25 mL) and stirred at r.t. for
12 h. The solvent was evaporated under vacuum and the last trace
of AcOH was removed through coevaporation with toluene (3 × 50
mL) to obtain a crude residue. This was purified by column chroma-
tography over silica gel (60–120 mesh) using CHCl3–MeOH (49:1)
to afford the corresponding dihydroxy glucose (4.1 g, 89%). To a
stirred solution of this compound (4.0 g, 12.9 mmol) in anhyd
CH2Cl2 (20 mL) at 0 °C was added TBDMS-Cl (1.94 g, 12.9 mmol)
and imidazole (2.63 g, 38.7 mmol), and the mixture was allowed to
stir at this temperature for 1.5 h. The organic layer was washed with
H2O (3 × 30 mL), dried (Na2SO4) and evaporated to give a gummy
mass, which was purified by column chromatography over silica gel
(60–120 mesh). Quick elution with CHCl3–PE (1:1) gave 4 (4.9 g,
89%) as a gummy liquid; [a]D25 –22.0 (c 0.54, CHCl3).
ESI-MS: m/z = 472 (M + Na)+.
Anal. Calcd for C22H35N3O5Si: C, 58.77; H, 7.85; N, 9.35. Found:
C, 58.65; H, 7.78; N, 9.21.
2-Azido-2-(6-benzyloxy-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxole-5-yl)ethanol (7)
To a solution of 6 (2.7 g, 6.01 mmol) in THF was added Bu4NF
(2.84 g, 9.01 mmol) and the mixture was stirred at r.t. for 24 h. The
solvent was evaporated under reduced pressure and the residue was
extracted with CHCl3 (3 × 30 mL). The combined extracts were
washed with H2O (2 × 30 mL), dried (Na2SO4) and evaporated to
afford a crude product. Purification by column chromatography
over silica gel furnished 7 (1.6g, 80%) as a gummy material from
CHCl3–PE (3:2) eluate; [a]D25 –41.6 (c 0.56, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.07 (s, 6 H), 0.91 (s, 9 H), 1.30
(s, 3 H), 1.47 (s, 3 H), 3.73–3.83 (m, 2 H), 3.98–4.03 (m, 1 H), 4.09–
4.14 (m, 2 H), 4.59 (d, 1 H, J = 3.7 Hz), 4.66 (d, 1 H, J = 11.8 Hz),
4.71 (d, 1 H, J = 11.8 Hz), 5.91 (d, 1 H, J = 3.7 Hz), 7.25–7.36 (m,
5 H).
IR (neat): 3478, 2103, 1455, 1378, 1258, 1215, 1163, 1077, 1021,
858 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33 (s, 3 H), 1.50 (s, 3 H), 3.40
(dd, 1 H, J = 5.9, 11.6 Hz), 3.57 (dd, 1 H, J = 3.4, 11.6 Hz), 3.88 (m,
1 H), 3.92 (d, 1 H, J = 3.3 Hz), 4.25 (dd, 1 H, J = 3.3, 8.8 Hz), 4.44
(d, 1 H, J = 11.7 Hz), 4.66 (d, 1 H, J = 3.8 Hz), 4.71 (d, 1 H, J = 11.7
Hz), 5.98 (d, 1 H, J = 3.8 Hz), 7.29–7.40 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = –5.56 (2 × CH3), 18.1 (C), 25.8
(3 × CH3), 26.1 (CH3), 26.5 (CH3), 64.3 (CH2), 68.3 (CH), 72.2
(CH2), 79.3 (CH), 81.7 (CH), 82.3 (CH), 104.9 (CH), 111.4 (C),
127.6 (2 × CH), 127.7 (CH), 128.3 (2 × CH), 137.5 (C).
ESI-MS: m/z = 358 (M + Na)+.
ESI-MS: m/z = 447 (M + Na)+.
Anal. Calcd for C16H21N3O5: C, 57.30; H, 6.31; N, 12.53. Found: C,
57.12; H, 6.18; N, 12.28.
Anal. Calcd for C22H36O6Si: C, 62.23; H, 8.55. Found: C, 62.15; H,
8.51.
[1-(6-Benzyloxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-
5-yl)-2-hydroxyethyl]carbamic Acid Benzyl Ester (2)
Methanesulfonic Acid (6-Benzyloxy-2,2-dimethyltetrahydro-
furo[2,3-d][1,3]dioxol-5-yl)-2-(tert-butyldimethylsilyloxy)ethyl
Ester (5)
A solution of 7 (1.6 g, 4.77 mmol) and PPh3 (1.5 g, 5.72 mmol) in
moist THF (15 mL) was stirred at r.t. for 24 h. The solvent was
evaporated under reduced pressure and the crude product was sub-
jected to column chromatography over basic alumina. Elution with
CHCl3 furnished a crude amino alcohol (1.0 g, 68%). To a stirred
solution of this amino alcohol (0.9 g, 2.91 mmol) in MeOH at 0 °C
was added NaHCO3 (0.97 g) and benzyl chloroformate (0.6 g, 0.5
mL), and the mixture was stirred at r.t. for 3 h. The solvent was
evaporated, H2O (1.0 mL) was added and the mixture was then ex-
tracted with CHCl3 (3 × 20 mL). The combined extracts were
washed with H2O (3 × 10 mL), dried (Na2SO4) and evaporated in
vacuo to yield a crude residue, which was purified by column chro-
matography over silica gel (60–120 mesh). Elution with CHCl3 fur-
MeSO2Cl (1.0 mL, 1.47 g, 12.9 mmol) was added dropwise to an
ice-cold solution of 4 (4.5 g, 10.6 mmol) in anhyd CH2Cl2 (30 mL)
and the mixture was stirred for 10 min. Et3N (2.9 mL) was then add-
ed dropwise and the stirring was continued at this temperature for 1
h. The organic layer was washed repeatedly with aq sat. solution of
NaHCO3 (2 × 10 mL) and H2O (3 × 30 mL), dried (Na2SO4) and
25
evaporated to give 5 (4.8 g, 90%) as a yellow gummy liquid; [a]D
–19.1 (c 0.46, CHCl3).
IR (neat): 1638, 1459, 1357, 1255, 1176, 1078, 924 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.08 (s, 6 H), 0.90 (s, 9 H), 1.30
(s, 3 H), 1.48 (s, 3 H), 3.07 (s, 3 H), 3.87 (dd, 1 H, J = 6.0, 12.0 Hz),
4.06–4.10 (m, 2 H), 4.35 (dd, 1 H, J = 2.8, 7.9 Hz), 4.57 (d, 1 H,
J = 2.8 Hz), 4.59 (d, 1 H, J = 10.1 Hz), 4.69 (d, 1 H, J = 11.0 Hz),
5.03–5.07 (m, 1 H), 5.87 (d, 1 H, J = 3.4 Hz), 7.29–7.40 (m, 5 H).
25
nished 2 (800 mg, 62%) as a thick liquid; [a]D –20.0 (c 0.49,
CHCl3).
IR (neat): 3423, 1709, 1520, 1455, 1378, 1217, 1162, 1075, 1024
cm–1.
ESI-MS: m/z = 525 (M + Na)+.
Synthesis 2006, No. 6, 1035–1039 © Thieme Stuttgart · New York

1038
A. Roy et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 1.32 (s, 3 H), 1.48 (s, 3 H), 2.89
(br s, 1 H), 3.68 (m, 2 H), 3.98 (d, 1 H, J = 3.0 Hz), 4.00–4.10 (m,
1 H), 4.33 (dd, 1 H, J = 3.1, 6.5 Hz), 4.46 (d, 1 H, J = 11.6 Hz), 4.62
(d, 1 H, J = 4.0 Hz), 4.65 (d, 1 H, J = 12.3 Hz), 4.96–5.09 (m, 2 H),
5.39 (br s, 1 H), 5.93 (d, 1 H, J = 3.8 Hz), 7.31 (br s, 10 H).
Anal. Calcd for C16H23NO9: C, 51.47; H, 6.21; N, 3.75. Found: C,
51.29; H, 6.09; N, 3.50.
Acetic Acid 5-Acetoxy-2-acetoxymethyl-1-acetyl-4-benzyloxy-
piperidin-3-yl Ester (11)
To a solution of O-benzylated product 9 (35 mg, 0.14 mmol) in py-
ridine (2 mL) was added Ac2O (0.2 mL). The mixture was stirred at
r.t. for 12 h. The crude product obtained after evaporation of solvent
was purified by column chromatography over silica gel (60–120
mesh) to give 11 (40 mg, 69%) as a gummy liquid; [a]D +6.5 (c
0.6, CHCl3).
1H NMR (300 MHz, CDCl3): d (no integration is given due to over-
lap of signals) = 1.99–2.17 (several overlapped s), 2.55–2.64 (m),
3.16 (dd, J = 11.2, 13.4 Hz), 3.75 (t, J = 9.3 Hz), 3.80 (t, J = 9.3
Hz), 3.98 (dd, 1 H, J = 5.5, 13.6 Hz), 4.11–4.19 (m), 4.41–4.53 (m),
4.68–4.89 (m), 4.92–5.05 (m), 5.27 (br s), 7.24–7.33 (m).
13C NMR (75 MHz, CDCl3): d = 21.0 (CH3), 21.18 (CH3), 21.22
(CH3), 21.8 (CH3), 22.0 (CH3), 38.2 (CH2), 43.8 (CH2), 49.2 (CH),
54.3 (CH), 59.2 (CH2), 60.0 (CH2), 70.66 (CH), 70.72 (CH), 72.2
(CH), 72.3 (CH), 75.0 (CH2), 75.2 (CH2), 78.2 (CH), 128.0 (CH),
128.2 (CH), 128.3 (CH), 128.8 (CH), 138.3 (C), 169.5 (C), 169.7
(C), 170.2 (C), 170.4 (C), 170.6 (C), 170.8 (C), 171.0 (C).
13C NMR (75 MHz, CDCl3): d = 26.6 (CH3), 27.1 (CH3), 52.8 (CH),
63.7 (CH2), 67.3 (CH2), 72.3 (CH2), 78.7 (CH), 82.39 (CH), 82.44
(CH), 105.1 (CH), 112.2 (C), 128.3 (CH), 128.5 (CH), 128.6 (CH),
128.9 (CH), 129.0 (CH), 129.1 (CH), 136.8 (C), 137.2 (C), 157.3
(C).
25
ESI-MS: m/z = 444 (M + H)+, 466 (M + Na)+.
Anal. Calcd for C24H29NO7: C, 65.00; H, 6.59; N, 3.16. Found: C,
64.86; H, 6.47; N, 2.89.
[1-(3-Benzyloxy-4,5-dihydroxytetrahydrofuran-2-yl)-2-hy-
droxyethyl]carbamic Acid Benzyl Ester (8)
Compound 2 (0.75 g, 1.7 mmol) was dissolved in a mixture of
TFA–H2O (3:2, 5 mL) and the solution was kept at r.t. for 5 h, when
TLC showed complete disappearance of the starting material. The
solvent was evaporated under reduced pressure and the last trace of
trifluoroacetic acid was co-evaporated with benzene to afford 8 as a
gummy residue (0.61 g, 89%), which was sufficiently pure and used
in the next step.
ESI-MS: m/z = 444 (M + Na)+.
1H NMR (300 MHz, CDCl3): d = 1.94 (br s, 3 H, 3 × OH), 3.43 (t,
1 H, J = 7.5 Hz), 3.70 (apparent t, 1 H), 3.86 (m, 1 H), 4.03 (d, 1 H,
J = 8.1 Hz), 4.49 (br s, 1 H), 4.74 (d, 1 H, J = 11.7 Hz), 4.93 (d, 1
H, J = 11.7 Hz), 5.16 (s, 2 H), 5.55 (s, 1 H), 7.35 (s, 10 H).
Anal. Calcd for C21H27NO8: C, 59.85; H, 6.46; N, 3.32. Found: C,
59.67; H, 6.38; N, 3.05.
Acknowledgment
ESI-MS: m/z = 426 (M + Na)+.
A.R. gratefully acknowledges the Council of Scientific and Indus-
trial Research, New Delhi, India for providing him a Senior Re-
search Fellowship.
4-Benzyloxy-2-hydroxymethylpiperidine-3,5-diol (9)
To a solution of 8 (0.5 g, 1.24 mmol) in MeOH was added 10% Pd/
C (0.1 g) and the mixture was hydrogenated for 24 h, when TLC
showed complete disappearance of the starting material. The cata-
lyst was filtered off, washed with MeOH and the total filtrate was
concentrated to give pure 9 (140 mg, 45%) as a sticky gum; [a]D
+2.6 (c 1.1, MeOH).
1H NMR (300 MHz, D2O): d = 3.26 (br s, 2 H), 3.40 (t, 1 H, J = 6.3
Hz), 3.75 (m, 3 H), 4.06 (m, 2 H), 4.61 (s, 2 H), 7.33 (s, 5 H).
13C NMR (75 MHz, D2O): d = 45.8 (CH2), 56.8 (CH), 59.5 (CH2),
66.7 (CH), 67.2 (CH), 73.3 (CH2), 76.8 (CH), 128.9 (CH), 129.0
(CH), 129.1 (CH), 137.7 (C).
References
25
(1) (a) De Raadt, A.; Ekhart, C. W.; Ebner, M.; Stutz, A. E. Top.
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Eds.; Springer: Berlin, Heidelberg, 1997, 158. (c) Sinnott,
M. L. Chem. Rev. 1990, 90, 1171.
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1985, 4, 81. (b) Tsukamoto, K.; Uno, A.; Shimada, S.;
Imokaw, G. Clin. Res. 1989, 37A, 722.
ESI-MS: m/z = 254 (M + H)+.
(3) Gruters, R. A.; Neefjes, J. J.; Tersmette, M.; De Goede, R. E.
Y.; Tulp, A.; Huisman, H. G.; Miedema, F.; Ploegh, H. L.
Nature 1987, 330, 74.
Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56; N, 5.53. Found: C,
61.41; H, 7.45; N, 5.30.
(4) Yagi, M.; Kouno, T.; Aoyagi, Y.; Murai, H. Nippon Nogei
Kagaku Kaishi 1976, 50, 571; Chem. Abstr. 1977, 86,
167851r.
Acetic Acid 4,5-Diacetoxy-2-acetoxymethyl-1-acetylpiperidin-
3-yl Ester (10)
(5) Schmidt, D. D.; Frommer, W.; Muller, L.; Truscheit, E.
To a solution of 9 (0.1 g, 0.4 mmol) in MeOH was added 10%
Pd(OH)2/C (25 mg) and the mixture was hydrogenated for 6 h. The
catalyst was filtered off, the solvent was evaporated and the crude
residue was dried (over P2O5) in vacuo. To this crude residue (45
mg) dissolved in pyridine (2 mL) was added Ac2O (0.2 mL) and the
mixture was allowed to stir at r.t. for 12 h. The solvent was evapo-
rated in vacuo and the crude product obtained was purified by col-
umn chromatography over silica gel (60–120 mesh). Elution with
Naturwissenschaften 1979, 66, 584.
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1986, 34, 2243.
(7) Lindstrom, U. M.; Somfai, P. Tetrahedron Lett. 1998, 39,
7173.
(8) (a) Baxter, E. W.; Reitz, A. B. J. Org. Chem. 1994, 59,
3175. (b) Fleet, G. W. J.; Carpenter, N. M.; Petursson, S.;
Ramsdena, N. G. Tetrahedron Lett. 1990, 31, 409.
(c) Anzeveno, P. B.; Creemer, L. J. Tetrahedron Lett. 1990,
31, 2085. (d) Kiguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T.;
Hiramatsu, H. Tetrahedron Lett. 1995, 36, 253. (e) Poitout,
L.; Merrer, Y. L.; Depezay, J. C. Tetrahedron Lett. 1994, 35,
3293. (f) Merrer, Y. L.; Poitout, L.; Depezay, J. C.; Dosbaa,
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25
EtOAc–PE (3:22) afforded 10 (72 mg, 70%) as a thick liquid; [a]D
+3.1 (c 0.12, CHCl3).
1H NMR (300 MHz, CDCl3): d (no integration is given due to over-
lap of signals) = 2.03–2.16 (m), 2.71 (t-like), 3.12 (t-like, J = 12.3
Hz), 3.31 (t-like), 3.95–4.05 (m), 4.16–4.20 (m), 4.40 (br t), 4.55 (d,
J = 7.1 Hz), 4.73–5.04 (m), 5.15 (t, overlapping with other signal),
5.30–5.44 (m, overlapping with other signal).
ESI-MS: m/z = 396 (M + Na)+, 374 (M + H)+.
Synthesis 2006, No. 6, 1035–1039 © Thieme Stuttgart · New York

PAPER
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Synthesis of 1-Deoxynojirimycin Derivatives
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Synthesis 2006, No. 6, 1035–1039 © Thieme Stuttgart · New York