A nitro sugar mediated synthesis of 6-amino-1,5,6-trideoxy-1,5-imino-d-glucitol (6-amino-1,6-dideoxynojirimycin)

Article abstract of DOI:10.1016/j.tetasy.2009.02.033

6-Benzoylamino-3-O-benzyl-1,5,6-trideoxy-N-(1,1-diphenylmethyl)-1,5-imino-d-glucitol 12a and its epimer 6-benzoylamino-3-O-benzyl-1,5,6-trideoxy-N-(1,1-diphenylmethyl)-1,5-imino-l-iditol 12b, the protected forms of 6-amino-1,6-dideoxynojirimycin 4 and its C-5 epimer 5, respectively, were easily prepared from diacetone-d-glucose via 6-O-benzoyl-3-O-benzyl-1,2-O-isopropylidene-5-C-nitromethyl-α-d-glucofuranose 7a or 6-O-benzoyl-3-O-benzyl-1,2-O-isopropylidene-5-C-nitromethyl-β-l-idofuranose 7b. 6-Amino-1,6-dideoxynojirimycin 4 (an important precursor of a wide range of glycosidase inhibitors) was easily prepared from 1,5-imino-d-glucitol 12a.

Full text of DOI:10.1016/j.tetasy.2009.02.033

Tetrahedron: Asymmetry 20 (2009) 503–507
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A nitro sugar mediated synthesis of 6-amino-1,5,6-trideoxy-1,5-imino-D-glucitol
(6-amino-1,6-dideoxynojirimycin)
*
*
M. Begoña Pampín, Fernando Fernández, Juan C. Estévez , Ramón J. Estévez
Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
6-Benzoylamino-3-O-benzyl-1,5,6-trideoxy-N-(1,1-diphenylmethyl)-1,5-imino-
epimer 6-benzoylamino-3-O-benzyl-1,5,6-trideoxy-N-(1,1-diphenylmethyl)-1,5-imino-
protected forms of 6-amino-1,6-dideoxynojirimycin 4 and its C-5 epimer 5, respectively, were easily pre-
pared from diacetone- -glucose via 6-O-benzoyl-3-O-benzyl-1,2-O-isopropylidene-5-C-nitromethyl-
glucofuranose 7a or 6-O-benzoyl-3-O-benzyl-1,2-O-isopropylidene-5-C-nitromethyl-b- -idofuranose 7b.
6-Amino-1,6-dideoxynojirimycin 4 (an important precursor of a wide range of glycosidase inhibitors)
was easily prepared from 1,5-imino- -glucitol 12a.
D
-glucitol 12a and its
Received 27 January 2009
Accepted 24 February 2009
Available online 25 March 2009
L
-iditol 12b, the
D
a-D-
L
D
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
that results in an improvement in the glycosidase inhibitory
activity.4 In fact, some of the latter compounds are therapeutically
useful drugs.5
Glycobiology is an emerging research area in which glycosi-
dases have received considerable attention on account of their
involvement in a number of metabolic pathways.1 Accordingly,
the inhibition of glycosidases has become a powerful strategy for
the treatment of several important diseases, such as diabetes, can-
cer and viral infections, including AIDS.2 This situation has led to
considerable effort in recent years aimed at understanding the
structure types, action mechanisms and synthesis of glycosidase
inhibitors.3
Our strategy was first applied to the D-glucose 6-amino deriva-
tives of 1-DNJ, for example, compounds 4 and 5, which played an
important role in glycosidase studies, not only because of their
weak inhibition properties, but also because they are synthetic
precursors of a wide range of glycosidase inhibitors.6 Several
methods have been described for the synthesis of 1-DNJ and its
analogues.4 However, very few syntheses of 6-amino-1-deoxy-
nojirimycins have been reported.7
The most common glycosidase inhibitors are imino sugars such
as the polyhydroxylated nitrogen-containing ring skeletons identi-
cal to those of sugars that mimic the enzyme. The parent iminosug-
ar is nojirimycin 1 (Fig. 1), which can be regarded as the result of
Nitrosugars are powerful synthetic materials that combine the
synthetic potential of sugars and the chemical versatility of the
nitro group; for example, for the formation of carbon–carbon
bonds prior to conversion into a range of other functionalities,
including reduction to an amino group.8 In connection with our
recent investigations on nitrosugars,9 we report here the new syn-
thesis of 6-amino-1,6-dideoxynojirimycin 4, which is shown in
Scheme 1.
the replacement of the ring oxygen of
D-glucose by a nitrogen
atom. On the other hand, 1-deoxynojirimycin 2 (1-DNJ) and ana-
logues are the compounds where the hemiacetal functionality is
replaced by an aminomethylene group, a structural modification
OH
OH
NH2
NH2
OH
H
N
H
N
H
N
H
N
OH
N
HO
OH HO
OH
HO
OH HO
OH
HO
OH
OH
OH
OH
OH
OH
1
2
3
4
5
Figure 1.
* Corresponding authors.
E-mail address: ramon.estevez@usc.es (R.J. Estévez).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.033

504
M. Begoña Pampín et al. / Tetrahedron: Asymmetry 20 (2009) 503–507
BzO
O
BzO
HO
HO
HO
O
O
O
O
O
(i)
(ii)
(iii)
O
O
O
O
BzHN
O2N
BzHN
O
BnO
O
O
O
BnO
(iv)
BnO
7a:
7b:
BnO
8a:
8b:
9
OH
OH
OH
OH
6
BzHN
BzHN
BzHN
O
CHPh2
CHPh2
OH
CHPh2
AcO
O
N
N
(v)
OH
OH
N
HO
HO
BnO
HO
BnO
BzHN
BnO
BnO
OH
(44%)
10
OH
12a
12b (19%)
11
(vi)
+
Cl-
NH3
+
NH2
Cl-
HO
HO
OH
4
Scheme 1. Reagents and conditions: (i) KFꢀ2H2O, 18-crown-6 ether, CH3NO2, rt, 1 h (60% yield); (ii) H2, Ni-Raney, MeOH, rt (52% yield); (iii) NaIO4, CH2Cl2, H2O, SiO2, rt, 6 h
(86% yield); (iv) TFA, H2O, rt, 12 h; (v) H2NCHPh2, NaCNBH3, AcOH, MeOH, ꢁ78 to rt (63% yield); (vi) (a) Pd/C, HCOONH4, 70 °C, 1 h; (b) HCl (6 M), 50 °C, 3 d (64% yield).
of a 1:1.5 mixture of the D-gluco derivative 8a and the L-ido deriv-
2. Results and discussion
ative 8b, as established from the 1H NMR spectrum of the epimeric
mixture.
A Henry reaction of the known D
-glucose derivative ketone 610
The formation of compound 8a can be explained in terms of the
expected reduction of the nitro group of 7a to the amino group in
compound 13 (Scheme 3), which under the reaction conditions
rearranged spontaneously to 8a as a result of an intramolecular
transfer of its benzoyl group from the oxygen to the nitrogen. Com-
pound 8b should result from 7b in a similar manner.
with nitromethane, using KF as the base, gave a 60% yield of a
58:42 mixture of the C-5 nitromethyl- -glucofuranose 7a and
the C-5 nitromethyl-b-
-idofuranose 7b, as established by 1H
NMR spectroscopy. Careful chromatographic separation allowed
the epimer 7a to be isolated and its structure was established by
X-ray diffraction.11
a-D
L
Treatment of a suspension of the mixture of 8a + 8b and silica
gel in dichloromethane with aqueous sodium periodate at room
temperature resulted in an oxidative degradation of the 1,2-diole
system, which gave ketone 9 in 86% yield. Compound 9 was then
reacted with a mixture of trifluoroacetic acid and water in order
to remove the acetonide protecting group. The resulting compound
10 was reacted with diphenylmethylamine in acidic conditions and
underwent a heteroannulation process that provided the iminium
The ratio of 7a:7b can be explained in terms of the Felkin–Ahn
model (Scheme 2). Thus, the depicted attack of the nitronate anion
of nitromethane onto conformer 6a led to the major adduct 7a. On
the other hand, the alternative attack of this nitronate anion on the
carbonyl group of conformer 6b, which is less favoured than the
former, provided the minor stereoisomer 7b.
Hydrogenation of the mixture of 7a + 7b at room temperature,
using Raney-Ni as the catalyst, unexpectedly provided a 52% yield
O
O
BzO
BzO
O
O
O
O
HO
OBn
O
O
O
O
O
O2N
HO
BnO
O2N
O
O
O
BnO
Nü
6a
Nü
H
OBn
OBz
H
OBz
7a
6b
7b
Scheme 2.
O
O
BzO
O2N
HO
BzHN
Ph
H2N
O
O
O
O
O
O
HO
BnO
HO
BnO
HO
BnO
O
O
O
13
7a
8a
Scheme 3.

M. Begoña Pampín et al. / Tetrahedron: Asymmetry 20 (2009) 503–507
505
salt 11. This compound was reacted with sodium cyanoborohy-
4.1. 6-O-Benzoyl-3-O-benzyl-1,2-O-isopropylidene-5-C-
nitromethyl- -glucofuranose 7a and 6-O-benzoyl-3-O-
benzyl-1,2-O-isopropylidene-5-C-nitromethyl-b-L-
dride to give an epimeric mixture of 12a + 12b, as a result of hydro-
genation the C@N bond of 11, from which both piperidines 12a
(the thermodynamically more stable epimer) and 12b (the thermo-
dynamically less stable component) were isolated in 24% and 9%
yields, respectively, after careful column chromatography. The
structure of the minor component 12b was established by X-ray
diffraction (Fig. 2).12
a-D
idofuranose 7b
KFꢀ2H2O (0.46 g, 4.90 mmol) and 18-crown-6 ether (0.82 g,
3.10 mmol) were added to solution of ketone (1.19 g
a
6
(2.90 mmol) in nitromethane (18 mL) and the resulting suspension
was stirred at room temperature for 1 h. The reaction mixture was
added to a mixture of ice/water (50 mL) and extracted with ethyl
acetate (3 ꢂ 80 mL). The organic layers were then dried with anhy-
drous sodium sulfate, filtered and evaporated to give a residue,
which was purified by flash column chromatography (ethyl ace-
tate/hexane 1:3) to give 6-O-benzoyl-3-O-benzyl-1,2-O-isopropyl-
idene-5-C-nitromethyl-
6-O-benzoyl-3-O-benzyl-1,2-O-isopropylidene-5-C-nitromethyl-b-
-idofuranose 7b (0.36 g, 26%) as solids, which were crystallized
a-D-glucofuranose 7a (0.47 g, 34%) and
L
from a mixture of ethyl acetate and hexane.
Compound 7a: mp: 102–106 °C (ethyl acetate/hexane).
½
a 2D2
ꢃ
¼ ꢁ75:6 (c 1.00, CHCl3). IR (NaCl,
m
, cmꢁ1): 3454 (OH);
2854–3064 (CArH); 1722 (CO); 1554, 1375 (NO2). 1H NMR
(250 MHz, CDCl3) d 1.32 (s, 3H, CH3); 1.46 (s, 3H, CH3); 4.30 (d,
1H, J3,4 = 3.35 Hz, H-3); 4.38 (d, 1H, J4,3 = 3.35 Hz, H-4); 4.42–4.47
(m, 2H, CH2NO2); 4.54–4.60 (m, 2H, H-6 + H-60); 4.66 (d, 1H,
J2,1 = 3.65 Hz, H-2); 4.73 (d, 1H, J = 11.87 Hz, CHPh); 4.80 (s, 1H,
OH); 4.91 (d, 1H, J = 11.87 Hz, CHPh); 6.02 (d, 1H, J1,2 = 3.65 Hz,
H-1); 7.31–7.61 (m, 8H, 8 ꢂ HPh); 7.98–8.01 (m, 2H, 2 ꢂ HPh).
13C NMR (62.8 MHz, CDCl3) d 26.17 (CH3); 26.56 (CH3); 65.34
(CH2); 72.40 (CH2); 73.05 (CH2); 77.62 (CH); 77.76 (C); 81.38
(CH); 82.99 (CH); 104.53 (CH); 112.19 (C); 128.21 (2 ꢂ CArH);
128.45 (2 ꢂ CArH); 128.67 (CArH); 128.79 (2 ꢂ Ar CArH); 129.06
(CAr); 129.54 (2 ꢂ CArH); 133.39 (CArH); 135.47 (CAr); 165.64
(CO). MS (CI) m/z 474 [(M+H)+, 1]; 105 (38); 91 [(PhCH2)+, 81],
28 (100).
Figure 2. Molecular structure of compound 12b in the solid state.
Finally, removal of the benzyl and benzoyl protecting groups of
12a, by treatment with HCOONH4 as a hydrogen source and Pd/C
as the catalyst followed by acidic hydrolysis with HCl (6 M), fur-
nished the known six-membered iminosugar 4 (54% yield), which
was isolated as its dihydrochloride salt.
Compound 7b: mp: 109–111 °C (ethyl acetate/hexane).
½
a 2D2
ꢃ
¼ ꢁ38:0 (c 1.90, CHCl3). IR (NaCl,
m
max, cmꢁ1): 3454 (OH);
2854–3089 (CArH); 1722 (CO); 1554, 1375 (NO2). 1H NMR
(250 MHz, CDCl3) d 1.33 (s, 3H, CH3); 1.45 (s, 3H, CH3); 4.27 (d,
1H, J3,4 = 3.35 Hz, H-3); 4.31 (s, 1H, OH); 4.39 (1H, d, J4,3
=
3.35 Hz, H-4); 4.49–4.64 (m, 5H, H-6 + H-60 + CH2NO2 + CHPh);
4.69 (d, 1H, J2,1 = 3.35 Hz, H-2); 4.74 (d, 1H, J = 11.8 Hz, CHPh);
6.01 (d, 1H, J1,2 = 3.35 Hz, H-1); 7.33–7.60 (m, 8H, 8 ꢂ H-Ph);
7.96–8.01 (m, 2H, 2 ꢂ H-Ph). 13C NMR (62.8 MHz, CDCl3) d 26.60
(CH3); 27.09 (CH3); 65.90 (CH2); 72.52 (CH2); 73.90 (C); 78.96
(CH2); 79.20 (CH); 81.80 (CH); 82.70 (CH); 104.90 (CH); 112.70
(C); 128.90 (4 ꢂ CArH); 129.20 (2 ꢂ CArH); 129.30 (2 ꢂ CArH);
129.80 (CAr); 130.02 (CArH); 133.70 (CArH); 136.02 (CAr); 166.05
(CO). MS (CI) m/z 105 (38); 91 [(PhCH2)+, 86], 61 (100); 28 (87).
3. Conclusion
In summary, we have described a new route to 6-amino-1-
dideoxynojirimycins that is shorter than the rare previous exam-
ples. Work is now in progress to optimize this synthetic approach
in order to apply it to hexoses other than D-glucose and thus to gain
access to novel 6-amino-1-deoxynojirimycin analogues that could
show improved activity profiles.
4. Experimental
4.2. 5-C-[(Benzoylamino)methyl]-3-O-benzyl-1,2-O-isopro-
pylidene-
3-O-benzyl-1,2-O-isopropylidene-b-
a
-
D
-idofuranose 8a and 5-C-[(benzoylamino)methyl]-
-glucofuranose 8b
Melting points were determined using a Kofler Thermogerate
apparatus and are uncorrected. Specific rotations were recorded
on a JASCO DIP-370 optical polarimeter. Infrared spectra were re-
corded on an MIDAC Prospect-IR spectrophotometer. Nuclear mag-
netic resonance spectra were recorded on a Bruker DPX-250
apparatus. Mass spectra were obtained on a Hewlett Packard
5988A mass spectrometer. Elemental analyses were obtained from
the Elemental Analysis Service at the University of Santiago de
Compostela. Thin layer chromatography (TLC) was performed
using Merck GF-254 type 60 silica gel and ethyl acetate/hexane
mixtures as eluants; the TLC spots were visualized with Hanessian
mixture. Column chromatography was carried out using Merck
type 9385 silica gel. Solvents were purified as per Ref. 13. Solutions
of extracts in organic solvents were dried with anhydrous sodium
sulfate.
L
Raney-Ni (7.5 mL, 1 g/10 mL) was added to a deoxygenated
solution of a 1:1 mixture of 7a + 7b (0.5 g, 1.05 mmol) in methanol
(50 mL) and the resulting suspension was stirred at room temper-
ature under a hydrogen atmosphere (P = 1 atm) for 15 h. The
mixture was then filtered through CeliteÒ, which was washed with
methanol (50 mL), and the filtrate was evaporated to dryness. The
residue was purified by flash column chromatography (ethyl
acetate/hexane 2:1) to give 0.24 g (52%) of a 1:1.5 mixture of
the epimers 5-C-[(benzoylamino)methyl]-3-O-benzyl-1,2-O-iso-
propylidene-
methyl]-3-O-benzyl-1,2-O-isopropylidene-b-
(NaCl,
max, cmꢁ1): 3378 (OH); 3064–2878 (CArH); 1640 (CO). 1H
NMR (250 MHz, CDCl3) d 1.32 (s, 3H, CH3a); 1.34 (s, 3H, CH3b);
a-
D-glucofuranose 8a and 5-C-[(benzoylamino)-
L-idofuranose 8b. IR
m

506
M. Begoña Pampín et al. / Tetrahedron: Asymmetry 20 (2009) 503–507
1.47 (s, 3H, CH3a); 1.49 (s, 3H, CH3b); 3.09 (dd, 1H, J = 4.39 Hz,
J = 13.99 Hz, CHNHBza); 3.25 (br s, 1H, OHb); 3.33 (br s, 1H, OHa);
3.46 (d, 2H, J = 11.80 Hz, CH2OHa); 3.56 (dd, 1H, J = 4.39 Hz,
J = 13.99 Hz, CHNHBzb); 3.66 (d, 2H, J = 11.80 Hz, CH2OHb); 4.01
(dd, 2H, J = 8.58 Hz, J = 13.99 Hz, 2 ꢂ CHNHBz(a+b)); 4.23 (d, 2H,
J3,4 = 3.029, 2 ꢂ H3(a+b)); 4.23 (d, 2H, J4,3 = 3.029, 2 ꢂ H4(a+b)); 4.35
(s, 2H, 2 ꢂ OH(a+b)); 4.49–4.75 (m, 6H, 2 ꢂ CH2Ph(a+b) + 2 ꢂ H2(a+b));
5.99 (d, 1H, J12 = 3.84 Hz, H1a); 6.03 (d, 1H, J1,2 = 3.84 Hz, H1b);
6.82–6.89 (m, 2H, 2 ꢂ NHBz(a+b)); 7.27–7.79 (m, 16H, 16 ꢂ H-
Ph(a+b)); 7.75–7.79 (m, 4H, 4 ꢂ H-Ph(a+b)). 13C NMR (62.8 MHz,
CDCl3) d 25.87 (CH3a); 25.94 (CH3b); 26.34 (CH3a); 26.36 (CH3b);
43.33 (Ca); 43.37 (Cb); 63.12 (CH2a); 63.75 (CH2b); 71.69 (CH2a);
71.86 (CH2b); 74.91 (CH2a); 75.19 (CH2b); 78.85 (CHa); 78.95
(CHb); 81.10 (CHa); 81.32 (CHb); 82.80 (CHa); 83.23 (CHb); 103.98
(CHa); 104.29 (CHb); 111.51 (Ca); 111.53 (Cb); 126.86, 127.89,
127.95, 128.10, 128.20, 128.37, 128.44, 131.40, 131.46 (20 ꢂ CArH);
133.22 (CAr-a); 133.45 (CAr-b); 135.63 (CAr-a); 136.05 (CAr–b); 168.80
(COa); 169.25 (COb). MS (CI) m/z 444 [(M+H)+, 100]; 443 [(M)+, 5];
442 [(MꢁH)+, 13]; 386 (63); 91 [(PhCH2)+, 70].
(11 mL) at ꢁ78 °C. The resulting reaction mixture was stirred at
ꢁ78 °C for 30 min and sodium cyanoborohydride (0.2 g,
3.12 mmol) was then added in three portions over 45 min. The
mixture was stirred for 2 h at ꢁ78 °C, allowed to warm up to room
temperature and then stirred for 22 h. Saturated aqueous sodium
bicarbonate (50 mL) was added and the mixture was extracted
with dichloromethane (3 ꢂ 50 mL). The organic layers were dried
with anhydrous sodium sulfate, filtered, evaporated in vacuo and
the resulting residue was purified by flash column chromato-
graphy (ethyl acetate/hexane 1:2 to 1:1) to give 6-benzoylamine-
3-O-benzyl-1,5,6-trideoxy-N-(1,1-diphenylmethyl)-1,5-imino-D-
glucitol 12a (0.35 g, 44%) as an amorphous solid and 6-benzoyl-
amine-3-O-benzyl-1,5,6-trideoxy-N-(1,1-diphenylmethyl)-1,5-
imino-L-iditol 12b (0.15 g, 19%) as a yellow solid, which was
crystallized from a mixture of ethyl acetate and hexane.
Compound 12a: ½a D22
ꢃ
¼ ꢁ1:3 (c 0.50, CHCl3). IR (NaCl, mmax
,
cmꢁ1): 3365 (OH); 3063–2871 (CArH); 1659 (CO). 1H NMR
0
(250 MHz, CDCl3) d 1.91 (dd, 1H, J1,1 = 11.52 Hz; J1,2 = 10.15 Hz,
H-1); 2.14 (br s, 2H, 2 ꢂ OH); 2.63–2.69 (m, 1H, H-5); 3.01 (dd,
1H, J1 ,1 = 11.52 Hz; J1 ,2 = 4.39 Hz, H-10); 3.15 (t, 1H, J3,4 = 8.50 Hz,
H-3); 3.55 (t, 1H, J4,3 = 8.50 Hz, H-4); 3.64–3.77 (m, 2H, H-6 + H-
60); 4.33–4.43 (m, 1H, H-2); 4.72 (d, 1H, J = 11.52 Hz, CHPh); 4.95
(d, 1H, J = 11.52 Hz, CHPh); 5.42 (s, 1H, CHPh2); 6.56–6.61 (m,
1H, NHBz); 7.16–7.53 (m, 20H, 20 ꢂ H-Ph). 13C NMR (62.8 MHz,
CDCl3) d 36.95 (CH2); 51.05 (CH2); 62.17 (CH); 64.77 (CH); 69.28
(CH); 71.32 (CH); 74.57 (CH2); 85.38 (CH); 126.72, 126.99,
127.04, 127.38, 127.60, 127.68, 127.89, 128.19, 128.36, 128.41,
129.96, 131.64 (20 ꢂ CArH); 133.48 (CAr); 137.05 (CAr); 138.43
(CAr); 141.39 (CAr); 168.80 (CO). MS (CI) m/z 523 [(M+H)+, 25];
388 [(MꢁCH2NHBz)+, 37]; 167 (100); 91 [(PhCH2)+, 49].
0
0
4.3. 6-Benzoylamino-3-O-benzyl-6-deoxy-1,2-O-isopropyl-
idene-a-D-xylo-hexofuran-5-one 9
A solution of a 1:1.5 mixture of the epimers 8a + 8b (0.23 g,
0.53 mmol) in dichloromethane (4 mL) was added to a suspension
of silica gel (1.30 g), dichoromethane (2 mL) and a solution of
NaIO4 (0.23 g, 1.07 mmol) in H2O (1.80 mL). The resulting mixture
was stirred at room temperature for 6 h. The reaction mixture was
filtered through CeliteÒ, which was washed with dichloromethane
(25 mL), and the filtrate was evaporated to dryness. The residue
was purified by flash column chromatography (ethyl acetate/
hexane 1:2) to give 6-benzoylamine-3-O-benzyl-6-deoxy-1,2-O-
Compound 12b: mp: 128–130 °C (ethyl acetate/hexane).
½
a 2D2
ꢃ
¼ þ10:2 (c 2.42, CHCl3). IR (NaCl,
m
max, cmꢁ1): 3355 (OH);
isopropylidene-
a
-
D
-xylo-hexofuran-5-one 9 (0.19 g, 86%) as an
3084–2855 (CArH); 1640 (CO). 1H NMR (250 MHz, CDCl3) d 2.56
oil. ½a 2D2
ꢃ
¼ ꢁ94:8 (c 1.20, CHCl3). IR (NaCl,
m
max, cmꢁ1): 3063–
(dd, 1H, J1,1 = 11.52 Hz; J1,2 = 10.15 Hz, H-1); 2.86–3.22 (m, 4H,
0
2871 (CArH); 1735 (CO); 1659 (CO). 1H NMR (250 MHz, CDCl3)
d 1.33 (s, 3H, CH3); 1.48 (s, 3H, CH3); 4.33 (d, 1H, J3,4 = 3.51 Hz,
H-3); 4.46 (d, 1H, J = 11.72 Hz, CHPh); 4.57–4.62 (m, 4H,
CH2NHBz + CHPh + H-4); 4.81 (d, 1H, J2,1 = 3.51 Hz, H-2); 6.11
(d, 1H, J1,2 = 3.51 Hz, H-1); 6.83–6.86 (m, 1H, NHBz); 7.17–7.31
(m, 5H, 5 ꢂ H-Ph); 7.42–7.54 (m, 3H, 3 ꢂ H-Ph); 7.79–7.82
(m, 2H, 2 ꢂ H-Ph). 13C NMR (62.8 MHz, CDCl3) d 26.14 (CH3);
26.77 (CH3); 49.03 (CH2); 72.33 (CH2); 81.55 (CH); 83.48 (CH);
84.57 (CH); 105.96 (CH); 112.43 (C); 126.94 (2 ꢂ CArH); 127.39
(2 ꢂ CArH); 127.95 (CArH); 128.37 (4 ꢂ CArH); 131.47 (CArH);
133.82 (CAr); 136.46 (CAr); 166.95 (CO); 203.76 (CO). MS (CI) m/z
412 [(M+H)+, 100]; 354 (20); 91 [(PhCH2)+, 87].
2 ꢂ OH + H-10 + H-5); 3.52 (t, 1H, J3,4 = 8.50 Hz, H-3); 3.61–4.02
(m, 4H, H-2 + H-4 + H-6 + H-60); 4.78 (d, 1H, J = 11.52 Hz, CHPh);
4.90 (d, 1H, J = 11.52 Hz, CHPh); 4.95 (s, 1H, CHPh2); 6.80–6.84
(m, 1H, NHBz); 7.13–7.65 (m, 20H, 20 ꢂ H-Ph). 13C NMR
(62.8 MHz, CDCl3) d 35.07 (CH2); 48.97 (CH2); 57.83 (CH); 70.16
(CH); 70.32 (CH); 72.05 (CH); 74.58 (CH2); 83.54 (CH); 126.82,
127.15, 127.28, 127.36, 127.42, 127.84, 127.90, 128.45, 128.63,
128.73, 131.64 (20 ꢂ CArH); 134.33 (CAr); 138.52 (CAr); 141.39
(CAr); 142.67 (CAr); 167.40 (CO). MS (CI) m/z 523 [(M+H)+, 99];
388 [(M–CH2NHBz)+, 100]; 167 (85); 91 [(PhCH2)+, 68].
4.6. 6-Amino-1,5,6-trideoxy-1,5-imino-D-glucitol dihydro-
chloride 4
4.4. 6-Benzoylamino-3-O-benzyl-6-deoxy-a-D-xylo-hexofuran-
5-one 10
Pd/C (10%) (185 mg) and HCOONH4 (60 mg, 0.95 mmol) were
added to a deoxygenated solution of compound 12a (70.5 mg,
0.134 mmol) in methanol (4 mL) and the resulting suspension
was stirred at 70 °C under an argon atmosphere for 1 h. The reac-
tion mixture was filtered through CeliteÒ, which was washed with
methanol (10 mL). The filtrate was concentrated to dryness and the
residue dissolved in H2O (10 mL) and washed with dichlorometh-
ane (3 ꢂ 10 mL). The aqueous solution was evaporated to dryness,
dissolved in aqueous HCl (6 M, 3 mL), stirred for 3 d at 50 °C and
evaporated. The residue was dissolved in methanol and ethyl ether
was added to give a white solid, which was filtered off and identi-
Compound 9 (0.640 g, 1.55 mmol) was dissolved in a mixture
(1:1) of trifluoroacetic acid and H2O (28 mL) and the resulting
solution was stirred at room temperature for 12 h. The reaction
was evaporated to dryness and coevaporated with toluene
(2 ꢂ 1.5 mL) to give a yellow residue of 6-benzoylamine-3-O-benz-
yl-6-deoxy-a-D-xylo-hexofuran-5-one 10, which was used in the
next step without further purification.
4.5. 6-Benzoylamino-3-O-benzyl-1,5,6-trideoxy-N-(1,1-di-
phenylmethyl)-1,5-imino-D-glucitol 12a and 6-benzoylamine-3-
fied as 6-amino-1,5,6-trideoxy-1,5-imino-D-glucitol dihydrochlo-
O-benzyl-1,5,6-trideoxy-N-(1,1-diphenylmethyl)-1,5-imino-
iditol 12b
L
-
ride
4
(17 mg, 54%). mp 187–188 °C (methanol/ethyl ether).
½
a 2D2
ꢃ
¼ þ11:5 (c 0.12, H2O). IR (NaCl,
m
max, cmꢁ1): 3425 (OH). 1H
0
NMR (250 MHz, CDCl3)
d
3.92 (dd, 1H, J1,1 = 11.52 Hz;
A solution of compound 10 (570 mg) in methanol (11 mL) was
added dropwise to a solution of diphenylmethylamine (1.22 mL,
1.24 mmol) and acetic acid (0.07 mL, 1.24 mmol) in methanol
J1,2 = 12.11 Hz, H-1); 4.25–4.49 (m, 6H, H-10 + H-3 + H-4 + H-
5 + H-6 + H-60); 4.60–4.78 (m, 1H, H-2). 13C NMR (62.8 MHz, CDCl3)
d 40.82 (CH2); 47.97 (CH2); 57.14 (CH); 68.18 (CH); 72.60 (CH);

M. Begoña Pampín et al. / Tetrahedron: Asymmetry 20 (2009) 503–507
507
76.95 (CH). HRMS: Calculated for C6H15N2O3 (M+H)+ 163.1083;
found 163.1095.
5. (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Curr. Top. Med. Chem. 2003, 3, 561; (b)
Platt, F. M.; Neises, G. R.; Dwek, R. A.; Butters, T. D. J. Biol. Chem. 1994, 269,
8362; (c) Block, X.; Lu, X.; Platt, F. M.; Foster, G. R.; Gerlich, W. H.; Blumberg, B.
S.; Dwek, R. A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 2235; (d) Mann, J.; Davidson,
R. S.; Hobbs, J. B.; Banthorpe, D. V.; Harborne, J. B. Natural Products; Longman
Scientific & Technical: England, 1994. p 442.
6. (a) McCort, I.; Fort, S.; Duéault, A.; Depezay, J.-C. Biorg. Med. Chem. 2000, 8, 135;
(b) Heightman, T. D.; Vasella, A. Angew. Chem., Int. Ed. 1999, 38, 750.
7. (a) Tite, T.; Lallemand, M.-C.; Poupon, E.; Kunesch, N.; Tillequin, F.; Gravier-
Pelletier, C.; Le Merrer, Y.; Husson, H.-P. Biorg. Med. Chem. 2004, 12, 5091; (b)
Kilonda, A.; Compernolle, F.; Peeters, K.; Joly, G. J.; Toppet, S.; Hoornaert, G.
Tetrahedron 2000, 56, 1005; (c) Ref. 6a.
8. (a) Barret, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86, 751; (b) Nitroalkanes
and Nitroalkenes in Synthesis, Tetrahedron Symposia, Barret, A. G. M., Ed.; 1990;
Vol. 46, p 7313.; (c) Noboru, O. In The Nitro Group in Organic Synthesis; Feuer, H.,
Ed.; Organic Nitro Chemistry Series; Wiley-VCH, 2001; (d) Luzzio, F. A.
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Acknowledgements
We thank the Spanish Ministry of Science and Innovation for
financial support (CTQ2005-00555) and for
a FPU grant to
Fernando Fernández, and the University of Santiago de Compostela
for a grant to Begoña Pampín.
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