Concise synthesis of 1-deoxy-4-O-β-D-galactopyranosyl-D-nojirimycin avoiding a glycosylation step

Article abstract of DOI:10.1016/S0040-4039(00)02165-1

2′,6′-Di-O-benzyl-2,3:5,6:3′,4′-tri-O-isopropylide nelactose dimethyl acetal was used as starting material for the preparation of the until now unknown 4-O-β-D-galactopyranosyl-D-xylo-hexos-5-ulose derivatives 7-9, through selective C-5 oxidation of its partially deprotected derivatives 4-6. Hydrolysis of 7-9 with aq. CF₃COOH led to deprotected 1,5-dicarbonyl disaccharides 11-12, diastereoselectively transformed without purification into 1-deoxy-4-O-β-D-galactopyranosyl-D-nojirimycin derivatives in about 60% yield, through a double reductive amination reaction.

Full text of DOI:10.1016/S0040-4039(00)02165-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1139–1142
Concise synthesis of
1-deoxy-4-O-b-
D
-galactopyranosyl- -nojirimycin avoiding a
D
glycosylation step†,‡
Felicia D’Andrea, Giorgio Catelani,* Manuela Mariani and Barbara Vecchi
Dipartimento di Chimica Bioorganica e Biofarmacia, Universita` di Pisa, Via Bonanno, 33, I-56126 Pisa, Italy
Received 5 October 2000; revised 13 November 2000; accepted 22 November 2000
Abstract—2%,6%-Di-O-benzyl-2,3:5,6:3%,4%-tri-O-isopropylidenelactose dimethyl acetal was used as starting material for the prepara-
tion of the until now unknown 4-O-b- -galactopyranosyl- -xylo-hexos-5-ulose derivatives 7–9, through selective C-5 oxidation of
its partially deprotected derivatives 4–6. Hydrolysis of 7–9 with aq. CF3COOH led to deprotected 1,5-dicarbonyl disaccharides
11–12, diastereoselectively transformed without purification into 1-deoxy-4-O-b- -galactopyranosyl- -nojirimycin derivatives in
about 60% yield, through a double reductive amination reaction. © 2001 Elsevier Science Ltd. All rights reserved.
D
D
D
D
The class of compounds known as iminosugars or
azasugars, in which the ring oxygen atom of a sugar is
replaced by NH, has proven to include potent
inhibitors of glycosidases and glycoprotein-processing
enzymes2 which are intensely investigated for their ther-
apeutic potentiality as antiviral, anti-HIV, antidiabetic,
and anticancer agents.3 1-Deoxynojirimycin (1,5-
have hypoglycemic activity8 owing to its potent
inhibitory activity for sucrase and 2-O-a- -glucopyra-
nosyl-DNJ is more efficient than DNJ against treha-
lases.7 Furthermore some sialyl Lewisx-type analogues
containing a DNJ unit have been proposed recently as
anti-inflammatory agents because they are recognized
by the selectines, receptors involved in leukocyte adhe-
sion and migration processes.9,10
D
dideoxy-1,5-imino-
D
-glucitol; DNJ) is
a
powerful
inhibitor of a-glucosidases and several of its derivatives
have been synthesized and tested for their biological
properties.3
We present in this communication an easy and
diastereoselective approach to 1-deoxy-4-O-b-D-galacto-
pyranosyl- -nojirimycin (1) so far prepared only
D
Some glycosylated DNJ derivatives were isolated from
natural products4,5 or synthesized6,7 and their effect on
various glycosidases has been investigated.4,7 For
through enzymatic or chemical glycosylation.6,10
The rationale of our synthetic procedure starting from
lactose 3 is depicted in Scheme 1 and requires, as the
instance 4-O-a-
D
-glucopyranosyl-DNJ was shown to
Scheme 1.
Keywords: 1-deoxy-4-b-
D-galactopyranosyl-
D-nojirimycin; aminocyclization; b-D-galactopyranosyl-D-xylo-hexos-5-uloses; lactose.
* Corresponding author. E-mail: giocate@farm.unipi.it
†
Dedicated to Prof. Pierre Sinay¨ on the occasion of his 62nd birthday.
‡
Part 13 of the series, ‘Rare and Complex Saccharides from
D-Galactose and other Milk-derived Carbohydates’; for Part 12, see Ref. 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02165-1

1140
F. D’Andrea et al. / Tetrahedron Letters 42 (2001) 1139–1142
key steps, a double reductive amination of the so far
unknown 4-O-b- -galactopyranosyl- -xylo-hexos-5-
ulose derivatives, such as 2.
monosaccharide series15 [NaBH3CN (2.2 equiv.),
NH4OAc (10 equiv.)/MeOH, 60°C, 2–3 h] giving the
corresponding azadisaccharides 13 and 14 in acceptable
yields (55–60% based on the uloses 7–9). The extension
of the reaction to a hindered primary amine, i.e. benz-
hydrylamine, similarly gave pure 15 (54% yield) from 9.
The structures of 13–15 were assigned on the basis of
the corresponding analytical16 and NMR data.17 The
D
D
The starting compounds for our synthesis were the diol
4 and tetraol 5, readily obtained from lactose (3)
through a previously described procedure.11 The selec-
tive C-5 oxidation of 4 and 5 was achieved on their
O-dibutylstannylidene derivatives (Scheme 2) through
treatment with dibutyltin oxide (1.05 equiv.) in reflux-
ing toluene and, after a change of the solvent from
toluene to chloroform, a direct oxidation with NBS
(1.05 equiv.; rt; 1 h). After evaporation of the solvent,
flash chromatography of the residue led to the pure
uloses 8 (98% yield) and 9 (88% yield). Very interesting
and useful is, in the case of tetraol 5, the high regiose-
lectivity of the oxidation at position 5, only one by-
product (ꢀ10% yield)12 derived by oxidation on the
1
most significant H NMR data were those of the H-1ax
and H-1eq protons well characteristic of the DNJ unit
located, for example in the case of 15, at l 1.95 (dd,
J
J
1ax,1eq=11.2, J1ax,2=10.6 Hz) and at l 3.07 (dd,
1eq,2=4.4 Hz). Finally the 1-deoxy-4-O-b-
D-galactopy-
ranosyl-
D
-nojirimycin (1) was obtained in nearly quan-
titative yields by hydrogenolysis of 13–14 over 10%
palladium on charcoal (500 mg/mmol) in methanol (20
ml/mmol) under acidic conditions (HCl 1.3 M, 8 ml/
mmol). The physico-chemical properties of 118 were
identical to those reported.6
D
-galacto unit being formed.
The 6-O-benzyl ether 7 was obtained from 4 (88%
yield) through regiospecific benzylation (BnBr,
Bu4NBr) of the 5,6-stannylidene acetal followed by
oxidation of 6 with 4-methylmorpholin-N-oxide in the
presence of catalytic amounts of tetrapropylammonium
perruthenate. In each case, the 5-keto derivatives 7–9
were characterized, and their analytical13 and NMR
data14 were in agreement with the proposed structures.
The complete stereoselectivity of the aminocyclization
reaction we have found can be ascribed, as previously
suggested,15 to the hydride attack step on the cyclic
iminium ion intermediate, formed after the first amina-
tion reaction of the more reactive aldehydic group. An
intramolecular hydride transfer from the reducing agent
bonded to a free hydroxyl group (OH-4 and/or OH-6)
was tentatively proposed as an explanation for the high
diastereoselectivity observed with completely15a or
The complete removal of the acetal groups of 7–9 was
easily achieved with 90% aqueous trifluoroacetic acid,
to give the 1,5-dicarbonyl disaccharides 11 and 12 as
crude materials complicated by complex mixtures of
tautomeric forms. Although the NMR spectra of these
1,5-dicarbonyl disaccharides were not interpreted, their
structures were firmly proven by subsequent reactions.
The crude products containing 11 and 12 were sub-
jected to a double reductive amination under conditions
analogous to those previously reported for the
partially15b deprotected
D-xylo-hexos-5-ulose deriva-
tives. This hypothesis is, however, ruled out by the
present findings on the OH-4 and OH-6 protected
derivative 11. An alternative explanation could be
based on stereoelectronic19 and conformational factors
providing an axial hydride attack on the more stable
(all equatorial) conformer of the cyclic iminium ion
intermediate, but a confirmation of this hypothesis
requires further studies on appropriately designed
derivatives.
Scheme 2. a: (1) Bu2SnO, PhCH3, reflux, 12 h; (2) BnBr, Bu4NBr, CHCl3, rt, 30 min; b: (1) Bu2SnO, PhCH3, reflux, 12 h; (2) NBS,
CHCl3, rt, 1 h; c: TPAP (7%)/NMO, CH2Cl2, 30 min; d: 90% aq. CF3COOH, rt, 20 min; e: X-NH+3AcO−, NaBH3CN, MeOH,
60°C, 2 h; f: H2, Pd/C (10%), MeOH–HCl.

F. D’Andrea et al. / Tetrahedron Letters 42 (2001) 1139–1142
1141
Rf 0.45 (1:9 hexane/EtOAc); mp 110–116°C; [h]D −38.1 (c
0.94, CHCl3).
In conclusion, our synthetic approach offers a simple
method for preparing azadisaccharides avoiding a gly-
cosylation step, in a highly stereoselective way and with
acceptable chemical yields. We are now planning to
14. The NMR characterization was made directly on 7–9
and/or on their peracetylated derivatives. As an example,
the NMR data for the tri-O-acetyl derivative of 9 are
reported: lH (CD3CN, 200 MHz): 1.36 and 1.48 (2 s,
each 3 H, C(CH3)2), 1.88, 2.02 and 2.05 (3 s, each 3 H, 3
x CH3CO), 3.33 and 3.34 (2 s, each 3 H, 2 x OCH3), 3.42
(ddd, 1 H, J6’a,6’b=9.67 Hz, J5’,6’a=7.26 Hz, J5’,6’b=5.75
extend this synthetic scheme to other 4-O-b-
D-galac-
topyranosyl- -xylo-hexos-5-uloses differently protected
D
in order to examine the stereoselectivity of the
aminocyclization reaction and to use our galactosylated
DNJ derivatives as starting materials for the synthesis
of biologically active complex glycan analogues.
Hz, H-6%b), 3.56 (dd, 1 H, H-6%a), 3.71 (dd, 1 H, J1’,2’
7.79 Hz, J2’,3’=10.10 Hz, H-2%), 3.91 (ddd, 1 H, J4’,5’
=
=
1.20 Hz, H-5%), 4.20 (dd, 1 H, J3,4=1.78 Hz, H-3), 4.29
(dd, 1 H, J2,3=7.06 Hz, H-2), 4.39 (d, 1 H, J1,2 =5.87
Hz, H-1), 4.41 (m, 1 H, H-4), 4.39 and 4.51 (AB system,
2 H, JA,B=11.92 Hz, benzylic CH2); 4.46 (d, 1 H, H-1%);
4.69 and 4.89 (AB system, 2 H, JA,B=11.23 Hz, benzylic
CH2), 4.82 and 5.22 (AB system, 2 H, JA,B=18.08 Hz,
H-6a and H-6b), 4.98 (dd, 1 H, J3%,4%=3.60 Hz, H-3%), 5.32
(dd, 1 H, H-4%); 7.30–7.34 (m, 10 H, phenyl H); lC
(CD3CN, 50 MHz) 20.55, 20.79 and 20.92 (3 x CH3CO),
27.30 and 27.45 (C(CH3)2); 54.50 and 56.15 (2 x OCH3);
68.18 (C-6%); 68.95 (C-6); 68.74 (C-4%); 72.57 (C-5%); 73.64
(C-3%); 73.91 and 75.89 (2 benzylic CH2); 76.39 (C-2);
77.88 (C-2%); 79.48 (C-3); 81.93 (C-4); 102.47 (C-1%);
105.98 (C-1); 111.59 (C(CH3)2); 128.67–129.30 (phenyl
CH); 139.19 (2 phenyl C); 170.15, 170.85 and 170.85 (3 x
CꢀO); 204.78 (C-5).
Acknowledgements
Financial support from Universita` di Pisa and Minis-
tero della Ricerca Scientifica e Tecnologica (MURST,
Roma) is gratefully acknowledged.
References
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16. Compound 13. Solid foam, (Found: C, 66.46; H, 6.59; N,
2.34; C33H41NO9 requires: C, 66.54; H, 6.94; N, 2.35), Rf
0.32 (9:1 CHCl3/MeOH); mp 55–58°C; [h]D +35.7 (c 0.74,
CHCl3); Compound 14. Syrup, (Found: C, 61.81; H,
7.10; N, 2.81; C26H35NO9 requires: C, 61.77; H, 6.98; N,
2.77), Rf 0.33 (8:2 CH2Cl2/MeOH); [h]D +5.9 (c 0.64,
MeOH); Compound 15. Solid foam, (Found: C, 69.89; H,
6.95; N, 2.09; C39H45NO9 requires: C, 69.73; H, 6.75; N,
2.08), Rf 0.72 (8:2 CHCl3/MeOH); mp 70–73°C; [h]D
−10.5 (c 0.95, CHCl3).
17. Selected NMR data: Compound 13: lH (CDCl3, 200
MHz) 2.52 (dd, 1 H, J1ax,1eq=12 Hz, J1ax,2=10 Hz,
H-1ax), 2.80 (m, 1 H, H-5), 3.16 (dd, 1 H, J1eq,2=4.6 Hz,
H-1eq); 4.25 (d, 1 H, J1%,2%=7.6 Hz, H-1%); lC (CDCl3, 50
MHz) 48.55 (C-1); 58.90 (C-5); 68.73 (C-4%); 68.93, and
69.35 (C-6, and C-6%); 71.97 (C-2); 73.33 (C-3%); 73.33
(C-5%); 77.47 (C-3); 79.22 (C-2%), 82.39 (C-4); 103.36 (C-
1%); Compound 14: lH (CDCl3/CD3OD, 200 MHz) 2.54 (t
broad, 1 H, J=10.7 Hz, H-1ax), 2.67 (m, 1 H, H-5), 3.17
(m, 1 H, H-1eq); 4.39 (d, 1 H, J1%,2%=7.2 Hz, H-1%); lC
(CDCl3/CD3OD, 50 MHz) 48.37 (C-1); 60.05 (C-5); 60.28
(C-6); 68.93 (C-6%); 69.06 (C-4%); 71.57 (C-2); 73.23 (C-3%);
73.35 (C-5%); 77.19 (C-3); 79.47 (C-2%), 80.99 (C-4); 103.10
(C-1%). Compound 15: lH (CDCl3, 200 MHz) 1.95 (t
broad, 1 H, J1ax,1eq=11.2 Hz, J1ax,2=10.6 Hz, H-1ax),
2.47 (m, 1 H, H-5), 3.07 (dd, 1 H, J1eq,2=4.4 Hz, H-1eq);
4.47 (d, 1 H, J1%,2%=7.4 Hz, H-1%); lC (CDCl3, 50 MHz)
49.97 (C-1); 57.21 (C-6); 62.79, and 63.50 (C-5, and
CHPh2); 69.03 (C-6%); 69.03 (C-4%); 70.19 (C-2); 73.20
7. Asano, N.; Oseki, K.; Kaneko, E.; Matsui, K. Carbohydr.
Res. 1994, 258, 255–266.
8. Yoshikuni, Y.; Ezure, Y.; Seto, T.; Mori, K.; Watanabe,
M.; Enomoto, H. Chem. Pharm. Bull. 1989, 37, 106–109.
9. Ogawa, H.; Harada, Y.; Kyotani, Y.; Ueda, T.;
Kitazawa, S.; Kandori, K.; Seto, T.; Ishiyama, K.;
Kojima, M.; Ohgi, T.; Ezure, Y.; Kise, M. J. Carbohydr.
Chem. 1998, 17, 729–738.
10. Kiso, M.; Katagiri, H.; Furui, H.; Hasegawa, A. J.
Carbohydr. Chem. 1992, 11, 627–644.
11. Catelani, G.; D’Andrea, F.; Puccioni, L. Carbohydr. Res.
2000, 324, 204–209.
12. Selected 13C NMR data: lC (CDCl3, 50 MHz): 67.87 and
68.59 (C-6 and C-6%); 75.85, 76.76, 78.43, 79.17, 81.69,
84.37 (6 pyranosic CH); 101.41 (C-1%); 105.68 (C-1);
201.99 and 210.77 (C-5 and C-4% or C-3%).
13. Compound 7. Syrup, (Found: C, 66.95; H, 7.22;
C41H52O12 requires: C, 66.83; H, 7.11); Rf 0.53 (1:1
hexane/EtOAc); [h]D −19.9 (c 0.95, CHCl3). Compound
8. Syrup, (Found: C, 62.78; H, 7.21; C34H46O12 requires:
C, 63.14; H, 7.17); Rf 0.56 (2:8 hexane/EtOAc); [h]D
−17.7 (c 1.36, CHCl3). Compound 9. Solid foam, (found:
C, 60.79; H, 6.70; C31H42O12 requires: C, 61.37; H, 6.98);

1142
F. D’Andrea et al. / Tetrahedron Letters 42 (2001) 1139–1142
(C-3%); 73.53 (C-5%); 77.00 (C-3); 79.49 (C-2%), 81.47 (C-4);
103.62 (C-1%).
18. 4-O-b- -Galactopyranosyl-(1->4)-1,5-dideoxy-1,5-imino-
MeOH–H2O (lit.6 247–248°C); [h]D+41.32 (c 1.01, H2O)
1
(lit.6 [h]D+42.44); H NMR and 13C NMR (Me2SO) data
D
identical to those previously reported.6
19. Stevens, R. V. Acc. Chem. Res. 1984, 17, 289.
D
-glucitol (1). mp 241–246°C, white crystals from
.