First stereocontrolled reduction of isoxazoline by hydrogenolysis: A new route to iminosugars via cyclic sulfates

Article abstract of DOI:10.1055/s-2002-32967

The synthesis of four new trihydroxylated piperidines, considered as analogues of 1-deoxynojirimycin (DNJ) and 1-deoxymannojirimycin (DMJ), was achieved using cyclic sulfate substituted isoxazoline derivatives. The key step is the one-pot reduction of an

Full text of DOI:10.1055/s-2002-32967

LETTER
1359
First Stereocontrolled Reduction of Isoxazoline by Hydrogenolysis:
A New Route to Iminosugars via Cyclic Sulfates
A
N
ew Route to Imino
a
sugars via
C
r
yclic
S
i
a
Laboratoire SEESIB, UMR 6504, Université Blaise Pascal, 63177 Aubière cedex, France
Fax +33(4)73407717; E-mail: mlemaire@chimtp.univ-bpclermont.fr
b
Département de chimie, Faculté des Sciences et de Génie, Université Laval, Québec, G1K 7P4, Canada
Received 13 May 2002
cyclization of aminoketoses provided by aldolase cata-
lyzed synthesis,5,6 or by reductive amination of aldoketo-
ses.7,8 In other cases, the cyclization of an 2-aminopolyol
with a suitable leaving group has led to the desired piper-
Abstract: The synthesis of four new trihydroxylated piperidines,
considered as analogues of 1-deoxynojirimycin (DNJ) and 1-deoxy-
mannojirimycin (DMJ), was achieved using cyclic sulfate substitut-
ed isoxazoline derivatives. The key step is the one-pot reduction of
an isoxazoline to an amine which undergoes intramolecular attack idines.9
on the sulfate ester with high stereoselectivity and regioselectivity.
Some trihydroxylated piperidine derivatives have been
The isoxazoline precursors were obtained by the 1,3-dipolar cy-
cloaddition reaction between 2,2-dimethyl-4-vinyl-1,3-dioxolane
and 1-benzyloxy-2-nitroethane.
synthesized and their inhibitory effects have been evaluat-
ed.9–11 For instance, 1,4,5-trideoxy-1,5-imino-D-lyxo-
hexitol 4 was active against -D-glucosidase, -D-glucosi-
dase and -D-galactosidase.11
Key words: cyclic sulfates, iminosugars, piperidines, cycloaddi-
tions, glycosidase inhibitors
-2-Isoxazolines (C, Scheme 1) have proven versatile in-
termediates and have been fully employed for the synthe-
sis of aminosugars.12–19 However, very few developments
for iminosugar preparation have been described in the lit-
erature.20,21 -2-Isoxazolines are usually obtained by 1,3-
dipolar cycloaddition reaction of nitrile oxides (generated
in situ from primary nitro derivatives) with alkenes
(Scheme 1). We have already described the chemo-enzy-
matic synthesis of optically pure isoxazolines of type C
and their conversion into 3-deoxyfructose by controlled
reduction and hydrolysis.22 We thought that these com-
pounds C could provide a new route to polyhydroxylated
piperidines.
Polyhydroxylated piperidines – also known as iminosug-
ars or azasugars - are a class of compounds of great inter-
est, due to their extraordinary biological properties. They
are potent inhibitors of glycosidase and glycoprotein-pro-
cessing enzymes and are widely investigated for their an-
tiviral (anti-HIV), antidiabetic and anticancer activities.1,2
A large number of naturally occurring iminosugars and
their synthetic analogs are known. 1-Deoxynojirimycin
(DNJ) 1, 1-deoxymannojirimycin (DMJ) 2 and fagomine
3 are typical examples (Figure). Their effectiveness has
made the development of numerous glycosidase inhibi-
tors a matter of considerable interest to the synthetic
chemist.3,4 Many such compounds have been prepared by
Our retrosynthetic scheme starting from alkene 5 and nitro
compound 6 is depicted in Scheme 1. The key step is the
OH
OH
OH
OH
HO
OH
HO
OH
OH
OH
HO
OH
OH
OH
N
H
N
H
N
H
N
H
1
2
3
4
Figure
OH
O
O
HO
O
OBn
O
OBn
O
O
S
O
O
R
5
N
+
H
A
B
O
N
C
O
N
OBn
O2N
R =CH2OH, CH2OBn
6
Scheme 1
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1359,1361,ftx,en;G12902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1360
M. Lemaire et al.
LETTER
one-pot reduction and cyclization of an isoxazoline cyclic equiv for 14) (Scheme 3). Anhydrous conditions were
sulfate of type B to obtain piperidines A.
very important to prevent competitive hydrolysis of the
imine intermediate into ketone. Furthermore, without so-
dium carbonate, formation of unidentified by-products
was observed. In basic medium, the reduction of the isox-
azoline was followed by the opening of cyclic sulfate ring
by the intermediate amine and the zwitterionic piperidines
15 and 16 were obtained in 82% and 40% yield, respec-
tively after purification by cation exchange (Dowex®
50WX8, H+ form).27 In both cases, the reaction was highly
stereo- and regioselective and the benzyl group was not
cleaved; this latter operation requires acidic conditions
(vide infra). These piperidines were fully characterized
and the relative configurations were established by NMR
studies (NOE) and also by comparison with the already
described piperidine 4 (vide infra ( )-4).11 In the crude re-
action product, only one stereomer was detected by NMR
spectroscopy and isolated after purification. From the
product structures, it was deduced that the hydrogen had
been delivered on the side of the isoxazoline cycle, which
was hindered by the cyclic sulfate group. Such a diastere-
oselectivity, as well as the complete regioselectivity for
the cyclization, were unexpected. Piperidine 15 can be
considered as an analog of 1-deoxymannojirimycin 2 and
16 (configurations described for the first time for a trihy-
droxypiperidine) as a 1-deoxynojirimycin 1 analog.
The first step of our synthesis involved a 1,3-cycloaddi-
tion reaction of a nitrile oxide generated in situ from nitro
compound 622 with the commercially available alkene 5
(Scheme 2). The improved Mukaiyama procedure23,24 was
applied and afforded isoxazolines anti-7 and syn-8 in 51%
and 14% yield, respectively. These diastereomers were
easily separated and used separately in the next steps.
Complete removal of the ketal groups was achieved in
methanol in the presence of Amberlyst® 15 at room tem-
perature, to give the crude diols 9 and 10. Following a
classical procedure,25 cyclic sulfites 11 and 12 were ob-
tained in 88% and 77% yield, respectively (calculated
from 7 and 8). As usual, cyclic sulfites were mixtures of
two isomers (not separated) having different configura-
tions at the sulfur atom.25 In the next step, the sulfite syn-
12 was oxidized into syn-14 in 94% yield with catalytic
RuCl325 in the presence of NaIO4 in CH3CN/H2O. Howev-
er, these conditions were inappropriate in the case of anti-
11, for which partial oxidation of the benzyl group was
observed. This side reaction was avoided by replacement
of RuCl3 by ruthenium (IV) oxide26 and sulfate 13 was
isolated in 84% yield.
The reduction of the isoxazoline was performed by hydro-
genolysis over 10% Pd/C in anhydrous methanol in the
presence of sodium carbonate (0.5 equiv for 13 and 1
O
O
1) Et3N, 1,4-phenylenediisocyanate,
toluene, reflux, 12 h
+
OBn
O
O
+
5
6
OBn
anti–7
syn–8
2) H2O, reflux, 6 h
O
N
O
N
51 %
SOCl2, pyridine
CH2Cl2, 0-25 °C, 4 h
14 %
X
OH
O
MeOH, H+
HO
anti–7
O
OBn
OBn
syn–8 r.t., 48 h
O
N
O
N
anti–9
syn–10
anti–11 syn–12
X = SO
88 %
77 %
RuO2, NaIO4,
CH3CN, H2O,
rt, 43 h
RuCl3, NaIO4,
CH3CN, H2O,
rt, 3 h
94 %
84 %
anti–13 syn–14 X = SO2
Scheme 2
OH
HO
O
OH
O
H2SO4, H2O,
dioxane, 1 h
S
O
O3SO
82 %
OR
R=Bn
O
N
OBn
OBn
82 %
H
N
anti–13
17
O
N
H2
15
H2, Pd/C,
H2, Pd/C,
MeOH/H2O 9/1,
AcOH, rt, 48 h
38 %
anhyd MeOH/Na2CO3,
rt, 6 h
90 %
O
O
OH
S
O
OH
(±)-4 R=H
O3SO
O
O3SO
OBn
OBn
O
N
OH
syn–14
40 %
N
N
H2
18
H2
16
Scheme 3
Synlett 2002, No. 8, 1359–1361 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Route to Iminosugars via Cyclic Sulfates
1361
(16) Jaeger, V.; Mueller, I.; Paulus, E. F. Tetrahedron Lett. 1985,
26, 2997.
(17) Jaeger, V.; Schroeter, D. Synthesis 1990, 556.
(18) Wade, P. A.; D’Ambrosio, S. G.; Price, D. T. J. Org. Chem.
1995, 60, 6302.
(19) de Blas, J.; Carretero, J. C.; Dominguez, E. Tetrahedron:
Asymmetry 1995, 6, 1035.
(20) Schaller, C.; Vogel, P.; Jaeger, V. Carbohydr. Res. 1998,
314, 25.
(21) Mueller, R.; Leibold, T.; Paetzel, M.; Jaeger, V. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1295.
(22) Gefflaut, T.; Martin, C.; Delor, S.; Besse, P.; Veschambre,
H.; Bolte, J. J. Org. Chem. 2001, 66, 2296.
The sulfate group of piperidine 15 was removed with con-
centrated H2SO4 and water in dioxane28 (Scheme 3). The
piperidine 17 was isolated in 82% yield. The piperidine
( )-4 was obtained in 38% yield (not optimized) after
hydrogenolysis of the benzyl protecting group over Pd/C
in the presence of acetic acid.29 Analytical data were
identical to those described for compound 4.11 Following
the same procedure, the zwitterionic piperidine 18 was
isolated in 90% yield. All piperidines were characterized
and their analytical data are in agreement with the pro-
posed structures.30
(23) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82,
5339.
(24) Kantorowski, E. J.; Brown, S. P.; Kurth, M. J. J. Org. Chem.
1998, 63, 5272.
(25) Byun, H. S.; He, L. L.; Bittman, R. Tetrahedron 2000, 56,
7051.
(26) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110,
7538.
(27) Typical Procedure for Preparation of 15. A solution of 13
(1.08 g, 3.45 mmol) in anhyd MeOH (50 mL) was stirred
under H2 in the presence of 10% Pd/C (500 mg) and anhyd
Na2CO3 (183 mg, 1.73 mmol) for 6 h. The solids were
removed by filtration through a membrane filter (0.2 m)
and the filtrate concentrated under vacuum. The residue was
neutralized with HCl 1N, then purified over an acidic resin
(Dowex 50WX8, 200-400 mesh) using water as eluent.
Compound 15 was isolated as a white solid in 82% yield
(892 mg).
In conclusion, we have opened a new route to trihydroxy-
lated piperidines with access to various configurations;
four new analogs of natural compounds such as DNJ and
DMJ were isolated. Our approach, with a highly stereo-
and regioselective key step, offers simple procedures and
acceptable chemical yields. As no racemization steps can
occur in our methodology, this should lead easily to enan-
tiomerically pure compounds starting from the already de-
scribed isoxazolines 9 and 10.22 Preparation of such
compounds and their evaluation as glycosidase inhibitors
are under investigation. We plan to extend this methodol-
ogy to chiral alkenes and other nitro compounds to have
access to chiral piperidines and other functionalities (R
group shown in structure A, Scheme 1).
Acknowledgement
(28) Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G.
P.; Zanirato, V. Tetrahedron 1999, 55, 5923.
(29) Ghavami, A.; Johnston, B. D.; Pinto, B. M. J. Org. Chem.
2001, 66, 2312.
We thank the Centre National de la Recherche Scientifique (CN-
RS), France, for the award of a research fellowship (EG) and the
Université Blaise Pascal for financial support.
(30) All new compounds reported here were racemic and gave
satisfactory spectral data (1H and 13C NMR, IR, mass).
Selected spectral data (1H and 13C), 15: 1H NMR (300 MHz,
D2O): = 1.78 (ddd, 1 H, J = 13 Hz), 1.96 (ddd, 1 H, J = 13,
3.5, 3.5 Hz), 3.24 (dd, 1 H, J = 14, 1 Hz), 3.52 (m, 1 H), 3.63
(dd, 1 H, J = 11, 8 Hz), 3.71 (dd, 1 H, J = 11, 8 Hz), 3.81
(dd, 1 H, J = 14, 3 Hz), 4.03 (ddd, 1 H, J = 13, 3.5, 3.5 Hz),
4.61 (s, 2 H), 4.75 (m, 1 H), 7.43 (m, 5 H). 13C NMR (100
MHz, D2O): = 30.3 (C4), 48.6 (C1), 57.8 (C5), 66.9 (C3),
71.8 (C6 or C7), 75.7 (C2), 75.9 (C7 or C6), 131.3–131.6
(C9-10-11), 139.8 (C8). 17: 1H NMR (300 MHz, D2O): = 1.86
(AB, 1 H, J = 13 Hz), 1.91 (AB, 1 H), 3.21 (dd, 1 H, J = 14,
1 Hz), 3.46 (dd, 1 H, J = 14, 3 Hz), 3.53 (m, 1 H), 3.66 (dd,
1 H, J = 11, 8 Hz), 3.75 (dd, 1 H, J = 11, 4 Hz), 3.99 (m, 1
H), 4.17 (m, 1 H), 4.65 (s, 2 H), 7.46 (m, 5 H). 13C NMR (75
MHz, D2O): = 29.8 (C4), 50.9 (C1), 57.9 (C5), 67.6 (C3),
69.6 (C2), 72.0 (C6 or C7), 76.0 (C6 or C7), 131.4–131.7
(C9-10-11), 140.0 (C8). 18: 1H NMR (300 MHz, D2O): = 1.80
(ddd, 1 H, J = 13 Hz), 2.00 (ddd, 1 H, J = 13, 3.5, 3.5 Hz),
3.28 (dd, 1 H, J = 14, 1 Hz), 3.42 (dddd, 1 H, J = 13, 8, 4, 3.5
Hz), 3.68 (dd, 1 H, J = 12.5, 8 Hz), 3.81 (dd, 1 H, J = 12.5,
4 Hz), 3.86 (dd, 1 H, J = 14, 3 Hz), 4.08 (ddd, 1 H, J = 13,
References
(1) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.;
Nash, R. J. Phytochemistry 2001, 56, 265.
(2) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645.
(3) Stütz, A. E. Iminosugars as Glycosidase Inhibitors:
Nojirimycin and Beyond; Wiley-VCH: Weinheim, 1999, .
(4) Chapleur, Y. Carbohydrate Mimics – Concepts and
Methods; Wiley-VCH: Weinheim, 1998.
(5) Kajimoto, T.; Liu, K. K. C.; Pederson, R. L.; Zhong, Z.;
Ichikawa, Y.; Porco, J. A. J.; Wong, C.-H. J. Am. Chem. Soc.
1991, 113, 6187.
(6) Takayama, S.; Martin, R.; Wu, R.; Laslo, K.; Siuzdak, G.;
Wong, C.-H. J. Am. Chem. Soc. 1997, 119, 8146.
(7) Hecquet, L.; Lemaire, M.; Bolte, J.; Demuynck, C.
Tetrahedron Lett. 1994, 35, 8791.
(8) Lemaire, M.; Valentin, M. L.; Hecquet, L.; Demuynck, C.;
Bolte, J. Tetrahedron: Asymmetry 1995, 6, 67.
(9) Jang, K. C.; Jeong, I. Y.; Yang, M. S.; Choi, S. U.; Park, K.
H. Heterocycles 2000, 53, 887.
(10) Ichikawa, Y.; Igarashi, Y.; Ichikawa, M.; Suhara, Y. J. Am.
Chem. Soc. 1998, 120, 3007.
(11) Andersen, S. M.; Ekhart, C.; Lundt, I.; Stütz, A. E.
Carbohydr. Res. 2000, 326, 22.
4.5, 3.5 Hz), 4.79 (m, 1 H). 13C NMR (75 MHz, D2O):
30.1 (C4), 48.5 (C1), 59.7 (C5), 64.0 (C6), 68.5 (C3), 75.6
=
(C2). 16: 1H NMR (400 MHz, (CD3)2SO): = 1.42 (ddd, 1
H, J = 13, 13, 13 Hz), 2.00 (ddd, 1 H, J = 13, 4.5, 4.5 Hz),
2.81 (dd, 1 H, J = 13, 11 Hz), 3.40 (m, 1 H), 3.50 (m, 1 H),
3.56–3.80 (m, 3 H), 4.12 (m, 1 H), 4.55 (AB, 2 H, J = 12 Hz),
7.36 (m, 5 H). 13C NMR (100 MHz, D2O): = 32.2 (C4), 44.7
(C1), 53.7 (C5), 68.1 (C3), 69.6 (C6), 72.6 (C7), 74.4 (C2),
127.9–128.6 (C9-10-11), 137.9 (C8).
(12) Jaeger, V.; Schwab, W.; Buss, V. Angew. Chem., Int. Ed.
Engl. 1981, 20, 601.
(13) Mueller, I.; Jaeger, V. Tetrahedron Lett. 1982, 23, 4777.
(14) Jaeger, V.; Schohe, R. Tetrahedron 1984, 40, 2199.
(15) Jaeger, V.; Mueller, I. Tetrahedron 1985, 41, 3519.
Synlett 2002, No. 8, 1359–1361 ISSN 0936-5214 © Thieme Stuttgart · New York