First stereocontrolled synthesis and biological evaluation of 1,6-dideoxy-L-nojirimycin

Article abstract of DOI:10.1016/S0957-4166(02)00752-8

The first synthesis of 1,6-dideoxy-L-nojirimycin in enantiomerically pure form has been achieved in nine steps from L-xylose in an overall yield of 15%. The biological activity of this compound as a glycosidase inhibitor provided useful information on str

Full text of DOI:10.1016/S0957-4166(02)00752-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 47–51
First stereocontrolled synthesis and biological evaluation of
1,6-dideoxy- -nojirimycin
L
Aymeric Bordier,a Philippe Compain,a Olivier R. Martin,a,* Kyoko Ikedab and Naoki Asanob
aInstitut de Chimie Organique et Analytique, CNRS, Universite´ d’Orle´ans, BP 6759, 45067 Orle´ans, France
bFaculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Japan
Received 17 October 2002; accepted 11 November 2002
Abstract—The first synthesis of 1,6-dideoxy-
-xylose in an overall yield of 15%. The biological activity of this compound as a glycosidase inhibitor provided useful
information on structure–activity relationships in the family of 1,5-iminoalditols. © 2003 Elsevier Science Ltd. All rights reserved.
L-nojirimycin in enantiomerically pure form has been achieved in nine steps from
L
As potent glycosidase inhibitors,1 iminosugars have
been a subject of enduring scientific interest over the
last three decades. An important new phase in the
development of this dynamic field of research is starting
to emerge. Recently, the scope of biological activities of
iminoalditols has been extended to the inhibition of
various carbohydrate-processing enzymes such as gly-
cosyl transferases,2 nucleoside3 and glycogen4 phospho-
rylases, and sugar nucleotide mutase.5 Since these
enzymes are involved in a number of essential physio-
logical processes, iminosugars have tremendous poten-
tial as therapeutic agents6 in a wide range of diseases
including viral infections,7 tumor metastasis8 and lyso-
somal storage disorders.9 Some iminoalditols are cur-
rently engaged in clinical trials and the first therapeutic
applications seem now to be very close.10 For example,
initial clinical data have recently demonstrated the
effectiveness of N-butyl-1-deoxynojirimycin against
Gaucher’s disease, a severe lysosomal storage disorder
for which no chemotherapy is currently available.9,11
In order to gain rapid access to new iminosugars of
biological interest, we have designed a general strategy,
starting from
D- or L-xylose, for the synthesis of 1,5-
iminoxylitols analogs I bearing a diverse range of func-
tionalities at C-5. Our retrosynthetic analysis hinges on
the diastereocontrolled chain extension of the xylose-
derived imine III (Scheme 1). Structural diversity may
be introduced at C-5 by using the wide library of
organometallic or heteroatomic nucleophiles available.
Careful choice of reaction conditions can give selec-
tively one or the other of the two possible epimers at
C-5 in II.
Herein, we wish to report on our preliminary results
concerning the first stereocontrolled synthesis of 1,6-
dideoxy-
regarded as 4-epi-1-deoxy-
epi-1-deoxy- -rhamnojirimycin, its biological evalua-
L
-nojirimycin. As this compound can be
L
-fuconojirimycin or as 2-
L
tion as a glycosidase inhibitor may provide useful
information on structure–activity relationships in the
Scheme 1.
* Corresponding author. Fax: +33 2 38 41 72 81; e-mail: olivier.martin@univ-orleans.fr
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00752-8

48
A. Bordier et al. / Tetrahedron: Asymmetry 14 (2003) 47–51
Dess–Martin periodinane oxidation of the corresponding
family of 1,5-iminohexitols. Five syntheses of 1,6-
primary alcohol.
dideoxy-D-nojirimycin have been reported in the litera-
ture.12 They have in common the fact that they are not
stereospecific for a given sugar derivative except for the
efficient approach described by Hollingsworth et al. from
Having the key imine 4 in hand, we first investigated the
addition of methyllithium to the CꢀN bond in the pres-
ence of a monodentate Lewis acid (BF3·Et2O) to obtain
D
-glucose.12e Nevertheless, considering the exorbitant
the precursor of 1,6-dideoxy-
L
-nojirimycin (Scheme 3).
-sorbose-
cost of L-glucose, this approach would not be practical
Previous studies15 in our group on related
L
for the large scale preparation of
tives.
L-nojirimycin deriva-
derived imines indicated that the absolute configuration
of the newly created stereogenic center could be predicted
according to the open transition state model A, with an
antiperiplanar conformation due to electrostatic repul-
sion (Scheme 3).16 Addition of MeLi at −78°C to the imine
4 thus preactivated provided after purification the
expected amine 5a as a single diastereoisomer in 80%
yield. The absolute configuration of the stereogenic center
was unambiguously established to be S at the stage of the
piperidinol product. Addition of vinylmagnesium bro-
mide to 4 was also found to be completely diastereoselec-
tive as judged by proton NMR spectroscopy of the crude
product. It is noteworthy that the addition of methylmag-
nesium chloride to the N-benzyl nitrone analogue of
imine 4 was found to be poorly diastereoselective (si-face
addition, de <24%) with an improvement in the presence
of 1 equiv. of TMSOTf (de=74%).17,18
The synthesis of the key imine intermediate 4 was
performed in six steps and 45% overall yield from -xylose
L
following a protecting group strategy to isolate and then
oxidize the hydroxyl group at C-5 (Scheme 2). Conden-
sation of L-xylose with acetone catalyzed by H2SO4 in the
presence of CuSO4 afforded the diol 113 in 94% yield after
deprotection of the less stable isopropylidene group under
aqueous acidic conditions. Regioselective tritylation of
the primary alcohol in 1, followed by benzylation of the
3-position and cleavage of the trityl group using HBr in
glacial acetic acid provided the five-unprotected xylofura-
nose derivative 214 in 73% yield for the three steps. Finally
the imine 4 was cleanly prepared in quantitative yield by
condensation of benzylamine with aldehyde 3 obtained by
Scheme 2. Reagents and conditions: (a) dry acetone, CuSO4 (1.9 equiv.), H2SO4 (0.3 equiv.), 22 h then aq. HCl (0.2%), 7 h, 94%;
(b) TrCl (1.1 equiv.), pyridine, 50°C, 22 h, 93%; (c) BnBr (1.3 equiv.), NaH (1.6 equiv.), n-Bu4NI (0.05 equiv.), THF, 4 h, 94%;
(d) HBr/AcOH, 10°C, 1 min, 83%; (e) Dess–Martin periodinane (1.1 equiv.), CH2Cl2, 0°C to rt; 4 h, 67%; (f) BnNH2 (1.05 equiv.),
,
4 A molecular sieves, CH2Cl2, 4°C, 16 h, quant.
Scheme 3. Reagents and conditions: (a) MeLi (4 equiv.) or vinylMgBr (4 equiv.), BF3·Et2O (5 equiv.), Et2O, −78°C, 4 h, 80%
(R=Me), 69% (R=vinyl), de >98%.

A. Bordier et al. / Tetrahedron: Asymmetry 14 (2003) 47–51
49
The last key step of our strategy was the formation of
the piperidine ring by means of intramolecular reduc-
tive amination of the unmasked aminoxylose hemiketal
derived from 5a (Scheme 4). Surprisingly, this one-pot
process was particularly difficult to optimize, in con-
trast to our observations in the sorbofuranose series.15a
This result may be explained by the relative instability
of the intermediate aldehyde 6 or of the related cyclic
hemiaminal under aqueous acidic conditions. After
extensive studies, the best experimental conditions were
found to involve exposing 5a to a mixture of glacial
acetic acid and aq. HCl at room temperature for 5 h,
followed by the addition of NaBH3CN to the reaction
mixture. After purification by flash chromatography,
the expected piperidinol 7 was obtained in 41% yield.
The conversion of the allylic amine 5b led to an
untreatable mixture of products, and the configuration
at C-5 was not firmly established. Finally, removal of
the benzyl groups in 7 was conducted by hydrogenation
in the presence of 10% Pd/C to provide 1,6-dideoxy-L-
nojirimycin 819 in high yield after purification by chro-
matography on ion-exchange resin [Dowex 1-X2, (OH−
form)].
The inhibitory effects of 8 on various glycosidases, as
well as those of 1-deoxy-
-fuconojirimycin 10 and 1,6-dideoxy-
L
-rhamnojirimycin 9, 1-deoxy-
-nojirimycin 11
for comparison, are gathered in Table 1. As was found
for 1,6-dideoxy- -iminosugar 8
-nojirimycin 11,20 the
showed no significant inhibition of a- or b- -glucosi-
L
D
D
L
D
Scheme 4. Reagents and conditions: (a) AcOH/HCl 5N (10/1), 5 h, then NaBH3CN (9 equiv.), 96 h, 41%; (b) H2, Pd/C, MeOH,
HCl 5N cat., 24 h, quant.
Table 1. Inhibition values towards selected glycosidases
Enzyme
IC50 (mM)
a-L-Rhamnosidase
Penicillium decumbens
a-Fucosidase
Bovine epididymis
Human placenta
a-Glucosidase
52
(490)c,d
ND
ND
94
29
NDe
ND
0.09f
ND
ND
(0.0013)c,g
Rice
Yeast
(32%)a
NIb
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
NIh
NIh
NIh
NIh
NIh
Rat intestinal maltase
Rat intestinal isomaltase
Rat intestinal sucrase
b-Glucosidase
(45%)a
1000
(26%)a
Sweet almond
(38%)a
ND
ND
(780)c,i
a Inhibition rate at 1000 mM.
b NI: less that 50% inhibition at 1000 mM.
c Inhibition constant Ki in mM.
d Taken from Ref. 23.
e ND: not determined.
f Taken from Ref. 24.
g Taken from Ref. 25.
h Taken from Ref. 20.
i Taken from Ref. 12a.

50
A. Bordier et al. / Tetrahedron: Asymmetry 14 (2003) 47–51
dases. Comparison of the inhibition values between 8
and 1-deoxyfuconojirimycin 10 indicated that the a-
fucosidase active site can discriminate by over three or
four orders of magnitude inhibitors differing only by
the relative orientation of the OH group at C-4. These
results confirmed the conclusion of the study by
Winchester et al. who suggested that the minimum
1998, 37, 8615; (c) Kline, P. C.; Schramm, V. L. Biochem-
istry 1993, 32, 13212.
4. Jakobsen, P.; Lundbeck, J. M.; Kristiansen, M.; Brein-
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M. D.; Nash, R. J.; Griffiths, R. C.; McNeil, M.; Grewal,
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B.; Wrodnigg, T. M.; Stu¨tz, A. E. J. Carbohydr. Chem.
2000, 19, 435; (b) Durantel, D.; Branza-Nichita, N.;
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L
-
structural requirement for inhibition of a-
is satisfied when the configurations at C-2, C-3 and C-4
correspond to those of
-fucose.21 Interestingly, com-
pound 8 (=2-epi-1-deoxy- -rhamnojirimycin) is a good
inhibitor of a- -rhamnosidase of Penicilium decumbens,
whereas 1-deoxy- -rhamnojirimycin 9 showed no sig-
L-fucosidase
L
L
L
L
nificant inhibition at 750 mM.22 The weak inhibitory
activity of 9 was confirmed by Wong et al. (Ki=490
mM).23 On the basis of modelling and structure–activity
studies, Fleet et al. suggested that potent inhibitors of
rhamnosidase mimic the conformation of the relevant
glycopyranosyl cation intermediate, postulated to be
4
the H3 half-chair form. For example the lowest energy
conformation (4C1) of 5-epi-1-deoxy-
L
-rhamnojir-
imycin, a very good inhibitor of a-
L-rhamnosidase
(IC50=5 mM), was found to be an excellent match with
the 4H3 half-chair structure of the rhamnopyranosyl
cation, whereas the lowest energy conformation (1C4) of
1-deoxy-
-rhamnojirimycin 9 was not.22 However, this
L
hypothesis does not explain the good inhibitory activity
of 8, the 1C4 conformation of which is a very poor
mimetic of the 4H3 half-chair structure of the
rhamnopyranosyl cation.
9. Butters, T. D.; Dwek, A.; Platt, F. M. Chem. Rev. 2000,
100, 4683.
10. Alper, J. Science 2001, 291, 2338.
11. Cox, T.; Lachmann, R.; Hollak, C.; Aerts, J.; van Weely,
S.; Hrebicek, M.; Platt, F.; Butters, T.; Dwek, R.; Moy-
ses, C.; Gow, I.; Elstein, D.; Zimran, A. The Lancet 2000,
355, 1481.
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Z.; Ichikawa, Y.; Porco, J. A.; Wong, C.-H. J. Am.
Chem. Soc. 1991, 113, 6187; (b) Di, J.; Rajanikanth, B.;
Szarek, W. A. J. Chem. Soc., Perkin Trans. 1 1992, 2151;
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Acta 1998, 81, 2043.
In conclusion, we have achieved the first synthesis of
1,6-dideoxy-
form in nine steps from
L
-nojirimycin 8 in enantiomerically pure
-xylose in an overall yield of
L
15%. The biological activity of this compound provided
useful information on structure–activity relationships in
the family of 1,5-iminoalditols. Future work will focus
on the extension of this synthetic strategy to other
1,5-iminoxylitol derivatives bearing a diverse range of
functionality at C-5.
Acknowledgements
14. Streicher, H.; Meisch, J.; Bohner, C. Tetrahedron 2001,
57, 8851.
This work was supported by CNRS and the University
of Orle´ans.
15. (a) Godin, G.; Compain, P.; Masson, G.; Martin, O. R.
J. Org. Chem. 2002, 67, 6960; (b) Masson, G.; Compain,
P.; Martin, O. R. Org. Lett. 2000, 2, 2971.
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8 are in good agreement with the reported data for
1,6-dideoxy-D
-nojirimycin 1012 with specific rotation of
the opposite sign: [h]2D0 −12 (c 1.6, MeOH); lit.12c [h]2D0
+11 (c 1, MeOH); HRFABMS m/z 148.0972 [M+H]+
(C6H14NO3 requires 148.0974).
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