Efficient access to azadisaccharide analogues

Article abstract of DOI:10.1016/S0040-4039(01)00756-0

The synthesis of various aminocyclitols as pseudo-azadisaccharide candidates for glycosidase inhibition is described. The strategy involves the reductive amination with several amines of polyhydroxycycloheptanones resulting from a tandem alkylation-cyclis

Full text of DOI:10.1016/S0040-4039(01)00756-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4475–4478
Efficient access to azadisaccharide analogues
Christine Gravier-Pelletier, William Maton, Thomas Lecourt and Yves Le Merrer*
Universite´ Rene´ Descartes, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS,
45, rue des Saints-Pe`res, 75270 Paris Cedex 06, France
Received 10 April 2001; revised 30 April 2001; accepted 6 May 2001
Abstract—The synthesis of various aminocyclitols as pseudo-azadisaccharide candidates for glycosidase inhibition is described.
The strategy involves the reductive amination with several amines of polyhydroxycycloheptanones resulting from a tandem
alkylation–cyclisation of C2-symmetrical bis-epoxides derived from
D-mannitol. © 2001 Elsevier Science Ltd. All rights reserved.
As part of an ongoing program1,2 directed towards the
design and synthesis of new glycosidases and glycosyl-
transferases inhibitors, our goal was to develop a short
and convergent route to carbasugars and aminocycli-
tols. Indeed, due to protonation of the nitrogen atom at
physiological pH, aminocyclitols can be considered as
mimics of the positively charged transition state which
is claimed to arise during these enzymatic reactions.3
The charge can be localised either at anomeric oxygen
or carbon atoms, or at the exocyclic oxygen atom,
depending on the nature, a or b, of the glycosidase,
thus giving rise to the rational design of potent transi-
tion state analogues as competitive inhibitors of these
enzymes. Therapeutic applications of such inhibitors
can be directed towards diabetes, cancer or viral infec-
tions,4 justifying the intense synthetic efforts devoted to
these challenging compounds.5,6 Furthermore, in order
to improve the selectivity of the interaction between the
enzyme and the potent inhibitor, it has been shown that
it is often beneficial to also mimic the aglycone part of
the di- or poly-saccharide to enhance the observed
inhibition; so that many current strategies deal with
access to pseudo-azadisaccharides.2,7,8
playing various sizes and configurations, the nitrogen
atom being either substituted or not. It is noteworthy
that such a structure may be exemplified by voglibose9
or acarbose,10 which are both already used as
antidiabetics.
The retrosynthesis of the target compounds is outlined
in Scheme 1 and relies on a strategy we recently
described,11 which involves a one-pot tandem alkyla-
tion–cyclisation of C2-symmetrical bis-epoxides derived
from
D-mannitol.
Carbasugars or aminocyclitols can result from the
reduction or the reductive amination of the correspond-
ing polyhydroxycycloalcanones, which are first masked
as their dithioketals. We have shown that by selecting
appropriate protective groups for the secondary alcohol
functions of the starting bis-epoxide, the carbocyclisa-
tion involving 1,4-Brook12 rearrangement could be
directed towards the major formation of enantiomeri-
cally pure dithioketals of either cyclohexanone or cyclo-
heptanone. Thus, for P=methylethylidene, C6 rings are
mainly formed, while for P=benzyl, C7 rings predomi-
nate whether the configuration of the bis-epoxide is
In this context, we have been aiming at developing a
new route to enantiomerically pure aminocyclitols dis-
D
-manno or
L-ido (Scheme 2). The overall yield ranges
from 63 to 82%.
Scheme 1.
Keywords: glycosidases; pseudo-azasaccharide; carbasugars; aminocyclitols; reductive amination.
* Corresponding author. Tel.: +33(0)142862176; fax: +33(0)142868387; e-mail: yves.le-merrer@biomedicale.univ-paris5.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00756-0

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Scheme 2. Major cyclitols available from either 1a or 1b (Si=TBDMS).
Access to aminocyclitols requires dithioketal hydrolysis.
It was first carried out on cycloheptanone 2a or 2b
according to smooth Stork conditions13 involving
bis(trifluoro acetoxy)iodobenzene (BTI) in aqueous ace-
tonitrile at 20°C to afford the expected cycloheptanone
4a or 4b in good yield (Scheme 3).14 However, depend-
ing on the assays, the yield happened to decease to 50%
in a few cases. It seems that this difficulty could be
overcome by careful monitoring of the quantity of
water introduced since excess of water could lead to
decomposition of BTI.15 Alternatively, this dethioketal-
isation could be achieved in the presence of N-bromo-
succinimide (NBS) in aqueous acetone16 at −30°C to
give the corresponding cycloheptanone in 80% repro-
ducible yield. Further LiAlH4 reduction of the cyclo-
heptanone 4b cleanly afforded the expected carbasugar
5b in 70% yield.
either to unreacted starting material or to degradation
products.17
In order to limit side reactions, NBS dithioketal hydroly-
sis of the cyclohexane 3a was achieved at −30°C and
was followed by sodium borohydride reduction of the
resulting ketone 6a immediately after its isolation, with-
out intermediate purification, thus affording a 82:18
mixture of the alcohols R-7a/S-7a in 80% overall yield
(Scheme 4).14 Conditions of this reaction are now being
studied to improve the diastereoselectivity towards the
formation of a single isomer, either R-7a or S-7a.18
With cycloalcanones in hand, we next turned to the
preparation of the targeted aminocyclitols via their
reductive amination with various amines in order to
reach pseudo-azadisaccharides displaying both func-
tional and configurational diversity. The reductive ami-
nation was carried out under Mattson et al.
conditions19 involving the mild and effective titanium-
(IV) isopropoxide as Lewis acid to catalyze imine
NBS conditions were best for allowing recovery of
cyclohexanones from their dithioketals in reasonable
yield. Indeed, most of the classical methods (Table 1) to
complete this hydrolysis on C6 rings failed, leading
Scheme 3.
Table 1. Summary of typical assays of dithioketal hydrolysis of the cyclohexanone 3a
Reagent
Solvent
Temperature (°C)
Result
Et3OBF4
CH2Cl2
20
Degradation
Starting material
Starting material
28% of 6a
Degradation
34% of 6a
HgCl2, K2CO3
HgCl2, K2CO3
Hg(ClO4)2, K2CO3
DDQ, H2O traces
NBS
(CH3)2CO/H2O
CH3CN/H2O
THF/H2O
CH3CN
(CH3)2CO/H2O
Reflux
Reflux
20
Reflux
20

C. Gra6ier-Pelletier et al. / Tetrahedron Letters 42 (2001) 4475–4478
4477
Scheme 4.
formation followed by its in situ reduction in the pres-
ence of sodium cyanoborohydride (Table 2).14 Thus,
the imine formation efficiently occurred at 20°C by
addition of neat amine (benzylamine, butylamine, 1,3-
di-tert-butyldimethylsilyloxy-2-propylamine or methyl
of n-tetrabutylammonium fluoride in THF to give the
corresponding alcohol (12–15). The deprotection of
benzyl ethers, and N-benzyl amines for 12a and 12b,
involved hydrogenolysis in the presence of palladium
black in acetic acid. For the compound 15a, this reac-
tion was carried out by sodium in liquid ammonia.
Subsequent purification by ion-exchange chromatogra-
phy afforded the targeted pseudo-azadisaccharides (16–
19).
6-amino-6-deoxy-2,3,4-tri-O-benzyl-a-D-glucopyrano-
side,20 2 equivalents), to a mixture of the cyclohep-
tanone 4a or 4b (1 equivalent) with Ti(OiPr)4 (1.25
equivalent) and was followed by successive addition of
absolute ethanol and NaBH3CN (4 equivalents) to
afford the expected N-substituted aminocycloheptanol
(8–11) in yields ranging from 47 to 91%.
In summary, various aminocyclitols were obtained in a
straightforward manner via reductive amination of
enantiomerically pure cycloheptanones resulting from a
one-pot tandem alkylation–cyclisation of C2-symmetri-
Removal of the tert-butyldimethylsilyl protective
groups was easily achieved in the presence of an excess
cal bis-epoxides derived from D-mannitol. According to
Table 2. Summary of the various aminocyclitols obtained.14 Yield is given for each step

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C. Gra6ier-Pelletier et al. / Tetrahedron Letters 42 (2001) 4475–4478
this strategy, the synthesised aminocyclitols have been
8. Johns, B. A.; Jonhson, C. R. Tetrahedron Lett. 1997, 39,
749–752.
9. Yoshioka, K.; Azukari, K.; Ashida, K.; Kasamatsu, Y.;
Yokoo, S.; Yoshida, T.; Kondo, M. Horm. Metab. Res.
1997, 29, 407–408.
10. Yee, H. S.; Fong, N. T. Pharmacotherapy 1996, 16,
792–805.
11. Le Merrer, Y.; Gravier-Pelletier, C.; Maton, W.; Numa,
M.; Depezay, J.-C. Synlett 1999, 1322–1324.
12. Moser, W. H. Tetrahedron 2001, 57, 2065–2084 and
references cited therein.
N-substituted by several
(HOCH2)2CH and methyl a-
R
groups: R=n-Bu,
D
-glucoside as respectively
N-butyl-1-deoxynojirimycin,21 voglibose9 and azadisac-
charide analogues. Their biological activity towards
various glycosidases will be evaluated and compared to
that of the corresponding aminocyclitol (R=H). Access
to aminocyclitol analogues from C6 derivatives is now
in progress and will be reported in due course.
13. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287–290.
14. Satisfactory analytical and/or spectroscopic data were
obtained for all new compounds.
Acknowledgements
15. Yu, C.; Jiang, Y.; Liu, B.; Hu, L. Tetrahedron Lett. 2001,
42, 1449–1452.
16. Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36,
3553–3560.
17. Instability of such compounds was emphasised by the
isolation of an a,b-ethylenic ketone resulting from b-elim-
ination of tert-butyldimethylsilyl ether in the following
case:
Contribution to the synthesis of the aminocyclitols 17a
and 19a by D. Paumier (D.E.A. student) and D.
Quaglieri (technician student), respectively, is gratefully
acknowledged.
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