Access to homoglyconojirimycins via ring isomerisation of pentahydroxylated azepanes

Article abstract of DOI:10.1055/s-2007-973884

N-Benzyl pentahydroxyazepanes undergo ring isomerization during mesylation of the hydroxyl group β to the nitrogen via a neighboring nitrogen participation involving a transient aziridinium species which is trapped by chlorine. The resulting chloromethyl

Full text of DOI:10.1055/s-2007-973884

LETTER
905
Access to Homoglyconojirimycins via Ring Isomerisation of Penta-
hydroxylated Azepanes
Access to
H
omo
a
glyconojir
o
imycins Liu,a,b Yongmin Zhang,a,b Yves Blériot*a
a
Ecole Normale Supérieure, Département de Chimie, Institut de Chimie Moléculaire (FR 2769), UMR 8642, CNRS-ENS-UPMC Paris 6,
24 Rue Lhomond, 75231 Paris Cedex 05, France
Fax +33(1)44323397; E-mail: yves.bleriot@ens.fr
b
ZJU-ENS Joint Laboratory of Medicinal Chemistry, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058,
P. R. of China
Received 12 January 2007
structures lack the important hydroxymethyl group at C-5
and do not closely mimic the parent pyranoside. We report
herein a similar approach applied to pentahydroxylated
azepanes, which affords six-membered iminosugar C-gly-
Abstract: N-Benzyl pentahydroxyazepanes undergo ring isomer-
ization during mesylation of the hydroxyl group b to the nitrogen
via a neighboring nitrogen participation involving a transient aziri-
dinium species which is trapped by chlorine. The resulting chloro-
methyl tetrahydroxypiperidines have been converted into the cosides bearing a hydroxymethyl group at C-5 and a chlo-
corresponding homoglyconojirimycins.
romethyl functionality at C-1 ready for further
transformation (Scheme 1).
Key words: azasugars, aziridinium, glycosidases, piperidines, ring
contractions
R1
N
R1
N
X
X
Nu
OR2
Over the years, polyhydroxylated piperidines have attract-
ed a lot of attention from the synthetic community1 be-
cause of their interesting structures and potent biological
activities including glycosidase inhibition.2 More recent-
ly, iminosugars have found new therapeutic applications
including a nonhormonal approach to male contraception3
and potential immunosuppressive activity.4
R3O
OH
OR2
R3O
R2O
R2O
β-hydroxyl
activation
R1
N+
R1
N
X
Nu
X
Nojirimycin was the first natural piperidine azasugar
isolated5 but its hemiaminal function makes this com-
pound quite unstable. Nature has solved this problem by
producing a vast number of chemically stable 1-deoxy de-
rivatives such as deoxynojirimycin6 and 1-C-derivatives
including homoglyconojirimycins,7 both families display-
ing strong inhibition on glycosidases. Homoglyconojiri-
mycins are of interest since the presence of an extra
methylene group at C-1 improves the selectivities of these
piperidines towards glycosidases. Considering the high
potential of iminosugars as drug candidates,8 new routes
to homoglyconojirimycins and iminosugar-C-glycosides
are still needed.9 Ring expansion of substituted hy-
droxymethyl pyrrolidines towards piperidines is well
documented10 as is the similar transformation of hy-
droxymethyl piperidines to azepane and azepine scaf-
folds.11 These heterocyclizations involve activation of the
hydroxyl group b to the nitrogen, formation of a transient
aziridinium species which is subsequently attacked by a
nucleophile at the methine carbon to furnish the expanded
ring. Ring contraction of activated b-hydroxyazepanes
through a similar aziridinium intermediate has only been
reported by Le Merrer12 and Lohray13 who have used this
strategy to generate tetrasubstituted piperidines. These
R3O
R2O
LG
R3O
OR2
R2O
OR2
aziridinium
intermediate
Le Merrer's work: X = H
this work: X = CH2OR
Scheme 1
Cbz
N
Cbz
Cbz
N
N
BnO
BnO
BnO
BnO
BnO
BnO
BnO
OH
OH
BnO
BnO
OH
OH
OH
OH
1
2
3
Cbz
N
BnO
BnO
BnO
OH
OH
4
Figure 1
SYNLETT 2007, No. 6, pp 0905–0908
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3.
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4.
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Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973884; Art ID: D01307ST
© Georg Thieme Verlag Stuttgart · New York

906
T. Liu et al.
LETTER
Our group14 and Dhavale15 have recently reported the syn-
thesis and the biological evaluation of pentahydroxylated
azepanes. During our route, cis-dihydroxyazepanes 1–4
have been obtained (Figure 1) that constitute useful pre-
cursors to generate iminosugar C-glycoside derivatives
via the ring-contraction strategy described above.
1. TBDMSCl,
pyridine, r.t.
2. BnBr, NaH,
DMF, r.t.
3. TBAF, 4 Å MS,
THF, r.t.
6
Bn
N
Bn
N
BnO
BnO
BnO
BnO
BnO
BnO
7
5
1
4
OH
3
2
OH
OH
OBn
Ring expansion of piperidines towards azepanes has been
shown to work well with N-benzyl derivatives but not
with N-tosyl analogues11e emphasizing the requirement
for a rather nucleophilic endocyclic nitrogen. Conversion
of the Z-protected azepanes 1–4 to the more nucleophilic
N-benzyl derivatives 5–8 was thus needed and we found
that hydrogenolysis with Lindlar’s catalyst in methanol in
the presence of catalytic triethylamine followed by
chemoselective N-benzylation of the crude dihy-
droxyamine with benzyl bromide and potassium carbon-
ate afforded the desired N-benzyl cis-diols 5–8 in good
yield (Table 1).
5 (1S,2S,5R)
6 (1R,2R,5R)
7 (1S,2S,5S)
8 (1R,2R,5S)
9 (56%)
10 (47%)
11 (37%)
12 (45%)
Scheme 2
after tedious column chromatography. Compulsory selec-
tive protection of the 2-hydroxyl group in compounds 5–
8 was achieved as follows. Silylation of the less hindered
b-hydroxyl group in azepanes 5–8 and benzylation of the
remaining free 2-hydroxyl group followed by desilylation
with TBAF afforded the desired b-hydroxyazepanes 9–12
in satisfactory yield (Scheme 2).
Ring isomerisation of diols 5–8 avoiding protection steps
was attempted but regioselective activation of the b-hy-
droxyl group did not take place and only a small amount
of the 2-hydroxy chloromethyl piperidines were isolated
The key ring-contraction step was then investigated.
When treated with MsCl in dichloromethane in the pres-
ence of triethylamine, b-hydroxyazepanes 9–12 yielded
the desired chloromethyl piperidines 13–16 in high
yields (Table 2).16 To confirm that the reaction proceeds
with overall retention of configuration as previously
observed12 and to take advantage of these new chloro-
methyl piperidines, compounds 13–16 were converted
into the corresponding homoglyconojirimycins. A two-
step literature procedure17 including chlorine displace-
ment by an acetate followed by deacetylation furnished
the primary alcohols 17–20 in moderate yield (un-
optimized). Final hydrogenolysis under acidic conditions
quantitatively afforded the chlorohydrates of known a-
homonojirimycin (a-HNJ, 21),18 b-homomannojirimycin
(b-HMJ, 22),19 and very recently reported b-L-homoi-
donojirimycin (23) and a-L-homogulonojirimycin (24,20
Table 2). L-homoazasugar 23 was assayed towards a
range of commercially available glycosidases and was
found to be a poor a-L-fucosidase (15% of inhibition at 1
mM concentration) and b-glucosidase (19% of inhibition
at 1 mM concentration) inhibitor.
Table 1 Synthesis of N-Benzyl cis-Diols 5–8
Entry
N-Cbz derivative
N-Benzyl derivative Yield (%)
Cbz
Bn
N
BnO
N
BnO
BnO
BnO
BnO
BnO
OH
OH
1
90
89
82
OH
OH
1
5
Cbz
N
Bn
N
BnO
BnO
BnO
BnO
BnO
BnO
OH
BnO
OH
2
OH
BnO
OH
6
2
Cbz
N
Bn
N
BnO
BnO
BnO
In summary, a general strategy involving activation of the
hydroxyl group b to the nitrogen has been applied to a se-
ries of N-benzyl pentahydroxyazepanes to afford a new
set of ring-contracted chloromethyl tetrahydroxypipe-
ridines which are useful 1-C-iminosugar precursors. Fur-
ther manipulation of the chloromethyl moiety furnished
the corresponding homoglyconojirimycins. Work is now
in progress to explore this strategy with other available
azepanes.21
OH
BnO
OH
3
4
OH
BnO
OH
3
7
Cbz
N
Bn
N
BnO
BnO
BnO
BnO
BnO
OH
OH 78
OH
OH
Representative Experimental Procedures
Typical Procedure for N-Benzylation of Azepanes
4
8
Dihydroxyazepane 1 (218 mg, 0.36 mmol) was dissolved in EtOH
(18 mL) and a catalytic amount of Et3N (24 mL) was added followed
by Lindlar’s catalyst (218 mg). The reaction vessel was purged from
Synlett 2007, No. 6, 905–908 © Thieme Stuttgart · New York

LETTER
Access to Homoglyconojirimycins
907
Table 2 Synthesis of Chloromethyl Piperidines 13–16
Entry b-Hydroxyazepane
Chloromethyl piperidine
Yield (%) Hydroxymethyl piperidine Yield (%) Homoglyconojirimycin
Bn
H⋅HCl
Bn
N
Bn
N
N
BnO
BnO
BnO
N
BnO
BnO
Cl
OBn
BnO
BnO
OH
OBn
HO
HO
HO
OH
OH
OH
OBn
HO
1
79
51
BnO
13
BnO
17
OH
21
9
Bn
N
H⋅HCl
Bn
Bn
N
BnO
BnO
BnO
N
N
BnO
BnO
Cl
OBn
BnO
BnO
OH
OBn
OH
OH
BnO
OH
OBn
HO
2
54
38
BnO
BnO
OH
BnO
22
14
18
10
Bn
N
H⋅HCl
Bn
N
Bn
N
N
BnO
BnO
Cl
OBn
BnO
BnO
OH
OBn
OH
OH
BnO
OH
OBn
HO
3
4
86
75
26
39
BnO
BnO
OH
BnO
23
15
19
11
Bn
N
Bn
Bn
N
H⋅HCl
N
N
BnO
BnO
Cl
OBn
BnO
BnO
OH
OBn
HO
HO
OH
OH
BnO
BnO
OH
OBn
BnO
16
BnO
OH
20
24
12
air and filled with H2. The suspension was stirred under an H2 atmo-
sphere for 4 h by which time TLC (cyclohexane–EtOAc–HCOOH,
3:2:0.1) showed a complete reaction. The reaction mixture was fil-
tered through a Celite® plug, eluted with MeOH and concentrated to
afford the N-deprotected azepane as an oil. This oil was dissolved
in a mixture of EtOH–H2O (7:1, 1 mL) and K2CO3 (153 mg, 1.1
mmol) followed by addition of benzyl bromide (55 mL, 0.46 mmol).
The reaction mixture was refluxed for 2 h, extracted with CH2Cl2,
dried with MgSO4 and concentrated. Purification by flash column
chromatography (cyclohexane–EtOAc, 5:2) afforded the N-benzyl-
azepane 5 (183 mg, 90% yield) as an oil.
References and Notes
(1) (a) Afarinkia, K.; Bahar, A. Tetrahedron: Asymmetry 2005,
16, 1239. (b) Pearson, M. S. M.; Mathé-Allainmat, M.;
Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159.
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Typical Procedure for Ring Contraction of Azepanes
b-Hydroxyazepane 9 (82 mg, 0.128 mmol) was dissolved in dry
CH2Cl2 (1.2 mL) under argon and the solution was cooled at 0 °C.
Then, Et3N (36 mL, 0.258 mmol) followed by MsCl (15 mL, 0.194
mmol, of a 0.1% v/v solution of MsCl in CH2Cl2) were added. The
reaction mixture was stirred at 0 °C for 2 h and the solution was con-
centrated. Purification by flash column chromatography (cyclohex-
ane–EtOAc, 25:1) afforded the corresponding chloromethyl
piperidine 13 (67 mg, 0.101 mmol, 79% yield) as an oil.
(7) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
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(9) For reported strategies to iminosugar C-glycosides, see:
Dhavale, D. D.; Matin, M. M. ARKIVOC 2005, (iii), 110;
and references cited therein.
Acknowledgment
We thank C. Bello and Prof. P. Vogel (Swiss Federal Institute of
Technology, Lausanne) for glycosidase inhibition assays. Tao Liu
thanks the Ecole Normale Supérieure for a post-doctoral fellowship.
Synlett 2007, No. 6, 905–908 © Thieme Stuttgart · New York

908
T. Liu et al.
LETTER
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