Iminosugars from α,β-epoxyamides. Part 1: Synthetic approach to hydroxylated piperidine derivatives

Article abstract of DOI:10.1016/j.tetlet.2003.09.116

A new synthetic route towards iminosugars starting from chiral epoxyamides is described. The strategy, by which a single precursor, the α,β-epoxyamide obtained from 6-O-trityl-2, 3-O-isopropylidene-D-ribose and a sulphur ylide, can be transformed into different iminosugars, is based on the combination of a regioselective epoxide opening and stereospecific intramolecular displacements.

Full text of DOI:10.1016/j.tetlet.2003.09.116

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8353–8356
Iminosugars from a,b-epoxyamides. Part 1: Synthetic approach
to hydroxylated piperidine derivatives
M. Soledad Pino-Gonza´lez,* Carmen Assiego and F. Jorge Lo´pez-Herrera†
Departamento de Bioqu´ımica, Biolog´ıa Molecular y Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Ma´laga,
29071 Ma´laga, Spain
Received 27 June 2003; revised 22 July 2003; accepted 17 September 2003
Abstract—A new synthetic route towards iminosugars starting from chiral epoxyamides is described. The strategy, by which a
single precursor, the a,b-epoxyamide obtained from 6-O-trityl-2,3-O-isopropylidene-D-ribose and a sulphur ylide, can be
transformed into different iminosugars, is based on the combination of a regioselective epoxide opening and stereospecific
intramolecular displacements.
© 2003 Elsevier Ltd. All rights reserved.
The syntheses of a,b-epoxyamides in a highly stereose-
lective manner by reaction of monosaccharides, prop-
erly functionalized, with stabilized sulfonium ylides,
have been performed by our group in the last years.10,11
These systems with a high degree of functionality repre-
sent new, readily available, optically active building
blocks for use in synthesis. Our preliminary studies
showed these epoxyamides as precursors of C-gly-
cosides, by intramolecular cyclisation by oxirane ring
opening.12 Now, our strategy is leading to synthesize
azasugars and related products.
Iminosugars have been the object of an intense research
effort during last years,1,2 due to their remarkable bio-
logical activities such as selective glycosidase and glyco-
syltransferases inhibitors. Several studies have
confirmed the value of these compounds in inhibiting
the human immunodeficiency virus (HIV) replication.3
It has also been demonstrated their therapeutic applica-
tions for the treatment of hyperglycemia and disorders
related to these conditions such as obesity and dia-
betes.4 These useful biological properties have
prompted the search for more efficient and/or more
selective compounds and iminosugar derivatives of
great structural diversity have been prepared3,5 or iso-
lated from natural sources.6,7
Since the epoxyamide 1 is obtained in quantitative yield
with complete stereoselectivity,13 firstly we started with
this easily available
from
D-ribose derivative (only three steps
D
-ribose) to reach our objectives. Two strategies
Homoiminosugars (also named homoazasugars), with
an additional anomeric hydroxymethyl such as a-HMJ
and b-HMJ (homomannojirimycins) as well as some
glycosides, are natural products and their syntheses
have preceded their isolation from cultivated plants;
this incorporated substituent might provide additional
selectivity.8,9 It has been also described that
monomethyl amides analogues showed strong competi-
tive inhibition against glucosaminidases8 (Fig. 1).
were established (Scheme 1).
This paper reports the synthesis of piperidinic
homoiminosugars precursors from chiral epoxyamides.
Keywords: iminosugar; azasugar; hydroxylated piperidines;
epoxyamide; C-glycosides; sulphur ylides.
* Corresponding author. Tel.: +34-952134260; fax: +34-952131941;
e-mail: pino@uma.es
† Recently deceased. In memoriam.
Figure 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.116

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M. S. Pino-Gonza´lez et al. / Tetrahedron Letters 44 (2003) 8353–8356
Scheme 1.
(a) Cyclisation by nucleophilic displacement on C-6:
Introduction of the heteroatom (nitrogen) at C-2 by a
regioselective opening14 of the epoxide group in 1,
hydroxy group transformation at C-6, with configura-
tional inversion or retention and intramolecular cyclisa-
tion to piperidines
displacement of a good leaving group at C-6.
2
and
3
by stereospecific
(b) Cyclisation by nucleophilic displacement on C-3:
Introduction of the heteroatom at C-6 in 1, with subse-
quent 5-exo cyclisation to afford the functionalized
pyrrolidines 4.
In this paper we describe the development of the first
strategy (a). The protected polyhydroxypiperidines can
be prepared alternatively by means of two synthetic
routes: (a) previous transformation at C-6 and subse-
quent epoxide opening (Scheme 2) and (b) epoxide
opening followed by selective hydroxyl group protec-
tion (Schemes 3 and 5).
In the first approach, the epoxyamide 1 was treated
with mesyl chloride in pyridine at 0°C giving the mesyl-
ated product 5. The oxirane ring of 5 was opened with
complete regioselectivity by benzyl amine with subse-
quent intramolecular displacement of mesyl group giv-
ing the imino sugar 2a and the C-glycoside 6a (only two
steps from the epoxyamide 1 and five from
D-ribose).
The formation of these products can be justified by the
mechanism depicted in Scheme 2 (via a“2a, via b“6a).
The acetylation of 2a and 6a in the usual manner
afforded the products 2b and 6b. Characteristic features
Scheme 2. Reagents and conditions: (a) Me2CO, H+; (b) TrCl,
py; (c) Me2S+CH2CONEt2,Cl−, 20% NaOH (aq) CH2Cl2; (d)
MsCl, py; (e) H2NBn, MeOH; (f) Ac2O, py.
1
of the H and 13C NMR spectra and COSY experi-
ments, provided strong evidence for the proposed struc-
tures of 2a, 2b, 6a and 6b.
In order to avoid the formation of C-glycoside 6a an
alternative route was developed (Scheme 3). The epox-
ide 1 was treated with sodium azide in AcOH/DMF to
give the azide derivative 7 with complete regioselectiv-
ity. The selective protection of the OH group on C-3
was achieved with TBDMSOTf and 2,6-lutidine in
methylene chloride at 0°C (8c:9c, 2:1). The transforma-
tion of 8c into the mesylate 10c with mesyl chloride in
pyridine (95% yield) and the further treatment of the
azide group with Ph3P in THF, followed by addition of
water, gave the functionalized homoiminosugar 2c in
83% yield.
product 11c failed but gave the C-glycoside 13, which
could be characterized by spectroscopic data. The for-
mation of 13 can be justified by a 1,7 O“O migration
of the TBDMS group in basic media15 and further
attack of O-C3 with intramolecular substitution of the
mesyl group (Scheme 4).
The silyl group migration was avoided when 7 was
protected with the triisopropylsilyl ether (TIPS).16 The
regioselectivity observed was higher to that of TBDMS
group (Table 1). Selective protection with other groups
were tested: treatment of 7 with t-butyldiphenylsilyl
chloride afforded 9e as the major product; this opposite
regioselectivity can be justified by a p-p stacking inter-
action with the trityl group. The reaction with benzyl
bromide yielded a mixture 1:1 of benzylated products.
The formation of a -epimer of 2c was intended via the
D
formation of the epoxide 12c. Preliminary assays
toward the formation of the terminal epoxide from

M. S. Pino-Gonza´lez et al. / Tetrahedron Letters 44 (2003) 8353–8356
8355
Scheme 3. Reagents and conditions: (a) NaN3, AcOH, DMF;
(b) TBDMSOTf, 2,6-lutidine, CH2Cl2, 0°C; (c) MsCl, py,
0°C; (d) i-Ph3P, THF; ii-H2O; (e) 2% TFA in CH2Cl2.
Scheme 5. Reagents and conditions: (a) MsCl, py, 0°C; (b) 2%
TFA in CH2Cl2; (c) 1 M solid NaOMe in CHCl3; (d) i-Ph3P,
CHCl3; ii-H2O.
1
reaction by H NMR, showing the epoxide formation
according to the signals (ppm) at 3.44 (m, H-6), 2.61
and 2.84 (2dd, H-7,7%). When the azide group was
reduced with Ph3P/CHCl3 followed by water addition,
the subsequent intramolecular oxirane opening led to
the 6-exo product 3d as the more favoured over the
7-endo product 14 by a ratio of 4:1. The structural
assignments for 3d and 14 were based on their NMR
spectroscopic data: 2.75 (m, H-6), 3.42, 3.76 (m, H-7,7%)
and 58.0 (C-6), 63.0 (C-7) for 3d; 3.85 (m, H-6), 2.93
(m, H-7,7%) and 71.02 (C-6), 46.34 (C-7) for 14.
The present syntheses of 2a, 2c and 3d from the ribose
derivative 1 have demonstrated the utility of a,b-
epoxyamides in the formation of hydroxylated piperidi-
nes. Summing up, we have reported an efficient
methodology for the preparation of iminosugars based
on the combination of a regioselective epoxide opening
and a stereospecific cyclisation. The scope of this strat-
egy can still be enhanced by the use of different
monosaccharide starting materials.
Scheme 4.
Table 1. Regioselectivity in the hydroxyl group protection
Series
R
Reactive
Relation products 8:9
c
d
e
f
TBDMS
TIPS
TBDPS
Bn
TBDMSOTf
TIPSOTf
TBDPSCl
BnBr
2:1
3:1
0:1
1:1
Acknowledgements
The formation of epoxide 12d from the derivated 11d
was accomplished as depicted in Scheme 5. The mesyla-
tion of 8d followed by the deprotection of trityl group
afforded 11d. The treatment of 11d with solid sodium
methoxide in CDCl3, permitted us to monitorize the
This research was supported with funds from the Direc-
cio´n General de Investigacio´n Cient´ıfica y Te´cnica (Ref.
BQU2001-1576) and by the Direccio´n General de Uni-
versidades e Investigacio´n, Consejer´ıa de Educacio´n y
Ciencia, Junta de Andaluc´ıa (FQM 0158).

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M. S. Pino-Gonza´lez et al. / Tetrahedron Letters 44 (2003) 8353–8356
11. Heras Lo´pez, A. M.; Pino-Gonza´lez, M. S.; Sarabia-Gar-
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