Intramolecular 1,3-dipolar cycloaddition of N-alkenyl nitrones en route to glycosyl piperidines

Article abstract of DOI:10.1016/j.tetlet.2009.10.023

Stereoselective intramolecular 1,3-dipolar cycloaddition of homochiral N-(alkenylglycosyl)nitrones, prepared by allylation of C-(glycosyl)nitrones and subsequent oxidation, is described. The previously described 2-aza-Cope rearrangement was not observed f

Full text of DOI:10.1016/j.tetlet.2009.10.023

Tetrahedron Letters 50 (2009) 7152–7155
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular 1,3-dipolar cycloaddition of N-alkenyl nitrones en route
to glycosyl piperidines
Eduardo Marca a, Ignacio Delso a, Tomás Tejero a, Jesús T. Vázquez b, Rosa L. Dorta b, Pedro Merino a,
*
a Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza, CSIC, E-50009 Zaragoza, Aragon, Spain
b Instituto Universitario de Bio-Orgánica ‘Antonio González’, Departamento de Química Orgánica, Universidad de La Laguna, E-38206, La Laguna, Tenerife, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective intramolecular 1,3-dipolar cycloaddition of homochiral N-(alkenylglycosyl)nitrones,
prepared by allylation of C-(glycosyl)nitrones and subsequent oxidation, is described. The previously
described 2-aza-Cope rearrangement was not observed for these substrates, but evidences of E/Z isomer-
ism during the cycloaddition were obtained. The obtained cycloadducts can serve as key precursors of
imino disaccharide analogues. This is exemplified by a short route to a protected 2-furanosyl-4-
hydroxy-6-phenyl piperidine.
Received 11 September 2009
Revised 30 September 2009
Accepted 2 October 2009
Available online 8 October 2009
Dedicated to Professor José Barluenga on the
occasion of his 70th birthday
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Nitrones
Intramolecular dipolar cycloaddition
Piperidines
Iminodisaccharides
Carbohydrate mimics can play critical roles in many biological
events such as cell–cell recognition and adhesion, cell growth and
differentiation.1 In particular, during the last years there has been
a considerable interest in the synthesis of iminosugar di- and oligo-
saccharides2 and their C-linked analogues,3 which can be regarded
as imino-C-disaccharides of general type 1. This interest has been
propelled by the desire for synthetic imino-C-disaccharides 1 with
increased hydrolytic stability, enzyme inhibition properties and/or
unique conformational preferences in comparison to the natural
counterparts.4 Other variations of the pseudoglycosidic linkage
may consist of different sequences of atoms including nitrogen,5 sul-
fur6 and extended carbon-containing chains7 as in the case of the
antidiabetic8 MDL25,637 2 and compound 3.9
initiated several years ago a research programme aiming at the syn-
thesis of saturated nitrogen heterocycles bearing a glycosyl unit
using nitrones as appropriate starting materials. In 2003, we re-
ported13 the preparation of glycosylpyrrolidinessuch asthe galacto-
syl derivative 6 through an intermolecular 1,3-dipolar cycloaddition
between C-glycosyl nitrones and methyl acrylate as the key step.
More recently, we have demonstrated that the intramolecular
cycloaddition of N-alkenyl nitrones, prepared by stereoselective
On the other hand, compounds having a direct bond between
subunits (Fig. 1, n = 0 in 1) have also become the compounds of inter-
est.10 In the de novo design of imino disaccharide analogues, the
introduction of a direct link between the units can be very useful
as it may contribute to fix a biologically active conformation. As a
consequence, new synthetic methodologies leading to these classes
of substrates are highly desirable. In this context, Goti and co-work-
ers11 have developed the synthesis of 4 in which a pyranose is di-
rectly linked to a hydroxylated pyrrolidine and, more recently,
Sharma et al. reported12 the synthesis of 5 from b-amino acids. We
* Corresponding author. Tel./fax: +34 976 762075.
E-mail address: pmerino@unizar.es (P. Merino).
Figure 1. Imino-C-disaccharides.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.023

E. Marca et al. / Tetrahedron Letters 50 (2009) 7152–7155
7153
allylation of N-benzyl nitrones14 and subsequent oxidation of the
Table 1
Stereoselective allylation of nitrones 6, 7 and 14a
resulting homoallyl hydroxylamines, is an excellent route for the
synthesis of substituted 4-hydroxy-piperidines and, in particular,
pipecolic acids.15 Such a type of intramolecular 1,3-dipolar cyclo-
addition presented some controversy regarding the actual course
of the reaction, which has been proposed to take place in part via
either a 2-aza-Cope rearrangement16 or an E/Z isomerization17 of
the nitrones.
In this Letter we present a successful implementation of our
intramolecular cycloaddition-based strategy represented by the
synthesis of a protected glycosyl piperidine from the correspond-
ing C-(glycosyl) nitrone. In addition, we present the structural
proofs for E/Z isomerization18 during the course of the intramolec-
ular cycloaddition, in a marked contrast with those findings previ-
Entry
Nitrone
Additiveb
Hydroxylamine
Yieldc (%)
drd
1
2
3
4
5
6
7
8
9
6
6
Nonee
ZnBr2
8
8
96
98
98
97
97
85
98
98
97
1:4.4
1:4.0
1:10
1:1.2
1:1.5
1:3.0
3.3:1
5.5:1
1.2:1
6
7
7
Et2AlCl
Nonee
ZnBr2
8
9
9
7
Et2AlCl
Nonee
ZnBr2
9
14
14
14
15
15
15
Et2AlCl
a
All the reactions were carried out using 1.2 equiv of allylmagnesium bromide in
Et2O as a solvent at 0 °C unless otherwise indicated.
b
1.0 equiv of additive was employed.
c
Isolated yield after purification of the mixture of adducts.
ously reported by us for a D-glyceraldehyde nitrone, for which the
d
syn/anti ratios determined by integration in 1H NMR of the crude product.
existence of a 2-aza-Cope rearrangement was demonstrated.19
Starting C-(glycosyl) nitrones 6, 7 and 14 were prepared from
the corresponding aldehydes as described.20 The diastereoselective
allylation of nitrones21 6 and 7, to give hydroxylamines 8 and 9,
respectively, proceeded in excellent yields and moderate to good
diastereomeric ratios depending on the substrate and the Lewis
acid used as an additive (Scheme 1, Table 1).
e
2.0 equiv of Grignard reagent was used.
In contrast to previously reported allylation of homochiral C-(a-
alkoxy) nitrones,21 low stereocontrol was observed for nitrones 6
and 7. In both cases the same major adduct was obtained whatever
the conditions were employed. The absolute configuration of the
obtained homoallylic hydroxylamine 8 was unambiguously deter-
mined by single-crystal X-ray analysis.22 In the case of 9 suitable
crystals could not be obtained and the configuration was deduced
by X-ray analysis of a further derivative as discussed below. Oxida-
tion of hydroxylamines 8 and 9 with manganese(IV) oxide as
reported by Goti and co-workers23 afforded N-alkenyl nitrones
10 and 11, respectively, in good yields.
Heating compounds 10 and 11 in toluene at 100 °C in a sealed
tube afforded a mixture of cycloadducts from which the major
adduct was identified (2D NMR) as the exo–exo isomer in both cases.
Theabsolute configuration of themajor adduct12 wasdeduced from
the precursor hydroxylamine 8. The absolute configuration of
Scheme 2. Possible reaction paths for the intramolecular 1,3-dipolar cycloaddition
of nitrones 6 and 7. (SG: see Scheme 1). Only transition structures leading to
cycloadducts with the sugar moiety in an exo orientation have been considered.
cycloadduct 13a was determined (and thus that of the precursor 9)
bysingle-crystalX-ray analysis.22 In additionto the exo–exocycload-
ducts 12a and 13a, minor adducts in which the phenyl group
adopted an endo orientation were obtained. Such Ph-endo isomers
could arise, in principle, from either 2-aza-Cope rearrangement or
E/Z isomerization of the corresponding N-alkenyl nitrone. In the pre-
vious reports16,17 it was not possible to determine the origin of the
minor adduct (aza-Cope vs E/Z isomerism) because racemic com-
pounds were used and in consequence the two possible Ph-endo iso-
mers (Scheme 2, b and c series) were enantiomers. In our case the
presence of the chiral sugar moiety (SG) makes possible to distin-
guish between the two different Ph-endo compounds which actually
are diastereomers (Scheme 2).
Fortunately, the configuration of both 12b and 13b was fully
assessed by single-crystal X-ray crystallography.22 Such an ulti-
mate confirmation of the absolute configuration of 12b and 13b
demonstrates the existence of a partial E/Z isomerization of the
Scheme 1. Reagents and conditions: (i) allylMgBr, Et2O, 0 °C, additive (see Table 1),
4 h; (ii) MnO2, CH2Cl2, 0 °C, 8 h; (iii) toluene, sealed tube, 100 °C, 72 h.

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E. Marca et al. / Tetrahedron Letters 50 (2009) 7152–7155
Figure 3. Perspective view (ORTEP) of 18. Non-hydrogen atoms are drawn as 50%
thermal ellipsoids while hydrogens are drawn at an arbitrary size.
stereochemical preferences are independent of the Lewis acid
used.
Scheme 3. Reagents and conditions: (i) allylMgBr, Et2O, 0 °C, additive (see Table 1),
4 hl; (ii) MnO2, CH2Cl2, 0 °C, 8 h; (iii) toluene, sealed tube, 100 °C, 72 h; (iv) Zn,
AcOH, 60 °C.
Oxidation of 15 (MnO2, 76%) and further intramolecular cyclo-
addition (toluene, sealed tube, 100 °C, 72 h, 90%) of the resulting
N-alkenyl nitrone 16 exclusively furnished the exo–exo cycload-
duct 17 in 90% isolated chemical yield. The absolute configuration
of cycloadduct 17 could also be confirmed by an X-ray analysis.22
Finally, cleavage of the N–O bond with zinc in acetic acid provided
the protected imino-C-disaccharide 18. The all-cis configuration of
the piperidine ring was revealed from the complete structural
analysis (2D NMR) of 18, which also comprised a single-crystal
X-ray determination as illustrated in Figure 3.
In conclusion, a synthetic sequence starting from C-(glycosyl)
nitrones and leading to imino-C-disaccharide analogues has been
shown. The intramolecular dipolar cycloaddition of intermediate
N-(alkenylglycosyl) nitrones took place with partial E/Z isomeriza-
tion of the nitrones as demonstrated by the absolute configuration
(determined by X-ray crystallography) of the obtained cycload-
ducts. Further studies on this sort of intramolecular cycloadditions
as well as elaboration of different cycloadducts to other iminodi-
saccharide analogues will be described in the near future.
precursor N-alkenyl nitrones in contrast with the previous results
observed in our laboratories with a D-glyceraldehyde-derived nit-
rone for which the 2-aza-Cope rearrangement was predominant.19
Whereas the major adducts (a series) were formed through transi-
tion structure C, minor compounds (b series) should be formed
through transition structure D. Nevertheless, the absence in the
crude product of the reaction of minor adducts 12c and 13c (which
should be formed through A) does not allow to exclude the possi-
bility of a 2-aza-Cope rearrangement since the rearranged nitrone
may lead to major adduct (a series) through transition state B.
We also applied our strategy to
D-ribosyl-nitrone 14 easily
available from
D
-ribose as described.20 Also in this case no stereo-
control was observed in the allylation reaction (Table 1, entries 7–
9) but surprisingly, the syn adduct 15 was obtained in all cases as
the major stereoisomer (Scheme 3).
In spite of the above-mentioned lack of stereocontrol, the ob-
served trend of the additives is in agreement with the preferential
formation of the syn adduct.24 The absolute configuration of the
Acknowledgements
hydroxylamine 15 was confirmed by
a single-crystal X-ray
analysis.22
We thank the Ministerio de Educación y Ciencia (Spain, Grants
CTQ2007-67532-C02-01/BQU and CTQ2007-67532-C02-02/BQU)
and Gobierno de Aragón (Grupo Consolidado E-10) for financial
support. E.M. thanks MEC (FPU Programme) for a pre-doctoral
grant.
The opposite stereochemical outcome of the allylation reaction
for 7 and 14 could be rationalized by the relative configuration of
the dioxolane moiety at b-position of the reactive nitrone carbon
atom; such a dioxolane establishes the preferred Houk model25
in each case leading to the attack of the nucleophile by opposite
faces in both nitrones (Fig. 2). Whereas for 14 it is possible to apply
a typical Houk model, leading to the syn adduct, in the case of nit-
rone 7 there are important unfavourable steric interactions be-
tween the dioxolane and the incoming nucleophile thus the
preferred (more reactive) conformation is that shown in Figure 2.
A similar model is applicable for nitrone 6 which exhibits the same
stereofacial selectivity as nitrone 7, indicating that the observed
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.10.023.
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