Highly stereoselective synthesis of imino-C-di- and trisaccharides as hydrolytically stable glycomimetics

Article abstract of DOI:10.1016/j.tet.2012.05.126

A new straightforward route to glycomimetics containing a piperidine unit is reported. The key step of the methodology is the intramolecular 1,3-dipolar cycloaddition of easily accessible glycosyl alkenyl nitrones. The reaction takes place in most cases with a complete selectivity in favor of the exo-exo adduct, which facilitates the synthesis of all-cis piperidines bearing the glycosyl units. The direct transformation of adducts into the final imino-C-di and trisaccharide analogues is achieved in one step using simple reagents. Inhibition properties against two glycosidases have been tested but no positive results have been found.

Full text of DOI:10.1016/j.tet.2012.05.126

Tetrahedron 68 (2012) 6674e6687
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly stereoselective synthesis of imino-C-di- and trisaccharides
as hydrolytically stable glycomimetics
,
b
a
a,
*
Eduardo Marca a, Ignacio Delso a , Tomas Tejero , Pedro Merino
ꢀ
a
ꢀ
Laboratorio de Sintesis Asimetrica, Departamento de Sintesis y Estructura de Biomoleculas, Instituto de Sintesis Quimica y Catalisis Homgenea (ISQCH), Universidad de Zaragoza,
CSIC, 50009 Zaragoza, Spain
b Servicio de Resonancia Magnetica Nuclear, Centro de Quimica y Materiales de Aragon (CEQMA), Universidad de Zaragoza, CSIC, 50009 Zaragoza, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 April 2012
Received in revised form 28 May 2012
Accepted 30 May 2012
Available online 12 June 2012
A new straightforward route to glycomimetics containing a piperidine unit is reported. The key step of
the methodology is the intramolecular 1,3-dipolar cycloaddition of easily accessible glycosyl alkenyl
nitrones. The reaction takes place in most cases with a complete selectivity in favor of the exoeexo
adduct, which facilitates the synthesis of all-cis piperidines bearing the glycosyl units. The direct
transformation of adducts into the final imino-C-di and trisaccharide analogues is achieved in one step
using simple reagents. Inhibition properties against two glycosidases have been tested but no positive
results have been found.
Keywords:
Carbohydrates
Piperidines
Nitrones
Ó 2012 Elsevier Ltd. All rights reserved.
Glycomimetics
1. Introduction
enzyme. An example can be given by 1-deoxynojirimycin-derived
glycomimetics 1 and 2, which showed inhibitory activity against rat
Oligosaccharides are involved in a great number of physiological
processes related to metabolism and energy storage.1 They also
help regulate several cellular processes through their interaction
with membrane receptors and proteins.2 Consequently the en-
zymes responsible for the synthesis and modification of oligosac-
charides, such as glycosidases and glycosyltransferases,3 are the
object of many inhibitory studies.4 Indeed, a lot of carbohydrate
mimics, mainly optically active polyhydroxylated saturated nitro-
gen heterocycles have been synthesized and studied as glycosidase
inhibitors.5 On the other hand, to find or design potent and specific
inhibitors of glycosyltransferases is more difficult probably because
the active sites and structural motifs of those enzymes are heavily
conserved.6 Therefore, there is a considerable interest in the syn-
thesis of glycomimetics for use in medicinal chemistry and drug
development.7
intestinal maltase (EC. 3.2.1.20) with IC50 values of 2.3
1.70
M, respectively,9 whereas 1-deoxynojirimycin alone showed
an IC50 value of 28
M against the same enzyme.10 Following this
approach a variety of imino di- and oligosaccharides have been
prepared and tested as inhibitors of glycosidases and glycosyl-
transferases.8 In addition to 1 and 2 examples are given by com-
mM and
m
m
pounds 3 and 4 that competitively inhibited b-1,4-endoglucanases
(Fig. 1).11
Similarly, compound 5 exhibited a potent inhibitor activity
(Ki¼25 M) of human pancreatic -amylase, whereas the imino-
m
a
sugar unit alone showed a modest activity (Ki¼18 mM) against the
same enzyme.12 However, in several occasions iminodisaccharides
are not ideal drug candidates due to their low metabolic stability
toward endogenous glycosidases, which become into a poor bio-
availability. This difficulty could be overcome by replacing the
glycosidic bond with a CeC bond, which cannot be hydrolyzed. The
resulting glycomimetics, called imino-C-disaccharides, should dis-
play high receptor affinity and selectivity in addition to enhanced
metabolic stability and bioavailability.13 In fact, considerable effort
has been focused on the design and synthesis of those compounds,
which often required dedicated approaches depending on the
particular target.14 In this context, we have described the synthesis
of glycosyl pyrrolidines (Fig. 2, n¼0), which can be considered
pseudoimino-C-disaccharides (the two monosaccharide analogues
A strategy that has demonstrated a high efficiency in designing
more specific inhibitors of both glycosidases and glycosyl-
transferases consists of incorporating additional carbohydrate units
to an iminosugar scaffold.8 The scaffold can be designed in a similar
way to known simple inhibitors and the additional carbohydrate
units according to the corresponding binding site of the target
* Corresponding author. Tel./fax: þ34 976 762075; e-mail address: pmerino@
unizar.es (P. Merino).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.126

E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
6675
methods17 from appropriate precursors depending on the nature of
the substituent R. The N-disubstituted homoallylhydroxylamines D
could be easily accessed in a stereoselective way from C-glycosyl
nitrones E following our previously reported methodology on
allylation of nitrones.18 The N-monosubstituted homoallylhydrox-
ylamines F would be obtained from nitrones of type C (R1¼Ph)
through transoximation processes as reported.19
2. Results and discussion
2.1. Synthesis of nitrones
We selected several substrates bearing different sugar units in
order to provide the methodology outlined in Scheme 1 with the
required versatility. The sugar units and the nomenclature
employed along this paper are presented in Chart 1.
Fig. 1. Iminooligosaccharides.
Fig. 2. Iminodisaccharides and C-analogues.
are directly linked; X¼no atom) through inter-molecular 1,3-
dipolar cycloaddition between C-glycosyl nitrones and methyl
acrylate.15
In this paper we present full details16 of a direct high-yielding
approach to imino-C-disaccharides, based on an intramolecular
cycloaddition of alkenyl glycosyl nitrones. Our retrosynthetic ap-
proach is presented in Scheme 1.
The first step illustrates the intention to create a hydroxyl group
at the 4-position of the piperidine A after N,O-cleavage of adduct B.
The key step of the approach is the intramolecular cycloaddition of
alkenyl nitrones C to give adducts B. Nitrones C should be prepared
by either condensation (from F and G) or oxidation (from D)
Chart 1. Sugar residues (SG).
We reported that N-benzyl homoallylhydroxylamines 6e13 can
be prepared through stereocontrolled allylation of N-benzyl nitro-
nes in good yields and diastereoselectivities.16,18 The required epi-
meric C-phenyl nitrones 24e27 and 28e31 were readily prepared
from 6e9 and 10e13, respectively, by oxidation with man-
ganese(IV) oxide according to the method developed by Brandi and
co-workers.20 In all cases, the oxidation was completely regiose-
lective and only the C-phenyl-N-homoallyl nitrones bearing a sugar
unit at the nitrogen side were obtained as single isomers
(Scheme 2, Table 1). The expected (Z)-configuration was confirmed
Scheme 1. Retrosynthetic analysis.
Scheme 2. Synthesis of C-(phenyl)-N-alkenylsugar nitrones. (i) MnO2, CH2Cl2, rt, 6 h
(for SG see Table 1 and Chart 1).

6676
E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
Table 1
Synthesis of C-phenyl nitrones (Scheme 1)a
SG
Hydroxylamine
Nitrone
Yieldb (%)
a
a
a
a
b
a
a
a
-
-
-
-
D
D
D
D
-gal
6
7
8
9
10
11
12
13
24
25
26
27
28
29
30
31
82
80
78
81
82
90
92
89
-lyxo
-xylo
-ribo
-ribo
-lyxo
-xylo
-ribo
-D
-
-
-
D
D
D
a
For R1 see Chart 1.
Isolated yield.
b
Scheme 4. 2-Aza-Cope rearrangement of nitrones 37 and 41.
by 1H NMR 2D NOESY experiments and the previously described
ASIS effect for nitrones.21
Nitrones bearing two glycosyl units were prepared from mono-
substituted hydroxylamines 14e17, easily accessible through trans-
oximation of C-arylnitrones as reported by us19 and other groups.22
Condensation of 14e17 with aldehydes 18e23 provided access to
nitrones 32e42 in good chemical yields (Scheme 3, Table 2).
Again, only the (Z)-isomer was obtained as confirmed by NMR
experiments and in the case of 34 by X-ray crystallography.23
progress and applicability of the strategy since the same major
adduct will be obtained in the intramolecular cycloaddition of
couples 12e/13a and 12i/13b. Moreover, as discussed in previous
reports24 it cannot be discarded that a 2-aza-Cope rearrangement
takes place during the next cycloaddition step (see below).16
2.2. Intramolecular cycloaddition
The intramolecular 1,3-dipolar cycloaddition of glycosyl N-
alkenyl nitrones provides potentially useful stereoselectively
functionalized bicyclic intermediates.25 The scope of glycosyl
nitrones 24e42 in the reaction was demonstrated by the following
results. Heating of nitrones in toluene at 100 ꢀC in a sealed tube for
72 h provided the corresponding cycloadduct in good yields. Under
these conditions, the reaction of C-phenyl nitrones 24e31 pro-
ceeded smoothly to give adducts as mixtures of exoeexo and
endoeexo (or exoeendo) isomers, the former being obtained pre-
dominantly (Scheme 5, Table 3).
Scheme 3. Synthesis of nitrones bearing two glycosyl units. (i) MgSO4, CH2Cl2, rt, 4 h
(for S1G and S2G see Table 2 and Chart 1).
Nitrones 24e42 proved to be stable at room temperature with
the exception of 37 and 41, which were obtained as inseparable
mixtures together with the corresponding rearranged nitrones 43
and 44 (Scheme 4). This result was not unexpected to us, since the
2-aza-Cope rearrangement of N-alkenyl nitrones with complete
transfer of chirality had been reported from our laboratory for
similar substrates.24 In any case, this result does not affect to the
Table 2
Scheme 5. Synthesis of bicyclic adducts bearing one glycosyl units. (i) Toluene, 100 ꢀC,
72 h, sealed tube (for sugar unit see Table 3 and Chart 1).
Synthesis of nitrones bearing two sugar units (Scheme 2)a
SG1
SG2
Hydroxyl-amine Aldehyde Nitrone Yieldb (%)
D
D
D
-gly
-gly
-gly
a
a
a
a
-
D
-gal
D
14
14
14
15
15
16
16
16
16
18
19
20
21
21
18
19
21
22
23
21
32
33
34
35
36
37
38
39
40
41
42
78
79
81
77
76
88c
73
73
78
75c
72
-Me-
-Et-
-Et-
-gal
A marked effect of relative stereochemistry was observed on
endo/exo selectivity with these nitrones. While slightly higher
yields are observed for nitrones 28e31 (entries 5e8), better se-
lectivities are obtained with nitrones 24e27 having a relative syn-
disposition between the allyl group and the Nb stereogenic center
(entries 1e4). Exceptions to this behavior are found with nitrones
26 (Table 3, entry 3) and 28 (Table 3, entry 5), which afforded the
exoeexo isomer as the only product of the reaction.
D
D
-gal
-gal
a
a
-
-
D
-gal
-gal
D
BnOCH2
D
D
D
D
D
-gly
-gly
-gly
-gly
-gly
a -gal
a-Me-
a-Et- -gal
b-Me- -gluco
b-MeO-
-D
D
-gal
D
D
D
-gluco 16
17
b
-D
-ribo BnOCH2
A complete selectivity was obtained in all cases with nitrones
32e42 bearing two glycosyl units (Scheme 6, Table 4). Only the
exoeexo isomer was detected in the crude reaction mixture. In the
a
b
c
For S1G and S2G see Chart 1.
Isolated yield.
Obtained as a mixture of rearranged nitrones (see text).

E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
6677
the assigned configuration to major compounds.23 For minor ad-
ducts, X-ray analyses of 45b, 46b, and 51b confirmed their absolute
configuration as well as the existence of partial E/Z isomerization of
nitrones during the cycloaddition step. In fact, the intramolecular
cycloaddition of N-alkenyl nitrones 24e32 might be preceded by
either an E/Z isomerization or a 2-aza-Cope rearrangement as
suggested in previous reports (Scheme 7).26
Table 3
Cycloadducts with one sugar unit (Scheme 5)a
Entry
SG
Nitrone
Adduct
dr (a/b)b,c
Yieldd (%)
1
2
3
4
5
6
7
8
a
a
a
a
b
a
a
a
-
-
-
-
D
D
D
D
-gal
24
25
26
27
28
29
30
31
45
46
47
48
49
50
51
52
82:18
75:25
>95:5
76:24
>95:5
66:34
59:41
68:32
82
80
78
81
82
90
92
89
-lyxo
-xylo
-ribo
-ribo
-lyxo
-xylo
-ribo
-D
-
-
-
D
D
D
a
For SG see Chart 1.
b
Measured by integration of the corresponding 1H NMR signals in the crude
mixture.
c
For adducts 45e48, a and b series refer to exoeexo and exoeendo adducts, re-
spectively. For adducts 49e52, a and b series refer to exoeexo and endoeexo adducts,
respectively.
d
Isolated yield.
Scheme 6. Synthesis of bicyclic adducts bearing two glycosyl units. (i) Toluene, 100 ꢀC,
72 h, sealed tube (for sugar unit see Table 4 and Chart 1).
Scheme 7. E/Z isomerism and thermal-induced 2-aza-Cope rearrangement in N-al-
kenyl nitrones.
case of cycloadduct 53 (Table 4, entry 1) an abnormal low yield was
obtained and the compound was accompanied by an unknown
impurity that could not be separated by any chromatographic
technique.
The relative endo/exo configuration of cycloadducts 45e63 was
assigned on the basis of 1D and 2D NMR and NOE information. In
particular NMR analysis of exoeexo adducts revealed an NOE be-
tween the two endo protons of the substituted carbons that can be
accounted for only by such a configuration. Moreover, that effect
was not observed for minor endo/exo (or exo/endo) isomers, when
isolated. The absolute configuration was ascertained by X-ray
crystallography.23 Single crystals of 46a, 48a, 49a, and 61 confirmed
In several instances, E/Z isomerization of nitrones, which has
been demonstrated to be a rotational process,27 has been used to
explain the stereochemical outcome of dipolar cycloadditions.28 On
the other hand, recent experimental and theoretical studies carried
out in our laboratories24 pointed out that the thermal 2-aza-Cope
rearrangement of N-alkenyl nitrones is also possible. Both rear-
ranged nitrones (Z)-A and B give rise to the same exoeexo major
cycloadduct
C through transition states TS1a and TS1b, re-
spectively. The difference of the stereochemical outcome of the
reaction arises from the minor adducts. In the case of racemic
compounds26a it is not possible to determine the origin of the mi-
nor adduct (E/Z isomerization versus 2-aza-Cope rearrangement)
because the two possible minor products are enantiomers. How-
ever, the presence of a homochiral sugar moiety (as in the case of
nitrones 24e42) converts the two minor adducts endoeexo and
exoeendo being formed from nitrones B (through TS2) and (E)-A
(through TS3), respectively, into distinguishable diastereomers. The
X-ray-based determination of the absolute configuration of those
minor adducts served as an ultimate confirmation of the existence
of E/Z isomerism in the intramolecular dipolar cycloaddition of
nitrones 24e42 since the elucidated structures corresponded to
exoeendo adducts E and not endoeexo adducts D. This result is in
Table 4
Cycloadducts with two sugar units (Scheme 6)a
SG1
SG2
Nitrone
Adduct
drb,c
Yieldd (%)
D
D
D
-gly
-gly
-gly
a
a
a
a
-
D
-gal
32
33
34
35
36
37
38
39
40
41
42
53
54
55
56
57
58
59
60
61
62
63
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
36
89
82
70
80
85
84
77
75
80
83
-Me-D-gal
-Et-
-Et-
D
D
-gal
-gal
a
a
-
-
D
-gal
-gal
D
BnOCH2
D
D
D
D
D
-gly
-gly
-gly
-gly
-gly
a -gal
a-Me-
a-Et- -gal
b-Me- -gluco
b-MeO- -gluco
-D
D
-gal
a marked contrast to a similar reaction reported by us with D-
D
glyceraldehyde derived nitrones, which only showed evidences of
D
2-aza-Cope rearrangement.25
D
b
-D
-ribo
BnOCH2
a
For S1G and S2G see Chart 1.
2.3. Synthesis of imino-C-di- and trisaccharides
b
Measured by integration of the corresponding 1H NMR signals in the crude
mixture.
c
With the cycloadducts 45e63 successfully prepared in a very
good diastereomeric ratio, the next step in the methodology
Only the exoeexo adduct was obtained as the product of the reaction.
d
Isolated yield.

6678
E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
entailed the conversion of the bicyclic unit into a piperidine ring.
The cleavage of the NeO bond can be carried out without affecting
acid-sensitive protecting groups by using zinc in acetic acid under
mild conditions.25 Under these conditions, major exoeexo adducts
46a, 49a, 50a, and 51a were transformed into all-cis 2-glycosyl-4-
hydroxy-6-phenyl piperidines 64e67 (Scheme 8). The same re-
action conditions were applied to the minor adduct 51b and gly-
cosylpiperidine 68 was obtained in good yield, thus demonstrating
a good scope for the methodology. Single crystals of 66 were
Scheme 9. Synthesis of 6-hydroxymethyl-4-hydroxy-C-glycosylpiperidines. (i) 66%
AcOH, rt, 14 h; then NaIO4, SiO2, CH2Cl2, rt, 1.5 h; then NaBH4, 10:1 Et2O/H2O; (ii) H2,
Pd(OH)2/C, MeOH, 100 bar, rt, 3 h.
aqueous trifluoroacetic acid, which guarantees the hydrolysis of all
the acetonides. The remaining N,O bond was reduced by in situ
catalytic hydrogenation in the presence of Pearlman’s catalyst. The
unprotected glycomimetics 74e78 were isolated in good chemical
yields after purification by semipreparative HPLC (reverse phase).
Scheme 8. Synthesis of 6-phenyl-4-hydroxy-C-glycosylpiperidines. (i) Zn, AcOH, 60 ꢀC,
4 h.
obtained and the absolute configuration was ascertained by X-ray
analysis,23 thus confirming the assigned configuration to the pre-
cursor 50a.
Moreover, it is also possible to carry out the conversion of the
dioxolane moiety into a hydroxymethyl group prior to N,O-cleav-
age. The process involves the regioselective deprotection of the
primary acetonide and oxidation of the resulting diol.
Acetonide hydrolysis was carried out with acetic acid and the
resulting diol was cleaved by the action of sodium metaperiodate.
The emerging aldehyde was reduced in situ with sodium borohy-
dride to afford the final alcohol. By applying this variation exoeexo
adducts 55a, 58a, and 60a were converted into hydroxymethyl
derivatives 69e71 (Scheme 9). Further N,O-cleavage of 69 and 71
was achieved by catalytic hydrogenation in the presence of Pearl-
man’s
catalyst
that
furnished
2-glycosyl-4-hydroxy-6-
hydroxymethylpiperidines 72 and 73, respectively.
The direct obtention of completely deprotected imino-C-di- and
trisaccharides is also possible through a one-pot procedure. Start-
ing from the corresponding cycloadducts 54a, 55a, 56a, 58a, and
60a, compounds 74e78 were obtained (Scheme 10). The trans-
formation was carried out by treating the cycloadducts with
Scheme 10. Synthesis of deprotected imino-C-di- and trisaccharides. (i) 9:1 TFA/H2O,
rt, 4 h; then H2, Pd(OH)2/C, MeOH, 100 bar, 3 h.

E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
6679
3. Biological studies
reduced pressure to give the crude product, which was purified by
column chromatography in the stated eluent.
The iminoglycomimetics 74e78 have been evaluated for their
inhibitory activities toward
a
-glucosidase from Saccharomyces
5.2.1. (R,Z)-N-(R,Z)-N-Benzylidene-1-((3aR,5R,5aS,8aS,8bR)-2,2,7,7-
tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:40,50-d]pyran-5-yl)
but-3-en-1-amine oxide (24). Yield 0.662 g, 82%; white solid; mp
cerevisae and -glucosidase from almonds. Unfortunately low in-
b
hibition (20e50%) was observed at high concentration (1 mM) of
compounds 74e78. Affinity assays performed for these compounds
128e130 ꢀC; Rf¼0.65 (Hex/EtOAc 9:1); [
a
]
D
25 ꢁ51 (c 1.13, CHCl3). 1H
against
monds,
a
a
-glucosidase from S. cerevisae,
-galactosidase from green coffee bean,
b
-glucosidase from al-
-galactosidase
NMR (CDCl3, 400 MHz) d (ppm) 1.23 (s, 3H), 1.33 (s, 3H), 1.47 (s, 3H),
b
1.59 (s, 3H), 2.69e2.76 (m, 1H), 2.84 (ddd, 1H, J¼7.4, 10.7, 14.4 Hz),
4.05 (ddd, 1H, J¼3.0, 9.6, 10.7 Hz), 4.24 (dd, 1H, J¼1.5, 8.0 Hz),
4.27e4.30 (m, 2H), 4.56 (dd, 1H, J¼2.3, 8.0 Hz), 5.02e5.05 (m, 1H),
5.17 (dd, 1H, J¼1.7, 17.1 Hz), 5.55 (d, 1H, J¼5.0 Hz), 5.76 (tdd, 1H,
J¼7.2, 10.1, 17.3 Hz), 7.39e7.50 (m, 4H), 8.24e8.28 (m, 2H). 13C NMR
from Escherichia coli and a-L-fucosidase from Bovine kidney by STD-
NMR 1H experiments29 showed no interaction.
4. Conclusions
(CDCl3, 400 MHz) d (ppm) 24.3, 25.0, 26.0, 26.2, 33.3, 67.9, 70.1, 70.7,
The readily accessible alkenyl glycosyl nirones 24e42 have
proven to be excellent and practical building blocks for the syn-
thesis of a variety of imino-C-di- and trisaccharide analogues. The
synthetic methodology consisting of an intramolecuar 1,3-dipolar
cyloaddition and further elaboration of the resulting cycloadducts
permitted synthetic manipulations to be applied to the dioxolane
ring culminating in the obtention of hydroxymethyl derivatives. At
the same time, it is also possible to transform the cycloadducts into
completely deprotected glycomimetics in a straightforward way
involving a one-pot procedure by using simple and easily accessible
reagents. The scope and versatility of the methodology is demon-
strated by the synthesis of di- and trisaccharide glycomimetics
linked either directly or through flexible chains containing one or
two carbon atoms, bearing in all cases a piperidine unit. Further
studies directed at developing new syntheses of different imino-
glycomimetics are currently undergoing in our laboratories.
70.8, 74.9, 96.6, 109.0, 109.2, 118.4, 128.5, 128.8, 130.4, 133.4, 136.2.
Anal. Calcd for C22H29NO6: C, 65.49; H, 7.24; N, 3.47. Found: C,
65.68; H, 7.19; N, 3.60.
5.2.2. (R,E)-N-Benzylidene-1-((3aR,4R,6R,6aR)-6-methoxy-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)but-3-en-1-amine ox-
ide (25). Yield 0.555 g, 80%; yellow oil; Rf¼0.46 (Hex/EtOAc 8:2);
[
a
]
25 þ29 (c 0.87, CHCl3). 1H NMR (CDCl3, 400 MHz)
d (ppm) 1.23 (s,
D
3H), 1.49 (s, 3H), 2.66e2.72 (m, 1H), 2.91e2.99 (m, 1H), 3.33 (s, 3H),
4.20 (ddd, 1H, J¼3.0, 9.5, 10.8 Hz), 4.46 (dd, 1H, J¼3.3, 9.5 Hz), 4.53
(d, 1H, J¼5.8 Hz), 4.70 (dd, 1H, J¼3.3, 5.8 Hz), 4.89 (s, 1H), 5.05e5.08
(m, 1H), 5.19 (ddd, 1H, J¼1.3, 3.1, 17.1 Hz), 5.80 (tdd, 1H, J¼7.2, 10.1,
17.2 Hz), 7.37 (s, 1H), 7.41e7.44 (m, 3H), 8.23e8.26 (m, 2H). 13C NMR
(CDCl3, 400 MHz) d (ppm) 24.8, 26.2, 34.1, 54.5, 74.2, 79.1, 79.3, 85.1,
107.0, 112.5, 118.5, 128.4, 128.8, 130.3, 133.5, 136.0. Anal. Calcd for
C19H25NO5: C, 65.69; H, 7.25; N, 4.03. Found: C, 65.51; H, 7.42; N,
3.89.
5. Experimental section
5.1. General
5.2.3. (R,E)-N-Benzylidene-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)but-3-en-1-amine ox-
ide (26). Yield 0.661 g, 78%; colorless oil; Rf¼0.23 (Hex/EtOAc 7:3);
The reaction flasks and other glass equipment were heated in an
oven at 130 ꢀC overnight and assembled in a stream of Ar. All re-
actions were monitored by TLC on silica gel 60 F254; the position of
the spots were detected with 254 nm UV light or by spraying with
either 5% ethanolic phosphomolybdic acid or Mostain solution.
Column chromatography was carried out in a Buchi 800 MPLC
system or a Combiflash apparatus, using silica gel 60 microns and
with solvents distilled prior to use. Melting points were un-
corrected. 1H and 13C NMR spectra were recorded on Bruker Avance
400 or 500 instrument in the stated solvent. Chemical shifts are
[a
]
25 ꢁ11 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3)
d (ppm) 1.43 (s,
D
3H), 1.63 (s, 3H), 2.77e2.83 (m, 1H), 3.05 (ddd, 1H, J¼7.5, 11.0,
14.3 Hz), 4.18 (d, 1H, J¼3.2 Hz), 4.28 (ddd, 1H, J¼2.7, 9.4, 11.1 Hz),
4.34 (d, 1H, J¼11.2 Hz), 4.72e4.75 (m, 2H), 4.81 (dd, 1H, J¼3.1,
9.3 Hz), 5.13 (dd, 1H, J¼1.6, 10.1 Hz), 5.26 (dd, 1H, J¼1.5, 17.1 Hz),
5.79e5.90 (m, 1H), 6.07 (d, 1H, J¼3.8 Hz), 7.26e7.52 (m, 9H),
8.16e8.18 (m, 2H). 13C NMR (400 MHz, CDCl3)
d (ppm) 26.3, 26.8,
34.4, 72.3, 73.9, 80.2, 81.9, 81.9, 105.1, 112.1, 118.6,127.6, 128.0, 128.4,
128.5, 128.6, 130.1, 130.4, 133.2, 135.6, 137.0. Anal. Calcd for
C25H29NO5: C, 70.90; H, 6.90; N, 3.31. Found: C, 70.98; H, 6.74; N,
3.51.
reported in parts per million (
d) relative to CHCl3 (
d¼7.26) in CDCl3.
Optical rotations were taken on a JASCO DIP-370 polarimeter. Ele-
mental analysis was performed on a Perkin Elmer 240B micro-
analyzer or with a PerkineElmer 2400 instrument.
5.2.4. (R,E)-N-Benzylidene-1-((3aR,5R,6R,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)but-3-en-1-amine ox-
ide (27). Yield 0.686 g, 81%; white solid; mp 119e121 ꢀC; Rf¼0.2
25
5.2. General procedure for the synthesis of nitrones
(Hex/EtOAc 8:2); [
a
]
þ42 (c 0.95,CHCl3). 1H NMR (400 MHz,
D
CDCl3)
d
(ppm) 1.24 (s, 3H), 1.51 (s, 3H), 2.44 (ddd, 1H, J¼4.4, 7.2,
Method A. A cooled (0 ꢀC) solution of the corresponding hy-
droxylamine (1 mmol) in anhydrous dichloromethane (15 mL) was
treated with activated manganese(IV) oxide (0.12 g, 1.4 mmol). The
resulting mixture was stirred at 0 ꢀC under an inert atmosphere for
6 h; the reaction mixture was then filtered through a short pad of
Celite and dried over magnesium sulfate. The filtrate was evapo-
rated under reduced pressure to give the crude product, which was
purified by column chromatography in the stated eluent.
Method B. To a well-stirred solution of the corresponding alde-
hyde (2 mmol) in dichloromethane (25 mL) a solution of the cor-
responding hydroxylamine (2 mmol) was added in one portion. The
resulting solution was treated with magnesium sulfate (2 mmol)
and stirring was maintained at room temperature for 4 h. The re-
action mixture was then filtered and the filtrate evaporated under
14.6 Hz), 3.01 (ddd, 1H, J¼7.3, 10.1, 15.0 Hz), 4.10 (td, 1H, J¼4.1,
10.1 Hz), 4.24 (dd, 1H, J¼3.8, 8.6 Hz), 4.34 (t, 1H, J¼4.0 Hz), 4.40 (dd,
1H, J¼4.3, 8.6 Hz), 4.65 (d, 1H, J¼11.5 Hz), 4.71 (d, 1H, J¼11.5 Hz),
4.96e5.01 (m, 1H), 5.11 (dd, 1H, J¼1.6, 17.1 Hz), 5.54 (d, 1H,
J¼3.5 Hz), 5.71 (tdd, 1H, J¼7.0, 10.2, 17.1 Hz) ,7.16e7.38 (m, 9H),
8.15e8.20 (m, 2H). 13C NMR (400 MHz, CDCl3)
d (ppm) 26.4, 26.9,
31.9, 72.5, 76.1, 78.0, 78.3, 78.8, 103.8, 113.1, 118.4,127.8, 128.2, 128.3,
128.5, 128.7, 130.3, 130.4, 133.5, 136.2, 137.7 . Anal. Calcd for
C25H29NO5: C, 70.90; H, 6.90; N, 3.31. Found: C, 70.79; H, 6.81; N,
3.17.
5.2.5. (S,E)-N-Benzylidene-1-((3aR,4R,6R,6aR)-6-methoxy-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)but-3-en-1-amine ox-
25
ide (28). Yield 0.570 g, 82%; syrup; Rf¼0.7 (Hex/EtOAc 8:2); [
a]
D

6680
E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
ꢁ47 (c 1, CHCl3). 1H NMR (CDCl3, 400 MHz)
d
(ppm) 1.22 (s, 3H),1.40
65.3, 66.5, 70.3, 70.8, 70.9, 75.1, 77.8, 96.6, 109.3, 109.6, 110.0, 118.7,
133.0, 136.7. Anal. Calcd for C21H33NO8: C, 59.00; H, 7.78; N, 3.28.
Found: C, 59.23; H, 7.61; N, 3.36.
(s, 3H), 2.40e2.47 (m, 1H), 2.52e2.58 (m, 1H), 2.71 (td, 1H, J¼4.2,
8.4 Hz, H5), 3.36 (s, 3H), 3.73 (d, 1H, J¼13.1 Hz), 4.03 (d, 1H,
J¼13.1 Hz), 4.29 (d, 1H, J¼3.7 Hz), 4.48 (d, 1H, J¼6.1 Hz), 4.61 (d, 1H,
J¼6.1 Hz), 4.96 (s, 1H), 5.02 (d, 1H, J¼10.1 Hz), 5.10 (dd, 1H, J¼1.4,
17.1 Hz), 5.75e5.85 (m, 1H), 6.27 (s, 1H), 7.17e7.31 (m, 5H). 13C NMR
5.2.10. (R,Z)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-N-(2-((3aR,5-
R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo
(CDCl3, 400 MHz)
d
(ppm) 25.0, 26.7, 29.1, 56.1, 62.3, 66.4, 83.5, 85.7,
[4,5-b:40,50-d]pyran-5-yl)ethylidene)but-3-en-1-amine
oxide
87.9, 112.1, 112.5, 117.2, 127.3, 128.3, 129.1, 136.2, 138.1. Anal. Calcd
for C19H27NO5: C, 65.31; H, 7.79; N, 4.01. Found: C, 65.43; H, 7.65; N,
4.30.
(33). Yield 0.698 g, 79%; white solid; mp 109e111 ꢀC; Rf¼0.32
25
(EtOAc); [
a
]
ꢁ34 (c 1.04, CH2Cl2). 1H NMR (400 MHz, CD2Cl2)
D
d
(ppm) 1.27 (s, 6H), 1.29 (s, 3H), 1.34 (s, 3H), 1.38 (s, 3H), 1.44 (s,
3H), 2.01e2.08 (m, 1H), 2.56e2.74 (m, 3H), 3.60e3.66 (m, 1H),
3.75 (dd, 1H, J¼6.1, 8.8 Hz), 3.95 (ddd, 1H, J¼1.7, 4.6, 8.9 Hz), 4.02
(dd, 1H, J¼6.4, 8.7 Hz), 4.09 (dd, 1H, J¼1.8, 7.9 Hz), 4.25 (dd, 1H,
J¼2.4, 5.0 Hz), 4.37 (td, 1H, J¼6.3, 8.1 Hz), 4.77 (dd, 1H, J¼2.4,
7.9 Hz), 5.01e5.04 (m, 1H), 5.06e5.11 (m, 1H), 5.42 (d, 1H,
J¼5.0 Hz), 5.65 (tdd, 1H, J¼7.1, 10.1, 17.1 Hz), 6.72 (dd, 1H, J¼5.2,
5.2.6. (S,E)-N-Benzylidene-1-((3aR,4R,6R,6aR)-6-methoxy-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)but-3-en-1-amine ox-
ide (29). Yield 0.625 g, 90%; colorless oil; Rf¼0.24 (Hex/EtOAc 8:2);
[
a]
25 þ72 (c 1.00,CHCl3). 1H NMR (400 MHz, CDCl3)
d (ppm) 1.33 (s,
D
3H), 1.51 (s, 3H), 2.46e2.52 (m, 1H), 2.86 (ddd, 1H, J¼7.2, 10.8,
13.9 Hz), 3.22 (s, 3H), 4.07 (ddd,1H, J¼2.9, 9.4,10.7 Hz), 4.51 (dd,1H,
J¼3.6, 9.2 Hz), 4.59 (d, 1H, J¼5.9 Hz), 4.75 (dd, 1H, J¼3.5, 5.8 Hz),
4.85 (s, 1H), 5.04e5.07 (m, 1H), 5.20 (ddd, 1H, J¼1.3, 3.0, 17.0 Hz),
5.74e5.84 (m, 1H), 7.37 (s, 1H), 7.39e7.44 (m, 3H), 8.25e8.28 (m,
6.0 Hz). 13C NMR (100 MHz, CD2Cl2)
d (ppm) 26.1, 26.7, 27.0, 27.7,
27.8, 28.5, 29.8, 34.1, 66.4, 68.1, 72.4, 72.9, 74.6, 76.9, 79.0, 98.4,
110.5, 111.1, 111.3, 120.1, 134.8, 138.0. Anal. Calcd for C22H35NO8: C,
59.85; H, 7.99; N, 3.17. Found: C, 59.97; H, 8.05; N, 3.01.
2H). 13C NMR (100 MHz, CDCl3)
d (ppm) 24.7, 26.1, 32.2, 54.6, 76.4,
78.4, 79.4, 85.2, 106.5, 112.5, 118.5, 128.4, 130.0, 130.5, 132.9, 134.7.
Anal. Calcd for C19H25NO5: C, 65.69; H, 7.25; N, 4.03. Found: C,
65.73; H, 7.38; N, 3.82.
5.2.11. (R,Z)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-N-(3-((3aR,5-
R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo
[4,5-b:40,50-d]pyran-5-yl)propylidene)but-3-en-1-amine
oxide
(34). Yield 0.738 g, 81%; white solid; mp 122e124 ꢀC; Rf¼0.3
25
5.2.7. (S,E)-N-Benzylidene-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)but-3-en-1-amine ox-
ide (30). Yield 0.779 g, 92%; colorless oil; Rf¼0.2 (Hex/EtOAc 7:3);
(EtOAc); [
d
a
]
ꢁ43 (c 0.93, CH2Cl2). 1H NMR (400 MHz, CD2Cl2)
D
(ppm) 1.23e1.24 (m, 9H), 1.30 (s, 3H), 1.34 (s, 3H), 1.41 (s, 3H),
1.69 (dd, 1H, J¼7.5, 14.8 Hz), 1.95e2.04 (m, 1H), 2.40e2.47 (m,
2H), 2.57e2.67 (m, 1H), 3.49e3.56 (m, 1H), 3.62e3.72 (m, 2H),
3.96e4.01 (m, 2H), 4.04 (dd, 1H, J¼1.8, 7.9 Hz), 4.20 (dd, 1H, J¼2.3,
5.1 Hz), 4.34 (td, 1H, J¼6.4, 7.9 Hz), 4.49 (dd, 1H, J¼2.3, 7.9 Hz),
4.97e5.09 (m, 2H), 5.39 (d, 1H, J¼5.1 Hz), 5.60 (tdd, 1H, J¼7.1, 10.1,
17.1 Hz), 6.62 (t, 1H, J¼5.8 Hz). 13C NMR (100 MHz, CD2Cl2)
[
a
]
25 ꢁ29 (c 1.10, CHCl3). 1H NMR (400 MHz, CDCl3)
d (ppm) 1.31 (s,
D
3H), 1.51 (s, 3H), 1.99e2.05 (m, 1H), 2.78 (ddd, 1H, J¼6.9, 10.9,
13.8 Hz), 3.98 (d, 1H, J¼3.2 Hz), 4.10 (dt, 1H, J¼2.9, 10.8 Hz), 4.48 (d,
1H, J¼11.5 Hz), 4.69e4.75 (m, 3H), 5.01 (d, 1H, J¼10.2 Hz), 5.07 (dd,
1H, J¼1.4, 17.1 Hz), 5.70 (tdd, 1H, J¼7.0, 10.1, 17.1 Hz), 5.92 (d, 1H,
J¼3.8 Hz), 7.35e7.44 (m, 9H), 8.21e8.27 (m, 2H). 13C NMR
d
(ppm) 23.0 ,24.1, 24.7, 25.1, 25.8, 25.9, 26.1, 26.5, 32.1, 66.2, 67.4,
(100 MHz, CDCl3)
d
(ppm) 26.4, 26.8, 32.0, 70.0, 71.8, 75.7, 78.9, 81.5,
70.6, 70.9, 72.5, 75.0, 77.0, 96.5, 108.3, 108.9, 109.3, 118.2, 132.9,
139.1. Anal. Calcd for C23H37NO8: C, 60.64; H, 8.19; N, 3.07. Found:
C, 60.49; H, 8.33; N, 2.91.
104.9, 112.1, 118.4, 128.3, 128.4, 128.5, 128.7, 128.9, 130.0, 130.4,
132.8, 135.0, 136.7. Anal. Calcd for C25H29NO5: C, 70.90; H, 6.90; N,
3.31. Found: C, 71.05; H, 7.11; N, 3.04.
5.2.12. (R,Z)-1-((3aR,5R,5aS,8aS,8bR)-2,2,7,7-Tetramethyltetrahydro-
3aH-bis[1,3]dioxolo[4,5-b:40,50-d]pyran-5-yl)-N-(3-((3aR,5R,5a-
S,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
b:40,50-d]pyran-5-yl)propylidene)but-3-en-1-amine oxide (35). Yield
5.2.8. (S,E)-N-Benzylidene-1-((3aR,5R,6R,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)but-3-en-1-amine ox-
ide (31). Yield 0.754 g, 89%; white solid; mp 128e130 ꢀC; Rf¼0.10
25
(Hex/EtOAc 8:2); [
a]
þ17 (c 1.04, CHCl3). 1H NMR (400 MHz,
0.887 g, 76%; white solid; mp 105e107 ꢀC; Rf¼0.14 (Hex/EtOAc 6:4);
D
25
CDCl3)
d
(ppm) 1.27 (s, 3H), 1.52 (s, 3H), 2.47e2.54 (m, 1H),
[a
]
ꢁ57 (c 1.26, CHCl3). 1H NMR (400 MHz, CDCl3)
d (ppm)
D
2.81e2.90 (m, 1H), 3.67 (dd, 1H, J¼4.4, 9.0 Hz), 3.91 (td, 1H, J¼5.3,
10.3 Hz), 4.35 (dd, 1H, J¼5.4, 9.0 Hz), 4.45 (t, 1H, J¼4.0 Hz), 4.54 (d,
1H, J¼11.7 Hz), 4.76 (d, 1H, J¼11.6 Hz), 4.97e5.03 (m, 1H), 5.09 (dd,
1H, J¼1.5, 17.1 Hz), 5.62e5.73 (m, 2H), 7.19e7.36 (m, 9H), 8.13e8.18
1.23e1.24 (m, 15H), 1.32 (s, 3H), 1.33 (s, 3H), 1.57e1.77 (m, 2H),
2.33e2.63 (m, 4H), 3.65 (ddd, 1H, J¼1.7, 4.9, 8.7 Hz), 3.74 (ddd, 1H,
J¼3.1, 9.5, 10.5 Hz), 3.97e4.06 (m, 4H), 4.09 (dd, 1H, J¼1.6, 8.0 Hz),
4.20 (dd, 3H, J¼2.3, 5.0 Hz), 4.49 (dd, 2H, J¼2.3, 7.9 Hz), 4.96e4.99
(m, 1H), 5.04 (ddd, 1H, J¼1.3, 3.2, 17.1 Hz), 5.39e5.41 (m, 2H), 5.63
(tdd, 1H, J¼7.2, 10.1, 17.1 Hz), 6.71 (t, 1H, J¼6.0 Hz). 13C NMR
(m, 2H). 13C NMR (100 MHz, CDCl3)
d (ppm) 26.6, 26.8, 33.4, 72.1,
77.3, 77.4, 77.6, 78.9, 103.8, 113.2, 118.6, 128.0, 128.2, 128.3, 128.4,
128.7, 130.1, 130.3, 132.8, 134.6, 137.2. Anal. Calcd for C25H29NO5: C,
70.90; H, 6.90; N, 3.31. Found: C, 70.72; H, 7.06; N, 3.49.
(100 MHz, CDCl3) d (ppm) 23.2, 24.4, 24.5, 25.1, 25.2, 26.1, 26.2, 26.3,
26.4, 26.5, 33.4, 67.6, 68.2, 70.5, 71.0, 71.1, 71.2, 71.4, 72.9, 73.4, 96.9,
96.9, 108.7, 109.3, 118.2, 134.1, 141.2. Anal. Calcd for C29H45NO11: C,
59.68; H, 7.77; N, 2.40. Found: C, 59.81; H, 7.59; N, 2.67.
5.2.9. (R,Z)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-N-(((3aR,5R,5a-
S,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
b:40,50-d]pyran-5-yl)methylene)but-3-en-1-amine oxide (32). Yield
5.2.13. (R,Z)-N-(2-(Benzyloxy)ethylidene)-1-((3aR,5R,5aS,8aS,8bR)-
2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:40,50-d]py-
25
0.667 g, 78%; sticky foam; Rf¼0.43 (Hex/EtOAc 1:1); [
a]
ꢁ86 (c
D
1.02, CH2Cl2). 1H NMR (400 MHz, CD2Cl2)
d
(ppm) 1.22 (s, 3H), 1.25
ran-5-yl)but-3-en-1-amine oxide (36). Yield 0.689 g, 77%; colorless
25
(s, 3H), 1.27 (s, 3H), 1.32e1.33 (m, 6H), 1.48 (s, 3H), 2.01 (ddd, 1H,
J¼3.2, 7.3, 14.1 Hz), 2.59 (ddd, 1H, J¼6.8, 10.8, 14.2 Hz), 3.62 (ddd,
1H, J¼3.3, 8.0, 11.0 Hz), 3.70 (dd, 1H, J¼6.8, 8.6 Hz), 4.00 (dd, 1H,
J¼6.4, 8.6 Hz), 4.26 (dd, 1H, J¼2.0, 5.0 Hz), 4.38 (dd, 1H, J¼6.6,
14.5 Hz), 4.51e4.56 (m, 2H), 4.89 (dd, 1H, J¼1.4, 5.2 Hz), 4.98e5.01
(m, 1H), 5.06 (dd, 1H, J¼1.6, 17.0 Hz), 5.43 (d, 1H, J¼5.0 Hz), 5.68
(tdd, 1H, J¼7.1, 10.1, 17.1 Hz), 6.64 (d, 1H, J¼5.3 Hz). 13C NMR
oil; Rf¼0.3 (Hex/EtOAc 7:3); [
a]
ꢁ46 (c 1.10, CHCl3). 1H NMR
D
(400 MHz, CDCl3)
d
(ppm) 1.29 (s, 3H), 1.32 (s, 3H), 1.44 (s, 3H), 1.55
(s, 3H), 2.63e2.75 (m, 2H), 3.91 (dt, 1H, J¼4.1, 9.6 Hz), 4.17 (dd, 1H,
J¼1.4, 9.4 Hz), 4.22 (dd, 1H, J¼1.6, 8.0 Hz), 4.29 (dd, 1H, J¼2.3,
5.0 Hz), 4.47 (d, 1H, J¼4.5 Hz), 4.48 (d, 1H, J¼4.5 Hz), 4.54e4.58 (m,
3H), 5.09 (dd,1H, J¼1.8, 10.1 Hz), 5.17 (dd,1H, J¼1.7, 17.1 Hz), 5.52 (d,
1H, J¼5.0 Hz), 5.71 (tdd, 1H, J¼7.2, 10.1, 17.2 Hz), 6.97 (t, 1H,
(100 MHz, CD2Cl2)
d
(ppm) 24.5, 25.1, 25.5, 26.2, 26.3, 26.8, 32.8,
J¼4.4 Hz), 7.29e7.39 (m, 5H). 13C NMR (100 MHz, CDCl3)
d (ppm)

E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
6681
24.3, 24.9, 25.9 (2C), 32.0, 60.4, 66.9, 67.2, 69.90, 70.5, 70.8, 71.0,
96.5, 108.5, 109.1, 117.6, 127.6, 128.3, 131.2, 134.1, 135.3. Anal. Calcd
for C24H33NO7: C, 64.41; H, 7.43; N, 3.13. Found: C, 64.57; H, 7.28; N,
3.38.
4H), 4.59 (dd,1H, J¼1.4, 6.0 Hz), 4.90 (s, 1H), 5.03e5.13 (m, 2H), 5.60
(tdd, 1H, J¼7.1, 10.1, 17.1 Hz), 6.72 (t, 1H, J¼4.4 Hz), 7.21e7.30 (m,
5H). 13C NMR (100 MHz, CD2Cl2)
d (ppm) 25.3, 26.5, 32.5, 56.2, 65.3,
73.5, 77.0, 81.5, 85.3, 86.1, 109.7, 113.8, 119.0, 127.7, 127.9, 128.4,
132.1, 137.2, 138.4. Anal. Calcd for C21H29NO6: C, 64.43; H, 7.47; N,
3.58. Found: C, 64.52; H, 7.66; N, 3.41.
5.2.14. \(S,Z)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-N-(2-
((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]
dioxolo[4,5-b:40,50-d]pyran-5-yl)ethylidene)but-3-en-1-amine ox-
5.3. Intramolecular 1,3-dipolar cycloaddition. General
procedure
25
ide (38). Yield 0.645 g, 73%; sticky foam; Rf¼0.32 (EtOAc); [
a]
D
ꢁ23 (c 1.00, CH2Cl2). 1H NMR (400 MHz, CD2Cl2)
d (ppm)
1.23e1.25 (m, 9H), 1.30 (s, 3H), 1.35 (s, 3H), 1.41 (s, 3H), 2.40e2.46
(m, 1H), 2.59e2.67 (m, 3H), 3.55 (ddd, 1H, J¼3.3, 8.1, 11.1 Hz), 3.78
(dd, 1H, J¼4.8, 8.9 Hz), 3.91e3.96 (m, 2H), 4.05 (dd, 1H, J¼1.8,
7.9 Hz), 4.22 (dd, 1H, J¼2.4, 5.0 Hz), 4.31 (ddd, 1H, J¼5.0, 6.0,
8.1 Hz), 4.52 (dd, 1H, J¼2.4, 7.9 Hz), 4.98 (dd, 1H, J¼1.8, 10.2 Hz),
5.06 (dd, 1H, J¼1.7, 17.1 Hz), 5.38 (d, 1H, J¼5.0 Hz), 5.68 (tdd, 1H,
J¼7.1, 10.1, 17.2 Hz), 6.71 (t, 1H, J¼5.7 Hz). 13C NMR (100 MHz,
A solution of the corresponding nitrone (1.5 mmol) in toluene
(15 mL) was heated in a sealed tube at 100 ꢀC for 72 h at which time
the solvent was evaporated under reduced pressure to give the
crude product, which was analyzed by 1H NMR for determining the
diastereoselectivity and purified by column chromatography in the
stated eluent.
CD2Cl2)
d
(ppm) 24.1, 24.8, 25.0, 25.8, 25.8, 26.7, 27.8, 33.3, 64.4,
5.3.1. (2S,4S,6R)-2-Phenyl-6-((3aR,5R,5aS,8aS,8bR)-2,2,7,7-
tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:40,50-d]pyran-5-yl)-
66.4, 70.5,71.0, 72.7, 75.9, 76.4, 96.5, 108.6, 109.2, 109.7, 117.8,
133.6, 136.7. Anal. Calcd for C22H35NO8: C, 59.85; H, 7.99; N, 3.17.
Found: C, 60.01; H, 7.73; N, 3.03.
7-oxa-1-azabicyclo[2.2.1]heptane (45a). Yield 0.413 g, 66%; white
25
solid; mp 179e181 ꢀC; Rf¼0.69 (CH2Cl2/Et2O 95:5); [
a
]
ꢁ92 (c
D
1.00, CHCl3). 1H NMR (CDCl3, 400 MHz)
d (ppm) s 1.32 (s, 3H), 1.33
5.2.15. (S,Z)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-N-(3-((3aR,5R,5a-
S,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
(s, 3H), 1.45 (s, 3H), 1.51 (s,3H), 1.80 (dd, 1H, J¼7.8, 12.0 Hz) ,
1.90e1.96 (m, 1H), 1.98e2.04 (m, 1H), 2.17 (dd, 1H, J¼8.4, 11.6 Hz),
3.32 (ddd, 1H, J¼4.3, 7.7, 10.4 Hz), 3.59 (dd, 1H, 0.8, 10.3 Hz), 4.02
(dd, 1H, J¼4.7, 8.3 Hz), 4.27 (dd, 1H, J¼2.1, 4.9 Hz) ,4.58 (dd, 1H,
J¼2.1, 8.0 Hz), 4.68 (dd, 1H, J¼1.3, 8.1 Hz), 4.98 (t, 1H, J¼4.8 Hz), 5.51
(d, 1H, J¼4.9 Hz), 7.20e7.22 (m, 1H), 7.30e7.34 (m, 2H) , 7.40e7.42
b:40,50-d]pyran-5-yl)propylidene)but-3-en-1-amine oxide (39). Yield
25
0.665 g, 73%; white solid; mp 93e95 ꢀC; Rf¼0.3 (EtOAc); [
a]
D
ꢁ47
(c 0.95, CH2Cl2). 1H NMR (400 MHz, CD2Cl2)
d (ppm) 1.26 (s, 3H), 1.27
(s, 6H), 1.33 (s, 3H), 1.37 (s, 3H), 1.44 (s, 3H), 1.65e1.81(m, 2H),
2.41e2.50 (m, 3H), 2.63e2.71 (m, 1H), 3.53 (ddd, 1H, J¼3.3, 8.0,
10.7 Hz), 3.66 (ddd, 1H, J¼1.7, 4.9, 8.6 Hz), 3.80 (dd, 1H, J¼4.9, 8.9 Hz),
3.96 (dd, 1H, J¼6.2, 8.9 Hz), 4.06 (dd, 1H, J¼1.8, 7.9 Hz), 4.24 (dd, 1H,
J¼2.3, 5.1 Hz), 4.34 (ddd, 1H, J¼5.0, 6.1, 8.0 Hz), 4.53 (dd, 1H, J¼2.3,
7.9 Hz), 5.01e5.04 (m, 1H), 5.08 (ddd, 1H, J¼1.4, 3.3, 17.1 Hz), 5.43
(d, 1H, J¼5.1 Hz), 5.60e5.72 (m, 1H) , 6.68 (t, 1H, J¼5.9 Hz). 13C NMR
(m, 2H). 13C NMR (CDCl3, 100 MHz)
d (ppm) 24.2, 25.0, 26.0, 26.1,
36.8, 42.3, 65.5, 69.7 (2C), 70.6, 71.1, 71.2, 79.4, 96.6, 108.6, 108.8,
126.6 (2C),128.3, 144.2. Anal. Calcd for C22H29NO6: C, 65.49; H, 7.24;
N, 3.47. Found: C, 65.68; H, 7.18; N, 3.65.
5.3.2. (2R,4S,6R)-2-Phenyl-6-((3aR,5R,5aS,8aS,8bR)-2,2,7,7-
tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:40,50-d]pyran-5-yl)-
7-oxa-1-azabicyclo[2.2.1]heptane (45b). Yield 0.091 g, 15%; white
(100 MHz, CD2Cl2) d (ppm) 23.4, 24.5, 25.1, 25.4, 26.2, 26.3, 26.4, 27.1,
33.7, 66.9, 67.7, 70.9, 71.3, 72.9, 76.2, 76.6, 96.9, 108.6, 109.3, 110.0,
118.4, 133.9 , 139.7. Anal. Calcd for C23H37NO8: C, 60.64; H, 8.19; N,
3.07. Found: C, 60.48; H, 8.31; N, 3.18.
solid; mp 177e179 ꢀC; Rf¼0.5 (CH2Cl2/Et2O 95:5); [
a
]
25 ꢁ92 (c 1.00,
D
CHCl3). 1H NMR (CDCl3, 400 MHz)
d (ppm) 1.14 (s, 3H), 1.28 (s, 3H),
1.29 (s, 3H), 1.50 (s, 3H), 1.68 (dd, 1H, J¼7.8, 11.8 Hz), 1.77e1.86 (m,
2H), 2.29e2.36 (m, 1H), 3.26 (ddd, 1H, J¼4.8, 7.8, 10.1 Hz), 3.55 (dd,
1H, J¼1.3, 10.1 Hz), 4.20 (dd, 1H, J¼2.1, 4.9 Hz), 4.52 (dd, 1H, J¼2.1,
8.0 Hz), 4.59 (dd, 1H, J¼1.5, 8.0 Hz), 4.70 (dd, 1H, J¼6.3, 10.1 Hz),
5.03 (t, 1H, J¼5.2 Hz), 5.41 (d, 1H, J¼4.9 Hz), 7.28e7.33 (m, 2H),
5.2.16. (S,Z)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-N-(2-
((2R,3S,4R,5S,6S)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-
yl)ethylidene)but-3-en-1-amine oxide (40). Yield 1.125 g, 78%;
25
white solid; mp 81e83 ꢀC; Rf¼0.25 (Hex/EtOAc 1:1); [
a
]
þ11 (c
D
1.00, CH2Cl2). 1H NMR (400 MHz, CD2Cl2)
d
(ppm) 1.23 (s, 3H), 1.29
7.41e7.42 (m, 3H). 13C NMR (CDCl3, 100 MHz)
d (ppm) 24.1, 25.0,
(s, 3H), 2.43 (dddd, 1H, J¼1.8, 3.3, 6.6, 11.2 Hz), 2.59e2.71 (m, 2H),
2.84 (ddd, 1H, J¼3.9, 5.3, 17.1 Hz), 3.17e3.24 (m, 1H), 3.34 (td, 1H,
J¼3.0, 9.5 Hz), 3.43 (ddd, 1H, J¼3.8, 7.6, 9.6 Hz), 3.53 (d, 1H,
J¼9.6 Hz), 3.58 (d, 1H, J¼8.8 Hz), 3.61e3.63 (m, 2H), 3.76 (dd, 1H,
J¼5.0, 8.9 Hz), 3.92 (dd, 1H, J¼6.2, 8.9 Hz), 4.26e4.33 (m, 1H), 4.41
(d, 1H, J¼11.9 Hz), 4.49 (d, 1H, J¼11.9 Hz), 4.57 (d, 1H, J¼10.7 Hz),
4.74 (dd, 1H, J¼7.1, 10.8 Hz), 4.81 (s, 2H), 4.97e5.00 (m, 2H), 5.05
(ddd, 1H, J¼1.3, 3.0, 17.0 Hz), 5.59e5.69 (m, 1H), 6.71 (t, 1H,
J¼5.7 Hz), 7.10e7.13 (m, 2H), 7.16e7.28 (m, 18H). 13C NMR
25.7, 26.1, 35.3, 38.8, 58.7, 70.2, 70.3 (2C), 70.5, 70.7, 71.0, 81.8, 96.3,
108.4, 127.4, 128.0, 128.9, 136.0. Anal. Calcd for C22H29NO6: C, 65.49;
H, 7.24; N, 3.47. Found: C, 65.72; H, 7.43; N, 3.58.
5. 3. 3 . ( 2R , 4S, 6S) - 2- ( ( 3aS, 4R , 6 S, 6 aS) -6 - M et h oxy-2 , 2 -
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-phenyl-7-oxa-1-
azabicyclo[2.2.1]heptane (46a). Yield 0.302 g, 58%; white solid; mp
153e155 ꢀC; Rf¼0.63 (CH2Cl2/Et2O 95:5); [
a
]
25 þ5 (c 1.08, CHCl3). 1H
D
NMR (CDCl3, 400 MHz)
d (ppm) 1.30 (s, 3H), 1.45 (s, 3H), 1.89 (dd,
(100 MHz, CD2Cl2)
d
(ppm) 25.4, 27.1, 29.4, 33.7, 66.8, 69.6, 73.8,
1H, J¼7.9, 11.5 Hz), 2.00e2.05 (m, 2H), 2.20 (dd, 1H, J¼8.4, 11.3 Hz),
3.30 (s, 3H), 3.49 (ddd, 1H, J¼4.3, 8.0, 9.7 Hz), 3.86 (dd, 1H, J¼3.3,
9.7 Hz), 4.05 (dd, 1H, J¼4.5, 8.3 Hz), 4.54 (d, 1H, J¼5.8 Hz),4.84 (s,
1H), 4.88 (dd,1H, J¼3.4, 5.8 Hz), 5.00 (t,1H, J¼4.9 Hz), 7.32e7.42 (m,
75.2, 75.6, 75.8, 76.2, 76.3, 76.9, 78.7, 79.4, 82.2, 87.2, 110.1, 118.5,
127.9, 128.0, 128.1 (2C), 128.2, 128.3 (2C), 128.4 (2C), 128.7 (2C),
134.0, 136.4, 138.7, 138.8 (2C), 139.2. Anal. Calcd for C44H51NO8: C,
73.21; H, 7.12; N, 1.94. Found: C, 73.09; H, 6.92; N, 2.15.
5H). 13C NMR (CDCl3, 100 MHz)
d (ppm) 24.8, 26.2, 36.9, 42.2, 54.4,
64.8, 69.8, 79.3, 79.5, 81.9, 85.1,107.0,112.1, 126.6, 126.7,128.3, 144.1.
Anal. Calcd for C19H25NO5: C, 65.69; H, 7.25; N, 4.03. Found: C,
65.58; H, 7.36; N, 4.24.
5.2.17. (S,Z)-N-(2-(Benzyloxy)ethylidene)-1-((3aR,4R,6R,6aR)-6-
methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)but-3-
en-1-amine oxide (42). Yield 0.564 g, 72%; white solid; mp
25
72e74 ꢀC; Rf¼0.19 (Hex/EtOAc 6:4); [
a]
ꢁ36 (c 1.08, CH2Cl2). 1H
5. 3. 4. (2R, 4S, 6R)-2-((3aS, 4R, 6S, 6aS)-6-Methoxy-2, 2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-phenyl-7-oxa-1-
azabicyclo[2.2.1]heptane (46b). Yield 0.099 g, 19%; white solid; mp
D
NMR (400 MHz, CDCl3) d (ppm) 1.26 (s, 3H), 1.41 (s, 3H), 2.20e2.28
(m, 1H), 2.69 (ddd, 1H, J¼7.5, 10.6, 14.5 Hz), 3.28 (s, 1H), 3.50e3.67
(m, 3H), 4.42 (d, 1H, J¼4.3 Hz), 4.45 (d, 1H, J¼4.3 Hz), 4.47e4.53 (m,
134e136 ꢀC; Rf¼0.3 (CH2Cl2/Et2O 95:5); [
a]
25 þ6 (c 1.00, CHCl3). 1H
D

6682
E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
NMR (CDCl3, 400 MHz)
d
(ppm) 0.99 (s, 3H), 1.19 (s, 3H), 1.78 (dd,
NMR (CDCl3, 100 MHz) d (ppm) 25.5, 26.6, 36.0, 42.5, 54.6, 70.0,
1H, J¼7.9, 11.7 Hz), 1.83 (dd, 1H, J¼6.3, 11.7 Hz), 1.94e1.98 (m, 1H),
2.31e2.34 (m, 1H), 3.25 (s, 3H), 3.42 (ddd, 1H, J¼4.6, 8.0, 9.4 Hz),
3.81 (dd, 1H, J¼3.5, 9.5 Hz), 4.47 (d, 1H, J¼5.9 Hz), 4.69e4.74 (m,
2H), 4.78 (dd,1H, J¼3.6, 5.9 Hz), 5.06 (t,1H, J¼5.2 Hz), 7.30e7.46 (m,
70.4, 79.3, 81.4, 85.4, 88.8, 109.0, 112.8, 126.7, 126.8, 128.4, 143.8.
Anal. Calcd for C19H25NO5: C, 65.69; H, 7.25; N, 4.03. Found: C,
65.62; H, 7.21; N, 4.10.
5H). 13C NMR (CDCl3, 100 MHz)
d
(ppm) 24.9, 25.6, 35.5, 38.685,
5. 3. 9. (2S, 4R, 6R) -2-((3aS, 4 R, 6S, 6aS)-6-Me thoxy-2, 2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-phenyl-7-oxa-1-
54.3, 58.2, 70.6, 79.3, 81.8, 82.5, 85.1, 106.8, 111.9, 127.6, 128.1, 129.2,
135.7. Anal. Calcd for C19H25NO5: C, 65.69; H, 7.25; N, 4.03. Found: C,
65.48; H, 7.32; N, 4.19.
azabicyclo[2.2.1]heptane (50a). Yield 0.318 g, 61%; white solid; mp
25
125e127 ꢀC; Rf¼0.7 (CH2Cl2/Et2O 9:1); [
a]
þ72 (c 1, CHCl3). 1H
D
NMR (400 MHz, CDCl3)
d (ppm) 1.30 (s, 3H), 1.47 (s, 3H), 1.65e1.69
5.3.5. (2R,4S,6S)-2-((3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-6-phenyl-7-oxa-1-
azabicyclo[2.2.1]heptane (47a). Yield 0.508 g, 80%; white solid; mp
(m,1H),1.95 (dd,1H, J¼7.9,12.0 Hz),1.99e2.03 (m,1H), 2.20 (dd,1H,
J¼8.4, 11.6 Hz), 3.29e3.35 (m, 1H), 3.36 (s, 3H), 3.93 (dd, 1H, J¼3.5,
9.4 Hz), 4.03 (dd, 1H, J¼4.7, 8.3 Hz), 4.54 (d, 1H, J¼5.9 Hz), 4.61 (dd,
1H, J¼3.5, 5.9 Hz), 4.91e4.94 (m, 2H), 7.17e7.21(m, 1H), 7.27e7.30
151e153 ꢀC; Rf¼0.53 (CH2Cl2/Et2O 97:3); [
a]
25 ꢁ32 (c 1.15,CHCl3). 1H
D
NMR (400 MHz, CDCl3)
d
(ppm) 1.31 (s, 3H),1.47 (s, 3H),1.87 (dd,1H,
(m, 2H), 7.40e7.42 (m, 2H). 13C NMR (100 MHz, CDCl3)
d (ppm) 24.9,
J¼7.9, 11.9 Hz), 1.98e2.05 (m, 1H), 2.06e2.12 (m, 1H), 2.18 (dd, 1H,
J¼8.4, 11.7 Hz), 3.51 (ddd, 1H, J¼4.4, 7.9, 10.1 Hz), 3.95 (dd, 1H, J¼4.7,
8.3 Hz), 4.09 (dd, 1H, J¼3.1, 10.1 Hz), 4.24 (d, 1H, J¼3.1 Hz), 4.56 (d,
1H, J¼11.9 Hz), 4.63 (d, 1H, J¼3.8 Hz), 4.68 (d, 1H, J¼11.9 Hz), 5.02 (t,
1H, J¼4.9 Hz), 5.90 (d, 1H, J¼3.8 Hz), 7.12e7.24 (m, 6H), 7.29e7.35
26.1, 36.4, 42.3, 54.8, 67.7, 69.8, 78.5, 79.6, 82.0, 84.8, 107.3, 112.4,
126.6, 126.7, 128.2, 144.1. Anal. Calcd for C19H25NO5: C, 65.69; H,
7.25; N, 4.03. Found: C, 65.81; H, 7.16; N, 4.21.
5.3.10. (2S,4R, 6S)-2-((3aS,4R, 6S,6aS)-6-Methoxy-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-phenyl-7-oxa-1-
(m, 4H). 13C NMR (100 MHz, CDCl3)
d (ppm) 26.2, 26.7, 37.1, 42.5,
64.5, 70.1, 72.2, 79.5, 81.7, 82.8, 83.1, 104.8, 111.5, 126.6, 126.8, 127.5,
127.7, 128.3, 128.4, 137.6, 144.0. Anal. Calcd for C25H29NO5: C, 70.90;
H, 6.90; N, 3.31. Found: C, 71.04; H, 7.18; N, 3.02.
azabicyclo[2.2.1]heptane (50b). Yield 0.168 g, 32%; syrup; Rf¼0.3
þ32 (c 1.00, CHCl3). 1H NMR (400 MHz,
25
(CH2Cl2/Et2O 9:1); [
a]
D
CDCl3)
d
(ppm) 1.05 (s, 3H), 1.19 (s, 3H), 1.58 (ddt, 1H, J¼2.6, 5.0,
7.6 Hz), 1.71e1.79 (m, 2H), 2.39e2.46 (m, 1H), 3.38 (s, 3H), 3.43
(ddd, 1H, J¼5.4, 8.0, 9.8 Hz), 3.86 (dd, 1H, J¼3.7, 9.7 Hz), 4.49 (d, 1H,
J¼6.0 Hz), 4.54 (dd, 1H, J¼3.7, 5.9 Hz), 4.76 (dd, 1H, J¼6.3, 10.2 Hz),
4.86 (s, 1H), 4.97 (t, 1H, J¼5.2 Hz), 7.23e7.27 (m, 1H), 7.32e7.36 (m,
5.3.6. (2R,4S,6S)-2-((3aR,5R,6R,6aR)-6-(Benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-6-phenyl-7-oxa-1-
azabicyclo[2.2.1]heptane (48a). Yield 0.400 g, 63%; white solid; mp
25
94e96 ꢀC; Rf¼0.31 (Hex/EtOAc 9:1); [
a
]
þ55 (c 1.00, CHCl3). 1H
2H), 7.41e7.44 (m, 2H). 13C NMR (100 MHz, CDCl3)
d 25.5, 25.8, 36.4,
D
NMR (400 MHz, CDCl3)
d
(ppm) 1.26 (s, 3H), 1.51 (s, 3H), 1.62 (dd,
37.8, 54.8, 59.9, 70.1, 79.5, 80.1, 81.7, 84.9, 107.0, 112.4, 127.2, 128.3,
136.9. Anal. Calcd for C19H25NO5: C, 65.69; H, 7.25; N, 4.03. Found:
C, 65.81; H, 7.40; N, 3.87.
1H, J¼8.6, 11.5 Hz), 1.93e1.99 (m, 1H), 2.01e2.06 (m, 1H), 2.09 (dd,
1H, J¼8.4, 11.7 Hz), 3.19 (ddd, 1H, J¼3.0, 5.2, 8.4 Hz), 3.86 (dd, 1H,
J¼4.6, 8.3 Hz), 3.96 (dd, 1H, J¼3.0, 8.8 Hz), 4.00 (dd, 1H, J¼5.1,
9.9 Hz), 4.42 (t, 1H, J¼3.8 Hz), 4.55 (d, 1H, J¼11.6 Hz), 4.67 (d, 1H,
J¼11.6 Hz), 4.87 (t, 1H, J¼4.9 Hz), 5.66 (d, 1H, J¼3.7 Hz), 7.11e7.16
(m, 1H), 7.18e7.25 (m, 5H), 7.29e7.35 (m, 4H). 13C NMR (100 MHz,
5.3.11. (2S,4R,6R)-2-((3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-6-phenyl-7-oxa-1-
azabicyclo[2.2.1]heptane (51a). Yield 0.343 g, 54%; white solid; mp
CDCl3)
d
(ppm) 26.5, 26.9, 34.9, 42.8, 67.4, 70.3, 72.3, 77.9, 78.5, 79.0,
102e104 ꢀC; Rf¼0.67(CH2Cl2/Et2O 95:5);[
a
]
25 ꢁ16 (c1.03, CHCl3).1H
D
79.5, 103.6, 112.6, 126.8 (2C), 127.7, 128.1, 128.2, 128.4, 138.1, 144.0 .
Anal. Calcd for C25H29NO5: C, 70.90; H, 6.90; N, 3.31. Found: C,
70.77; H, 6.73; N, 3.43.
NMR (400 MHz, CDCl3) d (ppm) 1.31 (s, 3H), 1.40e1.47 (m, 1H), 1.50
(s, 3H), 1.70 (dd, 1H, J¼8.0, 11.8 Hz), 1.96e2.02 (m, 1H), 2.13 (dd, 1H,
J¼8.4, 11.7 Hz), 3.32e3.38 (m, 1H), 3.85 (d, 1H, J¼3.3 Hz), 3.97 (dd,
1H, J¼4.8, 8.3 Hz), 4.18 (dd,1H, J¼3.3, 9.3 Hz), 4.42 (d,1H, J¼11.7 Hz),
4.62 (d, 1H, J¼3.9 Hz), 4.69 (d, 1H, J¼11.7 Hz), 4.87 (t, 1H, J¼4.9 Hz),
5.99 (d, 1H, J¼3.9 Hz), 7.15e7.19 (m, 1H), 7.25e7.28 (m, 3H),
5.3.7. (2R,4S,6R)-2-((3aR,5R,6R,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-6-phenyl-7-oxa-1-
azabicyclo[2.2.1]heptane (48b). Yield 0.127 g, 20%; yellow oil;
7.32e7.40 (m, 6H). 13C NMR (100 MHz, CDCl3)
d (ppm) 26.3, 26.8,
25
Rf¼0.31 (Hex/EtOAc 9:1); [
a
]
þ53 (c 1.00, CHCl3). 1H NMR
36.0, 42.6, 67.4, 69.9, 71.6, 78.4, 81.3, 81.7, 82.4, 105.5, 111.5, 126.6
(2C), 128.0, 128.1, 128.2, 128.5, 137.2, 144.0. Anal. Calcd for
C25H29NO5: C, 70.90; H, 6.90; N, 3.31. Found:C, 70.82; H, 6.85; N, 3.19.
D
(400 MHz, CDCl3)
d
(ppm) 1.24 (s, 3H), 1.37 (dd, 1H, J¼8.7, 11.2 Hz),
1.47 (s, 3H), 1.64 (dd, 1H, J¼6.5, 11.5 Hz), 2.02 (dtd, 1H, J¼2.5, 5.3,
10.9 Hz), 2.34 (dddd, 1H, J¼2.6, 5.5, 10.3, 11.5 Hz), 3.31 (ddd, 1H,
J¼2.9, 5.8, 8.6 Hz), 3.86 (dd, 1H, J¼2.9, 8.9 Hz), 3.93 (dd, 1H, J¼4.3,
8.9 Hz), 4.37 (t, 1H, J¼4.0 Hz), 4.51 (d, 1H, J¼11.6 Hz), 4.60e4.64 (m,
2H), 4.89 (t, 1H, J¼5.1 Hz), 5.66 (d, 1H, J¼3.7 Hz), 7.18e7.31 (m, 10H).
5.3.12. (2S,4R,6S)-2-((3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-6-phenyl-7-oxa-1-
azabicyclo[2.2.1]heptane (51b). Yield 0.241 g, 38%; white solid; mp
13C NMR (100 MHz, CDCl3)
d
(ppm) 26.4, 26.8, 35.7, 36.3, 59.2, 70.2,
151e153 ꢀC; Rf¼0.43 (CH2Cl2/Et2O 95:5); [
a
]
25 þ10 (c 0.60,MeOH). 1H
D
72.3, 77.7, 78.6, 79.0, 80.8,103.5,112.6,127.5 (2C),127.8,128.2,128.4,
128.5, 136.5, 137.9. Anal. Calcd for C25H29NO5: C, 70.90; H, 6.90; N,
3.31. Found: C, 70.86; H, 6.88; N, 3.19.
NMR (400 MHz, CDCl3) d (ppm) 1.29 (s, 3H), 1.49 (s, 3H), 1.52 (dd, 1H,
J¼6.8, 10.4 Hz), 1.69 (dd, 1H, J¼6.4, 11.4 Hz), 2.35e2.42 (m, 1H), 3.42
(ddd,1H, J¼5.2, 8.2, 8.9 Hz), 3.75 (d,1H, J¼3.3 Hz), 4.16 (dd,1H, J¼3.3,
9.4 Hz), 4.31 (d, 1H, J¼11.9 Hz), 4.52 (d, 1H, J¼3.9 Hz), 4.56 (d, 1H,
J¼11.9 Hz), 4.73 (dd,1H, J¼6.4,10.3 Hz), 4.91 (t,1H, J¼5.1 Hz), 5.88 (d,
1H, J¼3.8 Hz), 7.13e7.16(m, 2H), 7.29e7.31(m, 4H), 7.35e7.38(m, 3H),
5. 3. 8. (2S, 4R, 6R)-2-((3aR, 4 R, 6R, 6aR)-6-Methoxy-2, 2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-phenyl-7-oxa-1-
azabicyclo[2.2.1]heptane (49a). Yield 0.474 g, 91%; white solid; mp
7.41e7.44 (m, 2H).13C NMR (100 MHz, CDCl3)
d (ppm) 26.4, 26.8, 36.1,
25
132e134 ꢀC; Rf¼0.62 (CH2Cl2/Et2O 9:1); [
a
]
ꢁ28 (c 1.00, CHCl3).
37.3, 59.8, 70.0, 71.3, 80.8, 81.2, 81.5, 82.5, 105.3, 111.6, 127.5, 127.6,
127.9, 128.4, 128.5, 128.7, 136.6. Anal. Calcd for C25H29NO5: C, 70.90; H,
6.90; N, 3.31. Found: C, 70.71; H, 7.11; N, 3.25.
D
1H NMR (CDCl3, 400 MHz)
d (ppm) 1.32 (s, 3H) 1.47 (s, 3H)
1.64e1.70 (m, 1H), 1.79 (dd, 1H, J¼7.9, 11.6 Hz), 2.03e2.08 (m, 1H),
2.15 (dd, 1H, J¼8.3, 11.7 Hz), 3.09 (ddd, 1H, J¼4.7, 7.9, 11.0 Hz), 3.35
(s, 3H), 3.91 (dd, 1H, J¼4.9, 8.1 Hz), 4.03 (d, 1H, J¼10.6 Hz), 4.49 (d,
1H, J¼5.9 Hz), 4.59 (d, 1H, J¼6.0 Hz), 4.99 (t, 1H, J¼4.9 Hz), 5.02 (s,
1H), 7.19e7.22 (m, 1H), 7.23e7.31 (m, 2H), 7.40e7.42 (m, 2H). 13C
5.3.13. (2S,4R,6R)-2-((3aR,5R,6R,6aR)-6-(Benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-6-phenyl-7-oxa-1-
azabicyclo[2.2.1]heptane (52a). Yield 0.356 g, 56%; colorless oil;

E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
6683
Rf¼0.27 (Hex/EtOAc 7:3); [
a
]
25 þ66 (c 0.70,CHCl3).1H NMR (400 MHz,
77.2, 78.7, 96.4,108.2,108.9,109.3. Anal. Calcd forC23H37NO8: C, 60.64;
H, 8.19; N, 3.07. Found: C, 60.78; H, 8.00; N, 2.95.
D
CDCl3)
d
(ppm) 1.38 (s, 3H), 1.61 (s, 3H), 1.74 (dd, 1H, J¼8.4, 11.6 Hz),
2.01 (dtd, 1H, J¼2.7, 4.8, 11.9 Hz), 2.16 (dd, 1H, J¼8.4, 11.7 Hz),
1.99e2.05(m, 1H), 3.10 (td, 1H, J¼5.2, 8.4 Hz), 3.85 (dd, 1H, J¼4.6,
8.3 Hz), 3.95 (s,1H), 4.01 (dd,1H, J¼5.1, 8.8 Hz), 4.55(d,1H, J¼11.9 Hz),
4.62(t,1H, J¼4.1 Hz), 4.81(d,1H, J¼11.9 Hz), 4.97(t,1H, J¼4.9 Hz), 5.81
(d, 1H, J¼3.9 Hz), 7.19e7.34 (m, 1H), 7.26e7.31 (m, 5H), 7.35e7.38 (m,
5 . 3 .18 . ( 2 R , 4 S , 6 R ) - 2 - ( ( 3 a R , 5 R , 5 a S , 8 a S , 8 b R ) - 2 , 2 , 7 , 7 -
Tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:40,50-d]pyran-5-yl)-
6-(2-((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis
[1,3]dioxolo[4,5-b:40,50-d]pyran-5-yl)ethyl)-7-oxa-1-azabicyclo[2.2.1]
heptane (56a). Yield0.613 g, 70%;whitesolid;mp 73e75 ꢀC;Rf¼0.39
4H). 13C NMR (100 MHz, CDCl3)
d (ppm) 26.7, 26.8, 35.0, 42.3, 67.5,
70.4, 72.0, 77.0, 78.7, 79.1, 79.1, 103.9, 112.6, 126.7, 126.8, 127.9, 128.0,
128.2, 128.4, 137.5, 143.9. Anal. Calcd for C25H29NO5: C, 70.90; H, 6.90;
N, 3.31. Found: C, 70.77; H, 7.12; N, 3.48.
(Hex/EtOAc 7:3); [
a
]
25 ꢁ47 (c 0.94, CHCl3). 1H NMR (400 MHz, CDCl3)
D
d
(ppm) 1.29 (s, 3H), 1.31 (s, 3H), 1.32 (s, 3H), 1.34 (s, 3H), 1.43 (s, 3H),
1.44 (s, 3H),1.47 (s, 3H),1.51 (s, 3H),1.63e1.81 (m, 8H), 2.83e2.90 (m,
1H),3.04e3.10(m,1H),3.49(d,1H, J¼10.1 Hz), 3.73e3.78(m,1H),4.08
(dd, 1H, J¼1.3, 8.0 Hz), 4.24 (dd, 1H, J¼2.0, 4.9 Hz), 4.27 (dd, 1H, J¼2.1,
5.1 Hz), 4.54e4.59 (m, 2H), 4.62e4.65 (m, 1H), 4.82 (t, 1H, J¼4.7 Hz),
5.47 (d, 1H, J¼4.9 Hz), 5.52 (d, 1H, J¼5.1 Hz). 13C NMR (100 MHz,
5.3.14. (2S,4R,6S)-2-((3aR,5R,6R,6aR)-6-(Benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-6-phenyl-7-oxa-1-
azabicyclo[2.2.1]heptane (52b). Yield 0.165 g, 26%; colorless oil;
25
Rf¼0.27 (Hex/EtOAc 7:3); [
a]
þ67 (c 0.95,CHCl3). 1H NMR
CDCl3) d (ppm) 24.2, 24.3, 24.9, 25.0, 26.0, 26.0, 26.1, 26.1, 26.7, 32.0,
D
(400 MHz, CDCl3)
d
(ppm) 1.25 (s, 3H), 1.45 (s, 3H), 1.59 (dd, 1H,
36.8, 39.3, 69.8, 70.5,70.6,71.0, 71.1(2C), 71.2(2C), 72.9(2C), 79.3, 96.5
(2C),108.2,108.5,108.7,108.9. Anal. Calcd for C29H45NO11: C, 59.68; H,
7.77; N, 2.40. Found: C, 59.44; H, 7.59; N, 2.62.
J¼8.5, 11.4 Hz), 1.70 (dd, 1H, J¼6.6, 11.6 Hz), 2.04e2.13 (m, 1H), 2.28
(dddd, 1H, J¼2.6, 5.5, 10.2, 11.7 Hz), 3.11 (td, 1H, J¼5.3, 8.4 Hz), 3.63
(dd, 1H, J¼4.5, 8.8 Hz), 3.80 (dd, 1H, J¼4.7, 8.8 Hz), 4.19 (d, 1H,
J¼11.2 Hz), 4.37 (d, 1H, J¼11.2 Hz), 4.42 (t, 1H, J¼4.2 Hz), 4.63 (dd,
1H, J¼6.7, 10.0 Hz), 4.96 (t, 1H, J¼5.1 Hz), 5.70 (d, 1H, J¼3.8 Hz),
7.09e7.11 (m, 2H), 7.17e7.24 (m, 4H), 7.25e7.29 (m, 2H), 7.36e7.38
5.3.19. (2S,4S,6R)-2-(Benzyloxymethyl)-6-((3aR,5R,5aS,8aS,8bR)-
2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:40,50-d]py-
ran-5-yl)-7-oxa-1-azabicyclo[2.2.1]heptane (57a). Yield 0.537 g,
(m, 2H). 13C NMR (100 MHz, CDCl3)
70.6, 72.0, 77.3, 77.3, 79.6, 79.8, 81.2, 104.0, 112.6, 127.8, 127.8, 128.0,
128.2, 128.6, 128.9, 136.2, 137.5. Anal. Calcd for C25H29NO5: C, 70.90;
H, 6.90; N, 3.31. Found: C, 70.65; H, 7.04; N, 3.41.
d
(ppm) 26.7, 26.8, 35.1, 37.2,
80%; sticky foam; Rf¼0.42 (Hex/EtOAc 8:2); [
a
]
25 ꢁ60 (c 1.00, CHCl3).
D
1HNMR (400 MHz, CDCl3)
d
(ppm)1.32 (s, 3H),1.37 (s, 3H),1.47 (s, 3H),
1.51 (s, 3H),1.51e1.59 (m, 1H),1.69e1.75 (m, 2H),1.88 (tdd,1H, J¼3.9,
7.4, 9.0 Hz), 3.17e3.27 (m, 3H), 3.55 (dd, 1H, J¼1.3, 10.3 Hz), 3.63 (dd,
1H, J¼7.1, 9.5 Hz), 4.28 (dd, 1H, J¼2.2, 5.0 Hz), 4.54 (d, 1H, J¼11.8 Hz),
4.60 (dd, 1H, J¼2.2, 8.0 Hz), 4.68 (dd, 1H, J¼1.6, 8.0 Hz) , 4.72 (d, 1H,
J¼11.8 Hz), 4.86 (t,1H, J¼4.9 Hz), 5.51 (d,1H, J¼4.9 Hz), 7.27e7.31 (m,
5.3.15. (2R,4R,6S)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-((3aR,5-
R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo
[4,5-b:40,50-d]pyran-5-yl)-7-oxa-1-azabicyclo[2.2.1]heptane
(53a). Yield 0.231 g, 36%; 1H NMR (400 MHz, CDCl3) selected sig-
1H), 7.32e7.39 (m, 4H). 13C NMR (100 MHz, CDCl3)
d (ppm) 24.1, 24.9,
25.9, 26.0, 36.4, 36.8, 65.2, 66.8, 69.6, 70.6, 71.0, 71.1, 72.9, 73.2, 78.9,
96.5,108.5,108.8,127.5, 127.7,128.3,136.7. Anal. Calcd for C24H33NO7:
C, 64.41; H, 7.43; N, 3.13. Found: C, 64.58; H, 7.29; N, 3.36.
nals: d 1.30 (s, 3H), 1.34 (s, 3H), 1.34 (s, 3H), 1.43 (s, 3H), 1.45 (s, 3H),
1.49 (s, 4H), 1.67 (dd, 1H, J¼7.7, 11.8 Hz), 1.84e1.92 (m, 1H),
2.00e2.07 (m, 1H), 3.43e3.49 (m, 1H), 3.58 (dd, 1H, J¼1.2, 10.1 Hz),
3.70e3.78 (m, 2H), 4.00 (dd, 1H, J¼5.8, 7.7 Hz), 4.13e4.21 (m, 1H),
4.24 (dd, 1H, J¼2.1, 4.9 Hz), 4.56 (dd, 1H, J¼2.0, 8.0 Hz), 4.63 (dd, 1H,
J¼1.5, 8.0 Hz), 4.89 (t, 1H, J¼5.2 Hz), 5.49 (d, 1H, J¼4.9 Hz).
5.3.20. (2S,4S,6R)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-((3aR,5-
R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo
[4,5-b:40,50-d]pyran-5-yl)-7-oxa-1-azabicyclo[2.2.1]heptane
(58a). Yield 0.545 g, 85%; white solid; mp 57e59 ꢀC; Rf¼0.41
25
5.3.16. (2R,4S,6R)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-
(((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]di-
oxolo[4,5-b:40,50-d]pyran-5-yl)methyl)-7-oxa-1-azabicyclo[2.2.1]
heptane (54a). Yield 0.589 g, 89%; white solid; mp 159e161 ꢀC;
(CH2Cl2/Et2O 9:1); [
a
]
ꢁ45 (c 1.00, CHCl3). 1H NMR (400 MHz,
D
CDCl3) d (ppm) 1.30 (s, 3H),1.32 (s, 3H),1.35 (s, 3H),1.42 (s, 3H),1.44 (s,
3H), 1.47 (s, 3H), 1.69e1.78 (m, 2H), 1.80e1.92 (m, 2H), 2.84e2.89 (m,
1H), 3.14 (ddd, 1H, J¼4.3, 7.7, 10.3 Hz) , 3.47 (d, 1H, J¼10.4 Hz), 3.88
(ddd, 1H, J¼4.7, 6.1, 9.3 Hz), 3.97 (dd, 1H, J¼4.7, 8.6 Hz), 4.15 (dd, 1H,
J¼6.2, 8.6 Hz), 4.25 (dd, 1H, J¼1.5, 5.0 Hz), 4.54e4.59 (m, 2H), 4.90 (t,
1H, J¼4.8 Hz), 5.47 (d, 1H, J¼4.9 Hz). 13C NMR (100 MHz, CDCl3)
Rf¼0.21 (Hex/EtOAc 7:3); [
a
]
25 ꢁ3 (c 0.99, CHCl3). 1H NMR (400 MHz,
D
CDCl3)
d
(ppm) 1.32e1.34 (m, 9H), 1.37 (s, 3H), 1.45 (s, 3H), 1.47e1.55
(m, 2H), 1.57e1.60 (m, 2H), 1.62 (s, 3H), 1.69 (ddd, 1H, J¼1.4, 11.0,
14.7 Hz), 1.77 (dd, 1H, J¼8.0, 11.4 Hz), 3.02e3.13 (m, 2H), 3.61 (t, 1H,
J¼8.0 Hz), 3.94 (dd,1H, J¼6.5, 8.2 Hz), 4.13e4.20 (m, 3H), 4.28 (dd,1H,
J¼2.3, 4.9 Hz), 4.58 (dd, 1H, J¼2.3, 7.8 Hz), 4.78 (t, 1H, J¼4.8 Hz), 5.51
d
(ppm) 24.1, 25.0, 25.1, 26.0, 26.1, 27.1, 36.7, 37.0, 65.5, 68.6, 69.6, 69.8,
70.5, 71.0, 71.1, 78.4, 79.8, 96.5, 108.5, 108.8, 109.1. Anal. Calcd for
C21H33NO8: C, 59.00; H, 7.78; N, 3.28. Found: C, 58.86; H, 7.63; N, 3.45.
(d, 1H, J¼4.9 Hz). 13C NMR (100 MHz, CDCl3)
d (ppm) 24.2, 25.1, 25.2,
25.9, 26.5, 26.6, 34.5, 37.9, 40.0, 63.8, 65.6, 65.8, 68.8, 70.6, 70.8, 73.4,
77.2, 78.3, 96.3,108.5,108.8,109.1. Anal. Calcd for C22H35NO8: C, 59.85;
H, 7.99; N, 3.17. Found: C, 59.97; H, 8.05; N, 3.28.
5.3.21. (2S,4R,6S)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-
(((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]di-
oxolo[4,5-b:40,50-d]pyran-5-yl)methyl)-7-oxa-1-azabicyclo[2.2.1]
heptane (59a). Yield 0.556 g, 84%; not absolutely pure, only NMR
5.3.17. (2R,4S,6R)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-(2-
((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]di-
oxolo[4,5-b:40,50-d]pyran-5-yl)ethyl)-7-oxa-1-azabicyclo[2.2.1]hep-
tane (55a). Yield 0.560 g, 82%; sticky foam; Rf¼0.23 (Hex/EtOAc 1:1);
signals are reported. 1H NMR (400 MHz, CDCl3)
d 1.31 (s, 6H),1.33 (s,
3H), 1.38 (s, 3H), 1.44 (s, 3H), 1.48e1.51 (m, 4H), 1.68e1.77 (m, 3H),
2.03e2.14 (m, 1H), 2.80 (dt, 1H, J¼4.2, 8.4 Hz), 2.98e3.10 (m, 1H),
3.78e3.89 (m, 2H), 3.93 (dd, 1H, J¼5.1, 8.5 Hz), 4.07e4.24 (m, 3H),
4.29 (dd, 1H, J¼2.3, 5.1 Hz), 4.58 (dd, 1H, J¼2.3, 7.9 Hz), 4.85 (t, 1H,
[a]
25 ꢁ33 (c 0.97, CH2Cl2). 1H NMR (400 MHz, CDCl3)
d (ppm) 1.29 (s,
D
3H), 1.30 (s, 3H), 1.31 (s, 3H), 1.39 (s, 3H), 1.41 (s, 3H), 1.47 (s, 5H),
1.51e1.71 (m, 5H),1.80e1.89 (m, 1H), 2.82 (dq, 1H, J¼4.7, 7.5 Hz), 2.93
(dt, 1H, J¼4.7, 7.8 Hz), 3.62 (dd, 1H, J¼6.8, 8.4 Hz), 3.64e3.71(m, 1H),
3.94 (dd, 1H, J¼6.6, 8.4 Hz), 4.06e4.15 (m, 2H), 4.24 (dd, 1H, J¼2.3,
5.1 Hz), 4.54 (dd, 1H, J¼2.3, 7.9 Hz), 4.77 (t, 1H, J¼4.8 Hz), 5.48 (d, 1H,
J¼4.8 Hz), 5.50 (d, 1H, J¼5.0 Hz). 13C NMR (100 MHz, CDCl3)
d 24.5,
24.9, 25.3, 26.0, 26.0, 27.1, 36.6, 36.7, 39.2, 64.0, 64.5, 68.7, 69.8, 70.5,
70.8, 72.6, 78.7, 79.5, 96.5, 108.3, 108.9, 109.1.
5.3.22. (2S,4R,6S)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-(2-
((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]di-
oxolo[4,5-b:40,50-d]pyran-5-yl)ethyl)-7-oxa-1-azabicyclo[2.2.1]
J¼5.1 Hz). 13C NMR (100 MHz, CDCl3)
d (ppm) 24.3, 24.9, 25.1, 25.9,
26.0, 26.6, 26.7, 32.3, 34.7, 39.0, 65.7, 67.2, 67.5, 69.6, 70.4, 70.8, 72.4,

6684
E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
heptane (60a). Yield 0.526 g, 77%; white solid; mp 68e70 ꢀC;
stirred at 60 ꢀC for 4 h, then filtered and the solid was washed with
water. The filtrate was neutralized by addition of 5 M NaOH and
then extracted with dichloromethane (3ꢂ50 mL). The combined
organic extracts were washed sequentially with a saturated aque-
ous solution of EDTA and brine. The organic layer was separated,
dried over magnesium sulfate, filtered, and evaporated under re-
duced pressure. The resulting crude product was purified by radial
chromatography in the adequate eluent.
In order to obtain an acceptable reproducibility, the commercial
Zn powder (5 g) was firstly stirred in HCl 0.5 N (12.5 mL) for 1 min,
filtered, and washed with HCl 0.5 N, water (3ꢂ4 mL), EtOH 95%
(2ꢂ8 mL), and Et2O (8 mL). Then the metal was dried at vacuum
overnight in presence of P2O5.
Rf¼0.26(Hex/EtOAc 7:3); [
a
]
25 ꢁ41 (c 1.03, CHCl3).1H NMR (400 MHz,
D
CDCl3)
d
(ppm) 1.31 (s, 6H),1.34 (s, 3H),1.39 (s, 3H),1.44e1.51 (m, 9H),
1.65e1.77 (m, 4H), 1.83e1.89 (m, 1H), 2.71e2.78 (m, 2H), 3.70 (ddd,
1H, J¼1.5, 3.4, 9.5 Hz), 3.84e3.90 (m, 1H), 3.98 (dd, 1H, J¼4.7, 8.6 Hz),
4.10 (dd, 1H, J¼1.7, 7.9 Hz), 4.14 (dd, 1H, J¼6.0, 8.6 Hz), 4.27 (dd, 1H,
J¼2.3, 5.1 Hz), 4.56 (dd, 1H, J¼2.3, 7.9 Hz), 4.83 (t, 1H, J¼4.8 Hz), 5.51
(d, 1H, J¼5.1 Hz). 13C NMR (100 MHz, CDCl3)
d (ppm) 24.3, 24.9, 25.3,
26.0, 26.0, 27.2, 28.0, 33.3, 36.7, 39.8, 67.8, 68.0, 68.7, 69.8, 70.5, 70.9,
73.0, 78.7, 79.3, 96.5, 108.3, 108.9 (2C). Anal. Calcd for C23H37NO8: C,
60.64; H, 8.19; N, 3.07. Found: C, 60.83; H, 8.31; N, 2.94.
5.3.23. (2S,4R,6S)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-
(((2R,3S,4R,5S,6S)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-
2-yl)methyl)-7-oxa-1-azabicyclo[2.2.1]heptane (61a). Yield 0.812 g,
5. 4 .1. ( 2 R , 4 S, 6 S) - 2- ( ( 3 aS , 4 R , 6 S, 6 aS ) - 6 - M e t h o xy-2 , 2 -
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-phenylpiperidin-4-
25
75%; white solid; mp 164e166 ꢀC; Rf¼0.25 (CH2Cl2/Et2O 9:1); [
a]
D
ꢁ9 (c 0.50, CHCl3). 1H NMR (400 MHz, CDCl3)
d
(ppm) 1.27 (s, 3H),
ol (64). Yield 0.210 g, 60%; yellow solid; mp 62e64 ꢀC; Rf¼0.27
25
1.33 (s, 3H), 1.39e1.45 (m, 1H), 1.61e1.71 (m, 3H), 1.81 (ddd, 1H,
J¼4.5, 7.0, 11.6 Hz), 1.93 (ddd, 1H, J¼2.3, 10.5, 13.1 Hz), 2.68 (dt, 1H,
J¼4.2, 8.0 Hz), 3.08 (dq, 1H, J¼4.2, 8.2 Hz), 3.20 (t, 1H, J¼9.2 Hz),
3.36 (td, 1H, J¼3.1, 9.6 Hz), 3.56e3.70 (m, 5H), 3.78e3.85 (m, 2H),
4.09e4.14 (m, 1H), 4.46e4.52 (m, 2H), 4.60 (dd, 1H, J¼5.7, 11.7 Hz),
4.77e4.82 (m, 2H), 4.84 (s, 2H), 7.10e7.14 (m, 2H), 7.20e7.32 (m,
(CH2Cl2/Et2O 3:7); [
a
]
ꢁ7 (c 1.00, CH2Cl2). 1H NMR (400 MHz,
D
CDCl3)
d
(ppm) 1.28 (s, 3H), 1.38 (dd, 1H, J¼5.5, 11.3 Hz), 1.45 (s, 3H),
1.46e1.57 (m, 1H), 2.06e2.16 (m, 3H), 2.42 (tdd, 1H, J¼2.3, 4.5,
11.9 Hz), 3.14 (ddd, 1H, J¼2.6, 8.8, 11.3 Hz), 3.33 (s, 3H), 3.75e3.93
(m, 3H), 4.57 (d, 1H, J¼5.9 Hz), 4.71 (dd, 1H, J¼3.6, 5.9 Hz), 4.90 (s,
1H) , 7.26e7.44 (m, 5H). 13C NMR (100 MHz, CDCl3)
d (ppm) 24.7,
18H). 13C NMR (100 MHz, CDCl3)
d
(ppm) 25.2, 27.0, 36.9, 38.5, 39.8,
25.2, 30.3, 39.1, 43.7, 54.6, 59.4, 69.1, 79.1, 82.9, 84.9, 106.5, 112.6,
126.8, 127.4, 128.5, 136.5. Anal. Calcd for C19H27NO5: C, 65.31; H,
7.79; N, 4.01. Found: C, 65.52; H, 7.89; N, 3.87.
63.6, 68.9, 69.0, 69.9, 73.3, 74.9, 75.0, 75.5, 77.0, 78.6, 78.6, 78.8,
79.2, 82.6, 87.1, 108.9, 127.6, 127.6, 127.7, 127.8 (2C), 127.9 (2C), 128.3
(2C), 128.4 (2C), 138.1, 138.2, 138.6 (2C). Anal. Calcd for C44H51NO8:
C, 73.21; H, 7.12; N, 1.94. Found: C, 73.01; H, 7.41; N, 2.13.
5. 4. 2. (2S, 4R, 6R)-2-((3aR, 4R, 6R, 6aR)-6-Methoxy-2, 2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-phenylpiperidin-4-
5.3.24. (2S,4R,6R)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-6-
(((2S,3R,4S,5S,6S)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-
ol (65). Yield 0.252 g, 72%; white solid; mp 101e103 ꢀC; Rf¼0.43
25
(CH2Cl2/Et2O 95:5); [
a
]
þ10 (c 0.6, MeOH). 1H NMR (CDCl3,
D
yloxy)methyl)-7-oxa-1-azabicyclo[2.2.1]heptane
(62a). Yield
400 MHz)
d
(ppm) 1.24e1.36 (m, 4H), 1.43 (d, 1H, J¼11.6 Hz), 1.49 (s,
0.885 g, 80%; white solid; mp 120e122 ꢀC; Rf¼0.19 (Hex/EtOAc 7:3);
3H),1.80e20 (br s, 2H), 2.09 (ddt,1H, J¼1.9, 4.1,11.6 Hz), 2.15 (ddt,1H,
J¼1.9, 4.3,11.9 Hz), 2.71 (ddd,1H, J¼2.2, 9.3,11.4 Hz), 3.32 (s, 3H), 3.65
(dd,1H, J¼2.4,11.4 Hz),3.83(ddd,1H, J¼4.5,10.8,15.5 Hz),4.12(dd,1H,
J¼1.3, 9.2 Hz), 4.58 (d, 1H, J¼6.0 Hz), 4.71 (dd, 1H, J¼1.2, 6.0 Hz), 4.96
[
a]
25 þ35 (c 1.25, CHCl3). 1H NMR (400 MHz, CDCl3)
d (ppm) 1.27 (s,
D
3H), 1.33 (s, 3H), 1.39e1.45 (m, 1H), 1.61e1.71 (m, 3H), 1.81 (ddd, 1H,
J¼4 .5, 7.0, 11.6 Hz), 1.93 (ddd, 1H, J¼2.3, 10.5, 13.1 Hz), 2.68 (dt, 1H,
J¼4.2, 8.0 Hz), 3.08 (dq, 1H, J¼4.2, 8.2 Hz), 3.20 (t, 1H, J¼9.2 Hz),
3.36 (td, 1H, J¼3.1, 9.6 Hz), 3.56e3.70 (m, 5H), 3.78e3.85 (m, 2H),
4.09e4.14 (m, 1H), 4.46e4.52 (m, 2H ), 4.60 (dd, 1H, J¼5.7, 11.7 Hz),
4.77e4.82 (m, 2H), 4.84 (s, 2H), 7.10e7.14 (m, 2H), 7.20e7.32 (m,
18H). 13C NMR (100 MHz, CDCl3) 25.2, 27.0, 36.9, 38.5, 39.8, 63.6,
68.9, 69.0, 69.9, 73.3, 74.9, 75.0, 75.5, 77.0, 78.6 (2C), 78.8, 79.2, 82.6,
87.1, 108.9, 127.6 (2C), 127.7 (2C), 127.8 (2C), 127.9, 128.3 (2C), 128.4,
138.1, 138.2, 138.6 (2C). Anal. Calcd for C44H51NO9: C, 71.62; H, 6.97;
N, 1.90. Found: C, 71.81; H, 7.18; N, 2.11.
(s, 1H), 7.31e7.40 (m, 5H). 13C NMR (CDCl3, 100 MHz)
d (ppm) 25.2,
26.6, 37.8, 44.0, 55.6, 57.7, 59.1, 69.6, 81.6, 85.4, 90.4,109.6,111.2126.6,
127.3,128.5,143.8. Anal. Calcd for C19H27NO5: C, 65.31; H, 7.79;N, 4.01.
Found: C, 65.46; H, 7.68; N, 4.12.
5. 4. 3. (2S, 4R, 6R) -2-((3aS, 4R, 6S, 6aS)-6-Me thoxy-2, 2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-6-phenylpiperidin-4-
ol (66). Yield 0.213 g, 61%; white solid; mp 87e89 ꢀC; Rf¼0.13
25
(CH2Cl2/Et2O 3:7); [
a]
þ7 (c 0.56, CHCl3). 1H NMR (400 MHz,
D
CDCl3) d (ppm) 1.25e1.34 (m, 3H), 1.43 (s, 3H), 1.46 (s, 3H), 1.58 (dd,
5.3.25. (2R,4R,6S)-2-(Benzyloxymethyl)-6-((3aR,4R,6R,6aR)-6-
methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7-oxa-
1-azabicyclo[2.2.1]heptane (63a). Yield 0.487 g, 83%;white solid;mp
1H, J¼2.5, 11.5 Hz), 1.90e2.13 (m, 3H), 2.17e2.22 (m, 1H), 3.11e3.18
(m,1H), 3.26 (s, 3H), 3.73 (dd,1H, J¼2.0,11.4 Hz), 3.86e3.94 (m, 2H),
4.55 (d, 1H, J¼5.9 Hz), 4.72 (dd, 1H, J¼3.5, 5.9 Hz), 4.84 (s, 1H),
7.25e7.28 (m, 1H), 7.31e7.35 (m, 2H), 7.39e7.45 (m, 2H). 13C NMR
100e102 ꢀC; Rf¼0.33 (Hex/EtOAc 4:6); [
a]
D
25 þ20 (c 0.98, MeOH). 1H
NMR (400 MHz, CDCl3)
d
(ppm) 1.24 (s, 3H),1.39 (s, 3H) ,1.47e1.55 (m,
(400 MHz, CDCl3) d (ppm) 24.7, 26.1, 29.7, 30.3, 25.5, 36.5, 43.2, 54.6,
2H),1.58e1.64(m, 2H), 2.83e2.89(m,1H), 3.00 (tt,1H, J¼6.2,12.3 Hz),
3.15 (dd, 1H, J¼6.2, 9.6 Hz), 3.29 (s, 3H), 3.58 (dd, 1H, J¼7.6, 9.5 Hz),
3.90 (dd,1H, J¼1.1, 10.8 Hz), 4.36e4.41 (m, 2H), 4.50 (d,1H, J¼6.0 Hz),
4.56(d,1H, J¼11.8 Hz), 4.77(t,1H, J¼4.8 Hz), 4.94(s,1H), 7.15e7.30 (m,
54.6, 59.3, 69.3, 79.4, 82.9, 85.1, 106.9, 112.4, 125.5, 126.9, 127.4,
128.5. Anal. Calcd for C19H27NO5: C, 65.31; H, 7.79; N, 4.01. Found: C,
65.48; H, 7.63; N, 4.23.
5H). 13C NMR (100 MHz, CDCl3)
d
(ppm) 25.4, 26.5, 35.8, 36.5 , 54.5,
5.4.4. (2S,4R,6R)-2-((3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-6-phenylpiperidin-4-
ol (67). Yield 0.238 g, 56%; yellow solid; mp 128e130 ꢀC; Rf¼0.25
67.0, 69.9, 73.1, 73.2, 78.8, 81.3, 85.3, 88.5, 108.9, 112.6, 127.4, 127.6,
128.2, 138.3 Anal. Calcd for C21H29NO6: C, 64.43; H, 7.47; N, 3.58.
Found: C, 64.57; H, 7.29; N, 3.73.
(CH2Cl2/Et2O 3:7); [
a
]
25 ꢁ8 (c 1.12, MeOH). 1H NMR (400 MHz, CDCl3)
D
d
(ppm) 1.07 (q, 1H, J¼11.4 Hz), 1.24 (s, 3H), 1.40e1.49 (m, 4H),
5.4. Cleavage of N,O-bond by reduction with Zn. Synthesis of
compounds 64e68. General procedure
1.54e1.58 (m, 2H), 1.97e2.03 (m, 2H), 3.07 (ddd, 1H, J¼2.1, 9.2,
11.2 Hz), 3.61 (dd, 1H, J¼2.2, 11.4 Hz), 3.63e3.72 (m, 1H), 3.86 (d, 1H,
J¼3.1 Hz), 4.01 (dd, 1H, J¼3.1, 9.1 Hz), 4.39 (d, 1H, J¼11.7 Hz), 4.56 (d,
1H, J¼3.8 Hz), 4.65 (d,1H, J¼11.7 Hz), 5.84 (d,1H, J¼3.8 Hz), 7.14e7.34
A solution of the corresponding bicycle (0.15 mmol) in a mixture
of THF (1.5 mL), acetic acid (1.5 mL), and water (3 mL) is treated
with Zn powder (1.3 g, 20 mmol) and the resulting mixture was
(m, 10H). 13C NMR (400 MHz, CDCl3)
d (ppm) 26.2, 26.7, 36.4, 43.1,
54.0, 59.3, 69.3, 71.8, 81.2, 81.9, 83.3, 104.8, 111.7, 126.9, 127.3, 127.9,

E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
6685
128.1, 128.4, 128.6, 134.6 (2C). Anal. Calcd for C25H31NO5: C, 70.57; H,
7.34; N, 3.29. Found: C, 70.68; H, 7.52; N, 3.41.
(d, 1H, J¼10.2 Hz), 4.27 (dd, 1H, J¼1.5, 5.0 Hz), 4.56e4.62 (m, 2H),
4.85 (t, 1H, J¼4.9 Hz), 5.47 (d, 1H, J¼5.0 Hz). 13C NMR (100 MHz,
CDCl3) d (ppm) 24.3, 25.0, 26.0, 26.0, 34.8, 37.0, 64.8, 65.0, 68.5, 69.7,
5.4.5. (2S,4R,6S)-2-((3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-6-phenylpiperidin-4-
70.6, 70.9, 71.1, 79.1, 96.5, 108.6, 108.9. Anal. Calcd for C17H27NO7: C,
57.13; H, 7.61; N, 3.92. Found: C, 57.28; H, 7.43; N, 4.19.
ol (68). Yield 0.264 g, 62%; yellow solid; mp 60e62 ꢀC; Rf¼0.1
25
(CH2Cl2/Et2O 3:7); [
a]
ꢁ18 (c 0.72, MeOH). 1H NMR (400 MHz,
5.5.3. ((2S,4R,6S)-6-(2-((3aR,5R,5aS,8aS,8bR)-2,2,7,7-
Tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:40,50-d]pyran-5-yl)
D
CDCl3) d (ppm) 1.26 (s, 3H),1.30e1.37 (m,1H),1.46 (s, 3H),1.79e1.85
(m, 2H), 2.11e2.16 (m, 2H), 3.39e3.45 (m, 2H), 3.86e3.93 (m, 2H),
4.33e4.39 (m, 2H), 4.53e4.62 (m, 3H), 5.88 (d, 1H, J¼3.8 Hz),
ethyl)-7-oxa-1-azabicyclo[2.2.1]heptan-2-yl)methanol
(71). Yield
25
0.305 g, 79%; sticky foam; Rf¼0.63 (CHCl3/MeOH 9:1); [
a]
D
ꢁ47 (c
7.15e7.33(m, 10H). 13C NMR (100 MHz, CDCl3)
d
(ppm) 26.4, 26.9,
1.05, CHCl3). 1H NMR (400 MHz, CDCl3)
d (ppm) 1.31 (s, 3H),1.34 (s,
34.0, 39.4, 49.6, 51.3, 65.0, 71.7, 81.8, 82.3, 104.8, 111.8, 126.6, 126.9,
127.8, 128.0, 128.5, 128.6, 137.1 (2C). Anal. Calcd for C25H31NO5: C,
70.57; H, 7.34; N, 3.29. Found: C, 70.39; H, 7.49; N, 3.38.
3H), 1.46 (s, 3H), 1.49 (s, 3H), 1.49e1.83 (m, 8H), 2.30e2.41 (bs, 1H),
2.54 (s, 1H), 2.75e2.83 (m, 1H), 2.95 (ddd, 1H, J¼4.4, 8.6, 12.8 Hz),
3.26e3.42(m,1H), 3.70(ddd,1H, J¼1.6, 3.6, 9.4 Hz), 4.12 (dd,1H, J¼1.7,
7.9 Hz), 4.27 (dd, 1H, J¼2.3, 5.1 Hz), 4.57 (dd,1H, J¼2.3, 7.9 Hz), 4.78 (t,
1H, J¼4.9 Hz), 5.52 (d, 1H, J¼5.1 Hz). 13C NMR (100 MHz, CDCl3)
5.5. Transformation of dioxolane ring into hydroxymethyl
group. Synthesis of compounds 69e71. General procedure
d(ppm)24.3,24.9,26.0, 26.0, 27.9, 33.3,34.7, 39.7, 65.0, 67.4, 67.8, 68.6,
70.5, 70.9, 73.0, 78.7, 96.5, 108.3, 109.0. Anal. Calcd for C19H31NO7: C,
59.20; H, 8.11; N, 3.63. Found: C, 59.09; H, 8.03; N, 3.58.
A solution of the corresponding dioxolane (0.28 mmol) in 66%
acetic acid (5 mL) was stirred at room temperature for 14 h and the
solvent was evaporated under reduced pressure. The residue was
taken-up in CH2Cl2 (30 mL) and washed with saturated aqueous
NaHCO3. The aqueous layer was extracted withCH2Cl2 (2ꢂ10 mL) and
the combined organic extracts were dried over magnesium sulfate,
and the solvent evaporated under reduced pressure to give the crude
diol, which was used in the next step without further purification.
A suspension of silica gel (660 mg) in CH2Cl2 (5.5 mL) was
treated with a solution of NaIO4 (90 mg) in water (0.7 mL) and the
resulting mixture was vigorously stirred at room temperature for
30 min at which time a solution of the diol obtained in the first step
in CH2Cl2 (0.6 mL) was added, and the resulting mixture was stirred
at room temperature for 1.5 h. After this time, the mixture was
filtered through a short pad of Celite and the filtrate was evaporated
under reduced pressure to give a residue, which was dissolved into
10:1 Et2O/H2O (0.55 mL). The resulting solution was treated with
NaBH4 (32 mg, 0.8 mmol) and the reaction mixture was stirred for
1 h at room temperature, at which time solid NH4Cl (146 mg,
2.7 mmol) was added. When the gas evolution finished, the solu-
tion was concentrated under reduced pressure and the residue was
dissolved in CHCl3 (25 mL) and washed with water (2ꢂ10 mL). The
organic layer was dried over magnesium sulfate and evaporated
under reduced pressure, to yield the crude product, which was
purified by column chromatography in the stated eluent.
5.6. Cleavage of N,O-bond by hydrogenation. Synthesis of
compounds 72 and 73. General procedure
A solution of the corresponding alcohol (0.15 mmol) in MeOH
(5 mL) was treated with a catalytic amount of Pearlamn’s catalyst
(Pd(OH)2/C) and the resulting mixture was hydrogenated at 100 bar
for 3 h. After this time, the mixture was filtered through a short pad
of Celite, and the filtrate evaporated under reduced pressure, to
obtain the crude product, which was purified by column chroma-
tography in the stated eluent.
5.6.1. (2R,4S,6R)-2-(Hydroxymethyl)-6-(2-((3aR,5R,5aS,8aS,8bR)-
2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:40,50-d]py-
ran-5-yl)ethyl)piperidin-4-ol (72). Yield 0.318 g, 82%; syrup;
25
Rf¼0.55 (CHCl3/MeOH 9:1); [
a
]
D
ꢁ9 (c 0.4, CHCl3). 1H NMR
(400 MHz, MeODþD2O)
d
(ppm) 1.24 (s, 3H), 1.30 (s, 3H), 1.30e1.40
(m, 5H), 1.41 (s, 3H), 1.54e1.65 (m, 3H), 1.82e1.88 (m, 1H), 1.97 (ddd,
1H, J¼1.9, 4.0, 11.0 Hz), 2.17 (ddd, 1H, J¼2.0, 4.2, 10.9 Hz), 4.76 (br s,
3H, ex. D2O), 3.05e3.16 (m, 2H), 3.51 (dd, 1H, J¼6.3, 11.8 Hz),
3.64e3.71 (m, 2H), 3.74 (tt, 1H, J¼4.4, 11.2 Hz), 4.08 (dd, 1H, J¼1.8,
7.9 Hz), 4.25 (dd, 1H, J¼2.4, 5.1 Hz), 4.52 (dd, 1H, J¼2.3, 7.9 Hz), 5.40
(d, 1H, J¼4.2 Hz). 13C NMR (100 MHz, MeOD)
d (ppm) 24.6, 24.1,
26.4, 27.4, 31.1, 35.4, 38.6, 57.1, 58.7, 63.1, 66.8, 69.0, 70.9, 72.3 (2C),
74.1, 98.0, 109.8, 110.3. Anal. Calcd for C19H33NO7: C, 58.90; H, 8.58;
N, 3.61. Found: C, 59.15; H, 8.67; N, 3.46.
5.5.1. ((2R,4S,6R)-6-(2-((3aR,5R,5aS,8aS,8bR)-2,2,7,7-
Tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:40,50-d]pyran-5-yl)
ethyl)-7-oxa-1-azabicyclo[2.2.1]heptan-2-yl)methanol
0.316 g, 82%; sticky foam; Rf¼0.1 (Hex/EtOAc 1:1); [
CHCl3). 1H NMR (400 MHz, CDCl3)
(69). Yield
5.6.2. (2S,4R)-2-(Hydroxymethyl)-6-(2-((3aR,5R,5aS,8aS,8bR)-
2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:40,50-d]py-
ran-5-yl)ethyl)piperidin-4-ol (73). Yield 0.333 g, 86%; syrup;
a
]
25 ꢁ50 (c 0.97,
D
d
(ppm) 1.31 (s, 3H), 1.33 (s, 3H),
25
1.44 (s, 3H), 1.50 (s, 3H), 1.52e1.80 (m, 8H), 2.81 (ddd, 1H, J¼4.6, 7.2,
14.2 Hz), 2.94 (ddd, 1H, J¼4.3, 8.6, 13.1 Hz), 3.29e3.39 (m, 2H),
3.68e3.73 (m, 2H), 4.12 (dd, 1H, J¼1.8, 7.9 Hz), 4.27 (dd, 1H, J¼2.3,
5.1 Hz), 4.56 (dd, 1H, J¼2.3, 7.9 Hz), 4.78 (t, 1H, J¼4.9 Hz), 5.50 (d,
Rf¼0.19 (Hex/EtOAc 7:3); [
a
]
ꢁ25 (c 0.95, MeOH). 1H NMR
D
(400 MHz, MeODþD2O)
d
(ppm) 1.34 (s, 6H), 1.41 (s, 3H), 1.51 (s,
3H), 1.56e1.88 (m, 6H), 2.01e2.08 (m, 1H), 2.18e2.23 (m, 1H),
3.09e3.19 (m, 2H), 3.58 (dd, 1H, J¼6.9, 11.6 Hz), 3.73e3.78 (m, 3H),
4.18 (dd, 1H, J¼1.7, 7.9 Hz), 4.36 (dd, 1H, J¼2.4, 5.1 Hz), 4.63 (dd, 1H,
J¼2.3, 7.9 Hz), 4.76 (bs, 3H, ex. D2O), 5.50 (d, 1H, J¼5.1 Hz). 13C NMR
1H, J¼5.1 Hz). 13C NMR (100 MHz, CDCl3)
d (ppm) 24.4, 24.9, 26.0
(2C), 27.0, 32.4, 34.7, 39.5, 64.9, 66.9, 67.2, 68.7, 70.4, 70.8, 72.5, 78.7,
96.5, 108.2, 108.9. Anal. Calcd for C19H31NO7: C, 59.20; H, 8.11; N,
3.63. Found: C, 59.39; H, 7.97; N, 3.49.
(100 MHz, MeOD)
d (ppm) 24.6, 25.1, 26.4, 26.7, 30.6, 35.1, 38.5,
56.4, 58.8, 62.8, 66.6, 68.5, 71.9, 72.3 (2C), 74.1, 98.0, 109.9, 110.4.
Anal. Calcd for C19H33NO7: C, 58.90; H, 8.58; N, 3.61. Found: C, 59.15;
H, 8.41; N, 3.87.
5 . 5 . 2 . ( ( 2 S , 4 S , 6 R ) - 6 - ( ( 3 a R , 5 R , 5 a S , 8 a S , 8 b R ) - 2 , 2 , 7 , 7 -
Tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:40,50-d]pyran-5-yl)-
7-oxa-1-azabicyclo[2.2.1]heptan-2-yl)methanol (70). Yield 0.286 g,
5.7. Synthesis of unprotected glycomimetics. Synthesis of
compounds (74e78). General procedure
25
80%; sticky foam; Rf¼0.12 (Hex/EtOAc 4:6); [
a
]
D
ꢁ38 (c 0.79,
CHCl3). 1H NMR (400 MHz, CDCl3)
d
(ppm) 1.30 (s, 3H), 1.34 (s, 3H),
1.39e1.45 (s, 4H), 1.48 (s, 3H), 1.64 (dd, 1H, J¼7.9, 11.6 Hz), 1.71 (dd,
1H, J¼7.8, 12.1 Hz), 1.82e1.89 (m, 2H), 3.07 (ddd, 1H, J¼4.8, 8.1,
12.8 Hz), 3.17 (ddd, 1H, J¼4.3, 7.8, 10.2 Hz), 3.39e3.40 (m, 2H), 3.51
A suspension of the corresponding bicycle (0.3 mmol) in TFA/
water 9:1 (10 mL) was stirred at room temperature for 4 h. Then the
solvent was evaporated, and the residue solved in MeOH (5 mL). A

6686
E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
catalytic amount of Pd(OH)2 was added, and the mixture was hy-
drogenated at 100 bar for 3 h. After this time, the mixture was fil-
tered through a short pad of Celite, and the solvent evaporated
under reduced pressure, to obtain the crude product, which was
56.7, 61.7, 61.7, 64.8, 64.9, 67.1, 67.7, 68.4, 68.9, 69.2, 69.5, 71.1, 71.5,
72.0, 92.3, 96.4. HRMS (ESIþ) m/z calcd for C12H23NNaO8 (MþNaþ):
332.1310; found: 332.1311. Anal. Calcd for C12H23NO8: C, 46.60; H,
7.49; N, 4.53. Found: C, 46.71; H, 7.61; N, 4.38.
purified by semipreparative HPLC (Atlantis dC18 OBD
5 mM
18ꢂ100 mm column; flow. 12.5 mL/min; H2O), to give the pure
products (mixture of anomers) as very hygroscopic foams. The
detection was carried out by an UPLC-ELSD system, in the same
conditions used in the purification step.
5.7.5. (3R,4S,5R,6R)-6-(2-((2S,4R,6S)-6-((S)-1,2-Dihydroxyethyl)-4-
hydroxypiperidin-2-yl)ethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol
25
(78). Yield 0.079 g, 78%; white foam; [
a]
þ27 (c 0.99, H2O). 1H
D
NMR (500 MHz, D2O), mixture of anomers:
d (ppm) 1.27e1.39 (m,
1H), 1.43e1.61 (m, 3.6H), 1.64e1.82 (m, 3.5H), 2.01e2.07 (m, 1H),
2.18e2.28 (m, 1H), 3.16e3.27 (m, 1H), 3.28e3.38 (m, 1.7H),
3.49e3.58 (m, 3.7H), 3.65e3.93 (m, 1.7H), 3.82e3.93 (m, 2.5H), 4.44
5.7.1. (3R,4S,5R,6R)-6-(((2S,4S,6R)-6-((S)-1,2-Dihydroxyethyl)-4-
hydroxypiperidin-2-yl)methyl)tetrahydro-2H-pyran-2,3,4,5-tetraol
(74). Yield 0.063 g, 65%; white foam; [
(500 MHz, D2O)
a
]
D
25 þ26 (c 1, H2O). 1H NMR
(d, 0.7H, J¼7.9 Hz,
b
anomer), 5.12 (d, 0.30H, J¼3.8 Hz,
a anomer).
(ppm) 25.6, 28.7,
d
(ppm), mixture of anomers: 1.34e1.46 (m, 2H),
13C NMR (125 MHz, D2O), mixture of anomers:
d
1.86e2.1 (m, 3.1H), 2.17e2.22 (m, 1H), 3.21e3.25 (m, 1H), 3.36 (dd,
0.7H, J¼7.9, 9.9 Hz), 3.38e3.48 (m, 1H), 3.52 (dd, 0.7H, J¼3.3,
9.9 Hz), 3.56e3.63 (m, 1H), 3.63e3.68 (m, 2.2H), 3.70e3.79 (m,
2.2H), 3.87 (ddd, 1H, J¼4.3, 11.0, 15.5 Hz), 4.15 (dd, 0.3H, J¼4.1,
30.1, 36.0, 55.6, 55.7, 57.2, 57.2, 61.7, 65.3, 68.2, 69.2, 69.4, 70.0, 70.4,
70.8, 71.7, 72.9, 74.0, 92.2, 96.3. HRMS (ESIþ) m/z calcd for
C14H28NO8 (MþHþ): 338.1809; found: 338.1824. Anal. Calcd for
C14H27NO8: C, 49.84; H, 8.07; N, 4.15. Found: C, 50.03; H, 8.16; N,
4.34.
8.1 Hz), 4.46 (d, 0.7H, J¼7.9 Hz,
b
anomer), 5.13 (d, 0.3H, J¼3.7 Hz,
a
anomer). 13C NMR (125 MHz, D2O), mixture of anomers:
d (ppm)
25.6, 28.7, 30.1, 36.0, 55.6, 55.7, 57.2, 57.2, 61.7, 65.3, 68.2, 69.2, 69.4,
70.0, 70.4, 70.8, 71.8, 72.9, 74.0, 92.2, 96.3. HRMS (ESIþ) m/z calcd
for C13H25NNaO8 (MþNaþ): 346.1467; found: 346.1475. Anal. Calcd
for C13H25NO8: C, 48.29; H, 7.79; N, 4.33. Found: C, 48.49; H, 7.93; N,
4.06.
Acknowledgements
This study was supported by the Ministerio de Ciencia e
ꢀ
Innovacion (MICINN) and FEDER Program (Madrid, Spain, project
ꢀ
CTQ2010-19606) and the Gobierno de Aragon (Zaragoza, Spain,
Bioorganic Chemistry Group. E-10). E.M. thanks MEC for a FPU
predoctoral grant.
5.7.2. (3S,4R,5S,6S)-6-(2-((2R,4S,6R)-6-((S)-1,2-Dihydroxyethyl)-4-
hydroxypiperidin-2-yl)ethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol
25
(75). Yield 0.074 g, 73%; white foam; [
a
]
þ27 (c 0.99, H2O). 1H
Supplementary data
D
NMR (500 MHz, D2O), mixture of anomers:
d (ppm) 1.23e1.46 (m,
2H), 1.51e1.96 (m, 4.45H), 2.05e2.15 (m, 1H), 2.19e2.30 (m, 1H),
3.15e3.26 (m, 1.9H), 3.35 (dd, 0.75H, J¼7.9, 9.9 Hz), 3.49e3.63 (m,
2.70H), 3.63e3.70 (m, 2.5H), 3.82e3.94 (m, 1.45H), 4.43 (d, 0.75H,
ORTEP diagrams corresponding to X-ray analyses of compounds
34, 45b, 46a, 46b, 48a, 49a, 51b, 61a, 66. 1H and 13C-APT NMR
spectra of compounds 24e36, 38e42, 45e78. HRMS mass spectra
of compounds 74e78. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2012.05.126. These data include MOL files and InChiKeys of the
most important compounds described in this article.
J¼7.9 Hz,
b
anomer), 5.13 (d, 0.25H, J¼3.7 Hz,
a
anomer). 13C NMR
(125 MHz, D2O), mixture of anomers:
d
(ppm) 25.6, 28.7, 30.1, 36.0,
55.6, 55.7, 57.2, 57.2, 61.7, 65.3, 68.2, 69.2, 69.4, 70.0, 70.4, 70.8, 71.7,
72.9, 74.0, 92.2, 96.3. HRMS (ESIþ) m/z calcd for C14H27NNaO8
(MþNaþ): 360.1580; found: 360.1585. Anal. Calcd for C14H27NO8: C,
49.84; H, 8.07; N, 4.15. Found: C, 49.66; H, 8.25; N, 3.97.
References and notes
1. Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay, P., Eds.;
Wiley-VCH: Weinheim, 2000.
5.7.3. (3S,4R,5S,6S)-6-(2-((2R,4S,6R)-4-Hydroxy-6-((2R,3R,4S,5R)-
3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)piperidin-2-yl)ethyl)
tetrahydro-2H-pyran-2,3,4,5-tetraol (76). Yield 0.079 g, 62%; white
2. Gabius, H.-J. The Sugar Code; Wiley-Blackwell: Weinheim, 2000.
3. Trincone, A.; Giordano, A. Curr. Org. Chem. 2006, 10, 1163e1193; (a) Vocadlo, D.
J.; Withers, S. G. In Glycosidase-Catalyzed Oligosaccharide Synthesis; Ernst, B.,
Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Vol. 2; (b)
Qian, X.; Sujino, K.; Palcic, M. M.; Ratcliffe, R. M. J. Carbohydr. Chem. 2002, 21,
911e942.
4. (a) Gloster, T. M.; Davies, G. J. Org. Biomol. Chem. 2010, 8, 305e320; (b) Mohan,
S.; Pinto, B. M. Carbohydr. Res. 2007, 342, 1551e1580; (c) Lillelund, V. H.; Jensen,
H. H.; Liang, X. F.; Bols, M. Chem. Rev. 2002, 102, 515e553; (d) Tatsuta, K. Pure
Appl. Chem. 1996, 68, 1341e1346.
5. (a) Iminosugar: From Synthesis to Therapeutic Applications; Compain, P., Martin,
O. R., Eds.; Wiley: Chichester, UK, 2007; (b) Iminosugars as Glycosidase In-
hibitors: Nojirimycin and Beyond; Stutz, A. E., Ed.; Wiley-VCH: Weinheim, Ger-
many, 1999; (c) Pearson, M. S. M.; Mathe-Allainmat, M.; Fargeas, V.; Lebreton, J.
Eur. J. Org. Chem. 2005, 2159e2191; (d) Nishimura, Y. Heterocycles 2006, 67,
461e488; (e) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1645e1680; (f) Winchester, B. G. Tetrahedron: Asymmetry
2009, 20, 645e651; (g) Cipolla, L.; Ferla, B. L.; Gregori, M. Comb. Chem. High
Throughput Screen. 2006, 9, 571e582.
foam; [
of anomers:
a
]
25 þ36 (c 1.05, MeOH). 1H NMR (500 MHz, CDCl3), mixture
D
d
(ppm) selected signals 1H NMR (500 MHz, CDCl3)
d
(ppm) 4.44 (d, 1H, J¼7.9 Hz,
anomer), 4.53 (d, 0.37H, J¼7.3 Hz,
anomer), 5.19 (d, 0.32H, J¼3.7 Hz,
0.23H, J¼2.8 Hz, anomer), 5.21 (d, 0.3H, J¼2.6 Hz,
NMR (125 MHz, CDCl3), mixture of anomers:
anomer), 94.3 ( anomer), 94.3 ( anomer), 94.4 (
anomer), 98.7 ( anomer), 98.8, 98.9 (
b
anomer), 4.51 (d, 0.45H, J¼7.7 Hz,
anomer), 5.12 (d, 0.3H,
anomer), 5.21 (d,
anomer). 13
C
b
b
J¼3.8 Hz,
a
a
a
a
d
(ppm) 94.2 (
b
a
b
a
b
b anomer), 98.7 (
a
anomer). HRMS (ESIþ) m/z
calcd for C17H31NNaO11 (MþNaþ): 448.1789; found: 448.1786. Anal.
Calcd for C17H31NO11: C, 47.99; H, 7.34; N, 3.29. Found: C, 48.17; H,
7.14; N, 3.41.
6. (a) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077e3092; (b) Ka-
jimoto, T.; Node, M. Synthesis 2009, 3179e3210; (c) Compain, P.; Martin, O. R.
Curr. Top. Med. Chem. 2003, 3, 541e560; (d) Whalen, L. J.; Greenberg, W. A.;
Mitchell, M. L.; Wong, C.-H. In Iminosugar: From Synthesis to Therapeutic Ap-
plications; Compain, P., Martin, O. R., Eds.; Wiley: Chichester, UK, 2007;
pp 153e176; (e) Merino, P.; Tejero, T.; Delso, I.; Hurtado-Guerrero, R.; Gomez-
SanJuan, A.; Sadaba, D. Mini-Rev. Med. Chem., in press.
5.7.4. (3R,4S,5R,6R)-6-((2R,4S,6S)-6-((S)-1,2-Dihydroxyethyl)-4-
hydroxypiperidin-2-yl)tetrahydro-2H-pyran-2,3,4,5-tetraol
(77). Yield 0.063 g, 68%; white foam; [
a]
25 þ18 (c 1, H2O). 1H NMR
D
(500 MHz, D2O), mixture of anomers:
d
(ppm) 1.28e1.42 (m, 2H),
2.00e2.07 (m, 1H), 2.18e2.26 (m, 1H), 3.10e3.27 (m, 1H), 3.30e3.40
(m, 1H), 3.44 (dd, 1H, J¼7.9, 10.0 Hz), 3.56 (dd, 0.6H, J¼3.4, 10.0 Hz),
3.58e3.67 (m, 2.4H), 3.75e3.78 (m, 0.6H), 3.78e3.89 (m, 2H),
3.99e4.04 (m, 1H), 4.11e4.14 (s, 0.4H), 4.53 (d, 0.6H, J¼7.9 Hz,
7. (a) Wong, C. H. Acc. Chem. Res. 1999, 32, 376e385; (b) D’Alonzo, D.; Guaragna,
A.; Palumbo, G. Curr. Med. Chem. 2009, 16, 473e505; (c) Carbohydrate Mimics;
Chapleur, Y., Ed.; Wiley: New York, NY, 1998; (d) Ernst, B.; Magnani, J. L. Nat. Rev.
Drug Discov. 2009, 8, 661e677; (e) Bernardi, A.; Cheshev, P. Chem.dEur. J. 2008,
b
anomer), 5.22 (d, 0.4H, J¼2.9 Hz,
a
anomer). 13C NMR (125 MHz,
(ppm) 30.5, 30.6, 32.5, 32.5, 56.4, 56.5,
ꢁ
14, 7434e7441; (f) Pistara, V.; Rescifina, A.; Punzo, F.; Greco, G.; Barbera, V.;
D2O), mixture of anomers:
d
Corsaro, A. Eur. J. Org. Chem. 2011, 7278e7287.

E. Marca et al. / Tetrahedron 68 (2012) 6674e6687
6687
8. Merino, P.; Delso, I.; Marca, E.; Tejero, T.; Matute, R. Curr. Chem. Biol. 2009, 3,
253e271.
20. Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetrahedron Lett. 2001, 42,
6503e6505.
9. For 1: Yoshikuni, Y.; Ezure, Y.; Seto, T.; Mori, K.; Watanabe, M.; Enomoto, H.
Chem. Pharm. Bull. 1989, 37, 106e109; For 2: Asano, N.; Oseki, K.; Kaneko, E.;
Matsui, K. Carbohydr. Res. 1994, 258, 255e266.
10. Kato, A.; Kato, N.; Kano, E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto, T.; Banba, Y.;
Ouchi, H.; Takahata, H.; Asano, N. J. Med. Chem. 2005, 48, 2036e2044.
11. Liotta, L. J.; Bernotas, R. C.; Wilson, D. B.; Ganem, B. J. Am. Chem. Soc. 1989, 111,
783e785.
12. Numao, S.; Damager, I.; Li, C.; Wrodnigg, T. M.; Begum, A.; Overall, C. M.; Brayer,
G. D.; Withers, S. G. J. Biol. Chem. 2004, 279, 48282e48291.
13. Robina, I.; Vogel, P. Synthesis 2005, 675e702.
14. Vogel, P.; Gerber-Lemaire, S.; Juillerat-Jeanneret, L. In Iminosugar: From Syn-
thesis to Therapeutic Applications; Compain, P., Martin, O. R., Eds.; Wiley: Chi-
chester, UK, 2007; pp 87e130.
21. ASIS: Aromatic Solvent Induced Shift. See: Aurich, H.-G.; Franzke, M.; Kessel-
heim, H. D. Tetrahedron 1992, 48, 663e668.
22. (a) Wolfe, S.; Akuche, C.; Ro, S.; Wilson, M.-C.; Kim, C.-K.; Shi, Z. Can. J. Chem.
2003, 81, 915e936; (b) Polonski, T.; Chimiak, A. J. Org. Chem. 1976, 41,
2092e2095; (c) Hercheid, J. M.; Ottenheijm, H. C. J. Tetrahedron Lett. 1978,
5143e5146; (f) Hu, J.; Miller, M. J. J. Am. Chem. Soc. 1997, 119, 3462e3468.
23. The authors have deposited the atomic coordinates for the structures with the
Cambridge Crystallographic Data Centre. Deposition numbers are as follows: 34,
CCDC 876853; 45b, CCDC 749563; 46a, CCDC 749564; 46b, CCDC 749565; 48a
CCDC 876854; 49a, CCDC 749567;51b, CCDC 876855; 61a, CCDC 876856 and 66,
CCDC 749568. The coordinates can be obtained, on request, from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
24. Merino, P.; Mannucci, V.; Tejero, T. Tetrahedron Lett. 2007, 48, 3385e3388; (b)
Delso, I.; Tejero, T.; Goti, A.; Merino, P. J. Org. Chem. 2011, 76, 4139e4143.
25. Merino, P.; Mannucci, V.; Tejero, T. Eur. J. Org. Chem. 2008, 3943e3959.
26. (a) Hoffmann, R. W.; Endesfelder, A. Liebigs Ann. Chem. 1986, 1823e1836; (b)
Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1988, 53, 1957e1965.
15. Merino, P.; Franco, S.; Merchan, F. L.; Romero, P.; Tejero, T.; Uriel, S. Tetrahedron:
Asymmetry 2003, 14, 3731e3743.
16. For a preliminary communication see: Marca, E.; Delso, I.; Tejero, T.; Vazquez, J.
T.; Dorta, R. L.; Merino, P. Tetrahedron Lett. 2009, 50, 7152e7155.
17. (a) Merino, P. In Science of Synthesis, Knowledge Updates; Schaumann, E., Ed.;
George Thieme: Stuttgart, 2011; Vol. 2010/4, pp 325e403; (b) Merino, P. In
Science of Synthesis; Bellus, D., Padwa, A., Eds.; George Thieme: Stuttgart, 2004;
Vol. 27, pp 511e580.
18. (a) Merino, P.; Mannucci, V.; Tejero, T. Tetrahedron 2005, 61, 3335e3347; (b)
Merino, P.; Delso, I.; Mannucci, V.; Tejero, T. Tetrahedron Lett. 2006, 47,
3311e3314; (c) Delso, I.; Tejero, T.; Goti, A.; Merino, P. Tetrahedron 2010, 66,
1220e1227; For a review see: (d) Merino, P.; Tejero, T.; Delso, I.; Mannucci, V.
Curr. Org. Synth. 2005, 2, 479e498.
27. Jennings, W. B.; Boyd, L. C.; Waring, D. R. J. Chem. Soc., Perkin Trans. 2 1976,
610e613.
28. (a) Ali, S. A.; Almuallem, H. A. Tetrahedron 1992, 48, 5273e5282; (b) Boyle, L.
W.; Peagram, M. J.; Whitham, G. H. J. Chem. Soc. B 1971, 1728e1733; (c) Tamura,
O.; Yamaguchi, T.; Noe, K.; Sakamoto, M. Tetrahedron Lett. 1993, 34, 4009e4010;
(d) Piotrowska, D. G. Tetrahedron Lett. 2006, 47, 5363e5366; (e) Ondrus, V.;
Orsag, M.; Fisera, L.; Pronayova, N. Tetrahedron 1999, 55, 10425e10436.
~
29. (a) Roldos, V.; Canada, F. J.; Jimenez-Barbero, J. ChemBioChem 2011,12, 990e1005;
(b) Haselhorst, T.; Lamerz, A. C.; von Itzstein, M. Methods Mol. Biol. 2009, 534,
375e396; (c) Viegas, A.; Manso, J.; Nobrega, F. L.; Cabrita, E. J. J. Chem. Educ. 2011,
88, 990e994; (d) Krishnan, V. V. Curr. Anal. Chem. 2005, 1, 307e320.
19. Diez-Martinez, A.; Gultekin, Z.; Delso, I.; Tejero, T.; Merino, P. Synthesis 2010,
678e688.