Cycloaddition reactions on activated exo-glycals

Article abstract of DOI:10.1016/j.tetasy.2005.06.027

Cycloaddition reactions of activated exo-glycals and nitrones proceeded only under microwave activation, with excellent facial selectivities on furanoglycosylidenes and good stereocontrol on the nitrone producing only two diastereomeric spiroisoxazolidine

Full text of DOI:10.1016/j.tetasy.2005.06.027

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2459–2474
Cycloaddition reactions on activated exo-glycals
a
a,
b
a,
*
*
´
Gerald Enderlin, Claude Taillefumier, Claude Didierjean and Yves Chapleur
aGroupe SUCRES, UMR 7565 CNRS, Universite´ Henri Poincare´ Nancy 1, BP 239 F-54506 Nancy-Vandoeuvre, France
bGroupe Biostructures, LCM3B, UMR 7036 CNRS, Universite´ Henri Poincare´ Nancy 1, Institut de Chimie et Physique
Mole´culaires et Biomole´culaires, BP 239 F-54506 Nancy-Vandoeuvre, France
Received 24 May 2005; accepted 15 June 2005
Abstract—Cycloaddition reactions of activated exo-glycals and nitrones proceeded only under microwave activation, with excellent
facial selectivities on furanoglycosylidenes and good stereocontrol on the nitrone producing only two diastereomeric spiroisoxazol-
idines. a/b-Spiro sugar-isoxazolidines are obtained from pyrano exo-glycals. The cycloaddition reaction with nitrile oxide proceeds
at room temperature and gives open-chain isoxazoles due to facile b-elimination of the sugar ring oxygen on the intermediate
isoxazoline ring system. All the heterocycles obtained this way can be regarded as nucleoside analogues.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Wittig olefination of sugar lactones.7a,b Several other
approaches to exo-glycals have been reported, especially
over the last five years, using stepwise procedures,8a–g
or Ramberg–Ba¨cklund rearrangements.9a,b
Cycloaddition reactions have been widely explored as
important carbon-carbon bond forming reactions. In
particular, the 1,3-dipolar cycloaddition of nitrones
and nitrile oxides is amongst the most widely studied
reaction forming one carbon–carbon bond and one car-
bon–oxygen bond. High regioselectivities are generally
observed with activated double bonds, the carbon–oxy-
gen bond being formed at the c-position. The N–O bond
cleavage of these heterocycles provides an entry to other
classes of compounds such as 1,3-amino alcohols.
Numerous applications of the nitrone–olefin cycloaddi-
tion (NOC)1a,b or nitrile oxide–olefin cycloaddition
(INOC) can be found in the literature.2a,b Many differ-
ent olefins have been tested in this type of cycloaddition
including carbohydrate-derived olefins.3a–c
INOC or NOC reaction of exo-glycals are supposed to
yield anomeric spiroisoxazoli(di)ne derivatives, which
can be regarded as spironucleoside analogues10 or as ste-
reodiverse scaffolds.11 One example of bioactive spiro-
heterocyclic sugar derivatives is hydantocidin,12–15
which is believed to be a mimic of adenosine.16 More-
over some isoxazoli(di)ne derivatives with antibacterial
and antifungal properties have recently been reported.17
RajanBabu was the first to report the reaction of an
anomeric exo-methylene sugar with benzonitrile oxide
leading with high regio- and stereocontrol to a spiro-
isoxazoline.18 Some examples of an NOC reaction of
5,6- and 3,4-unsaturated sugars have been reported
and found useful for the synthesis of carbocycles via
the Ferrier carbocyclisation.19 More recently, further
examples of nitrile oxide cycloaddition with substituted
exo-glycals has been reported by Lieberknecht.20 The
cycloaddition of glyoxylic nitrones and nitrile oxide with
1-methylene exo-glycals has also been reported by Ike-
gami et al.21 while our work was in progress. Subsequent
work by the same authors on the thermal cycloaddition
of nitrones on exo-methylene sugars recently
appeared.22 To the best of our knowledge, activated
exo-glycals, recently introduced by our group,7a have
never been considered in cycloaddition reactions.23
exo-Glycals are olefinic sugars with an exocylic carbon–
carbon double bond at the anomeric centre. This new
class of compounds did not attract much attention until
recently.4 Almost at the same time, two general
approaches to such compounds from lactones were
proposed by us for the synthesis of anomeric dichloro-
olefins,5a–c and by Wilcox using Tebbe methylenation
for exo-methylene glycals.6 More recently, we reported
the facile formation of activated exo-glycals using the
*
Corresponding authors. Tel.: +33 383 68 47 73; fax: +33 383 68 47
80; e-mail: claude.taillefumier@sucres.uhp-nancy.fr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.027

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G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
Herein, we report the details of our first results obtained
in nitrones and nitrile oxides cycloadditions on this par-
ticular class of exo-glycals having an usual capto-dative
substituent arrangement on the double bond.24
2. Results
2.1. Nitrone–exo-glycal cycloadditions
The readily available E exo-glycal 17a was chosen as the
model compound. Reaction with nitrone 2 was first
attempted under standard thermal conditions, but no
reaction occurred even in refluxing toluene. Microwave
activation (MA) in a focussed microwave oven, ensured
a clean reaction of nitrone 2 with 1 (E isomer), giving a
mixture of two isomers in a 4:1 ratio and 50% yield. On
the basis of previous studies from our group,25 all reac-
tions on the olefinic sugar 1 took place from the less hin-
dered b face. Attack of the nitrone was also assumed to
take place from this face. The C-4 configuration in the
isoxazolidine ring being normally dictated by the geom-
etry of the starting olefin, the two compounds obtained
were supposed to be the C-3 epimers 6 and 7 resulting
from endo/exo attacks of the nitrone. Determination
of the absolute configuration at C-3 by the J3,4 coupling
constant measurement proved to be difficult due to very
close values, 7.0 and 8.0 Hz. NOE difference spectro-
scopy, showing no interaction between H4 and H9 in
both isomers, as expected from the stereochemistry
depicted on Scheme 1, supported the hypothesis of
structure 6 and 7. X-ray analysis26 of the major isomer
6 obtained as a crystalline material showed a trans-ori-
entation of the two substituents at C-3 and C-4 of the
isoxazolidine ring and also confirmed the C-4 and C-5
configurations (Fig. 1). As expected, the E geometry of
1 gives an (R)-configuration at C-4 and the configura-
tion at C-5 results from attack of the less hindered b face
Figure 1. ORTEP diagram corresponding to the X-ray molecular
structure of compound 6.
of olefin 1. As for the trans-relationship between the two
substituents at C-3 and C-4, this can be the result
of cycloaddition in the endo mode with the Z nitrone
or exo mode with the E nitrone (see below). Nitrone 3
was also submitted to cycloaddition under microwave
activation with olefin 1. As shown by 1H NMR of
the crude, the presence of only two isomers was undeni-
able but they were obtained as an inseparable mixture.
From our previous observations, structures 8 and 9 were
proposed for these two isomers.
The reaction of the unsubstituted nitrone 5 with 1 under
microwave activation both for the formation of the nit-
rone and the subsequent cycloaddition gave only one
isomer 10 in 75% yield (Table 1, entry 3). This confirmed
the initial hypothesis that cycloadditions with nitrones 2
and 3 gave two isoxazolidines, epimeric at C-3, rather
than an anomeric mixture.
Table 1. Results of cycloadditions of nitrones with furano-exo-glycals
1, 11, 12 and 13
R1
H
Entry Starting
exo-glycals
Nitrones Products trans/cis Yield
O
O
Ratio
(%)
i
O
O
+
N
OMe
O
1
1
2
3
5
3
2
5
3
2
4
5
3
2
4
5
6, 7
8, 9
10
4:1
2:1
—
2:1
1.2:1
—
2.3:1
1.7:1
1:1
—
7.4:1
6:1
50
76
75
80
65
84
86
58
89
92
94
57
96
89
R2
O
O
2
3
1
1
2 R1 = nPr, R2 = Me
3 R1 = Ph, R2 = Me
1
4
5
6
7
8
9
10
11
12
13
14
11
11
11
12
12
12
12
13
13
13
13
14, 15
16, 17
18
4 R1 = nPr, R2 = CH2Ph
5 R1 = H, R2 = CH2Ph
19, 20
21, 22
23, 24
25
R1
O
4
H
N
5'
O
R2
4'
3
7
R3
O
26, 27
28, 29
30, 31
32
9
O
COOMe
O
O
2.4:1
—
6 R1 = Me, R2 = nPr, R3 = H
7 R1 = Me, R2 = H, R3 = nPr
8 R1 = Me, R2 = Ph, R3 = H
9 R1 = Me, R2 = H, R3 = Ph
The same set of reactions was carried out with the four
nitrones 2, 3, 4 and 5 on the Z isomer 11 and the two
ribo derivatives 12 and 13 (Scheme 2). The latter were
readily obtained from the corresponding lactones
according to our previously described procedure.25
10 R1 = CH2Ph, R2 = R3 = H
Scheme 1.

G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
2461
MeO
O
MeO
O
O
MOMO
MOMO
H
O
O
O
OMe
O
H
H
O
O
O
O
O
O
O
11
12
13
R1
R1
R1
1
O
1
O
1
O
MOMO
MOMO
H
4'
N
N
N
5'
O
7
O
7
O
R3
R3
R3
5
5
7
5
R2
R2
R2
O
3
3
H
H
3
4
4
4
8 9
8 9
O
8 9
COOMe
COOMe
O
COOMe
O
O
O
O
O
14 R1 = Me, R2 = Ph, R3 = H
15 R1 = Me, R2 = H, R3 = Ph
16 R1 = Me, R2 = nPr, R3 = H
17 R1 = Me, R2 = H, R3 = nPr
18 R1 = Bn, R2 = R3 = H
19 R1 = Me, R2 = H, R3 = Ph
20 R1 = Me, R2 = Ph, R3 = H
21 R1 = Me, R2 = H, R3 = nPr
22 R1 = Me, R2 = nPr, R3 = H
23 R1 = Bn, R2 = H, R3 = nPr
24 R1 = Bn, R2 = nPr, R3 = H
25 R1 = Bn, R2 = R3 = H
26 R1 = Me, R2 = Ph, R3 = H
27 R1 = Me, R2 = H, R3 = Ph
28 R1 = Me, R2 = nPr, R3 = H
29 R1 = Me, R2 = H, R3 = nPr
30 R1 = Bn, R2 = nPr, R3 = H
31R1 = Bn, R2 = H, R3 = nPr
32 R1 = Bn, R2 = R3 = H
Scheme 2.
In all cases, only two isomers were obtained. The results
are summarised in Table 1. The first conclusion drawn
from these studies is the excellent facial selectivity on
the olefin. In each case only one anomer was isolated
for each isomer. In the case of exo-glycals 1 and 11,
the a face being sterically congested, it is obvious that
nitrone attack occurred from the b face. This is less evi-
dent for the ribo derivatives 12 and 13 where both faces
of the lactone are substituted. Previous results from our
group showed that reactions on such olefinic bonds usu-
ally gave mixture of anomers.7,25,27 Nevertheless, the ste-
ric hindrance induced by the dioxolane group is far
larger than that induced by the MOM protected
hydroxymethyl at C4, thus only b-anomers were
formed. In all cases, (Table 1, entries 6, 10 and 14) the
reaction of exo-glycals with nitrone 5 gave, in very good
yield, a single cycloadduct resulting from attack on the
less hindered face.
Figure 2. ORTEP diagram corresponding to the X-ray molecular
structure of compound 20.
˚
In all this series, structural evidence for the b configura-
tion at the anomeric carbon (C-5) was first supported by
X-ray crystal structure of the ribo-isoxazolidine deriva-
tive 20 (Fig. 2)28. The stereochemical assignments of
these structures were also achieved by NOE difference
measurements. H4–H9 proton interaction is an indica-
tor of the C-4 configuration. When starting from Z
exo-glycals, an NOE effect is expected for both a- and
b-anomers. Thus, molecular modelling of 27 and its
a-anomer showed a H4–H9 distance of about 2.8 and
this distance was estimated at 3.7 A in the case of the
anomeric compound of 6, thus no NOE interactions
are expected in this case. The results of H-4/H-9 NOE
measurements, which are given in Table 2, are consistent
with this prediction. NOE interactions between H-3 and
H-4 were also used to determine the cis–trans arrange-
ment of each cycloadduct. The absolute configurations
around the isoxazolidine ring were established on this
basis by correlation with the known absolute configura-
tions of 6 and 20. It is also noteworthy that the trans-
isomers were always the first eluted compounds from
the silica gel chromatography.
˚
2.3 A, respectively. This does not hold true for the
cycloadducts obtained from E-exo-glycals where no
NOE interactions are expected whatever the anomeric
configuration. In the crystal structure of b-compounds
6 and 20 formed from E-exo-glycals, the H-4 and H-9
1
Table 2 brings together a series of H and 13C chemical
shifts values, which were also very helpful for stereo-
˚
protons are located at 3.9 and 3.7 A, respectively and
chemical determination. One can observe that the 13C

2462
G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
Table 2. NMR parameters for the fused furano-isoxazolidines 6, 7, 10 and 14–32
Compounds
1H Chemical shifts (d)
Coupling constants (Hz)
13C Chemical shifts (d)
NCH3 C-3 C-4
NOE difference
measurements (%)
H-3
D-gulo Derivatives
H-4
NCH3 CO2CH3 J3,4
H-3/H-4 H-4/H-9
6
2.84
3.39
—
3.34
3.55
—
2.70
2.85
2.59
2.86
—
2.64
2.71
2.85
—
3.65
3.75
3.61
3.31
3.69
3.68
3.39
3.72
—
8.0
7.0
—
—
—
9.5
8.0
7.9
—
43.71
48.40
42.70
46.86
—
43.67
43.95
45.27
—
73.82 60.88
69.65 59.04
—
5
—
—
—
—
—
—
—
—
—
14
2.7
2.8
—
7
8a
9a
10
14
15
16
17b
18
—
—
—
—
—
—
c
3.55–4.10 3.80
58.45 54.08
76.2 59.52
74.92 58.22 13
4.32
3.92
3.42
—
3.87
4.18
3.47
—
70.22 57.04
—
—
—
—
—
c
3.51–3.67 3.93
—
3.77
—
—
56.37 51.74
5
D-ribo Derivatives
19
20
21
22
23
24
25
26
27
28
29
30
31
32
3.87
3.60–3.69 2.61
3.61–3.70 2.86
3.67
3.36
3.71
3.75
3.72
3.75
3.72
3.67
3.40
3.73
3.74
3.76
3.72
3.74
8.5
6.8
8.0
6.7
7.9
—
43.08
47.30
45.85
47.88
—
78.02 74.46
73.48 62.76 10
—
—
—
—
—
—
—
—
3
4.50
2.84
3.24
3.13
3.28
3.47
3.33
2.66
2.68
—
73.63 62.42
72.92 59.53
71.59 61.22
67.79 59.08
71.59 59.45
75.25 59.56
74.91 58.52
70.81 58.02
71.24 54.81
66.64 58.50
67.54 53.80
62.71 51.68
—
8.6
—
—
—
—
7.4
—
2.5
—
—
—
d
3.47–3.58 3.47–3.58
3.52 (2H) 3.90
4.24
3.93
3.34–3.37 3.54
2.63
3.66
3.7–3.82
4.20 (2H) 3.91
—
—
—
—
c
—
3.93
4.22
2.64
2.71
2.81
2.63
—
9.5
8.2
7.2
7.4
—
43.44
44.30
46.01
43.87
—
2.6
d
—
3.90
3.62
3.90
4.2
6
d
—
8.0
7.9
—
—
3.5
c
d
—
—
a Compounds 8 and 9 could not be separated.
b Compound 17 was not separated from 16.
c Compounds with a methylene group at C3.
d NOE difference could not be measured unambiguously.
chemical shifts of C-3 and C-4 of trans-isomers are at a
lower field compared to the corresponding cis-isomers.
The opposite tendency was noticed for the 13C chemical
shifts values of the N–Me group in cycloadducts 6–17
R1
OBn
O
1
i
O
and 19–29. Comparisons of H NMR chemical shifts
BnO
BnO
N
+
R2
values of H-3, H-4 protons and N–CH3, CO2CH3
methyl groups in both cis- and trans-isomers were also
very fruitful. In cycloadducts bearing a propyl group
at C-3 (isomers 6/7, 21/22, 23/24 and 30/31), the H-3
and H-4 of the trans-isomers are at a lower field than
in the corresponding cis-isomers. The opposite is ob-
served in the couple of isomers 14/15, 19/20 and 26/27
all substituted by a phenyl group at C-3. For the latter,
one can point out a large difference between the chemi-
COOMe
OBn
33
1
2
2 R = nPr, R = Me
3 R = Ph, R = Me
4 R = H, R = CH Ph
1
2
1
2
2
OBn
O
OBn
O
COOMe
R3
BnO
BnO
BnO
BnO
O
R1
N
+
BnO
R2
BnO
R3
O
N
R2
MeOOC
R1
3
cal shift values of the methyl ester group between cis-
1
1
2
1
2
3
and trans-isomers. The H dCH of trans-cycloadducts
35 R = Me, R = Ph, R = H
34 R = Me, R = Ph, R = H
3
1
2
3
14, 19 and 26 is ꢀ3.67 ppm while in the corresponding
1
2
3
36 R = Me, R = H, R = Ph
37 R = Me, R = H, R = Ph
1
2
3
cis-cycloadducts 15, 20 and 27, due to the presence of
1
2
3
39 R = Me, R = H, R = nPr
38 R = Me, R = nPr, R = H
40 R = Me, R = H, R = nPr
1
2
3
a shielding zone, dCH ꢀ 3.39 ppm.
1
2
3
41 R = CH Ph, R
= R = H
3
2
Our attention next turned to pyranose exo-glycals,
which could behave differently in the cycloaddition reac-
tions. Some precedents can be found in the literature
using exo-methylene glycals with nitrile oxides18,20 and
nitrones.22 The cycloaddition reactions were attempted
on 33 (Scheme 3), obtained as a Z-isomer only, with nit-
rones 2 and 3 under microwave activation. The situation
appeared much more complex than previously described
OMOM
OMOM
O
COOMe
O
MOMO
MOMO
MOMO
MOMO
MOMO
CO Me
O
N
MOMO
42
2
Bn
43
Scheme 3. (i) Microwave irradiation.

G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
2463
Table 3. Results of nitrone cycloadditions with pyrano-exo-glycals 33
and 42
by us and careful examination of the crude reaction mix-
tures was needed. With nitrone 3, four cycloadducts 34,
35, 36 and 37 were obtained in a 1.3:8.1:3.5:1 ratio (in
order of elution) in 90% yield. 35, 36 and 37 obtained
as pure compounds were completely analysed by
NMR spectroscopy. This was not the case of isomer
34 (first eluted compound), which could not be sepa-
rated from 35 but its presence was shown unambigu-
ously by NMR, in particular by the signals of the N–
Me group (d1H 2.81 ppm, d13C 45.48 ppm) and the
methyl ester group (d1H 3.60 ppm). The configuration
of the four synthesised compounds 34–37 was per-
formed as follows: assuming a concerted mechanism
for NOC reactions, the single configuration at C-4 as de-
picted in Scheme 3 is related to the Z geometry of the
starting exo-glycal 33. Thus the four isomers obtained
are diastereoisomers at C-3 and/or C-5. Determination
of the cis/trans relationship between substituents at
C-3 and C-4 is based on the proton chemical shift of
the Me-ester group. As in the furano series it was ob-
served that among the four isomers two have a methyl
group, which appear abnormally at a higher field (3.27
and 3.37 ppm) compared to 3.54 and 3.60 ppm (Table
4). As already explained, this shift towards high fields
indicates a cis-relationship between the C-3 phenyl
group and the C-4 methyl ester. The 13C chemical shift
of the anomeric carbon is usually a good indicator in
sugar chemistry to discriminate between a- and b-iso-
mers.29 In the case of spirosugar-heterocycles, a-ano-
mers appear at a higher field than the corresponding
b-anomers. Accordingly, the first and fourth eluted com-
pounds, which have the higher values for the anomeric
carbon (107.80 and 106.95, respectively) were assumed
to be the b-anomers 34 and 37 while the second and
third eluted compounds are the a-anomers 35 and 36.
It is worth noting that like in the furano series, the
two trans-isomers 34 and 35 are the less polar com-
pounds and are obtained in a greater amount (trans/
cis: 2:1).
Entry Starting
exo-glycals
Nitrones Products,
ratio
trans/cis Yield
(a/b)
(%)
Ratio
1
2
33
3
2
34, 35, 36, 37 2:1,
90
64
1.3:8.1:3.5:1
38, 39, 40
5.9:4.1:1
41
(5:1)
33
1.1:1,
(1:1.6)
(1:0)
3
4
33
42
5
5
68
72
43
(1:0)
cis- and trans-orientation. Nevertheless, the C-3 con-
figuration of cycloadducts 38–40 was tentatively as-
signed by comparison of the 13C NMR spectral data
of the N–Me group. In the cis-compounds 36 and 37,
the N–Me group appears around 44 ppm while it is at
a lower field in the trans-cycloadducts 34 and 35 (see Ta-
ble 4). We took advantage of this difference (>4 ppm) to
distinguish between the cis- and trans-isomers among
the three isolated compounds 38, 39 and 40. The cis/
trans-arrangement of substituents at C3 and C4 was also
determined by NOE difference measurements (see Table
4). Determination of the anomeric configuration was
again established by comparison of the 13C data of C-
5. Compounds having C-5 chemical shifts at 106.59
and 106. 96 ppm should be the b-isomers and were ob-
tained in the greater proportion, (a/b ꢁ1:1.6). Once
more, such as in the furano series, we have noticed that
trans-isomers are less polar than the cis one. This obser-
vation reinforces all our structural assignments. The
reaction of exo-glycal 33 with nitrone 5, generated in
situ was next examined. Interestingly, only one cycload-
duct 41 was obtained in 68% yield (Table 3, entry 3),
which is the result of a complete a selectivity in this case.
Similarly, compound 43 was obtained as the sole isomer
(72% yield) from the reaction of olefin 42 with nitrone 5.
The cycloaddition from the a-face of 33 was favoured
(a/b 5:1), in agreement with reported results on the
1,3-dipolar cycloaddition of 1-methylene-sugar with
nitrile oxides.18,20 These results are also consistent with
the reported formation of a mixture of anomeric cyclo-
adducts in the Lewis acid catalysed (a/b ꢁ11:1) or ther-
mal (a/b ꢁ1:1) reaction of 1-methylene-analogue of 33
with glyoxylic nitrones (R1 = COOEt in structure 2).
However, only one epimer at C3 of the isoxazolidine
ring was formed accounting for a total facial selectivity
on the nitrone.21 This is in sharp contrast with our
results, the observed trans/cis ratio of the C3–C4 sub-
stituents of isoxazolidines is the opposite of the endo–
exo attack. In the case of the cycloaddition of olefin
33 with nitrone 2, three cycloadducts 38–40 were also
obtained (38/39/40 5.9:4.1:1, 64% yield, Table 3), a
fourth isomer being detected in trace amount. In these
compounds the presence of a propyl group at C-3 in-
stead of a phenyl group did not allow us to discriminate
between the cis- and trans-isomers by comparison of the
1H NMR chemical shifts of the ester methyl group. In
Table 4. NMR data for compounds 34–40
Compound
1H d (ppm)
CO2CH3
H-3/H-4 NOE
difference
13C d
(ppm)
C-5
13C d
(ppm)
NCH3
measurements
(%)
34 (b-trans)
35 (a-trans)
36 (a-cis)
37 (b-cis)
38 (b-trans)
39 (a-cis)
3.60
3.54
3.37
3.27
3.61
3.58
3.70
—
—
14
10
—
107.80
105.78
104.34
106.95
106.96
104.16
106.59
45.48
47.0
44.01
44.14
48.73
43.95
43.84
5.6
a
40 (b-cis)
a NOE difference could not be measured due to signals overlapping.
2.2. Nitrile oxide-exo-glycal cycloadditions
The reaction of nitrile oxide with some activated exo-
glycals was next examined. Benzonitrile oxide 44, gener-
ated in situ from the corresponding hydroxyiminoyl
chloride and triethylamine was reacted with the E olefin
1. This cycloaddition proceeded at room temperature in
6 h to give single adduct 46 in 52% yield. The same
3
addition the comparison of the J3,4 coupling constants
was not reliable enough to distinguish between the

2464
G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
reaction was carried out on Z-isomer 11 and gave only
one adduct in 72% yield, which proved identical to 46.
This suggested that the stereochemistry at carbon 4 of
the expected isoxazoline ring, normally dictated by the
olefin stereochemistry, was destroyed during the pro-
(Scheme 5). It shows that furano-spiroisoxazolidine
templates are stable in acidic medium. The equilibration
of furano- to pyrano-isoxazolidine does not occur and
that the anomeric configuration is also preserved.
1
cess. Indeed, careful examination of the H NMR spec-
tra of 46 showed that H-4 was no longer present. The
presence of a hydroxyl proton was also clear, thus estab-
lishing the isoxazole ring structure of 46. This heterocy-
cle aromatisation can be explained by the initial
formation of the expected cycloadduct 45 bearing an
acidic proton at C-4, which is abstracted under the
rather basic cycloaddition conditions, the sugar ring
oxygen elimination follows providing 46.24
Me
N
OH
HO
O
O
H
N
O
Ph
HO
nPr
HO
HO
OH COOMe
HO
COOMe
HO OH
48
49
Scheme 5. Representative deprotected compounds.
3. Discussion
The same b-elimination was observed in the reaction of
olefin 33 with benzonitrile oxide 44, which gave only one
compound 47 in 35% yield (Scheme 4). This poor yield
shows again the low reactivity of 33 compared to the
methylene analogue. In fact exo-glycals with a methyl-
ene group either of the gluco18 or galacto21 series or with
a methyl or phenyl substituent on the double bond have
been reported to be good substrates in the INOC
reaction.20
Not unexpectedly, cycloadditions performed with exo-
glycals seem very sensitive to the steric hindrance of
both the nitrone and the trisubstituted olefinic bond.
Excellent yields (75–92%) were obtained upon reaction
of furano exo-glycals with the unsubstituted nitrone 5
giving only one stereogenic centre at C4 (isoxazolidine
numbering), the absolute configuration of which is dic-
tated by the starting olefin geometry. The fact that a sin-
gle adduct was obtained in each case strongly supports
an excellent facial control on the carbohydrate template.
The b-selectivity, which is systematically observed with
furano exo-glycals, can be explained by the overcrowd-
ing of the a-face by the fused dioxolane-protecting
group.
MeO
O
O
N
H
O
i
+
O
O
O
O
44
The importance of stereoelectronic control in the NOC
is well known1a and the endo attack is largely pre-
ferred.30a,b However, the steric bulk of the two partners
play an important role, favouring or disfavouring the
endo attack. In our cycloaddition reaction, the absolute
configuration at C3 is dictated by the endo/exo attack of
the nitrone. Thus, the observed trans/cis ratio of the C3–
C4 substituents of isoxazolidines is the opposite of the
endo/exo attack. In the furano series, the yields and
cis/trans ratio of the different isoxazolidines are signifi-
cantly different and should deserve comment. The first
point is that with nitrones 3, 4 and 5, yields are good
to excellent between 75% and 96%. This was not the case
with the butylidenemethylamine N-oxide 2, which was
used as an E/Z mixture and gave cycloadducts in 50–
58% average yields. The lower reactivity of this nitrone
cannot be only the fact of steric hindrance because nit-
rone 4, which is also substituted by a propyl group, gave
better yields (89–96%).
1 (E)
11 (Z)
N
O
H
O
4
O
H
COOMe
O
O
O
45
N
OH
O
Ph
O
O
O
COOMe
O
46
BnO
BnO
1'
1
2
N
5'
O
BnO
5
3
Ph
COOMe
OH
47
OBn
4
The cycloaddition of nitrone 3 with (E)-olefins 1 and 12
(Table 1, entries 2 and 7) gave comparable trans/cis
ratios, 2:1 (76%) and 2.3:1 (86%), respectively. Assum-
ing that nitrone 3 reacts via the more stable Z isomer,
it is believed that cycloadditions on 1 and 12 preferen-
tially took place via the endo attack pictured by A
(Fig. 3) to provide the observed major trans-isomers 8
and 19. A substantial amount of cis-isomers 9 and 20
was formed via the exo attack (B, Fig. 3). It is worth
noting that the corresponding Z olefins 11 and 13
behaved differently upon reaction with nitrone 3. The
Scheme 4. Benzonitrile oxide cycloaddition reactions.
The deprotection of representative compounds bearing
acetonides was next examined in order to evaluate the
robustness of the synthesised compounds. Removal of
the acetonides of compounds 7 and 46 was carried out
very cleanly and quantitatively from treatment with
25% v/v TFA in water at room temperature to give
the free spirosugar-heterocycle 48 and isoxazole 49

G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
2465
More insights on these mechanisms should arise from
the computational evaluation of the different transition
states.31a,b
Me
R
(Z)
(Z)
O
N
O
O
N
O
R
Me
(E)
CO2Me
(E)
CO2Me
O
O
TS A (endo)
TS B (exo)
4. Conclusion
Me
R
The results reported herein show that the capto-dative
olefins 1, 11, 12 and 13 are good substrates in the nit-
rone-cycloaddition reaction, provided that the reactions
were carried out under microwave activation. Almost no
reaction was observed under standard thermal condi-
tions. These cycloadditions provide new spirohetero-
cycles with good stereoselectivities and yields.
Excellent facial selectivities on the sugar olefins were ob-
served with these bicyclic furanose exo-glycals due to the
presence of the dioxolane-protecting group near the
anomeric centre. The endo mode for the Z nitrone cyclo-
addition is preferred as postulated in most NOC
reactions.
(Z)
(Z)
MOMO
O
N
N
O
MOMO
R
CO2Me
O
CO2Me
O
Me
Z
(Z)
O
O
TS D (exo)
TS C (endo)
Me
(Z)
Ph
(E)
O
R
N
N
MOMO
O
O
CO2Me
COOMe
O
(Z)
OBn
O
TS F (endo)
TS E (endo)
Figure 3. Postulated transition state representation.
Pyranose exo-glycal 33 also gave good yields in NOC
reactions with nitrones 2, 3 and 5. However, due to
the steric hindrance of both faces of the sugar ring, facial
selectivity is not complete and the cycloaddition reac-
tions give a/b mixtures. Here again the endo mode of
cycloaddition is preferred with the Z nitrone 3. The
reaction is much more complex to rationalise with nit-
rone 2 since no selectivity was observed. The reactivity
was similar in the nitrile oxide reaction of furano exo-
glycals 1, 11 and pyrano exo-glycal 33. A sugar ring
opening was observed, may be due to the basic reaction
medium giving chiral isoxazoles. All the new com-
pounds formed in these cycloadditions easily obtained
chiral scaffolds suitable for the construction of stereo-
diverse peptidomimetics libraries. All the new com-
pounds, which can be easily deprotected, can also be
regarded as spironucleosides and should therefore
present interesting biological properties.
trans-selectivity is dramatically enhanced with olefin 13
(trans/cis 7.4:1, Table 1, entry 11), compared to olefin
11 (trans/cis 2:1, Table 1, entry 4). It clearly demon-
strates the influence of the sugar part in the endo/exo
selectivity of the reaction. Assuming that nitrone 3
reacts as a Z form, major isomer 26 would be formed
via TS C (endo) and the minor cis-isomer 27 via TS D
(exo). The low proportion of cis-diastereoisomer 27
tends to demonstrate that TS D (depicted as a ribo con-
figuration in Fig. 3) is much more congested in the case
of ribo-derivatives than in the case of gulo-derivatives.
This is confirmed by the 6:1 ratio in favour of the
trans-orientation (compound 28), obtained when react-
ing nitrone 2 with olefin 13 (Table 1, entry 12). Indeed
the same nitrone 2 gave a 1.2:1 ratio of trans/cis-isomers
when reacting with the (Z)-gulo olefin 11 (Table 1, entry
5). endo-TS E could also contribute to the formation of
the minor cis-compound 29 (Table 1, entry 12) if the
reaction occur from the E form of nitrone 2. Conse-
quently, TS E is certainly also very congested in the ribo
series.
5. Experimental
5.1. General methods
5.1.1. General indications. FTIR spectra were recorded
on a Perkin–Elmer Spectrum 1000 on NaCl windows or
KBr pellets. 1H NMR and 13C spectra were recorded on
a Bruker AC 250 or on a Bruker DRX 400 spectrometer.
Chemical shifts (d) are given in ppm and coupling con-
stants (J) in hertz (Hz). Multiplicities of NMR signals
are designed as s (singlet), d (doublet), t (triplet), q
(quartet), br (broad), m (multiplet, for unresolved lines).
1H assignments were confirmed by homonuclear 2D
COSY correlated experiments. Attribution of 13C sig-
nals are based on the J-modulated spin-echo sequence
and/or heteronuclear two-dimensional techniques. 13C
NMR spectra were recorded with complete proton
decoupling. Mass spectra were recorded on a Trio
1000 Thermo Quest spectrometer in the electron impact
mode or a Platform Micromass spectrometer in the elec-
tro spray mode. Specific rotations were determined on a
Perkin–Elmer 141 polarimeter (10 cm cell). Elemental
In the case of pyrano exo-glycals, facial selectivity was
dependent on the nature of the nitrone and decreased
when going from nitrone 5 to 3 and then 2. With the
unsubstituted nitrone 5, facial selectivity on the olefin
was complete giving only a cycloadducts 41 and 43
(Table 3, entries 3 and 4). A 5:1 a/b ratio was obtained
when reacting olefin 33 with the little crowded nitrone 3
(Table 3, entry 1) and the more crowded nitrone 2 gave
opposite results (a/b 1:1.6, Table 3, entry 2). With
regard to the cis/trans ratio, in the reaction of olefin
33 with nitrone 3, the trans-isomers were predominant,
in particular the a-trans-isomer 35 (trans/cis 2:1, Table
3, entry 1). Assuming that nitrone 3 reacts in its Z form,
the reaction of 3 proceeds preferentially via the endo at-
tack depicted in F giving the trans adduct. Reaction of
nitrone 2 with olefin 33 was not selective (trans/cis
1.1:1, Table 3, entry 2).

2466
G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
analyses were obtained with a Thermofinnigan Flash
EA 1112 apparatus. Analytical thin-layer chromatogra-
phy was performed on Merck 60 F254 pre-coated silica
gel plates. Compounds were visualised with UV light
and (or) 30% methanolic H2SO4-heat as developing
agent. Preparative chromatography was performed on
silica gel 60 (230–40 mesh ASTM). Reverse phase HPLC
was performed with a Gilson 321 apparatus equipped
with a C18 chromasil column. Detection was carried
out using a Polymer Laboratories evaporator light scat-
tering 1000 (PL ELS 1000). Melting points were deter-
mined in capillaries on a Tottoli apparatus and are
uncorrected. N-Butylidenemethylamine N-oxide 2,32
N-benzylidenemethylamine N-oxide 332 and N-butylide-
nebenzylamine N-oxide 433 were prepared as described.
Eluted second (Rf 0.38, silica gel, 50% EtOAc in hexane)
26
was 7 as a yellow oil; ½aꢂD ¼ ꢃ70.1 (c 1.1, CHCl3);
mmax (neat) 2986.82, 2959.31, 2936.85, 1744.98,
1
1458.15; H NMR (CDCl3, 400 MHz,): d 0.91 (t, 3H,
J 7.0 Hz, CH3 propyl), 1.22 (s, 3H, CH3 acetal), 1.26
(m, 2H, CH2 propyl), 1.38 (s, 3H, CH3 acetal), 1.39 (s,
3H, CH3 acetal), 1.43 (s, 3H, CH3 acetal), 1.50 (m,
2H, CH2 propyl), 2.85 (s, 3H, N–CH3), 3.39 (m, 1H,
H-3), 3.55 (d, 1H, J3,4 7.0 Hz, H-4), 3.75 (s, 3H,
CO2CH3), 3.77 (dd, 1H, J4 ;5 6.1, Jgem 8.6 Hz, H-50),
0
0
0
3.95 (dd, 1H, J7,8 3.5, J4 ;7 8.6 Hz, H-7), 4.18 (dd, 1H,
J4 ;5 6.1 Hz, Jgem 8.6 Hz, H-50), 4.35 (m, 1H, H-40),
4.63 (m, 1H, H-8), 4.74 (d, 1H, J8,9 6.0 Hz, H-9); 13C
NMR (CDCl3, 100.6 MHz): d 14.67 (CH3 propyl),
20.67 (CH2 propyl), 25.53, 25.83, 26.21, 26.43
(4 · CH3 acetal), 32.48 (CH2 propyl), 48.40 (N–CH3),
52.14 (CO2CH3), 59.04 (C-4), 66.46 (C-50), 69.65 (C-3),
75.66 (C-40), 80.17 (C-8), 81.31 (C-7), 84.05 (C-9),
110.28 (C acetal), 113.58 (C-5), 114.68 (C acetal),
169.79 (CO2CH3). m/z (EI+) 416.2 [(M+1)+, 8%],
415.1 [(M)+, 11%], 400.1 [(MꢃCH3)+, 13%], 340.1
(25), 102.0 (65), 100.8 (100); HRMS m/z (ES+) calcd
for C20H34NO8 [M+H]+ 416.2284, found 416.2281.
0
0
5.2. Cycloaddition reactions with N-butylidenemethyl-
amine N-oxide 2, N-benzylidenemethylamine N-oxide 3
and N-butylidenebenzylamine N-oxide 4, under micro-
wave activation. General procedure
A solution of exo-glycal 1, 11–13 or 33 and a threefold ex-
cess of nitrones 2–4 (1.5 equiv) in toluene (0.7 mL/mmol)
in a septum-sealed glass tube was heated at 120–140 ꢁC in
a focussed microwave oven (Discoverꢂ CEM) for 22–
100 min until the exo-glycal was completely consumed
(TLC control). Purification of the crude reaction mixtures
by silica gel column chromatography with EtOAc–hex-
ane as eluent afforded spiroisoxazolidines 6–9, 14–17,
19–24, 26–31 and 34–40 (50–96% yields).
5.2.2. Methyl (3R,4R,5S,7S,8R,9R)-8,9-isopropylidene-
dioxy-2-methyl-7-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-
3-phenyl-1,6-dioxa-2-azaspiro[4.4]nonane-4-carboxylate
8 and methyl (3S,4R,5S,7S,8R,9R)-8,9-isopropylidene-
dioxy-2-methyl-7-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-
3-phenyl-1,6-dioxa-2-azaspiro[4.4]nonane-4-carboxylate 9.
Compound 1 (429 mg, 1.36 mmol) was converted to 8
and 9 according to the general procedure. Reaction
time: 25 min; 76% yield (328 mg, 0.73mmol). 8/9 2:1
5.2.1. Methyl (3R,4R,5S,7S,8R,9R)-8,9-isopropylidene-
dioxy-2-methyl-7-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-
3-propyl-1,6-dioxa-2-azaspiro[4.4]nonane-4-carboxylate
6 and methyl (3S,4R,5S,7S,8R,9R)-8,9-isopropylidene-
dioxy-2-methyl-7-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-
3-propyl-1,6-dioxa-2-azaspiro[4.4]nonane-4-carboxylate 7.
Compound 1 (500 mg, 1.60 mmol) was converted to 6
(200 mg, 0.48 mmol) and 7 (50 mg, 0.12 mmol) accord-
ing to the general procedure. Reaction time: 25 min;
50% yield. 6/7 4:1.
1
(inseparable mixture). H NMR (CDCl3, 400 MHz): d
1.24, 1.37, 1.40, 1.47 (4 · s, CH3 acetal), 2.59 (s, 0.66
NCH3, compound 8), 2.86 (s, 0.34 NCH3, compound
9), 3.31 (s, 0.34 CO2CH3, compound 9), 3.61 (s, 0.66
CO2CH3, compound 8), 3.65–4.29 (m, 4H), 4.30–4.48
(m, 1H), 4.59–4.77 (m, 2.66H), 4.86 (br d, 0.34H),
7.20–7.48 (5H, Ar); 13C NMR (CDCl3, 100.6 MHz): d
24.8–26.4 (4 · CH3 acetal), 42.7 (N–CH3, compound
8), 46.8 (N–CH3, compound 9), 51.1 (CO2CH3, com-
pound 9), 51.6 (CO2CH3, compound 8), 61.3, 63.1,
65.8, 72.7, 75.0, 75.3, 77.9, 79.6, 80.7, 80.9, 82.7, 83.3,
109.5, 112.2, 112.7, 112.9, 114.0, 127.2–128.4 (Ar),
134.7 and 135.6 (Cipso), 168.0 (CO2CH3, compound
9), 170.7 (CO2CH3, compound 8). m/z (EI+) 451.1
[(M+2)+, 4%], 450.1 [(M+1)+, 15%], 449.0 [(M)+,
10%], 434.0 [(MꢃCH3)+, 5%], 403.0 (20), 133.9 (100).
HRMS m/z (ES+) calcd for C23H32NO8 [M+H]+
450.2128, found 450.2115.
Eluted first (Rf 0.48, silica gel, 50% EtOAc in hexane)
25
was 6 as a solid; mp 92 ꢁC; ½aꢂD ¼ ꢃ159.1 (c 1, CHCl3);
mmax (KBr) 2987.04, 2959.59, 2936.62, 1742.82, 1458.12;
1H NMR (CDCl3, 400 MHz): d 0.87 (t, 3H, J 7.2 Hz,
CH3 propyl), 1.20 (s, 3H, CH3 acetal), 1.20–1.35 (m,
2H, CH2 propyl), 1.35 (s, 3H, CH3 acetal), 1.36 (s,
3H, CH3 acetal), 1.40 (s, 3H, CH3 acetal), 1.45–1.60
(m, 2H, CH2 propyl), 2.70 (s, 3H, N–CH3), 2.84 (m,
1H, H-3), 3.34 (d, 1H, J3,4 8.08 Hz, H-4), 3.65 (m, 4H,
CO2CH3, H-50), 3.90 (dd, 1H, J7,8 4.0, J4 ;7 8.1 Hz, H-
0
7), 4.17 (dd, 1H, J4 ;5 6.7, Jgem 8.4 Hz, H-50), 4.32 (m,
1H, H-40), 4.56 (d, 1H, J8,9 5.9 Hz, H-9), 4.62 (dd, 1H,
J8,9 5.9, J7.8 4.0 Hz, H-8); 13C NMR (CDCl3,
100.6 MHz): d 14.13 (CH3 propyl), 19.35 (CH2 propyl),
25.09, 25.43, 25.67, 26.57 (4 · CH3 acetal), 33.68 (CH2
propyl), 43.71 (N–CH3), 51.82 (CO2CH3), 60.88 (C-4),
66.00 (C-50), 73.82 (C-3), 75.48 (C-40), 79.71 (C-8),
81.06 (C-7), 83.00 (C-9), 109.80 (C acetal), 112.22 (C-
5), 112.87 (C acetal), 172.17 (CO2CH3). Anal. Calcd
for C20H33NO8: C, 57.82; H, 8.01; N, 3.37. Found: C,
57.68; H, 8.11; N, 3.37.
5.2.3. Methyl (3R,4S,5S,7S,8R,9R)-8,9-isopropylidenedi-
oxy-2-methyl-7-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-
phenyl-1,6-dioxa-2-azaspiro[4.4]nonane-4-carboxylate 14
and methyl (3S,4S,5S,7S,8R,9R)-8,9-isopropylidenedi-
oxy-2-methyl-7-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-
phenyl-1,6-dioxa-2-azaspiro[4.4]nonane-4-carboxylate 15.
Compound 11 (270 mg, 0.86 mmol) was converted to 14
(170 mg, 0.35 mmol) and 15 (80 mg, 0.16 mmol) accord-
ing to the general procedure. Reaction time: 16 min,
130 ꢁC; 80% yield. 14/15 2:1. Eluted first (Rf 0.68, silica
gel, 50% EtOAc in hexane) was 14 as a glassy solid; mp
0
0

G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
2467
25
178 ꢁC; ½aꢂD ¼ þ1.8 (c 1.1, CHCl3); mmax (KBr) 3434.82,
5), 112.79 (C acetal), 113.19 (C acetal), 169.25
(CO2CH3). Anal. Calcd for C20H33NO8: C, 57.82; H,
8.01; N, 3.37. Found: C, 57.49; H, 8.10; N, 3.47.
1
3331.85, 3129.40, 2992.94, 1745.81, 1658.93; H NMR
(CDCl3, 400 MHz): d 1.34 (s, 3H, CH3 acetal), 1.38 (s,
3H, CH3 acetal), 1.44 (s, 3H, CH3 acetal), 1.45 (s, 3H,
CH3 acetal), 2.64 (s, 3H, N–CH3), 3.68 (s, 3H,
Compound 17 was inseparable from 16.
CO2CH3), 3.75 (dd, 1H, J4 ;5 7.2, Jgem 8.0 Hz, H-50),
3.87 (d, 1H, J3,4 9.5 Hz, H-4), 4.09 (ddd, 1H,
0
0
5.2.5. Methyl (3S,4R,5S,7R,8R,9R)-8,9-isopropylidenedi-
oxy-2-methyl-7-[(methoxymethoxy)methyl]-3-phenyl-1,6-
dioxa-2-azaspiro[4.4]nonane-4-carboxylate 19 and methyl
(3R,4R,5S,7R,8R,9R)-8,9-isopropylidenedioxy-2-methyl-
7-[(methoxymethoxy)methyl]-3-phenyl-1,6-dioxa-2-aza-
spiro[4.4]nonane-4-carboxylate 20. Compound 12
(200 mg, 0.69 mmol) was converted to 19 (179 mg,
0.42 mmol) and 20 (78 mg, 0.18 mmol) according to
the general procedure. Reaction time: 90 min; 86% yield.
19/20 2.3:1. Eluted first (Rf 0.60, silica gel, 30% EtOAc
0
J4 ;7 ¼ 7.6, J7,8 2.5, J7,9 1,0 Hz, H-7), 4.20 (m, 1H, H-
50), 4.26 (pseudo q, 1H, J 7.5 Hz, H-40), 4.32 (d, 1H,
J3,4 9.5 Hz, H-3), 4.78–4.80 (m, 2H, H-8, H-9), 7.25–
7.41 (m, 5H, PhH); 13C NMR (CDCl3, 100.6 MHz): d
25.18 (CH3 acetal), 25.99 (2 · CH3 acetal), 27.07 (CH3
acetal), 43.67 (N–CH3), 52.23 (CO2CH3), 59.52 (C-4),
66.3 (C-50), 76.2 (C-3), 76.32 (C-8), 80.20 (C-9), 83.8
(C-40), 85.9 (C-7), 110.19 (C-5), 111.95 113.76 (2 · C
acetal), 128.38–129.11 (5C, Ar), 137.76 (Cipso), 168.88
(CO2CH3). Anal. Calcd for C23H31NO8: C, 61.46; H,
6.95; N, 3.12. Found: C, 61.91; H, 6.99; N, 3.20.
in hexane) was 19 as a yellow solid; mp 53 ꢁC;
25
½aꢂD ¼ ꢃ127.3 (c 1, CHCl3; mmax (KBr) 3064.22,
1
3031.72, 2989.66, 2951.01, 1741.82; H NMR (CDCl3,
Eluted second (Rf 0.45, silica gel, 50% EtOAc in hexane)
was 15 as a glassy solid; mp. 133–135 ꢁC; ½aꢂD ¼ ꢃ50.1
400 MHz): d 1.32 (s, 3H, CH3 acetal), 1.44 (s, 3H,
CH3 acetal), 2.61 (s, 3H, N–CH3), 3.41 (s, 3H,
CH2OCH3), 3.60–3.69 (m, 5H, CO2CH3, H-4 and
7-CHH), 3.83 (dd, 1H, J7,7-CHH 6.4, Jgem 10.2 Hz,
7-CHH), 3.87 (br d, 1H, J3.4 8.5 Hz, H-3), 4.35 (dt,
1H, J7,7-CHH 8.0, J7,8 1,0 Hz, H-7) 4.68 (d, 1H, Jgem
6.4 Hz, CHHOCH3), 4.70 (d, 1H, J8.9 5.7 Hz, H-9),
4.73–4.79 (m, 2H, CHHOCH3 and H-8), 7.31–7.41 (m,
5H, Ph). 13C NMR (CDCl3, 100.6 MHz): d 25.79
(CH3 acetal), 26.41 (CH3 acetal), 43.08 (N–CH3),
52.11 (CO2CH3), 55.43 (CH2OCH3), 64.46 (C-4), 68.73
(7-CH2), 78.02 (C-3), 82.54 (C-8), 83.26 (C-9), 84.61
(C-7), 96.81 (CH2OCH3), 112.94, 113.98 (C acetal,
C-5), 128.21–128.90 (5C, Ar), 136.35 (Cipso), 171.36
(CO2CH3). Anal. Calcd for C21H29NO8: C, 59.56; H,
6.90; N, 3.31. Found: C, 59.52; H 6.91; N, 3.41.
26
(c 0.4, CHCl3); mmax (KBr) 3431.20, 3330.44, 3129.77,
2990.97, 1759.54, 1654.31; 1H NMR (CDCl3,
400 MHz): d 1.33 (s, 3H, CH3 acetal), 1.35 (s, 3H, CH3
acetal), 1.43 (s, 3H, CH3 acetal), 1.47 (s, 3H, CH3 acetal),
2.71 (s, 3H, N–CH3), 3.39 (s, 3H, CO2CH3), 3.78 (pseudo
t, 1H, Jgem 8.0 Hz, H-50), 3.92 (d, 1H, J3,4 8.0 Hz, H-3),
4.11–4.17 (m, 2H, H-50, H-7), 4.18 (d, 1H, J3,4 8.0 Hz,
H-4), 4.30 (m, 1H, H-40), 4.67 (d, 1H, J8,9 5.9 Hz, H-9),
4.77 (dd, 1H, J7,8 3.8, J8,9 5.9 Hz, H-8), 7.25–7.40 (m,
5H, PhH); 13C NMR (CDCl3, 100.6 MHz): d 24.91,
25.56, 25.66, 26.49 (4 · CH3 acetal), 43.95 (N–CH3),
51.22 (CO2CH3), 58.22 (C-4), 65.92 (C-50), 74.92 (C-3),
75.33 (C-40), 79.84 (C-8), 81.76 (C-7), 85.24 (C-9),
109.67 (C-5), 111.79 113.62 (2 · C acetal), 127.99–
128.23 (Ar), 134.42 (Cipso), 167.13 (CO2CH3). HRMS
m/z (ES+) calcd for C23H32NO8 [M+H]+ 450.2128,
found 450.2134.
Eluted second (Rf 0.32, silica gel, 30% EtOAc in hexane)
25
was 20 as a solid; mp 135 ꢁC; ½aꢂD ¼ ꢃ9.0 (c 1.1,
CHCl3); mmax (KBr) 2979.65, 2948.43, 1749.84; 1H
NMR (CDCl3, 400 MHz): d 1.29 (s, 3H, CH3 acetal),
1.43 (s, 3H, CH3 acetal), 2.86 (s, 3H, N–CH3), 3.36 (s,
3H, CO2CH3), 3.41 (s, 3H, CH2OCH3), 3.61–3.70 (m,
2H, H-4 and 7-CHH), 3.72 (dd, 1H, J7,7-CHH 7.6, Jgem
10.6 Hz, 7-CHH), 4.38 (pseudo t, 1H, J 7.5 Hz, H-7),
4.50 (br d, 1H, J3.4 6.8 Hz, H-3), 4.69 (br s, 2H,
CH2OCH3), 4.75 (d, 1H, J8.9 5.8 Hz, H-8 or H-9), 4.91
(d, 1H, J8.9 5.8 Hz, H-8 or H-9), 7.28–7.40 (m, 5H,
Ph); 13C NMR (CDCl3, 100.6 MHz): d 25.36 (CH3 ace-
tal), 26.47 (CH3 acetal), 47.30 (N–CH3), 51.61
(CO2CH3), 55.58 (CH2OCH3), 62.76 (C-4), 68.69 (7-
CH2), 73.48 (C-3), 82.34 (C-8 or C-9), 83.59 (C-8 or C-
9), 84.30 (C-7), 96.92 (CH2OCH3), 112.81 (C acetal),
116.07 (C-5), 127.59–128.58 (5C, Ar), 134.88 (Cipso),
168.46 (CO2CH3). Anal. Calcd for C21H29NO8: C,
59.56; H, 6.90; N, 3.31. Found: C, 59.68; H 6.88, N, 3.30.
5.2.4. Methyl (3S,4S,5S,7S,8R,9R)-8,9-isopropylidenedi-
oxy-2-methyl-7-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-
propyl-1,6-dioxa-2-azaspiro[4.4]nonane-4-carboxylate 16.
Compound 11 (420 mg, 1.34 mmol) was converted to 16
and 17 according to the general procedure. Yield 65%
(354 mg, 0.85 mmol). 16/17 1.2:1. Data for compound
16: solid; mp 53 ꢁC; Rf 0.40 (silica gel, 30% EtOAc
25
in hexane); ½aꢂD ¼ þ3.5 (c 1, CHCl3); mmax (KBr)
1
3434.80, 3128.92, 2992.93, 1739.12, 1665.16; H NMR
(CDCl3, 400 MHz): d 0.91 (t, 3H, J 7.1 Hz, CH3 propyl),
1.29 (s, 3H, CH3 acetal), 1.35 (m, 2H, CH2 propyl), 1.35
(s, 3H, CH3 acetal), 1.41 (s, 3H, CH3 acetal), 1.42 (m,
1H, CHH propyl), 1.45 (s, 3H, CH3 acetal), 1.52 (m,
1H, CHH propyl), 2.85 (s, 3H, N–CH3), 3.42 (m, 1H,
H-3), 3.47 (d, 1H, J3,4 7.9 Hz, H-4), 3.69–3.76 (m, 4H,
CO2CH3, H-50), 3.99 (dd, 1H, J7,8 3.9, J4 ;7 7.8 Hz, H-
0
7), 4.15 (dd, 1H, J4 ;5 6.7, Jgem 8.2 Hz, H-50), 4.22 (m,
1H, H-40), 4.57 (d, 1H, J8,9 5.9 Hz, H-9), 4.70 (dd, 1H,
J7,8 3.9, J8,9 5.9 Hz, H-8); 13C NMR (CDCl3,
100.6 MHz): d 14.11 (CH3 propyl), 19.38 (CH2 propyl),
24.58 (CH3 acetal), 25.52 (2C, CH3 acetal), 26.67 (CH3
acetal), 35.13 (CH2 propyl), 45.27 (N–CH3), 51.85
(CO2CH3), 57.04 (C-4), 65.88 (C-50), 70.22 (C-3), 75.70
(C-40), 79.71 (C-8), 82.52 (C-7), 85.04 (C-9), 109.65 (C-
0
0
5.2.6. Methyl (3R,4R,5S,7R,8R,9R)-8,9-isopropyliden-
edioxy-2-methyl-7-[(methoxymethoxy)methyl]-3-propyl-
1,6-dioxa-2-azaspiro[4.4]nonane-4-carboxylate 21 and
methyl (3S,4R,5S,7R,8R,9R)-8,9-isopropylidenedioxy-2-
methyl-7-[(methoxymethoxy)methyl]-3-propyl-1,6-dioxa-
2-azaspiro[4.4]nonane-4-carboxylate 22. Compound 12
(204 mg, 0.71 mmol) was converted to 21 (101 mg,

2468
G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
1
0.26 mmol) and 22 (58 mg, 0.15 mmol) according to the
general procedure. Reaction time: 95 min; 58% yield. 21/
22 1.7:1.
2875.62, 1742.90, 1497.23, 1455.76; H NMR (CDCl3,
400 MHz): d 0.92 (t, 3H, J 7.3 Hz, CH3 propyl), 1.27
(s, 3H, CH3 acetal), 1.34 (m, 1H, CHH propyl), 1.43
(s, 3H, CH3 acetal), 1.44 (m, 1H, CHH propyl), 1.64
(m, 2H, CH2 propyl), 3.01 (dd, 1H, Jgem 9.9, J7,CHH
7.0 Hz, 7-CHH), 3.13 (m, 1H, H-3), 3.26 (m, 4H,
CH2OCH3, 7-CHH), 3.33 (d, 1H, J3.4 7.9 Hz, H-4),
3.72 (s, 3H, CO2CH3), 3.76 (d, 1H, J 13.9 Hz, CHHPh),
4.13 (dd, 1H, J7,8 3.8, J7,CHH 7.0 Hz, H-7), 4.14 (d, 1H,
J 13.0 Hz, CHHPh), 4.34 (d, 1H, Jgem 16.0 Hz,
CHHOCH3), 4.35 (d, 1H, Jgem 16.0 Hz, CHHOCH3)
4.58 (pseudo s, 2H, H-8, H-9), 7.24–7.37 (m, 5H, Ph);
13C NMR (CDCl3, 100.6 MHz): d 14.22 (CH3 propyl),
19.21 (CH2 propyl), 25.54 (CH3 acetal), 26.18 (CH3 ace-
tal), 33.87 (CH2 propyl), 51.91 (CO2CH3), 55.12
(CH2OCH3), 60.50 (CH2Ph), 61.22 (C-4), 68.09 (7-
CH2), 71.59 (C-3), 82.37 (C-9), 83.07 (C-8), 83.86 (C-
7), 96.25 (CH2OCH3), 112.50 (C-5), 113.20 (C acetal),
127.0–128.8 (5C, Ar), 137.51 (Cipso), 172.28 (CO2CH3).
m/z (EI+) 466.4 [(M+1)+, 3%], 465.2 [(M)+, 18%], 450.2
[(MꢃCH3)+, 4%], 434.2 (5), 422.1 (7), 390.1 (63), 343.1
(50), 311.1 (100). HRMS m/z (ES+) calcd for
C24H36NO8 [M+H]+ 466.2441, found 466.2437.
Eluted first (Rf 0.39, silica gel, 30% EtOAc in
25
hexane) was 21 as a yellow oil; ½aꢂD ¼ ꢃ89.9 (c 0.9,
CHCl3); mmax (neat) 2958.36, 2935.47, 2875.78,
1
1742.91, 1459.14; H NMR (CDCl3, 400 MHz): d 0.92
(t, 3H, J 7.3 Hz, CH3 propyl), 1.30 (s, 3H, CH3 acetal),
1.35 (m, 2H, CH2 propyl), 1.45 (s, 3H, CH3 acetal), 1.53
(m, 2H, CH2 propyl), 2.66 (s, 3H, N–CH3), 2.84 (m, 1H,
H-3), 3.28 (d, 1H, J3.4 8.0 Hz, H-4), 3.37 (s, 3H,
CH2OCH3), 3.54 (pseudo t, 1H, J 9.7 Hz, 7-CHH),
3.65–3.78 (m, 4H, CO2CH3 and 7-CHH), 4.27 (dd,
1H, J7,7-CHH 7.3, J7,7-CHH 9.7 Hz, H-7), 4.60–4.73 (m,
4H, H-8, H-9 and CH2OCH3); 13C NMR (CDCl3,
100.6 MHz): d 14.24 (CH3 propyl), 19.51 (CH2 propyl),
25.65 (CH3 acetal), 26.42 (CH3 acetal), 33.98 (CH2
propyl), 45.85 (N–CH3), 51.18 (CO2CH3), 55.43
(CH2OCH3), 62.42 (C-4), 68.69 (7-CH2), 73.63 (C-3),
82.58 (C-8), 83.29 (C-9), 84.31 (C-7), 96.83 (CH2OCH3),
112.78 (C acetal), 116.70 (C-5), 169.51 (CO2CH3). m/z
(EI+) 390.1 [(M+1)+, 10%], 389.0 [(M)+, 12%], 374.1
[(MꢃCH3)+, 6%], 358.0 (8), 343.1 (40), 314.0 (65),
311.1 (100). HRMS m/z (ES+) calcd for C18H32NO8
[M+H]+ 390.2128, found 390.2130.
Eluted second (Rf 0.38, silica gel, 30% EtOAc in hexane)
was 24 as a yellow oil; ½aꢂD ¼ ꢃ27.0 (c 1, CHCl3); mmax
26
(neat) 2955.62, 2875.20, 1751.74, 1497.42; 1H NMR
(CDCl3, 400 MHz): d 0.84 (t, 3H, J 7.1 Hz, CH3 propyl),
1.17–1.42 (m, 7H, CH3 acetal, 2 · CH2 propyl), 1.46 (s,
3H, CH3 acetal), 3.35 (s, 3H, CH2OCH3), 3.47–3.58 (m,
3H, 7-CHH, H-3, H-4), 3.65 (dd, 1H, Jgem 10.0, J7,CHH
7.6 Hz, 7-CHH), 3.75 (s, 3H, CO2CH3), 4.02 (d, 1H,
J 13.5 Hz, CHHPh), 4.26 (d, 1H, J 13.0 Hz, CHHPh),
4.34 (pseudo t, 1H, J 7.6 Hz, H-7), 4.58 (2, 2H, Jgem
10.7 Hz, CH2OCH3), 4.67 (dd, 1H, J8,9 6.0, J4,9
0.7 Hz, H-9), 4.79 (d, 1H, J8,9 6.0 Hz), 7,25–7.40 (m,
5H, Ph); 13C NMR (CDCl3, 100.6 MHz): d 14.05
(CH3 propyl), 19.99 (CH2 propyl), 25.09 (CH3 acetal),
26.27 (CH3 acetal), 32.45 (CH2 propyl), 51.61
(CO2CH3), 55.35 (CH2OCH3), 59.08 (C-4), 65.21
(CH2Ph), 67.79 (C-3), 68.26 (7-CH2), 81.96 (C-8),
83.41 (C-9), 84.03 (C-7), 96.54 (CH2OCH3), 112.52 (C-
5), 116.20 (C acetal), 127.20–128.82 (5C, Ar), 137.29
(Cipso), 169.38 (CO2CH3). m/z (EI+) 466.4 [(M+1)+,
10%], 465.2 [(M)+, 28%], 450.2 [(MꢃCH3)+, 7%], 434.1
(7), 422.1 (9), 390.1 (85), 311.1 (92), 105.9 (100). HRMS
m/z (ES+) calcd for C24H36NO8 [M+H]+ 466.2441,
found 466.2455.
Eluted second (Rf 0.12, silica gel, 30% EtOAc in hexane)
was 22 as a yellow oil; ½aꢂD ¼ ꢃ45.7 (c 1.4, CHCl3); mmax
25
(neat) 2958.34, 2875.45, 1751.04, 1676.28, 1459.02;
1H NMR (CDCl3, 400 MHz): d 0.93 (t, 3H, J 5.8 Hz,
CH3 propyl), 1.28 (s, 3H, CH3 acetal), 1.35 (m, 2H,
CH2 propyl), 1.44 (s, 3H, CH3 acetal), 1.45 (m, 2H,
CH2 propyl), 2.68 (s, 3H, N–CH3), 3.24 (m, 1H, H-3),
3.38 (s, 3H, CH2OCH3), 3.47 (d, 1H, J3.4 6.7 Hz, H-4),
3.52–3.70 (m, 2H, 7-CH2), 3.75 (s, 3H, CO2CH3), 4.30
(pseudo t, 1H, J 7.3 Hz, H-7), 4.65 (s, 2H, CH2OCH3),
4.70 (d, 1H, J8.9 5.8 Hz, H-8 or H-9), 4.78 (d, 1H, J8.9
5.8 Hz, H-8 or H-9); 13C NMR (CDCl3, 100.6 MHz):
d 14.18 (CH3 propyl), 20.21 (CH2 propyl), 25.16 (CH3
acetal), 26.31 (CH3 acetal), 31.70 (CH2 propyl), 47.88
(N–CH3), 51.73 (CO2CH3), 55.41 (CH2OCH3), 59.53
(C-4), 68.41 (7-CH2), 72.92 (C-3), 83.53 (C-9),
83.95 (C-8), 84.88 (C-7), 96.72 (CH2OCH3), 112.59
(C acetal), 117.32 (C-5), 169.47 (CO2CH3). m/z
(EI+) 391.2 [(M+2)+, 2.5%], 390.1 [(M+1)+, 12%],
389.1 [(M)+, 20%], 374.1 [(MꢃCH3)+, 8%], 358.1 (7),
343.1 (40), 314.0 (90), 311.1 (100). HRMS m/z
(ES+) calcd for C18H32NO8 [M+H]+ 390.2128, found
390.2119.
5.2.8. Methyl (3R,4S,5S,7R,8R,9R)-8,9-isopropylidenedi-
oxy-2-methyl-7-[(methoxymethoxy)methyl]-3-phenyl-1,6-
dioxa-2-azaspiro[4.4]nonane-4-carboxylate 26 and methyl
(3S,4S,5S,7R,8R,9R)-8,9-isopropylidenedioxy-2-methyl-
7-[(methoxymethoxy)methyl]-3-phenyl-1,6-dioxa-2-aza-
spiro[4.4]nonane-4-carboxylate 27. Compound 13
(200 mg, 0.69 mmol) was converted to 26 (243 mg,
0.57 mmol) and 27 (33 mg, 0.08 mmol) according to
the general procedure. Reaction time: 90 min; 94% yield.
5.2.7. Methyl (3R,4R,5S,7R,8R,9R)-8,9-isopropyliden-
edioxy-2-benzyl-7-[(methoxymethoxy)methyl]-3-propyl-
1,6-dioxa-2-azaspiro[4.4]nonane-4-carboxylate 23 and
methyl (3S,4R,5S,7R,8R,9R)-8,9-isopropylidenedioxy-2-
benzyl-7-[(methoxymethoxy)methyl]-3-propyl-1,6-dioxa-
2-azaspiro[4.4]nonane-4-carboxylate 24. Compound 12
(300 mg, 1.04 mmol) was converted to 23 (215 mg,
0.46 mmol) and 24 (214 mg, 0.46 mmol) according to
the general procedure. Reaction time: 100 min; 89%
yield. 23/24 1:1. Eluted first (Rf 0.52, silica gel, 30%
26/27 7.4:1. Eluted first (Rf 0.46, silica gel, 30% EtOAc
25
in hexane) was 26 as a yellow oil; ½aꢂD ¼ ꢃ11.8 (c 1.1,
CHCl3); mmax (neat) 3033.18, 2989.38, 2951.95,
1
EtOAc in hexane) was 23 as
½aꢂD ¼ ꢃ199.6 (c 1, CHCl3); mmax (neat) 2953.36,
a
yellow oil;
1742.76; H NMR (CDCl3, 400 MHz): d 1.39 (s, 3H,
26
CH3 acetal), 1.50 (s, 3H, CH3 acetal), 2.64 (s, 3H, N–

G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
2469
CH3), 3.39 (s, 3H, CH2OCH3), 3.54 (dd, 1H, J7,7-CHH
8.7, Jgem 10.2 Hz, 7-CHH), 3.67 (s, 3H, CO2CH3), 3.71
(dd, 1H, J7,7-CHH 5.8, Jgem 10.2 Hz, 7-CHH), 3.93 (d,
1H, J3.4 9.5 Hz, H-4), 4.24 (br d, 1H, J3.4 9.5 Hz, H-3),
4.35 (dd, 1H, J7,7-CHH 5.8, J7,CHH 8.6 Hz, H-7) 4.68 (s,
2H, CH2OCH3), 4.81 (br s, 2H, H-8 and H-9), 7.28–
7.39 (m, 5H, Ph); 13C NMR (CDCl3, 100.6 MHz): d
25.14 (CH3 acetal), 26.11 (CH3 acetal), 43.44
(N–CH3), 51.91 (CO2CH3), 55.37 (CH2OCH3), 59.56
(C-4), 68.16 (7-CH2), 75.25 (C-3), 82.01 (C-8 or C-9),
84.92 (C-7), 84.61 (C-8 or C-9), 96.77 (CH2OCH3),
113.04, 113.14 (C acetal and C-5), 127.98–128.74 (5C,
Ar), 137.31 (Cipso), 168.98 (CO2CH3). Anal. Calcd for
C21H29NO8: C, 59.56; H, 6.90; N, 3,31. Found: C,
59.45; H, 6.84; N, 3.42.
(7-CH2), 70.81 (C-3), 82.38 (C-8), 84.92 (C-7), 85.76
(C-9), 97.11 (CH2OCH3), 113.38 (C-5), 115.33 (C ace-
tal), 170.23 (CO2CH3). Anal. Calcd for C18H31NO8: C,
55.51; H, 8.02; N, 3,60. Found: C, 55.87; H, 8.04; N,
3.80.
Eluted second (Rf 0.17, silica gel, 30% EtOAc in hexane)
25
was 29 as a yellow oil; ½aꢂD ¼ ꢃ131.7 (c 0.9, CHCl3);
mmax (neat) 2958.49, 2875.61, 1750.56, 1458.53; 1H
NMR (CDCl3 400 MHz): d 0.91 (t, 3H, J 7.3 Hz CH3
propyl), 1.26 (m, 2H, CH2 propyl), 1.34 (s, 3H, CH3 ace-
tal), 1.50 (s, 3H, CH3 acetal), 1.87 (m, 1H, CHH pro-
pyl), 2.63 (m, 4H, N–CH3 and H-3), 3.34 (s, 3H,
CH2OCH3), 3.53 (pseudo t, 1H, J 9.9 Hz, 7-CHH),
3.68–3.74 (m, 4H, CO2CH3, 7-CHH), 3.90 (d, 1H, J3,4
7.4 Hz, H-4), 4.27 (dd, 1H, J7-CHH 4.9, J7,CHH 4.9 Hz,
H-7), 4.57 (d, 1H, J8,9 5.9 Hz, H-9), 4.61 (AB, 2H,
CH2OCH3), 4.77 (d, 1H, J8,9 5.9 Hz, H-8); 13C NMR
(CDCl3, 100.6 MHz): d 14.20 (CH3 propyl), 20.11
(CH2 propyl), 24.97 and 25.89 (2 · CH3 acetal), 29.14
(CH2 propyl), 43.87 (N–CH3), 51.44 (CO2CH3),
54.81 (C-4), 55.26 (CH2OCH3), 68.22 (7-CH2), 71.24
(C-3), 83.12 (C-8), 83.55 (C-7), 84.99 (C-9), 96.75
(CH2OCH3), 112.98 and 113.38 (C-5 and C acetal),
168.02 (CO2CH3). m/z (EI+) 390.0 [(M+1)+, 8%],
389.1 [(M)+, 9%], 374.1 [(MꢃCH3)+, 5%], 358.1 (8),
343.1 (32), 314.0 (50), 311.1 (82), 101.9 (95), 85.9
(100). HRMS m/z (ES+) calcd for C18H32NO8
[M+H]+ 390.2128, found 390.2137.
Eluted second (Rf 0.21, silica gel, 30% EtOAc in hexane)
25
was 27 as a solid; mp. 65 ꢁC; ½aꢂD ¼ ꢃ169.7 (c 1,
CHCl3); mmax (KBr) 3430.24, 3128.86, 2993.47,
1
1753.44; H NMR (CDCl3, 400 MHz): d 1.39 (s, 3H,
CH3 acetal), 1.52 (s, 3H, CH3 acetal), 2.71 (s, 3H, N–
CH3), 3.37 (s, 3H, CH2OCH3), 3.40 (s, 3H, CO2CH3),
3.61 (pseudo t, 1H, J 9.7 Hz, 7-CHH), 3.84 (dd, 1H,
J7,7-CHH 4.9, Jgem 9.7, 7-CHH), 3.93 (br d, 1H, J3,4
8.2 Hz, H-3), 4.22 (d, 1H, J3,4 8.2 Hz, H-4), 4.36 (dd,
1H, J7,7-CHH 9.4, J7,7-CHH 4.8 Hz, H-7) 4.68 (AB, 2H,
CH2OCH3), 4.71 (d, 1H, J8.9 6.0 Hz, H-8 or H-9), 4.85
(d, 1H, J8.9 6.0 Hz, H-8 or H-9), 7.25–7.41 (m, 5H, Ph);
13C NMR (CDCl3, 100.6 MHz): d 25.29 (CH3 acetal),
26.17 (CH3 acetal), 44.30 (N–CH3), 51.43 (CO2CH3),
55.53 (CH2OCH3), 58.52 (C-4), 67.24 (7-CH2), 74.91
(C-3), 82.22 (C-8 or C-9), 85.56 (C-7), 87.89 (C-8 or C-
9), 96.97 (CH2OCH3), 113.36, 113.44 (C acetal and C-
5), 127.95–128.35 (5C, Ar), 134.83 (Cipso), 167.35
(CO2CH3). Anal. Calcd for C21H29NO8: C, 59.56; H,
6.90; N, 3.31. Found: C, 59.47; H, 6.90; N, 3.11.
5.2.10. Methyl (3S,4S,5S,7R,8R,9R)-8,9-isopropyliden-
edioxy-2-benzyl-7-[(methoxymethoxy)methyl]-3-propyl-
1,6-dioxa-2-azaspiro[4.4]nonane-4-carboxylate 30 and
methyl (3R,4S,5S,7R,8R,9R)-8,9-isopropylidenedioxy-2-
benzyl-7-[(methoxymethoxy)methyl]-3-propyl-1,6-dioxa-
2-azaspiro[4.4]nonane-4-carboxylate 31. Compound 13
(200 mg, 0.069 mmol) was converted to 30 (220 mg,
0.47 mmol) and 31 (90 mg, 0.19 mmol) according to
the general procedure. Reaction time: 100 min; 96%
5.2.9. Methyl (3S,4S,5S,7R,8R,9R)-8,9-isopropylidenedi-
oxy-2-methyl-7-[(methoxymethoxy)methyl]-3-propyl-1,6-
dioxa-2-azaspiro[4.4]nonane-4-carboxylate 28 and methyl
(3R,4S,5S,7R,8R,9R)-8,9-isopropylidenedioxy-2-methyl-
7-[(methoxymethoxy)methyl]-3-propyl-1,6-dioxa-2-aza-
spiro[4.4]nonane-4-carboxylate 29. Compound 13
(300 mg, 1.04 mmol) was converted to 28 (200 mg,
0.51 mmol) and 29 (30 mg, 0.08 mmol) according to
the general procedure. Reaction time: 45 min; 57% yield.
yield. 30/31 2.4:1. Eluted first (Rf 0.58, silica gel, 30%
25
EtOAc in hexane) was 30 as an oil; ½aꢂD ¼ ꢃ40.3 (c
1.1, CHCl3); mmax (neat) 2954.84, 2875.51, 1740.68,
1496.73; 1H NMR (CDCl3, 400 MHz): d 1H NMR
(CDCl3, 400 MHz): d 0.74 (t, 3H, J 7.2 Hz, CH3 propyl),
1.10 (m, 1H, CHH propyl), 1.25–1.38 (m, 2H, CH2 pro-
pyl), 1,35 (s, 3H, CH3 acetal), 1.47–1.60 (m, 4H, CH3
acetal, CHH propyl), 3.32 (s, 3H, CH2OCH3), 3,45
(pseudo t, 1H, Jgem 10.1 Hz, 7-CHH), 3.60 (dd, 1H, Jgem
10.1, J7,7-CHH 5.6 Hz, 7-CHH), 3.62 (d, 1H, J3,4 4.7, H-
4) 3.66 (m, 1H, H-3), 3.76 (s, 3H, CO2CH3), 4.15 (d, 1H,
J 12.8 Hz, CHHPh), 4.29–4.37 (m, 2H, J 12.7, J7,CHH
7.3 Hz, CHHPh, H-7), 4.55 (s, 2H, CH2OCH3), 4.58
(d, 1H, J8,9 6.0 Hz, H-9), 4.71 (d, 1H, J8,9 6.0 Hz, H-
8), 7,25–7.46 (m, 5H, PhH); 13C NMR (CDCl3,
100.6 MHz): d 13.73 (CH3 propyl), 19.47 (CH2 propyl),
24.98 and 25.98 (CH3 acetal), 36.75 (CH2 propyl), 52.13
(CO2CH3), 55.39 (CH2OCH3), 58.50 (C-4), 62.30
(CH2Ph), 66.64 (C-3), 68.14 (7-CH2), 82.00 (C-8),
84.26 (C-7), 85.38 (C-9), 96.74 (CH2OCH3), 113.13 (C-
5), 117.81 (C acetal), 127.3–129.5 (5C, Ar), 137,50 (Cip-
so), 170.45 (CO2CH3). Anal. Calcd for C24H35NO8: C,
61.92; H, 7.58; N, 3.01. Found: C, 61.96; H, 7.57; N,
3.15.
28/29 6:1. Eluted first (Rf 0.43, silica gel, 30% EtOAc in
25
hexane) was 28 as a yellow oil; ½aꢂD ¼ ꢃ9.3 (c 1.1,
CHCl3); mmax (neat) 2956.83, 2875.94, 1742.36,
1458.44; 1H NMR (CDCl3, 400 MHz): d 0.92 (t, J
7.2 Hz, 3H, CH3 propyl), 1.20–1.42 (m, 6H, CH3 acetal,
CH2 and CHH propyl), 1.51 (m, 4H, CH3 acetal, CHH
propyl), 2.81 (s, 3H, N–CH3), 3.34–3.37 (m, 4H,
CH2OCH3 and H-3), 3.52 (dd, 1H, J7,CHH 9.2,
Jgem10.3 Hz, 7-CHH), 3.54 (d, 1H, J3.4 7.2 Hz, H-4),
3.65 (dd, 1H, J7,CHH 5.6, Jgem 10.3 Hz, 7-CHH), 3.73
(s, 3H, CO2CH3), 4.30 (dd, 1H, J7,CHH 5.6, J7,CHH
5.8 Hz, H-7), 4.60 (d, 1H, J8,9 6.0 Hz, H-9), 4.64 (s,
2H, CH2OCH3), 4.74 (d, 1H, J8,9 6.0 Hz, H-8); 13C
NMR (CDCl3, 100.6 MHz): d 14.51 (CH3 propyl),
19.87 (CH2 propyl), 25.38 (CH3 acetal), 26.43 (CH3 ace-
tal), 35.73 (CH2 propyl), 46.01 (N–CH3), 52.37
(CO2CH3), 55.75 (CH2OCH3), 58.02 (C-4), 68.53

2470
G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
Eluted second (Rf 0.42, silica gel, 30% EtOAc in hexane)
J7,7-CHH 1.5 Jgem 11.6 Hz, 7-CHH), 3.84 (d, 1H, J9,10
9.5 Hz, H-10), 3.95 (m, 3H, H-3, H-8, 7-CHH), 4.09
(pseudo t, 1H, J8,9 9.5, J9,10 9.5 Hz, H-9), 4.16 (m, 1H,
H-7), 4.57 (d, 1H, J 12.1 Hz, CHHPh), 4.63 (d, 1H, J
12.1 Hz, CHHPh), 4.78 (d, 1H, J 10.8 Hz, CHHPh),
4.85 (d, 1H, J 11.8 Hz, CHHPh), 4.94 (d, 1H, J
10.8 Hz, CHHPh), 5.02 (AB, 2H, J 11.0 Hz, CH2Ph),
5.18 (d, 1H, J 11.7 Hz, CHHPh), 7.28–7.43 (m, 25H,
Ph); 13C NMR (CDCl3, 100.6 MHz): d 44.01 (N–
CH3), 51.1 (CO2CH3), 59.2 (C-4), 68.2 (7-CH2), 72.9
(C-7), 73.3 (CH2Ph), 74.3 (C-3), 75.0 75.4 75.7
(3 · CH2Ph), 78.1 (C-8), 80.3 (C-10), 83.7 (C-9), 104.2
(C-5), 127.4–128.5 (25C, Ar), 135.3, 138.0, 138.2,
138.5, (5 · Cipso), 170.0 (CO2CH3). Anal. Calcd for
C45H47NO8: C, 74.05; H, 6.49; N, 1.92. Found: C,
74.2; H, 6.56; N, 2.03.
25
was 31 as an oil; ½aꢂD ¼ ꢃ97.4 (c 0.9, CHCl3); mmax
(neat) 3088.35, 3063.27, 3030.10, 2954.94, 1748.12,
1
1496.92; H NMR (CDCl3, 400 MHz): d 0.90 (t, 3H, J
7.2 Hz, CH3 propyl), 1.17–1.40 (m, 5H, CH3 acetal
and CH2 propyl), 1,50 (s, 3H, CH3 acetal), 1.62 (m,
1H, CHH propyl), 1.91 (m, 1H, CHH propyl), 3,24
(m, 1H, 7-CHH), 3.29 (s, 3H, CH2OCH3), 3.53 (m,
1H, 7-CHH), 3.72 (s, 3H, CO2CH3), 3.70–3.82 (m, 2H,
H-3 and CHHPh) 3.90 (br d, 1H, J3,4 8.0 Hz, H-4),
4.16–4.30 (m, 2H, H-7, CHHPh), 4.44 (br s, 2H,
CH2OCH3), 4.56 (d, 1H, J8,9 5.8 Hz, H-9), 4.71 (d,
1H, J8,9 5.8 Hz, H-8), 7.25–7.46 (m, 5H, PhH); 13C
NMR (CDCl3, 100.6 MHz): d 14.28 (CH3 propyl),
20.32 (CH2 propyl), 25.08 and 26.01 (CH3 acetal),
29.77 (CH2 propyl), 51.65 (CO2CH3), 53.80 (C-4),
55.37 (CH2OCH3), 60.55 (CH2Ph), 67.54 (C-3), 68.20
(7-CH2), 82.18 (C-8 or C-9), 83.81 (C-7), 85.35 (C-8 or
C-9), 96.71 (CH2OCH3), 113.06, 113.18 (C-5 and C ace-
tal), 127.3–129.5 (5C, Ar), 137,50 (Cipso), 168.16
(CO2CH3). m/z (EI+) 465.3 [(M)+, 2.5%], 450.2
[(MꢃCH3)+, 1%], 390.2 (7), 343.1 (7), 311.0 (11), 161.9
(12), 90.9 (100). Anal. Calcd for C24H35NO8: C, 61.92;
H, 7.58; N, 3.01. Found: C, 62.00; H, 7.48; N, 3.34.
Eluted fourth was 37, (Rf 0.28, silica gel, 30% EtOAc in
26
hexane), oil; ½aꢂD ¼ þ16.6 (c 2.5, CHCl3); mmax (neat)
3088.20, 3063.31, 1753.11, 1719.85, 1496.53; 1H
NMR (CDCl3, 400 MHz): d 2.72 (s, 3H, N–CH3), 3.18
(d, 1H, J7,CHH 9.2 Hz, H-7), 3.27 (s, 3H, CO2CH3),
3.63–3.70 (m, 2H, H-9, H-10), 3.73 (dd, 1H, J7,CHH
10.6, J7,7-CHH 1.8 Hz, 7-CHH), 3.75–3.87 (m, 2H, H-8,
7-CHH), 4.03 (d, 1H, J3,4 7.3 Hz, H-4), 4.12 (d, 1H,
J3,4 7.3 Hz, H-3), 4.49 (d, 1H, J 12.1 Hz, CHHPh),
4.59 (d, 1H, J 10.6 Hz, CHHPh), 4.71 (d, 1H, J
12.0 Hz, CHHPh), 4.81 (d, 1H, J 10.6 Hz, CHHPh),
4.89 (d, 1H, J 10.9 Hz, CHHPh), 4.95 (d, 1H, J
10.9 Hz, CHHPh), 4.96 (d, 1H, J 10.9 Hz, CHHPh),
5.05 (d, 1H, J 11.0 Hz, CHHPh), 7.12–7.16 (m, 2H,
PhH), 7.27–7.33 (m, 23H, PhH); 13C NMR (CDCl3,
100.6 MHz): d 44.14 (N–CH3), 52.09 (CO2CH3), 58.46
(C-4), 68.86 (7-CH2), 73.97 (CH2Ph), 74.9 (C-7), 75.48,
76.18, 76.4 (3 · CH2Ph), 77.60 (2C, C-3, C-8), 82.6 (C-
10), 84.5 (C-2), 107.20 (C-5), 127.5–128–6 (25C, Ar),
134.38, 138.45, 138.56, 138.7, 138.9 (5 · Cipso), 168.4
(CO2CH3). Anal. Calcd for C45H47NO8: C, 74.05; H,
6.49; N, 1.92. Found: C, 73.91; H, 6.44; N, 1.65.
5.2.11.
Methyl
(3R,4S,5S,7R,8R,9S,10R)-8,9,10-
tris(benzyloxy)-7-[(benzyloxy)methyl]-2-methyl-3-phenyl-
1,6-dioxa-2-azaspiro[4.5]decane-4-carboxylate 34, methyl
(3S,4R,5R,7R,8R,9S,10R)-8,9,10-tris(benzyloxy)-7-[(benz-
yloxy)methyl]-2-methyl-3-phenyl-1,6-dioxa-2-azaspiro[4.5]-
decane-4-carboxylate 35, methyl (3R,4R,5R,7R,8R,9S,
10R)-8,9,10-tris(benzyloxy)-7-[(benzyloxy)methyl]-2-meth-
yl-3-phenyl-1,6-dioxa-2-azaspiro[4.5]decane-4-carboxylate
36 and methyl (3S,4S,5S,7R,8R,9S,10R)-8,9,10-tris(benz-
yloxy)-7-[(benzyloxy)methyl]-2-methyl-3-phenyl-1,6-dioxa-
2-azaspiro[4.5]decane-4-carboxylate 37. Compound 33
(311 mg, 0.50 mmol) was converted to 34 (33 mg,
0.043 mmol), 35 (212 mg, 0.27 mmol), 36 (90 mg,
0.117 mmol) and 37 (26 mg, 0.034 mmol) according to
the general procedure. Reaction time: 36 min; 90% yield.
34/35/36/37 1.3:8.1:3.5:1. Eluted first was 34, mixed with
5.2.12. Methyl (3S,4S,5S,7R,8R,9S,10R)-8,9,10-tris(benz-
yloxy)-7-[(benzyloxy)methyl]-2-methyl-3-propyl-1,6-di-
oxa-2-azaspiro[4.5]decane-4-carboxylate 38, methyl (3S,
4R,5R,7R,8R,9S,10R)-8,9,10-tris(benzyloxy)-7-[(benzyl-
oxy)methyl]-2-methyl-3-propyl-1,6-dioxa-2-azaspiro[4.5]-
decane-4-carboxylate 39 and methyl (3R,4S,5S,7R,8R,
9S,10R)-8,9,10-tris(benzyloxy)-7-[(benzyloxy)methyl]-2-
methyl-3-propyl-1,6-dioxa-2-azaspiro[4.5]decane-4-carbox-
ylate 40. Compound 33 (500 mg, 0.84 mmol) was con-
verted to 38 (200 mg, 0.28 mmol), 39 (140 mg,
0.20 mmol) and 40 (34 mg, 0.048 mmol) according to
the general procedure. Reaction time: 33 min, 64% yield.
35. Eluted second was 35, (Rf 0.45, silica gel, 30%
25
EtOAc in hexane), oil; ½aꢂD ¼ þ18.0 (c 1, CHCl3), mmax
(neat) 3088.23, 3063.66, 3031.26, 2917.80, 2869.77,
1747.97, 1652.77, 1496.44; 1H NMR (CDCl3,
400 MHz): d 2.83 (s, 3H, N–CH3), 3.54 (s, 3H,
CO2CH3), 3.70–3.82 (m, 4H, H-3, H-4, H-8 and 7-
CHH), 3.84 (dd, 1H, Jgem 10.9, J 8.0 Hz, 7-CHH),
3.94 (d, 1H, J9,10 10.2 Hz, H-10), 4.03–4.15 (m, 2H, H-
7 and H-9), 7.25–7.60 (m, 25H, Ar); 13C NMR (CDCl3,
100.6 MHz):
d
47.0 (N–CH3), 51.1 (C-4), 52.0
(CO2CH3), 60.8 (C-3), 68.5 (7-CH2), 72.7 (C-7), 73.3
(CH2Ph), 75.3 (CH2Ph), 75.7 (CH2Ph), 75.8 (CH2Ph),
78.3 (C-8), 78.6 (C-10), 83.9 (C-9), 105.8 (C-5), 127.3–
128.6 (25C, Ar), 135.1–138.8 (5 · Cipso), 167.5
(CO2CH3). HRMS m/z (ES+) calcd for C45H48NO8
[M+H]+ 730.3380, found 730.3394.
38/39/40 5.9:4.1:1. Eluted first (Rf 0.42, silica gel, 30%
25
EtOAc in hexane) was 38 as a yellow oil; ½aꢂD ¼ þ13.0
(c 0.5, CHCl3); mmax (neat) 2929.47, 2956.21, 2871.72,
1746.62, 1454.35, 1361.74; 1H NMR (CDCl3,
400 MHz): d 0.92 (t, 3H, J 7.2 Hz, CH3 propyl), 1.29–
1.67 (m, 4H, 2 · CH2 propyl), 2.92 (s, 3H, N–CH3),
3.35 (d, 1H, J3.4 8.7 Hz, H-4), 3.55 (m, 1H, H-3), 3.61
(s, 3H, CO2CH3), 3.65 (dd, 1H, Jgem = 11.4, J7,7-CHH
1.5 Hz, 7-CHH), 3.77 (pseudo t, 1H, J 9.3 Hz, H-8),
3.83 (dd, 1H, Jgem 11.4, J7,7CHH 3.6 Hz, 7-CHH), 3.89
(d, 1H, J9.10 9.9 Hz, H-10), 3.98–4.07 (m, 2H, H-7, H-
Eluted third was 36, (Rf 0.42, silica gel, 30% EtOAc in
25
hexane), oil; ½aꢂD ¼ þ38.6 (c 0.4, CHCl3); mmax (neat)
1
2869.31, 1748.15, 1496.39, 1454.00; H NMR (CDCl3,
400 MHz): d 2.80 (s, 3H, N–CH3), 3.37 (s, 3H,
CO2CH3), 3.64 (d, 1H, J3,4 8.4 Hz, H-4), 3.82 (dd, 1H,

G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
2471
9), 4.51 (d, 1H, JAB 12.4 Hz, CHHPh), 4.60 (d, 1H, JAB
12.4 Hz, CHHPh), 4.69 (d, 1H, JAB 10.8 Hz, CHHPh),
4.82 (d, 1H, JAB 11.6 Hz, CHHPh), 4.88–4.98 (m, 3H,
3 · CHHPh), 5.06 (d, 1H, JAB 11.6 Hz, CHHPh); 13C
NMR (CDCl3, 100.6 MHz,): d 14.09 (CH3 propyl),
19.22 (CH2 propyl), 35.67 (CH2 propyl), 48.73 (N–
CH3), 51.91 (CO2CH3), 58.10 (C-4), 67.1 (C-3), 68.31
(7-CH2), 72.54 (C-7), 73.15 (CH2Ph), 75.11 (CH2Ph),
75.28 (CH2Ph), 75.60 (CH2Ph), 78.21 and 78.25 (C-8
and C-10), 83.66 (C-9), 106.80 (C-5), 127.1 and 128.4
(20C, Ar), 138.13, 138.16, 138.41, 138.59 (4 · Cipso),
168.48 (CO2CH3). Anal. Calcd for C42H49NO8: C,
72.49; H, 7.10; N, 2.01. Found: C, 71.32; H, 7.24; N,
2.07.
5.3. Cycloaddition reactions with N-methylidenebenzyl-
amine N-oxide 5 formed in situ under microwave activa-
tion. General procedure
A solution of N-benzylhydroxylamine (prepared by
NaBH3CN reduction of benzaldehyde oxime,34 0.75
mmol, 1.25 equiv) and paraformaldehyde (1.1 mmol,
1.8 equiv) in EtOH (0.7 mL) in a septum-sealed glass
tube was heated at 40 ꢁC in a focussed microwave oven
(Discoverꢂ CEM) for 10 min The exo-glycal 1, 11–13,
33 or 42 (0.6 mmol) was added and the mixture heated
in the microwave oven at 80 ꢁC for 20 min The reaction
was monitored by TLC before a new addition of N-benz-
ylhydroxylamine (0.75 mmol) and paraformaldehyde
(1.1 mmol). After heating at 80 ꢁC for 20 min, the reac-
tion was controlled again. A third addition of N-benz-
ylhydroxylamine (0.75 mmol) and paraformaldehyde
(1.1 mmol) was performed and after heating at 80 ꢁC
for another 20 min the reaction was complete. Silica
gel column chromatography of the crude mixture with
EtOAc-hexane as eluent afforded spiroisoxazolidines
10, 18, 25, 32, 41 and 43 (68–92% yields).
Eluted second (Rf 0.23, silica gel, 30% EtOAc in hexane)
25
was 39 as a yellow oil; ½aꢂD ¼ þ31.8 (c 1.1, CHCl3); mmax
(neat) 2929.69, 2956.39, 2871.63, 1751.54, 1496.91,
1
1453.99; H NMR (CDCl3, 400 MHz): d 0.91 (t, 3H, J
7.2 Hz, CH3 propyl), 1.10–1.35 (m, 2H, CH2 propyl),
1.45 (m, 1H, CHH propyl), 2.01 (m, 1H, CHH propyl),
2.73 (m, 4H, N–CH3, H-3), 3.32 (d, 1H, J3,4 7.2 Hz, H-
4), 3.58 (s, 3H, CO2CH3), 3.70–3.80 (m, 2H, H-10, 7-
CHH), 3.84–3.92 (m, 2H, H-8, 7-CHH), 3.97 (m, 1H,
H-9), 4.03 (m, 1H, J7,8 9.7 Hz, H-7), 4.49 (d, 1H, J
12.2 Hz, CHHPh), 4.59 (d, 1H, J 12.2 Hz, CHHPh),
4.72 (d, 1H, J 10.9 Hz, CHHPh), 4.75 (d, 1H, J
11.8 Hz, CHHPh), 4.87 (d, 1H, J 12.2 Hz, CHHPh),
4.93 (d, 1H, J 11.1 Hz, CHHPh), 4.96 (d, 1H, J
11.1 Hz, CHHPh), 5.08 (d, 1H, J 12.2 Hz, CHHPh);
13C NMR (CDCl3, 100.6 MHz): d 14.15 (CH3 propyl),
20.39 (CH2 propyl), 29.02 (CH2 propyl), 43.95
(NCH3), 51.45 (CO2CH3), 55.98 (C-4), 68.21 (7-CH2),
70.73 (C-3), 72.77 (C-7), 73.33 (CH2Ph), 74.98 (CH2Ph),
75.39 (CH2Ph), 75.61 (CH2Ph), 77.99 (C-8), 79.97
(C-10), 83.72 (C-9), 104.00 (C-5), 127.35–128.44
(20C, Ar), 137.99, 138.27, 138.56, (4 · Cipso), 168.17
(CO2CH3). m/z (EI+) 697.3 [(M+2)+, 3.7%], 695.9
[(M+1)+, 5.2%], 694.8 [(M)+, 1.2%], 605.2
[(M+1ꢃBn)+, 2.7%], 604.2 [(MꢃBn)+, 2.8%], 541.5
(5), 419.1 (10), 104.8 (100); HRMS m/z (ES+) calcd
for C42H50NO8 [M+H]+ 696.3536, found 696.3536.
5.3.1. Methyl (4R,5S,7S,8R,9R)-8,9-isopropylidenedi-
oxy-2-benzyl-7-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,6-
dioxa-2-azaspiro[4.4]nonane-4-carboxylate 10. Com-
pound 1 (178 mg, 0.56 mmol) was converted to 10
(189 mg, 0.42 mmol) in 75% yield. Yellow oil; Rf 0.59
26
(silica gel, 50% EtOAc in hexane); ½aꢂD ¼ ꢃ91.2 (c 2.0,
CHCl3); mmax (neat) 3063.66, 3030.59, 2987.22,
1
1742.69; H NMR (CDCl3, 400 MHz): d 1.24 (s, 3H,
CH3 acetal), 1.42 (s, 6H, 2CH3 acetal), 1.50 (s, 3H,
CH3 acetal), 3.55 (m, 1H, H-3), 3.69 (m, 4H, CO2CH3,
H-50), 3.80 (m, 1H, H-4), 3.85 (m, 1H, H-7), 4.10 (m,
1H, H-3), 4.20 (pseudo t, 1H, J 7.6 Hz, H-50), 4.39 (m,
1H, J4 ;5 7.0 Hz, H-40), 4.61 (dd, 1H, J8,9 5.5, J7,8
4.1 Hz, H-8), 4.69 (m, 1H, H-9), 7.26–7.43 (m, 5H,
Ph); 13C NMR (CDCl3, 100.6 MHz): d 25.25, 25.57,
25.96, 26.94 (4· CH3 acetal), 52.14 (CO2CH3), 54.08
(C-4), 58.45 (C-3), 66.14 (C-50), 75.45 (C-40), 79.83 (C-
8), 81.41 (C-7), 83.31 (C-9), 110.02 (C acetal), 113.26
(C acetal), 116,0 (C-5), 127.4–128.9 (5C, Ar), 137.07
(Cipso), 171.57 (CO2CH3). m/z (EI+) 450.4 [(M+1)+,
3%], 449.1 [(M)+, 7%], 434.2 [(MꢃCH3)+, 7%], 418.3
(5), 417.1 (20), 100.8 (14), 90.9 (100); HRMS m/z
(ES+) calcd for C23H32NO8 [M+H]+ 450.2128, found
450.2121.
0
0
Eluted third (Rf 0.11, silica gel, 30% EtOAc in hexane)
25
was 40 as a yellow oil, ½aꢂD ¼ þ12.4 (c 0.4, CHCl3); mmax
1
(neat) 2960, 1734, 1454; H NMR (CDCl3, 400 MHz):
d 0.86–1.0 (m, 3H, CH3 propyl), 1.23–1.45 (m, 2H, CH2
propyl), 1.45–1.70 (m, 1H, CHH propyl), 2.01 (m, 1H,
CHH propyl), 2.69 (br s, 3H, N–CH3), 2.83 (m, 1H,
H-3), 3.28 (m, 1H, H-7), 3.56–3.75 (m, 6H, H-8, H-9,
H-10 and CO2CH3), 3.90 (m, 2H, H-10, 7-CHH),
4.48–4.94 (CH2Ph), 7.17–7.34 (m, 20H, Ph); 13C NMR
(CDCl3, 100.6 MHz): d 13.98 (CH3 propyl), 20.02
(CH2 propyl), 29.45 (CH2 propyl), 43.84 (NCH3),
52.07 (CO2CH3), 55.17 (C-4), 68.88 (7-CH2), 73.48 (C-
3), 73.76 (CH2Ph), 74.82 (C-7), 75.00 (CH2Ph), 75.85
(CH2Ph), 76.03 (CH2Ph), 77.60 (C-8), 82.00 (C-10),
83.83 (C-9), 106.59 (C-5), 127.28–129.81 (20C, Ar),
138.24, 138.49, 138.62, 138.80 (4 · Cipso), 169.11
(CO2CH3). m/z (EI+) 695.9 [(M)+, 2.1%], 595.3
[(Mꢃ100.6)+, 6%], 563.2 (7%), 180.9 (83%), 91.0
(100%); HRMS m/z (ES+) calcd for C42H50NO8
[M+H]+ 696.3536, found 696.3510.
5.3.2. Methyl (4S,5S,7S,8R,9R)-8,9-isopropylidenedioxy-
2-benzyl-7-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,6-dioxa-
2-azaspiro[4.4]nonane-4-carboxylate 18. Compound 11
(176 mg, 0.56 mmol) was converted to 18 (213 mg,
0.47 mmol) in 84% yield. Glassy solid; Rf 0.24 (silica gel,
26
30% EtOAc in hexane); ½aꢂD ¼ þ25.5 (c 1 CHCl3; mmax
)
(KBr) 2986.72, 2940.56, 1741.37; 1H NMR (CDCl3,
400 MHz): d 1.29 (s, 3H, CH3 acetal), 1.40 (s, 3H,
CH3 acetal), 1.48 (s, 3H, CH3 acetal), 1.50 (s, 3H, CH3
acetal), 3.51 (m, 1H, H-3), 3.67 (m, 1H, H0-3), 3.72
(pseudo t, 1H, J 7.7 Hz, H-50), 3.77 (s, 3H, CO2CH3),
3.93 (m, 2H, H-4, H-7), 4.06 (d, 1H, Jgem 12.8 Hz,
CH2Ph), 4.18 (dd, 1H, Jgem 7.7, J4 ;5 7.5 Hz, H-50),
0
0
4.26 (pseudo q, 1H, J4 .5 ¼ 7.5; J4 ;7 7.2 Hz, H-40), 4.45
0
0
0
(m, 1H, CHHPh), 4.55 (d, 1H, J8,9 5.8 Hz, H-9), 4.64

2472
G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
(dd, 1H, J8,9 5.8, J7,8 4.0 Hz, H-8), 7.25–7.46 (m, 5H,
Ph); 13C NMR (CDCl3, 100.6 MHz): d 24.64, 25.50,
25.68, 26.07 (4 · CH3 acetal), 51.74 (C-4), 52.13
(CO2CH3), 56.37 (C-3), 62.99 (CH2Ph), 66.08 (C-50),
75.82 (C-40), 79.95 (C-8), 82.48 (C-7), 84.89 (C-9),
109.87 (C acetal), 113.55 (C acetal), 115.71 (C-5),
127.4–129.5 (5C, Ar), 137.70 (Cipso), 169.94 (CO2CH3).
m/z (EI+) 450.4 [(M+1)+, 2%], 449.1 [(M)+, 7%], 434.2
[(MꢃCH3)+, 7%], 418.3 (5), 417.1 (20), 100.8 (18), 90.9
(100); HRMS m/z (ES+) calcd for C23H32NO8
[M+H]+ 450.2128, found 450.2124.
5.3.5. Methyl (4R,5R,7R,8R,9S,10R)-8,9,10-tris(benz-
yloxy)-7-[(benzyloxy)methyl]-2-benzyl-1,6-dioxa-2-aza-
spiro[4.5]decane-4-carboxylate
41. Compound
33
(178 mg, 0.30 mmol) was converted to 41 (147 mg,
0.20 mmol) in 68% yield, yellow oil; Rf 0.47 (silica
26
gel, 30% EtOAc in hexane); ½aꢂD ¼ þ35.0 (c 1, CHCl3);
mmax (neat) 3088.00, 3062.94, 3030.27, 2919.33, 2865.47,
1
1745.72, 1496.70; H NMR (CDCl3, 400 MHz): d 3.63
(s, 3H, CO2CH3), 3.64–4.20 (m, 11H, J7-CHH,7-CHH
11.5, J7,CHH 4.9 Hz, 2 · H-3, H-4, H-7, H-8, H-9, H-
10, 2 · 7-CHH and NCH2Ph), 4.52 (d, 1H, J 12.1Hz,
CHHPh), 4.62 (d, 1H, J 12.1 Hz, CHHPh), 4.71 (d,
1H, J 10.9 Hz, CHHPh), 4.85 (d, 1H, J 11.6 Hz,
CHHPh), 4.90 (d, 1H, J 10.9 Hz, CHHPh), 4.95 (s,
2H, CH2Ph), 5.12 (d, 1H, J 11.6 Hz, CHHPh), 7.30–
7.36 (m, 25H, Ph); 13C NMR (CDCl3, 100.6 MHz): d
52.17 (CO2CH3), 53.74 (C-3), 68.78 (7-CH2), 72.87
(1C), 73.31 (CH2Ph), 75.21 (CH2Ph), 75.73 (2C, CH2–
Ph), 78.24 (1C), 78.36 (1C), 83.95 (1C), 106.21 (C-5),
127.50–127.98 (25C, Ar), 138.21–138.75 (5C, Cipso),
168.56 (CO2CH3). Anal. Calcd for C45H47NO8: C,
74.05; H, 6.49; N, 1.92. Found: C, 74.41; H, 6.43; N,
2.03.
5.3.3. Methyl (4R,5S,7R,8R,9R)-8,9-isopropylidenedi-
oxy-2-benzyl-7-[(methoxymethoxy)methyl]-1,6-dioxa-2-
azaspiro[4.4]nonane-4-carboxylate 25. Compound 12
(180 mg, 0.62 mmol) was converted to 25 (242 mg,
0.57 mmol) in 92% yield. Yellow oil; Rf 0.28 (silica gel,
26
30% EtOAc in hexane); ½aꢂD ¼ ꢃ80.6 (c 1.3, CHCl3);
mmax (neat) 3030.48, 2988.08, 2949.80, 1742.50;
1H NMR (CDCl3, 400 MHz): d 1.30 (s, 3H, CH3 acetal),
1.46 (s, 3H, CH3 acetal), 3.32 (s, 3H, CH2OCH3), 3.52
(m, 2H, 2 · H-3), 3.68 (pseudo t, 1H, J 7.7 Hz, 7-
CHH), 3.72 (s, 3H, CO2CH3), 3.90 (m, 1H, H-4), 4.02
(d, 1H, J 12.7 Hz, CHHPh), 4.10 (m, 1H, H-7), 4.25
(m, 1H, 7-CHH), 4.47 (m, 3H, CH2OCH3 and CHHPh),
4.65 (m, 1H, H-8), 4.68 (s, 1H, H-9), 7.27–7.34 (m, 5H,
Ph); 13C NMR (CDCl3, 100.6 MHz): d 25.66 (CH3 ace-
tal), 26.43 (CH3 acetal), 52.13 (CO2CH3), 54.77
(CH2OCH3), 55.38 (CH2Ph), 59.45 (C-4), 62.85 (7-
CH2), 71.59 (C-3), 82.37 (C-9), 83.07 (C-8), 83.86
(C-7), 96.25 (CH2OCH3), 112.50 (C-5), 113.20 (C
acetal), 127.62–129.17 (5C, Ar), 137.51 (Cipso), 172.28
(CO2CH3). m/z (EI+) 424.2 [(M+1)+, 1.5%],
423.1 [(M)+, 3%], 408.1 [(MꢃCH3)+, 1%], 392.1 (5),
391.1 (20), 389.9 (2), 90.9 (100); HRMS m/z (ES+)
calcd for C21 H30NO8 [M+H]+ 424.1971, found
424.1984.
5.3.6. Methyl (4R,5R,7R,8R,9S,10R)-8,9,10-tris(meth-
oxymethoxy)-7-[(methoxymethoxy)methyl]-2-benzyl-1,6-
dioxa-2-azaspiro[4.5]decane-4-carboxylate
43. Com-
pound 42 (180 mg, 0.44 mmol) was converted to 43
(172 mg, 0.31 mmol) in 72% yield, yellow oil; Rf 0.23
25
(silica gel, 50% EtOAc in hexane); ½aꢂD ¼ þ27 (c 0.9,
CHCl3); mmax (neat) 2949, 1743, 1454; 1H NMR (CDCl3,
400 MHz): d 3.35, 3.42, 3.44, 3.46 (4s, 12H, CH3 acetal),
3.50–4.20 (m, 14H, 2 · H-3, H-4, 7-CH2, H-7, H-8, H-9,
H-10, CO2CH3, CH2Ph), 4.62 (br s, 2H, CH2OCH3),
4.73 (d, 1H, J 6.5 Hz, CHHOCH3), 4.80–4.87 (m, 4H,
2 · CH2OCH3), 4.96 (d, 1H, J 6.5 Hz, CHHOCH3),
7.27–7.42 (m, 5H, Ph); 13C NMR (CDCl3,
100.6 MHz): d 52.17 (CO2CH3), 54.18, 55.20, 55.40
(CH3 acetal), 65.88 (CH2OCH3), 72.06, 76.40, 78.53,
81.18, (C-7, C-8, C-9, C-10), 96.72, 98.48, 98.85, 99.41
(CH2OCH3), 105.97 (C-5), 127.62–129.52 (Ar), 136.67
(Cipso), 168.87 (CO2CH3). m/z (EI+) 546.4 [(M+1)+,
5%], 545.1 [(M)+, 10%], 514.1 [(MꢃCH3O)+, 20%],
452.1 [(MꢃBn), 27%], 360.0 (55), 90.9 (100); HRMS
m/z (ES+) calcd for C25H40NO12 [M+H]+ 546.2551,
found 546.2533.
5.3.4. Methyl (4S,5S,7R,8R,9R)-8,9-isopropylidenedi-
oxy-2-benzyl-7-[(methoxymethoxy)methyl]-1,6-dioxa-2-
azaspiro[4.4]nonane-4-carboxylate 32. Compound 13
(180 mg, 0.62 mmol) was converted to 32 (235 mg,
0.55 mmol) in 89% yield. Yellow oil; Rf 0.30 (silica gel,
26
30% EtOAc in hexane); ½aꢂD ¼ ꢃ44.7 (c 0.8, CHCl3);
m
max (neat) 2986.83, 2948.86, 1741.33; 1H NMR (CDCl3,
400 MHz): d 1.35 (s, 3H, CH3 acetal), 1.55 (s, 3H, CH3
acetal), 3.32 (s, 3H, CH2OCH3), 3.41 (m, 1H, 7-CHH),
3.58 (dd, 1H, J7,CHH 5.4, Jgem 11,0 Hz, 7-CHH), 3.74
(s, 3H, CO2CH3), 3.91 (d, 1H, J3,4 7.9 Hz, H-4), 4.13
(m, 2H, CH2Ph), 4.20 (m, 2H, H-3), 4.31 (m, 1H, H-
7), 4.53 (m, 2H, CH2OCH3), 4.61 (d, 1H, J8,9 6.0 Hz,
H-8), 4.73 (d, 1H, J8,9 6.0 Hz, H-9), 7.26–7.41 (m, 5H,
Ph); 13C NMR (CDCl3, 100.6 MHz): d 24.89 (CH3 ace-
tal), 25.88 (CH3 acetal), 51.68 (C-4), 52.07 (CO2CH3),
55.37 (CH2OCH3), 56.20 (CH2Ph), 62.71 (C-3), 68.07
(7-CH2), 82.03 (C-9), 84.44 (C-7), 85.11 (C-8), 96.73
(CH2OCH3), 113.13 (C acetal), 116.77 (C-5), 127.4–
129.2 (5C, Ar), 136.83 (Cipso), 170.04 (CO2CH3). m/z
(EI+) 424.3 [(M+1)+, 1.5%], 423.1 [(M)+, 4%], 408.2
[(MꢃCH3)+, 2%], 392.2 (6), 391.1 (20), 389.9 (2), 90.9
(100). HRMS m/z (ES+) calcd for C21H30NO8
[M+H]+ 424.1971, found 424.1964.
5.4. Cycloaddition reaction with benzonitrile oxide 44.
General procedure
A solution of benzohydroximoyl chloride (0.30 g,
2 mmol, 2 equiv) and triethylamine (0.266 mL, 2 mmol,
2 equiv) in dichloromethane (5 mL) was added to a solu-
tion of exo-glycal 1, 11 or 33 (1 mmol) in dichlorometh-
ane (2 mL) and the mixture stirred at room temperature
for 6 h. The solvent was then evaporated and the solid
residue purified by silica gel column chromatography
to afford compounds 46 (52% yield from 1, 72% from
11) and 47 (32% yield from 33).
5.4.1. Methyl (10R,20R,30S,40R)-3-phenyl-5[(10,20-40,50-
diisopropylidenedioxy,30-hydroxy)pentyl]-isoxazole-4-carb-
oxylate 46. Compound 1 (300 mg, 0.95 mmol) was

G. Enderlin et al. / Tetrahedron: Asymmetry 16 (2005) 2459–2474
2473
converted to 46 (210 mg, 0.48 mmol) in 52% yield. Yel-
low oil; Rf 0.40 (silica gel, 30% EtOAc in hexane);
½aꢂD ¼ þ26.2 (c 0.9, CHCl3); 1H NMR (CDCl3,
400 MHz): d 1.34 (s, 3H, CH3 acetal), 1.41 (s, 3H,
CH3 acetal), 1.49 (s, 3H, CH3 acetal), 1.72 (s, 3HCH3
acetal), 2.32 (d, 1H, J 5.1 Hz, OH), 3.60 (m, 1H, H-
(m, 1H, H–(CH2) propyl), 1.82 (m, 1H, H–(CH2) pro-
0
0
pyl), 3.22 (s, 3H, N–Me), 3.54 (dd, 1H, J1 .2 6.4, Jgem
12.0 Hz, H-20), 3.65 (dd, 1H, J1 .2 4.0, Jgem 12.0 Hz,
0
0
H-20), 3.70 (s, 3H, Me ester), 3.78 (d, 1H, J3.4 5.8 Hz,
H-4), 3.87 (m, 1H, H-10), 4.14 (dd, 1H, J7.8 6.4, J1 .7
0
4.3 Hz, H-7), 4.33 (m, 2H, H-8, H-3), 4.39 (d, 1H, J8.9
5.0 Hz, H-9); 13C NMR (100 MHz, D2O): d 15.38 (Me
propyl), 21.87 (CH2 propyl), 29.96 (CH2 propyl), 47.89
(N–Me), 55.51 (Me ester), 58.22 (C-4), 64.71 (C-20),
72.46 (C-10), 73.05 (C-8), 74.98 (C-3), 76.22 (C-9),
83.10 (C-7), 120.42 (C-5), 172.24 (C(O)OMe). HRMS
m/z (ES+) calcd for C14H25NO8Na [M+Na]+
358.1478, found 358.1482.
30), 3.73 (s, 3H, CO2CH3), 3.83 (dd, 1H, J4 ;5 7.3, Jgem
0
0
8.0 Hz, H-50), 3.95 (dd, 1H, J4 ;5 7.3, Jgem 8.0 Hz, H-
0
0
50), 4.08 (m, 1H, H-40), 4.60 (dd, 1H, J1 ;2 6.6, J2 ;3
0
0
0
0
3.6 Hz, H-20), 5.90 (d, 1H, J1 ;20 6.6 Hz, H-10), 7.43–
7.44 (m, 3H, PhH), 7.58–7.60 (m, 2H, PhH); 13C
NMR (CDCl3, 100.6 MHz): d 25.12, 25.16, 26.10,
26.18 (4 · CH3 acetal), 51.88 (CO2CH3), 65.58 (C-50),
68.59 (C-30), 71.61 (C-10), 76.17 (C-40), 78.34 (C-20),
109.40 (C-4), 109.51, 110.95 (2 · C acetal), 127.94–
129.80 (6C, Ar), 161.77, 161.98 (C-3, C-5), 174.85
(CO2CH3). Anal. Calcd for C22H27NO8: C, 60.96; H,
6.28; N, 3.23. Found: C, 60.60; H, 6.32; N, 3.13.
0
5.5.2. Methyl (10R,20R,30S,40R)-3-phenyl-5[(10,20,30,40,50-
hydroxy)pentyl]-isoxazole-4-carboxylate 49. Compound
46 (59 mg, 0.13 mmol) was converted to 49 (48
25
mg) quantitatively. Solid, mp 103 ꢁC; ½aꢂD ¼ þ13.2 (c
0.8, CH3OH); mmax (KBr) 3338.32, 3139.26, 1708.71,
1608.14; 1H NMR (CD3OD, 400 MHz): d 3.67 (dd,
5.4.2. Methyl (10R,20S,30R,40R)-3-phenyl-5-[40-hydroxy-
10,20,30,50-tetra(benzyloxy)pentyl]-isoxazole-4-carboxyl-
ate 47. Compound 33 (838 mg, 1.40 mmol) was con-
verted to 47 (350 mg, 0.49 mmol) in 35% yield. Yellow
1H, J4 ;5 8.8, Jgem 19.0 Hz, H-50), 3.77 (dd, 1H, J4 ;5
0
0
0
0
8.8, Jgem 19.0 Hz, H-50), 3.82 (s, 3H, CO2CH3), 3.91
(m, 1H, H-40), 3.98 (dd, 1H, H-30, J2 ;3 2.7, J3 ;4
0
0
0
0
9.6 Hz, H-30), 4.20 (dd, 1H, J2 ;3 2.7, J1 ;2 14.3 Hz, H-
0
0
0
0
oil; Rf 0.48 (silica gel, 30% EtOAc in hexane);
25
20), 5.56 (d, 1H, J1 ;2 14.3 Hz, H-10), 7.57–7.62 (m, 5H,
PhH); 13C NMR (CD3OD, 100.6 MHz): d 52.32
(CO2CH3), 64.06 (C-50), 67.13 (C-10), 70.53 (C-30),
74.01 (C-20), 75.02 (C-40), 111.09 (C-4), 129.20–130.92
(6C, Ar), 163.57, 163.73 (C-3, C-5), 179.18 (CO2CH3).
HRMS m/z (ES+) calcd for C16H19NO8Na [M+Na]+
376.1008, found 376.1012.
0
0
½aꢂD ¼ þ38.7 (c 0.6, CHCl3); mmax (neat) 3088.02,
3030.90, 1731.72, 1596.39; 1H NMR (CDCl3,
400 MHz): d 2.95 (d, 1H, J 5.1 Hz, OH), 3.52 (s, 3H,
CO2CH3), 3.62 (dd, 1H, J4 ;5 5.5, Jgem 9.7 Hz, H-50),
0
0
3.67 (dd, H, J4 ;5 3.6, Jgem 9.7 Hz, H-50), 3.70 (dd, 1H,
0
0
J2 ;3 5.2, J3 ;4 6.8 Hz, H-30), 4.07 (m, 1H, H-40), 4.39
0
0
0
0
(dd, 1H, J1 ;2 6.1, J2 .3 4.6 Hz, H-20), 4.45–4.59 (m, 4H,
2 · CH2Ph), 4.63 (d, 1H, J 11.6 Hz, CHHPh), 4.69 (d,
1H, J 11.6 Hz, CHHPh), 4.78 (d, 1H, J 11.4 Hz,
CHHPh), 4.83 (d, 1H, J 11.3 Hz, CHHPh), 5.63 (d,
0
0
0
0
Acknowledgements
1H, J1 ;2 6.1 Hz, H-10), 7.20–7.35 (m, 20H, PhH), 7.45–
7.52 (m, 3H, PhH), 7.56–7.61 (m, 2H, PhH); 13C NMR
(CDCl3, 100.6 MHz): d 51.62 (CO2CH3), 70.78 (C-40),
70.96 (C-50), 72.83, 73.15, 73.34 (3 · CH2Ph), 74.68 (C-
10), 75.12 (CH2Ph), 77.66 (C-30), 79.81 (C-20), 109.88
(C-4), 127.47–129.89 (26C, Ar), 137.14, 137.57, 137.95,
137.98 (4 · Cipso), 161.56 (C-5), 162.03 (C-3), 174.52
(CO2CH3). Anal. Calcd for C44H43NO8: C, 74.03; H,
6.07; N, 1.96. Found: C, 73.94; H, 6.10; N, 2.08.
0
0
We thank the ÔService Commun de Diffraction X sur
´
´
Monocristaux (Universite Henri Poincare, Nancy 1)
for providing access to crystallographic experimental
facilities.
References
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5.5. Deprotection of 7 and 46
The same protocol was applied for the deprotection of 7
and 46. The procedure was described for compound 7.
Compound 7 (140 mg, 0.33 mmol) was treated with a
25 vol % TFA/H2O solution (2 mL) at room tempera-
ture until the complete disappearance of the starting
material (Rf 0.38, silica gel, 50% EtOAc in hexane).
The mixture was concentrated in vacuo and coevapo-
rated with toluene (3·) and MeOH (3·) to quantitatively
give compound 48.
5.5.1. Methyl (3S,4R,5S,7S,8R,9R)-8,9-dihydroxy-7-
[(10R)-10,20-dihydroxyethyl]-2-methyl-3-propyl-1,6-dioxa-
2-azaspiro[4.4]nonane-4-carboxylate 48. Compound 7
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583–587; (c) Lakhrissi, M.; Chapleur, Y. J. Org. Chem.
1994, 59, 5752–5757.
(47 mg, 0.11 mmol) was converted to 48 (37 mg) quanti-
25
tatively. Solid, mp 105–108 ꢁC; ½aꢂD ¼ ꢃ21.2 (c 1.0,
1
CH3OH); H NMR (400 MHz, D2O): d 0.86 (t, 3H, J
7.2 Hz, Me–propyl), 1.36 (m, 2H, CH2 propyl), 1.54

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