The 1,3-dipolar cycloaddition reaction of chiral carbohydrate-derived nitrone and olefin: Towards long-chain sugars

Article abstract of DOI:10.1016/j.carres.2013.06.022

The thermal and microwave-activated 1,3-dipolar cycloadditions of several α,β-unsaturated esters derived from d-mannose and chiral nitrones derived from threitol have been studied as a model reaction en route to eleven carbon long chain carbohydrates. Ver

Full text of DOI:10.1016/j.carres.2013.06.022

Carbohydrate Research xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
The 1,3-dipolar cycloaddition reaction of chiral carbohydrate-derived
nitrone and olefin: towards long-chain sugars
⇑
Hassan Oukani , Nadia Pellegrini-Moïse, Olivier Jackowski, Françoise Chrétien, Yves Chapleur
Université de Lorraine, UMR 7565 SRSMC, F-54506 Nancy, France
CNRS, UMR 7565 SRSMC, F-54506 Nancy, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The thermal and microwave-activated 1,3-dipolar cycloadditions of several
a
,b-unsaturated esters
Received 20 May 2013
Received in revised form 22 June 2013
Accepted 24 June 2013
Available online xxxx
derived from
en route to eleven carbon long chain carbohydrates. Very high facial selectivity is observed for the chiral
nitrones whereas the olefin facial selectivity varies with the substrate. The presence of a dioxolane ring
to the olefinic bond is beneficial to the facial selectivity of the olefin whereas a pyranose ring is not. The
combination of a -mannose derivative and a -threitol-derived nitrone is a matched pair suitable for the
D-mannose and chiral nitrones derived from threitol have been studied as a model reaction
a
D
L
Keywords:
Chiral olefin
Chiral nitrone
1,3-Dipolar cycloaddition
Long-chain sugar
synthesis of long chain sugars with nine contiguous chiral centres. Finally complete facial selectivity was
observed with exo-glycals which gave a single cycloadduct.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Cycloaddition reactions are powerful process which has found
numerous applications in the synthesis of heterocycles and in nat-
Pentoses and hexoses are among the most abundant sugars, but
higher-carbon sugars, having more than six carbons in the chain
are biologically important. LDHepp, KDO, KDN and neuraminic acid
are the most representative members of the heptose, octose and
nonose series.1
ural product synthesis.13 The 1,3-dipolar cycloaddition between a
nitrone and an olefin is particularly interesting as it give rise to
the formation of one C–C and one C–O bond with concomittent
creation of three chiral contiguous centres in one step. Ample stud-
ies on this cycloaddition using sugars as chiral partners can be
found in the literature.14 However, examples of dipolar cycloaddi-
tion reactions involving two chiral sugar partners are scarce.15
Disaccharide mimics have been elaborated by the reaction of chiral
sugar derived nitrone and olefin.16 An elegant approach to higher-
carbon sugars has been pioneered by Paton group using 1,3 dipolar
cycloaddition of a nitrile oxide and an olefin derived from two pen-
tose derivatives.17
Here we report some of the results of model studies towards the
stereocontrolled formation of undecose sugars using the nitrone–
olefin cycloaddition. Our approach relies on the use of four carbon
derived nitrones to be coupled with activated olefins derived from
hexose sugar. This study considered several threose derived
nitrones and three mannose derived olefins which would react to
give eleven-carbon chain sugars related to hikozamine (Scheme 1).
Even more longer sugars have been found in Nature. This is the
case for the undecose moiety of complex antibiotic nucleosides
such as hikizimycin (1)2 or tunicamycins (2)3 and its congeners:
streptovirudins,4 corynetoxines,5 mycosposidine, antibiotic
24010,6 MM19290 (Fig. 1).7 Interestingly, it has been shown re-
cently that biosyntheses of this last class of compounds would pro-
ceed through the radical coupling of a nucleoside radical onto a
glucosamine 5,6-exo-glycal.8 The synthesis of these complex high-
er-carbon sugars is still a challenge.9 One of the main synthetic dif-
ficulties relies in the presence of the highly functionalized eleven
carbon atom chain with up to nine contiguous chiral centres. Thus
the obvious strategy which would consist of the assembly of two
shorter chains is complicated by the necessary creation, at the
same time, of two chiral centres at the linking point with high dia-
stereoselection. Total and partial syntheses of hikizimycin (1)10 or
protected forms of the core eleven carbon sugar hikosamine (3),11
have been achieved by several groups.12
2. Results and discussion
2.1. Nitrone syntheses
⇑
Corresponding author. Tel.: +33 383 68 47 73; fax: +33 383 68 47 80.
A series of threose derived nitrones were prepared using known
procedures. We considered N-Me nitrones and N-benzyl nitrone,
the former being less synthetically useful but giving more simple
E-mail address: yves.chapleur@univ-lorraine.fr (Y. Chapleur).
Present address: Département de Chimie et Environnement, Université Sultan
Mouley Sliman, B.P. 523 Beni-Mellal, Morocco.
0008-6215/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2013.06.022
Please cite this article in press as: Oukani, H.; et al. Carbohydr. Res. (2013), http://dx.doi.org/10.1016/j.carres.2013.06.022

2
H. Oukani et al. / Carbohydrate Research xxx (2013) xxx–xxx
OH OH
H2N
HO
O
OH
H
H2N
N
O
O
OH OH
N
OH
OH
O
N
O
OH
O
O
N
N
RO
O
OH
OH
H
HO
NH2
O
1
2
HO
OH
OH
Figure 1. Structures of hikizimycin (1) and tunicamycins (2).
OH OH OH
6
Table 1
5
4
HO
HO
O
OH
Significant proton chemical shifts and coupling constants of cycloadducts
1
11
OH
NH2
OH
Compound
d H3
J3,4
d H4
J4,5
d H5
J5,6
d H6
J6,7
OH
10
11
12
13
14
23
24
25
27
3.95
3.92
3.80
4.10
4.05
3.82
4.67
3.71
4.11
4.6
4.5
5
7.5
—
6.9
9.2
8.5
6.5
3.25
3.32
3.10
3.25
3.3
3.76
2.82
4.00
3.57
5.3
5.5
4.5
7.5
7.5
3.9
7.0
2.5
6.7
3.57
3.43
3.45
3.51
3.48
4.00
3.90
4.09
3.40
5.3
5.5
5.5
7.6
7
—
—
—
—
4.93
4.50
4.60
4.80
4.51
—
—
—
—
9.2
9.5
9
7.6
—
—
—
—
—
OH OH OH
Hikosamine (3)
Z
OH
OP
HO
OH OH
+
HO
NH2
OH
P'O
PO
OP OP
R
N
O
ROOC
OP
OP OP
Analogously nitrone
benzylhydroxylamine19,20
The nitrone 18, enantiomer of 6 (Scheme 4), was prepared by
the same way starting from -threitol.
7
was prepared from
5
and N-
Scheme 1. Planned access to long-chain sugars such as hikosamine.
D
O
O
O
O
O
O
OBn
OBn
OBn
CHO
i
ii
2.2. Cycloaddition of nitrones with open-chain mannose
derived olefins
OH
N
R
O
The first compound was prepared from di-O-isopropylidene-D-
4
5
6
R = Me
R = Bn
mannofuranose by a controlled Wittig reaction which gave the
open-chain derivative 8 in 65% yield.21 The ethyl ester was pre-
ferred over the methyl ester because of a strong tendency of the
latter to cyclize to the C-glycosyl compound. The cycloaddition
reaction was conducted with ester 8 and nitrone 6 in refluxing
toluene for 24 h to give a 2:1 mixture of two adducts. Chromato-
graphic separation of this mixture gave the two diastereoisomers
10 and 13 in 58% and 31% yield respectively. NOE is useful in the
determination of isoxazolidine structures,14f,22 however in this
7
Scheme 2. Reagents and conditions: (i) Swern oxidation; (ii) MeNHOH, HCl,
MeONa/MeOH, 70% or BnNHOH, 80%.
NMR spectra. Nitrone 6 was prepared in 70% yield from the alde-
hyde 5 obtained from the known 1-O-benzyl-2,3-O-isopropyli-
dene-
L
-threitol 418 and N-methylhydroxylamine (Scheme 2).
OBn
1
OBn
1
O
O
O
O
Me
N
5
6
H
Me
N
5
6
H
O
O
O
O
4
4
O
H
COOEt
O
O
H
H
H
H
H
H
H
i
O
+
COOEt
COOEt
RO
RO
RO
O
O
O
O
O
O
8 R = H
10 R = H
13 R = H
14
9
R = Ac
R = Ac
ii
11 R = Ac
12 R = Bz
Me
N
O
6
OAc OAc
OAc
iii
10
7
AcO
9
3
OBn
11
5
8
4
2
1
OAc
10
OAc OAc
EtOOC
15
Scheme 3. Reagents and conditions: (i) 6, 1 equiv, toluene, 110 °C, 48 h, 89% from 8, 82% from 9; (ii) BzCl, pyridine, DMAP cat., 3 h, 92%; (iii) MeOH, H2O, HCl 1:1:1, reflux, 3 h
then Ac2O, pyridine, 59%.
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H. Oukani et al. / Carbohydrate Research xxx (2013) xxx–xxx
3
to nitrone 6. This cycloaddition reaction gave the expected adducts
11 and 14 in a 2:1 ratio in an overall yield of 82% showing the ab-
sence of effect of the substitution at O-9 on the diastereoselection.
The presence of two diastereoisomers over the four possible
diastereoisomers in the reaction of 8 or 9 with nitrone 6 could be
attributed to a modest facial selectivity of one of the two partners
associated with an excellent facial selectivity of the other. To
explore this point, we performed the reaction of 8 with two other
nitrones, the achiral nitrone 16 prepared from benzaldehyde with-
out facial selectivity and nitrone 18, enantiomer of 6, obtained
Me
O
O
i
1
N
O
H
2
H
H
4
O
H
6
O
COOEt
N
5
H
OH
O
CH3
17
16
4 isomers
OBn
1
OBn
O
O
Me
N
from D-tartaric acid (Scheme 4). The reaction with the latter will
O
O
O
4
i
shed light on the matched or mismatched character of the chiral
olefin-chiral nitrone pair. The reaction of 8 with both nitrones in
refluxing toluene led to a mixture of four diastereoisomers in
84% and 85% yield respectively. From the first mixture 17, one
the main product was obtained as a pure compound in 45% yield.
The three other compounds were isolated in 39% yield as a mixture
of three adducts in a 2:1:1 as determined by 1H NMR (structures
not shown). The structure of 17 remained difficult to establish
due to proton signal overlap. The embedding of the H-2 signal with
the ester CH2 group signal precludes the determination of the J1,2
coupling constant and the determination of the configuration at
C-1 of 17. Only the J2,3 = 6.5 Hz and J3,4 = 7.8 Hz could be measured
from the H-3 signal, which confirmed the expected trans relation-
ship of H-2 and H-3 and the anti relationship between H-3 and H-4
suggesting the absolute configuration at C-3 and C-2.
The cycloaddition reaction between 8 and 18 gave roughly the
same results and provided 19 as a mixture of four isomers. From
the mixture one pure major isomer in 51% yield and a mixture of
three diastereoisomers in 34% yield were obtained as shown by
1H NMR (structures not shown). The structure of the major com-
pound was also difficult to establish due to signal overlapping in
particular the signals of H-6 and H-5 were not accessible. Only
the two 3J of 6 Hz and 2.5 Hz could be measured from the signal
of H-4.
O
H
H
H
H
5
6
H
O
COOEt
N
OH
O
O
O
Me
18
19
4 isomers
Scheme 4. Reagents and conditions: (i) 8, toluene reflux, 24 h.
case, due to signal overlaps it was almost impossible to achieve
NOE difference experiments. Even NOESY experiments were diffi-
cult to interpret. Thus we used examination of the coupling
constants in the 1H NMR spectrum (see Table 1). The observed
J4,5 = 5.3 and J5,6 = 5.3 Hz in the isoxazolidine ring (carbohydrate
numbering shown in Scheme 3) allowed the determination of the
relative configuration of 10. With the hypothesis that the E config-
uration of olefin 8 is retained during the cycloaddition, H-5 and H-
6 are in a trans relationship with a J5,6 = 5 Hz. Given the J4,5 = 5 Hz
one should conclude that all the substituents around the ring of the
major isomer 10 are in a trans arrangement. The determination of
the absolute configuration of the cycloadduct 10 was more critical.
In the absence of crystalline material, we made use of NMR and
comparison with literature data.23,16a To help this determination,
a series of derivatives of 10 was prepared.
The benzoate 12 was prepared in 92% yield by standard acyla-
tion of adduct 10. Most of proton signals can then be assigned. In
particular, H-4 and H-5 were clearly identified as sharp double
doublets with J3,4 = 5 Hz, J4,5 = 4.5 Hz J5,6 = 5.5 Hz. Interestingly a
coupling constant J6,7 = 9 Hz was found suggesting an anti arrange-
ment of the two protons thus allowing a tentative assignment of
the absolute configuration at C-6 as shown in Scheme 3 and thus
all configurations of the adduct 10.
In order to corroborate the above described assignments, the ace-
tal groups were removed by acid hydrolysis (MeOH, H2O and HCl)
and the resulting alcohols were acetylated to give 15 in 59% yield.
Compound 15 was fully analysed by 1H NMR. On the basis of the cou-
pling constants between adjacentprotons, it is possible todetermine
the relative configuration of acyclic sugars: a large 3J value (>6 Hz)
being indicative of an anti arrangement whereas the syn one corre-
sponds to a small 3J value (<3 Hz).24 Vicinal coupling constants
between 6.5 Hz and 8.5 Hz were found for J3,4, J5,6, J6,7, J7,8, J9,10 in fa-
vour of an anti relationship between these protons whereas smaller
coupling constants of 3 Hz were found for J2,3, J8,9 which should be in
a syn relationship. This strongly supports the absolute configuration
proposed in Scheme 3 for the major cycloadduct 10.
For the second isomer 13, the patterns of the isoxazolidine ring
proton signals were enlarged due to slow inversion at nitrogen. The
signal of H-4 appeared as a broad singlet but recording of the NMR
spectrum at 45 °C allowed a sharpening of this H-4 signal which
became a resolved double doublet with J3,4 = J4,5 = 7.5 Hz. The cou-
pling constant between H-5 and H-6 of 7.6 Hz suggested a trans
arrangement of H-4, H-5 and H-6.
The dioxolane ring next to the olefinic bond of compound 8 is
obviously of crucial importance in the facial stereocontrol. It
seemed interesting to study the influence of this ring size on the
facial selectivity by changing the five membered-ring for a pyra-
nose ring. In addition, given the C2 symmetry of D-mannose, chain
extension at C-6 instead of C-1 would led to the same long chain
carbohydrate but with a different set of protective groups. Thus
the olefinic substrate 20 was prepared from methyl-a-D-mannopy-
ranoside by a routine sequence involving selective protection and
oxidation at C-6. Wittig olefination gave the required unsaturated
ester 20 as the pure E isomer.
The cycloaddition reaction with nitrone 6 took place only above
100 °C in toluene and gave three diastereoisomers as shown by 1H
NMR of the crude reaction mixture (Scheme 5). From this mixture
it was possible to isolate a pure minor diastereoisomer 21 in 13%
yield and a second mixture of two inseparable diastereoisomers
in 45% yield in a ratio 1.8:1 determined by integration of the
OBn
11
Me
O
N
9
O
COOMe
O
BnO
BnO
5
7
COOMe
i
O
3
O
O
O
1
O
O
OMe
OMe
20
21
The influence of a protecting group on the free hydroxyl of 8
was evaluated by preparing the O-9 acetate 9 which was opposed
Scheme 5. Reagents and conditions: (i) 6, toluene reflux, 48 h, 58%.
Please cite this article in press as: Oukani, H.; et al. Carbohydr. Res. (2013), http://dx.doi.org/10.1016/j.carres.2013.06.022

4
H. Oukani et al. / Carbohydrate Research xxx (2013) xxx–xxx
N-Me signals in the proton NMR spectrum. It was impossible to
identify the H-7 and H-8 signals due to overlapping. Only the signal
of H-6 was clearly a double doublet with J = 6.5 and 1.5 Hz. One
may assume that the large coupling constant corresponds to J6,7
in a trans relationship as expected from the E configuration of
the double bond of 20. Clearly this approach did not give interest-
ing diastereoselections likely due to the poorer facial selectivity of
the sugar olefin 20 as compared to olefin 8. This confirmed the ben-
eficial influence of the dioxolane ring on the facial selectivity of the
olefin.
O
O
O
MeOOC
H
4
O
O
O
11
H
COOMe
i
O
O
1
5
H
Bn
OBn
6
N
O
O
O
O
O
22
25
O
O
O
MeOOC
H
O
O
O
i
H
O
2.3. Cycloaddition of nitrones with
glycals
D-mannose-derived exo-
O
H
OBn
COOMe
N
O
Bn
O
O
O
O
exo-Glycals, easily available by Wittig reaction of lactones,
proved to be interesting synthetic intermediates.25 In particular,
it has been shown that the anomeric trisubstituted double bond
is reactive in 1,3-dipolar cycloadditions and exhibits a very high
27
26
facial selectivity.14f,16b,26 exo-Glycal 22 derived from
D-mannono-
Scheme 7. Reagents and conditions: (i) 7, microwave activation, 150 °C, toluene,
1 h, 83% from 22, 60% from 26.
1,4-lactone was first considered in a cycloaddition reaction with
chiral nitrone 6 under microwave activation. Indeed, we have
shown earlier that the trisubstituted double bond of exo-glycals
is less reactive in cycloaddition reaction and reacts faster under
microwave activation.14f Heating the two components at 150 °C
in toluene in a sealed vessel for 1 h gave after chromatographic
purification a set of two adducts 23 and 24 in a 4/1 ratio in 90%
overall yield (Scheme 6).
perform NOESY spectrum of 25 and some significant interactions
were observed, for example between the methoxy group and H-
11 protons establishing the nitrone attack by the bottom face of
the olefin.
As a model study, the reductive cleavage of the NO bond of
compound 25 was investigated. The use of SmI2 in THF at 0 °C, or
Zn in acetic acid, NiCl2–NaBH4 in MeOH or H2; Pd(OH)2/C in MeOH
gave no reaction or untraceable mixtures. Finally, hydrogenation of
the N–O bond using H2, 10% Pd/C in EtOH gave some results. It was
possible to isolate the O-debenzylated compound in 14% yield, the
N- and O-debenzylated compound in 10% yield and the open chain
derivative in 15% yield together with unreacted starting material in
15% yield. The presence of benzyl protecting groups certainly pre-
cludes clean reaction and reproducibility.
As shown in our previous studies, the cycloaddition likely took
place anti to the 2,3-dioxolane group of 22.14f Indeed, the
a config-
uration of both isomers was confirmed by the C-6 chemical shifts
of d = 116.5 and 111.4 for 23 and 24 respectively.14f The absolute
stereochemistries at C-4 and C-5 were established by proton
NMR from the coupling constants between H-3, H-4 and H-5
respectively. For the major isomer 23, the observed J4,5 = 3.9 Hz
was in favour of a trans arrangement of these protons in the isox-
azolidine spiro ring system.14f,27 In the case of the minor isomer 24,
the coupling constants J4,5 = 7 Hz suggested a cis arrangement of H-
4 and H-5. This result confirmed the previously observed excellent
facial selectivity of exo-glycals14f and the good facial selectivity of
the nitrone 6.
In order to improve this facial selectivity we turned to the N-
benzyl nitrone 7 which has been shown to exhibit excellent facial
selectivity both in cycloaddition28 and nucleophilic addition.29
exo-Glycal 22 and its E isomer 26 were reacted with nitrone 7
under microwave activation at 150 °C in toluene for 1 h. In each
case a single isomer was observed and compounds 25 and 27 were
isolated in 83% and 60% yield respectively (Scheme 7). As before
the relative stereochemistries were deduced from the proton
NMR spectra and the coupling constants. In compound 25, the
J4,5 = 2.5 Hz was in favour of a trans arrangement of these protons
whereas in compound 27 the larger J4,5 = 6.7 Hz supports the pro-
posed cis arrangement of H-4 and H-5.14f,27 The large coupling con-
stants J3,4 = 8.5 Hz in 25 and 6.5 Hz in 27 support the anti
relationship of H-3 and H-4 in both systems. We were able to
2.4. Discussion
Taken together our results show that the cycloaddition of chiral
nitrone and unsaturated esters of carbohydrates is an efficient syn-
thetic process to link two sugar units. The process is always highly
regioselective as generally observed with activated olefins. Prece-
dents from literature have shown that nitrones bearing a dioxolane
ring at the
in cycloaddition28 or in nucleophilic addition reactions.29
A first interesting result is that the combination of -nitrone 6
and olefin 8 proceeded with high diastereoselection in excellent
agreement with previous data reported for the reaction of -threi-
a position exhibit remarkable facial selectivities either
L
L
tol-derived nitrones having a 2,3-dioxolane ring where the forma-
tion of the S isomer at C-4 is reported to be predominant if not
exclusive.28 The observed diastereoselectivity can be rationalized
on the basis of well established facts in the 1,3-dipolar cycloaddi-
tion field. Concerning the olefinic partner, it is known that
a-alk-
oxy olefins like 8 or 20 react preferentially on the ground state
O
O
O
O
MeOOC
MeOOC
H
4
H
O
O
O
O
O
O
11
H
COOMe
H
i
O
O
1
O
5
H
H
OBn
OBn
6
N
N
+
O
O
Me
Me
O
O
O
O
O
O
22
23
24
Scheme 6. Reagents and conditions: 6, microwave activation, 150 °C, toluene, 1 h, 90%.
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H. Oukani et al. / Carbohydrate Research xxx (2013) xxx–xxx
5
anti Felkin-Ahn
Me
O
H
O
H
N
O
O
BnOH2C
O
Felkin-Ahn
O
H
H
CH2OBn
N
H
N
N
R
R
Me
O
COOEt
O
O
O
O
H
H
H
H
H
Su
Su
COOEt
H
COOEt
H
R
H
COOEt
O
alkoxy outside
R
10
13
alkoxy inside
endo TS (I)
endo TS (II)
O
Felkin-Ahn
O
anti Felkin-Ahn
H
Me
BnOH2C
H
O
N
O
H
O
O
N
Me
CH2OBn
COOEt
H
H
O
COOEt
alkoxy outside
exo TS (IV)
O
O
H
R
H
O
R
alkoxy inside
exo TS (III)
Figure 2. The four possible transition states in the reaction of 8 with nitrone 6.
conformation which places the alkoxy towards the olefinic bond
(inside alkoxy effect)30 although exceptions are known. Concerning
TS (III) and (IV) are less favoured because of strong steric interac-
tions between the ester group of 8 and the nitrone 6 side-chain.
the
a
-alkoxy nitrone there are some precedents in the literature
When using the D-nitrone 18, as shown in Figure 3, the combi-
showing that the facial selectivity is excellent28 and is in agree-
ment with the Felkin-Ahn model (FA) where the attack would take
place preferentially anti to the alkoxy group in the conformation
where the alkyl group points towards the nitrone group.28d More-
over an endo transition state (TS) is always preferred in the 1,3-
dipolar cycloaddition of non-cyclic nitrones.13a Combination of
nation of the inside alkoxy effect for the olefin 8 and the FA model
for the nitrone 18 led to an exo TS (V) for the cycloaddition in
which steric interactions between the ester group and the nitrone
side chain are present. Consequently TS (V) is by far less favoured
over the three other than its analogue (I) is over (II–IV) TS. The two
other endo TS combine either the outside alkoxy conformation
with the FA model or the inside alkoxy conformation with the less
favourable FA model. Finally TS (VIII) is probably the less favoured
as it is an exo TS combining both an anti Felkin Ahn attack of the
nitrone on the less favoured conformation of the olefin (alkoxy out-
side). This should explain the formation of four diastereisomers in
this case. The same considerations apply for the reaction of 8 with
an achiral nitrone in which there is no favoured face. In the case of
olefin 20, the facial selectivity of the olefin is believed to be poorer
these requirements led to the conclusion that for the L-nitrone 6
of the four possible transition states, the endo TS (I, Fig. 2) which
combines the inside alkoxy effect and the FA model will be fa-
voured over the three other TS. This led to an all trans substituent
arrangement around the isoxazolidine ring which was found in 10.
The second endo transition state which combines the other faces of
both the olefin and the nitrone will also be favoured over the two
other exo TS leading to the second all trans adduct 13. The two exo
Me
H
N
Me
Felkin-Ahn
H
O
O
O
Felkin-Ahn
N
O
O
O
H
N
R
COOEt
R
H
H
O
O
R
O
O
H
H
R
H
COOEt
alkoxy inside
Su
COOEt
alkoxy outside
H
O
R
19
exo TS (V)
endo TS (VI)
O
O
R
O
O
R
H
anti Felkin-Ahn
anti Felkin-Ahn
H
H
H
O
H
N
O
H
N
Me
Me
O
COOEt
alkoxy outside
O
O
H
H
R
H
COOEt
alkoxy inside
endo TS (VII)
H
O
R
exo TS (VIII)
Figure 3. The four possible transition states in the reaction of olefin 8 with nitrone 18.
Please cite this article in press as: Oukani, H.; et al. Carbohydr. Res. (2013), http://dx.doi.org/10.1016/j.carres.2013.06.022

6
H. Oukani et al. / Carbohydrate Research xxx (2013) xxx–xxx
COOMe
60 (63–200 m) (Merck) using hexanes (H), cyclohexane (cycloH) or
O
O
ethyl acetate (EA) mixtures. FTIR spectra were recorded on a Per-
kin–Elmer spectrum 1000 on NaCl windows. Melting points were
determined with a Tottoli apparatus and are uncorrected. Optical
rotations were measured on an Anton Paar MC300 polarimeter.
1H and 13C NMR spectra were recorded on a Bruker spectrometer
DPX250 (250 MHz and 62.9 MHz, respectively) and DRX400
(400 MHz and 100.6 MHz, respectively). For complete assignment
of 1H and 13C signals, two-dimensional 1H,1H COSY and 1H,13C cor-
relation spectra were recorded. Chemical shifts (d) are given in
ppm relative to the solvent residual peak. For sake of clarity, atom
numbering is given on the different schemes rather than resulting
from the IUPAC naming of compounds given in the compound
names. The following abbreviations are used for multiplicity of
NMR signals: s = singlet, d = doublet, t = triplet, q = quadruplet,
m = multiplet, and br = broad signal. MS spectra were recorded
on a Waters Platform and HRMS on a Bruker MicroTOFQ apparatus.
Microanalyses were recorded on a Thermofinnigan Flash EA1112
apparatus. Microwave syntheses were performed on a CEM Dis-
cover mono-mode oven the temperature being controlled by stan-
dard external IR-sensor. Compounds 4,18 7,19 8,21a and 921b are
known compounds prepared by literature procedures.
COOMe
O
O
O
O
R
N
R
N
H
H
H
H
O
O
BnOH2C
BnOH2C
O
O
O
O
endo TS (IX)
exo TS (X)
Figure 4. The two possible transition states in the reaction of olefin 22 and 26 with
nitrone 7.
than that of olefin 8. Probably the inside alkoxy effect is less pro-
nounced and does not strongly favour one TS over the others
explaining the formation of three diastereoisomers.
For the reactions of exo-glycals, analogous explanations are va-
lid. In these cases the diastereoselection relies mainly on the facial
selectivity of the nitrone, the facial selectivity of the olefin being-
almost exclusively anti to the dioxolane ring. With nitrone 6, the
Felkin-Ahn model should apply, leading to the major isomer 23,
via the endo TS IX depicted in Figure 4. The formation of a minor
isomer 24 arose from the attack of the exo-glycal by the other face
nitrone via an exo TS. It is interesting to note that the formation of
this minor isomer did not occur with the N-benzylated nitrone 7. In
this case, the exo transition state should be destabilized by interac-
tion of the benzyl group with the sugar ring. For the formation of
27, such an interaction may exist in the endo transition state and
adduct 27 probably results from the exo transition state X.
4.2. General procedures for nitrone–olefin cycloadditions
4.2.1. Procedure A: thermal cycloadditions
A solution of olefin (1 mmol) and nitrone (2 mmol) in toluene
(20 mL/mmol) was heated under reflux until olefin consumption
(TLC monitoring). Purification of the crude reaction mixtures by sil-
ica gel column chromatography with EtOAc–cyclohexane mixtures
afforded the spiroxazolidine.
3. Conclusions
In conclusion the 1,3-dipolar cycloaddition between a chiral nit-
rone and a chiral enoate both derived from sugars is an efficient
process to couple two chiral subunits with the formation of three
new chiral centres leading to the formation of nine contiguous chiral
4.2.2. Procedure B: microwave assisted nitrone–olefin
cycloadditions
A solution of exo-glycal (1 mmol) and nitrone (2 mmol) in tolu-
ene (2 mL/mmol) in a septum-sealed glass tube was heated at 130–
150 °C in a focused microwave oven (Discover CEM) for 30–60 min
until exo-glycal consumption (TLC monitoring). Purification of the
crude reaction mixtures by silica gel column chromatography with
EtOAc–cyclohexane mixtures afforded the spiroxazolidine.
centres. In this approach, towards high carbon sugars, the
nose derived olefin and the -threitol-derived nitrone
constitute a matched pair which produces good diastereoselectiv-
ity. The -threitol derived nitrone 18 with the same olefin 8 is
D-man-
8
L
6
D
poorly diastereoselective as is non-chiral nitrone 16, pointing out
the modest facial selectivity of olefin 8. Unexpectedly olefin 20 also
had a poor facial selectivity towards 6. It is clear that the facial
selectivity of olefin 8 flanked by a dioxolane ring is by far higher
than the facial selectivity of 20 in which the olefin bond is flanked
by a pyranose ring. Studies towards the use of more conformation-
ally restricted olefin with higher facial selectivity like exo-glycals
provide a good solution to the construction of higher-carbon sug-
ars using the nitrone–olefin cycloaddition approach. The reaction
of N-benzyl nitrone 7 with Z or E exo-glycals gave excellent diaste-
reoselectivities resulting in the formation of a single adduct in each
case. Nevertheless, the chemical cleavage of the N–O bond of these
adducts remains rather a difficult process due to the steric hin-
drance around this bond induced by the N-benzyl group and by
the spiro ring system. Adjustment of these protecting groups is a
crucial point to solve to make this approach synthetically useful.
This point is now under scrutiny in our group.
4.3. [N(Z)]-N-Oxide-N-[[(4S,5S)-2,2-dimethyl-5-
[(phenylmethoxy)methyl]-1,3-dioxolan-4-yl]methylene]-
methanamine (6)
Compound 6 was prepared from 5 (8.8 g, 35 mmol) according to
the method of Dondoni et al.19 using N-methylhydroxylamine
(2.9 g) to give 6 (6.8 g, 70%) as a syrup, ½a D25
ꢀ
18.0 (c 1, CHCl3); Rf
0.13 (EA); IR (film), 1615 cmꢁ1 1H NMR (CDCl3, 400 MHz): d 1.43
;
(s, 3H, Me), 1.49 (s, 3H, Me), 3.71 (br s, 3H, NMe), 3.78 (dd, 1H,
J1,2 = 6.6, J1,1 = 10.6 Hz, H-1), 3.92 (dd, 1H, J1 ,2 = 2.8 Hz, H-10),
4.21 (ddd, 1H, J2,3 = 7.2 Hz, H-2), 4.63 (s, 2H, CH2Ph), 5.05 (dd,
1H, J3,4 = 5.7 Hz, H-3), 6.85 (d, 1H, H-4), 7.33 (m, 5H, Ar); 13C
NMR (CDCl3 62.9 MHz): d 26.4 (Me acetal), 26.9 (Me acetal), 52.7
(NMe), 71.4 (C-1), 72.9 (C-3), 73.7 (OCH2Ph), 79.6 C-2), 110.8 (C
quat acetal), 127.6 (Ar), 127.8 (Ar), 128.3 (Ar), 138.0 (C-4), 138.1
(Cipso); MS (HR-ESI) calcd for C15H21NNaO4 [M+Na]+ 302.1363,
found: 302.1382.
0
0
4. Experimental
4.1. General methods
4.4. 1-C-[(3S,4R,5R)-4-[Ethoxycarbonyl]-3-[(4S,5S)-5-
(phenylmethyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
(methyl)-5-isoxazolidinyl]-1,2:4,5-bis-O-(1-methylethylidene)-
(1S)-D-manno-pentitol (10)
All reactions were carried out in commercially available dry sol-
vents. TLC analyses were performed using standard procedures on
Kieselgel 60 F254 plates (Merck). Compounds were visualized using
UV light (254 nm) and (or) 30% methanolic H2SO4/heat as develop-
ing agent. Column chromatography was performed on silica gel SI
Procedure A using 8 and 6, 58%, gum, ½a D25
ꢀ
27 (c 1, CHCl3); Rf
1H NMR (CDCl3,
0.35 (cycloH/EA 3:2); IR (film), 3503, 1731 cmꢁ1
;
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H. Oukani et al. / Carbohydrate Research xxx (2013) xxx–xxx
7
400 MHz): d 1.27 (t, 3H, Me, COOEt), 1.36 (s, 3H, Me), 1.37 (s, 3H,
4.7. 1-C-[(3R,4S,5S)-4-[Ethoxycarbonyl]-3-[(4S,5S)-5-
Me), 1.41 (s, 3H, Me), 1.44 (s, 3H, Me), 1.45 (s, 3H, Me), 1.46 (s,
3H, CH-3), 2.39 (d, 1H, J = 8.8 Hz, OH), 2.75 (s, 3H, NMe), 3.25
(dd, 1H, J3,4 = 4.6, J4,5 = 5.3 Hz, H-4), 3.57 (dd, 1H, J5,6 = 5.3 Hz, H-
(phenylmethyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
(methyl)-5-isoxazolidinyl]-1,2:4,5-bis-O-(1-methylethylidene)-
(1S)-D-manno-pentitol (13)
0
5), 3.63 (dd, 1H, J1,1 = 10.2, J1,2 = 5.5 Hz, H-1), 3.68 (dd, 1H,
0
J1 ,2 = 4.4 Hz, H-10), 3.89 (br dd, 1H, J9,10 = 8.8 Hz, H-9), 3.95 (dd,
Procedure A using 8 and 6, 31%, gum, ½a D25
ꢀ
ꢁ12.9 (c 1, CHCl3); Rf
1H, J2,3 = 7.9 Hz, H-3), 4.03 (m, 1H, H-10), 4.04 (m, 1H, H-11),
4.07 (m, 1H, H-110), 4.09 (m, 1H, H-2), 4.19 (q, 2H, CH2, COOEt),
4.31 (dd, 1H, J6,7 = 9.2, J7,8 = 6.8 Hz, H-7), 4.42 (dd, 1H,
J8,9 = 0.9 Hz, H-8), 4.61 (s, 2H, OCH2Ph), 4.93 (dd, 1H, H-6), 7.31–
7.41 (m, 5H, Ar); 13C NMR (CDCl3 62.9 MHz): d 14.1 (Me, COOEt),
24.7 (Me acetal), 25.4 (Me acetal), 26.8 (Me acetal), 26.9 (Me ace-
tal), 27.1 (Me acetal), 27.2 (Me acetal), 44.9 (Me, NMe), 53.9 (C-
5), 61.3 (CH2, COOEt)), 67.1 (C-11), 69.1 (C-9), 70.5 (C-1), 73.1 (C-
4), 73.5 (OCH2Ph), 75.3 (C-8), 76.4 (C-10), 76.8 (C-7), 77.7 (C-3),
78.3 (C-6, C-2), 108.6 (C quat acetal), 109.3 (C quat acetal), 109.8
(C quat acetal), 127.6 (C-Ar), 127.7 (Ar), 128.4 (Ar), 138.0 (Cipso),
172.8 (CO); MS (HR-ESI) calcd for C31H48NO11 [M+H]+ 610.3222,
found: 610.3225.
0.29 (cycloH/EA 3:2); 1H NMR (CDCl3, 400 MHz recorded at 45 °C):
d: 1.20 (t, 3H, COOCH-2CH-3), 1.32 (s, 3H, Me), 1.33 (s, 6H, 2 x Me),
1.38 (s, 3H, Me), 1.41 (s, 3H, Me), 1.42 (s, 3H, Me), 2.58 (brs, 1H,
OH), 2.74 (s, 3H, NMe), 3.25 (dd, 1H, J3,4 = J4,5 = 7.5 Hz, H-4), 3.51
0
(dd, 1H, J5,6 = 7.6 Hz, H-5), 3.52 (dd, 1H, J1,1 = 10.2, J1,2 = 5.7 Hz,
H-1), 3.58 (dd, 1H, J1 ,2 = 4.5 Hz, H-10), 3.83 (br d, 1H,
0
J9,10 = 6.5 Hz, H-9), 3.99 (m, 1H, H-11), 4.04 (q, 2H, COOCH2), 4.05
0
(m, 2H, H-7, H-10), 4.10 (m, 1H, H-3), 4.15 (dd, 1H, J10,11 = 7.0,
J11,11 = 10.7 Hz, H-110), 4.21 (m, 1H, H-2), 4.37 (dd, 1H, J7,8 = 6.6,
0
J8,9 = 0.9 Hz, H-8), 4.53 (s, 2H, OCH2Ph), 4.80 (dd, 1H, J6,7 = 7.6 Hz,
H-6), 7.29 (m, 5H, Ar); 13C NMR (CDCl3 100 MHz, recorded at
45 °C): d: 14.3 (CH3, COOEt), 25.2 (Me acetal), 25.7 (Me acetal),
27.0 (Me acetal), 27.1 (Me acetal), 27.7 (Me acetal), 47.3 (brs, 3H,
NMe), 53.9 (C-5), 61.1 (C-11), 67.5 (CH2, COOEt), 69.6 (C-9), 70.0
(C-4), 71.1 (C-1), 73.7 (OCH2Ph), 76.1 (C-8), 76.5 (C-10), 78.0 (C-
2, C-3), 79.4 (C-6), 80.3 (C-7), 109.1 (C quat acetal), 109.5 (C quat
acetal), 110.2 (C quat acetal), 127.8 (Ar), 127.9 (Ar), 128.5 (Ar),
138.3 (Cipso), 170.0 (CO); MS (HR-ESI) calcd for C31H48NO11
[M+H]+ 610.3222, found: 610.3250.
4.5. 1-C-[(3S,4R,5R)-4-[Ethoxycarbonyl]-3-[(4S,5S)-5-
(phenylmethyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
(methyl)-5-isoxazolidinyl]-1,2:4,5-bis-O-(1-methylethylidene)-
(1S)-D-manno-pentitol (11)
Procedure A using 9 and 6, 54%, gum, ½a D25
ꢁ17.6 (c 0.5,
ꢀ
CHCl3); Rf 0.30 (H/EA 3:1); 1H NMR (CDCl3, 250 MHz): d 0.90–
0.95 (t, 3H, Et), 1.20–1.42 (6s, 18H, 6 Me), 2.00 (s, 3H, Ac), 2.70
(s, 3H, NMe), 3.32 (dd, 1H, J3,4 = 4.5, J4,5 = 5.5 Hz, H-4), 3.43 (dd,
1H, J5,6 = 5.5 Hz, H-5), 3.62 (m, 2H, H-10, H-1), 3.92 (dd, 1H,
J2,3 = 7.5 Hz, H-3), 3.98 (m, 2H, H-110, H-11), 4.05 (m, 1H, H-2),
4.15 (q, 2H, CH2, Et), 4.20 (m, 1H, H-10), 4.22 (dd, 1H, J6,7 = 9.5,
J7,8 = 7 Hz, H-7), 4.35 (dd, 1H, J8,9 = 2 Hz, H-8), 4.50 (dd, 1H, H-
6), 4.55 (s, 2H, CH2Ph), 5.35 (dd, 1H; J9,10 = 6 Hz, H-9), 7.30 (m,
5H, Ph).
4.8. 1-C-[(3R,4S,5S)-4-[Ethoxycarbonyl]-3-[(4S,5S)-5-
(phenylmethyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
(methyl)-5-isoxazolidinyl]-3-O-acetyl-1,2:4,5-bis-O-(1-
methylethylidene)-(1S)-D-manno-pentitol (14)
Procedure A using 9 and 6, 27%, gum, Rf 0.43 (H/EA 3:2); IR
(film), 1720, 1716 cmꢁ1 1H NMR (CDCl3, 250 MHz): d 1.25 (t, 3H,
;
Et), 1.30–1.45 (6s, 18H, 6 Me), 2.05 (s, 3H, Ac), 2.70 (s, 3H, NMe),
3.3 (m, 1H, H-4), 3.48 (dd, 1H, J4,5 = 7.5, J5,6 = 7 Hz, H-5), 3.5 (dd,
1H, J1,1 = 10, J1,2 = 6 Hz, H-1), 3.55 (dd, 1H, J1 ,2 = 6 Hz, H-10), 3.95
(m, 4H, H-11, H-110, COOCH2), 4.05 (m, 1H, H-3), 4.12 (m, 1H, H-
2), 4.25 (m, 1H, H-7), 4.40 (dd, 1H, J7,8 = 9, J8,9 = 3.4 Hz, H-8), 4.51
(m, 3H, H-6, CH2 Ph), 5.25 (dd, 1H, J9,10 = 6 Hz, H-9), 7.28 (m, 5H,
Ph).
0
0
4.6. 1-C-[(3S,4R,5R)-4-[Ethoxycarbonyl]-3-[(4S,5S)-5-
(phenylmethyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
(methyl)-5-isoxazolidinyl]-3-O-benzoyl-1,2:4,5-bis-O-(1-
methylethylidene)-(1S)-D-manno-pentitol (12)
To a solution of 10 (70 mg, 0.11 mmol) in pyridine (2 mL) was
added benzoyl chloride (30 mg) and DMAP (2 mg). After 3 h, meth-
anol (1 mL) was added and the solvent was evaporated under re-
duced pressure. The residue was dissolved in dichloromethane
(20 mL) and the organic phase was washed with 3 N HCl (5 mL),
water till pH 7, 3 N sodium hydroxide (5 mL) and water. After dry-
ing over magnesium sulfate, filtration and concentration, the resi-
due was purified by column chromatography (H/EA 3.5:1) to give
4.9. 1-C-[(3S,4R,5R)-4-[Ethoxycarbonyl]-1C-[1S-1,2-di-O-acetyl-
3-(phenylmethyloxymethyl)-L-glycerol]-2-(methyl)-5-
isoxazolidinyl]-1,2,3,4,5-penta-O-acetyl)-(1S)-D-manno-pentitol
(15)
To a solution of compound 10 (90 mg, 0.15 mmol) in methanol
(3 mL) was added 6 N hydrochloric acid (6 mL). The solution was
heated at reflux for 3 h. After cooling, strongly basic resin was
added till neutral. After filtration, the solvents were evaporated un-
der vacuum, the residue was codistilled twice with pyridine
(10 mL). The residue was taken up in pyridine and acetic anhydride
(1 mL) was added. After stirring for 12 h at rt, standard work-up
used for the synthesis of 12 was applied and gave pure 15, 69 mg
12, 42 mg, 92% as a white solid, ½a D25
ꢁ19.5 (c 0.8, CHCl3); Rf 0.3
ꢀ
(H/EA 3:1); 1H NMR (CDCl3, 250 MHz): d 0.80 (t, 3H, Et), 1.20–
1.50 (6s, 18H, 6Me), 2.60 (s, 3H, NMe), 3.10 (dd, 1H, J4,5 = 4.5,
J3,4 = 5 Hz, H-4), 3.45 (dd, 1H, J5,6 = 5.5 Hz, H-5), 3.60 (dd, 2H, H-1,
H-10), 3.80 (m, 3H, H-3; COOCH2), 4.00–4.10 (m, 3H, H-2, H-11;
H-110), 4.30 (m, 2H, H-7, H-10), 4.45 (dd, 1H, J7,8 = 7.5, J8,9 = 1 Hz,
H-8), 4.60 (m, 3H, J6,7 = 9 Hz, H-6, CH2Ph), 5.61 (dd, 1H,
J9,10 = 5.5 Hz, H-9), 7.10–8.00 (m, 10H; 2Ph); 13C NMR (CDCl3
62.9 MHz): d 13.7 (CH3), 25.3 (acetal), 25.5 (acetal), 26.4 (acetal),
26.8 (acetal), 27.16 (acetal), 44,9 (NMe), 54.5 (C-5), 61.1 (CH2Et),
65.9 (C-1), 70.5 (C-11), 70.6 (C-9), 73.0(C-4), 73.4 (CH2Ph) 75.7
(C-8), 76.1 (C-7), 76.9 (C-10), 77.4 (C-6), 77.9 (C-2), 78.3 (C-3),
108.9 (acetal), 109.2 (C quat acetal), 109.8 (C quat acetal), 127.6
(Ar), 128.3 (Ar), 129.7 (Ar), 130.4 (Ar), 132.9 (Ar), 137.9 (Ar),
165.8 (CO), 172.0 (CO). Anal. Calcd for C38H51NO12: C, 63.94; H,
7.20; N, 1.96. Found: C, 64.01; H, 7.15.
59%, as a gum, ½a 2D5
ꢀ
22 (c 1, CHCl3); Rf 0.8 (H/EA 3:2); IR (film),
1721, 1725 cmꢁ1
;
1H NMR (CDCl3, 400 MHz): d 1.30 (t, 3H, Et),
2.05 (7s, 21H, 7 Me), 2.75 (s, 3H, NMe), 3.20 (m, 2H, H-4, H-5),
0
0
3.42 (dd, 1H, J1,2 = 5; J1,1 = 10 Hz, H-1), 3.44 (dd, 1H, J1 ,2 = 6 Hz,
H-10), 4.12 (dd, 1H, J10,11 = 5, J11,11 = 12.5 Hz, H-11), 4.20 (m, 3H;
0
COOCH2, H-110), 4.44 (2d, 2H, CH2Ph), 4.60 (dd, 1H,
J5,6 = J6,7 = 7 Hz, H-6), 5.12 (m, 1H, J9,10 = 8.5, J10,11 = 5 Hz,
0
J10,11 = 3 Hz, H-10), 5.20 (dd.1H, J3,4 = 8, J2,3 = 4 Hz, H-3), 5.24 (dd,
1H, J7-8 = 6.5 Hz, H-7), 5.35 (dd, 1H, J8,9 = 3 Hz, H-8), 5.41 (m, 1H,
H-2), 5.45 (dd, 1H, J9,10 = 8.5 Hz, H-9), 7.28 (m, 5H, Ph); 13C NMR
(CDCl3 62.9 MHz DEPT 135): d 13.9 (Et), 20.4, 20.5, 20.6, 20.7,
Please cite this article in press as: Oukani, H.; et al. Carbohydr. Res. (2013), http://dx.doi.org/10.1016/j.carres.2013.06.022

8
H. Oukani et al. / Carbohydrate Research xxx (2013) xxx–xxx
20.8, 29.5 (Me acetate), 43.8 (MeN), 50.3, 53.3, 61.5, 61.6, 67.3,
67.8, 68.2, 68.8, 70.4, 70.6, 71.78, 73.1, 79.7, 127.6 (Ar), 127.7
(Ar), 128.2 (Ar). Anal. Calcd for C36H49NO18: C, 55.16; H, 6.30; N,
1.78. Found: C, 55.0; H, 6.2.
Ph), 4.60 (s, 2H, CH2Ph), 4.87 (s, 1H, H-1), 4.90 (d, 1H, CH2Ph), 5.00
(dd, 1H, J5,6 = 1.5; J6,7 = 6.5 Hz, H-6), 7.30–7.41 (m, 10H, 2Ph).
4.14. 1-C-[(3S,4R,5R)-4-[Methoxycarbonyl]-3-[(4S,5S)-5-
(phenylmethyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
(methyl)-5-isoxazolidinyl]-1,4-anhydro-1,2:4,5-bis-O-(1-
4.10. [N(Z)]-N-Oxide-N-[[(4R,5R)-2,2-dimethyl-5-
[(phenylmethoxy)methyl]-1,3-dioxolan-4-yl]methylene]-
methanamine (18)
methylethylidene)-(1R)-D-manno-pentitol (23)
Procedure B using 22 and 6, 72%, gum, ½a D25
ꢀ
24.1 (c 1.0, CHCl3);
;
The procedure used for the synthesis of 6 was used to provide
Rf 0.45 (cycloH/EA 3:2); IR (film), 1737 cmꢁ1 1H NMR (CDCl3,
18 as a syrup, ½a 2D5
ꢀ
ꢁ19.0 (c 0.9, CHCl3); Rf 0.13 (Ethylacetate);
400 MHz): d 1.33 (s, 3H, Me), 1.39 (s, 3H, Me), 1.40 (s, 3H, Me),
1.42 (s, 3H, Me), 1.43 (s, 3H, Me), 1.51 (s, 3H, Me), 2.93 (s, 3H,
1H NMR (CDCl3, 250 MHz): d 1.40 (s, 3H, Me), 1.45 (s, 3H, Me),
0
0
3.70 (s, 3H, NMe), 3.80 (dd, 1H, ; J1,1 = 10, J1,2 = 6 Hz, H-1), 3.90
NMe), 3.59 (dd, 1H, J1,2 = 6.3, J1,1 = 10.3 Hz, H-1), 3.71 (dd, 1H,
0
(dd, 1H, J1 2 = 2.5 Hz, H-10), 4.20 (m, 1H, H-2), 4.70 (s, 2H, CH2Ph),
J1 ,2 = 3.4 Hz, H-10), 3.73 (s, 3H, OMe), 3.76 (dd, J3,4 = 6.9,
0
5.10 (dd, 1H, J3,4 = 6, J2,3 = 7 Hz, H-3), 6.95 (d, 1H, H-4), 7.28 (m,
5H, Ph); 13C NMR (CDCl3 62.9 MHz): d 26.3 (Me acetal), 26.9 (Me
acetal), 52.8 (NMe), 71.3 (C-1), 72.9 (C-3), 73.8 (OCH2Ph), 79.6 C-
2), 110.9 (C quat acetal), 127.6 (Ar), 127.8 (Ar), 128.3 (Ar), 138.0
J4,5 = 3.9 Hz, H-4), 3.82 (dd, J2,3 = 7.2 Hz, H-3), 3.95 (dd, 1H,
0
J10,11 = 5.2, J11,11 = 8.7 Hz, H-11), 3.98 (ddd, 1H, J2,3 = 7.2 Hz, H-2),
4.00 (dd, 1H, H-5), 4.05 (m, 2H, H-9, H-110), 4.33 (m, 1H, H-10),
4.57 (d, 1H, J7,8 = 5.9 Hz, H-7), 4.59 (d, 1H, J = 12.4 Hz, OCH-2Ph),
4.64 (d, 1H, OCH-2Ph), 4.77 (dd, 1H, J8,9 = 3.8 Hz, H-8), 7.35 (m,
5H, Ar); 13C NMR (CDCl3 100 MHz): d 24.2 (Me acetal), 25.2 (Me
acetal), 25.5 (Me acetal), 26.6 (Me acetal), 27.1 (Me acetal), 27.2
Me acetal), 47.4 (NMe), 52.1 (OMe), 55.0 (C-5), 66.3 (C-11), 1.0
(C-1), 1.5 (C-4) 73.2 (C-10), 73.4 (OCH2Ph), 78.2 (C-3), 79.1 (C-8),
79.5 (C-2), 79.9 (C-9), 84.7 (C-7), 109.1 (C quat acetal), 109.9 (C
quat acetal), 113.2 (C quat acetal), 116.5 (C-6), 27.6 (Ar), 127.7
(Ar), 128.4 (Ar), 138.1 (Cipso), 169.8 (CO); MS (HR-ESI) calcd for
(C-4), 138.1 (C ipso); MS (HR-ESI) calcd for
C15H21NNaO4
[M+Na]+ 302.1363, found: 302.1374.
4.11. 1-C-[(4R,5R)-4-[Ethoxycarbonyl]-3-[phenyl]-2-(methyl)-5-
isoxazolidinyl]-1,2:4,5-bis-O-(1-methylethylidene)-(1S)-
D-
manno-pentitol (17)
Procedure A using 8 and 10, 45%, foam, ½a D25
ꢀ
13.2 (c 0.6, CHCl3);
Rf 0.56 (H/EA 3:2); 1H NMR (CDCl3, 400 MHz): d 0.80 (t, 3H, Et),
1.38 (s, 3H, Me), 1.40 (s, 3H, Me), 1.45 (s, 3H, Me), 1.46 (s, 3H,
Me), 2.50 (d, 1H, J6,OH = 7.5 Hz, OH), 2.61 (s, 3H, NMe), 3.56–
3.77(m, 3H, COOCH2, H-2), 3.90 (m, 1H, H-1), 3.92 (m, 1H, H-6),
4.06–4.12 (m, 3H, H-7, H-8, H-80), 4.25 (dd, 1H, J3,4 = 7.8,
J4,5 = 6.8 Hz, H-4), 4.46 (dd, 1H, J5,6 = 1.0 Hz, H-5), 5.01 (dd, 1H,
J2,3 = 6.5 Hz, H-3), 7.29–7.38 (m, 5H, Ar); 13C NMR (CDCl3
100 MHz): d 13.8 (CH3), 25.0 (Me, acetal), 25.7 (Me, acetal), 26.8
(Me, acetal), 27.1 (Me, acetal), 43.6 (NMe), 58.5 (C-2), 60.7 (CH2,
COOEt), 67.3 (C-8), 69.5 (C-6), 75.7 (C-5, C-1), 76.4 (C-7), 78.0 (C-
3), 78.3 (C-4), 109.0 (C quat acetal), 109.5 (C quat acetal), 128.3
(Ar), 128.5 (Ar), 135.7 (C ipso), 170.5 (CO); MS (HR-ESI) calcd for
C
30H44NO11 [M+H]+ 594.2909, found: 594.2931.
4.15. 1-C-[(3R,4R,5R)-4-[Methoxycarbonyl]-3-[(4S,5S)-5-
(phenylmethyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
(methyl)-5-isoxazolidinyl]-1,4-anhydro-1,2:4,5-bis-O-(1-
methylethylidene)-(1R)-D-manno-pentitol (24)
Procedure B using 22 and 6, 18%, gum, ½a D25
ꢀ
65.3 (c 0.3, CHCl3);
1H NMR (CDCl3,
Rf 0.33 (cycloH/EA 3:2); IR (film), 1736 cmꢁ1
;
400 MHz): d 1.36 (s, 3H, Me), 1.37 (s, 3H, Me), 1.39 (s, 3H, Me),
1.42 (s, 3H, Me), 1.44 (s, 3H, Me), 1.52 s, 3H, Me), 2.82 (br m, 1H,
H-4), 2.88 (s, 3H, NMe), 3.45 (m, 2H, H-1, H-10), 3.48 (s, 3H, Me),
3.90 (d, 1H, J4,5 = 7.0 Hz, H-5), 3.97–4.08 (m, 4H, H-2, H-9, H-11,
H-110), 4.26 (m, 1H, H-10), 4.53 (d, 1H, J = 12.3 Hz, OCH2Ph), 4.59
(d, 1H, J7,8 = 5.7 Hz, H-7), 4.60 (d, 1H, OCH2Ph), 4.67 (dd, 1H,
J2,3 = 6.2, J3,4 = 9.2 Hz, H-3), 4.84 (dd, 1H, J8,9 = 3.7 Hz, H-8), 7.33
(m, 5H, Ar); 13C NMR (CDCl3 100 MHz): d 24.6 (Me acetal), 25.4
(Me acetal), 26.8 (Me acetal), 26.9 (Me acetal), 27.6 (Me acetal),
27.9 Me acetal), 46.2 (NMe), 1.5 (OMe), 4.1 (C-5), 67.0 (C-11),
70.6 (C-1), 73.0 (C-10), 73.4 (C-, CH2Ph), 75.6 (C-3), 79.5 (C-8, C-
2), 80.1 (C-9), 84.8 (C-7), 109.3 (C quat acetal), 110.1 (C quat ace-
tal), 111.4 (C-6), 113.5 (C quat acetal), 127.6 (Ar), 128.4 (Ar),
137.9 (C ispo), 167.9 (CO); MS (HR-ESI) calcd for C30H44NO11
[M+H]+ 594.2909, found: 594.2924.
C
24H37NO8 [M+H]+ 466.2435, found: 466.2425.
4.12. 1-C-[(3R,4R,5R)-4-[Ethoxycarbonyl]-3-[(4R,5R)-5-
(phenylmethyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
(methyl)-5-isoxazolidinyl]-1,2:4,5-bis-O-(1-methylethylidene)-
(1S)-D-manno-pentitol (19)
Procedure A using 8 and 18, 51%, foam, ½a D25
ꢀ
19 (c 0.8, CHCl3); Rf
0.45 (H/EA 2:1); 1H NMR (CDCl3, 400 MHz): d 1.25 (t, 3H, Et), 1.30–
1.45 (6s, 18H, 6Me), 2.30 (1H, OH), 2.85 (s, 3H, NMe), 3.00 (dd, 1H,
0
J3,4 = 6, J4,5 = 2.5 Hz, H-4), 3.6 (dd, 1H, J1,2 = 6, J1,1 = 10 Hz, H-1), 3.7
(m, 2H, H-10, H-5); 3.85 (bd, 1H, J9,10 = 7 Hz, H-9); 4.0–4.1 (m, 5H,
H-3, H-6, H-10, H-11, H-110), 4.3 (m, 3H, COOCH2, H-2), 4.4 (dd,
1H, J7,8 = 6.5, J6,7 = 10 Hz, H-7); 4.5 (d, 1H, H-8), 4.7 (s, 2H, CH2Ph);
7.28 (m, 5H, Ph).
4.16. 1-C-[(3S,4R,5R)-4-[methoxycarbonyl]-3-[(4S,5S)-5-
(phenylmethyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
(phenylmethyl)-5-isoxazolidinyl]-1,4-anhydro-1,2:4,5-bis-O-(1-
4.13. 1-C-[(3R,4S,5S)-4-[Methoxycarbonyl]-3-[(4S,5S)-5-
(phenylmethyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
(methyl)-5-isoxazolidinyl]-5-(methyl 2,3-O-isopropylidene-4-
methylethylidene)-(1R)-D-manno-pentitol (25)
Procedure B using 22 and 7, 83%, gum, ½a D25
ꢀ
+27.9 (c 0.9, CHCl3);
O-phenylmethylene-(5S)-
a-
D-lyxopyranoside) (21)
1H NMR (CDCl3, 400 MHz): d 1.30 (s, 3H, Me), 1.33 (s, 3H, Me), 1.39
(s, 3H, Me), 1.41 (s, 3H, Me), 1.45 (s, 3H, Me), 1.53 (s, 3H, Me), 3.52
Procedure A using 20 and 6, 13%, gum, ½a D25
ꢀ
17.5 (c 0.7, CHCl3);
(dd, 1H, J1,1 = 10, J1,2 = 6.5 Hz, H-1), 3.64 (ddd, 1H, J1 ,2 = 2.5,
J2,3 = 7.0 Hz, H-2), 3.70 (dd, 1H, H-10), 3.71 (dd, 1H, J3,4 = 8.5 Hz,
H-3), 3.80 (s, 3H, OMe), 4.00 (dd, 1H, J4,5 = 2.5 Hz, H-4), 4.02 (m,
1H, H-11), 4.05 (m, 1H, H-9), 4.08 (m, 1H, H-110), 4.09 (d, 1H, H-
5), 4.28 (d, 1H, J = 12 Hz, NCH2Ph), 4.37 (m,1H, H-10), 4.40 (d,
1H, NCH2Ph), 4.54 (d, J = 12.2 Hz, OCH2Ph), 4.55 (d, 1H,
J7,8 = 6.0 Hz, H-7), 4.61 (d,1H, OCH-2Ph), 4.73 (dd, 1H, J7,8 = 6.0,
0
0
Rf 0.38 (H/EA); 1H NMR (CDCl3, 400 MHz): d 1.25–1.45 (4s, 12H,
4Me), 2.75 (s, 3H, NMe), 3.12 (dd, 1H, J4,5 = 8, J3,4 = 7 Hz, H-4),
3.22 (s, 3H, OMe), 3.50 (dd, 1H, J7,8 = 2, J8,9 = 7.5 Hz, H-8), 3.56
(m, 2H, H-11, H-110), 3.65 (s, 3H, COOMe), 3.72 (m, 1H, H-10),
3.8 (dd, 1H, J9,10 = 5 Hz, H-9), 3.85 (m, 2H, H-5, H-7), 4.10 (d, 1H,
J2,3 = 5.5 Hz, H-2), 4.24 (dd, 1H, H-3), 4.44 (d, 1H, Jgem = 11 Hz CH2-
Please cite this article in press as: Oukani, H.; et al. Carbohydr. Res. (2013), http://dx.doi.org/10.1016/j.carres.2013.06.022

H. Oukani et al. / Carbohydrate Research xxx (2013) xxx–xxx
9
J8,9 = 4.0 Hz, H-8), 7.15,7.43 (m, 10H, Ar); 13C NMR (CDCl3
100 MHz): d 24.5 (Me acetal), 25.5 (Me acetal), 26.0 (Me acetal),
27.0 (Me acetal), 27.4 (Me acetal), 27.6 (Me acetal), 52.5 (OMe),
56.2 (C-5), 63.2 (NCH2Ph), 66.4, (C-11), 69.5 (C-4), 71.9 (C-1),
73.8 (OCH2Ph, C-10), 78.4 (C-3), 79.4 (C-8), 80.2 (C-9), 80.3 (C-2),
85.1 (C-7), 109.5 (C quat acetal), 110.1 (C quat acetal), 113.7 (C
quat acetal), 118.3 (C-6), 125.7 (Ar), 128.0 (Ar), 128.0 (Ar), 128.1
(Ar), 128.8 (Ar), 128.9 (Ar), 130.3 (Ar), 137.4 (C ipso), 138.7 (C ipso),
170.6 (CO); MS (HR-ESI) calcd for C36H48NO11 [M+H]+ 670.3222,
found: 670.3232.
Am. Chem. Soc. 1985, 107, 7761–7762; (c) Jarosz, S. Curr. Org. Chem. 2008, 12,
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Praly, J. P.; Chen, G. R.; Gola, J.; Hetzer, G. Eur. J. Org. Chem. 2000, 2831–2838.
10. (a) Ikemoto, N.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 9657–9659; (b)
Ikemoto, N.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 2524–2536.
11. Uchida, K.; Das, B. C. Biochimie 1973, 55, 635–636.
12. (a) Secrist, J. A. I.; Barnes, K. D. J. Org. Chem. 1980, 45, 4526–4528; (b)
Danishefsky, S.; Maring, C. J. Am. Chem. Soc. 1985, 107, 7762–7764; (c)
Danishefsky, S. J.; Maring, C. J. J. Am. Chem. Soc. 1989, 111, 2193–2204; (d)
Fürstner, A.; Wuchrer, M. Chem. Eur. J. 2006, 12, 76–89.
13. (a) Confalone, P. N.; Huie, E. M. In The [3+2] Nitrone-Olefin Cycloaddition
Reaction; Organic Reactions, J. Wiley: 1988; Vol. 36, pp 1–173.; (b) Gothelf, K. V.;
Jorgensen, K. A. Chem. Rev. 1998, 98, 863–909; (c)Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products;
Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons, 2002; (d)Cycloaddition
Reactions in Organic Synthesis; Kobayashi, S., Jorgensen, K. A., Eds.; John Wiley &
Sons, 2002; (e)Nitrile Oxides Nitrones and Nitronates in Organic Synthesis: Novel
Strategies in Synthesis; Feuer, H., Ed.; John Wiley & Sons, 2008.
4.17. 1-C-[(3R,4S,5R)-4-[methoxycarbonyl]-3-[(4S,5S)-5-
(phenylmethyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
(phenylmethyl)-5-isoxazolidinyl]-1,4-anhydro-1,2:4,5-bis-O-(1-
methylethylidene)-(1R)-D-manno-pentitol (27)
Procedure B using 22 and 7, 60%, gum, ½a D25
ꢀ
+101 (c 0.9, CHCl3);
IR (film), 1743 cmꢁ1; 1H NMR (CDCl3, 400 MHz): d 1.28 (s, 3H, Me),
1.40 (s, 3H, Me), 1.41 (s, 3H, Me), 1.42 (s, 6H, Me), 1.46 (s, 3H, Me),
3.40 (d, 1H, J4,5 = 6.7 Hz, H-5), 3.57 (dd, 1H, J3,4 = 6.5 Hz, H-4), 3.58
14. (a) Bernet, B.; Vasella, A. Helv. Chim. Acta 1979, 62, 1990–2016; (b) Koumbis, A.
E.; Gallos, J. K. Curr. Org. Chem. 2003, 7, 585–628; (c) Gallos, J. K.; Koumbis, A. E.
Curr. Org. Chem. 2003, 7, 397–426; (d) Osborn, H. M. I.; Gemmell, N.; Harwood,
L. M. J. Chem. Soc., Perkin Trans. 1 2002, 1, 2419–2438; (e) Benltifa, M.; Vidal, S.;
Gueyrard, D.; Goekjian, P. G.; Msaddek, M.; Praly, J.-P. Tetrahedron Lett. 2006,
47, 6143–6147; (f) Enderlin, G.; Taillefumier, C.; Didierjean, C.; Chapleur, Y.
Tetrahedron: Asymmetry 2005, 16, 2459–2474; (g) Fisera, L. Top. Heterocycl.
Chem. 2007, 7, 287–323; (h) Stecko, S.; Jurczak, M.; Panfil, I.; Furman, B.;
Grzeszczyk, B.; Chmielewski, M. C. R. Chim. 2011, 14, 102–125.
0
(dd, 1H, J1,1 = 10, J1,2 = 5.5 Hz, H-1), 3.70 (s, 3H, OMe), 3.71 (m,
1H, H-9), 3.72 (dd, 1H, J1 ,2 = 3.0 Hz, H-10), 4.02 (d, 1H, Jgem = 14.7 Hz,
0
0
NCH2Ph), 4.08 (d, 1H, J10,11 = 4.5, J11,11 = 8.7 Hz, H-11), 4.11 (m, 1H,
H-3), 4.14 (d, 1H, J10,11 = 6.0 Hz, H-110), 4.30 (ddd, J 2,3 = 8.0 Hz, H-
0
2), 4.31 (d, 1H, NCH2Ph), 4.39 (ddd, 1H, J9,10 = 8.6 Hz, H-10), 4.51 (d,
1H, J = 12.0 Hz, OCH2Ph), 4.59 (d, 1H, J7,8 = 5.5 Hz, H-7), 4.60 (d, 1H,
OCH2Ph), 4.70 (dd, 1H, J8,9 = 3.3 Hz, H-8), 7.31 (m, 10H, Ar); 13C
NMR (CDCl3 100 MHz): d 25.3 (Me acetal), 25.8 (Me acetal), 26.1
(Me acetal), 27.3 (Me acetal), 27.4 (Me acetal), 27.5 (Me acetal),
52.4 (OMe), 56.8 (C-5), 60.8 (NCH2Ph), 67.8 (C-11), 71.2 (C-1),
7.85 (C-4), 73.1 (C-10), 73.9 C(OCH2Ph), 76.1 (C-3), 77.9 (C-4),
79.5 (C-9), 79.7 (C-8), 83.4 (C-7), 109.9 (C quat acetal), 110.3 (C quat
acetal), 112.4 (C-6), 113.4 (C quat acetal), 127.4 (Ar), 127.9 (Ar),
128.0 (Ar), 128.2 (Ar), 128.6 (Ar), 128.7 (Ar), 137.7 (C ipso NBn),
138.4 (C ipso OBn), 172.4 (CO); MS (HR-ESI) calcd for C36H48NO11
[M+H]+ 670.3222, found: 670.3246.
15. (a) Cardona, F.; Salanski, P.; Chmielewski, M.; Valenza, S.; Goti, A.; Brandi, A.
Synlett 1998, 1444–1446; (b) Socha, D.; Jurczak, M.; Frelek, J.; Klimek, A.;
Rabiczko, J.; Urbanczyk-Lipkowska, Z.; Suwinska, K.; Chmielewski, M.;
Cardona, F.; Goti, A.; Brandi, A. Tetrahedron: Asymmetry 2001, 12, 3163–3172;
(c) Socha, D.; Pasniczek, K.; Jurczak, M.; Solecka, J.; Chmielewski, M. Carbohydr.
Res. 2006, 341, 2005–2011.
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Acknowledgment
21. (a) Collins, P. M.; Overend, W. G.; Shing, T. S. J. Chem. Soc., Chem. Commun. 1982,
297–298; (b) Lopez Herrera, F. J.; Pino Gonzalez, M. S.; Nieto Sampedro, M.;
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We thank Sanofi-Aventis for a fellowship to O.J.
22. DeShong, P.; Dicken, C. M.; Staib, R. R.; Freyer, A. J.; Weinreb, S. M. J. Org. Chem.
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Supplementary data
23. Duff, F. J.; Vivien, V.; Wightman, R. H. Chem. Commun. 2000, 2127–2128.
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2013.06.
022.
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