Synthesis of ketosyl spiro-isoxazolidine by 1,3-dipolar cycloaddition of 1-methylenesugars with nitrones - A new access to C-glycosyl amino acids

Article abstract of DOI:10.3987/com-02-s52

The 1,3-dipolar cycloaddition reactions of 1-methylenesugars (1a-c) with nitrones (2 and 5) were carried out diastereoselectively under the catalysis of BF₃·Et₂O at low temperature and afforded the α-stereoselective spiro ketosyl iso

Full text of DOI:10.3987/com-02-s52

HETEROCYCLES, Vol.59, No. 2, 2003, pp. 547 - 571, Recieved 6th August, 2002
SYNTHESIS OF KETOSYL SPIRO-ISOXAZOLIDINE BY
1,3-DIPOLAR CYCLOADDITION OF 1-METHYLENE-
SUGARS WITH NITRONES
─A NEW ACCESS TO C-GLYCOSYL AMINO ACIDS#
Xiaoliu Li, Hideyo Takahashi, Hiro Ohtake, and Shiro Ikegami*
School of Pharmaceutical Sciences, Teikyo University
Sagamiko, Kanagawa 199-0195, Japan
Tel.: +81-426-85-3728; Fax: +81-426-85-1870; e-mail: shi-ike@pharm.teikyo-u.ac.jp
Abstract - The 1,3-dipolar cycloaddition reactions of 1-methylenesugars (1a~c)
with nitrones (2 and 5) were carried out diastereoselectively under the catalysis
of BF3 • Et2O at low temperature and afforded the α-stereoselective spiro ketosyl
isoxazolidines in good to excellent yields. The reductive isoxazolidine
ring-opening of the spiro moiety with the treatment of zinc and acetic acid
resulted in a new kind of C-glycosyl amino acid possessing a ketose form,
providing an access to C-glycosyl amino acids. The structures of the synthesized
compounds were confirmed by the spectroscopic analyses.
INTRODUCTION
Spiro-glycoside ring substructures, such as spiro-nucleoside, spiro-orthoesters, and spiro-ketal have been
found in many biologically active natural products.1-3 The strong biological activity of these compounds
have triggered great interest in building such substructures.4-6 Of the conventional method,
cyclo-glycosidation reactions were used for the syntheses of the spiro-glycosides, especially for that of
spiro-ketal. However, recent studies revealed that the rigid spiro system of a spiro-ketodisaccharide made
the stereoselectivity of cyclo-ketosylation different from that of linear ketosylation.5e,6,7 While the
ketosylations of ketopyranoses could provide the thermodynamic stable α-ketodisaccharides
exclusively,6b,6c,7 the cyclo-ketosylation of forming the spiro-ketodisaccharide preferred the
α,β-stereoselectivity to the α,α-selectivity in the two spiro anomeric carbons, affording the mixture of
α,α- and α,β-isomers.6b,6d The stereoselective and efficient formation of a spiro-anomeric center is still a
great challenge.
#Dedicated to Professor Yuichi Kanaoka on the occasion of his 75th birthday.

1,3-Dipolar cycloadditions of nitrones with alkenes, as one of the most important methods of cyclization
reactions, have been widely used in organic synthesis.8 With this reaction up to three new contiguous
chiral centers could be created in one step. A stereoselective cycloaddition could be achieved by choosing
an appropriate nitrone or alkene which contains either an electron-donating or electron-withdrawing
substituent. Moreover, the use of Lewis acid could also control the stereoselectivity by forming metallic
complexes with the nitrones or alkenes.8c,8d,8g,9
Although the utility of the 1,3-dipolar cycloaddition in the synthesis of carbohydrate derivatives has been
recently reported,8e~h,10 very few of the application of this methodology in the formation of
spiro-glycoside has been briefly studied so far.11 As an extension of our recent work on the syntheses of
ketosyl glycosides and spiro-ketodisaccharides using 1-methylenesugars as the precursor,6b,7d,7e we
describe in this article the stereoselective synthesis of glycosyl spiro-isoxazolidine by the 1,3-dipolar
cycloaddition of nitrone to 1-methylenesugar and the further exploration of converting the spiro
isoxazolidine to new C-glycosyl amino acids.
RESULTS AND DISCUSSION
Most of nitrones are relatively stable and easily accessible compounds and they have been successfully
used in organic synthesis.8,12 The nitrones (2) and (5) were readily prepared according to the Dondoni’s
procedure13 by the reaction of ethyl glyoxalate with the corresponding N-benzylhydroxylamine and
N-methylhydroxylamine, respectively.
Considering the achievements of the stereoselective 1,3-dipolar cycloadditions of nitrones to alkenes8,9
and the stereoselective glycosidations of 1-methylenesugars (1) 6b,7d,7e catalysed by Lewis acids, we firstly
examined the cycloaddition of the 1-methylenesugar (1a) with the nitrone (2) under various conditions
(Scheme 1). The results are listed in Table 1.
BnO
BnO
6
O
6
O 5
8
8
BnO
BnO
BnO
1
O
7
7
4
BnO
BnO
BnO
BnO
2
N
COOEt
Bn
3
5
O
Bn
N
O
10
10
9
9
1
+
+
2
4
3
COOEt
BnO
O N
BnO
BnO
COOEt
Bn
2
4a
1a
3a
Scheme 1
It should be noted that the 1,3-dipolar cycloaddition of 1a with 2 proceeded diastereoselectively and gave
only two anomeric isomers (3a) and (4a) possessing R-configuration on C-3, although the 1,3-dipolar
cycloadditions of the 1-methylenesugars (1a) with the nitrones (2) should be supposed to afford four
diastereomers, that is, two anomeric isomers having R-configuration on C-3 (3a and 4a) and their
diastereomers with S-configuration on C-3 (3s and 4s) (as shown in Figure 2). The reaction did not

produce the other two anomeric isomers (3s) and (4s).
Table 1 1,3-Dipolar cycloaddition of the methylenesugar (1a) with nitrone (2)a
Entry
Conditions
3a (%)
(α-isomer)
33.2
4a (%)
(β-isomer)
2.2
α : β
1
2
15.1 : 1.0
14.9 : 1.0
5.1 : 1.0
BF3
BF3
•
•
OEt2 (0.3 eq.), CH2Cl2, -78°C, 4 h
OEt2 (1.3 eq.), CH2Cl2, -78°C, 4 h
56.8
57.2
71.9
87.5
67.8
3.8
11.2
6.4
3
BF3 • OEt2 (0.5 eq.), CH2Cl2, rt, 3 h
4
11.3 : 1.0
10.9 : 1.0
12.1 : 1.0
BF3 •OEt2 (1.3 eq.), CH2Cl2, -78°C, 4 h→0°C
5b
8.0
BF3 OEt2 (1.3 eq.), CH2Cl2, -78°C, 4 h→0°C
•
6
5.6
BF3 • OEt2 (1.5 eq.), Et2O, -78°C, 4 h→rt
ZnBr2 (1.5 eq.), CH2Cl2, rt, 24 h
ZnBr2 (1.5 eq.), Et2O, rt, 24 h
ZnCl2 (1.5 eq.), CH2Cl2, rt, 24 h
Et2AlCl (1.5 eq.), CH2Cl2, rt, 4 h
AlCl3 (1.5 eq.), CH2Cl2, rt, 4 h
TiCl4 (1.0 eq.), CH2Cl2, rt, 4 h
benzene, reflux, 24 h
7
8
28.1
18.2
18.4
22.1
16.3
12.7
43.4
35.9
13.2
29.5
18.4
14.8
10.5
52.3
1.0 : 1.3
1.5 : 1.0
1.0 : 1.6
1.2 : 1.0
1.1 : 1.0
1.2 : 1.0
1.0 : 1.2
9
10
11
12
13
a: 1a (0.2 mmol) and 2 (0.25 mmol) were used.
b: 2.0 equiv. of 2 was used.
As shown in Table 1, the cycloaddition reaction of the 1-methylenesugar (1a) with the nitrone (2) under
the catalysis of BF3 • Et2O provided a mixture of the α- and β-anomeric isomers, ketosyl
spiro-isoxazolidines (3a) and (4a) with the α-isomer (3a) as the predominant (Entries 1~6). In the
presence of a catalytic amount of BF3 •Et2O (0.3 equiv.), the reaction of 1a with 2 (1.25 equiv.) at -78°C
gave the adducts (3a) and (4a) in low yield (35.4%) and in a α,β-stereoselective ratio of 15.1 : 1 with the
nearly 58% recovery of the starting material (1a) (Entry 1), indicating that the stoichiometric amounts of
the Lewis acid might be necessary for the reaction. In fact, the use of BF3 •Et2O in 1.3 equiv. afforded the
products (3a) and (4a) in the overall yield of 60.6% without the remarkable change of the
α-stereoselectivity (Entry 2). Moreover, increasing the reaction temperature up to 0°C after reacting at
-78°C for 4 h resulted in a good yield (78.3%) of the adducts (3a) and (4a) with a satisfying
α-stereoselectivity (Entry 4, this condition is called as Procedure A). Under this condition, an excessive
use of the nitrone (2) (2.0 equiv.) provided an excellent yield (95.5%) of the products with a similar
stereoselectivity (Entry 5).
However, other Lewis acids, such as ZnBr2, ZnCl2, Et2AlCl, AlCl3, and TiCl4, were found not to be
efficient to this reaction and gave a poor stereoselectivity (Entries 7~12), although it has been recently

observed that the Lewis acids, such as ZnBr2 and Et2AlCl could induce the 1,3-dipolar cycloaddition of
some nitrone and enolic compounds to proceed in contrary stereoselective way.9
Further experiments showed that the reaction temperature could remarkably influence the reaction
stereoselectivity and reactivity (Entries 2, 3, 4, and 13). A considerable decrease of the stereoselectivity
was observed when the reaction was performed at room temperature with 0.5 equiv. of BF3 •Et2O catalyst
(Entry 3). Moreover, while the cycloaddition could not complete at -78°C in the presence of 1.3 equiv. of
BF3 •Et2O (Entry 2), the reaction could efficiently proceed in benzene at reflux to afford the mixture of 3a
and 4a in excellent overall yield of 95.7% without using any Lewis acid catalyst (Entry 13, this condition
is called as Procedure B). Unfortunately, the stereoselectivity of the reaction was not satisfied. The
reaction stereoselectivities observed above were identical with those in the cycloglycosylations of
forming spiro-ketodisaccharides.6b
The reaction stereoselectivity was slightly affected by the nature of the solvent due to the anomeric
effects.14 For example, the use of Et2O instead of CH2Cl2 was of benefit to the α-stereoselectivity in the
reaction (Entries 6, 8).
The 1,3-dipolar cycloaddition reactions of 1b~c to 2 and 1a~c to 5 were also carried out according to
Procedure A and Procedure B, respectively (Scheme 2), and the similar stereoselectivity as in the
reaction of 1a to 2 was obtained. The results are summarized in Table 2. In the case of mannose derivative
(1c) possessing an axial 2-benzyloxy group, the reaction exhibited an increase of β-stereoselectivity under
each condition of Procedure A and B in comparison with the cases of glucose derivative (1a) and
galactose derivative (1b).
BnO
BnO
1
3
3
1
R
R
R
R
BnO
6
O 5
6
O 5
3
1
8
8
1
O
7
7
4
4
4
R
R
R
R
2
N
COOEt
R
3
R
N
O
4
O
2
10
9
10
R
+
BnO
BnO
9
1
+
2
4
3
COOEt
2
BnO
O N
R
2
R
R
COOEt
R
R = Bn
4a~c
7a~c
R = Bn
2
5
R = Bn
3a~c
6a~c
1a~c
R = Me
R = Me
R = Me
( -isomer)
α
( -isomer)
β
1
2
3
4
R
R
R
R
H
H
H
BnO
H
a (Glc)
b (Gal)
c (Man)
BnO
BnO
BnO
H
BnO
H
BnO
Scheme 2

Table 2 1,3-Dipolar cycloadditions of the methylenesugar (1a~c) with nitrones (2) and (5)
Entry
Nitrones
Conditions
(Procedure)
A
Products (Yield %)
1
α : β
1
2
3a (71.9)
4a (6.4)
11.3 : 1.0
14.8 : 1.0
5.4 : 1.0
1.0 : 1.2
1.0 : 1.0
1.0 : 1.8
9.1 : 1.0
8.8 : 1.0
1.9 : 1.0
1.0 : 1.0
1.0 : 1.1
1.0 : 3.1
1a
1b
1c
1a
1b
1c
1a
1b
1c
1a
1b
1c
2
2
2
2
2
2
5
5
5
5
5
5
3b (72.6)
3c (58.0)
3a (43.4)
3b (31.0)
3c (23.4)
6a (70.1)
6b (68.6)
6c (53.7)
6a (41.0)
6b (37.5)
6c (12.3)
4b (4.9)
4c (10.8)
4a (52.3)
4b (31.5)
4c (42.1)
7a (7.7)
A
A
B
B
B
A
A
A
B
B
B
3
4
5
6
7
8
7b (7.8)
7c (28.6)
7a (41.4)
7b (41.3)
7c (38.2)
9
10
11
12
Procedure A: 1-Methylenesugar (0.2 mmol), nitrone (0.25 mmol), BF3 OEt2 (1.3 eq.), CH2Cl2, -78°C, 4 h→0°C.
•
Procedure B: 1-Methylenesugar (0.2 mmol), nitrone (0.25 mmol), benzene, reflux, 24 h.
In order to study the effect of the protecting groups on the reaction stereoselectivity, the 1,3-dipolar
cycloaddition of the acetyl-protected 1-methylenesugar (8) with the nitrone (2) was examined under the
similar conditions as in the Procedure A using 1.5 equiv. of BF3•OEt2 (Scheme 3), and a similar result,
except a decreased reactivity, was obtained as shown in the Table 3. Interestingly, a substantial decrease
of the α-stereoselectivity was not observed, although the existence of the equatorial 2-O-acetyl group
usually caused a remarkable increase of the β-stereoselectivity in a common glycosylation reaction due to
its neighboring group participation effect.14
AcO
AcO
AcO
AcO
O
O
AcO
10
AcO
AcO
AcO
O
AcO
COOEt
Bn
O
Bn
N
O
AcO
N
+
+
AcO
COOEt
O N
Bn
AcO
COOEt
8
2
9
Scheme 3
Table 3 1,3-Dipolar cycloaddition of the 2,3,4,5-tetra-O-acetyl-1-methylenesugar (8) with nitrone (2)
Entry
Conditions
9 (α)
10 (β)
α : β
1
2
No reaction
BF3•OEt2 (1.5 eq.), CH2Cl2, -78°C, 1 h
BF3• OEt2 (1.5 eq.), CH2Cl2, -78°C, 1 h→rt, 4 h
72.6%
7.3%
9.9 : 1.0

The 1,3-dipolar cycloaddition reactions of 1a~c with the nitrile oxide (11) which was generated in situ
from the corresponding ethyl chlorooximidoacetate under a basic condition were also studied. The
reaction proceeded stereospecifically at room temperature and provided the ketosyl spiro-isoxazoline (12)
as the sole product (Scheme 4). This stereospecific result was consistent with the RajanBau’s
observation.15
Cl
N C
HO
O
COOEt
BnO
Et N
1
3
3
BnO
R
R
3
1
6
O 5
R
R
8
7
4
i
4
R
4
COOEt
3
O
2
N C
R
COOEt
+
10
9
BnO
1
O
2
BnO
2
R
N
R
11
1a~c
12a~c (α-isomer)
12 (%)
1
2
3
4
R
R
R
R
H
H
H
BnO
H
55.2
66.2
70.0
a (Glc)
BnO
BnO
H
BnO
H
b (Gal)
BnO
BnO
c (Man)
Scheme 4 Reaction conditions: (i) CH2Cl2, rt
The structures and configurations of the synthesized spiro-isoxazolidines and spiro-isoxazolines were
1
determined by the analyses of their spectral data of H NMR, 13C NMR and 2D-COSY, and by the
NOESY experiments. It has been shown that in the 13C NMR spectra of C-glycosides16 and ketosyl
spiro-disaccharides6b the signals of the anomeric carbon in the α-isomers appeared in higher field than
those in the β-isomers. From this point of view, the anomeric configurations of the products were
assigned by the comparison of the anomeric 13C NMR spectral data between each two anomeric isomers.
Careful examination of vicinal proton-coupling constants unambiguously suggested a chair conformation
for the six membered sugar rings (See the EXPERIMENTAL for the proton assignments). Accordingly,
the configuration of the anomeric carbon and the relative orientation of the isoxazolidine ring substituents
were further established from the NOE observations between H3 and H4, H4 and H10 as exemplified by the
analyses of compounds (3a) and (4a) in Figure 1 (Also see Table 4).
The respective irradiations of H4a and H4b in 3a resulted in the enhancements of the signals for H10 and H3.
The enhancements on H10 and H3 caused by H4a were bigger than those resulted from H4b. When H10 was
irradiated, the similar results that the interaction between H4a and H10 was stronger than H4b and H10 were
observed, indicating that H10 to H4a and H4a to H3 should be in cis-orientation as shown in Figure 1.
Comparatively, in compound (4a) stronger effects of H4b to H3and H10were observed, supporting the

conformation shown in Figure 1.
0.82%
2.38%
BnO
H
H
8.46%
6
O
8
1
7
1.85%
BnO
BnO
O
Bn
5
2
N
a
b
10
9
H
H
H
BnO
4
BnO
3
6
8
H
7
O
b
H
4
BnO
BnO
3
a
5
1.72%
H
COOEt
10
COOEt
9
1
2
1.05%
BnO
O
N
6.06%
3.00%
Bn
4a
3a
Figure 1 NOE analyses of compounds (3a) and (4a)
Table 4 Selected NOE data of the ketosyl spiro-isoxazolidines 3a~c, 4a~c, 9 and 10
3a (%)
4a (%)
4b (%)
3c (%)
4c (%)
9 (%)
10 (%)
H4a→H10
H4a→H4b
H4a→H3
H4b→H10
H4b→H4a
H4b→H3
H10→H4a
H10→H4b
2.38
1.05
1.85
1.51
1.71
5.59
0.86
13.71
8.46
0.82
7.57
1.85
2.31
0.70
19.17
6.06
1.72
15.20
3.00
0.70
1.00
12.66
7.01
4.12
13.21
1.69
-
6.52
2.73
0
15.07
5.83
5.11
16.27
1.87
-
26.82
9.46
0.95
18.05
2.62
-
17.82
6.87
4.96
16.76
2.02
-
2.87
2.62
-
-
-
-
-
-
Similarly, the configurations of the other isooxazolidine compounds except 3b were established on the
basis of their NOE experiments (See Table 4). As for the compound (3b), since the signals of the H4a and
H4b were overlapped, it was difficult to distinguish the NOE effects resulted from H4a or H4b. The
structure was deduced by the comparison of the signals of the anomeric carbons with its diastereomer
(4b) whose configuration were assigned by NOE experiment. In addition, the configurations obtained
from the NOE experiments as above were also supported by the molecular modeling calculation results
using MacroModel program17 as shown in Figure 2.
The conformations and their corresponding energies (∆E) of the compounds (3a) and (4a), and their
diastereomers (3s) and (4s) were calculated17 using MacroModel 6.0 with the MM2* force field18 with
LOMD (Low Mode) conformational search technique.19 The most stable conformations of the
diastereomers and the corresponding minimized energies are shown in Figure 2. It was found that in all

cases the pyranoid rings took the energetically favoured chair form. In the cases of 3a and 4a being
anomeric isomers with the R-configuration on C-3, the stable conformers from the most stable one to the
20th were in the almost same conformations, but in the cases of 3s and 4s having S-configuration on C-3,
there were a variety of conformations among the stable conformers from the first one to the 20th.
Moreover, the calculated energies corresponding the most stable conformers of 3a and 4a were much
lower than those of 3s and 4s, that is, the R-diastereomer (C-3) of 3a and 4a were more
thermodynamically stable than the S-diastereomer (C-3) of 3s and 4s. With the calculation results it was
reasonable to understand the reaction stereoselectivity that the 1,3-dipolar cycloadditions of
1-methylenesugars (1a~c) with nitrones (2) and (5) afforded only two of the four diastereomers in each
case.
BnO
BnO
BnO
O
O
COOEt
H
BnO
BnO
O
Bn
N
BnO
S
*
*
*
S
BnO
BnO
O
N
*
COOEt
H
Bn
3s(S)(α)
(∆E = -10.70 kcal)
4s(S) (β)
(∆E = -5.30 kcal)
BnO
BnO
6
O
8
H
7
O
4
3
BnO
BnO
BnO
BnO
O
5
Bn
10
R
COOEt
N
9
*
*
*
BnO
R
BnO
O
1
N2
Bn
*
H
COOEt
3a(R) (α)
(∆E = -46.08 kcal)
4a(R) (β)
(∆E = -40.51 kcal)
∆∆E = ∆E3a - ∆E3s = -46.08 – (-10.70) = -29.38 kcal ∆∆E = ∆E4a - ∆E4s = -40.51 – (-5.30) = -35.21 kcal
Figure 2 Energy minimized conformations of 3a and 4a and their two diastereomers (3s) and (4s)
(The benzyls on pyranoid rings and all protons were omitted after minimization for clarity)
It has been revealed that the carbohydrate-protein interaction played very important roles in carbohydrate
biology,20 and great attentions have recently been attracted on the syntheses of glycopeptides and glycosyl
amino acids, and their analogues.21,22 With the convenient preparation of the ketosyl spiro-isoxazolidine
in hands, we extended our study by approaching a new access to C-glycosyl amino acids from the ketosyl
spiro-isoxazolidines in virtue of the reductive cleavage of the N-O bond.
A variety of the reductive isoxazolidine ring–opening methods which generated β-amino alcohol have
been developed.8a,8b For example, the catalytic hydrogenation with palladium or Raney nickel and the

treatment of the isoxazolidine with zinc and acid were commonly used. The hydrogenation catalyzed by
Pd(OH)2/C (20%) of the spiro-isoxazolidine (6a) was firstly tried in hope that the cleavage of the O-N
bond and debenzylation would be finished by using this one step reaction. However, the reaction was
found not to proceed efficiently and produced an inseparable mixture most likely due to the inactivation
of the catalyst by the generated amino group. After careful examination, the best result of reductively
cleaving the N-O bond was obtained. The treatment of ketosyl spiro-isoxazolidines (6a~c) with activated
zinc powder in AcOH/Ac2O solution at room temperature afforded the ring-opened products (13a~c)
(C-glycosyl amino acids) and the recyclized products (14a~b) (Scheme 5)
BnO
BnO
9
R
BnO
1
1
3
3
1
Me
R
3
R
R
R
R
H
3
7
6
8
1
6
O 5
8
4
O
2
7
4
8
H
i
4
7
R
O
4
NAc
4
4
2
3
COOEt
R
R
5
3
BnO
5
6
BnO
10
9
1
10
2
9
BnO
1
R
2
COOEt
2
OH
NAc
R
O
2
O N
Me
R
O
Me
13a~c
14a~b
6a~c
1
2
3
4
R
R
R
R
14
13
H
H
H
BnO
H
BnO
H
39.6%
46.1%
45.8%
40.2%
a (Glc)
BnO
BnO
H
b (Gal)
-
42.9%
BnO
BnO
c (Man)
Scheme 5 Reaction conditions: (i) Zn, AcOH, Ac2O, rt
In the reaction, the chiral carbons in the products (13a~c) (C*-2) and (14a~b) (C*-3) conserved the
configurations on the corresponding chiral carbons (C*-3) in compounds (6a~c). The R-configuration on
this carbon was further confirmed by the analyses of NOE experiments with 14a~b as shown in Figure 3.
1.86%
3.09%
4.65%
2.12%
3.35%
6.35%
8.66%
11.78%
BnO
Ha
Hb
Hb
H
BnO
Ha
H
BnO
6
O
H
8
6
O
7
H
4
2
8
7
BnO
BnO
3
4
2
5
3
5
NAc
Me
10
9
BnO
NAc
Me
10
1
O
9
1
O
BnO
BnO
O
O
14b
14a
Figure 3 The NOE analyses of compounds (14a) and (14b)

Finally, the debenzylation of the C-glycosyl amino acid (13a) was completed by the catalytic
hydrogenation on Pd(OH)2/C and afforded the corresponding C-glycosyl amino acid (15) as shown in
Scheme 6. The spectral properties of 15 were identical with the structure shown.
9
BnO
9
HO
7
1
8
3
7
1
O
8
3
R
*
2
O
BnO
BnO
4
COOEt
R
6
HO
HO
4
COOEt
i
6
BnO 5
*
HO 5
2
OH
NAc
OH
NAc
Me
Me
15
Scheme 6 Reaction conditions: (i) Pd(OH)2/C, H2, MeOH.
13a
In summary, stereoselective formation of glycosyl spiro-isoxazolidine was achieved by the 1,3-dipolar
cycloaddition of 1-methylenesugar with nitrone and provided two anomeric isomers. While the reaction
showed low stereoselectivity under thermodynamic conditions (Procedure B), the cycloaddition
promoted by BF3•Et2O at -78°C (Procedure A) gave the α-isomer predominantly. The stereoselectivity
was similar to that in the cycloketosylation in our previous report.6b The treatment of the
spiro-isoxazolidine (6a) with Zn in AcOH and Ac2O solution resulted in the reductive cleavage of O-N
bond with the retention of the configuration at the chiral carbon (C*-3), and followed by debenzylation
using the catalytic hydrogenation the C-glycosyl amino acid with a ketose-like structure was obtained,
providing a new access to the C-glycosyl amino acids.
EXPERIMENTAL
General methods. ⎯ Melting points were measured on a YANACO Micro Melting Point Apparatus and
were uncorrected. IR spectra were recorded on a Jasco FT/IR-800 Fourier-transform infrared
spectrophotometer. 1HNMR, 13CNMR and COSY spectra were measured on a JEOL ECP 600 (600 MHz)
NMR spectrometers using tetramethylsilane (Me4Si) as an internal standard. MS spectra and HRMS
spectra were carried out on a JEOL JMS-SX102A mass spectrometer with FAB (Fast Atomic
Bombardment) using 3-Nitrobenzyl alcohol (NBA) as the matrix. Optical rotations were measured with a
Jasco DIP-370 digital polarimeter. TLC was performed on precoated plates (Merck TLC aluminum sheets
silica 60 F254) with detection by UV light or with phosphomolybdic acid in EtOH/H2O followed by heating.
Column chromatography was performed using SiO2 (Wakogel C-200, Wako).
Calculations. ⎯ Low-mode searches (LOMD)19 for compounds (3a) and (4a), and their diastereomers
(3s) and (4s) were performed using MacroModel ver. 6.018 with the MM2* derivative of MM2 force field
on a Silicon Graphics IRIS-Indigo workstation. LOMD for each compound was continued until around
5,000 conformers were generated.

General procedure of 1,3-dipolar cycloadditions of the 1-methylenesugars (1) with nitrones (2).
Procedure A: Under the catalysis of a Lewis acid: ⎯ To a solution of 1a (107 mg, 0.2 mmol), 2 (52
mg, 0.25 mmol) and Molecular sieves 4A (MS 4A, 300 mg) in 4 mL of CH2Cl2 was added BF3•Et2O (32
µL, 0.25 mmol, 1.3 equiv.) under Argon atmosphere at –78°C. The solution was stirred at the same
temperature for 4 h, then the reaction temperature was gradually increased up to 0°C, then, triethylamine
(0.1 mL) was added to quench the reaction. The solvent was removed under reduced pressure, and the
residue was applied on silica gel column chromatography using AcOEt : Hexane (1 : 5) as the eluent to
afford 107.6 mg (71.9%) of 3a and 9.5 mg (6.4%) of 4a. With the same procedure, different conditions
with various Lewis acids were examined and the results are summarized in Table 1.
Procedure B: In the absence of Lewis acid: ⎯ A solution of 1a (107 mg, 0.2 mmol) and 2 (52 mg,
0.25 mmol) in 5 mL of benzene was refluxed under Argon for 24 h. The reaction was monitored by TLC
(AcOEt : Hexane = 1 : 2). After the completion of the reaction, the solvent was removed under reduced
pressure. The residue was submitted to silica gel column chromatography using AcOEt : Hexane (1 : 5) as
the eluent to afford 3a (64.5 mg, 43.4%) and 4a (77.8 mg, 52.3%).
Following the procedures of A and B, the 1,3-dipolar cycloadditions of 1b, 1c with 2, and 1a~c with 5
were carried out and afforded the corresponding products. Similarly, the reaction of 8 with 2 under the
conditions in Procedure A provided the products (9) and (10). The results are listed in Table 2 and Table
3, respectively.
Ethyl (3R,5R,8R,9S,10R)-2-benzyl-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (3a)
Colorless syrup, [α]25D: +68.80° (c 1.0, CHCl3); IR (neat) 3063.33, 3030.54, 2907.80, 2866.57, 1954.13,
1871.18, 1811.38, 1743.86, 1604.97, 1541.31, 1496.94, 1450.50, 1363.84, 1288.61, 1209.51, 1157.43,
1072.55, 906.65, 871.93, 736.90, 698.32 cm-1; 1HNMR (CDCl3): δ (ppm) 1.23 (t, 3H, J = 7.15 Hz, CH3),
2.49 (dd, 1H, J = 13.20 Hz, J = 8.25 Hz, 4-H), 2.59 (dd, 1H, J = 12.65 Hz, J = 7.15 Hz, 4-H), 3.57 (d, 1H,
J = 9.90 Hz, 10-H), 3.60 (t, 1H, J = 7.70 Hz, 3-H), 3.65 (dd, 1H, J = 10.99 Hz, J = 2.20 Hz, 7-CH2), 3.76
(dd, 1H, J = 11.00 Hz, J = 2.65 Hz, 7-CH2), 3.78 (t, 1H, J = 9.35 Hz, 8-H), 3.88 (br d, 1H, J = 8.80 Hz,
7-H), 3.89 (t, 1H, J = 9.35 Hz, 9-H), 4.06~4.18 (m, 3H, two OCH2- and one NCH2Ph), 4.19 (d, 1H, J =
13.75 Hz, one NCH2Ph), 4.49 (d, 1H, J = 12.09 Hz, CH2Ph), 4.58 (d, 1H, J = 10.45 Hz, CH2Ph), 4.62 (d,
1H, J = 12.05 Hz, CH2Ph), 4.70 (d, 1H, J = 11.54 Hz, CH2Ph), 4.82 (d, 1H, J = 10.44 Hz, CH2Ph), 4.88 (d,
1H, J = 11.00 Hz, CH2Ph), 4.90 (d, 1H, J = 10.99 Hz, CH2Ph), 5.03 (d, 1H, J = 11.54 Hz, CH2Ph),
7.17~7.18 (m, 2H, ArH), 7.25~7.39 (m, 23H, ArH); 13CNMR (CDCl3): δ (ppm) 14.07 (CH3), 41.24 (4-C),
61.13 (OCH2), 61.38 (NCH2Ph), 65.65 (3-C), 68.22 (7-CH2), 72.19 (7-C), 73.42 (CH2Ph), 74.83 (CH2Ph),
75.40 (CH2Ph), 75.45 (CH2Ph), 78.03 (8-C), 79.57 (10-C), 83.90 (9-C), 105.41 (5-C), 127.35 (Ar), 127.56
(Ar), 127.59 (Ar), 127.71 (Ar), 127.77 (Ar), 127.78 (Ar), 127.81 (Ar), 127.91 (Ar), 128.18 (Ar), 128.30

(Ar), 128.31 (Ar), 128.38 (Ar), 128.46 (Ar), 129.36 (Ar), 136.21 (Ar), 138.07 (Ar), 138.12 (Ar), 138.27
(Ar), 138.51 (Ar), 169.59 (C=O); HRMS (FAB) calcd for C46H49NO8Na 766.3356, Found: 766.3353.
Ethyl (3R,5S,8R,9S,10R)-2-benzyl-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (4a)
White solid, mp 104~105°C; [α]25D: +22.40° (c 1.0, CHCl3); IR (KBr): 3088.41, 3063.33, 3030.54,
2976.52, 2916.72, 2870.43, 1954.13, 1880.82, 1817.17, 1740.00, 1604.97, 1496.94, 1454.50, 1394.70,
1
1358.05, 1188.30, 1172.86, 1078.34, 1062.91, 1030.11, 995.39, 891.22, 752.33, 698.32; HNMR
(CDCl3): δ (ppm) 1.10 (t, 3H, J = 7.15 Hz, CH3), 2.51 (dd, 1H, J = 12.65 Hz, J = 8.25 Hz, 4-H), 2.83 (dd,
1H, J = 13.19 Hz, J = 8.24 Hz, 4-H), 3.57 (d, 1H, J = 9.90 Hz, 10-H), 3.65 (t, 1H, J = 9.90 Hz, 8-H), 3.67
(dd, 1H, J = 10.99 Hz, J = 1.65 Hz, 7-CH2), 3.73 (dd, 1H, J = 10.99 Hz, J = 4.40 Hz, 7-CH2), 3.86 (t, 1H,
J = 8.24 Hz, 3-H), 3.91 (qd, 2H, J = 7.15 Hz, J = 1.10 Hz, OCH2-), 3.98 (t, 1H, J = 9.35 Hz, 9-H),
3.99~4.01 (m, 1H, 7-H, overlapped with 9-H), 4.16 (d, 1H, J = 12.65 Hz, NCH2Ph), 4.49 (d, 1H, J =
12.64 Hz, NCH2Ph), 4.53 (d, 1H, J = 12.65 Hz, CH2Ph), 4.54 (d, 1H, J = 9.90 Hz, CH2Ph), 4.63 (d, 1H, J
= 12.09 Hz, CH2Ph), 4.71 (d, 1H, J = 11.55 Hz, CH2Ph), 4.84 (d, 1H, J = 11.00 Hz, CH2Ph), 4.85 (d, 1H,
J = 11.45 Hz, CH2Ph), 4.88 (d, 1H, J = 11.00 Hz, CH2Ph), 4.96 (d, 1H, J = 11.55 Hz, CH2Ph), 7.17~7.18
13
(m, 2H, ArH), 7.25~7.38 (m, 23H, ArH); CNMR (CDCl3): δ (ppm) 13.95 (CH3), 41.18 (4-C), 61.08
(OCH2), 64.80 (NCH2Ph), 65.52 (3-C), 68.77 (7-CH2), 72.09 (7-C), 73.47 (CH2Ph), 74.98 (CH2Ph), 75.19
(CH2Ph), 75.53 (CH2Ph), 78.25 (8-C), 78.37 (10-C), 83.81 (9-C), 107.96 (5-C), 127.50 (Ar), 127.59 (Ar),
127.67 (Ar), 127.73 (Ar), 127.79 (Ar), 127.83 (Ar), 127.84 (Ar), 127.85 (Ar), 128.23 (Ar), 128.25 (Ar),
128.30 (Ar), 128.38 (Ar), 129.28 (Ar), 136.29 (Ar), 137.73 (Ar), 137.97 (Ar), 138.04 (Ar), 138.41 (Ar),
170.64 (C=O); HRMS (FAB) calcd for C46H49NO8Na 766.3356, Found: 766.3359.
Ethyl (3R,5R,8S,9S,10R)-2-benzyl-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (3b)
25
Colorless syrup, [α]D = +66.00° (c 1.0, CHCl3); IR (neat): ν 3063.33, 3030.54, 2912.87, 2870.43,
1741.93, 1496.94, 1454.50, 1367.70, 1273.17, 1207.59, 1103.42, 1060.98, 736.90, 698.32 cm-1; 1H NMR
(CDCl3): δ 1.20 (t, 3H, J = 7.15 Hz, CH3), 2.56 (d, 2H, J = 7.70 Hz, 4-H), 3.51 (dd, 1H, J = 8.80 Hz, J =
4.95 Hz, 7-CH2), 3.61 (br t, 2H, J = 8.80 Hz, 3-H and 7-CH2), 3.87 (dd, 1H, J = 9.89 Hz, J = 2.75 Hz,
9-H), 4.05~4.11 (m, 6H, 7-H, 10-H, 8-H, two H of OCH2 and one H of NCH2Ph), 4.17 (d, 1H, J = 13.75
Hz, NCH2Ph), 4.42 (d, 1H, J = 11.54 Hz, CH2Ph), 4.46 (d, 1H, J = 11.55 Hz, CH2Ph), 4.63 (d, 1H, J =
11.54 Hz, CH2Ph), 4.69 (d, 1H, J = 12.09 Hz, CH2Ph), 4.71 (d, 1H, J = 12.65 Hz, CH2Ph), 4.74 (d, 1H, J
= 11.55 Hz, CH2Ph), 4.93 (d, 1H, J = 11.55 Hz, CH2Ph), 5.07 (d, 1H, J = 11.55 Hz, CH2Ph), 7.26~7.37 (m,
25H, ArH); 13C NMR (CDCl3): δ 14.06 (CH3), 41.07 (4-C), 61.15 (NCH2Ph), 61.44(OCH2), 65.73 (3-C),
67.97 (7-CH2), 70.76 (7-C), 72.27 (CH2Ph), 73.27 (CH2Ph), 74.28 (10-C), 74.80 (CH2Ph), 75.46 (CH2Ph),
76.06 (8-C), 81.21 (9-C), 106.20 (5-C), 127.49 (Ar), 127.54 (Ar), 127.65 (Ar), 127.70 (Ar), 127.91 (Ar),
128.09 (Ar), 128.14 (Ar), 128.16 (Ar), 128.18 (Ar), 128.36 (Ar), 128.40 (Ar), 129.32 (Ar), 136.46 (Ar),

138.07 (Ar), 138.36 (Ar), 138.77 (Ar), 169.69 (C=O); HRMS (FAB) calcd for C46H49NO8Na 766.3356,
Found: 766.3365.
Ethyl (3R,5S,8S,9S,10R)-2-benzyl-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (4b)
25
Colorless syrup, [α]D = +36.50° (c 1.0, CHCl3); IR (neat): ν 3063.33, 3030.54, 2932.80, 2880.52,
1742.02, 1604.97, 1496.94, 1454.50, 1365.51, 1278.22, 1208.60, 1110.02, 1061.58, 906.28, 736.90,
698.32 cm-1; 1H NMR (CDCl3): δ 1.12 (t, 3H, J = 7.15 Hz, CH3), 2.55 (dd, 1H, J = 12.65 Hz, J = 8.80 Hz,
4-H), 2.88 (dd, 1H, J = 12.65 Hz, J = 7.15 Hz, 4-H), 3.52 (dd, 1H, J = 9.35 Hz, J = 7.15 Hz, 7-CH2), 3.56
(dd, 1H, J = 9.35 Hz, J = 6.60 Hz, 7-CH2), 3.83 (t, 1H, J = 7.70 Hz, 3-H), 3.92 (q, 2H, J = 7.15 Hz,
OCH2), 3.93 (dd, 1H, J = 9.90 Hz, J = 2.75 Hz, 9-H), 3.96 (dd, 1H, J = 2.75 Hz, J = 1.65 Hz, 8-H),
4.03~4.09 (m, 2H, 7-H and 10-H), 4.16 (d, 1H, J = 13.75 Hz, NCH2Ph), 4.46 (d, 1H, J = 13.75 Hz,
NCH2Ph, overlapped), 4.46 (d, 1H, J = 11.55 Hz, CH2Ph, overlapped), 4.51 (d, 1H, J = 12.10 Hz, CH2Ph),
4.62 (d, 1H, J = 11.54 Hz, CH2Ph), 4.69~4.74 (m, 3H, CH2Ph), 4.97 (d, 1H, J = 11.54 Hz, CH2Ph), 4.97 (d,
13
1H, J = 10.99 Hz, CH2Ph), 7.23~7.36 (m, 25H, ArH); C NMR (CDCl3): δ 13.98 (CH3), 41.07 (4-C),
61.11 (NCH2Ph), 61.45(OCH2), 65.61 (3-C), 68.14 (7-CH2), 71.22 (7-C), 72.14 (CH2Ph), 72.88 (CH2Ph),
73.28 (10-C), 73.51 (CH2Ph), 74.65 (CH2Ph), 74.99 (8-C), 81.23 (9-C), 108.91 (5-C), 127.31 (Ar), 127.36
(Ar), 127.58 (Ar), 127.68 (Ar), 127.72 (Ar), 127.74 (Ar), 128.14 (Ar), 128.18 (Ar), 128.25 (Ar), 128.29
(Ar), 128.33 (Ar), 128.38 (Ar), 128.78 (Ar), 129.17 (Ar), 136.69 (Ar), 137.96 (Ar), 138.32 (Ar), 138.55
(Ar), 169.68 (C=O); HRMS (FAB) calcd for C46H49NO8Na 766.3358, Found: 766.3349.
Ethyl (3R,5R,8R,9S,10S)-2-benzyl-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (3c)
Colorless syrup, [α]D25 = +71.60° (c 1.0, CHCl3); IR (neat) ν 3063.33, 3030.54, 2903.22, 2866.57, 1741.93,
1496.94, 1450.50, 1367.70, 1207.59, 1095.70, 1028.18, 912.44, 736.90, 698.32 cm-1; 1H NMR (CDCl3): δ
1.21 (t, 3H, J = 7.15 Hz, CH3), 2.41 (br s, 1H, 4-H), 2.69 (dd, 1H, J = 13.47 Hz, J = 6.87 Hz, 4-H), 3.48
(br t, 1H, J = 7.15 Hz, 3-H), 3.63 (br s, 1H, 10-H), 3.68 (dd, 1H, J = 11.27 Hz, J = 1.65 Hz, 7-CH2), 3.79
(dd, 1H, J = 11.28 Hz, J = 3.85 Hz, 7-CH2), 3.83~3.86 (m, 2H, 9-H and 8-H), 4.04 (br d, 1H, J = 13.47
Hz, NCH2Ph), 4.06~4.15 (m, 4H, 7-H, OCH2 and one of NCH2Ph), 4.48 (d, 1H, J = 11.82 Hz, CH2Ph),
4.55 (br d, 1H, J = 10.99 Hz, CH2Ph), 4.64 (d, 1H, J = 11.55 Hz, CH2Ph), 4.68 (d, 1H, J = 11.82 Hz,
CH2Ph), 4.72 (d, 1H, J = 11.82 Hz, CH2Ph), 4.77 (d, 2H, J = 11.82 Hz, CH2Ph), 4.99 (br d, 1H, J = 10.73
Hz, CH2Ph), 7.17~7.19 (m, 2H, ArH), 7.23~7.39 (m, 23H, ArH); 13C NMR (CDCl3): δ 14.05 (CH3), 42.21
(4-C), 61.30 (NCH2Ph), 61.43 (OCH2), 64.94 (3-C), 68.84 (7-CH2), 72.99 (CH2Ph), 73.31 (CH2Ph), 73.71
(8-C), 74.32 (CH2Ph), 74.73 (7-C), 74.82 (CH2Ph), 77.45 (10-C), 81.42 (9-C), 105.86 (5-C), 126.96 (Ar),
127.30 (Ar), 127.52 (Ar), 127.62 (Ar), 127.66 (Ar), 127.68 (Ar), 127.70 (Ar), 127.93 (Ar), 127.95 (Ar),
128.07 (Ar), 128.17 (Ar), 128.26 (Ar), 128.30 (Ar), 128.31 (Ar), 128.43 (Ar), 128.54 (Ar), 129.60 (Ar),
138.25 (Ar), 138.44 (two C, Ar), 138.63 (Ar), 169.17 (C=O); HRMS (FAB) calcd for C46H49NO8Na

766.3356, Found: 766.3360.
Ethyl (3R,5S,8R,9S,10S)-2-benzyl-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (4c)
Colorless syrup, [α]D25 = +19.40° (c 1.0, CHCl3); IR (neat) ν 3063.33, 3030.54, 2909.01, 2868.50, 1740.00,
1496.94, 1450.50, 1369.63, 1205.66, 1095.70, 1028.18, 912.44, 736.90, 698.32 cm-1; 1H NMR (CDCl3): δ
1.14 (t, 3H, J = 7.15 Hz, CH3), 2.52 (dd, 1H, J = 12.65 Hz, J = 9.34 Hz, 4-H), 2.78 (dd, 1H, J = 13.20 Hz,
J = 7.42 Hz, 4-H), 3.72~3.77 (m, 2H, 7-CH2), 3.85 (dd, 1H, J = 9.07 Hz, J = 2.75 Hz, 9-H), 3.91~3.94 (m,
3H, 10-H, 8-H and 3-H), 3.98 (ddd, 1H, J = 9.90 Hz, J = 5.50 Hz, J = 2.47 Hz, 7-H), 4.03 (q, 2H, J = 7.15
Hz, OCH2), 4.17 (d, 1H, J = 12.92 Hz, NCH2Ph), 4.43 (d, 1H, J = 12.92 Hz, NCH2Ph), 4.53 (d, 1H, J =
10.72 Hz, CH2Ph), 4.56 (d, 1H, J = 12.10 Hz, CH2Ph), 4.64 (d, 1H, J = 11.55 Hz, CH2Ph), 4.68 (d, 1H, J
= 11.27 Hz, CH2Ph), 4.71 (d, 2H, J = 11.27 Hz, CH2Ph), 4.85 (d, 1H, J = 10.73 Hz, CH2Ph), 4.97 (d, 1H,
13
J = 11.54 Hz, CH2Ph), 7.17~7.19 (m, 2H, ArH), 7.24~7.36 (m, 23H, ArH); C NMR (CDCl3): δ 13.98
(CH3), 43.30 (4-C), 61.40(OCH2), 65.07 (NCH2Ph), 66.00 (3-C), 69.59 (7-CH2), 72.62 (CH2Ph), 73.38
(CH2Ph), 73.44 (7-C), 74.58 (CH2Ph), 74.83 (8-C), 75.08 (CH2Ph), 77.22 (10-C), 82.06 (9-C), 108.23
(5-C), 126.95 (Ar), 127.47 (Ar), 127.53 (Ar), 127.61 (Ar), 127.62 (Ar), 127.65 (Ar), 127.67 (Ar), 127.70
(Ar), 128.08 (Ar), 128.13 (Ar), 128.27 (Ar), 128.30 (Ar), 128.33 (Ar), 128.36 (Ar), 128.41 (Ar), 128.54
(Ar), 129.31 (Ar), 135.94 (Ar), 138.19 (Ar), 138.22 (Ar), 138.28 (Ar), 138.41 (Ar), 170.48 (C=O);
HRMS (FAB) calcd for C46H49NO8Na 766.3356, Found: 766.3352.
Ethyl (3R,5R,8R,9S,10R)-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-2-methyl-1,6-dioxa-2-aza-
spiro[4.5]decane-3-carboxylate (6a)
25
Colorless syrup, [α]D = +43.70° (c 1.0, CHCl3); IR (neat): ν 3063.33, 3030.54, 2897.43, 2870.43,
1952.20, 1869.25, 1745.79, 1496.94, 1454.50, 1363.84, 1294.39, 1209.51, 1070.62, 1028.18, 902.80,
736.90, 698.32 cm-1; 1H NMR (CDCl3): δ 1.26 (t, 3H, J = 7.15 Hz, CH3), 2.45 (dd, 1H, J = 13.20 Hz, J =
8.25 Hz, 4-H), 2.54 (dd, 1H, J = 13.20 Hz, J= 8.25 Hz, 4-H), 2.82 (s, 3H, NCH3), 3.34 (br t, 1H, J = 8.30
Hz, 3-H), 3.54 (d, 1H, J = 9.89 Hz, 10-H), 3.68 (dd, 1H, J = 11.00 Hz, J = 1.65 Hz, 7-CH2), 3.78 (dd, 1H,
J = 11.00 Hz, J = 2.75 Hz, 7-CH2), 3.80 (t, 1H, J = 9.90 Hz, 9-H), 3.90 (t, 1H, J = 9.35 Hz, 8-H), 3.96 (dt,
1H, J = 9.90 Hz, J = 2.20 Hz, 7-H), 4.15~4.20 (m, 2H, OCH2), 4.48 (d, 1H, J = 12.64 Hz, CH2Ph), 4.57 (d,
1H, J = 10.45 Hz, CH2Ph), 4.61 (d, 1H, J = 12.10 Hz, CH2Ph), 4.69 (d, 1H, J = 11.54 Hz, CH2Ph), 4.81 (d,
1H, J = 11.00 Hz, CH2Ph), 4.87 (d, 1H, J = 11.00 Hz, CH2Ph), 4.89 (d, 1H, J = 11.00 Hz, CH2Ph), 5.00 (d,
1H, J = 11.55 Hz, CH2Ph), 7.15~7.16 (m, 2H, ArH), 7.23~7.36 (m, 18H, ArH); 13C NMR (CDCl3): δ 12.75
(CH3), 40.94 (4-C), 43.81 (NCH3), 60.01 (OCH2), 66.90 (7-CH2), 68.14 (3-C), 70.89 (7-C), 72.17 (CH2Ph),
73.54 (CH2Ph), 74.04 (CH2Ph), 74.16 (CH2Ph), 76.66 (9-C), 78.07 (10-C), 82.63 (8-C), 103.78 (5-C),
126.26 (Ar), 126.28 (Ar), 126.40 (Ar), 126.43 (Ar), 126.45 (Ar), 126.58 (Ar), 126.60 (Ar), 126.71 (Ar),
126.98 (Ar), 127.01 (Ar), 127.04 (Ar), 127.07 (Ar), 127.17 (Ar), 136.68 (Ar), 136.77 (Ar), 136.96 (Ar),
137.21 (Ar), 167.88 (C=O); HRMS (FAB) calcd for C40H45NO8Na 690.3043, Found: 690.3040.

Ethyl (3R,5S,8R,9S,10R)-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-2-methyl-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (7a)
25
Colorless syrup, [α]D = +22.38° (c 1.0, CHCl3); IR (neat): ν 3063.33, 3030.54, 2918.22, 2887.80,
1951.70, 1866.89, 1744.98, 1496.94, 1454.50, 1394.66, 1359.88, 1210.56, 1076.26, 1028.38, 743.88,
698.32 cm-1; 1H NMR (CDCl3): δ 1.23 (t, 3H, J = 7.08 Hz, CH3), 2.42 (dd, 1H, J = 13.18 Hz, J = 7.81 Hz,
4-H), 2.82 (dd, 1H, J = 13.18 Hz, J= 8.24 Hz, 4-H), 2.94 (s, 3H, NCH3), 3.53 (d, 1H, J = 9.77 Hz, 10-H),
3.62 (dd, 1H, J = 10.50 Hz, J = 1.46 Hz, 7-CH2), 3.67 (t, 1H, J = 8.90 Hz, 3-H), 3.71 (t, 1H, J = 9.52 Hz,
8-H), 3.73 (dd, 1H, J = 10.50 Hz, J = 3.47 Hz, 7-CH2), 3.92~4.01 (m, 2H, 9-H and 7-H), 4.06~4.15 (m,
2H, OCH2), 4.49 (d, 1H, J = 12.21 Hz, CH2Ph), 4.52 (d, 1H, J = 11.96 Hz, CH2Ph), 4.60 (d, 1H, J = 12.45
Hz, CH2Ph), 4.68 (d, 1H, J = 11.48 Hz, CH2Ph), 4.83 (d, 2H, J = 10.74 Hz, CH2Ph), 4.80 (d, 1H, J =
10.98 Hz, CH2Ph), 4.93 (d, 1H, J = 11.72 Hz, CH2Ph), 7.14~7.17 (m, 2H, ArH), 7.26~7.36 (m, 18H,
13
ArH); C NMR (CDCl3): δ 14.23 (CH3), 40.92 (4-C), 45.24 (NCH3), 61.33 (OCH2), 67.90 (3-C), 68.60
(7-CH2), 71.73 (7-C), 73.43 (CH2Ph), 74.95 (CH2Ph), 74.15 (CH2Ph), 75.52 (CH2Ph), 78.15 (10-C), 78.24
(9-C), 83.76 (8-C), 107.18 (5-C), 127.52 (Ar), 127.55 (Ar), 127.61 (Ar), 127.63 (Ar), 127.70 (Ar), 127.75
(Ar), 127.77 (Ar), 127.88 (Ar), 128.09 (Ar), 128.13 (Ar), 128.18 (Ar), 128.21 (Ar), 128.24 (Ar), 137.58
(Ar), 137.80 (Ar), 137.95 (Ar), 138.26 (Ar), 169.84 (C=O); HRMS (FAB) calcd for C40H45NO8Na
690.3043, Found: 690.3040.
Ethyl (3R,5R,8S,9S,10R)-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-2-methyl-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (6b)
25
Colorless syrup, [α]D = +46.30° (c 1.0, CHCl3); IR (neat): ν 3063.33, 3030.54, 2914.80, 2872.36,
1745.79, 1496.94, 1454.50, 1209.51, 1136.21, 1101.49, 1059.05, 736.90, 698.32 cm-1; 1H NMR (CDCl3):
δ 1.23 (t, 3H, J = 7.15 Hz, CH3), 2.51 (dd, 2H, J = 8.24 Hz, J = 4.40 Hz, 4-H), 2.81 (s, 3H, NCH3), 3.34
(br t, 1H, J = 7.70 Hz, 3-H), 3.54 (dd, 1H, J = 8.52 Hz, J = 4.95 Hz, 7-CH2), 3.62 (t, 1H, J = 8.80 Hz,
7-CH2), 3.88 (dd, 1H, J = 10.18 Hz, J = 2.75 Hz, 9-H), 4.03 (d, 1H, J = 10.17 Hz, 10-H), 4.08 (dd, 1H, J
= 2.75 Hz, J = 1.38 Hz, 8-H), 4.12~4.16 (m, 3H, 7-H and OCH2), 4.10 (d, 1H, J = 11.55 Hz, CH2Ph), 4.45
(d, 1H, J = 11.55 Hz, CH2Ph), 4.60 (d, 1H, J = 11.55 Hz, CH2Ph), 4.67~4.73 (m, 3H, CH2Ph), 4.91 (d, 1H,
J = 11.55 Hz, CH2Ph), 5.03 (d, 1H, J = 11.55 Hz, CH2Ph), 7.25~7.35 (m, 20H, ArH); 13C NMR (CDCl3): δ
14.02 (CH3), 42.30 (4-C), 45.18 (NCH3), 61.20 (OCH2), 67.81 (7-CH2), 69.33 (3-C), 70.67 (8-C), 72.25
(CH2Ph), 73.33 (CH2Ph), 74.18 (7-C), 74.80 (CH2Ph), 75.31 (CH2Ph), 75.92 (10-C), 81.33 (9-C), 105.62
(5-C), 127.36 (Ar), 127.46 (Ar), 127.51 (Ar), 127.57 (Ar), 127.59 (Ar), 127.64 (Ar), 127.66 (Ar), 127.91
(Ar), 128.04 (Ar), 128.07 (Ar), 128.10 (Ar), 128.13 (Ar), 128.14 (Ar), 128.17 (Ar), 128.26 (Ar), 128.30
(Ar), 128.32 (Ar), 128.33 (Ar), 137.90 (Ar), 138.20 (Ar), 138.31 (Ar), 138.72 (Ar), 169.35 (C=O);
HRMS (FAB) calcd for C40H45NO8Na 690.3043, Found: 690.3038.
Ethyl (3R,5S,8S,9S,10R)-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-2-methyl-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (7b)

25
Colorless syrup, [α]D = +35.15° (c 1.0, CHCl3); IR (neat): ν 3063.33, 3030.54, 2910.84, 2891.64,
2870.32, 1745.79, 1604.97, 1496.94, 1454.50, 1359.86, 1210.68, 1098.35, 1039.80, 743.50, 698.32 cm-1;
1H NMR (CDCl3): δ 1.20 (t, 3H, J = 7.15 Hz, CH3), 2.45 (dd, 1H, J = 12.65 Hz, J = 7.70 Hz, 4-H), 2.84
(dd, 1H, J = 12.65 Hz, J = 8.80 Hz, 4-H), 2.93 (s, 3H, NCH3), 3.50 (dd, 1H, J = 8.45 Hz, J = 6.90 Hz,
7-CH2), 3.51 (t, 1H, J = 8.45 Hz, 7-CH2), 3.68 (br t, 1H, J = 7.70 Hz, 3-H), 3.92 (dd, 1H, J = 10.17 Hz, J
= 2.75 Hz, 9-H), 3.97 (dd, 1H, J = 2.75 Hz, J = 1.35 Hz 8-H), 4.03 (d, 1H, J = 10.17 Hz, 10-H),
4.11~4.15 (m, 3H, 7-H and OCH2), 4.42 (d, 1H, J = 11.82 Hz, CH2Ph), 4.47 (d, 1H, J = 11.82 Hz, CH2Ph),
4.59 (d, 1H, J = 11.27 Hz, CH2Ph), 4.68~4.73 (m, 3H, CH2Ph), 4.94 (d, 1H, J = 11.55 Hz, CH2Ph), 4.95 (d,
1H, J = 11.28 Hz, CH 2Ph), 7.24~7.36 (m, 20H, ArH); 13C NMR (CDCl3): δ 14.20 (CH3), 40.91 (4-C),
48.50 (NCH3), 60.29 (OCH2), 67.92 (7-CH2), 68.84 (3-C), 70.62 (8-C), 72.71 (CH2Ph), 73.38 (CH2Ph),
74.64 (7-C), 74.84 (CH2Ph), 74.86 (10-C), 74.99 (CH2Ph), 81.10 (9-C), 108.08 (5-C), 127.46 (Ar), 127.51
(Ar), 127.57 (Ar), 127.59 (Ar), 127.66 (Ar), 127.91 (Ar), 128.10 (Ar), 128.12 (Ar), 128.15 (Ar), 128.16
(Ar), 128.27 (Ar), 128.29 (Ar), 128.31 (Ar), 137.87 (Ar), 138.00 (Ar), 138.30 (Ar), 138.54 (Ar), 170.30
(C=O); HRMS (FAB) calcd for C40H45NO8Na 690.3043, Found: 690.3038.
Ethyl (3R,5R,8R,9S,10S)-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-2-methyl-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (6c)
25
Colorless syrup, [α]D = +80.80° (c 1.0, CHCl3); IR (neat): ν 3063.33, 3030.54, 2903.22, 2868.50,
1
1745.79, 1496.94, 1450.50, 1367.70, 1207.59, 1095.70, 1028.18, 968.38, 736.90, 698.32 cm-1; H NMR
(CDCl3): δ 1.28 (t, 3H, J = 7.15 Hz, CH3), 2.60~2.65 (m, 1H, 4-H), 2.73 (dd, 1H, J = 13.75 Hz, J= 8.25
Hz, 4-H), 2.77 (s, 3H, NCH3), 3.24 (br t, 1H, J = 8.25 Hz, 3-H), 3.73 (d, 1H, J = 2.48 Hz, 10-H), 3.75 (dd,
1H, J = 11.28 Hz, J = 1.93 Hz, 7-CH2), 3.86 (dd, 1H, J = 11.27 Hz, J = 3.57 Hz, 7-CH2), 3.93 (dd, 1H, J =
9.08 Hz, J = 2.48 Hz, 9-H), 3.94~3.97 (m, 1H, 7-H), 4.19 (t, 1H, J = 9.62 Hz, 8-H), 4.20 (q, 2H, J = 7.15
Hz, OCH2), 4.52 (d, 1H, J = 12.10 Hz, CH2Ph), 4.60 (d, 1H, J = 10.72 Hz, CH2Ph), 4.73 (d, 1H, J = 12.10
Hz, CH2Ph), 4.75 (d, 1H, J = 12.37 Hz, CH2Ph), 4.79 (d, 1H, J = 11.74 Hz, CH2Ph), 4.82 (d, 1H, J =
11.83 Hz, CH2Ph), 4.84 (d, 1H, J = 11.72 Hz, CH2Ph), 5.09 (d, 1H, J = 11.55 Hz, CH2Ph), 7.20~7.22 (m,
2H, ArH), 7.26~7.42 (m, 18H, ArH); 13C NMR (CDCl3): δ 14.06 (CH3), 43.12 (4-C), 45.31 (NCH3), 61.36
(OCH2), 68.80 (7-CH2), 69.03 (3-C), 72.95 (CH2Ph), 73.38 (CH2Ph), 73.53 (7-C), 74.31 (CH2Ph), 74.69
(CH2Ph), 74.80 (8-C), 77.54 (10-C), 81.64 (9-C), 105.26 (5-C), 127.27 (Ar), 127.46 (Ar), 127.53 (Ar),
127.58 (Ar), 127.59 (Ar), 127.87 (Ar), 127.90 (Ar), 127.93 (Ar), 128.14 (Ar), 128.20 (Ar), 128.26 (Ar),
128.37 (Ar), 138.31 (Ar), 138.46 (Ar), 138.50 (Ar), 138.59 (Ar), 169.15 (C=O); HRMS (FAB) calcd for
C40H45NO8Na 690.3043, Found: 690.3041.
Ethyl (3R,5S,8R,9S,10S)-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-2-methyl-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (7c)
25
Colorless syrup, [α]D = +35.00° (c 1.0, CHCl3); IR (neat): ν 3063.33, 3030.54, 2905.15, 2866.57,
1
1741.93, 1496.94, 1450.50, 1369.63, 1205.66, 1093.77, 1028.18, 910.51, 736.90, 698.32 cm-1; H NMR

(CDCl3): δ 1.29 (t, 3H, J = 7.15 Hz, CH3), 2.50 (dd, 1H, J = 12.92 Hz, J = 9.07 Hz, 4-H), 2.79 (dd, 1H, J
= 12.92 Hz, J= 7.43 Hz, 4-H), 2.97 (s, 3H, NCH3), 3.73 (br d, 1H, J = 10.45 Hz, 7-CH2), 3.76~3.79 (m,
2H, 3-H and 7-CH2), 3.88 (d, 1H, J = 2.48 Hz, 10-H), 3.91~3.93 (m, 1H, 9-H), 3.98~4.00 (m, 2H, 8-H
and 7-H), 4.17~4.22 (m, 2H, OCH2), 4.54 (d, 1H, J = 12.37 Hz, CH2Ph), 4.55 (d, 1H, J = 10.72 Hz,
CH2Ph), 4.66 (d, 1H, J = 12.06 Hz, CH2Ph), 4.71~4.76 (m, 3H, CH2Ph), 4.89 (d, 1H, J = 10.73 Hz,
CH2Ph), 5.01 (d, 1H, J = 11.82 Hz, CH2Ph), 7.19~7.20 (m, 2H, ArH), 7.27~7.39 (m, 18H, ArH); 13C NMR
(CDCl3): δ 14.06 (CH3), 43.42 (4-C), 48.74 (NCH3), 61.42 (OCH2), 68.11 (3-C), 69.32 (7-CH2), 72.57
(CH2Ph), 73.03 (7-C), 73.24 (CH2Ph), 74.41 (CH2Ph), 74.77 (8-C), 75.01 (CH2Ph), 76.71 (10-C), 81.96
(9-C), 107.73 (5-C), 127.40 (Ar), 127.54 (Ar), 127.56 (Ar), 127.59 (Ar), 127.63 (Ar), 127.92 (Ar), 128.22
(Ar), 128.26 (Ar), 128.39 (Ar), 138.23 (Ar), 138.26 (two C, Ar), 138.36 (Ar), 170.43 (C=O); HRMS
(FAB) calcd for C40H45NO8Na 690.3043, Found: 690.3045.
Ethyl (3R,5R,8R,9S,10R)-8,9,10-tris(acetyloxy)-7-(acetyloxymethyl)-2-benzyl-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (9)
25
Colorless syrup, [α]D = + 115.09° (c 1.0, CHCl3); IR (neat): ν 2958.12, 2879.65, 1755.51, 1605.28,
1
1496.94, 1450.50, 1371.35, 1221.18, 1090.56, 978.20 cm-1; HNMR (CDCl3) δ (ppm): 1.25 (t, 3H, J =
7.15 Hz, CH3), 1.99 (s, 3H, COCH3), 2.00 (s, 3H, COCH3), 2.01 (s, 3H, COCH3), 2.09 (s, 3H, COCH3),
2.51 (dd, 1H, J = 13.75 Hz, J = 8.80 Hz, 4-H), 2.74 (dd, 1H, J = 13.75 Hz, J = 7.70 Hz, 4-H), 3.51 (t, 1H,
J = 8.25 Hz, 3-H), 4.05 (dd, 1H, J = 12.65 Hz, J = 2.20 Hz, 7-CH2), 4.10~4.17 (m, 3H, 7-H and OCH2),
4.17 (d, 1H, J = 13.75 Hz, NCH2Ph), 4.22 (d, 1H, J = 13.75 Hz, NCH2Ph), 4.28 (dd, 1H, J = 12.65 Hz, J =
3.85 Hz, 7-CH2), 5.11 (t, 1H, J = 9.90 Hz, 8-H), 5.17 (d, 1H, J = 10.44 Hz, 10-H), 5.30 (t, 1H, J = 9.89 Hz,
9-H), 7.31 (br d, 1H, J = 7.15 Hz, ArH), 7.35 (t, 2H, J = 7.15 Hz, ArH), 7.41 (d, 2H, J = 7.15 Hz, ArH);
13CNMR (CDCl3) δ (ppm): 14.06 (CH3), 20.59 (CH3), 20.61 (two C, CH3), 20.74 (CH3), 41.19 (4-C), 60.98
(NCH2Ph), 61.52 (7-CH2 and OCH2), 64.67 (3-C), 67.97 (8-C), 69.16 (7-C), 69.76 (10-C), 71.70 (9-C),
103.69 (5-C), 127.73 (Ar), 128.30 (two C, Ar), 129.81 (two C, Ar), 135.08 (Ar), 168.74 (C=O), 169.53
(C=O), 169.92 (C=O), 170.01 (C=O), 170.71 (C=O); HRMS (FAB) calcd for C26H33NO12Na 534.1901,
Found: 534.1905.
Ethyl (3R,5S,8R,9S,10R)-8,9,10-tris(acetyloxy)-7-[acetyloxymethyl]-2-benzyl-1,6-dioxa-2-azaspiro-
[4.5]decane-3-carboxylate (10)
25
Colorless syrup, [α]D = + 57.20° (c 1.0, CHCl3); IR (neat): ν 2960.10, 2877.58, 1749.85, 1602.88,
1496.94, 1450.50, 1369.89, 1093.16, 978.09, 798.62 cm-1; 1HNMR (CDCl3) δ (ppm): 1.20 (t, 3H, J = 7.15
Hz, CH3), 1.99 (s, 3H, COCH3), 2.04 (s, 6H, COCH3), 2.13 (s, 3H, COCH3), 2.80 (dd, 1H, J = 13.20 Hz, J
= 8.25 Hz, 4-H), 2.74 (dd, 1H, J = 13.20 Hz, J = 7.15 Hz, 4-H), 3.79 (ddd, 1H, J = 9.90 Hz, J = 5.50 Hz, J
= 2.75 Hz, 7-H), 3.90 (t, 1H, J = 7.70 Hz, 3-H), 4.09~4.23 (m, 4H, NCH2Ph and OCH2 overlapped), 4.46
(d, 1H, J = 12.65 Hz, 7-CH2), 5.07 (t, 1H, J = 9.35 Hz, 8-H), 5.11~5.16 (m, 2H, 7-CH2 and 9-H), 5.25 (d,
1H, J = 9.35 Hz, 10-H), 7.29~7.37 (m, 5H, ArH); 13CNMR (CDCl3) δ (ppm): 14.03 (CH3), 20.55 (CH3),

20.58 (CH3), 20.63 (CH3), 20.81 (CH3), 36.95 (4-C), 61.49 (NCH2Ph), 61.78 (OCH2), 62.50 (7-CH2),
65.42 (3-C), 68.36 (8-C), 68.46 (7-C), 71.30 (10-C), 72.51 (9-C), 108.17 (5-C), 128.25 (Ar), 128.36 (two
C, Ar), 129.53 (two C, Ar), 135.80 (Ar), 168.68 (C=O), 168.82 (C=O), 169.30 (C=O), 169.72 (C=O),
170.16 (C=O); HRMS (FAB) calcd for C26H33NO12Na 534.1901, Found: 534.1909.
1,3-Dipolar cycloadditions of the 1-methylenesugars (1a~c) with the nitrile oxide (11): ⎯ 107 mg
(0.2 mmol) of 1a and 38 mg (0.25 mmol) of ethyl chlorooximidoacetate were dissolved in 2 mL of dry
Et2O under Argon atmosphere. To the solution was added 20 µL (0.14 mmol) of Et3N at rt. After stirring
for 10 min, other 15 µL (0.11 mmol) of Et3N was added. The forming suspension was stirred at rt for 3 h.
The reaction mixture was diluted by Et2O and washed with H2O. The organic solution was dried over
Na2SO4 and concentrated under reduced pressure. The residue was applied on silica gel column
chromatography eluted by AcOEt : Hexane (1 : 8 and then 1 : 5) to afford the adduct (12a) (72 mg, yield
55.2 %) and the reactant (1a) (35 mg, 32.7 %). The reactions of 1b~c with ethyl chlorooximidoacetate
were carried out with the same procedure and the results are shown in Scheme 4.
Ethyl (5R,8R,9S,10R)-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-1,6-dioxa-2-azaspiro[4.5]dec-2-
ene-3-carboxylate (12a)
Colorless syrup, [α]25D: +9.40° (c 1.0, CHCl3); IR (neat) 3063.33, 3030.54, 2982.31, 2924.44, 2868.50,
1956.06, 1875.04, 1811.38, 1722.64, 1593.40, 1496.94, 1450.50, 1408.21, 1363.84, 1278.96, 1219.16,
1122.71, 1089.91, 1028.18, 912.44, 856.50, 829.49, 738.83, 698.32 cm-1; 1HNMR (CDCl3): δ (ppm) 1.35
(t, 3H, J = 7.15 Hz, CH3), 2.97 (d, 1H, J = 18.14 Hz, 4-H), 3.04 (d, 1H, J = 18.14 Hz, 4-H ), 3.58 (br d,
1H, J = 11.00 Hz, 7-CH2), 3.68 (d, 1H, J = 9.90 Hz, 10-H), 3.76 (dd, 1H, J = 11.00 Hz, J = 2.75 Hz,
7-CH2), 3.82 (t, 1H, J = 9.89 Hz, 8-H), 4.03 (br d, 1H, J = 10.45 Hz, 7-H), 4.11 (t, 1H, J = 9.35 Hz, 9-H),
4.31 (q, 2H, J = 7.15 Hz, OCH2), 4.45 (d, 1H, J = 12.15 Hz, CH2Ph), 4.56 (d, 1H, J = 10.45 Hz, CH2Ph),
4.57 (d, 1H, J = 12.10 Hz, CH2Ph), 4.68 (d, 1H, J = 12.10 Hz, CH2Ph), 4.84 (d, 1H, J = 10.45 Hz, CH2Ph),
4.89 (d, 1H, J = 11.00 Hz, CH2Ph), 4.93 (d, 1H, J = 11.00 Hz, CH2Ph), 4.97 (d, 1H, J = 11.54 Hz, CH2Ph),
7.16~7.17 (m, 2H, ArH), 7.25~7.33 (m, 18H, ArH); 13CNMR (CDCl3): δ (ppm) 14.05 (CH3), 41.62 (4-C),
62.06 (OCH2), 67.94 (7-CH2), 72.86 (7-C), 73.46 (CH2Ph), 74.88 (CH2Ph), 74.97 (CH2Ph), 75.65 (CH2Ph),
77.48 (8-C), 78.39 (10-C), 83.64 (9-C), 110.90 (5-C), 127.70 (Ar), 127.74 (Ar), 127.78 (Ar), 127.82 (Ar),
127.90 (Ar), 127.97 (Ar), 128.01 (Ar), 128.37 (Ar), 128.43 (Ar), 128.52 (Ar), 137.55 (Ar), 137.76 (Ar),
138.01 (Ar), 138.23 (Ar), 152.50 (3-C), 160.09 (C=O); HRMS (FAB) calcd for C39H41NO8Na 674.2730,
Found: 674.2736.
Ethyl (5R,8S,9S,10R)-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-1,6-dioxa-2-azaspiro[4.5]dec-2-
ene-3-carboxylate (12b)
Colorless syrup, [α]25D: +11.60° (c 1.0, CHCl3); IR (neat) ν 3063.33, 3030.54, 2982.31, 2912.87, 2872.36,
1956.06, 1880.82, 1811.38, 1720.71, 1593.40, 1496.94, 1450.50, 1408.21, 1371.55, 1286.68, 1265.46,

1205.66, 1101.49, 1059.05, 1028.18, 914.37, 862.29, 740.76, 698.32 cm-1; 1HNMR (CDCl3) δ (ppm): 1.34
(t, 3H, J = 7.15 Hz, CH3), 2.93 (d, 1H, J = 18.15 Hz, 4-C), 3.08 (d, 1H, J = 18.15 Hz, 4-C), 3.46 (dd, 1H,
J = 8.79 Hz, J = 5.50 Hz, 7-CH2), 3.55 (dd, 1H, J = 9.35 Hz, J = 7.70 Hz, 7-CH2), 4.09~4.11 (m, 2H, 9-H
and 8-H), 4.17 (d, 1H, J = 9.90 Hz, 10-H), 4.22 (br d, 1H, J = 7.60 Hz, 7-H), 4.31 (qd, 2H, J = 7.15 Hz, J
= 1.10 Hz, OCH2), 4.41 (d, 1H, J = 11.54 Hz, CH2Ph), 4.44 (d, 1H, J = 12.10 Hz, CH2Ph), 4.61 (d, 1H, J =
11.55 Hz, CH2Ph), 4.71 (d, 1H, J = 12.00 Hz, CH2Ph), 4.73 (d, 1H, J = 11.55 Hz, CH2Ph), 4.77 (d, 1H, J
= 11.54 Hz, CH2Ph), 4.94 (d, 1H, J = 11.45 Hz, CH2Ph), 5.00 (d, 1H, J = 12.10 Hz, CH2Ph), 7.24~7.37 (m,
13
20H, ArH); CNMR (CDCl3) δ (ppm): 13.98 (CH3), 41.64 (4-C), 61.90 (OCH2), 67.89 (7-CH2), 71.59
(7-C), 72.51 (CH2Ph), 73.28 (9- or 8-C), 74.17 (CH2Ph), 74.80 (CH2Ph), 74.86 (CH2Ph), 75.08 (10-C),
80.93 (8- or 9-C), 111.55 (5-C), 127.50 (Ar), 127.65 (Ar), 127.70 (Ar), 127.76 (Ar), 127.99 (Ar), 128.07
(Ar), 128.21 (Ar), 128.33 (Ar), 128.35 (Ar), 128.38 (Ar), 137.69 (Ar), 137.75 (Ar), 137.97 (Ar), 138.38
(Ar), 152.28 (3-C), 160.10 (C=O); HRMS (FAB) calcd for C39H41NO8Na 674.2730, Found: 674.2733.
Ethyl (5R,8R,9S,10S)-8,9,10-tris(benzyloxy)-7-[benzyloxymethyl]-1,6-dioxa-2-azaspiro[4.5]dec-2-
ene-3-carboxylate (12c)
White solid, mp 96~97°C; [α]25D: +63.10° (c 1.0, CHCl3); IR (KBr) ν 3063.33, 3030.54, 2905.15,
2868.50, 1956.06, 1869.25, 1811.38, 1722.64, 1593.40, 1496.94, 1450.50, 1371.55, 1315.61, 1230.73,
1
1099.56, 1026.25, 912.44, 864.21, 740.76, 698.32 cm-1; HNMR (CDCl3) δ (ppm): 1.34 (t, 3H, J = 7.15
Hz, CH3), 3.04 (br d, 1H, J = 17.59 Hz, 4-C), 3.18 (d, 1H, J = 18.69 Hz, 4-C), 3.63 (dd, 1H, J = 11.55 Hz,
J = 1.65 Hz, 7-CH2), 3.76 (dd, 1H, J = 11.55 Hz, J = 4.40 Hz, 7-CH2), 3.91 (d, 1H, J = 2.20 Hz, 10-H),
3.98 (ddd, 1H, J = 9.90 Hz, J = 4.40 Hz, J = 2.20 Hz, 7-H), 4.03 (dd, 1H, J = 8.80 Hz, J = 2.20 Hz, 8-H),
4.10 (br t, 1H, J = 9.35 Hz, 9-H), 4.31 (qd, 2H, J = 7.15 Hz, J = 4.40 Hz, OCH2), 4.47 (d, 1H, J = 12.10
Hz, CH2Ph), 4.53 (br d, 1H, J = 10.45 Hz, CH2Ph), 4.63 (d, 1H, J = 12.09 Hz, CH2Ph), 4.68 (d, 1H, J =
11.55 Hz, CH2Ph), 4.76 (d, 1H, J = 12.09 Hz, CH2Ph), 4.80 (d, 1H, J = 11.55 Hz, CH2Ph), 4.81 (br d, 1H,
J = 11.00 Hz, CH2Ph), 5.01 (br d, 1H, J = 11.51 Hz, CH2Ph), 7.16~7.17 (m, 2H, ArH), 7.25~7.34 (m, 18H,
ArH); 13CNMR (CDCl3) δ (ppm): 14.05 (CH3), 43.48 (4-C), 62.14 (OCH2), 68.69 (7-CH2), 73.20 (CH2Ph),
73.32 (CH2Ph), 73.98 (CH2Ph), 74.31 (7-C), 74.36 (CH2Ph), 74.76 (8-C), 76.09 (10-C), 80.92 (9-C),
111.35 (5-C), 127.49 (Ar), 127.65 (Ar), 127.78 (Ar), 127.82 (Ar), 127.89 (Ar), 127.93 (Ar), 128.14 (Ar),
128.26 (Ar), 128.31 (Ar), 128.43 (Ar), 128.49 (Ar), 137.81 (Ar), 138.14 (Ar), 138.23 (Ar), 153.15 (3-C),
160.05 (C=O); HRMS (FAB) calcd for C39H41NO8Na 674.2730, Found: 674.2729.
Reductive cleavage of the O-N bond: ⎯ Activated zinc powder (230 mg, 4.0 mmol) was added to the
solution of 6a (67 mg, 0.1 mmol) in 2 mL of AcOH and 1.5 mL of Ac2O. The solution was stirred under
argon atmosphere at rt for 24 h, and the reaction was monitored by TLC (AcOEt : Hexane = 1:1). After
completion of the reaction, 30 mL of AcOEt were added. The solution was washed with H2O and
saturated aq. NaHCO3, and dried over MgSO4. After removing the solvent under reduced pressure, the
residue was applied on silica gel column chromatography (AcOEt : Hexane = 1 : 2.5) to afforded products

(13a) (32.6 mg, 45.8%) and (14a) (25.6 mg, 39.6%). Compounds (6b) and (6c) were treated following the
same procedure and the results are shown in Scheme 5.
Ethyl 2-[acetyl(methyl)amino]-5,6,7,9-tetra-O-benzyl-2,3-dideoxy-D-glycero-α-D-gulo-non-4-ulo-
pyranosonate (13a)
25
Colorless syrup, [α]D = -7.62° (c 0.42, CHCl3); IR (neat): ν 3267.81, 3063.33, 3030.54, 2930.23,
2866.57, 1738.07, 1651.27, 1620.40, 1495.01, 1454.50, 1406.28, 1365.77, 1209.51, 1143.93, 1070.62,
1028.18, 738.83, 700.25 cm-1; 1H NMR (CDCl3): δ 1.24 (t, 3H, J = 7.15 Hz, CH3), 1.73 (dd, 1H, J = 14.29
Hz, J = 11.00 Hz, 3-H), 1.84 (s, 3H, COCH3), 2.47 (dd, 1H, J = 14.29 Hz, J= 3.85 Hz, 3-H), 2.77 (s, 3H,
NCH3), 3.26 (d, 1H, J = 9.35 Hz, 5-H), 3.39 (dd, 1H, J = 10.44 Hz, J = 2.20 Hz, 9-H), 3.36 (t, 1H, J =
9.35 Hz, 6-H), 3.59 (dd, 1H, J = 10.44 Hz, J = 4.39 Hz, 9-H), 3.85 (ddd, 1H, J = 9.90 Hz, J = 4.40 Hz, J =
2.20 Hz, 8-H), 4.11~4.20 (m, 3H, OCH2 and 7-H), 4.38 (d, 1H, J = 12.65 Hz, CH2Ph), 4.51 (d, 1H, J =
12.10 Hz, CH2Ph), 4.57 (d, 1H, J = 11.00 Hz, CH2Ph), 4.69 (d, 1H, J = 11.00 Hz, CH2Ph), 4.84 (d, 1H, J
= 11.00 Hz, CH2Ph), 4.89 (d, 1H, J = 11.00 Hz, CH2Ph), 4.92 (d, 1H, J = 11.00 Hz, CH2Ph), 4.96 (d, 1H,
J = 11.00 Hz, CH2Ph), 5.35 (dd, 1H, J = 11.00 Hz, J = 3.85 Hz, 2-H), 7.19~7.21 (m, 2H, ArH), 7.26~7.35
13
(m, 18H, ArH); C NMR (CDCl3): δ 14.11 (CH3), 21.42 (COCH3), 32.95 (NCH3), 34.92 (3-C), 52.64
(2-C), 61.53 (OCH2), 68.87 (9-C), 70.54 (8-C), 73.29 (CH2Ph), 74.70 (CH2Ph), 75.50 (CH2Ph), 75.53
(CH2Ph), 78.52 (6-C), 82.23 (5-C), 83.46 (7-C), 97.56 (4-C), 127.53 (Ar), 127.59 (Ar), 127.72 (Ar),
127.81 (Ar), 127.85 (Ar), 128.22 (Ar), 128.31 (Ar), 128.33 (Ar), 128.38 (Ar), 128.62 (Ar), 137.83 (Ar),
137.92 (Ar), 138.39 (Ar), 138.70 (Ar), 170.83 (C=O), 173.33 (C=O); HRMS (FAB) calcd for
C42H49NO9Na 734.3305, Found: 734.3300.
(3R,5R,8R,9S,10R)-3-(N-Methylacetylamido)-8,9,10-tris(benzyloxy)-7-(benzyloxymethyl)-1,6-
dioxaspiro[4.5]decane-2-one (14a)
25
Colorless syrup, [α]D = +56.15° (c 0.80, CHCl3); IR (neat): ν 3063.33, 3030.54, 2945.57, 2903.26,
1754.22, 1654.62, 1603.30, 1495.05, 1454.50, 1385.60, 1213.58, 1068.66, 738.85 cm-1; 1H NMR (CDCl3):
δ 2.09 (s, 3H, COCH3), 2.22 (d, 2H, J = 10.45 Hz, 4-H), 2.68 (s, 3H, NCH3), 3.53 (d, 1H, J = 10.34 Hz,
10-H), 3.61 (br d, 1H, J = 11.00 Hz, 7-CH2), 3.77 (dd, 1H, J = 11.00 Hz, J = 1.85 Hz, 7-CH2), 3.82~3.86
(m, 2H, 8-H and 9-H), 4.05~4.08 (m, 1H, 7-H), 4.47 (d, 1H, J = 12.10 Hz, CH2Ph), 4.59 (d, 1H, J = 10.45
Hz, CH2Ph), 4.60 (d, 1H, J = 12.10 Hz, CH2Ph), 4.64 (d, 1H, J = 12.10 Hz, CH2Ph), 4.84 (d, 1H, J =
11.00 Hz, CH2Ph), 4.87 (d, 1H, J = 11.00 Hz, CH2Ph), 4.92 (d, 1H, J = 11.55 Hz, CH2Ph), 5.02 (d, 1H, J
= 11.55 Hz, CH2Ph), 5.74 (t, 1H, J = 10.45 Hz, 3-H), 7.16~7.18 (m, 2H, ArH), 7.26~7.33 (m, 18H, ArH);
13C NMR (CDCl3): δ 21.50 (COCH3), 31.89 (NCH3), 32.08 (4-C), 52.47 (3-C), 67.80 (7-CH2), 73.53
(CH2Ph), 73.66 (7-C), 74.87 (CH2Ph), 75.65 (CH2Ph), 75.67 (CH2Ph), 77.28 (8-C), 82.23 (10-C), 83.46
(9-C), 105.64 (5-C), 127.57 (Ar), 127.68 (Ar), 127.72 (Ar), 127.77 (Ar), 127.88 (Ar), 127.91 (Ar), 128.12
(Ar), 128.35 (Ar), 128.41 (Ar), 128.43 (Ar), 128.52 (Ar), 137.51 (Ar), 137.71 (Ar), 138.03 (Ar), 138.15
(Ar), 171.33 (C=O), 172.80 (C=O); HRMS (FAB) calcd for C40H43NO8Na 668.2887, Found: 688.2881.

Ethyl 2-[acetyl(methyl)amino]-5,6,7,9-tetra-O-benzyl-2,3-dideoxy-D-glycero-β-L-manno-non-4-ulo-
pyranosonate (13b)
Colorless syrup, [α]D25 = -4.20° (c 1.0, CHCl3); IR (neat): ν 3258.80, 3063.33, 3030.54, 2926.65, 2898.08,
1729.11, 1653.28, 1615.10, 1494.97, 1454.50, 1398.89, 1368.12, 1219.28, 1069.20, 1009.86, 743.24 cm-1;
1H NMR (CDCl3): δ 1.24 (t, 3H, J = 7.15 Hz, CH3), 1.80 (dd, 1H, J = 14.57 Hz, J = 11.00 Hz, 3-H), 1.91
(s, 3H, COCH3), 2.62 (dd, 1H, J = 14.58 Hz, J= 4.85 Hz, 3-H), 2.79 (s, 3H, NCH3), 3.34 (dd, 1H, J = 9.08
Hz, J = 6.05 Hz, 9-H), 3.41 (dd, 1H, J = 9.35 Hz, J = 6.88 Hz, 9-H), 3.74 (d, 1H, J = 9.89 Hz, 5-H),
3.93~3.94 (m, 1H, 7-H), 4.00 (td, 1H, J = 6.46 Hz, J = 1.37 Hz, 8-H), 4.09 (dd, 1H, J = 9.63 Hz, J = 2.75
Hz, 6-H), 4.11~4.20 (m, 2H, OCH2), 4.37 (d, 1H, J = 11.82 Hz, CH2Ph), 4.42 (d, 1H, J = 12.10 Hz,
CH2Ph), 4.59 (d, 1H, J = 11.54 Hz, CH2Ph), 4.71 (d, 1H, J = 11.27 Hz, CH2Ph), 4.76 (s, 2H, CH2Ph), 4.94
(d, 1H, J = 11.54 Hz, CH2Ph), 4.98 (d, 1H, J = 11.27 Hz, CH2Ph), 5.33 (dd, 1H, J = 11.00 Hz, J = 3.85 Hz,
2-H), 7.26~7.38 (m, 20H, ArH); 13C NMR (CDCl3): δ 14.11 (CH3), 21.48 (COCH3), 33.21 (NCH3), 35.03
(3-C), 52.81 (2-C), 61.46 (OCH2), 69.22 (9-C), 69.37 (8-C), 72.64 (CH2Ph), 73.23 (CH2Ph), 74.59
(CH2Ph), 75.02 (7-C), 75.54 (CH2Ph), 78.53 (5-C), 80.67 (6-C), 98.02 (4-C), 127.52 (Ar), 127.55 (Ar),
127.57 (Ar), 127.61 (Ar), 127.75 (Ar), 127.81 (Ar), 127.90 (Ar), 128.19 (Ar), 128.20 (Ar), 128.22 (Ar),
128.38 (Ar), 128.77 (Ar), 137.80 (Ar), 138.17 (Ar), 138.57 (Ar), 138.86 (Ar), 170.92 (C=O), 173.30
(C=O); HRMS (FAB) calcd for C42H49NO9Na 734.3305, Found: 734.3302.
(3R,5S,8S,9S,10R)-8,9,10-Tris(benzyloxy)-7-(benzyloxymethyl)-3-(methylacetylamido)-1,6-dioxa-
spiro[4.5]decane-2-one (14b)
25
Colorless syrup, [α]D = +34.00° (c 0.6, CHCl3); IR (neat): ν 3063.33, 3030.54, 2936.80, 2988.61,
1758.16, 1653.90, 1606.02, 1495.03, 1454.50, 1381.75, 1210.56, 1039.81, 978.22, 739.57 cm-1; 1H NMR
(CDCl3): δ 2.08 (s, 3H, COCH3), 2.21 (dd, 1H, J = 12.92 Hz, J = 9.34 Hz, 4-H), 2.26 (dd, 1H, J = 12.92
Hz, J = 10.72 Hz, 4-H), 2.66 (s, 3H, NCH3), 3.48 (dd, 1H, J = 9.08 Hz, J = 5.50 Hz, 7-CH2), 3.59 (dd, 1H,
J = 9.07 Hz, J = 8.25 Hz, 7-CH2), 3.75~3.80 (m, 2H, 8-H and 9-H), 3.91~3.94 (m, 1H, 7-H), 4.00 (d, 1H,
J = 9.89 Hz, 10-H), 4.43 (d, 1H, J = 11.82 Hz, CH2Ph), 4.47 (d, 1H, J = 11.82 Hz, CH2Ph), 4.61 (d, 1H, J
= 11.28 Hz, CH2Ph), 4.65 (d, 1H, J = 11.55 Hz, CH2Ph), 4.70 (d, 1H, J = 11.45 Hz, CH2Ph), 4.75 (d, 1H,
J = 11.45 Hz, CH2Ph), 4.93 (d, 1H, J = 11.00 Hz, CH2Ph), 5.06 (d, 1H, J = 11.54 Hz, CH2Ph), 5.72 (dd,
13
1H, J = 10.73 Hz, J = 9.62 Hz, 3-H), 7.27~7.37 (m, 20H, ArH); C NMR (CDCl3): δ 21.50 (COCH3),
31.97 (NCH3), 32.00 (4-C), 52.46 (3-C), 67.72 (7-CH2), 72.32 (6-C), 72.57 (CH2Ph), 73.48 (CH2Ph),
74.05 (8-C), 74.96 (CH2Ph), 75.69 (CH2Ph), 76.58 (10-C), 80.46 (9-C), 106.41 (5-C), 127.59 (Ar), 127.62
(Ar), 127.75 (Ar), 127.78 (Ar), 127.85 (Ar), 127.88 (Ar), 127.94 (Ar), 128.14 (Ar), 128.31 (Ar), 128.43
(Ar), 128.45 (Ar), 128.49 (Ar), 137.64 (Ar), 137.79 (Ar), 137.93 (Ar), 138.40 (Ar), 171.31 (C=O), 173.13
(C=O); HRMS (FAB) calcd for C40H43NO8Na 668.2887, Found: 688.2885.
Ethyl (2R)-2-[acetyl(methyl)amino]-5,6,7,9-tetra-O-benzyl-2,3-dideoxy-D-glycero-α-D-galacto-non-

4-ulopyranosonate (13c)
Colorless syrup, [α]D25 = -6.58° (c 1.0, CHCl3); IR (neat): ν 3280.10, 3063.33, 3030.54, 2918.83, 2890.26,
1736.84, 1653.08, 1621.12, 1494.90, 1454.50, 1381.28, 1212.67, 1143.93, 1075.10, 986.20, 736.86,
698.32 cm-1; 1H NMR (CDCl3): δ 1.25 (t, 3H, J = 7.15 Hz, CH3), 1.90 (dd, 1H, J = 14.50 Hz, J = 3.42 Hz,
3-H), 1.88 (s, 3H, COCH3), 2.41 (dd, 1H, J = 14.50 Hz, J= 11.96 Hz, 3-H), 2.74 (s, 3H, NCH3), 3.49 (br d,
1H, J = 10.50 Hz, 9-H), 3.59 (dd, 1H, J = 10.74 Hz, J = 4.88 Hz, 9-H), 3.69 (d, 1H, J = 2.44 Hz, 5-H),
3.82 (dd, 1H, J = 9.15 Hz, J = 2.44 Hz, 6-H), 3.90 (t, 1H, J = 9.13 Hz, 7-H), 4.11~4.21 (m, 3H, 8-H and
OCH2), 4.54 (d, 1H, J = 10.98 Hz, CH2Ph), 4.56 (d, 1H, J = 10.75 Hz, CH2Ph), 4.68~4.74 (m, 3H, CH2Ph),
4.87 (d, 1H, J = 11.23 Hz, CH2Ph), 4.99 (d, 1H, J = 11.48 Hz, CH2Ph), 5.05 (d, 1H, J = 11.64 Hz, CH2Ph),
13
5.34 (dd, 1H, J = 11.96 Hz, J = 3.42 Hz, 2-H), 7.17~7.39 (m, 20H, ArH); C NMR (CDCl3): δ 14.33
(CH3), 21.58 (COCH3), 33.06 (NCH3), 35.45 (3-C), 52.42 (2-C), 61.46 (OCH2), 68.87 (9-C), 69.96 (8-C),
72.80 (CH2Ph), 73.58 (CH2Ph), 74.37 (CH2Ph), 74.74 (CH2Ph), 75.19 (8-C), 77.59 (5-C), 79.17 (6-C),
97.61 (4-C), 127.42 (Ar), 127.45 (Ar), 127.48 (Ar), 127.51 (Ar), 127.75 (Ar), 127.78 (Ar), 127.81 (Ar),
127.85 (Ar), 128.05 (Ar), 128.11 (Ar), 128.17 (Ar), 128.28 (Ar), 137.90 (Ar), 138.27 (Ar), 138.41 (Ar),
138.49 (Ar), 170.62 (C=O), 173.85 (C=O); HRMS (FAB) calcd for C42H49NO9Na 734.3305, Found:
734.3308.
Ethyl 2-[acetyl(methyl)amino]-2,3-dideoxy-D-glycero-α-D-gulo-non-4-ulopyranosonate (15)
13a (71.1 mg, 0.1 mmol) was dissolved in 2 mL of methanol. To the solution was added 20 mg of
Pd(OH)2/C (20 wt%), and the mixture was stirred vigorously under H2 atmosphere at rt for 12 h. After the
reaction completed, the catalyst was removed by filtration through a Celite pad and the solvent was
evaporated under reduced pressure. The residue was purified by silica gel column chromatography
(AcOEt : MeOH : H2O = 4 : 2 :1) to afford 23.1 mg (65.8%) of the debenzylated product (15). Colorless
amorphous solid, [α]D25 = +69.11° (c 1.58, CH3OH); 1H NMR (CD3OD): δ 1.25 (t, 3H, J = 7.15 Hz, CH3),
2.11 (s 3H, COCH3), 2.15 (dd, 1H, J = 14.85 Hz, J = 9.35 Hz, 3-H), 2.59 (dd, 1H, J = 14.85 Hz, J = 4.12
Hz, 3-H), 3.03 (s, 3H, NCH3), 3.08 (d, 1H, J = 9.35 Hz, 5-H), 3.27 (t, 1H, J = 9.34 Hz, 7-H), 3.61~3.76
(m, 4H, 6-H, 8-H and two 9-H), 4.15~4.22 (m, 2H, OCH2), 5.20 (dd, 1H, J = 9.34 Hz, J = 3.85 Hz, 2-H);
13C NMR (CDCl3): δ 14.44 (CH3), 21.86 (COCH3), 31.88 (NCH3), 37.16 (3-C), 55.59 (2-C), 62.66 (OCH2),
62.78 (9-C), 71.62 (7-C), 74.11 (8-C), 75.75 (6-C), 76.15 (5-C), 98.27 (4-C), 172.90 (C=O), 174.64
(C=O); HRMS (FAB) calcd for C14H25NO9Na 374.1427, Found: 374.1425.
ACKNOWLEDGEMENTS
We are grateful to Misses J. Shimode and M. Kitsukawa for spectroscopic measurements. Partial financial
support for this research from the Ministry of Education, Culture, Sports, Science and Technology is
gratefully acknowledged. X L thanks the JSPS for a postdoctoral fellowship.

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