Stereoselective synthesis and structure elucidation of spiro-ketodisaccharides

TETRAHEDRON

Pergamon

Tetrahedron 57 .2001) 8053±8066

Stereoselective synthesis and structure elucidation

of spiro-ketodisaccharides

Xiaoliu Li,^aHideyo Takahashi,^aHiro Ohtake,^aMoto Shiro^band Shiro Ikegami^a,p

^aSchool of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan

^bRigaku Corporation, 3-9-12 Matsubara, Akishima, Tokyo 196-0003, Japan.

Received 29 June 2001; accepted 25 July 2001

AbstractÐCycloglycosylation of 3,4,5,7-tetra-O-benzyl-a-d-hept-2-ulopyranoses .2a±c) was carried out stereoselectively under the

catalysis of Lewis acid to afford two spiro-cyclodisaccharides 3a±c and 4a±c in good yields. The reaction provided the kinetic products

3a±c or the thermodynamic products 4a±c as the predominant products under different conditions, respectively. The unprotected

disaccharides 5a±c and 6a±c and the acetylated derivatives 7a±c and 8a±c were prepared by catalytic hydrogenation and followed by

acetylation. The structures of compounds 4a±c, 6a±c and 8a±c were con®rmed to be a,b-anomeric con®guration with chair±chair±chair

form for the tri-cycles based on the X-ray crystallographic analysis of 6a±c. The a,a-anomeric con®gurations of compounds 3a±c, 5a±c and

7a±c were determined based on the measurements of the three bond coupling constants ³J_C,Hbetween the C-1 and the H-3 of 7a±c. q 2001

1. Introduction

isomer 3a±c, but also a,b-isomer 4a±c as the major product

under the theromdynamic conditions.⁶The formation of the

unexpected a,b-isomer prompted us to investigate the

glycosylation reaction in details and to con®rm the struc-

tures of the products. We now report the stereoselective

synthesis of the spiro heptulopyrano-disaccharides and

their structural elucidation by X-ray crystallographic and

NMR analyses.

The interesting properties that the various kinds of cyclo-

dextrin inclusion complexes often exhibit enzymatic reac-

tivity have attracted great attention to the chemical synthesis

of cyclodextrins and their analogues.¹For example, the total

syntheses of natural and unnatural cyclodextrins, and some

cyclic macroethers containing or with pendent aldose

moieties have been reported in recent years.²However,

stereoselective and ef®cient synthesis of their analogues

involving different size of cycles or different kind of

glycosyl linkage is still an exciting challenge.

2. Results and discussion

The requisite starting materials, 3,4,5,7-tetra-O-benzyl-a-d-

hept-2-ulopyranoses .2a±c) were prepared as shown in

We have previously reported the ef®cient glycosidations of

methylenesugars and ketopyranoses under mild conditions,

in which the glycosidations took place a-stereoselectively

and afforded a-ketodisaccharides in excellent yields.^3,4

Taking advantage of the a-stereoselective glycosidation,

we assumed that the application of this a-stereoselective

reaction in the tandem manner of iterative glycosylation

and intramolecular cyclo-glycosylation using 3,4,5,7-tetra-

O-benzyl-a-d-hept-2-ulopyranose 2a±c would produce

a-1,2-glycosyl-linked cyclic ketosaccharides, providing a

convergent synthesis of cyclo-macroethers connecting

glycosyl residues.⁵However, the reaction was found to

give two isomers of spiro-ketodisaccharides, not only a,a-

OBn

R³

R¹

R

1

7

6

5

i

1

R⁴

O

3

OH

2

4

BnO

R²

OH

1a~c

2a~c

R¹

H

R²

OBn

H

R³

H

R⁴

OBn

H

Yield of 2 (%)

a

b

c

91.4%

93.8%

H

OBn

H

Keywords: cycloglycosylation; spiro-ketodisaccharide; a-d-hept-2-ulopyr-

anose; three-bond carbon±proton coupling constant J_C,H; X-ray crystal-

OBn

89.4%

3

lographic structure.

Corresponding author. Tel.: 181-426-85-3728; fax: 181-426-85-1870;

e-mail: shi-ike@pharm.teikyo-u.ac.jp

p

Scheme 1. Reagents and conditions: .i) N-Methylmorpholine N-oxide

.NMO) .2.0 equiv.), OsO₄.5% mol), acetone/H₂O .5:2), rt, overnight.

PII: S0040-4020.01)00775-X

8054

X. Li et al. / Tetrahedron 57 12001) 8053±8066

OP

R¹

O

R³

OP

R³

OP

R¹

OP

R⁴

R³

R¹

R⁴

PO

R²

R⁴

PO

O

R¹

OP

i or ii

O

R⁴

PO

O

OH

+

R³

R⁴

R²

O

R²

OH

OP

R¹

R²

PO

2a~c (P = Bn)

3a~c (α,α)

(P = Bn)

4a~c (α,β)

(P = Bn)

iii

iv

R¹

R²

R³

R⁴

5a~c (α,α)

(P = H)

6a~c (α,β)

(P = H)

a

b

c

H

OP

H

OP

H

7a~c (α,α)

(P = Ac)

8a~c (α,β)

(P = Ac)

Scheme 2. Reagents and conditions: .i) .Method A): TfOH .1.5 equiv.), CaSO₄, CH₂Cl₂, 2788C!rt; .ii) .Method B): TsOH .1.0 equiv.), TfONa .1.0 equiv.),

Et₂O, re¯ux; .iii) Pd.OH)₂/C, CH₃OH, H₂.1 atm), rt; .iv) Ac₂O, pyridine, rt.

Scheme

1

by the oxidation of the corresponding

and a,b-anomeric conformations by the instrumental

analysis.

1-methylenesugars .1a±c) using the combination of

N-methylmorpholine N-oxide .NMO) and OsO₄as the

oxidant.^7,8The reaction proceeded in high a-stereo-

selectivity with producing trace b-isomer.

While various anomeric activation methods have been used

in the glycosylation of ketoses,⁹there are a few reports on

the direct glycosylation of ketoses like 2a,^6,10excluding the

treatment of d-fructose and l-sorbose by strong protonic

acids.^11,12Thus, the reaction conditions were examined

with 2a as shown in Table 1. Although TMSOTf was a

very ef®cient catalyst for the glycosidation of 1-deoxy-

hept-2-ulopyranoses,⁴it seemed not effective for this

reaction .entry 1). Furthermore, in the presence of a TMS-

containing reagent, the primary 1-hydroxy group of 2a was

silylated to give the compound A¹³.entries 2 and 3). After

Treatment of 3,4,5,7-tetra-O-benzyl-a-d-hept-2-ulopyra-

noses .2a±c) with Lewis acid afforded two spiro ketodisac-

charides 3a±c and 4a±c, respectively .Scheme 2). This self-

condensation reaction might involve the tandem two steps

of glycosylation of 2a±c in which a disaccharide is formed

initially, and then intramolecular cycloglycosylation takes

place to give the products 3a±c and 4a±c. The structures of

the compounds 3a±c and 4a±c were con®rmed to be of a,a-

Table 1. Reaction conditions of 2a under the catalysis of a Lewis acid

Entry

Lewis acid .equiv.)

Solvents

Conditions

rt, 12 h

Yield .%)^a

3a: 4a^b

1.0:1.4

1

2

3

4

5

6

7

8

TMSOTf .1.0)

CH₂Cl₂

Et₂O

28.0^c,d

A .39.8%)^d

A .48.8%)^d

Trace^d

19.9^d

43.2

40.6

58.4

68.9

TMSOTf .1.0), CSA .1.0)

Yb.OTf)₃.0.2),TMSCl .1.5)

BF₃´Et₂O .1.5)

CSA .1.0)

TiCl₄.1.0)

SnCl₄.1.0)

TfOH .1.0)

TfOH .1.5)

TfOH .1.5), TfONa .2.0)

TfOH .1.5), TfOK .2.0)

TsOH .1.0)

2788C, 1 h!rt, 1 h

rt, 2 days

2788C, 1 h!rt, 2 h

08C, 4 h

1.0:1.0

1.0:1.1

1.0:1.0

1.0:1.1

1.1:1.0

1.5:1.0

2788C, 1 h!rt, 2 h

2788C, 1 h!rt, 1 h

2788C, 3 h

2788C, 1 h!rt, 2 h

08C, 1 h!rt, 2 h

2788C, 3 h!08C, 2 h

Re¯ux, 10 h

Re¯ux, 1 h

Re¯ux, 3 h

Re¯ux, 5 h

Re¯ux, 2 h

Re¯ux, 1 h

Re¯ux, 3 h

Re¯ux, 10 h

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

58.2

No reaction

48.9

THF

CH₂Cl₂

Et₂O

THF

CH₂Cl₂

Et₂O

1.2:1.0

1.0:6.9

1.0:6.3

1.0:5.8

1.0:6.5

1.0:7.0

54.3

25.4^d

29.0

Yb.OTf)₃.0.25)

TsOH .1.0), TfONa .1.0)

TsOH .1.0), TfOK .1.0)

TsOH .1.0), TsONa .1.0)

38.0

51.6

72.7

Many spots on TLC

47.1

59.8

1.0:1.6

1.0:6.7

1.0:7.1

27.2^d

a

Isolated yield.

Determined by H NMR.

10% of A was obtained.

2a was partially recovered.

b

c

d

1

X. Li et al. / Tetrahedron 57 12001) 8053±8066

Table 2. The cyclo-glycosylation of 2a±c under different conditions

8055

Entry

2

Method^a.reaction time)

Total yield^b.%)

3 .%)

4 .%)

3:4^c

1

2

3

4

5

6

7

2a

2b

2c

2a

2b

2c

A

65.9

56.4

68.9

72.7

75.9

78.0

84.1

1.1:1^d

1.1:1

1.7:1

1:7.0^d

1:5.1

1:1.6

1:2.1

29.9

43.5

26.5

25.4

B .5 h)

B .3 h)

B .5 h)

B .5 h)^e

12.5

30.5

27.3

63.4

47.5

56.8

a

Method A: TfOH .1.5 equiv.), CaSO₄, CH₂Cl₂, 2788C!rt; Method B: TsOH .1.0 equiv.), TfONa .1.0 equiv.), Et₂O, re¯ux.

Isolated yields.

Calculated according to the isolated yields except in the case of 2a .entries 1 and 4).

The ratio was estimated according to ¹H NMR spectrum.

KOTf .1.0 equiv.) was used instead of NaOTf .1.0 equiv.).

b

c

d

e

scanning with various Lewis acids such as SnCl₄, TiCl₄,

It was found that the reaction of 2a±c showed the similar

stereoselectivity under the conditions of Method A or

Method B. However, the a,a-stereoselectivity .3c) for 2c

was higher than that in the cases of 2a and 2b .entries 3, 6

and 7 in Table 2), probably owing to the axial 3-benzyloxy

group.

BF₃´Et₂O, and TfOH .entries 4±8), it was found that

under the mild conditions of 2788C, a strong Lewis acid

was necessary for promoting the reaction .entries 7±10),

and the formation of 3a and 4a in good yield was achieved

with 1.5 equiv. of TfOH in CH₂Cl₂solution .entry 9). More-

over, the solvent was also important in the reaction. For

example, the reaction did not proceed in Et₂O or THF

.entries 11 and 12) probably due to weakening the acidity

of the Lewis acid by solvation.

In addition, the isomerization test as exempli®ed by 3b

showed a partial inversion from 3b to 4b under the

thermodynamic conditions of Method B, indicating that

the a,b-isomers .4a±c) were more stable than the a,a-

isomers .3a±c).

The compounds 3a±c and 4a±c were debenzylated by

hydrogenolysis under the catalysis of Pd.OH)₂/C to give

the corresponding unprotected disaccharides 5a±c and

6a±c quantitatively. Sequentially, the compounds 5a±c

and 6a±c were acetylated with acetic anhydride in pyridine

to afford the acetylated derivatives 7a±c and 8a±c,

respectively, as shown in Table 3.

An attempt to prepare cyclic macroethers with tri-, tetra- or

pentasaccharide oligomers by the metallic cation Na¹or

K¹which facilitates to coordinate with 2a for the cyclic

macroether formation was also unsuccessful .entries 13

and 14).

Although the mixture of 3a and 4a could not be separated by

silica gel column chromatography, the pure 4a was obtained

as a white solid by repeated recrystallization of the mixture

of 3a and 4a .ratio 1:7) from ethyl acetate and hexane.

Debenzylation of the mixture of 3a and 4a, and then

acetylation followed by chromatography gave the

acetylated derivatives 7a and 8a. The unprotected

disaccharide 5a was obtained by the deacetylation of 7a.

The relative ratio of 3a and 4a was affected by the reaction

temperature, and 4a became the major product as the reac-

tion temperature increased .entries 9 and 10). This was

evidently supported by the experiments at re¯ux tempera-

ture .entries 15±23). As shown in entry 19, the reaction

provided 3a and 4a in 72.7% with the ratio of 1:7 after

re¯uxing the Et₂O solution for 5 h catalyzed by the combi-

nation of TsOH .1.0 equiv.) and TfONa .1.0 equiv.) which

might generate a proper amount of strong Lewis acid

.TfOH) in situ, promoting the reaction going well. Com-

paratively, the combination of TsOH and TsONa seemed

not strong enough for completing the reaction .entry 23).

The compounds 3a±c and 4a±c were proved to be spiro

ketodisaccharides by mass spectral .FAB¹) and NMR

analyses. The conformation of 4a±c and their derivatives

.6a±c and 8a±c) were con®rmed by the instrumental analy-

sis based on the X-ray crystallographic and NMR analyses.

The structures of 3a±c, 5a±c and 7a±c were elucidated

according to the three-bond carbon±proton coupling

As described above, the glycosylation of 2a proceeded

stereoselectively under the promotion of a Lewis acid.

The mild conditions at low temperature .2788C) with

TfOH .Method A) was bene®t to the formation of 3a, called

kinetic control product, and the thermodynamic product 4a

was predominant in re¯uxing Et₂O solution with TsOH±

TfONa or TfOK .Method B). Similarly, the reactions of

2b and 2c were performed under the same conditions of

Method A or Method B. Thus, the corresponding spiro-keto-

disaccharides 3b, 4b and 3c, 4c were afforded respectively,

and the results are shown in Table 2.

3

constants J_C,Hanalyses. The X-ray crystallographic

structures of 6a±c are shown in Fig. 1.

Table 3. The yields of the acetylated derivatives 7a±c and 8a±c

Compounds

7 .%)

8 .%)

a .Glc)

b .Gal)

c .Man)

82.1

83.7

80.6

80.5

75.2

8056

X. Li et al. / Tetrahedron 57 12001) 8053±8066

molecules. One is a direct interaction between hydroxy

groups in two molecules, and the other is through the

included water molecule. In the crystal of 6c, only the direct

hydrogen bonding interaction exists in multiple positions

between two molecules, making the crystal arrange

compactly.

Although X-ray analysis can provide the most accurate data

on the conformation of carbohydrate compounds, it is not a

common method due to the dif®culty for preparing

suitable single crystals of saccharides. So far only one of

di-hexulopyranose dianhydrides, di-b-d-fructopyranose

dianhydride¹⁵and its strontium complex¹⁶were reported

with X-ray crystallographic analyses. Moreover, to deter-

mine the anomeric con®guration of ketosaccharides by

NMR was not so easy as that of aldosaccharides, because

ketosaccharide does not have the anomeric proton .1-H),

which is commonly used to determine the anomeric con-

®guration of the aldosaccharide according to the vicinal

coupling constant between 1-H and 2-H. In virtue of the

rigid spiro tricyclic structure and molecular models, the

con®gurations of several di-hexulopyranose dianhydrides

could be estimated by ¹H- and ¹³C NMR, and NOE

analyses.^11,12,17

In recent years, the three-bond carbon±proton coupling

constant J_C,Hwhich related to the orientation of the 3-H

3

and the 1-C .Fig. 2) has been successfully used for the

determination of anomeric con®guration of keto-glycosides

in solution.^3,4,18The structures of 3a±c, 5a±c and 7a±c

were established by the comparison of the coupling

3

constants J_C-1,H-3of 7a±c with those of 8a±c and the

analysis of NOE.

Figure 1. X-Ray crystallographic structures of the unprotected products

6a±c represented with ball and sticks model .a) 6a, .b) 6b, and .c) 6c.

.Hydrogen atoms were omitted for clarity.)

The X-ray crystallographic structures of 6a±c revealed that

all of the three compounds have the same a,b-anomeric

conformation with the chair±chair±chair form in the

tricycles, a thermodynamically stable conformation. In

this conformation, the two pyranose rings as well as the

dioxane ring adopt the normal ⁴C₁forms and are per-

pendicular to the dioxane ring planar. The aglyconic

C₂±O₂bond for the a-anomeric pyranose ring takes axial

position, consisting with the expectation of anomeric effect.

Figure 2.

1

The structures of the compounds 6a±c deduced from H-

and ¹³C NMR spectral analysis were identical to the X-ray

crystallographic structures as shown in Fig. 1, indicating

that the compounds 6a±c had the same conformation in

crystal and in solution. Furthermore, the compounds 4a±c

and 8a±c gave similar sugar proton signals, that is, each

corresponding sugar proton in the compounds 4a±c, 6a±c,

and 8a±c showed similar split pattern. Consequently, the

compounds 4a±c, and 8a±c were proved to possess the

similar sugar skeleton of a,b-con®guration with chair±

chair±chair form the same as the compounds 6a±c. This

indicated that the alterations of the protection groups and

the polarity of solvent did not remarkably change the rigid

conformation of the spiro-ketodisaccharides, which was

further supported by the similar observation to the spectra

of the compounds 3a±c, 5a±c and 7a±c.

0

But for the b-anomeric pyranose ring, the aglyconic C₂±O₂

0

bond is equatorial, which seems inappropriate to the

anomeric effect.¹⁴On the other hand, in the special case

of the diheptulopyranose dianhydrides containing spiro

tricycles, there is a alternative reference .pyranose ring or

dioxane ring) for considering the anomeric effect in each

0

anomeric center of C₂and C₂. Thus, taken the dioxane ring

as the reference, this ring adopts the con®guration of

0

orienting both pyranonic C₂±O₆and C₂±O₆bonds axially,

which responds to the anomeric effects in the two anomeric

centers.¹²

1

In the crystals of 6a and 6b, water is included, and two kinds

of hydrogen bonding interactions exist between the

The H and ¹³C NMR spectra of the compounds 3a±c

showed the simple eight sugar proton and seven sugar

X. Li et al. / Tetrahedron 57 12001) 8053±8066

8057

Figure 3.

3

³J_C-1,H-3of the compounds 7a±c and 8a±c are listed in

Table 4.

Table 4. The three-bond coupling constants J_C-1,H-3of the compounds 7a

and 8a .Hz)

Compounds

7

8 .F^Hof 6)^a

As shown in Table 4, the coupling constants ³J_C-1,H-3values

for the a- and b-anomeric pyranose rings of 8a and 8b are

interrelated to the theoretical expectations from the dihedral

angles F^Hof the corresponding 6a and 6b.^18bIt was found

that the compounds 7a and 7b being of C₂-symmetry

0

H₃±C₁.b)

0

H₃±C₁.a)

a .Glc)

b .Gal)

c .Man)

1.5

1.7

1.6 .46.78)

1.9 .40.08)

1.1 .56.98)

2.7 .161.38)

2.5 .158.78)

1.7 .55.68)

3

showed similar coupling constant J_C-1,H-3values to that at

a

The dihedral angles F^H.C₁±C₂±C₃±H₃) of 6a±c were approximately

calculated from the dihedral angle of C₁±C₂±C₃±O₃and the bond

angle of H₃±C₃±O₃according to their X-ray crystallographic data.

the a-anomeric centers of the compounds 8a and 8b. There-

fore, the compounds 7a and 7b were attested to be in a,a-

anomeric con®guration, not in b,b-one. However, in the

case where 8c was mannose moiety, since the dihedral

angles F^Hof C₁±C₂±C₃±H₃for a-pyranose ring and

carbon signals corresponding to the monomeric unit of

3,4,5,7-tri-O-benzyl-d-glyco-hept-2-ulopyranose with the

normal ⁴C₁chair form, which implied that the two pyranose

rings should have the same conformation and the molecule

had C₂-symmetry. Therefore, the two anomeric carbons

should possess the same con®guration, namely, the

compounds 3a±c would be in either a,a- or b,b-anomeric

con®guration with ⁴C₁chair form of pryranose rings.¹⁷

Moreover, the compounds 5a±c and 7a±c gave rise to the

similar NMR spectral signals for the sugar protons and

carbons to the compounds 3a±c, meaning that the

compounds 3a±c, 5a±c and 7a±c might be in the similar

conformations for the spiro-tricycles. Thus, the anomeric

con®gurations of the compounds 3a±c, 5a±c and 7a±c

were determined by the technique based on the measure-

0

C₁±C₂±C₃±H₃for b-ring are similar due to the equatorial

0

3

3-proton, the coupling constants J_C-1,H-3are not so much

different and not suitable for distinguishing the anomeric

con®guration in the manno-ketosaccharides.

In order to establish the conformation of the a,a-isomers,

NOE experiments of 7a±c were performed by irradiating

the dioxane protons 1-H_aand 1-H_e.Fig. 4). While no NOE

interaction other than that with the geminate proton 1-H_e

was observed when the 1-H_awas irradiated, the irradiation

of 1-H_eresulted in NOE interactions with the axial 3-H and

the gem-1-H_a. Thus, 1-H_eand 3-H should be in cis-orienta-

tion. By virtue of molecular model and taking account of

the C₂-symmetric conformation and the NOE results,

the compounds 7a±c were con®rmed to possess the a,a-

anomeric con®guration with chair±boat±chair form for

the spiro-tricycles as shown in Fig. 4.

3

ment and comparison of the coupling constants J_C-1,H-3as

exempli®ed by 7a±c and 8a±c .For example, 7a and 8a in

Fig. 3). The three-bond carbon±proton coupling constants

Figure 4.

8058

X. Li et al. / Tetrahedron 57 12001) 8053±8066

technique²¹and GB/SA solvation calculation.²²It was

shown that in all cases the two pyranoid rings were in

energetically favored chair form. As for the dioxane ring,

it adopted the favorable chair conformation in the a,b-

isomer .6a±c), giving the chair±chair±chair conformation

for the spiro-tricycles which was identical to the results of

the X-ray crystallographic analysis. In the case of a,a-

isomer .5a±c) the calculation could not suggest the

energetically favorable conformation exactly. However,

the calculated energies of the most stable conformers of

the a,a-isomers .5a±c) were higher than those of the a,b-

isomers .6a±c) as shown in Table 5. The result indicated

that the a,b-isomers were stable than the a,a-isomers in the

three series, and further supported the a,b-stereoselectivity

of the cyclo-ketosylation under the thermodynamic reaction

conditions.

Figure 5. A lone pair of electrons on O-6 .or O-2) antiperiplanar to the bond

between C-2 and O-2 .or O-6).

As concluded above that the spiro-tricyclic compounds

4a±c, 6a±c and 8a±c with various protection groups had

the same conformation and gave rise to similar NMR

spectral signals on the sugar protons, the compounds 3a±c

and 5a±c should have the same a,a-anomeric con®guration

with chair±boat±chair form for the spiro-tricycles as 7a±c

considering their similar NMR spectral signals for the sugar

protons. The results were identical to the expectation of the

literature.¹²Obviously, this conformation was operated by

the exo-anomeric effects, placing a lone pair of electrons on

O-6 .or O-2) antiperiplanar to the bond between C-2 and

O-2 .or O-6) .as shown in Fig. 5).¹²As a result, the pyranoid

Mechanism for the formation of diketose dianhydrides by

the action of protonic acids on unprotected ketose has been

reported.^11a,11dIn view of the above discussion, the mechan-

ism for the formation of the spiro-ketodisaccharides 3a±c

and 4a±c from the corresponding a-d-hept-2-ulopyranoses

.2a±c) was proposed as shown in Scheme 3.

0

C₂±O₆bond and the O₂±C₁bond were kept in a gauche

relationship when viewed on the aglyconic C₂±O₂bond,

which gave rise to a less thermodynamically favorable

boat conformation for the dioxane ring.

According to this process, the reaction involved the two

steps of glycosylation and cycloglycosylation of 2a±c.

The ®rst step of glycosylation proceeded a-stereoselectively

to afford the linear a-disaccharide .D).^3,4In the second step,

the disaccharides .D) initially generated the stable tertiary

oxycarbenium ion intermediates .I) and .II) in the action of

The conformations and their corresponding energies .DE) of

the unprotected compounds 5a±c and 6a±c in water were

calculated¹⁹using MacroModel 6.0 with the mm2^pforce

®eld²⁰with LOMD .Low Mode) conformational search

Table 5. The differences of the calculated energy corresponding to the most stable conformation between the unprotected compounds 5a±c and 6a±c in water

a,a-Isomer .5)

DE_a,a.kcal/mol)

a,b-Isomer .6)

DE_a,b.kcal/mol)

DDE.DE_a,b2DE_a,a)

.kcal/mol)

a

a .Glc)

b .Gal)

c .Man)

2205.83

2208.39

2205.82

2208.10

2210.97

2209.05

22.27

22.58

23.23

a

The energy corresponding to the most stable conformation.

Scheme 3.

X. Li et al. / Tetrahedron 57 12001) 8053±8066

8059

Lewis acid, then intramolecular cycloglycosylation took

place in a-attack or b- attack manner to give the kinetic

products 3a±c or the thermodynamic products 4a±c, respec-

tively. Because of the equilibrium between I and II, and the

reversible cycloglycosylation, the reaction stereoselectivity

was mainly determined by the stability of the product and

the reaction conditions. Thus, under thermodynamic

conditions .re¯ux temperature), the more stable products

4a±c were predominant. Under kinetic conditions .low

temperature), the kinetic control products 3a±c were

formed with the competition of forming 4a±c. In addition,

the kinetic products 3a±c could isomerize to the thermo-

dynamically stable products 4a±c via the intermediates I

and II under the thermodynamic conditions. On the other

hand, it would be reasonably understood that the different

stereoselectivity was observed in the formations of the

cyclic spiro-ketodisaccharides .a,b-selectivity) and the

linear ketodisaccharides .a-selectivity) due to the stable

a,b- con®guration in the spiro-tricyclic structure.^3,4

ometer with graphite monochromated MoKa radiation at

123 K. Thin-layer chromatography .TLC) was performed

on precoated plates .Merck TLC aluminum sheets silica

60 F₂₅₄) with detection by UV light or with phospho-

molybdic acid in EtOH/H₂O followed by heating. Column

chromatography was performed using SiO₂.Wakogel

C-200, Wako).

3.2. Calculations

Low-mode searches .LOMD)²¹for compounds 5 and 6 in

water were performed using MacroModel version 6.0²⁰with

the mm2^pderivative of mm2 force ®eld on a Silicon

Graphics IRIS-Indigo workstation. LOMD for each

compound was continued until around 5,000 conformers

were generated. Solvation energies were established by

GB/SA model²²installed in the software.

3.3. General procedure of preparing 3,4,5,7-tetra-O-

benzyl-a-d-hept-2-ulopyranose -2)[7,8]. 3,4,5,7-Tetra-O-

benzyl-a-d-gluco-hept-2-ulopyranose -2a)

In conclusion, the cycloglycosylation of 3,4,5,7-tetra-O-

benzyl-a-d-hept-2-ulopyranoses .2a±c) was carried out

under the catalysis of Lewis acid to give two spiro-cyclo-

disaccharides 3a±c and 4a±c. While the reaction with

strong Lewis acid at low temperature resulted in the major

formation of the kinetic products 3a±c, the thermodynamic

products 4a±c were predominant in the use of weak Lewis

acid at higher temperature. Catalytic hydrogenation and

followed by acetylation of the products provided the

unprotected disaccharides 5a±c and 6a±c, and the

acetylated derivatives 7a±c and 8a±c, respectively. X-Ray

crystallographic analyses of 6a±c showed that the

compounds 4a±c, 6a±c and 8a±c were of a,b-anomeric

con®gurations with chair±chair±chair forms in the tri-

cycles. The compounds 3a±c, 5a±c and 7a±c were

con®rmed to possess a,a-anomeric con®gurations with

chair±boat±chair forms for the tri-cycles by the comparison

of the three-bond carbon±proton coupling constants ³J_C-1,C-3

between 7a±c and 8a±c, and by the NOE analyses of 7a±c.

The stable conformation of the spiro-ketodisaccharides

resulted in the stereoselectivities of the cyclo-ketoglycosyl-

ation different from that of the ketoglycosylation.

To a solution of 1.17 g .10.0 mmol) of N-methylmorpholine

N-oxide .NMO) in 50 mL of acetone and 10 mL of water

was added 1 mL .2.5% w) of osmium tetraoxide .OsO₄)

.0.1 mmol, 0.02 equiv.) in tert-butanol solution at room

temperature under argon atmosphere with stirring. The

solution was stirred for 5 min, then 2.7 g .5.0 mmol) of

2,6-anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-d-gluco-hept-

1-enitol .1a) was added. The reaction mixture was stirred

overnight, a slurry of 1.0 g of sodium hydrosul®te and 5.0 g

of Florisil^win 10 mL of water was added, the mixture was

stirred for 30 min, and ®ltered through a Celite pad. The

solid was washed thoroughly with acetone. The ®ltrate,

combined with the acetone washing, was neutralized to

pH<7 with diluted H₂SO₄.3 mol/L). The solution was

concentrated in vacuo to remove acetone, the resulting

aqueous solution was extracted with ethyl acetate. The

organic phase was dried over MgSO₄, and solvent was

removed under reduced pressure. The residue was applied

on silica gel chromatographic column using AcOEt/hexane

.1:1 v/v) as the eluent to afford a white solid product 2a,

2.60 g .91.4%). Mp 116±1178C, [a]²³142.58 .c 0.95,

D

CHCl₃) .lit.⁸mp 112.5±113.58C, [a]_D114.78).

3. Experimental

Following the procedure of preparing 2a, the diol 2b and 2c

were prepared from 1b and 1c, respectively.

3.1. General methods

Melting points were measured on a YANACO Micro Melt-

ing Point Apparatus and were uncorrected. IR spectra were

recorded on a Jasco FT/IR-800 Fourier-transform infrared

spectrometer. ¹H- and ¹³C NMR, 2D COSY, NOE and three

3.3.1. 3,4,5,7-Tetra-O-benzyl-a-d-galacto-hept-2-ulopyr-

anose -2b). Colorless syrup; [a]²⁵115.18, .c 1.0,

D

CHCl₃); IR .neat): 3433.71, 3088.41, 3064.30, 3030.54,

2922.51, 2874.29, 1954.15, 1876.85, 1809.45, 1720.71,

1604.97, 1585.68, 1496.94, 1454.50, 1400.49, 1363.84,

1207.59, 1097.63, 1028.18, 914.37, 881.58, 848.78,

3

bond carbon±proton coupling constants J_C,Hwere

measured on a JEOL ECP 600 .600 MHz) NMR spectro-

meter in CDCl₃or D₂O solutions using tetramethylsilane

.Me₄Si) or methanol .CH₃OH) as the internal standards,

respectively. Mass spectra .MS) and high resolution mass

spectra .HRMS) 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. X-Ray crystallographic measurements were

made on a Rigaku RAXIS-RAPID Imaging Plate Diffract-

1

819.85, 736.90, 689.32 cm²¹; H NMR.CDCl₃): d .ppm)

1.86 .s, br, 2H, OH), 3.45 .d, 1H, J10.99 Hz, 1-H),

3.51±3.53 .m, 3H, 1-H and two 7-H), 4.00 .s, br 3H, 3-H,

4-H and 5-H), 4.13 .t, br, 1H, J6.60 Hz, 6-H), 4.43 .d, 1H,

J11.54 Hz, CH₂Ph), 4.46 .d, 1H, J12.10 Hz, CH₂Ph),

4.59 .d, 1H, J11.55 Hz, CH₂Ph), 4.68 .d, 1H,

J11.00 Hz, CH₂Ph), 4.72 .d, 1H, J12.10 Hz, CH₂Ph),

4.76 .d, 1H, J11.54 Hz, CH₂Ph), 4.94 .d, 1H,

J11.55 Hz, CH₂Ph), 4.95 .d, 1H, J11.00 Hz, CH₂Ph),

8060

X. Li et al. / Tetrahedron 57 12001) 8053±8066

7.27±7.38 .m, 20H, ArH); ¹³C NMR.CDCl₃): d .ppm)

65.85 .1-C), 68.80 .7-C), 70.19 .6-C), 72.54 .CH₂Ph),

73.38 .CH₂Ph), 74.41 .5-C), 74.51 .CH₂Ph), 75.42

.CH₂Ph), 75.57 .3-C), 80.69 .4-C), 97.63 .anomeric 2-C),

127.50 .Ar), 127.56 .Ar), 127.61 .Ar), 127.78 .Ar), 127.84

.Ar), 127.88 .Ar), 128.01 .Ar), 128.20 .Ar), 128.36 .Ar),

128.39 .Ar), 128.41 .Ar), 128.43 .Ar), 137.74 .Ar), 137.89

.Ar), 138.31 .Ar), 138.62 .Ar); HRMS .FAB): calcd for

C₃₅H₃₈O₇Na 593.2516, found 593.2511.

.AcOEt/hexane1:4) to afford a mixture of 3a and 4a

80.3 mg .72.7%) .3a/4a1.0:7.0). Recrystallization of the

mixture from AcOEt/hexane three times gave the product 4a

as a white solid. Different reaction conditions were also

explored, and the results are shown in Table 1.

The cycloglycosylations of 2b and 2c were carried out under

the same conditions of Method A and Method B to afford

the corresponding spiro-ketodisaccharides 3b, 4b and 3c,

4c, respectively. The mixtures were separated by silica gel

chromatographic column .AcOEt/hexane1:4). The results

are listed in the Table 2.

3.3.2. 3,4,5,7-Tetra-O-benzyl-a-d-manno-hept-2-ulopyr-

anose -2c). White solid, mp 73±748C; [a]²⁵131.28, .c

D

1.0, CHCl₃); IR .KBr): 3416.35, 3088.41, 3063.33, 3030.54,

2868.50, 1954.13, 1878.90, 1809.45, 1726.50, 1604.97,

1496.94, 1454.50, 1394.70, 1367.70, 1275.10, 1207.59,

3.4.1. 3,4,5,7-Tetra-O-benzyl-a-d-galacto-hept-2-ulopyr-

anose 3⁰,4⁰,5⁰,7⁰-tetra-O-benzyl-a-d-galacto-hept-2⁰-ulo-

pyranose 1,2⁰:2,1⁰-dianhydride -3b). Colorless syrup;

1091.84, 1028.18, 902.80, 734.97, 698.32 cm²¹

;

¹H

[a]²⁷172.48, .c 1.0, CHCl₃); IR .neat): 3088.41,

NMR.CDCl₃): d .ppm) 1.78 .s, br, 1H, OH), 3.23 .d, 1H,

J11.55 Hz, 1-H), 3.56 .s, br, 1H, OH), 3.65±3.71 .m, 2H,

7-H), 3.82 .s, br, 1H, 3-H), 3.83 .d, 1H, J11.00 Hz, 1-H),

3.89 .t, 1H, J9.35 Hz, 5-H), 3.96±3.98 .m, 1H, 6-H), 4.12

.d, br, 1H, J9.35 Hz, 4-H), 4.50 .d, 1H, J12.10 Hz,

CH₂Ph), 4.53 .d, 1H, J11.55 Hz, CH₂Ph), 4.57 .d, 1H,

J11.55 Hz, CH₂Ph), 4.62 .d, 1H, J11.54 Hz, CH₂Ph),

4.77 .s, 2H, CH₂Ph), 4.87 .d, 1H, J11.00 Hz, CH₂Ph),

4.95 .d, 1H, J11.55 Hz, CH₂Ph), 7.17±7.39 .m, 20H,

ArH); ¹³C NMR.CDCl₃): d .ppm) 66.24 .1-C), 69.74

.7-C), 72.06 .6-C), 72.71 .CH₂Ph), 73.22 .CH₂Ph), 74.37

.CH₂Ph), 74.96 .CH₂Ph), 75.41 .5-C), 76.15 .3-C), 81.59

.4-C), 97.18 .anomeric 2-C), 127.55 .Ar), 127.59 .Ar),

127.70 .Ar), 127.74 .Ar), 127.97 .Ar), 128.21 .Ar),

128.23 .Ar), 128.28 .Ar), 128.31 .Ar), 128.35 .Ar),

128.40 .Ar), 128.45 .Ar), 137.77 .Ar), 138.19 .Ar),

138.27 .Ar), 138.40 .Ar); HRMS .FAB): calcd for

C₃₅H₃₈O₇Na 593.2516, found 593.2521.

D

3063.33, 3030.54, 2922.51, 2872.36, 1954.13, 1878.90,

1809.45, 1732.29, 1604.97, 1496.94, 1454.50, 1280.89,

1209.51, 1101.49, 1047.47, 912.44, 733.04, 696.39 cm²¹

;

¹H NMR.CDCl₃): d .ppm) 3.49 .dd, 1H, J9.35, 5.50 Hz,

7-H), 3.55 .d, 1H, J12.64 Hz, dioxane 1-H), 3.58 .dd, 1H,

J9.35, 7.70 Hz, 7-H), 3.73 .d, 1H, J12.64 Hz, dioxane

1-H), 3.91 .d, 1H, J9.90 Hz, 3-H), 3.96±3.99 .m, 1H,

6-H), 3.99 .d, 1H, J2.75 Hz, 5-H), 4.07 .dd, 1H, J9.90,

2.75 Hz, 4-H), 4.38 .d, 1H, J11.55 Hz, CH₂Ph), 4.43 .d,

1H, J11.55 Hz, CH₂Ph), 4.60 .d, 1H, J11.55 Hz,

CH₂Ph), 4.74 .d, 1H, J11.55 Hz, CH₂Ph), 4.76 .s, 1H,

CH₂Ph), 4.77 .d, 1H, J10.99 Hz, CH₂Ph), 4.92 .d, 1H,

J11.55 Hz, CH₂Ph), 4.95 .d, 1H, J11.55 Hz, CH₂Ph),

7.14±7.16 .m, 3H, ArH), 7.24±7.36 .m, 15H, ArH), 7.40±

7.42 .m, 2H, ArH); ¹³C NMR.CDCl₃): d .ppm) 63.93

.dioxane 1-C), 68.65 .7-C), 70.59 .6-C), 72.90 .CH₂Ph),

73.39 .CH₂Ph), 74.26 .CH₂Ph), 74.69, .CH₂Ph) 74.95

.5-C), 79.51 .3-C), 79.72 .4-C), 97.29 .anomeric 2-C),

127.11 .Ar), 127.46 .Ar), 127.49 .Ar), 127.51 .Ar),

127.52 .Ar), 128.16 .Ar), 128.17 .Ar), 128.31 .Ar),

128.33 .Ar), 128.35 .Ar), 137.98 .Ar), 138.65 .Ar),

138.80 .Ar), 138.83 .Ar); HRMS .FAB): calcd for

C₇₀H₇₂O₁₂Na 1127.4922, found 1127.4917.

3.4. Cycloglycosylation reactions of 3,4,5,7-tetra-O-

benzyl-a-d-gluco-hept-2-ulopyranose -2a)

Method A 1promoted by TfOH at low temperature). To a

solution of 2a .114 mg, 0.2 mmol) and calcium sulfate

anhydrous .Drierite^w) .500 mg) in 5.0 mL of dry dichloro-

methane were added 27 mL .0.3 mmol, 1.5 equiv.) of tri¯ic

acid .TfOH) at 2788C under argon atmosphere with stir-

ring. The solution was stirred at the same temperature for

1 h, then warmed up to room temperature gradually, stirred

at room temperature for 1 h. Three drops of triethylamine

.Et₃N) were added to quench the reaction. The solvent was

removed, and the residue was applied on silica gel column

chromatography eluted with AcOEt/hexane .1:4) to afford

76.1 mg .68.9%) of a mixture of 3a and 4a .1.1:1.0, the ratio

3.4.2. 3,4,5,7-Tetra-O-benzyl-a-d-manno-hept-2-ulopyr-

anose 3⁰,4⁰,5⁰,7⁰-tetra-O-benzyl-a-d-manno-hept-2⁰-ulo-

pyranose 1,2⁰:2,1⁰-dianhydride -3c). Colorless syrup;

[a]²⁵178.708, .c 1.0, CHCl₃); IR .neat): 3063.33,

D

3030.54, 2916.72, 2897.43, 2864.64, 1952.20, 1871.18,

1809.45, 1734.22, 1604.97, 1587.61, 1496.94, 1454.50,

1365.77, 1311.75, 1263.53, 1209.51, 1105.35, 1028.18,

1

908.58, 734.97, 698.32 cm²¹; H NMR.CDCl₃): d .ppm)

3.57 .d, 1H, J12.65 Hz, dioxane 1-H), 3.70 .dd, 1H,

J11.00, 1.65 Hz, 7-H), 3.74 .d, 1H, J2.75 Hz, 3-H),

3.79 .dd, 1H, J11.00Hz, 4.65 Hz, 7-H), 3.84±3.87 .m,

2H, 6-H and dioxane 1-H) 4.02 .dd, 1H, J9.35, 2.20 Hz,

4-H), 4.05 .t, 1H, J9.35 Hz, 5-H), 4.48 .d, 1H,

J12.09 Hz, CH₂Ph), 4.54 .d, 1H, J10.45 Hz, CH₂Ph),

4.63 .d, 1H, J11. 54 Hz, CH₂Ph), 4.64 .d, 1H,

J12.10 Hz, CH₂Ph), 4.74 .d, 1H, J12.10 Hz, CH₂Ph),

4.78 .d, 1H, J11.55 Hz, CH₂Ph), 4.84 .d, 1H,

J10.45 Hz, CH₂Ph), 5.02 .d, 1H, J11.55 Hz, CH₂Ph),

7.17±7.19 .m, 2H, ArH), 7.21±7.35 .m, 16H, ArH), 7.39±

7.40 .m, 2H, ArH); ¹³C NMR.CDCl₃): d .ppm) 60.53

.dioxane 1-C), 69.08 .7-C), 72.79 .CH₂Ph), 73.29

.CH₂Ph), 73.32 .6-C), 74.60 .CH₂Ph), 74.83.two C, 5-C

1

was determined according to the H NMR of the mixture).

Similarly, different conditions with various Lewis acids

were examined and the results are summarized in Table 1.

Method B 1promoted by the combination of TsOH and

NaOTf or KOTf at re¯ux temperature). To a solution of

2a .114 mg, 0.2 mmol) in 10 mL dry Et₂O was added

38.0 mg .0.2 mmol) of TsOH´H₂O and 34.4 mg

.0.2 mmol) of NaOTf. The mixture was re¯uxed through a

short molecular sieves 4 A .MS 4 A) column under the

argon atmosphere for 5 h until the reactant 2a disappeared

.TLC AcOEt/hexane1:2). After removing the solvent, the

residue was submitted to silica gel column chromatography

X. Li et al. / Tetrahedron 57 12001) 8053±8066

8061

and CH₂Ph), 75.39 .3-C), 81.13 .4-C), 98.18 .anomeric

2-C), 127.30 .Ar), 127.45 .Ar), 127.48 .Ar), 127.50 .Ar),

127.53 .Ar), 127.66 .Ar), 127.68 .Ar), 127.71 .Ar), 127.77

.Ar), 127.83 .Ar), 128.14 .Ar), 128.17 .Ar), 128.20 .Ar),

128.22 .Ar), 128.30 .Ar), 128.35 .Ar), 138.27 .Ar), 138.44

.Ar), 138.45 .Ar), 138.60 .Ar); HRMS: .FAB) calcd for

C₇₀H₇₂O₁₂Na 1127.4922, found 1127.4925.

J11.55 Hz, CH₂Ph), 4.63 .d, 1H, J12.10 Hz, CH₂Ph),

4.64 .d, 1H, J11.55 Hz, CH₂Ph), 4.67±4.73 .m, 4H,

CH₂Ph), 4.88±4.92 .m, 3H, CH₂Ph), 4.96 .d, 1H,

J10.99 Hz, CH₂Ph), 7.20±7.35 .m, 40H, ArH); ¹³C

NMR.CDCl₃): d .ppm) 55.34 .dioxane 1-C), 62.40 .dioxane

1-C), 67.95 .7-C), 68.10 .7-C), 69.42 .6-C), 71.64 .6-C),

72.57 .CH₂Ph), 73.10 .5-C), 73.40 .CH₂Ph), 73.51

.CH₂Ph), 73.55 .5-C), 73.99 .CH₂Ph), 74.70 .CH₂Ph),

74.72 .CH₂Ph), 74.88 .CH₂Ph), 75.75 .CH₂Ph), 76.35

.3-C), 80.18 .4-C), 80.48 .4-C), 80.86 .3-C), 95.73 .ano-

meric 2-C), 96.96 .anomeric 2-C), 127.32 .Ar), 127.35 .Ar),

127.43 .Ar), 127.46 .Ar), 127.50 .Ar), 127.56 .Ar), 127.67

.Ar), 127.77 .Ar), 127.79 .Ar), 127.96 .Ar), 127.97 .Ar),

127.99 .Ar), 128.02 .Ar), 128.09 .Ar), 128.10 .Ar), 128.17

.Ar), 128.20 .Ar), 128.27 .Ar), 128.30 .Ar), 128.36 .Ar),

128.38 .Ar), 128.40 .Ar), 128.45 .Ar), 137.75 .Ar), 137.86

.Ar), 137.98 .Ar), 138.41 .Ar), 138.51 .Ar), 138.67 .Ar),

138.74 .Ar), 138.91 .Ar); HRMS: .FAB) calcd for

C₇₀H₇₂O₁₂Na 1127.4922, found 1127.4920.

3.4.3. 3,4,5,7-Tetra-O-benzyl-a-d-gluco-hept-2-ulopyr-

anose 3⁰,4⁰,5⁰,7⁰-tetra-O-benzyl-a-d-gluco-hept-2⁰-ulo-

pyranose 1,2⁰:2,1⁰-dianhydride -4a). White solid, mp

151±1528C; [a]²⁵147.608, .c 1.0, CHCl₃); IR .KBr):

D

3088.41, 3063.33, 3030.54, 2907.08, 2864.64, 1950.27,

1871.18, 1811.38, 1747.72, 1604.97, 1496.94, 1454.50,

1369.63, 1359.98, 1280.89, 1209.51, 1155.50, 1097.63,

1070.62, 1028.18, 914.37, 736.90, 698.32 cm²¹

;

¹H

NMR.CDCl₃): d .ppm) 3.30 .d, 1H, J9.35 Hz, 3-H),

3.40 .d, 1H, J11.54 Hz, dioxane 1-H), 3.51±3.56 .m,

3H, 3-H, 5-H and 7-H), 3.64 .ddd, 1H, J9.90, 2.75 Hz,

J2.20 Hz, 6-H), 3.69 .ddd, 1H, J9.90, 2.75, 2.20 Hz,

6-H), 3.75±3.80 .m, 3H, 7-H, 4-H and 7-H), 3.83±3.87

.m, 3H, dioxane 1-H, 7-H and 5-H), 4.10 .t, 9.35 Hz,

4-H), 4.17 .d, 1H, J12.65 Hz, dioxane 1-H), 4.38 .d, 1H,

J12.65 Hz, CH₂Ph), 4.41 .d, 1H, J11.00 Hz, dioxane

1-H), 4.49 .d, 1H, J12.09 Hz, CH₂Ph), 4.55±4.59 .m,

3H, CH₂Ph), 4.68 .d, 1H, J11.55 Hz, CH₂Ph), 4.69 .d,

1H, J12.54 Hz, CH₂Ph), 4.73 .d, 1H, J10.45 Hz,

CH₂Ph), 4.80 .d, 1H, J11.00 Hz, CH₂Ph), 4.81 .d, 1H,

J11.00 Hz, CH₂Ph), 4.86 .d, 1H, J11.55 Hz, CH₂Ph),

4.87 .d, 1H, J11.00 Hz, CH₂Ph), 4.90 .d, 1H,

J1.10 Hz, CH₂Ph), 5.01 .d, 1H, J11.55 Hz, CH₂Ph),

7.13±7.15 .m, 4H, ArH), 7.22±7.36 .m, 36H, ArH); ¹³C

NMR.CDCl₃): d .ppm) 55.62 .dioxane 1-C), 62.33 .dioxane

1-C), 68.37 .7-C), 68.84 .7-C), 71.25 .6-C), 73.34 .6-C),

73.51 .CH₂Ph), 73.74 .CH₂Ph), 74.16 .CH₂Ph), 74.93

.CH₂Ph), 75.06 .CH₂Ph), 75.45 .CH₂Ph), 75.63 .CH₂Ph),

75.66 .CH₂Ph), 77.50 .5-C), 78.16 .5-C), 79.73 .3-C),

82.69 .3-C), 83.01 .4-C), 83.62 .4-C), 95.38 .anomeric

2-C), 96.34 .anomeric 2-C), 127.46 .Ar), 127.57 .Ar),

127.59 .Ar), 127.62 .Ar), 127.65 .Ar), 127.68 .Ar),

127.71 .Ar), 127.80 .Ar), 127.81 .Ar), 127.85 .Ar),

127.88 .Ar), 127.92 .Ar), 127.97 .Ar), 128.24 .Ar),

128.31 .Ar), 128.34 .Ar), 128.37 .Ar), 128.43 .Ar),

137.67 .Ar), 138.02 .Ar), 138.17 .Ar), 138.31 .Ar),

138.54 .Ar), 138.58 .Ar), 138.60 .Ar); HRMS .FAB):

calcd for C₇₀H₇₂O₁₂Na 1127.4922, found 1127.4928.

3.4.5. 3,4,5,7-Tetra-O-benzyl-a-d-manno-hept-2-ulopyr-

anose 3⁰,4⁰,5⁰,7⁰-tetra-O-benzyl-a-d-manno-hept-2⁰-ulo-

pyranose 1,2⁰:2,1⁰-dianhydride -4c). Colorless syrup;

[a]²⁵10.688 .c 5.0, CHCl₃); IR .neat): 3088.41,

D

3063.33, 3030.54, 2918.65, 2868.50, 1952.20, 1876.97,

1811.38, 1728.43, 1604.97, 1587.61, 1496.94, 1454.50,

1365.77, 1286.68, 1211.44, 1095.70, 1028.18, 910.51,

1

734.97, 696.39 cm²¹; H NMR.CDCl₃): d .ppm) 3.47 .dd,

1H, J8.35, 3.30 Hz, 4-H), 3.57 .d, 1H, J3.30 Hz, 3-H),

3.59 .d, 1H, J11.55 Hz, dioxane 1-H), 3.62 .d, 1H,

J11.55 Hz, dioxane 1-H), 3.69±3.72 .m, 1H, 6-H),

3.76±3.83 .m, 5H, three 7-H, 6-H and 3-H), 3.86 .dd, 1H,

J9.90, 2.20 Hz, 7-H), 3.91±3.96 .m, 4H, two dioxane 1-H

and two 5-H), 4.02 .dd, 1H, J9.35, 2.75 Hz, 4-H), 4.41 .d,

1H, J11.55 Hz, CH₂Ph), 4.44 .d, 1H, J11.55 Hz,

CH₂Ph), 4.51±4.60 .m, 5H, CH₂Ph), 4.63±4.70 .m, 5H,

CH₂Ph), 4.76 .d, 1H, J10.99 Hz, CH₂Ph), 4.85 .d, 1H,

J10.45 Hz, CH₂Ph), 4.86 .d, 1H, J12.10 Hz, CH₂Ph),

4.91 .d, 1H, J11.55 Hz, CH₂Ph), 7.19±7.36 .m, 38H,

ArH), 7.39±7.40 .m, 2H, ArH); ¹³C NMR.CDCl₃): d

.ppm) 58.77 .dioxane 1-C), 64.18 .dioxane 1-C), 69.35

.7-C), 69.98 .7-C), 71.73 .CH₂Ph), 72.60 .CH₂Ph), 73.22

.CH₂Ph), 73.83 .6-C), 74.27 .CH₂Ph), 74.55 .CH₂Ph), 74.65

.3-C), 74.68 .6-C), 74.80 .5-C), 75.10 .5-C), 75.11

.CH₂Ph), 75.13 .CH₂Ph), 75.14 .CH₂Ph), 75.15 .3-C),

79.05 .4-C), 81.30 .4-C), 94.87 .anomeric 2-C), 95.38

.anomeric 2-C), 127.32 .Ar), 127.40 .Ar), 127.47 .Ar),

127.54 .Ar), 127.56 .Ar), 127.61 .Ar), 127.62 .Ar),

127.64 .Ar), 127.65 .Ar), 127.72 .Ar), 127.96 .Ar),

128.01 .Ar), 128.08 .Ar), 128.28 .Ar), 128.31 .Ar),

128.38 .Ar), 137.91 .Ar), 138.15 .Ar), 138.17 .Ar),

138.30 .Ar), 138.38 .Ar), 138.59 .Ar), 138.64 .Ar),

138.65 .Ar); HRMS: .FAB) calcd for C₇₀H₇₂O₁₂Na

1127.4922, found 1127.4919.

3.4.4. 3,4,5,7-Tetra-O-benzyl-a-d-galacto-hept-2-ulopyr-

anose 3⁰,4⁰,5⁰,7⁰-tetra-O-benzyl-a-d-galacto-hept-2⁰-ulo-

pyranose 1,2⁰: 2,1⁰-dianhydride -4b). White solid, mp

115±116 8C; [a]²⁷137.78 .c 1.0, CHCl₃); IR .KBr):

D

3088.41, 3063.33, 3030.54, 2918.65, 2870.43, 1956.06,

1869.25, 1809.45, 1747.72, 1604.97, 1496.94, 1454.50,

1363.84, 1207.59, 1101.49, 1028.18, 937.52, 734.97,

1

698.32 cm²¹; H NMR.CDCl₃): d .ppm) 3.41±3.45 .m,

3H, 7-H, dioxane 1-H and 4-H), 3.59 .dd, 1H, J8.35,

3.88 Hz, 7-H), 3.69±3.80 .m, 5H, 7-H, 6-H, 3-H, dioxane

1-H and 7-H), 3.85 .dd, br, 1H, J8.80, 5.50 Hz, 6-H), 3.93

.d, 1H, J10.45 Hz, 3-H), 4.02±4.04 .m, 2H, 5-H and 4-H),

4.08 .d, 1H, J1.65 Hz, 5-H), 4.22 .d, 1H, J12.10 Hz,

dioxane 1-H), 4.28 .d, 1H, J11.54 Hz, CH₂Ph), 4.33±

4.37 .m, 3H, CH₂Ph), 4.46 .d, 1H, J11.55 Hz, dioxane

1-H), 4.54 .d, 1H, J11.00 Hz, CH₂Ph), 4.57 .d, 1H,

3.5. Debenzylation of 3a and 4a

The mixture of 3a and 4a .220 mg, 0.2 mmol) was dissolved

in 10 mL of methanol. To the solution 40 mg of Pd.OH)₂/C

.20 wt%) was added, and the mixture was stirred vigorously

under H₂atmosphere at room temperature for 12 h. The

reaction was monitored by TLC detection .AcOEt/i-PrOH/

H₂O5:3:1). After the reaction completed, the catalyst was

8062

X. Li et al. / Tetrahedron 57 12001) 8053±8066

removed by ®ltration through a Celite pad and the solvent

was evaporated in vacuum to give the mixture of the unpro-

tected products 5a and 6a quantitatively.

J13.20 Hz, dioxane 1-H), 4.29 .d, 1H, J12.10 Hz,

dioxane 1-H); ¹³C NMR.D₂O) d .ppm) 54.17 .dioxane

1-C), 61.37 .7-C), 61.42 .7-C), 62.41 .dioxane 1-C), 68.76

.3-C), 68.89 .5-C), 69.30 .5-C), 69.94 .4-C), 70.43 .6-C),

71.85 .4-C), 72.39 .6-C), 73.87 .3-C), 95.17 .anomeric

2-C), 96.62 .anomeric 2-C); HRMS: .FAB) calcd for

C₁₄H₂₄O₁₂Na 407.1166, found 407.1168.

Following the above procedure, the compounds 3b±c and

4a±c were debenzylated and quantitatively afforded the

compounds 5b±c and 6a±c, respectively.

3.5.5. a-d-manno-Hept-2-ulopyranose b-d-manno-hept-

2⁰-ulopyranose 1,2⁰:2,1⁰-dianhydride -6c). White solid,

3.5.1. a-d-galacto-Hept-2-ulopyranose a-d-galacto-hept-

2⁰-ulopyranose 1,2⁰:2,1⁰-dianhydride -5b). White solid,

mp 246±2508; [a]²⁵126.68 .c 0.5, H₂O); ¹H NMR

1

mp 155±1568C; [a]²⁵1201.48 .c 0.5, H₂O); H NMR

D

.D₂O): d .ppm) 3.27 .ddd, 1H, J9.35, 6.35, 2.20 Hz,

6-H), 3.33 .ddd, 1H, J9.90, 6.05, 2.20 Hz, 6-H), 3.38

.dd, 1H, J9.35, 3.30 Hz, 4-H), 3.40 .t, 1H, J9.90 Hz,

5-H), 3.45 .t, 1H, J9.90 Hz, 5-H), 3.49±3.56 .m, 4H,

7-H, 7-H, two dioxane 1-H), 3.61 .dd, 1H, J8.80,

3.30 Hz, 4-H), 3.62 .d, 1H, J3.30 Hz, 3-H), 3.63 .d, 1H,

J3.30 Hz, 3-H), 3.68 .d, br, 2H, J12.65 Hz, 7-H and

7-H), 3.81 .d, 1H, J12.65 Hz, dioxane 1-H), 3.90 .d, 1H,

J12.65 Hz, dioxane 1-H); ¹³C NMR .D₂O) d .ppm) 57.38

.dioxane 1-C), 60.92 .7-C), 61.29 .7-C), 63.67 .dioxane

1-C), 66.59 .5-C), 66.71 .5-C), 70.35 .3-C), 70.47 .3-C),

71.00 .4-C), 71.25 .4-C), 73.61 .6-C), 74.99 .6-C), 94.58

.anomeric 2-C), 94.99 .anomeric 2-C); HRMS: .FAB) calcd

for C₁₄H₂₄O₁₂Na 407.1166, found 407.1163.

.D₂O): d .ppm): 3.55 .d, 1H, J10.45 Hz, 3-H), 3.57±

3.62 .m, 2H, two 7-H), 3.62 .d, 1H, J12.65 Hz, dioxane

1-H, overlapped with 7-H), 3.74 .dd, 1H, J9.90, 3.30 Hz,

4-H), 3.80 .d, 1H, J12.65 Hz, dioxane 1-H), 3.83 .d, br,

1H, J3.30 Hz, 5-H), 3.86 .dd, br, 1H, J7.70, 4.40 Hz,

6-H); ¹³C NMR .D₂O): d .ppm): 61.34 .7-C), 63.49

.dioxane 1-C), 69.27 .5-C), 70.10 .4-C), 72.62 .3-C),

72.68 .6-C), 96.68 .anomeric 2-C); HRMS: .FAB) calcd

for C₁₄H₂₄O₁₂Na 407.1166, found 407.1165.

3.5.2. a-d-manno-Hept-2-ulopyranose a-d-manno-hept-

2⁰-ulopyranose 1,2⁰:2,1⁰-dianhydride -5c). Amorphous

1

solid; [a]²⁵199.28 .c 0.5, H₂O); H NMR .D₂O): d

D

.ppm) 3.38 .t, 1H, J9.35 Hz, 5-H), 3.41 .d, 1H,

J12.65 Hz, dioxane 1-H), 3.46±3.51 .m, 2H, 6-H and

7-H), 3.63 .dd, 2H, J9.35 Hz, J2.20 Hz, 4-H and 7-H,

overlapped), 3.76 .d, 1H, J12.65 Hz, dioxane 1-H), 3.77

.d, 1H, J3.85 Hz, 3-H); ¹³C NMR .D₂O): d .ppm) 60.98

.dioxane 1-C), 61.04 .7-C), 66.46 .5-C), 69.12 .3-C), 70.59

.4-C), 73.82 .6-C), 97.35 .anomeric 2-C); HRMS: .FAB)

calcd for C₁₄H₂₄O₁₂Na 407.1166, found 407.1160.

3.6. Acetylation of 5a and 6a

The mixture of 5a and 6a .76.8 mg, 0.2 mmol) was

dissolved in 5.0 mL of dry pyridine. The solution was

cooled with ice bath and 3.0 mL of acetic anhydride was

added, then the solution was stirred at room temperature

overnight. After completion of the reaction, the solution

was poured into 50 g ice water, and the mixture was

extracted with AcOEt .20 mL£3). The organic phase was

washed with water .30 mL) four times and dried over

MgSO₄. After removing solvent, the residue was

submitted to silica gel column chromatography .AcOEt/

hexane 1:1) to afford the acetylated derivatives 7a

.31.1 mg, 21.6%) and 8a .87.1 mg, 60.5%), .total:

118.2 mg, 82.1%).

3.5.3. a-d-gluco-Hept-2-ulopyranose b-d-gluco-hept-2⁰-

ulopyranose 1,2⁰:2,1⁰-dianhydride -6a). White solid,

mp.2508C; [a]²⁵142.008 .c 0.6, CHCl₃); ¹H

D

NMR.D₂O): d .ppm) 3.13 .d, 1H, J9.35 Hz, 3-H), 3.22

.d, 1H, J9.90 Hz, 3-H), 3.28 .t, br, 2H, J9.90 Hz, two

5-H, overlapped), 3.35 .t, 1H, J9.35 Hz, 4-H), 3.39 .d, 1H,

J12.10 Hz, dioxane 1-H), 3.44 .ddd, 1H, J9.90, 4.40,

2.20 Hz, 6-H), 3.46 .ddd, 1H, J9.90, 4.40, J2.20 Hz,

6-H), 3.56 .t, 1H, J9.35 Hz, 4-H), 3.61 .dd, 1H,

J12.09, 6.05 Hz, 7-H), 3.63 .dd, 1H, J12.09, 6.05 Hz,

7-H), 3.76 .dd, 1H, J12.09, 2.20 Hz, 7-H), 3.79 .dd, 1H,

J12.65, 2.20 Hz, 7-H), 3.83 .d, 1H, J13.19 Hz, dioxane

1-H), 3.93 .d, 1H, J12.65 Hz, dioxane 1-H), 4.26 .d, 1H,

J11.55 Hz, dioxane 1-H); ¹³CNMR.CHCl₃): d .ppm)

55.40 .dioxane 1-C), 61.65 .7-C), 62.00 .7-C), 63.43

.dioxane 1-C), 70.46 .5-C), 70.92 .5-C), 72.65 .3-C),

73.53 .6-C), 74.27 .4-C), 74.34 .4-C), 75.57 .6-C),

75.98 .3-C), 95.84 .anomeric 2-C), 96.96 .anomeric 2-C);

HRMS: .FAB) calcd for C₁₄H₂₄O₁₂Na 407.1166, found

407.1162.

Under the same conditions, the acetylations of the

compounds 5b±c and 6a±c were carried out and provided

the corresponding compounds 7b±c and 8a±c, respectively.

The results are shown in Table 3.

3.6.1. 3,4,5,7-Tetra-O-acetyl-a-d-gluco-hept-2-ulopyra-

nose 3⁰,4⁰,5⁰,7⁰-tetra-O-acetyl-a-d-gluco-hept-2⁰-ulopyra-

nose 1,2⁰:2,1⁰-dianhydride -7a). Colorless amorphous

solid; [a]²⁵1112.998 .c 1.0, CHCl₃); IR .KBr):

D

2959.16, 1749.65 .st), 1649.34, 1456.43, 1435.21,

1371.55, 1226.88, 1097.63, 1041.69, 978.03, 900.87,

798.63 cm²^{1 1}H NMR.CDCl₃): d .ppm) 1.99 .s, 3H,

;

3.5.4. a-d-galacto-Hept-2-ulopyranose b-d-galacto-hept-

2⁰-ulopyranose 1,2⁰:2,1⁰-dianhydride -6b). White solid,

CH₃CO), 2.02 .s, 3H, CH₃CO), 2.08 .s, 3H, CH₃CO), 2.17

.s, 3H, CH₃CO), 3.60 .d, 1H, J12.64 Hz, dioxane 1-H),

4.00 .d, 1H, J12.64 Hz, dioxane 1-H), 4.06 .dd, br, 2H,

J10.45 Hz, 6-H and 7-H, overlapped), 4.21 .dd, 1H,

J12.64, 4.40 Hz, 7-H), 5.09 .t, 1H, J9.89 Hz, 5-H),

5.09 .d, 1H, J10.45 Hz, 3-H), 5.48 .t, 1H, J9.90 Hz,

4-H); ¹³C NMR.CDCl₃): d .ppm) 20.55 .two C, CH₃),

20.60 .CH₃), 20.73 .CH₃), 61.64 .7-C), 62.68 .dioxane

1

mp 185±1888C; [a]²⁵186.08 .c 0.5, H₂O); H NMR

D

.D₂O) d .ppm) 3.36 .d, 1H, J9.90 Hz, 3-H), 3.40 .d, 1H,

J11.54 Hz, dioxane 1-H), 3.52 .s, 2H, 6-H and 6-H), 3.59

.dd, 1H, J11.54, 3.84 Hz, 7-H), 3.62±3.66 .m, 2H, 7-H

and 7-H), 3.67±3.74 .m, 4H, 7-H, 3-H, 4-H and 4-H), 3.81

.d, 1H, J12.64 Hz, dioxane 1-H, overlapped with 5-H),

3.81 .s, br, 1H, 5-H, oerlapped with dioxane 1-H), 3.96 .d,

X. Li et al. / Tetrahedron 57 12001) 8053±8066

8063

1-C), 68.11 .3-C), 69.32 .6-C), 69.65 .4-C), 72.46 .5-C),

96.30 .anomeric 2-C), 169.42 .CvO), 170.02 .CvO),

170.62 .CvO), 170.86 .CvO); HRMS: .FAB) calcd for

C₃₀H₄₀O₂₀Na 743.2011, found 743.2018.

5.02±5.06 .m, 2H, 3-H and 5-H), 5.10 .t, 1H,

J10.44 Hz, 5-H), 5.42 .dd, 1H, J10.45, 8.25 Hz, 4-H),

5.50 .t, 1H, J9.89 Hz, 4-H); ¹³C NMR.CDCl₃): d .ppm)

20.45 .CH₃), 20.55 .CH₃), 20.58 .CH₃), 20.63 .CH₃), 20.64

.two C, CH₃), 20.68 .CH₃), 20.73 .CH₃), 59.16 .dioxane

1-C), 61.29 .dioxane 1-C), 61.55 .7-C), 61.87 .7-C), 67.48

.4-C), 68.41 .5-C), 68.52 .6-C), 69.52 .3-C), 70.48 .4-C),

70.76 .6-C), 72.85 .two C, 5-C and 3-C), 94.14 .anomeric

2-C), 94.28 .anomeric 2-C), 168.76 .CvO), 169.36 .CvO),

169.48 .CvO), 169.95 .CvO), 170.00 .CvO), 170.21

.CvO), 170.59 .CvO), 170.65 .CvO); HRMS: .FAB)

calcd for C₃₀H₄₀O₂₀Na 743.2011, found 743.2013.

3.6.2. 3,4,5,7-Tetra-O-acetyl-a-d-galacto-hept-2-ulopyr-

anose 3⁰,4⁰,5⁰,7⁰-tetra-O-acetyl-a-d-galacto-hept-2⁰-ulo-

pyranose

1,2⁰:2,1⁰-dianhydride

-7b).

Colorless

amorphous solid; [a]²⁵1111.498 .c 1.0, CHCl₃); IR

D

.KBr): 2968.02, 1752.79 .st), 1649.34, 1434.45, 1371.55,

;

¹H

1225.66, 1088.62, 1053.09, 959.06, 911.01 cm²¹

NMR.CDCl3): d .ppm) 2.02 .s, 3H, CH₃CO), 2.08 .s, 3H,

CH₃CO), 2.19 .s, 3H, CH₃CO), 2.20 .s, 3H, CH₃CO), 3.61

.d, 1H, J12.64 Hz, dioxane 1-H), 4.08 .d, 1H,

J12.64 Hz, dioxane 1-H), 4.12 .dd, 1H, J11.00,

6.60 Hz, 7-H), 4.15 .dd, 1H, J10.99, 7.15 Hz, 7-H), 4.35

.t, J6.60 Hz, 4-H), 5.39±5.41 .m, 1H, 6-H), 5.44±5.46

.m, 2H, 3-H and 5-H); ¹³C NMR.CDCl₃): d .ppm) 20.59

.CH₃), 20.62 .CH₃), 20.64 .CH₃), 20.70 .CH₃), 61.27

.7-C), 63.01 .dioxane 1-C), 67.23 .3-C), 67.81 .5-C),

68.28 .4-C), 70.06 .6-C), 96.82 .anomeric 2-C), 169.87

.CvO), 170.09 .CvO), 170.30 .CvO), 170.94 .CvO);

HRMS: .FAB) calcd for C₃₀H₄₀O₂₀Na 743.2011, found

743.2010.

3.6.5. 3,4,5,7-Tetra-O-acetyl-a-d-galacto-hept-2-ulopyr-

anose 3⁰,4⁰,5⁰,7⁰-tetra-O-acetyl-b-d-galacto-hept-2⁰-ulo-

pyranose 1,2⁰:2,1⁰-dianhydride -8b). White solid, mp

120±1218C; [a]²⁵170.378 .c 0.8, CHCl₃); IR .KBr):

D

2968.81, 1755.44 .st), 1649.34, 1435.21, 1373.48,

1223.02, 1060.98, 958.74, 925.84, 902.80 cm²¹

;

¹H

NMR.CDCl₃): d .ppm) 1.95 .s, 3H, CH₃CO), 1.96 .s, 3H,

CH₃CO), 2.03 .s, 3H, CH₃CO), 2.05 .s, 3H, CH₃CO), 2.07

.s, 3H, CH₃CO), 2.08 .s, 3H, CH₃CO), 2.13 .s, 3H, CH₃CO),

2.14 .s, 3H, CH₃CO), 3.54 .d, 1H, J12.09 Hz, dioxane

1-H), 3.88 .d, 1H, J12.64 Hz, dioxane 1-H), 3.96 .d, 1H,

J12.10 Hz, dioxane 1-H), 4.01 .d, 1H, J12.09 Hz,

dioxane 1-H), 4.04±4.13 .m, 4H, 6-H, 7-H, 7-H and 6-H),

4.16 .dd, 1H, J10.45, 6.60 Hz, 7-H), 4.27 .dd, 1H,

J10.45, 7.15 Hz, 7-H), 4.93 .dd, 1H, J11.00, 3.30 Hz,

4-H), 5.09 .d, 1H, J10.45 Hz, 3-H), 5.33 .dd, 1H,

J10.45, 3.30 Hz, 4-H), 5.34 .d, 1H, J11.00 Hz, 3-H),

5.43 .dd, 1H, J3.30, 1.10 Hz, 5-H), 5.46 .dd, 1H,

J3.30, 1.65 Hz, 5-H); ¹³C NMR.CDCl₃): d .ppm) 20.49

.CH₃), 20.50 .CH₃), 20.59 .two C, CH₃), 20.62 .CH₃), 20.69

.three C, CH₃), 55.37 .dioxane 1-C), 60.97 .7-C), 61.50

.7-C), 61.85 .dioxane 1-C), 66.67 .5-C), 66.87 .3-C),

67.52 .6-C), 67.85 .5-C), 67.94 .3-C), 68.71 .4-C), 69.49

.4-C), 69.58 .6-C), 94.76 .anomeric 2-C), 95.34 .anomeric

2-C), 168.82 .CvO), 169.84 .CvO), 169.99 .two C,

CvO), 170.10 .CvO), 170.12 .CvO), 170.20 .CvO),

170.27 .CvO); HRMS: .FAB) calcd for C₃₀H₄₀O₂₀Na

743.2011, found 743.2009.

3.6.3. 3,4,5,7-Tetra-O-acetyl-a-d-manno-hept-2-ulopyra-

nose 3⁰,4⁰,5⁰,7⁰-tetra-O-acetyl-a-d-manno-hept-2⁰-ulo-

pyranose

1,2⁰:2,1⁰-dianhydride

-7c).

Colorless

amorphous solid; [a]²⁸1102.08 .c 1.0, CHCl₃); IR

D

.KBr): 2991.96, 2963.02, 1749.65 .st), 1649.34, 1433.28,

1371.55, 1226.88, 1147.79, 1091.84, 1053.26, 964.53,

900.87, 736.90 cm²¹; H NMR.CDCl₃): d .ppm) 1.97 .s,

1

3H, CH₃CO), 2.02 .s, 3H, CH₃CO), 2.09 .s, 3H, CH₃CO),

2.18 .s, 3H, CH₃CO), 3.59 .d, 1H, J12.19 Hz, dioxane

1-H), 3.70 .d, 1H, J12.65 Hz, dioxane 1-H), 4.04 .ddd,

1H, J9.90, 5.50, 2.20 Hz, 6-H), 4.12 .dd, 1H, J12.10,

2.20 Hz, 7-H), 4.25 .dd, 1H, J12.10, 5.50 Hz, 7-H), 5.23

.t, 1H, J9.90 Hz, 5-H), 5.38 .dd, 1H, J9.90, 3.30 Hz,

4-H), 5.41 .d, 1H, J3.30 Hz, 3-H); ¹³C NMR.CDCl₃): d

.ppm) 20.34 .CH₃), 20.63 .CH₃), 20.67 .CH₃), 20.70 .CH₃),

60.59 .dioxane 1-C), 62.36 .7-C), 65.74 .5-C), 68.45 .3-C),

69.26 .4-C), 69.92 .6-C), 96.44 .anomeric 2-C), 169.42

.CvO), 169.64 .CvO), 169.71 .CvO), 170.56 .CvO);

HRMS: .FAB) calcd for C₃₀H₄₀O₂₀Na 743.2011, found

743.2006.

3.6.6. 3,4,5,7-Tetra-O-acetyl-a-d-manno-hept-2-ulopyr-

anose 3⁰,4⁰,5⁰,7⁰-tetra-O-acetyl-b-d-manno-hept-2⁰-ulo-

pyranose

1,2⁰:2,1⁰-dianhydride

-8c).

Colorless

amorphous solid; [a]²⁵16.508 .c 1.0, CHCl₃); IR

D

3.6.4. 3,4,5,7-Tetra-O-acetyl-a-d-gluco-hept-2-ulopyr-

3⁰,4⁰,5⁰,7⁰-tetra-O-acetyl-b-d-gluco-hept-2⁰-ulo-

.KBr): 2959.12, 1751.86 .st), 1649.34, 1435.12, 1370.85,

anose

pyranose 1,2⁰:2,1⁰-dianhydride -8a). White solid, mp

1221.18, 1089.88, 1056.02, 978.05, 910.17, 741.21 cm²¹

;

¹H NMR.CDCl₃): d .ppm) 1.95 .s, 3H, CH₃CO), 2.00 .s,

3H, CH₃CO), 2.05 .s, 3H, CH₃CO), 2.07 .s, 3H, CH₃CO),

2.11 .2s, 6H, CH₃CO£2, overlapped), 2.12 .s, 3H, CH₃CO),

2.15 .s, 3H, CH₃CO), 3.60 .d, 1H, J12.09 Hz, dioxane

1-H), 3.74 .d, 1H, J12.09 Hz, dioxane 1-H), 3.89±3.93

.m, 2H, two 6-H), 3.91 .d, 1H, J12.10 Hz, dioxane 1-H,

overlapped with 6-H), 3.92 .d, 1H, J12.10 Hz, dioxane

1-H, overlapped with 6-H), 4.11 .dd, 1H, J12.10,

2.20 Hz, 7-H), 4.25 .dd, J12.10, 2.20 Hz, 7-H), 4.31 .dd,

J12.10, 6.05 Hz, 7-H), 4.36 .dd, J12.10, 6.60 Hz, 7-H),

5.00 .dd, J9.35, 3.30 Hz, 4-H), 5.22 .t, 1H, J8.80 Hz,

5-H), 5.23 .t, 1H, J8.90 Hz, 5-H), 5.24 .d, 1H, J3.30 Hz,

3-H), 5.29 .d, 1H, J3.85 Hz, 3-H), 5.34 .dd, 1H, J9.90,

3.30 Hz, 4-H); ¹³C NMR.CDCl₃): d .ppm) 20.49 .CH₃),

20.55 .CH₃), 20.60 .CH₃), 20.66 .CH₃), 20.68 .two C,

186±186.58C; [a]²⁵146.308 .c 1.0, CHCl₃); IR .KBr):

D

2955.31, 2910.94, 1747.72 .st), 1435.21, 1371.55, 1226.81,

1099.56, 1057.12, 1037.83, 993.46, 920.16, 900.87 cm²¹

;

¹H NMR.CDCl₃): d .ppm) 1.99 .s, 3H, CH₃CO), 2.03 .s,

3H, CH₃CO), 2.04 .s, 3H, CH₃CO), 2.05 .s, 3H, CH₃CO),

2.08 .s, 3H, CH₃CO), 2.09 .s, 3H, CH₃CO), 2.10 .s, 3H,

CH₃CO), 2.11 .s, 3H, CH₃CO), 3.53 .d, 1H, J12.10 Hz,

dioxane 1-H), 3.78 .d, 1H, J11.55 Hz, dioxane 1-H), 3.85

.d, 1H, J12.10 Hz, dioxane 1-H), 3.93 .ddd, 1H, J9.89,

4.39, 2.20 Hz, 6-H), 3.99 .dt, 1H, J11.00, 2.20 Hz, 6-H),

4.07 .d, 1H, J12.10 Hz, dioxane 1-H), 4.15 .dd, 1H,

J12.64, 2.20 Hz, 7-H), 4.20 .dd, 1H, J12.10, 2.20 Hz,

7-H), 4.25 .dd, 1H, J12.10, 4.40 Hz, 7-H), 4.30 .dd, 1H,

J12.65, 2.75 Hz, 7-H), 4.91 .d, 1H, J10.44 Hz, 3-H),

8064

X. Li et al. / Tetrahedron 57 12001) 8053±8066

CH₃), 20.71 .two C, CH₃), 58.59 .dioxane 1-C), 62.55 .7-C),

62.72 .7-C), 62.93 .dioxane 1-C), 65.84 .5-C), 66.45 .5-C),

67.89 .3-C), 69.11 .4-C), 69.15 .4-C), 69.56 .6-C), 69.84 .3-

C), 71.93 .6-C), 93.19 .anomeric 2-C), 93.70 .anomeric 2-

C), 169.51 .CvO), 169.65 .CvO), 169.68 .CvO), 169.78

.CvO), 169.96 .CvO), 170.01 .CvO), 170.68 .CvO),

170.74 .CvO); HRMS: .FAB) calcd for C₃₀H₄₀O₂₀Na

743.2011, found 743.2015.

unweighted and weighted agreement factors. The crystal-

lographic structure is shown in Fig. 1.a).

6b: Crystal data. Colorless block crystal, dimensions

0.35£0.20£0.15 mm, C₁₄H₂₄O₁₂´3H₂O, M438.38, mono-

clinic, space group P2₁, lattice parameters: a7.555.1),

Ê

b14.670.2),

c8.386.1) A,

b92.467.3)8,

V

928.6.2) A , Z2, D_calc1.568 g cm²³

,

F₀₀₀468.00,

Ê ³

m.MoKa)1.43 cm²¹. Data collection. Rigaku RAXIS-

RAPID Imaging Plate diffractometer, graphite mono-

chromated MoKa radiation, T123 K, 2u # 60:18: A total

of 44 images, corresponding to 220.08 oscillation angles,

were collected with teo different goniometer settings.

Exposure time was 0.10 min per degree. The camera radius

was 127.40 mm. Readout was performed in the 0.100 mm

pixel mode. Data were processed by the PROCESS-AUTO

program package. Of the 10730 re¯ections which were

collected, 2813 were unique .R_int0.025). A symmetry-

related absorption corrected using the program ABSCOR²³

was applied which resulted in transmission factors ranging

from 0.87 to 0.98. The data were corrected for Lorentz and

polarization effects. The structure was solved by direct

methods .SIR97)²⁴and expanded using Fourier tech-

niques.²⁵The non-hydrogen atoms were re®ned anisottropi-

cally. Hydrogen atoms were included but not re®ned. The

®nal cycle of full-matrix least-square re®nement was based

on 2813 observed re¯ections ꢀI . 23:00sꢀI; 2u , 60:06

and 262 variable parameters and converged with

unweighted and weighted agreement factors. The crystal-

lographic structure is shown in Fig. 1.b).

3.6.7. a-d-gluco-Hept-2-ulopyranose a-d-gluco-hept-2⁰-

ulopyranose 1,2⁰:2,1⁰-dianhydride -5a). Deacetylation

of 7a. To a solution of 7a .72 mg, 0.5 mmol) in methanol

.3 mL) was added KOH .3.0 mg, 0.05 mmol) at room

temperature, and the mixture was stirred for 1.5 h. After

the completion of the reaction, the mixture was concentrated

in vacuo and the residue was applied on a short silica gel

chromatographic column .AcOEt/i-PrOH/H₂O5:3:1) to

afford the unprotected product 7a .16.9 mg, 88.0%), color-

lessly amorphous solid, [a]²⁵1141.028 .c 0.9, H₂O); ¹H

D

NMR .D₂O): d .ppm): 3.35 .t, 1H, J9.90 Hz, 5-H), 3.38

.d, 1H, J9.90 Hz, 3-H), 3.66±3.70 .m, 4H, 7-H, 4-H,

dioxane 1-H and 6-H, overlapped), 3.81 .d, br, 1H,

J8.89 Hz, 7-H), 3.89 .d, 1H, J12.65 Hz, dioxane 1-H);

¹³C NMR .D₂O): d .ppm): 60.67 .7-C), 63.20 .dioxane

1-C), 69.64 .5-C), 73.45 .6-C), 73.53 .4-C), 75.44 .3-C),

96.56 .anomeric 2-C); HRMS: .FAB) calcd for

C₁₄H₂₄O₁₂Na 407.1166, found 407.1169.

3.7. X-Ray crystallographic measurements of single

crystals of 6a±c at 123 K

6c: Crystal data. Colorless block crystal, dimensions

0.30£0.20£0.10 mm, C₁₄H₂₄O₁₂, M384.34, monoclinic,

The unprotected compounds 5a±c and 6a±c were tried to be

recrystallized from the solution of H₂O/EtOH. It was found

that 5a±c could not crystallize from the solution. Single

crystals of the compounds 6a±c suitable for X-ray analysis

were obtained from the solution.

space group P2₁, lattice parameters: a6.2435.9),

Ê

b8.857.1),

c14.290.2) A,

b93.210.3)8,

V

789.0.2) A , Z2, D_calc1.618 g cm²³

,

F₀₀₀408.00,

Ê ³

m.MoKa)1.43 cm²¹. Data collection. Rigaku RAXIS-

RAPID Imaging Plate diffractometer, graphite mono-

chromated MoKa radiation, T123 K, 2u#60.08. A total

of 40 images, corresponding to 220.08 oscillation angles,

were collected with two different goniometer settings.

Exposure time was 0.20 min per degree. The camera radius

was 127.40 mm. Readout was performed in the 0.100 mm

pixel mode. Data were processed by the PROCESS-AUTO

program package. Of the 8072 re¯ections which were

collected, 4214 were unique .R_int0.031). A symmetry-

related absorption corrected using the program ABSCOR²³

was applied which resulted in transmission factors

ranging from 0.91 to 0.99. The data were corrected for

Lorentz and polarization effects. The structure was solved

by direct methods .SIR97)²⁴and expanded using

Fourier techniques.²⁵The non-hydrogen atoms were re®ned

anisottropically. Hydrogen atoms were included but not

re®ned. The ®nal cycle of full-matrix least-square re®ne-

ment was based on 2434 observed re¯ections ꢀI .

23:00sꢀI; 2u , 60:01 and 236 variable parameters

and converged with unweighted and weighted agreement

factors. The crystallographic structure is shown in

Fig. 1.c).

6a: Crystal data. Colorless platelet crystal, dimensions

0.40£0.10£0.03 mm, C₁₄H₂₄O₁₂´H₂O, M402.34, ortho-

rhomic, space group P2₁2₁2₁, lattice parameters:

Ê

a6.1538.2),

b11.5971.4),

c23.482.1) A,

V

Ê ³

1675.8.1)A , Z4, D_calc1.523 g cm²³

,

F₀₀₀816.00,

m.MoKa)1.35 cm²¹. Data collection. Rigaku RAXIS-

RAPID Imaging Plate diffractometer, graphite mono-

chromated MoKa radiation, T123 K, 2u # 60:08: A total

of 55 images, corresponding to 220.08 oscillation angles,

were collected with two different goniometer settings.

Exposure time was 3.50 min per degree. The camera radius

was 127.40 mm. Readout was performed in the 0.100 mm

pixel mode. Data were processed by the PROCESS-AUTO

program package. Of the 17401 re¯ections which were

collected, 2822 were unique .R_int0.054). A symmetry-

related absorption corrected using the program ABSCOR²³

was applied which resulted in transmission factors ranging

from 0.90 to 1.00. The data were corrected for Lorentz and

polarization effects. The structure was solved by direct

methods .SIR97)²⁴and expanded using Fourier tech-

niques.²⁵The non-hydrogen atoms were re®ned anisottropi-

cally. Hydrogen atoms were included but not re®ned. The

®nal cycle of full-matrix least-square re®nement was based

on 2819 observed re¯ections ꢀI . 23:00sꢀI; 2u , 60:04

and 244 variable parameters and converged with

The crystallographic data of 6a±c have been deposited at

the Cambridge Crystallographic Data Centre as supple-

mentary publication, no. 6a: CCDC-167645, 6b: CCDC-

X. Li et al. / Tetrahedron 57 12001) 8053±8066

8065

Marra, A. Chem. Commun. 1999, 2133±2145. .e) Borbas,

A.; Szabovik, G.; Antal, Z.; Herczegh, P.; Agocs, A.; Liptak,

A. Tetrahedron Lett. 1999, 40, 3639±3642.

167646, and 6c: CCDC-167647. Copies of the data can be

obtained free of charge on application to CCDC, 12 Union

Road, Cambridge CB2 1EZ, UK.

10. Horito, S.; Tada, M.; Hashimoto, H. Chem. Lett. 1991, 117±

120.

11. .a) Defaye, J.; Gadelle, A. Carbohydr. Res. 1985, 136, 53±65.

.b) Defaye, J.; Gadelle, A. Carbohydr. Res. 1986, 152, 89±98.

.c) Bock, K.; Pederson, C.; Defaye, J.; Gadelle, A. Carbohydr.

Res. 1991, 216, 141±148. .d) Benito, J. M.; Gomez-Garcia,

M.; Mellet, C. O.; Fernandez, J. M. G.; Defaye, J. Org. Lett.

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Acknowledgements

We are grateful to Mrs J. Shimode, M. Kitsukawa for spec-

troscopic measurements. Partial ®nancial support for this

research from the Ministry of Education, Science, Sports

and Culture of Japan is gratefully acknowledged. X. L.

thanks the JSPS for the postdoctoral fellowship.

12. For a recent review, see: Manley-Harris, M.; Richards, G. N.

Dihexulose dianhydrides. In Adv. Carbohydr. Chem.

Biochem.; Horton, D., Ed.; Academic: San Diego, 1997;

Vol. 52, pp. 207±266.

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Article Doi

Stereoselective synthesis and structure elucidation of spiro-ketodisaccharides

DOI: 10.1016/S0040-4020(01)00775-X

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Article abstract of DOI:10.1016/S0040-4020(01)00775-X

Full text of DOI:10.1016/S0040-4020(01)00775-X

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