An efficient synthesis of new 1′-C-methyl-α-O-disaccharides using 1-methylenesugars as the glycosyl donors

TETRAHEDRON

Pergamon

Tetrahedron 57 =2001) 4283±4295

An ef®cient synthesis of new 1⁰-C-methyl-a-O-disaccharides

using 1-methylenesugars as the glycosyl donors

Xiaoliu Li, Hiro Ohtake, Hideyo Takahashi and Shiro Ikegami^p

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

Received 8 December 2000; accepted 16 March 2001

AbstractÐA series of new 1⁰-C-methyl-a-disaccharides were ®rstly synthesized by the directly Lewis acid-catalyzed O-glycosidation of

1-methylenesugars used as glycosyl donors. The O-glycosidation afforded stereospeci®cally the corresponding 1⁰-methyl-a-O-glycosides

whose con®gurations were tentatively assigned by the NMR spectra, COSY and the C±H coupling constant ³J_{H22 ,Me21}. The O-glycosidation

of the acetyl protected 1-methylenesugars showed that the acetyl group at the C-2-O position was not effective to control the stereochemistry

of the product by neighboring group participation because of the formation of a tertiary oxycarbenium ion as a stable intermediate. q 2001

0

1. Introduction

of 1⁰-C-methyl-O-disaccharides using 1-methylenesugars

2 as the O-glycosyl donors and partly protected glucosides

3 and 4 as the glycosyl acceptors.

Carbohydrates play profound roles in mediating the cell±

cell recognition, moderating the behavior of enzymes and

other proteins, and ful®lling various functions in the

immune response due to their great deal of information-

carrying potential.¹With the understanding of the inter-

actions between carbohydrates and their receptors, a number

of carbohydrate analogues and mimetics have been success-

fully synthesized.²However, challenges still remain in

carbohydrate research ®eld, such as, designing and synthe-

sizing highly bioactive and low-toxic glycomimetics for the

elucidation of the carbohydrate recognition by biomolecules

in natural system and for the development of potential drug

candidates, and developing new methodology of glycosyl-

ation for the synthesis of complex saccharides.³

2. Results and discussions

The requisite 2,3,4,6-tetra-O-benzyl-1-methylenesugars

2a±c were prepared by the methylenation of their corre-

sponding sugar lactones 1a±c¹³with Tebbe's reagent^4,6,14

=Scheme 1).

The O-glycosidation employing 2,3,4,6-tetra-O-benzyl-1-

methylenesugar 2 as a typical glycosyl donor was illustrated

in Scheme 2. The mixture of 2,3,4,6-tetra-O-benzyl-1-

methylenesugar 2 and a glycosyl acceptor =1.1 equiv.),

1-Methylenesugars have been successfully used as pre-

cursors for C-glycoside syntheses employing by hydro-

boration,⁴hydroboration/Suzuki cross coupling reaction,⁵

radical reaction,⁶iodonium ion promoted reaction,^7±9epox-

idation/ring-opening reaction¹⁰and Lewis acid catalyzed

reaction.¹¹However, their O-glycosidations in which the

1-methylenesugars are used as glycosyl donors have not

been explored extensively.¹²In view of the electron rich

enol ether structure of 1-methylenesugar and its high sensi-

tivity to electrophiles, we turned our attention to develop the

application of 1-methylenesugar to the synthesis of 1⁰-C-

methyl-O-glycosides by the direct O-glycosylation cata-

lyzed by Lewis acid. We now describe a novel synthesis

Keywords: sugar lactones; 1-methylenesugars; 1⁰-C-methyl-a-disacchar-

ides; O-glycosidation; neighboring group participation.

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

p

Scheme 1. Reagents and conditions: =i) Cp₂TiMe₂=2.1 equiv.), toluene,

65±708C, 14 h.

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

PII: S0040-4020=01)00 319-2

4284

X. Li et al. / Tetrahedron 57 *2001) 4283±4295

Scheme 2. Reagents and conditions: =i) TfOH =0.05 equiv.), MS 4A, CH₂Cl₂, Ar, 2788C, 1 h.

Table 1. Glycosidation of 2 with 3 and 4 using TfOH as a catalyst

and general method for synthesizing 1⁰-C-methyl-O-a-

disaccharide compounds.

R¹

R²

R³

R⁴Yield of 5 =%) Yield of 6 =%)

a =Glc)

b =Gal)

c =Man) OBn

H

OBn

OBn OBn

H

OBn

H

OBn

98.1

93.9

90.4

80.1

71.4

75.2

As shown in Table 1, the three 1-methylenesugars 2a, 2b

and 2c exhibited similar glycosidation reactivity as the

glycosyl donors. The O-glycosylations of the glycosyl

acceptor 3 with the methylenesugars 2 afforded the corre-

sponding disaccharides 5 in more than 90% yields, though

the glycosylation of the compound 4 gave the disaccharides

6 in 70±80% yields. The difference in the yield of the glyco-

sylations might be attributed to the different reactivities and

steric requiements between the primary 6-OH in the

compound 3 and the secondary 4-OH in 4.

H

methyl 2,3,4-tri-O-benzyl-glucoside 3¹⁵or methyl 2,3,6-tri-

O-benzyl-glucoside 4,¹⁶were treated with a catalytic

amount =0.05 equiv.) of tri¯ouromethanesulfonic acid

=TfOH) in the presence of molecular sieves 4A =MS 4A)

at 278 to 2208C to afford O-glycosylation products exclu-

1

sively. H NMR indicated the formation of one anomeric

isomer which was determined to be a-con®guration by

Considering that the methylenesugars 2 with enol ether

structure were sensitive to electrophilic reagents,^7±9,11,18it

was necessary to explore an ef®cient Lewis acid catalyst

under the proper conditions for the O-glycosidation of 2.

The conditions for the glycosidation catalyzed by various

3

the C±H coupling constant J_H,Cbetween 2⁰-H and the

carbon of 1⁰-Me.¹⁷According to this procedure, a series of

1⁰-C-methyl-O-disaccharides 5 and 6 were obtained in

71±98% yields, respectively =Table 1), providing a feasible

Table 2. The glycosidation of 2a and 3 using various Lewis acids as a catalyst

Entry

Cat. =equiv.)

Solvent

Temp.

Time

5 =%)

7 =%)

8 =%)

2 recovered

87.7%

1

2

3

4

TsOH =0.1)

TsOPy =0.1)

MsOH =0.1)

MsOH =0.3)

TfOH =0.05)

TfOH =0.2)

TfOH =0.05)

ZrCl₄=0.2)

ZnCl₂=0.2)

ZnCl₂=0.5)

AlCl₃=0.5)

TiCl₄=0.1)

SnCl₄=0.1)

SnCl₄=0.2)

CH₂Cl₂

Et₂O

CH₂Cl₂

Toluene

CH₂Cl₂

Toluene

CH₂Cl₂

r.t.

29 h

5 h

24 h

3 h

5 min

10min

30min

20min

12 h

5.1

1.8

re¯ux

r.t.

no reaction

27.9

61.8

83.04.5

68.4

98.1

93.2

89.8

79.7

66.4

no reaction

30.7

70.4

15.6

3.5

78.1

77.2

58.8

75.1

9.9

10.5

57.5%

14.6

5

08C

2788C

08C

re¯ux

r.t.

re¯ux

r.t.

2.5

6^a

5.0

20.0

7

8

9^a

3.8

6.1

18.8

10

11^a

12

13

14

15

16

17

18

19^a

20SnCl

21

22

8.5

4.3

48 h

10h

6 h

24 h

15.9

8.7

22.2

5.2

4.2

17.1

6.0

47%

4.8

8.4

45%

87.1%

2 h

3.4

5.7

12.1

11.8

15 min

1 h

r.t.

08C

=0.2)

TMSOTf =0.1)

BF₃Et₂O =0.1)

4

78.08.5

76.1

±

10.9

trace

a

Without molecular sieves.

X. Li et al. / Tetrahedron 57 *2001) 4283±4295

4285

Scheme 3. Reagents and conditions: =i) TfOH =0.05 equiv.), MS 4A, CH₂Cl₂, r.t., 3 h; =ii) TfOH =0.25 equiv.), MS 4A, CH₂Cl₂, r.t., 2 h.

decomposed to give the by-product 7. For example, the

compound 7 =,9%) was obtained from the 1⁰-C-methyl-

disaccharide 6a under the treatment with 0.25 equiv. of

TfOH at room temperature for 2 h.

1

The H NMR, ¹³C NMR and 2D-COSY experiments and

mass spectral data of the disaccharides were in full accor-

dance with their structures. Table 3 summarizes the NMR

Figure 1.

spectral data of 1⁰-C-methyl and two anomeric carbons

3

=C-1, C-1⁰), and the C±H coupling constants J_{H22 ,Me21}

0

Lewis acids were examined using 2a and 3 and the results

are summarized in Table 2. It was found that the glyco-

sidation reaction in the presence of weak Lewis acids,

such as ZrCl₄=Entry 12) did not occur even at re¯uxing

temperature in dichloromethane =CH₂Cl₂) for 12 h.

However, when stronger Lewis acids were used, the reac-

tion could proceed more rapidly accompanied with the

increase of the by-products 7 =see Scheme 3) and 8 =Fig.

1). For example, in the presence of a catalytic amount of

strong Lewis acid =TfOH, 0.05 equiv.), the reaction could

®nish within 5 min at 08C in a good yield =83%) =Entry 5),

indicating that TfOH was strong enough for the glyco-

sidation of 2. Under milder conditions at 2788C in the

presence of 0.05 equiv. of TfOH, the reaction afforded the

product 5a in an excellent yield of 98% =Entry 7). Moreover,

the use of molecular sieves was necessary to keep anhydrous

reaction conditions, reducing the formation of the by-

product 8 =Entry 6, 9, 11 and 19).

between 2⁰-H and the carbon of 1⁰-C-methyl in the

compounds 5, 6, 11a and 18. It was shown that the signals

of the anomeric C-1⁰connected with a methyl group

appeared in more down®eld than those of the C-1 linked

with a proton. Moreover, the resonance of C-1⁰in the

compound 5 having a 1,6-O-glycosyl linkage shifted up®eld

in comparison with the corresponding compound 6 having a

1,4-O-glycosyl linkage. Similarly, in both ¹H NMR and ¹³

C

NMR spectra, the chemical shifts of 1⁰-C-methyl group in

the compound 5 were observed in more up®eld than those in

the corresponding compound 6.

The three-bond carbon-proton coupling constants

=³J_H23,C21) which is related to the C₁±C₂±C₃-H dihedral

angle have been applied to the conformational analysis of

It was found that the by-product 7 could result from

the decomposition of both the 1-methylenesugars 2 and

the 1⁰-C-methyldisaccharides 5 and 6 =Scheme 3). The

compound 7 was isolated in 12% yield when the 1-methyl-

enesugars 2 was treated with 0.05 equiv. of TfOH at room

temperature for 3 h. The TLC detection showed that under

strong conditions the 1⁰-C-methyldisaccharides 5 and 6

Figure 2.

3

Table 3. NMR data of 1⁰-CH₃and the two anomeric carbons =C-1 and C-1⁰) and the three bond C±H coupling constants J_{H22 ,Me21}

0

3

C-1⁰=ppm)

C-1=ppm)

0

J_{H22 ,Me21}=Hz)

0

Compounds

CH₃=ppm)

5a

5b

5c

6a

6b

6c

1.25

1.22

1.34

1.29

1.31

1.55

1.25

1.46

20.87

20.97

20.06

21.48

21.65

20.13

20.02

21.21

100.36

100.81

101.21

102.15

102.68

103.19

99.09

97.43

97.71

96.14

96.39

97.35

97.65

97.54

97.75

1.73

1.90

±

1.60

1.56

±

11a

18

1.65

1.96

100.98

4286

X. Li et al. / Tetrahedron 57 *2001) 4283±4295

Scheme 4. Reagents and conditions: =i) TfOH =0.5 equiv.), MS 4A, CH₂Cl₂, 08C, 1 h.

sugar molecules.¹⁷With this method, Hehre et al.¹⁹have

assigned the a- and b-anomeric con®gurations of the methyl

2,3,4,6-tetra-O-acetyl-glucosides A and B =Fig. 2) by

Table 4. The O-glycosidation of the acetyl 1-methylenesugars 9 and 10

Product

R¹

R²

Yield =%)

3

comparing their J_H22,Me21. The carbon-proton coupling

constants J_H22,Me21of the a-anomer A =1.6 Hz) and the

11a =Glc)

11b =Gal)

H

OAc

H

51.2

82.2

3

b-anomer B =2.5 Hz) indicated a synclinal and an antiper-

iplanar arrangements between 2-H and 1-Me, respectively.

Thus, the a-con®gurations of the disaccharides 5a±b and

6a±b were tentatively determined according to the relation-

1

the analyses of H NMR, ¹³C NMR, 2D-COSY and mass

3

spectra. Interestingly, the coupling constant J_{H22 ,Me21}

0

ship of the C±H coupling constants ³J_{H22 ,Me21}and the H±

0

=1.65 Hz) of the compound 11a =Table 3) was similar to

that of the a-anomer A of the model compound =1.6 Hz)

in Fig. 2 and to that of the corresponding benzyl

disaccharide 5a =1.73 Hz) which was tentatively

deduced to be an a-isomer. This result strongly supported

an a-anomeric con®guration in the compound 11a, in

other words, the 2-O-acetyl group of 11a did not show

any neighboring group participation in the glycosylation

reaction.

C₂±C₁±Me dihedral angle.^17,19The ³J_{H22 ,Me21}of 5 and 6

observed as less than 2 Hz showed that the 1⁰-C-methyl and

2⁰-H arranged in synclinal con®guration =Table 3).¹⁹In case

where 5c and 6c were mannoside, the equatorial 2⁰-H might

form similar dihedral angles =,608) with a-1⁰-CH₃and with

b-1⁰-CH₃, and it was dif®cult to assign the anomeric con®g-

uration.¹⁷

0

Generally, the stereoselectivity of O-glycosylation is

strongly dependent on the nature of the protecting groups,

especially an acyl group attached to C-2 of glycosyl donor

exhibits effective.²⁰For example, an acyl group such as

acetyl or benzoyl at C-2-O position usually directs the

formation of 1,2-trans linked O-glycosides due to the neigh-

boring group participation in the reaction. If a non-partici-

pating group such as benzyl or methyl attached at C-2-O,

a-linked O-glycoside is predominantly formed owing to

anomeric effects. In addition, the a-selectivity could be

affected by the nature of solvent, namely, a solvent of low

polarity is bene®t to the a-selectivity. It should be note-

worthy that the change of solvent did not affect the stereo-

selectivity in the glycosidations of 1-methylenesugars

=Entry 7 and 8 in Table 2), although usual O-glycosylation

gave a mixture of two anomers in the case of glycosyl donor

protected by non-participating group in moderate polar

solvent such as Et₂O, THF or 1,4-dioxane.²⁰

Comparing with the glycosidation of the benzyl 1-methyl-

enesugars 2 =in Scheme 2), the O-glycosidations of the

acetyl 1-methylenesugars 9 were carried out under stronger

conditions =TfOH, 0.5 equiv., 08C) =Scheme 4), indicating

that the glycosidation reactivity of the acetyl 1-methylene-

sugars 9 was lower than that of the benzyl ones due to the

electron withdrawing acetyl group. It was also found that

under these strong conditions the O-glycosidation of 9 and

10 was accompanied by the acetyl group migration from 4-

to 6-position in compound 10. The acetyl migration was

testi®ed by treating 10 under the identical conditions as

shown in Scheme 4 in the absence of the compound 9,

and the compound C was obtained =Scheme 5).

In order to further compare the anomeric con®gurations in

the compounds 5 and 6 with that in the compound 11, the

disaccharides 5 and 6 were transformed to their acylated

derivatives by ®rstly debenzylation and then acylation.

The unusual evidence of the stereoselective O-glycosidation

of the benzyl protected 1-methylenesugars prompted us to

extend the reaction to the acetyl protected moiety. The

b-anomers of 1⁰-C-methyl-O-disaccharides, in the cases of

glucose and galactose, might be obtained if the neighboring

group participation were present in the reaction. The

O-glycosidation of 2,3,4,6-tetra-O-acetyl-1-methylenesugar

derivatives 9a±b²¹and methyl 2,3,4-tri-O-acetyl-a-d-

glucoside 10²²were carried out in the presence of

0.5 equiv. of TfOH to form the anomerically single a-disac-

charides 11a±b in moderate yields as shown in Scheme 4

and Table 4.

Compounds 5 and 6 were debenzylated by catalytic hydro-

genation with palladium on charcoal [Pd=OH)₂/C, 20wt%]

as the catalyst =Scheme 6). The catalytic hydrogenation of

the compounds 5a and 5b in methanol furnished the

Scheme 5. Reagents and conditions: =i) TfOH =0.5 equiv.), MS 4A, CH₂Cl₂,

08C, 1 h.

The structures of the disaccharides 11 were con®rmed by

X. Li et al. / Tetrahedron 57 *2001) 4283±4295

4287

Scheme 6. Reagents and conditions: =i) Pd=OH)₂/C =20wt%), solvents, H ₂, r.t.; =ii) Pd=OH)₂/C =20wt%), t-BuOH, H₂, r.t.

compounds 12a and 12b in quantitative yields, respectively

=Entry 1 and 2 in Table 5). However, in the case of 5c, in

addition to the debenzylated product 12c =74.7%), a con-

comitant sugar ring-opened product 13 =22.3%) was formed

in methanol solution =Entry 3 in Table 5). The use of a bulky

and low reactive alcohol as the solvent was found to be

bene®t to the formation of the desired products 12c =Entry

3, 5 and 7 in Table 5). Thus, the debenzylation of 5c

Table 5. The debenzylation of the disaccharides 5a±c and 6a±c by catalytic hydrogenation

Entry

Compd.

Conditions

Product =Yield)

Ring opened product^a=Yield)

1

2

3

4

5

6

7

8

5a

5b

5c

6a

6b

6c

MeOH

EtOH

H₂=1 atm)

H₂=20atm)

H₂=1 atm)

H₂=20atm)

H₂=1 atm)

H₂=20atm)

H₂=1 atm)

12 h

24 h

10h

16 h

10h

48 h

16 h

10h

24 h

12a =,100%)

12b =,100%)

12c =74.7%)

12c =94.2%)

12c =90.7%)

12c =95.6%)

12c =98.5%)

15a =80.1%)

15a =89.2%)

15a =91.4%)

15b =80.5%)

15c =40.0%)

13 =22.3%)

14 =3.6%)

ⁱPrOH

^tBuOH

MeOH

^tBuOH

16 =16.9%)

16 =9.5%)

9

10

11

12

a

The structures of 13, 14 and 16 were determined by the analyses of their NMR spectra and MS =FAB), and were further con®rmed by their acetylated

derivatives whose ¹H NMR spectra showed one CH₃, two OCH₃=in the case of 14, one OCH₃and one OC₂H₅) and eight CH₃CO groups.

4288

X. Li et al. / Tetrahedron 57 *2001) 4283±4295

Scheme 7. Reagents and conditions: =i) Ac₂O, pyridine, r.t., overnight.

Table 6. The acetylation of the disaccharides 12 and 15

linkage seemed more unstable to the catalytic hydrogena-

tion condition than compounds 5. While compound 6a

provided the debenzylated product 15a in the yield of

R¹

R²

Yield =%)

t

11a =Glc)

11b =Gal)

17

H

OAc

±

OAc

H

±

97.4

96.4

75.3

66.3

91.4% in BuOH solution =Entry 10), the compound 6c

gave the corresponding debenzylated product 15c only in

40.0% yield =Entry 12). Moreover, when methanol was used

as the solvent, only in the case of 6a the debenzylated

product 15a was obtained accompanying by the ring-opened

by-product 16 =Entry 8 and 9 in Table 5). The results indi-

cated that 1⁰-C-methyldisaccharides having a ketoside were

less stable than the normal aldosyl disaccharides, probably

due to the steric hindrance caused by the replacement of a

proton with a methyl in the anomeric carbon 1⁰-C. The

18

±

afforded 12c in almost quantitative yield =98.4%) in ^tBuOH

solution =Entry 7 in Table 5). Furthermore, the increase of

the hydrogen pressure with shortening reaction time could

reduce the yield of the ring-opened by-products =Entry 4, 6

and 9 in Table 5). The compounds 6 with a 1,4-O-glycosyl

Scheme 8. Reagents and conditions: =i) BzCl, pyridine, r.t., 24 h; =ii) pNBzCl, pyridine, DMAP, r.t., 24 h, then 508C, 12 h.

X. Li et al. / Tetrahedron 57 *2001) 4283±4295

4289

Scheme 9. PÐprotecting group, HAÐLewis acid.

disaccharides intend to release the strains in the 1⁰-

anomeric carbon by opening the glycosidic sugar ring via

a nucleophilic solvolysis in the presence of the hydro-

genation catalyst.

0.05 equiv. of TfOH at ±788C. With this reaction, a series

of glucose, galactose, and mannose type of 1⁰-C-methyl-a-

disaccharides having 1,6- and 1,4-O-glycosyl linkage were

®rstly prepared, and the neighbouring group participation

was not observed in the O-glycosidation of acetyl protected

1-methylenesugars. The present process would be a facile

method for synthesizing a-ketosyl saccharides. Further

investigation of using 1-methylenesugars as the precursor

for the synthesis of saccharides is under way in our group.

The acetylations of the compounds 12a±b were carried out

by the treatment with acetic anhydride in pyridine to afford

the corresponding acetylated derivatives which were proved

to be identical to the compounds 11a±b by the comparison

1

of their H NMR and ¹³C NMR spectra. Under the same

conditions the compounds 12c and 15 were acetylated to

provide 17 and 18, respectively =Scheme 7 and Table 6).

Similarly, the compound 12a was benzoylated with benzoyl

chloride in pyridine to give the compound 19, and p-nitro-

benzoylated with p-nitrobenzoyl chloride promoted by

N,N-dimethylaminopyridine =DMAP) to afford the deriva-

tive 20 =Scheme 8).

4. Experimental

4.1. General methods

Melting points were measured on a YANACO Micro

Melting Point Apparatus and are uncorrected. IR spectra

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

infrared spectrometer. ¹H NMR, ¹³C NMR and COSY spec-

tra were measured on a JEOL JNM-GSX400 =400 MHz)

pulse Fourier-transform NMR spectrometer in CDCl₃or

CD₃OD solutions using tetramethylsilane =Me₄Si) as an

internal standard, and the three bond coupling constants

³J_C,Hwere measured on a JEOL ECP 600 =600 MHz)

NMR spectrometer in CDCl₃solution with an internal

standard of tetramethylsilane =Me₄Si). Mass spectra =MS)

and high resolution mass spectra =HRMS) were carried out

on a JEOL JMS-SX102A mass spectrometer using FAB

=Fast Atomic Bombardment). Optical rotations were

measured with a Jasco DIP-370digital polarimeter. Thin-

layer chromatography =TLC) was performed on precoated

plates =Merck TLC aluminum sheets silica 60F ₂₅₄) 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).

Considering the a-stereoselective O-glycosidation of the

1-methylenesugar and the results described so far, the

Lewis acid-catalyzed O-glycosidation of the 1-methylene-

sugar may likely proceeded in the following pathway as

shown in Scheme 9.

With this proposed reaction process, it was reasonable to

understand the a-stereoselectivity in the O-glycosidations

of 1-methylenesugars and no neighboring group partici-

pation in the O-glycosidation of the acetyl protected methyl-

enesugar 9. The combination of the 1-methylenesugar =an

electron rich enol ether) with catalytic Lewis acid =HA) led

to the intermediate I, a stable tertiary oxycarbenium ion.

The tertiary oxycarbenium ion would be further stabilized

by the interaction with the counter ion =A²) in the steric

favorable b-approach, resulting in that the oxycarbenium

ion might not need any more stabilization from the neigh-

boring group participation of 2-O-acetyl group in 9. Conse-

quently, the alcohol component =ROH) attacked the

anomeric carbon in the a-stereospeci®c way to form the

a-O-glycosides exclusively. On the other hand, taking into

account the steric hindrance and the anomeric effects caused

by the methyl group in 1⁰-C-methyl-disaccharides,^23±25the

repulsion by dipole±dipole or electron pair±electron pair

interaction caused b-isomer to be disfavored, preferably

forming the thermodynamic stable a-isomer.

4.1.1. General procedure 1: synthesis of the 1⁰-C-methyl-

a-O-disaccharides 5 and 6. A solution of 2 =0.1 mmol), 3

=or 4) =0.11 mmol) and molecular sieves 4A =MS 4A)

=100 mg) in dry CH₂Cl₂=2 mL) was stirred under argon

atmosphere at room temperature for 15 min. The solution

was cooled to 2788C, and 0.5 mL =0.05 equiv.) of TfOH

was added. The reaction mixture was stirred at 2788C for

1 h, then warmed up to 2208C gradually. The reaction was

monitored by TLC =Et₂O: Hexane1:1) and quenched with

one drop of triethylamine =Et₃N). After the removal of the

solvent, the residue was applied on a silica gel column chro-

matography using Et₂O: hexane =1:2, then 1:1.5) as the

eluent to afford the products 5 =or 6). The results are listed

in Table 1.

3. Conclusion

The stereoselective synthesis of 1⁰-C-methyl-a-disacchar-

ides are accessible via the direct O-glycosidation of

1-methylenesugars under the mild conditions of

4290

X. Li et al. / Tetrahedron 57 *2001) 4283±4295

4.1.2. General procedure 2: the exploration of the reac-

tion conditions of synthesizing 1⁰-C-methyl-a-O-disac-

charides using 2a and 3. A mixture of 2a =53.6 mg,

0.1 mmol), 3 =51.1 mg, 0.11 mmol), MS 4A =100 mg) and

the dry solvents =2 mL) was stirred under argon atmosphere

at room temperature for 15 min. The mixture was cooled to

the certain temperature, and a given amount of catalyst was

added in one portion. The reaction mixture was stirred at

same temperature for certain time, and worked up following

the General Procedure 1. The reaction results are summar-

ized in Table 2.

=d, 1H, J11.60Hz, CH ₂Ph), 4.50=d, 1H, J10.99 Hz,

CH₂Ph), 4.52 =d, 1H, J3.05 Hz, 1-H), 4.59±4.84 =m, 8H,

CH₂Ph), 4.92±4.97 =m, 3H, CH₂Ph), 7.21±7.34 =m, 35H,

ArH); ¹³C NMR =CDCl₃): d 20.97 =CH₃), 54.66 =CH₃O),

60.86 =6-C), 68.90 =6⁰-C), 69.76 =5⁰-C), 69.90=5-C),

72.17 =CH₂Ph), 73.01 =CH₂Ph), 73.11 =CH₂Ph), 74.47

=CH₂Ph), 74.81 =3-C), 74.99 =CH₂Ph), 75.07 =CH₂Ph),

75.71 =CH₂Ph), 78.89 =4-C), 79.85 =4⁰-C or 3⁰-C), 80.05

=2-C), 80.24 =2⁰-C), 82.25 =3⁰-C or 4⁰-C), 97.35 =1-C),

100.81 =1⁰-C), 127.29 =Ph), 127.40=Ph), 127.42 =Ph),

127.45 =Ph), 127.50=Ph), 127.53 =Ph), 127.55 =Ph),

127.61 =Ph), 127.71 =Ph), 127.77 =Ph), 127.91 =Ph),

127.93 =Ph), 128.07 =Ph), 128.12 =Ph), 128.32 =Ph),

128.37 =Ph), 128.40=Ph), 138.17 =Ph), 138.21 =Ph),

138.27 =Ph), 138.57 =Ph), 138.63 =Ph), 138.76 =Ph),

138.93 =Ph); HRMS =FAB): cacld for C₆₃H₆₈O₁₁Na

1023.4660, found 1023.4667.

4.1.3. Methyl O-11⁰-C-methyl-2⁰,3⁰,4⁰,6⁰-tetra-O-benzyl-

a-d-glucopyranosyl)-11⁰!6)-2,3,4-tri-O-benzyl-a-d-gluco-

side 15a). Following the General procedure 1, the

compound 5a =98.2 mg, 98.1%) was prepared from

53.6 mg =0.1 mmol) of 2a and 51.1 mg =0.11 mmol) of 3.

23

D

Colorless syrup; [a] 146.98 =c 1.0, CHCl₃); IR =neat):

3063.33, 3030.54, 2928.30, 1604.97, 1587.61, 1496.94,

1454.50, 1359.98, 1209.51, 1072.55, 1028.18, 910.51,

4.1.5. Methyl O-11⁰-C-methyl-2⁰,3⁰,4⁰,6⁰-tetra-O-benzyl-

a-d-mannopyranosyl)-11⁰!6)-2,3,4-tri-O-benzyl-a-d-

glucoside 15c). Following the General procedure 1, the

compound 5c =90.5 mg, 90.4%) was prepared from

53.6 mg =0.1 mmol) of 2b and 51.1 mg =0.11 mmol) of 3.

1

736.90, 698.32 cm²¹; H NMR =CDCl₃): d 1.25 =s, 3H,

CH₃), 3.26 =t, 1H, J9.16 Hz, 4-H), 3.30=d, 1H, J

9.76 Hz, 2⁰-H), 3.35 =s, 3H, CH₃O), 3.36±3.39 =m, 1H,

6-H), 3.48 =dd, 1H, J9.76 Hz, J3.66 Hz, 2-H), 3.56

=dd, 1H, J10.99 Hz, J1.83 Hz, 6⁰-H), 3.58±3.64 =m,

2H, 4⁰-H and 6⁰-H, overlapped), 3.69 =dd, 1H, J9.95 Hz,

J0.8 Hz, 6-H), 3.84±3.88 =m, 1H, 5-H), 3.89±91 =m, 1H,

5⁰-H), 3.97 =t, 1H, J9.46 Hz, 3-H), 4.04 =t, 1H, J9.47 Hz,

3⁰-H), 4.44 =d, 1H, J12.21 Hz, CH₂Ph), 4.50=d, 1H,

J11.29 Hz, CH₂Ph), 4.55±4.59 =m, 3H, 1-H and CH₂Ph,

overlapped), 4.65 =d, 1H, J11.90Hz, CH ₂Ph), 4.66 =d, 1H,

J11.29 Hz, CH₂Ph), 4.73±4.97 =m, 8H, CH₂Ph), 7.12±

7.14 =m, 2H, ArH), 7.24±7.35 =m, 33H, ArH); ¹³C NMR

=CDCl₃): d 20.87 =1⁰-CH₃), 54.98 =OCH₃), 60.77 =6-C),

68.87 =6⁰-C), 69.96 =5⁰-C), 71.13 =5-C), 73.13 =CH₂Ph),

73.16 =CH₂Ph), 74.36 =CH₂Ph), 74.76 =CH₂Ph), 75.13

=CH₂Ph), 75.26 =CH₂Ph), 75.76 =CH₂Ph), 78.57 =4⁰-C),

78.64 =4-C), 80.11 =2-C), 82.37 =3-C), 82.93 =3⁰-C), 84.12

=2⁰-C), 97.43 =1-C), 100.36 =1⁰-C), 127.28 =Ph), 127.30=Ph),

127.43 =Ph), 127.46 =Ph), 127.51 =Ph), 127.55 =Ph), 127.57

=Ph), 127.68 =Ph), 127.77 =Ph), 127.80=Ph), 127.83 =Ph),

127.94 =Ph), 127.95 =Ph), 127.98 =Ph), 128.23 =Ph), 128.09

=Ph), 128.16 =Ph), 128.21 =Ph), 128.22 =Ph), 128.25 =Ph),

128.28 =Ph), 128.31 =Ph), 128.37 =Ph), 138.18 =Ph), 138.28

=Ph), 138.35 =Ph), 138.40=Ph), 138.64 =Ph), 138.72 =Ph),

138.78 =Ph); HRMS =FAB): cacld for C₆₃H₆₈O₁₁Na

1023.4660, found 1023.4669.

23

Colorless syrup; [a]_D143.18 =c 1.0, CHCl₃); IR =neat):

3063.33, 3030.54, 2909.01, 1604.97, 1587.61, 1496.94,

1454.50, 1365.77, 1208.70, 1095.70, 910.50, 734.97,

1

698.32 cm²¹; H NMR =CDCl₃): d 1.34 =s, 3H, CH₃), 3.29

=s, 3H, OCH₃), 3.29 =t, 1H, J9.46 Hz, 4-H), 3.48 =d, 1H,

J9.77 Hz, 6-H), 3.49 =dd, 1H, J9.77 Hz, J2.74 Hz, 2-

H), 3.56 =dd, J10.29 Hz, J2.13 Hz, 6⁰-H), 3.61 =dd, 1H,

J10.99 Hz, J4.88 Hz, 6⁰-H), 3.65 =dd, 1H, J10.37 Hz,

J1.53 Hz, 6-H), 3.66±3.75 =m, 2H, 5-H and 5⁰-H, over-

lapped with 2⁰-H), 3.71 =d, 1H, J2.75 Hz, 2⁰-H, over-

lapped with 5-H and 5⁰-H), 3.92 =t, 1H, J9.77 Hz, 4⁰-H),

3.97 =t, 1H, J9.16 Hz, 3-H), 4.08 =dd, 1H, J9.15 Hz,

J2.75 Hz, 3⁰-H), 4.60=d, 1H, J3.67 Hz, 1-H), 4.40±

5.00 =m, 14 H, CH₂Ph), 7.12±7.38 =m, 35H, ArH); ¹³C

NMR =CDCl₃):d 20.06 =CH₃), 54.87 =CH₃O), 59.99 =6-C),

69.35 =6⁰-C), 69.73 =5-C), 72.03 =CH₂Ph), 72.79 =5⁰-C),

72.98 =CH₂Ph), 73.08 =CH₂Ph), 74.56 =3-C), 74.67 =2C,

CH₂Ph), 74.77 =CH₂Ph), 75.70=CH ₂Ph), 78.04 =4-C),

78.25 =2⁰-C), 79.93 =2-C), 80.92 =3⁰-C), 82.35 =4⁰-C),

97.54 =1-C), 101.21 =1⁰-C), 127.20=Ph), 127.36 =Ph),

127.47 =Ph), 127.49 =Ph), 127.51 =Ph), 127.56 =Ph), 127.59

=Ph), 127.60=Ph), 127.82 =Ph), 127.88 =Ph), 127.94 =Ph),

127.95 =Ph), 128.06 =Ph), 128.11 =Ph), 128.29 =Ph), 128.33

=Ph), 128.40=Ph), 138.12 =Ph), 138.21 =Ph), 138.50=Ph),

138.66 =Ph), 138.71 =Ph), 138.85 =Ph); HRMS =FAB): cacld

for C₆₃H₆₈O₁₁Na 1023.4660, found 1023.4683.

4.1.4. Methyl O-11⁰-C-methyl-2⁰,3⁰,4,⁰6⁰-tetra-O-benzyl-

a-d-galactopyranosyl)-11⁰!6)-2,3,4-tri-O-benzyl-a-d-

glucoside 15b). Following the General procedure 1, the

compound 5b =94.0mg, 93.9%) was prepared from

53.6 mg =0.1 mmol) of 2b and 51.1 mg =0.11 mmol) of 3.

4.1.6. Methyl O-11⁰-C-methyl-2⁰,3⁰,4⁰,6⁰-tetra-O-benzyl-

a-d-glucopyranosyl)-11⁰!4)-2,3,6-tri-O-benzyl-a-d-

glucoside 16a). Following the General procedure 1, the

compound 6a =80.2 mg, 80.1%) was prepared from

53.6 mg =0.1 mmol) of 2a and 51.1 mg =0.11 mmol) of 4.

23

Colorless syrup; [a]_D151.38 =c 1.0, CHCl₃); IR =neat):

3063.33, 3030.54, 2918.65, 1604.97, 1585.68, 1496.94,

1454.50, 1361.91, 1209.45, 1053.26, 912.44, 734.97,

23

Colorless syrup; [a]_D118.28 =c 1.0, CHCl₃); IR =neat):

1

698.32 cm²¹; H NMR =CDCl₃):d 1.22 =s, 3H, CH₃), 3.19

3063.33, 3030.54, 2903.22, 1604.97, 1587.61, 1496.94,

1454.50, 1361.91,1207.59, 1049.40, 912.44, 734.97,

=s, 3H, CH₃O), 3.21 =t, 1H, J9.46 Hz, 4-H), 3.33 =dd, 1H,

J10.38 Hz, J8.24 Hz, 6-H), 3.43±3.55 =m, 3H, 2-H and

two 6⁰-H, overlapped), 3.69 =dd, 1H, J10.37 Hz, J

1.52 Hz, 6-H), 3.81±3.85 =m, 1H, 5-H), 3.83 =d, 1H, J

10.07 Hz, 2⁰-H), 3.93±4.01 =m, 4H, 3-H, 3⁰-H, 4⁰-H and

5⁰-H, overlapped), 4.37 =d, 1H, J12.21 Hz, CH₂Ph), 4.43

1

698.32 cm²¹; H NMR =CDCl₃): d 1.29 =s, 3H, CH₃), 3.22

=d, 1H, J9.76 Hz, 2⁰-H), 3.37 =s, 3H, CH₃O), 3.47 =dd, 1H,

J9.77 Hz, J3.66 Hz, 2-H), 3.51 =dd, 1H, J10.68 Hz,

J1.83 Hz, 6-H), 3.61 =t, 1H, J9.16 Hz, 4⁰-H), 3.63±

3.67 =m, 3H, 5-H, 6-H and 6⁰-H, overlapped with 4⁰-H),

X. Li et al. / Tetrahedron 57 *2001) 4283±4295

4291

1

3.84 =t, 1H, J9.76 Hz, 3-H), 3.83±3.87 =m, 2H, 5⁰-H and

6⁰-H, overlapped with 3-H), 4.02 =t, 1H, J9.46 Hz, 4-H),

4.16 =t, 1H, J9.46 Hz, 3⁰-H), 4.36±4.55 =m, 8H, CH₂Ph),

4.57 =d, 1H, J3.35 Hz, 1-H), 4.64 =d, 1H, J12.20Hz,

CH₂Ph), 4.76±4.92 =m, 4H, CH₂Ph), 5.18 =d, 1H, J

11.60Hz, CH ₂Ph), 7.02±7.31 =m, 35H, ArH); ¹³C NMR

=CDCl₃): d 21.48 =CH₃), 55.31 =CH₃O), 68.96 =6-C), 69.42

=6⁰-C), 70.79 =5-C), 71.32 =5⁰-C), 73.13 =CH₂Ph), 73.15

=CH₂Ph), 73.24 =4-C), 73.42 =CH₂Ph), 74.91 =CH₂Ph),

75.21 =CH₂Ph), 75.33 =CH₂Ph), 75.40=CH ₂Ph), 78.88

=4⁰-C), 79.46 =2-C), 81.20=3-C), 82.64 =3 ⁰-C), 83.51

=2⁰-C), 97.71 =1-C), 102.15 =1⁰-C), 126.62 =Ph), 126.82

=Ph), 127.28 =Ph), 127.40=Ph), 127.54 =Ph), 127.57 =Ph),

127.64 =Ph), 127.78 =Ph), 127.82 =Ph), 127.87 =Ph), 127.94

=Ph), 127.98 =Ph), 128.02 =Ph), 128.05 =Ph), 128.07 =Ph),

128.13 =Ph), 128.17 =Ph), 128.22 =Ph), 128.28 =Ph), 128.33

=Ph), 128.37 =Ph), 128.43 =Ph), 129.05 =Ph), 137.88 =Ph),

138.06 =Ph), 138.14 =Ph), 138.40 =Ph), 138.46 =Ph), 138.66

=Ph), 140.23 =Ph); HRMS =FAB): cacld for C₆₃H₆₈O₁₁Na

1023.4660, found 1023.4673.

734.97 cm²¹; H NMR =CDCl₃): d 1.55 =s, 3H, CH₃), 3.38

=s, 3H, CH₃O), 3.51 =d, 1H, J2.74 Hz, 2⁰-H), 3.54 =dd, 1H,

J9.46 Hz, J3.05 Hz, 2-H), 3.61±3.71 =m, 4H, 5-H, one

6-H and two 6⁰-H), 3.71 =t, 1H, J9.15 Hz, 3-H, overlapped

with 6⁰-H), 3.84±3.94 =m, 3H, 6-H, 4⁰-H and 5⁰-H, over-

lapped), 4.10=d, 1H, J11.29 Hz, CH₂Ph), 4.15 =t, 1H,

J9.15 Hz, 4-H, overlapped with 3⁰-H), 4.17 =dd, 1H,

J8.85 Hz, J2.44 Hz, 3⁰-H, overlapped with 4-H), 4.33

=d, 1H, J11.90Hz, CH ₂Ph), 4.45±4.63 =m, 9H, CH₂Ph),

2.62 =d, 1H, J3.05 Hz, 1-H, overlapped with CH₂Ph), 4.70

=d, 1H, J11.91 Hz, CH₂Ph), 4.85 =d, 1H, J10.38 Hz,

CH₂Ph), 5.12 =d, 1H, J11.60Hz, CH ₂Ph), 7.17±7.33 =m,

35H, ArH); ¹³C NMR =CDCl₃): d 20.13 =CH₃), 55.16

=OCH₃), 68.67 =6-C), 69.86 =6⁰-C), 70.34 =5-C), 71.97

=4-C), 72.06 =CH₂Ph), 72.76 =5⁰-C), 73.06 =CH₂Ph), 73.13

=CH₂Ph), 73.26 =CH₂Ph), 74.75 =CH₂Ph), 74.94 =4⁰-C),

75.18 =CH₂Ph), 75.56 =CH₂Ph), 79.92 =2-C or 2⁰-C), 79.97

=2⁰-C or 2-C), 81.09 =3⁰-C), 81.74 =3-C), 97.74 =1-C), 103.19

=1⁰-C), 126.52 =Ph), 127.12 =Ph), 127.26 =Ph), 127.31 =Ph),

127.35 =Ph), 127.45 =Ph), 127.53 =Ph), 127.60=Ph), 127.69

=Ph), 127.79 =Ph), 127.85 =Ph), 128.02 =Ph), 128.08 =Ph),

128.11 =Ph), 128.17 =Ph), 128.20=Ph), 128.32 =Ph),

128.37 =Ph), 138.02 =Ph), 138.33 =Ph), 138.39 =Ph),

138.45 =Ph), 138.52 =Ph), 138.91 =Ph), 139.20=Ph);

HRMS =FAB): cacld for C₆₃H₆₈O₁₁Na 1023.4660, found

1023.4659.

4.1.7. Methyl O-11⁰-C-methyl-2⁰,3⁰,4⁰,6⁰-tetra-O-benzyl-

a-d-galactopyranosyl)-11⁰!4)-2,3,6-tri-O-benzyl-a-d-

glucoside 16b). Following the General procedure 1, the

compound 6b =71.5 mg, 71.4%) was prepared from

53.6 mg =0.1 mmol) of 2b and 51.1 mg =0.11 mmol) of 4.

23

Colorless syrup; [a]_D124.38 =c 1.0, CHCl₃); IR =neat):

3063.33, 3030.54,2912.87, 1604.97, 1585.68, 1496.94,

1454.50, 1361.91, 1194.08, 1145.55, 916.30, 733.04,

4.1.9. Decomposition of 2,3,4,6-tetra-O-benzyl-1-methyl-

enesugar 12a) in the presence of TfOH. To the solution of

2a =54 mg, 0.1 mmol) and MS 4A =100 mg) in 2 mL of dry

CH₂Cl₂was added 0.5 mL =0.05 equiv.) of TfOH at room

temperature. The solution was stirred for 3 h and then one

drop of Et₃N was added to neutralize the acid. The mixture

was concentrated and the residue was applied to a silica gel

column chromatography =Et₂O: Hexane1:2) to give the

compound 7 =8.0mg, 12.0%).

1

696.39 cm²¹; H NMR =CDCl₃): d 1.31 =s, 3H, CH₃), 3.37

=s, 3H, OCH₃), 3.39 =dd, 1H, J8.85 Hz, J5.49 Hz, 6⁰-H),

3.48 =dd, 1H, J6.71 Hz, J3.36 Hz, 2-H), 3.54 =d, 1H,

J8.24 Hz, 6⁰-H), 3.57±3.64 =m, 2H, 6-H and 5-H), 3.77±

3.85 =m, 3H, 3-H, 2⁰-H and 6-H), 3.97±4.00 =m, 2H, 4⁰-H

and 5⁰-H), 4.04 =t, 1H, J8.85 Hz, 4-H), 4.09 =dd, 1H,

J10.38 Hz, J1.83 Hz, 3⁰-H), 4.36±4.75 =m, 12H,

CH₂Ph, overlapped with 1-H), 4.57 =d, 1H, J2.75 Hz,

1-H, overlapped with CH₂Ph), 4.94 =d, 1H, J11.29 Hz,

CH₂Ph), 5.17 =d, 1H, J11.29 Hz, CH₂Ph), 7.05±7.36 =m,

35H, ArH); ¹³C NMR =CDCl₃): d 21.65 =CH₃), 55.28

4.1.10. Decomposition of 6a by TfOH. To a solution of 6a

=100 mg, 0.1 mmol) and MS 4A =100 mg) in 2 mL of dry

CH₂Cl₂was added 2.3 mL =0.25 equiv.) of TfOH at room

temperature. The solution was stirred for 2 h, neutralized by

Et₃N and concentrated in vacuum. The residue was

submitted to a silica gel column chromatography eluting

with Et₂O: Hexane =1:2, then 1:1) to afford the compounds

7 =5.8 mg, 9.0%) and 4 =4.5 mg, 8.4%).

0

=OCH₃), 68.90=6 -C), 69.39 =6-C), 69.87 =5⁰-C), 70.86

=5-C), 72.30=CH Ph), 72.65 =4-C), 73.08 =CH₂Ph), 73.18

2

=CH₂Ph), 73.41 =CH₂Ph), 74.58 =CH₂Ph), 74.68 =CH₂Ph),

75.14 =two C, 4⁰-C and CH₂Ph), 79.39 =2⁰-C), 79.48 =two

C, 2-C and 3⁰-C), 81.17 =3-C), 97.65 =1-C), 102.68 =1⁰-C),

126.56 =Ph), 126.74 =Ph), 126.78 =Ph), 127.24 =Ph), 127.31

=Ph), 127.39 =Ph), 127.48 =Ph), 127.50=Ph), 127.54 =Ph),

127.59 =Ph), 127.67 =Ph), 127.76 =Ph), 127.81 =Ph), 127.85

=Ph), 127.89 =Ph), 127.95 =Ph), 127.99 =Ph), 128.03 =Ph),

128.07 =Ph), 128.10 =Ph), 128.21 =Ph), 128.29 =Ph), 128.36

=Ph), 128.46 =Ph), 129.23 =Ph), 137.84 =Ph), 138.03 =Ph),

138.30=Ph), 138.36 =Ph), 138.63 =Ph), 138.90=Ph), 140.20

=Ph); HRMS =FAB): cacld for C₆₃H₆₈O₁₁Na 1023.4660,

found 1023.4666.

4.1.11. Compound 7 1benzyl 2,3,4,6-tetra-O-benzyl-1-C-

methyl-a-d-glucoside). Colorless syrup; [a]_D134.208 =c

1.0, CHCl₃); IR =neat): 3063.33, 3030.54, 2921.10,

2870.58,, 1604.35, 1585.68, 1496.94, 1454.50, 1363.84,

1090.80, 1048.39, 973.44, 736.60 cm²¹

;

¹H NMR

=CDCl₃): d 1.39 =s, 3H, CH₃), 3.39 =d, 1H, J9.36 Hz, 2-

H), 3.61±3.76 =m, 4H, two 6-H, 5-H and 3-H or 4-H), 4.13

=t, 1H, J9.31 Hz, 4-H or 3-H), 4.50±6.62 =m, 5H, CH₂Ph),

4.72 =d, 1H, J11.60Hz, CH ₂Ph), 4.81±4.97 =m, 4H,

CH₂Ph), 7.13±7.16 =m, 2H, ArH), 7.22±7.37 =m, 23H,

ArH); ¹³C NMR =CDCl₃): d 21.32 =CH₃), 62.59 =6-C),

68.84 =5-C), 71.71 =CH₂Ph), 73.37 =CH₂Ph), 74.95

=CH₂Ph), 75.35 =CH₂Ph), 75.45 =CH₂Ph), 78.77 =4-C),

83.09 =3-C), 84.41 =2-C), 100.89 =1-C), 127.15 =Ph),

127.17 =Ph), 127.49 =Ph), 127.56 =Ph), 127.64 =Ph),

127.76 =Ph), 127.91 =Ph), 128.19 =Ph), 128.24 =Ph),

128.28 =Ph), 128.32 =Ph), 128.34 =Ph), 128.36 =Ph),

4.1.8. Methyl O-11⁰-C-methyl-2⁰,3⁰,4⁰,6⁰-tetra-O-benzyl-

a-d-mannopyranosyl)-11⁰!4)-2,3,6-tri-O-benzyl-a-d-

glucoside 16c). Following the General procedure 1, the

compound 6c =75.3 mg, 75.2%) was prepared from

53.6 mg =0.1 mmol) of 2c and 51.1 mg =0.11 mmol) of 4.

23

Colorless syrup; [a]_D114.18 =c 1.0, CHCl₃); IR =neat):

3063.33, 3030.54, 2907.08, 2866.57, 1604.97, 1585.68,

1496.94, 1454.50, 1363.84, 1096.10, 1051.33, 912.44,

4292

X. Li et al. / Tetrahedron 57 *2001) 4283±4295

138.27 =Ph), 138.44 =Ph), 138.63 =Ph), 138.83 =Ph); HRMS

=FAB) calcd for C₄₂H₄₄O₆Na 667.3036, found: 667.3041.

=1-C), 99.09 =1⁰-C), 169.42 =CO), 169.77 =two C, CO),

169.81 =CO), 169.96 =CO), 170.07 =CO),170.54

=CO); HRMS =FAB): cacld for C₂₈H₄₀O₁₈Na: 687.2113,

found 687.2121.

4.1.12. Compound 8 12,3,4,6-tetra-O-benzyl-1-C-methyl-

a-d-glucose). White solid, mp: 92±938C; [a]_D124.708 =c

1.0, CHCl₃); IR =KBr): 3464.57, 3063.33, 3030.54, 2932.16,

2903.22, 2868.50, 1603.04, 1585.68, 1496.94, 1454.50,

1404.35, 1363.84, 1199.87, 1153.57, 1086.06, 1043.62,

1028.18, 976.10, 871.93, 850.71, 760.05, 738.83,

4.1.15. Methyl O-11⁰-C-methyl-2⁰,3⁰,4⁰,6⁰-tetra-O-acetyl-

a-d-galactopyranosyl)-11⁰!6)-2,3,4-tri-O-acetyl-a-d-

glucoside 111b). 34 mg =0.1 mmol) of 9b and 48 mg

=0.15 mmol) of 10 were treated as described in the General

procedure 3 to afford 54.6 mg of the disaccharide 11b

1

698.32 cm²¹; H NMR =CDCl₃): d 1.39 =s, 3H, CH₃), 2.86

25

=s, 1H, OH), 3.35 =d, 1H, J9.46 Hz, 2-H), 3.64 =t, 1H,

J9.77 Hz, 4-H), 3.64±3.66 =d, 1H, 6-H, overlapped with

4-H), 3.70=dd, 1H, J10.68 Hz, J4.27 Hz, 6-H), 3.98 =t,

1H, J9.15 Hz, 3-H), 3.99±4.05 =m, 1H, 5-H), 4.50 =d, 1H,

J12.21 Hz, CH₂Ph), 4.55 =d, 1H, J10.99 Hz, CH₂Ph),

4.59 =d, 1H, J12.21 Hz, CH₂Ph), 4.69 =d, 1H, J

10.99 Hz, CH₂Ph), 4.82 =d, 1H, J10.98 Hz, CH₂Ph), 4.88

=s, 2H, CH₂Ph), 4.92 =d, 1H, J11.29 Hz, CH₂Ph), 7.14±

7.16 =m, 2H, ArH), 7.24±7.33 =m, 18H, ArH); ¹³C NMR

=CDCl₃): d 26.57 =CH₃), 68.83 =6-C), 71.53 =5-C), 73.41

=CH₂Ph), 74.82 =CH₂Ph), 75.56 =CH₂Ph), 75.66 =CH₂Ph),

78.45 =4-C), 83.19 =3-C), 83.62 =2-C), 97.35 =1-C), 127.57

=Ph), 127.63 =Ph), 127.72 =Ph), 127.80=Ph), 127.82 =Ph),

127.89 =Ph), 127.95 =Ph), 128.27 =Ph), 128.32 =Ph), 128.33

=Ph), 128.40=Ph), 137.88 =Ph), 138.22 =Ph), 138.26 =Ph),

138.65 =Ph); HRMS =FAB) calcd for C₃₅H₃₈O₆Na 577.2566,

found: 577.2564.

=82.2%). Colorlessly sticky syrup; [a]_D1140.698 =c

1.0, CHCl₃); IR =neat): 2949.52, 1749.65, 1437.14,

1373.48, 1226.88, 1055.19, 958.74, 902.80 cm²¹

;

¹H

NMR =CDCl₃): d 1.35 =s, 3H, CH₃), 1.94 =s, 3H, CH₃CO),

2.01 =s, 3H, CH₃CO), 2.05 =s, 3H, CH₃CO), 2.07 =s, 3H,

CH₃CO), 2.09 =s, 3H, CH₃CO), 2.10=s, 3H, CH CO), 2.15

3

=s, 3H, CH₃CO), 3.43 =dd, 1H, J9.07 Hz, J2.14 Hz,

6-H), 3.48 =s, 3H, CH₃O), 3.55 =dd, 1H, J10.07 Hz,

J8.54 Hz, 6-H), 3.98 =dd, 1H, J11.29 Hz, 7.02 Hz,

6⁰-H) 4.05 =ddd, 1H, J10.38 Hz, J8.24 Hz, J2.14 Hz,

5-H), 4.19 =dd, 1H, J11.29 Hz, J5.49 Hz, 6⁰-H), 4.41

=ddd, 1H, J7.02 Hz, J5.49 Hz, 1.53 Hz, 5⁰-H), 4.85

=dd, 1H, J6.11 Hz, J2.75 Hz, 4-H), 4.88 =dd, 1H, J

6.11 Hz, J2.44 Hz, 3⁰-H), 4.93 =d, 1H, J3.66 Hz, 1-H),

5.25 =d, 1H, J10.68 Hz, 2⁰-H), 5.33 =dd, 1H, J 10.68 Hz,

J3.36 Hz, 2-H), 5.42 =dd, 1H, J3.36 Hz, J1.53 Hz,

4⁰-H), 5.49 =t, 1H, J9.77 Hz, 3-H); ¹³C NMR =CDCl₃): d

20.37 =1⁰-CH₃), 20.52 =CH₃), 20.58 =CH₃), 20.61 =CH₃),

20.65 =two C, CH₃), 20.70 =CH₃), 20.77 =CH₃), 55.30

=CH₃O), 60.79 =6-C), 62.14 =6⁰-C), 67.46 =5-C), 67.98

=5⁰-C), 68.41 =3-C), 68.51 =3⁰-C), 69.81 =4-C), 70.06

=4-C), 70.79 =2-C), 70.85 =2⁰-C), 96.27 =1-C), 99.68

=1⁰-C), 169.80=C O), 169.86 =CO), 169.96 =CO),

170.07 =CO), 170.15 =CO), 170.26 =CO), 170.39

=CO); HRMS =FAB): cacld for C₂₈H₄₀O₁₈Na: 687.2113,

found 687.2118.

4.1.13. General procedure 3: synthesis of the 1⁰-C-meth-

yl-a-O-disaccharides 11. A mixture of 9 =0.1 mmol), 10

=0.15 mmol), MS 4A =100 mg) and dry CH₂Cl₂=2 mL)

was stirred under argon atmosphere at room temperature

for 15 min. The mixture was cooled to 08C, and 4.5 mL

=0.5 equiv.) of TfOH was added. The reaction mixture

was stirred at 08C for 1 h. The reaction was monitored

by TLC =AcOEt: Hexane2:1) and quenched with tri-

ethylamine. After removing the solvent, the residue was

applied on a silica gel column chromatography using

AcOEt: hexane =1:1, then 1.5:1) as the eluent to afford the

products 11.

4.1.16. General procedure 4: debenzylation of the 1⁰-C-

methyl-a-O-disaccharides 5 and 6. A mixture of the disac-

charides 5 or 6 =1.0mmol), Pd=OH) ₂/C =200 mg) and alco-

hol =20mL) was stirred vigorously under H ₂atmosphere at

room temperature. The reaction was monitored by TLC

detection =CH₂Cl₂: CH₃OH9:1). After the reaction

completed the catalyst was removed by ®ltration and the

solvent was evaporated in vacuum, the residue was

submitted to a silica gel column chromatography using

CH₂Cl₂: MeOH =2:1) as the eluent to give the debenzylated

product 12 or 15, respectively. The results are shown in

Table 5.

4.1.14. Methyl O-11⁰-C-methyl-2⁰,3⁰,4⁰,6⁰-tetra-O-acetyl-

a-d-glucopyranosyl)-11⁰!6)-2,3,4-tri-O-acetyl-a-d-gluco-

side 111a). 34 mg =0.1 mmol) of 9a and 48 mg =0.15 mmol)

of 10 were treated as described in the General procedure 3

to afford 34 mg of the disaccharide 11a =51.2%). Colorlessly

25

sticky syrup; [a]_D1118.678 =c 1.67, CHCl₃); IR =neat):

2950.66, 1748.35, 1437.14, 1373.48, 1220.65, 1135.82,

1

1052.96, 958.74, 900.89 cm²¹; H NMR =CDCl₃): d 1.25

=s, 3H, CH₃), 1.89 =s, 3H, CH₃CO), 1.93 =s, 3H, CH₃CO),

1.95 =s, 3H, CH₃CO), 1.99 =s, 3H, CH₃CO), 2.01 =s, 3H,

CH₃CO), 2.02 =s, 3H, CH₃CO), 2.04 =s, 3H, CH₃CO),

3.33±3.38 =m, 1H, 6-H), 3.40±3.50 =m, 1H, 6-H), 3.44 =s,

3H, OCH₃), 3.99±4.02 =m, 1H, 5-H), 4.04±4.07 =m, 2H, two

6⁰-H), 4.17±4.22 =m, 1H, 5⁰-H), 4.77 =dd, 1H, J11.88 Hz,

J4.86 Hz, 2-H), 4.78 =t, 1H, J10.38 Hz, 4-H), 4.88 =d,

1H, J3.66 Hz, 1-H), 4.91 =d, 1H, J10.37 Hz, 2⁰-H), 4.97

=t, 1H, J10.07 Hz, 4⁰-H), 5.39 =t, 1H, J9.77 Hz, 3⁰-H),

5.43 =t, 1H, J10.07 Hz, 3-H); ¹³C NMR =CDCl₃): d 20.02

=1⁰-CH₃), 20.46 =CH₃), 20.51 =CH₃), 20.57 =two C, CH₃),

20.59 =CH₃), 20.66 =CH₃), 55.31 =OCH₃), 60.83 =6-C), 62.15

=6⁰-C), 67.92 =5-C), 68.35 =5⁰-C), 68.75 =4⁰-C), 69.75 =4-C),

69.94 =3-C), 70.75 =3⁰-C), 70.87 =2-C), 73.38 =2⁰-C), 96.14

4.1.17. Methyl O-11⁰-C-methyl-a-d-glucopyranosyl)-

11⁰!6)-a-d-glucoside 112a). 1⁰-C-methyl-a-disaccharide

5a =1.0g, 1.0mmol) was debenzylated in the solution of

methanol as described in the General Grocedure 4 to

give 12a =369 mg, 99.7%). Colorlessly glassy solid;

23

1

[a]_D1126.198 =c 1.57, CH₃OH); H NMR =CD₃OD): d

1.34 =s, 3H, CH₃), 3.05 =d, 1H, J9.53 Hz, 2⁰-H), 3.22±3.23

=m, 2H, two 6-H), 3.31±3.33 =m, 1H, 6⁰-H), 3.34 =s, 3H,

CH₃O), 3.50±3.71 =m, 8H, 6⁰-H, 5-H, 5⁰-H, 4-H, 4⁰-H, 3⁰-H,

3-H, 2⁰-H and 2-H), 4.59 =d, 1H, J4.03 Hz, 1-H); ¹³C

NMR =CD₃OD): d 21.08 =1⁰-CH₃), 55.80=CH O), 61.42

3

=6-C), 62.71 =6⁰-C), 71.89, 71.99, 72.16, 73.49, 74.02,

75.38, 75.62, 78.44 =2-C), 101.18 =1-C), 101.44 =1⁰-C)

X. Li et al. / Tetrahedron 57 *2001) 4283±4295

4293

=the other sugar carbons could not be determined); HRMS

=FAB): cacld for C₁₄H₂₆O₁₁Na 393.1373, found 393.1354.

=2 mL) as described in the General Procedure 4 to give

22

15b =14.9 mg, 80.5%). Colorlessly glassy solid; [a]_D

1

1172.78 =c 0.8, CH₃OH); H NMR =CD₃OD): d 1.57 =s,

3H, CH₃), 3.40=s, 3H, CH ₃O), 3.46 =dd, br, 1H, J

9.34 Hz, J3.85 Hz, 5-H), 3.51±3.54 =m, 1H, 5⁰-H), 3.60

=d, 1H, J9.89 Hz, 2⁰-H), 3.68 =dd, br, 2H, J6.05 Hz,

4.1.18. Methyl O-11⁰-C-methyl-a-d-galactopyranosyl)-

11⁰!6)-a-d-glucoside 112b). 1⁰-C-methyl-a-disaccharide

5b =300 mg, 0.3 mmol) was debenzylated in methanol as

0

described in the General Procedure 4 to give 12b

J2.20Hz, two 6 -H), 3.75±3.77 =m, 2H, 4-H and 3-H),

23

=111 mg, 100%). Colorlessly glassy solid; [a]_D

3.78 =dd, 1H, J6.05 Hz, J3.85 Hz, 2-H), 3.81±3.82 =m,

1

0

1145.598 =c 1.0, CHCl₃); H NMR =CD₃OD): d 1.44 =s,

3H, CH₃), 3.10±3.26 =m, 1H, 6-H), 3.41 =s, 3H, CH₃O),

3.41±3.44 =m, 1H, 6-H overlapped with CH₃O), 3.54 =d,

1H, J9.89 Hz, 2⁰-H), 3.61 =t, 1H, J9.16 Hz, 4-H),

3.66±3.74 =m, 5H, two 6⁰-H, 5-H, 5⁰-H and 3-H), 3.78

=dd, 1H, J9.90Hz, J3.29 Hz, 2-H), 3.91 =dd, 1H, J

2H, two 6-H), 3.88 =dd, 1H, J3.30Hz, J1.10Hz, 4 -H),

0

3.97 =dd, 1H, J6.05 Hz, J1.10Hz, 3 -H), 4.66 =d, 1H,

13

J3.85 Hz, 1-H); C NMR =CD₃OD): d 22.32 =1⁰-CH₃),

55.60=CH ₃O), 61.81 =6-C), 62.82 =6⁰-C), 71.15 =5-C),

71.98 =5⁰-C), 72.74, 73.00, 73.06, 74.21, 74.95, 76.01,

101.20 =1-C), 103.23 =1⁰-C) =the other sugar carbons could

not be determined); HRMS =FAB): cacld for C₁₄H₂₆O₁₁Na

393.1373, found 393.1367.

0

3.30Hz, J1.10Hz, 4 -H), 3.96 =td, 1H, J6.59 Hz, J

1.10Hz, 3 -H), 4.69 =d, 1H, J3.66 Hz, 1-H); ¹³C NMR

0

=CD₃OD): d 21.05 =1⁰-CH₃), 55.67 =CH₃O), 61.51 =6-C),

62.65 =6⁰-C), 71.20=5-C), 72.90 =5 ⁰-C), 72.23, 72.27,

72.65, 73.52, 75.17, 75.33, 101.24 =1-C), 101.77 =1⁰-C)

=the other sugar carbons could not be determined); HRMS

=FAB): cacld for C₁₄H₂₆O₁₁Na 393.1373, found 393.1382.

4.1.22. Methyl O-11⁰-C-methyl-a-d-mannopyranosyl)-

11⁰!4)-a-d-glucoside 115c). 1⁰-C-methyl-a-disaccharide

6c =50 mg, 0.05 mmol) was debenzylated in t-BuOH

=2 mL) as described in the General Procedure 4 to give

22

15c =7.4 mg, 40.0%). Colorlessly glassy solid; [a]_D

1

4.1.19. Methyl O-11⁰-C-methyl-a-d-mannopyranosyl)-

11⁰!6)-a-d-glucoside 112c). 1⁰-C-methyl-a-disaccharide

5c =100 mg, 0.1 mmol) was debenzylated in t-BuOH

=4 mL) as described in the General Procedure 4 to give

12c =36.4 mg, 98.4%). Colorlessly glassy solid;

1132.58 =c 0.4, CH₃OH); H NMR =CD₃OD): d 1.40=s,

3H, CH₃), 3.25±3.28 =m, 1H, 6⁰-H), 3.38 =dd, 1H, J

9.90Hz, J3.85 Hz, 6⁰-H), 3.40=s, 3H, CH O), 3.57 =t,

3

1H, J9.35 Hz, 4-H or 3-H), 3.59 =t, 1H, J9.35 Hz, 3-H

or 4-H), 3.61±3.72 =m, 5H, 2⁰-H, 5⁰-H, 5-H, 2-H and 4⁰-H),

25

1

0

[a]_D1102.798 =c 0.5, CH₃OH); H NMR =CD₃OD):

3.76±3.80=m, 2H, 3 -H and 6-H), 3.88 =dd, 1H, J9.35 Hz,

d 1.40=s, 3H, CH ), 3.26±3.29 =m, 1H, 6⁰-H), 3.39 =dd,

J3.30Hz, 6-H), 4.65 =d, 1H, J3.85 Hz, 1-H); ¹³C NMR

=CD₃OD): d 20.03 =1⁰-CH₃), 55.54 =CH₃O), 61.25 =6-C),

62.97 =6⁰-C), 68.08 =5⁰-C), 72.02 =5-C), 72.06, 72.99,

73.53, 74.79, 74.91, 75.39, 101.07 =1-C), 102.32 =1⁰-C)

=the other sugar carbons could not be determined);

HRMS =FAB): cacld for C₁₄H₂₆O₁₁Na 393.1373, found

393.1361.

3

1H, J9.35 Hz, J3.85 Hz, 6⁰-H), 3.41 =s, 3H, CH₃O),

3.57±3.72 =m, 7H, two 6-H, 2⁰-H, 5-H, 5⁰-H, 3-H and

4-H), 3.77 =dd, 1H, J4.40Hz, J2.96 Hz, 3⁰-H), 3.79±

3.80=m, 1H,

4

⁰-H), 3.88 =dd, 1H, J9.16 Hz,

J3.66 Hz, 2-H), 4.65 =d, 1H, J3.66 Hz, 1-H); ¹³C

NMR =CD₃OD): d 20.08 =1⁰-CH₃), 55.59 =CH₃O),

61.27 =6-C), 63.00 =6⁰-C), 68.12 =5-C), 72.03, 72.09,

73.03, 73.56, 74.81, 74.92, 75.43 =2-C), 101.11 =1-C),

102.36 =1⁰-C) =the other sugar carbons could not be

determined); HRMS =FAB): cacld for C₁₄H₂₆O₁₁Na

393.1373, found 393.1387.

4.1.23. General procedure 5: acetylation of the methyl O-

11⁰-C-methyl-a-d-glucopyranosyl)-11⁰!6)-a-d-glucoside

112a). 65 mg =0.17 mmol) of 12a was dissolved in 2.0mL of

dry pyridine and 1.2 mL of acetic anhydride. The solution

was stirred under the argon atmosphere at room temperature

overnight, then poured into 100 g ice-water. The mixture

was extracted with AcOEt =50mL £2). The organic phase

was washed with water =30mL £5), and dried over Na₂SO₄.

After removing the solvent the residue was applied on a

silica gel column chromatography eluting with AcOEt:

Hexane =1:1) to afford the acetylated product =110mg,

4.1.20. Methyl O-11⁰-C-methyl-a-d-glucopyranosyl)-

11⁰!4)-a-d-glucoside 115a). 1⁰-C-methyl-a-disaccharide

6a =50 mg, 0.05 mmol) was debenzylated in t-BuOH

=2 mL) as described in the General Procedure 4 to give

22

15a =16.9 mg, 91.4%). Colorlessly glassy solid; [a]_D

1141.28 =c 1.0, CH₃OH); H NMR =CD₃OD): d 1.38 =s,

1

25

3H, CH₃), 3.14 =d, 1H, J9.16 Hz, 2⁰-H), 3.27 =dd, 1H,

97.4%). Colorlessly sticky syrup; [a]_D119.028 =c 1.0,

0

J8.80Hz, J1.10Hz, 6 -H), 3.38±3.42 =m, 2H, 4-H and

CHCl₃); its NMR spectra were identical to those of the

compound 11a.

6⁰-H), 3.40=s, 3H, CH ₃O), 3.52 =ddd, 1H, J9.89 Hz,

J5.86 Hz, J2.57 Hz, 5-H), 3.59±3.69 =m, 5H, 5⁰-H,

2-H, 3-H, 3⁰-H and 4⁰-H), 3.81 =dd, 2H, J12.72 Hz,

J2.57 Hz, two 6-H), 4.67 =d, 1H, J3.67 Hz, 1-H); ¹³C

NMR =CD₃OD): d 22.38 =1⁰-CH₃), 55.66 =CH₃O), 61.86

=6-C), 62.99 =6⁰-C), 71.78 =5-C), 72.77 =5⁰-C), 73.05,

74.44, 74.53, 75.01, 75.54, 79.23 =2-C), 101.23 =1-C),

102.92 =1⁰-C) =the other sugar carbons could not be deter-

mined); HRMS =FAB): cacld for C₁₄H₂₆O₁₁Na 393.1373,

found 393.1370.

4.1.24. Acetylation of the methyl O-11⁰-C-methyl-a-d-

galactopyranosyl)-11⁰!6)-a-d-glucoside 112b). 12b

=37 mg, 0.10 mmol) was acetylated following the General

Procedure 5 to give 11b =64 mg, 96.4%). Colorlessly sticky

25

syrup; [a]_D1140.338 =c 1.0, CHCl₃).

4.1.25. Acetylation of the methyl O-11⁰-C-methyl-a-d-

mannopyranosyl)-11⁰!6)-a-d-glucoside

112c).

12c

=17 mg, 0.05 mmol) was acetylated following the General

Procedure 5 to give the compound 17 =methyl O-=1⁰-C-

methyl-2⁰,3⁰,4⁰,6⁰-tetra-O-acetyl-a-d-mannopyranosyl)-

=1⁰!6)-2,3,4-tri-O-acetyl-a-d-glucoside) =25 mg, 75.3%).

4.1.21. Methyl O-11⁰-C-methyl-a-d-galactopyranosyl)-

11⁰!4)-a-d-glucoside 115b). 1⁰-C-methyl-a-disaccharide

6b =50 mg, 0.05 mmol) was debenzylated in t-BuOH

4294

X. Li et al. / Tetrahedron 57 *2001) 4283±4295

25

Colorlessly sticky syrup; [a]_D1102.558 =c 1.49, CHCl₃);

rated NaHCO₃=20mL), successively, and dried over

Na₂SO₄. After removing the solvent the residue was applied

on a silica gel column chromatography using AcOEt:

Hexane =1:2) as the eluent to afford 73.0mg of the product

IR =neat): 2951.45, 1747.72, 1437.14, 1373.48, 1219.16,

1167.08, 1126.57, 1051.33, 958.74, 931.73, 900.87 cm²¹

;

¹H NMR =CDCl₃):d 1.29 =s, 3H, CH₃), 1.95 =s, 3H,

COCH₃), 2.01 =s, 3H, CH₃CO), 2.03 =s, 3H, CH₃CO), 2.06

=s, 3H, CH₃CO), 2.09 =s, 3H, CH₃CO), 2.11 =s, 3H, CH₃CO),

2.17 =s, 3H, CH₃CO), 3.46 =dd, 1H, J10.07 Hz, J

2.13 Hz, 6-H), 3.45 =s, 3H, CH₃O), 3.56 =dd, 1H, J

9.76 Hz, J8.23 Hz, 6-H), 4.02 =ddd, 1H, J10.07 Hz,

J8.24 Hz, J1.83 Hz, 5-H), 4.15±4.19 =m, 3H, 5⁰-H and

two 6⁰-H), 4.84 =dd, 1H, J10.07 Hz, J3.66 Hz, 4-H),

4.87 =d, 1H, J10.07 Hz, 2-H), 4.95 =d, 1H, J3.67 Hz,

1-H), 5.14±5.19 =m, 1H, 4⁰-H), 5.21 =d, 1H, J3.36 Hz.,

2⁰-H), 5.43 =dd, 1H, J10.07 Hz, J3.35 Hz, 3⁰-H), 5.50

=dd, 1H, J10.07 Hz, J9.46 Hz, 3-H); ¹³C NMR =CDCl₃):

d 19.16 =1⁰-CH₃), 20.58 =CH₃), 20.60 =CH₃), 20.63 =CH₃),

20.68 =two C, CH₃), 20.74 =CH₃), 20.77 =CH₃), 55.34

=OCH₃), 60.66 =6-C), 62.85 =6⁰-C), 65.87 =4⁰-H), 68.00

=5-C), 69.42 =5⁰-C), 69.67 =2-C), 69.72 =3-C), 70.01 =3⁰-C),

24

19 =yield 66.4%). White solid, mp. 1088C; [a]_D155.88

=c 1.0, CHCl₃); IR =KBr): 3067.19, 3034.40, 2963.02,

1732.29, 1603.04, 1452.57, 1315.61, 1273.17, 1178.65,

1095.70, 1068.69, 1026.25, 976.10, 709.89 cm²¹

;

¹H

NMR =CDCl₃): d 1.46 =s, 3H, CH₃), 3.61 =dd, 1H, J

10.38 Hz, J1.22 Hz, 6-H), 3.74 =s, 3H, CH₃O), 3.85 =t,

1H, J8.85 Hz, 6-H), 4.34 =dd, 1H, J12.21 Hz, J

6.71 Hz, 6⁰-H), 4.41 =t, br, 1H, J8.85 Hz, 5-H), 4.76 =dd,

1H, J11.90Hz, J1.83 Hz, 6⁰-H), 4.79±4.84 =m, 1H,

5⁰-H), 5.00 =dd, 1H, J10.37 Hz, J3.67 Hz, 2-H), 5.13

=t, 1H, J9.77 Hz, 4-H), 5.27 =d, 1H, J3.67 Hz, 1-H),

5.49 =d, 1H, J10.07 Hz, 2⁰-H), 5.59 =t, 1H, J9.77 Hz,

4⁰-H), 6.14 =t, 1H, J9.77 Hz, 3-H), 6.20=t, 1H, J

9.76 Hz, 3⁰-H), 7.21±7.63 =m, 21H, ArH), 7.75±8.20=m,

13

14H, ArH); C NMR =CDCl₃):d 20.56 =1⁰-CH₃), 55.67

0

70.96 =4-C), 71.35 =2⁰-C), 96.20=1-C), 99.72 =1 -C), 169.83

=CH₃O), 60.76 =6-C), 63.33 =6⁰-C), 68.67 =5-C), 69.15

=5⁰-C), 69.88, 70.04, 70.48, 71.22, 71.98, 74.47 =2-C),

96.65 =1-C), 99.60=1 ⁰-C), 128.16 =Ph), 128.45 =Ph),

128.32 =Ph), 128.39 =Ph), 128.42 =Ph), 128.62 =Ph), 128.74

=Ph), 129.07 =Ph), 129.08 =Ph), 129.15 =Ph), 129.21 =Ph),

129.52 =Ph), 129.58 =Ph), 129.72 =Ph), 128.86 =Ph), 129.89

=Ph), 129.93 =Ph), 130.11 =Ph), 132.93 =Ph), 133.03 =Ph),

133.07 =Ph), 133.30 =Ph), 133.46 =Ph), 165.47 =CO),

165.50=C O), 165.65 =CO), 165.68 =CO), 165.80

=CO), 165.82 =CO), 166.11 =CO) =the other sugar

carbons could not be determined); HRMS =FAB): cacld

for C₆₃H₅₄O₁₈Na: 1121.3208, found 1121.3207.

=CO), 169.86 =two C, CO), 169.93 =CO), 169.98

=CO), 170.20 =CO), 170.64 =CO); HRMS =FAB):

cacld for C₂₈H₄₀O₁₈Na: 687.2113, found 687.2110.

4.1.26. Methyl O-11⁰-C-methyl-2⁰,3⁰,4⁰,6⁰-tetra-O-acetyl-

a-d-glucopyranosyl)-11⁰!4)-2,3,6-tri-O-acetyl-a-d-gluco-

side 118). 1⁰-C-methyl-a-disaccharide 15 =17 mg, 0.05

mmol) was acetylated following the General Procedure 5

to give 18 =22 mg, 66.3%). Colorlessly sticky syrup;

23

[a]_D187.988 =c 2.03, CHCl₃); IR =neat): 2963.02,

1749.65, 1435.21, 1371.55, 1226.88, 1126.57, 1037.83,

1

985.74, 906.65, 736.90 cm²¹; H NMR =CDCl₃): d 1.46

=s, 3H, CH₃), 1.96 =s, 3H, CH₃CO), 2.02 =s, 3H, CH₃CO),

2.03 =s, 3H, CH₃CO), 2.05 =s, 3H, CH₃CO), 2.08 =s, 3H,

CH₃CO), 2.09 =s, 3H, CH₃CO), 2.12 =s, 3H, CH₃CO), 3.45

=s, 3H, CH₃O), 3.90±3.94 =m, 1H, 5-H), 4.02 =t, 1H,

J10.07 Hz, 4-H), 4.03 =dd, 1H, J12.21Hz, J2.14 Hz,

6⁰-H), 4.10±4.14 =m, 1H, 5 ⁰-H), 4.24 =dd, 1H, J12.21 Hz.

J2.14 Hz, 6⁰-H), 4.25 =dd, 1H, J11.91 Hz, J1.83 Hz,

6-H), 4.55 =dd, 1H, J11.91 Hz, J1.83 Hz, 6-H), 4.84 =s,

1H, 1-H), 4.85 =dd, 1H, J12.20Hz, J3.67 Hz, 2-H), 4.97

=d, 1H, J10.37 Hz, 2⁰-H), 5.06 =t, 1H, J9.77 Hz, 4⁰-H),

5.38 =t, 1H, J9.77 Hz, 3⁰-H), 5.48 =t, 1H, J8.24 Hz, 3-H);

¹³C NMR =CDCl₃): d 20.53 =CH₃), 20.59 =CH₃), 20.61

=CH₃), 20.65 =CH₃), 20.74 =CH₃), 20.79 =CH₃), 21.16

=1⁰-CH₃), 21. 22 =CH₃), 55.54 =OCH₃), 62.09 =6⁰-C), 63.15

=6-C), 68.75 =two C, 5-C and 5⁰-C), 68.85 =4⁰-C), 70.60

=3⁰-C), 70.97 =2-C), 71.25 =4-C), 71.68 =3-C), 74.28

=2⁰-C), 96.39 =1-C), 100.98 =1⁰-C), 168.92 =CO), 169.46

=CO), 169.75 =CO), 170.10 =CO), 170.40 =two C,

CO), 170.57 =CO); HRMS =FAB): cacld for

C₂₈H₄₀O₁₈Na: 687.2113, found 687.2125.

4.1.28. Methyl O-11⁰-C-methyl-2⁰,3⁰,4⁰,6⁰-tetra-O-1p-

nitrobenzoyl)-a-d-glucopyranosyl)-11⁰!6)-2,3,4-tri-O-

1p-nitrobenzoyl)-a-d-glucoside 120). To the solution of

37 mg =0.1 mmol) of 12a and 1.2 mg =0.01 mmol) of

4-dimethylaminopyridine =DMAP) in 1.5 mL of dry pyri-

dine a solution of 390mg =2.1 mmol) of 4-nitrobenzoyl

chloride in 0.5 mL of CH₂Cl₂was added at 08C with stirring

under the argon atmosphere. The resulting solution was

stirred at room temperature for 20h, then heated at 50 8C

for 12 h. To the solution 0.2 mL of water, then 30 mL of

CH₂Cl₂were added. The mixture was washed with water

=30mL £3), saturated NaHCO₃=30mL) and water =30mL),

successively. The organic solution was dried over Na₂SO₄

and concentrated under reduced pressure, the residue was

applied on a silica gel column chromatography =AcOEt:

Hexane1:1.5) to afford 114.3 mg of the product 20

24

=yield 80.8%). Pale yellow solid, mp. 185±1868C; [a]_D

148.408 =c 1.0, CHCl₃); IR =KBr): 3065.26, 3034.40,

2966.88, 2910.94, 1718.78, 1601.11, 1583.75, 1452.57,

1385.06, 1367.70, 1315.61, 1273.17, 1176.71, 1095.70,

989.60, 707.96 cm²¹; H NMR =CDCl₃): d 1.56 =s, 3H,

1

4.1.27. Methyl O-11⁰-C-methyl-2⁰,3⁰,4⁰,6⁰-tetra-O-benz-

oyl-a-d-glucopyranosyl)-11⁰!6)-2,3,4-tri-O-benzoyl-a-

d-glucoside 119). 120 mL =1.0mmol) of Benzoyl chloride

was added to a solution of 37 mg =0.1 mmol) of 12a in

1.0mL of dry pyridine at 0 8C with stirring under the

argon atmosphere. The solution was stirred at room

temperature for 24 h. To the solution one drop of water

was added to quench the reaction, then 20mL of CH ₂Cl₂

were added. The mixture was washed with water

=20mL £2), 3N H₂SO₄=20mL), water =20mL £2) and satu-

CH₃), 3.65 =dd, 1H, J10.07 Hz, J1.22 Hz, 6-H), 3.75

=s, 3H, CH₃O), 3.80=dd, 1H, J10.38 Hz, J2.24 Hz,

6-H), 4.37±4.42 =m, 1H, 6⁰-H), 4.44 =t, br, 1H, J

8.55 Hz, 5-H), 4.78±4.85 =m, 2H, 5⁰-H and 6⁰-H), 5.00

=dd, 1H, J10.07 Hz, J3.66 Hz, 2-H), 5.12 =t, 1H, J

9.47 Hz, 4-H), 5.25 =d, 1H, J3.36 Hz, 1-H), 5.55 =d, 1H,

J10.07 Hz, 2⁰-H), 5.60=t, 1H, J10.77 Hz, 4⁰-H), 6.14 =t,

1H, J10.76 Hz, 3-H), 6.17 =t, 1H, J10.08 Hz, 3⁰-H), 7.95

=d, 2H, J8.85 Hz, ArH), 8.08±8.29 =m, 24H, ArH), 8.37

=d, 1H, J8.85 Hz, ArH), 8.45 =d, 1H, J8.85 Hz, ArH);

X. Li et al. / Tetrahedron 57 *2001) 4283±4295

4295

¹³C NMR =CDCl₃): d20.56 =1⁰-CH₃), 55.88 =CH₃O), 60.54

=6-C), 63.71 =6⁰-C), 68.12 =5-C), 69.03 =5⁰-C), 70.33 =two

C), 71.13, 71.95, 72.05, 74.69 =2-C), 96.53 =1-C), 99.63

=1⁰-C), 123.71 =Ph), 123.74 =Ph), 123.78 =Ph), 123.80

=Ph), 123.83 =Ph), 123.93 =Ph), 124.00 =Ph), 130.67 =Ph),

130.71 =Ph), 130.78 =Ph), 130.95 =Ph), 130.98 =Ph), 131.04

=Ph), 131.09 =Ph), 133.26 =Ph), 133.44 =Ph), 133.48 =Ph),

133.71 =Ph), 133.87 =Ph), 150.88 =Ph), 150.94 =Ph), 150.96

=Ph), 150.97 =Ph), 151.03 =Ph), 151.07 =Ph), 163.50 =CO),

163.62 =CO), 163.74 =CO), 163.76 =CO), 163.85

=CO), 164.05 =CO), 164.28 =CO) =the other sugar

carbons could not be determined); HRMS =FAB): cacld

for C₆₃H₅₄O₁₈Na: 1121.3208, found 1121.3211.

7. Haudrechy, A.; Sinay, P. Carbohydr. Res. 1991, 216, 375±

379.

8. Noort, D.; Veenemann, G. H.; Boons, G. J. P. H.; van der

Marel, G. A.; Mulder, G. J.; van Boom, J. H. Synlett 1990,

205±206.

9. Witczak, Z. J.; Chhabra, R.; ChoJnacki, J. Tetrahedron Lett.

1991, 38, 2215±2218.

10. Lay, L.; Nicotra, F.; Panza, L.; Russo, G. Synlett 1995, 167±

168.

11. Lay, L.; Nicotra, F.; Panza, L.; Russo, G.; Caneva, E. J. Org.

Chem. 1992, 57, 1304±1306.

12. To the best of our knowledge, there were only two papers on

the O-glycosylations using 1-methylenesugar as the glycosyl

donor. =a) the reaction promoted by iodonium ion, see: Ref. 8.

=b) enzymatic reaction, see: Schlesselmann, P.; Fritz, H.;

Lehmann, J.; Uchiyama, T.; Brewer, C. F.; Hehre, E. J.

Biochemistry 1982, 21, 6606±6614.

Acknowledgements

13. Prepared from the corresponding 2,3,4,6-tetra-O-benzylhexo-

pyranose by the oxidation with acetic anhydride and DMSO.

see: Kuzuhara, H.; Fletcher Jr., H. G. J. Org. Chem. 1967, 32,

2531±2534.

We are grateful to Misses J. Shimode and M. Kitsukawa

for the spectroscopic measurements. Partial ®nancial

support for this research from the Ministry of Education,

Science, Sports and Culture of Japan is gratefully

acknowledged. L. X. L. is indebted to the JSPS for a post-

doctoral fellowship.

14. Csuk, R.; Glanzer, R. I. Tetrahedron 1991, 47, 1655±1664.

15. Liptak, A.; Jodal, I.; Nanasi, P. Carbohydr. Res. 1975, 44,

1±11.

16. Compound 4 was prepared by the modi®ed method of

Garegg's. see: Garegg, P.; Hultberg, H. Carbohydr. Res.

1981, 93, C10±C11.

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Article Doi

An efficient synthesis of new 1′-C-methyl-α-O-disaccharides using 1-methylenesugars as the glycosyl donors

DOI: 10.1016/S0040-4020(01)00319-2

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