Differential O-3/O-4 regioselectivity in the glycosylation of α and β anomers of 6-O-substituted N-dimethylmaleoyl-protected d-glucosamine acceptors

Available online at www.sciencedirect.com

Carbohydrate Research 342 (2007) 2522–2536

Diﬀerential O-3/O-4 regioselectivity in the glycosylation of a and

b anomers of 6-O-substituted N-dimethylmaleoyl-protected

D-glucosamine acceptors

a

b

´

Marıa L. Bohn, Marıa I. Colombo, Pablo L. Pisano, Carlos A. Stortz and

Edmundo A. Ru´veda^a,*

^aInstituto de Quı´mica Orga´nica y de Sı´ntesis (CONICET-UNR), Facultad de Ciencias Bioquı´micas y Farmace´uticas,

Suipacha 531, 2000 Rosario, Argentina

^bDepartamento de Quı´mica Orga´nica-CIHIDECAR, Facultad de Ciencias Exactas y Naturales, UBA,

Ciudad Universitaria, Pab. 2, 1428, Buenos Aires, Argentina

Received 19 June 2007; received in revised form 15 August 2007; accepted 16 August 2007

Available online 23 August 2007

Abstract—An assessment of the relative O-3/O-4 reactivities of both methyl a- and b-D-glycosides of N-dimethylmaleoyl (DMM) D-

glucosamine acceptors protected at O-6 with benzoyl (Bz), benzyl (Bn), and tert-butyldiphenylsilyl (TBDPS) groups is presented

using per-O-benzoylated b-^D-galactofuranosyl and per-O-acetylated a-D-galactopyranosyl trichloroacetimidates as glycosyl donors.

Using the former donor, the a anomer of the 6-O-benzoylated compound gave exclusive substitution at O-3, whereas the other two

compounds with a-conﬁguration kept this site as preferential. The b anomer of the 6-O-benzoylated compound gave the same

amounts of reaction products on O-3 and O-4, whereas the other b analogs carried a more reactive O-4. The same reactions were

carried out using as donor the less-reactive per-O-acetylated a-^D-galactopyranosyl trichloroacetimidate. Although the same trend

was found to occur, the O-4 was always relatively more reactive with the pyranosyl donor than with the furanosyl donor, when

keeping the remaining factors constant. Furthermore, the b anomers of the acceptor gave almost exclusive substitution at O-4. These

observations conﬁrm and extend the utility of these ‘matching’ donor and acceptor reactivities.

Keywords: Glucosamine acceptors; N-Dimethylmaleoyl group; Galactofuranosyl donor; Galactopyranosyl donor; Regioselectivity

1. Introduction

tempted showing that mixtures of 1!3- and 1!4-linked

disaccharides were actually obtained in most of the re-

ported cases. For instance, they showed that b-^D-galac-

tosylation of the glycosyl acceptors 1a and 1b with the

disarmed^ꢀglycosyl donor 2a gave exclusively the 1!4

disaccharides 3a and 3b in excellent yield.

In clear contrast, a-^L-fucosylation of 1b with the

armed donor 4a, under the same reaction conditions

gave, in good yield, a 3.6:1 mixture of 1!3 and 1!4

disaccharides 5a and 6a. As occurred with donor 2a,

the disarmed donor 4b reacted with 1b with total

The literature has provided many examples of selective

glycosylation at O-4 of b-^D-glucosamine derivatives hav-

ing only the O-3 and O-4 positions free. This reaction

suggested a higher reactivity for O-4, and this strategy

was sometimes employed to introduce a second glycosyl

donor on the less-reactive O-3 position. In 1998, Ellervik

and Magnusson published a critical analysis¹of previ-

ous publications where regioselective galactosylation of

6-O,N-protected glucosamine derivatives had been at-

^ꢀFor the principle of armed–disarmed glycosyl donor, see the review

by Fraser-Reid et al.²

*

Corresponding author. Tel./fax: +54 341 4370477; e-mail: ruveda@

iquios.gov.ar

doi:10.1016/j.carres.2007.08.006

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

2523

OR³

AcO

OR

OBn

AcO

OBn

O

R¹

O

X

HO

AcO

OAc

R²

Y

1a, R¹= O(CH₂)₂SiMe₃; R²= NPhth

1b, R¹= OC₆H₄OMe; R²= NTCP

1c, R¹= SPh; R²= NTCP

3a, R¹= O(CH₂)₂SiMe₃; R²= NPhth; R³= Bn

3b, R¹= OC₆H₄OMe; R²= NTCP; R³= Bn

3c, R¹= SPh; R²= NTCP; R³= Ac

2a, R = Bn; X = SPh; Y = H

2b, R = Ac; X = H; Y = OC(NH)CCl₃

2c, R = Ac; X = OMe; Y = H

1d, R¹= OTDS; R²= NTCP

3d, R¹= OTDS; R²= NTCP; R³= Ac

TDS = thexyldimethylsilyl; TCP = tetrachlorophtaloyl

R⁵O

OR⁴

OBn

O

OMe

OR³

OBn

O

R¹

HO

X

OBn

O

Y

O

R²

OR¹

R¹

OR³

O

OAc

HO

OR²

HO

OR⁴

NTCP

R³O

R²

OAc

R⁵O

5a, R¹= OC₆H₄OMe; R²= NTCP;

R³= R⁴= R⁵= Bn

6a, R¹= OC₆H₄OMe; R²= NTCP;

4a, X = H; Y = SPh;

R¹= R²= R³= Bn

4b, X = H; Y = SPh;

R¹= R²= R³= Ac

4c, X = OC(NH)CCl₃; Y = H;

R¹= Bn; R²= R³= Ac

7

R

³= R⁴= R⁵= Bn

6b, R¹= OC₆H₄OMe; R²= NTCP;

³= R⁴= R⁵= Ac

6c, R¹= SPh; R²= NTCP;

³= Bn; R⁴= R⁵= Ac

6d, R¹= OTDS; R²= NTCP;

³= Bn; R⁴= R⁵= Ac

5b, R¹= OC₆H₄OMe; R²= NTCP;

R³= R⁴= R⁵= Ac

R

5c, R¹= SPh; R²= NTCP;

R³= Bn; R⁴= R⁵= Ac

R

5d, R¹= OTDS; R²= NTCP;

³= Bn; R⁴= R⁵= Ac

R

OTBDPS

O

regioselectivity giving a mixture of 1!4 disaccharides 7

and 6b (the b/a stereoselectivity was 2:1).

HO

X

RN

H

On the basis of these observations, Ellervik and Mag-

nusson developed an eﬃcient sequential double-glyco-

sylation procedure (ﬁrst at O-4 and then at O-3) for

the synthesis of Le^xtrisaccharide and sLe^xtetrasaccha-

ride that avoids (at least in part) protecting group

manipulations. Simultaneously, Schmidt and co-work-

ers developed a similar approach for the synthesis of

Le^x, and Le^abuilding blocks and the Le^xpentasaccha-

ride.³They also found that, by b-D-galactosylation of

acceptors 1c and 1d with the disarmed donor 2b, the

1!4 disaccharides 3c and 3d were exclusively obtained

in excellent yield. In addition, a-^L-fucosylation of accep-

tors 1c and 1d with the armed donor 4c again gave mix-

tures of disaccharides 5c and 6c, and 5d and 6d,

respectively, in which the 1!3-linked disaccharides 5c

and 5d were (as observed by Ellervik and Magnusson)

the major products. Interestingly, the diﬀerent regiose-

lectivities in b-^D-galactosylation versus a-L-fucosylation

of acceptors 1a, 1b, 1c, and 1d are examples of ‘match–

mismatch’ regioselectivity.^ꢁ

Y

8a, R = Ac; X = OAll; Y = H

8b, R = Troc; X = H; Y = OAll

As further examples of ‘match–mismatch’ regioselec-

tivity, it is remarkable that the b-^D-glucosamine accep-

tor 8a, carrying the bulky tert-butyldiphenylsilyl

(TBDPS) group at O-6, was glycosylated at O-4 with to-

tal regioselectivity when coupled with the disarmed do-

nor 2b.^5cHowever, when the a-D-glucosamine diol

derivative 8b was glycosylated with 2b or 4c in a per-

chloric acid–silica promoted coupling, O-3 reacted

exclusively, independently of the nature (armed or dis-

armed) of the glycosyl donor.^5p

In a view that the regioselective glycosylation at O-4

or O-3 constitutes an eﬃcient and convenient strategy

for the synthesis of biologically important compounds

derived from ^D-glucosamine, we decided, as a continua-

tion of our study on the reactivity of N-protected glu-

cosaminyl acceptors,⁶to systematically examine the

inﬂuence of the conﬁguration of the anomeric carbon

and the eﬀect of the O-6 protecting group on the relative

reactivities of both free hydroxyl groups.⁷The benzoyl,

benzyl, and TBDPS groups, usually employed in carbo-

hydrate chemistry, were used at O-6 of N-dimethylma-

leimido (DMM) 3,4-diol derivatives in reaction with

two donors, the furanosyl and pyranosyl trichloroace-

timidates 9a^8,9and 2b,¹⁰of diﬀerent reactivity,¹¹as a

contribution to understand the relevance of the glycosyl

Later on, a series of publications appeared in the liter-

ature reporting that the O-4 of b-^D-glucosamine accep-

tors carrying a variety of protecting groups at N-2 and

O-6 was preferentially (if not exclusively) glycosylated

under diﬀerent reaction conditions.⁵

^ꢁFor an extension of the concept of ‘match–mismatch’, originally

suggested by Paulsen⁴referring to the yield in the reaction of one

donor/acceptor combination versus another, to the issue of regiose-

lectivity, see Fraser-Reid et al.²

2524

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

OR

donor to the regioselectivity of these glycosylation

reactions.¹²

O

HO

OMe

NDMM

DMMN

OMe

OBz

R

O

11a

12a, R = Bz

, R = Bz

O

OBz

12b, R = Bn

11b, R = Bn

RO

BzO

OMe

O

12c, R = TBDPS

11c, R = TBDPS

N

OBz

O

Acceptors 11a–c were prepared from methyl 2-amino-

2-deoxy-a-^D-glucopyranoside,^18,19which, upon treat-

ment with dimethylmaleic anhydride, followed by acetic

anhydride in pyridine,¹⁶aﬀorded triacetate 13a, easily

puriﬁed by column chromatography. After deacetyla-

tion and subsequent regioselective benzoylation of triol

13b, 11a was obtained in 74% yield, whereas 4,6-O-ben-

zylidene protection of 13b, followed by reductive open-

ing of the benzylidene group, aﬀorded 11b in 72%

yield. In turn, selective silylation of the 6-OH of 13b

gave 11c in 90% yield (Scheme 1).

Acceptors 12a–c were prepared from the known

compound 14.^16,20Regioselective benzoylation aﬀorded

12a in 55% yield. Alternatively, 4,6-O-benzylidene pro-

tection, followed by reductive opening of the benzyli-

dene group, aﬀorded 12b in 73% yield. Finally,

selective silylation of 14 gave 12c in 73% yield

(Scheme 2).

10a, R = H

9a, R = OC(NH)CCl₃

9b, R = OMe

10b, R = β-D-Galf

10c, R = β-D-Galp

Upon activation of these donors, neighboring-group

participation of the acyl group at O-2 ensures a b-selec-

tive coupling that leads to a simpler product analysis.

Donor 9a was also chosen because of the recent discov-

ery of furanoside components in a wide variety of natu-

ral products of biological signiﬁcance.^8,9,13,14For

instance, oligosaccharides derived from N-acetyl-^D-glu-

cosamine carrying ^D-galactopyranosyl and D-galactofur-

anosyl units have been shown to be components of the

mucin of Trypanosoma cruzi.¹⁵

The advantages of the DMM group are well known: it

is easily introduced, it is stable enough under a variety of

reaction conditions used in carbohydrate chemistry, it is

readily transformed into the N-acetyl derivative, etc.¹⁶

In addition, the trichloroacetimidate-promoted glycosy-

lations are widely used in the synthesis of

oligosaccharides.¹⁷

With these synthesized acceptors in hand, we per-

formed a number of coupling experiments. Each glucos-

aminyl diol was ﬁrst coupled with 1.1 equiv of the

galactofuranosyl imidate 9a, under activation with tri-

methylsilyl triﬂate (TMSOTf) at ꢀ25 ꢁC. In most of

the examples studied, the crude reaction mixtures were

2. Results and discussion

1

then analyzed by TLC and H NMR spectroscopy to

establish the isomeric ratios. The results were conﬁrmed

by isolation of the disaccharides or their corresponding

acetates by column chromatography. The results are

shown in Table 1. When the a-anomeric diol 11a was

glycosylated, the only compound obtained was the

1!3-linked disaccharide 15a in 68% yield. The corre-

sponding 1!4-linked compound was not detected by

Initially, we conﬁrmed that 9a is indeed more reactive

than 2b through competitive glycosylation experiments.

First, donors 9a and 2b were coupled separately with

methanol, and the resulting methyl glycosides 9b and

1

2c were analyzed by H NMR spectroscopy. When an

equimolecular mixture of both donors was allowed to

compete for 1 equiv of methanol, a 2.8:1 mixture of 9b

and 2c was obtained on the basis of the integration of

1

the methoxyl group signals in the H NMR spectrum

of the crude reaction mixture. In addition, when the

known acceptor 10a, carrying the N-dimethylmaleimido

group, was allowed to react with an equimolecular

mixture of both glycosyl donors, a 1.6:1 mixture of

disaccharides 10b and 10c was obtained, indicating

again that the furanosyl donor was preferred for

coupling.

In order to investigate the eﬀects of the factors men-

tioned above on the outcome of the regioselectivity,

the reactivities of acceptors 11a–c and 12a–c were exam-

ined when coupled, under identical reaction conditions,

with limiting amounts of the trichloroacetimidate do-

nors 9a and 2b.

OR

O

RO

DMMN

OMe

13a, R = Ac

a

b

13b, R = H

11a

11b

11c

c, d

e

Scheme 1. Reagents and conditions: (a) MeONa, MeOH, rt; (b)

benzoyl chloride, Py, ꢀ20 ꢁC; (c) benzaldehyde dimethyl acetal, CSA,

DMF; (d) BH₃ÆN(CH₃)₃, BF₃ÆOEt₂, CH₃CN; (e) TBDPSCl, imidazole,

DMF, rt.

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

2525

The assignment of the regioisomeric structures was

readily accomplished by acylating the disaccharide in

question and determining the chemical shift of the newly

downﬁeld-shifted proton.

OH

b, c

a

O

HO

OMe

NDMM

12a

12b

14

d

For example, in 15a, 15c, and 15e, acetylation gave

rise to signals at d_H5.24 (15b), 5.13 (15d), and 5.02

(15f), respectively, assignable to the glucosamine H-4,

whereas acetates 16b and 16d gave rise to a multiplet

at d_H6.41–6.33 and a double of doublet at d_H6.37 as

expected for the H-3 of a glucosamine moiety.

12c

Scheme 2. Reagents and conditions: (a) benzoyl chloride, Py, ꢀ40 ꢁC;

(b) benzaldehyde dimethyl acetal, CSA, DMF; (c) BH₃ÆN(CH₃)₂,

BF₃ÆOEt₂, CH₃CN; (d) TBDPSCl, imidazole, DMF, rt.

When the b-^D-glucosaminyl acceptors 12a–c were

coupled with 9a, mixtures of 1!3- and 1!4-linked

disaccharides 17a and 18a (1:1) and 17c and 18c

(1:2.9) and 17e and 18e (1:2.2), respectively, were ob-

tained (Table 1). Again, the analysis of the H NMR

spectra of acetates 17b (d_H5.22, H-4), 17d (d_H5.08,

1

TLC or H NMR spectroscopy. By contrast, the glyco-

sylation of diols 11b and 11c gave mixtures of regioisom-

ers 15c and 16a (3.2:1) and 15e and 16c (5:1),

respectively.

1

OR¹

O

OR¹

O

R²O

O

OBz

R²O

O

OBz

OMe

O

OMe

R²O

O

OBz

O

OBz

DMMN

OMe

DMMN

OMe

DMMN

OBz

15a, R¹= Bz; R²= H

16a, R¹= Bn; R²= H

17a, R¹= Bz; R²= H

18a, R¹= Bz; R²= H

18b, R¹= Bz; R²= Ac

18c, R¹= Bn; R²= H

18d, R¹= Bn; R²= Ac

15b, R¹= Bz; R²= Ac

15c, R¹= Bn; R²= H

15d, R¹= Bn; R²= Ac

15e, R¹= TBDPS; R²= H

15f, R¹= TBDPS; R²= Ac

16b, R¹= Bn; R²= Ac

16c, R¹= TBDPS; R²= H

16d, R¹= TBDPS; R²= Ac

17b, R¹= Bz; R²= Ac

17c, R¹= Bn; R²= H

17d, R¹= Bn; R²= Ac

17e, R¹= TBDPS; R²= H

17f, R¹= TBDPS; R²= Ac

18e, R¹= TBDPS; R²= H

18f, R¹= TBDPS; R²= Ac

Table 1. Ratios and yields of 3- and 4-linked disaccharides obtained after reaction of donors 9a and 2b with a- and b-glycosyl acceptors

OR¹

O

R²O

+

OC(NH)CCl₃

Acyl

HO

X

+

R²O

HO

DMMN

O

Y

Products, R²= Galf or Galp

Donor

Acceptor

Entry

Donor

Acceptor

Products

Ratio (1!3):(1!4)

Yields (%)

i

ii

9a (furanosyl)

2b (pyranosyl)

9a (furanosyl)

2b (pyranosyl)

11a, R¹= Bz, Y = OMe, X = H

11b, R¹= Bn, Y = OMe, X = H

11c, R¹= TBDPS, Y = OMe, X = H

11a, R¹= Bz, Y = OMe, X = H

11b, R¹= Bn, Y = OMe, X = H

11c, R¹= TBDPS, Y = OMe, X = H

12a, R¹= Bz, Y = H, X = OMe

12b, R¹= Bn, Y = H, X = OMe

12c, R¹= TBDPS, Y = H, X = OMe

12a, R¹= Bz, Y = H, X = OMe

12b, R¹= Bn, Y = H, X = OMe

12c, R¹= TBDPS, Y = H, X = OMe

Only 15a

15c + 16a

15e + 16c

19a + 20a

19c + 20c

19e + 20e

17a + 18a

17c + 18c

17e + 18e

22a + 23a

Only 23c

Only 23e

1:0

68

71

73

91

56

50

75

71

87

74

88

3.2:1

5:1

2:1^a

1:1

1.6:1

1:1

1:2.9

1:2.2

1:13^c

0:1

iii

iv

v

vi^b

vii

viii

ix

x

xi

xii

0:1

^aThis ratio was determined by ¹H NMR spectroscopy. The ratio determined by isolation of acetates 19b and 20b was 2.3:1.

^bAn inseparable mixture of disaccharides 19e and 20e together with trisaccharide 21 (28%) and unreacted 11a (9.6%) was obtained. The ratio of

regioisomeric disaccharides was determined as their corresponding acetates 19f and 20f.

^cThis ratio was determined by ¹H NMR spectroscopy. The minor disaccharide was better puriﬁed as its acetate 22b.

2526

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

H-4), 17f (d_H5.08, H-4), 18b (d_H5.70, H-3), 18d (d_H

5.65, H-3), and 18f (d_H5.68, H-3) was used to assign

their regioisomeric structures. As expected, all disaccha-

rides obtained in this part of the study were shown to be

b-linked, on the basis of the small coupling constant of

As shown in Table 1, the evaluation of the inﬂuence of

the conﬁguration at the anomeric carbons on the regio-

selective glycosylation of the anomeric glucosaminyl

diols 11a–11c and 12a–12c with donors 9a and 2b

showed qualitatively diﬀerent results. In the a anomers

11a–11c, as was previously observed in acylation¹⁵and

tosylation²¹reactions of 6-O-protected 2-amino-2-

deoxy-a-^D-glucopyranosides, the O-3 was preferentially

glycosylated, whereas in the b anomers 12a–12c, the

preference was, as it had been reported,^1,3,5at O-4.

However, and due to the inﬂuence of the 6-O-protecting

groups, some variations in the regioselectivity outcome

were observed. In addition, the reactivity of the dis-

armed donors (9a or 2b) also plays a role in the regio-

selectivity of these reactions.

A clear preference for the glycosylation at O-3 was

observed when the more reactive galactofuranosyl do-

nor 9a was used in reactions with the a acceptors 11a–

11c. The glycosylation of 11a carrying the electron-with-

drawing 6-O-benzoyl group represents an excellent

example of ‘match’ regioselectivity since the 1!3-linked

disaccharide 15a was exclusively observed. With 11b,

protected with the electron-donating benzyl group at

O-6, and 11c carrying the bulky TBDPS group, mixtures

of disaccharides were obtained; however, the preference

for the 1!3-linked compounds was still being observed.

It is worthwhile mentioning that the related acceptor 8b

was reported to have total regioselectivity for O-3,

although under quite diﬀerent reaction conditions.^5p

With the b acceptors 12b and 12c, preference for O-4

was observed—more marked with 12b—whereas no reg-

ioselectivity was observed with 12a.

When the a acceptors 11a–11c were glycosylated with

the less-reactive galactopyranosyl donor 2b, regioselec-

tivity was poor with 11a and was not detected with

11b. With 11c a completely diﬀerent result was obtained

in comparison with the related acceptor 8b.^5pUnder our

reaction conditions, 11c was the only acceptor that

aﬀorded an appreciable amount of a trisaccharide (21)

and further, the ratio of 1!3 and 1!4 disaccharides

was only 1.6:1. By contrast, the glycosylation of the b

acceptors 12a–12c showed preference for the O-4. The

galactosylation of acceptor 12a gave a 1:13 mixture of

1!3 and 1!4 disaccharides, whereas 12b and 12c, with

the electron-donating benzyl group and the bulky

TBDPS group at O-6, respectively, aﬀorded exclusively

the 1!4 disaccharides 23c and 23e. These galactosyla-

tions also constitute excellent examples of ‘match’

regioselectivity.

The inﬂuence of the reactivity of glycosyl donors in

glycosylation reactions has been fully analyzed, and

many publications have appeared in the literature.

Among them, the work of Koeller and Wong²²showed

systematic studies of the reactivity of a large number of

thioglycosides with the idea of developing a program-

mable one-pot oligosaccharide synthesis. It is also

0

the galactofuranose anomeric proton ðJ_{1 ;2}< 1 HzÞ and

by the characteristic C-1⁰¹³C NMR chemical shift.⁸

OR¹

OAc

AcO

OAc

AcO

O

R²O

O

R²O

O

AcO

DMMN

OMe

DMMN

OMe

AcO

19a, R¹= Bz; R²= H

19b, R¹= Bz; R²= Ac

19c, R¹= Bn; R²= H

19d, R¹= Bn; R²= Ac

20a, R¹= Bz; R²= H

20b, R¹= Bz; R²= Ac

20c, R¹= Bn; R²= H

20d, R¹= Bn; R²= Ac

19e, R¹= TBDPS; R²= H

19f, R¹= TBDPS; R²= Ac

20e, R¹= TBDPS; R²= H

20f, R¹= TBDPS; R²= Ac

OTBDPS

O

β−D−GalpO

DMMN

OMe

21

The regioselectivity of glycosylation of acceptors 11a–

12c in couplings with the less-reactive glycosyl donor2b

was also analyzed. The a-anomeric diols 11a and 11b

aﬀorded mixtures of 1!3- and 1!4-linked disaccha-

rides 19a and 20a (2:1) and 19c and 20c (1:1), respec-

tively, whereas acceptor 11c gave an inseparable

mixture of disaccharides 19e and 20e (50%), trisaccha-

ride 21 (28%), and unreacted acceptor 11c (9.6%). The

disaccharides were isolated as their corresponding ace-

tates 19f and 20f in a 1.6:1 ratio. The spectra of the cor-

responding acetates 19b (d_H5.11, H-4), 19d (d_H5.01, H-

4), 19f (d_H4.89, H-4), 20b (d_H6.27, H-3), 20d (d_H6.21,

H-3), and 20f (d_H6.25, H-3) were used to assign their

regioisomeric structures. By contrast, the b-^D-glucos-

aminyl acceptors 12a–c were preferentially glycosylated

at O-4 giving a 1:13 mixture of 22a and 23a, and exclu-

sively 23c and 23e, respectively (Table 1). As usual, the

analysis of the ¹H NMR spectra of the acetates 22b

(d_H5.09, H-4), 23b (d_H5.60, H-3), 23d (d_H5.50, H-3),

and 23f (d_H5.55, H-3) was used to assign their regioiso-

0

meric structures. On the basis of the value of the J_{1 ;2}

(ca. 7.9 Hz), all disaccharides obtained were shown to

contain the b-^D-galactopyranosyl moiety.

OR¹

OAc

AcO

OAc

AcO

O

R²O

O

OMe

R²O

O

AcO

DMMN

AcO

22a, R¹= Bz; R²= H

22b, R¹= Bz; R²= Ac

23a, R¹= Bz; R²= H

23b, R¹= Bz; R²= Ac

23c, R¹= Bn; R²= H

23d, R¹= Bn; R²= Ac

23e, R¹= TBDPS; R²= H

23f, R¹= TBDPS; R²= Ac

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

2527

remarkable that more recently, Fraser-Reid and co-

workers have shown that the nature (armed or dis-

armed) of the glycosyl donor has a great inﬂuence on

the regioselectivity of glycosylation reactions.¹²These

observations were the basis for the development of the

new concept for ‘matching’ donors with acceptors called

‘reciprocal donor acceptor selectivity’.²³In connection

with glycosylations of 3,4-diols derived from ^D-glucosa-

mine, Ellervick and Magnusson¹and Schmidt and co-

workers³had also observed that, for glycosylations with

the disarmed donor 2a or 2b, the 1!4-linked disaccha-

rides were obtained, whereas glycosylations with the

armed donors 4a or 4c aﬀorded mainly the 1!3-linked

compounds. Interestingly, we have observed that of

both disarmed donors analyzed in this study, the fur-

anosyl donor (9a) showed preference for the O-3 of

the a acceptors (11a–c) and the pyranosyl donor (2b),

as had been previously observed,^1,3,5for the O-4 of the

b acceptors (12a–c), respectively. In any case, it can be

observed that in the a acceptors the relative reactivity

at O-3 is higher than at O-4 and more marked with

the furanosyl donor than with the less-reactive pyran-

osyl one. Furthermore, the reactivity increases when

the substituent at O-6 changes from Bn to TBDPS to

Bz. On the other hand, the b anomers show a relatively

higher reactivity at O-4, which is clearly evident with the

less-reactive pyranosyl donor (Table 1). Although a

rationalization for these regioselectivities awaits further

insight, our observations conﬁrm and extend the utility

of these ‘matching’ donor and acceptor reactivities.

ring. All chemicals were used as purchased or puriﬁed

according to standard procedures.

3.1. Competition experiments

3.1.1. Competitive experiment of reactivity of donors 9a

and 2b with methanol. A suspension of donors 9a^8,9

and 2b¹⁰(0.11 mmol), anhyd MeOH (0.1 mmol), acti-

˚

vated 4 A molecular sieves (30 mg) in anhyd CH₂Cl₂

(7 mL), and CH₃CN (190 lL) was stirred at room tem-

perature. After 40 min, the mixture was cooled to

ꢀ30 ꢁC, TMSOTf (0.33 mmol) was slowly added, and

stirring was continued for 30 min. The mixture was then

neutralized by addition of solid NaHCO₃(190 mg) and

ﬁltered through a silica gel pad with copious washings

with EtOAc. The ﬁltrate was dried (Na₂SO₄) and evap-

orated. The ratio of 9b:2c was 2.8:1 by integration of the

signals at d 3.49 (s, 3H, OCH₃) in 9b and d 3.53 (s, 3H,

OCH₃) in 2c in the ¹H NMR spectrum of the crude reac-

tion mixture.

3.1.1.1. Data for 9b. R_f0.71 (7:3 hexane–EtOAc);

¹H NMR (300 MHz): d 8.15–7.85, 7.60–7.20 (m, 20H,

ArH), 6.11–6.05 (m, 1H, H-5), 5.64 (ddd, 1H, J_3,10.6,

J_3,21.3, J_3,45.4 Hz, H-3), 5.47 (dd, 1H, J_2,10.4 Hz, H-

2), 5.22 (br s, 1H, H-1), 4.80 (dd, 1H, J_6a,54.8, J_6a,6b

11.7 Hz, H-6a), 4.75 (dd, 1H, J_6b,56.6 Hz, H-6b), 4.67

(dd, 1H, J_4,53.5 Hz, H-4), 3.49 (s, 3H, OCH₃); ¹³C

NMR (50 MHz): d 165.98–165.34 (CO), 134.36–128.25

(C-Ar), 106.76 (C-1), 82.04 (C-4), 81.05 (C-2), 77.53

(C-3), 70.21 (C-5), 63.37 (C-6), 54.85 (OCH₃).

3.1.1.2. Data for 2c. R_f0.23 (7:3 hexane–EtOAc);

¹H NMR (300 MHz): d 5.39 (dd, 1H, J_4,51.1, J_4,3

3.3 Hz, H-4), 5.20 (dd, 1H, J_2,18.0, J_2,310.5 Hz, H-2),

5.02 (dd, 1H, H-3), 4.40 (d, 1H, H-1), 4.21 (dd, 1H,

J_6a,56.6, J_6a,6b11.2 Hz, H-6a), 4.14 (dd, 1H, J_6b,5

6.9 Hz, H-6b), 3.91 (ddd with appearance of dt, 1H,

H-5), 3.52 (s, 3H, OCH₃), 2.15, 2.07, 2.06, 1.99 (4s,

12H, COCH₃); ¹³C NMR (75 MHz): d 170.31–169.40

(CO), 101.98 (C-1), 70.87 (C-5), 70.53 (C-3), 68.71 (C-

2), 66.96 (C-4), 61.17 (C-6), 56.87 (OCH₃), 26.68–20.46

(COCH₃· 4).

3. Experimental

Melting points were determined on an Electrothermal

9100 apparatus and are uncorrected. The H and ¹³C

1

NMR spectra were recorded on Bruker AC 200 and

Bruker Avance 300 spectrometers for CDCl₃solutions

with Me₄Si as internal standard. For the 2D and COSY

experiments, Bruker standard software was employed.

Mass spectra were measured using MALDI-TOF

HRMS and HRFABMS at the UCR Mass Spectrome-

try Facility (Department of Chemistry, University of

California Riverside, USA) and Kent Mass Spectrome-

try (Kent, UK). Optical rotations were measured with a

Jasco DIP-1000 polarimeter. Column chromatography

was performed on Silica Gel 60 H, slurry packed, run

under low pressure of nitrogen and employing increas-

ing amounts of EtOAc in hexane as solvent (except

where noted). Analytical TLC was carried out using

Kieselgel GF254 (E. Merck) with a thickness of

0.20 mm. The homogeneity of all disaccharides prior

to the high-resolution mass spectral determination was

carefully veriﬁed by TLC. Reactions were routinely

run under a dry nitrogen atmosphere with magnetic stir-

3.1.2. Competitive glycosylation experiment of donors 9a

and 2b with acceptor 10a. A suspension of acceptor

10a⁶(0.1 mmol), donors 9a,^8,9and 2b¹⁰(0.1 mmol), acti-

˚

vated 4 A molecular sieves (146 mg) in anhyd CH₂Cl₂

(3.9 mL), and CH₃CN (126 lL) was stirred at room tem-

perature. After 40 min, the mixture was cooled to

ꢀ30 ꢁC, TMSOTf (0.4 mmol) was slowly added, and

stirring was continued for 3 h. The mixture was then

neutralized by addition of solid NaHCO₃(400 mg)

and ﬁltered through a silica gel pad with copious wash-

ings with EtOAc. The ﬁltrate was dried (Na₂SO₄) and

evaporated. The ratio of 10b:10c was 1.6:1 by integra-

2528

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

tion of the signals at 3.47 (s, 3H, OCH₃) in 10b and 3.44

(s, 3H, OCH₃) in 10c in the H NMR spectrum of the

crude reaction mixture.

workers,¹⁹methyl 2-amino-2-deoxy-a-D-glucopyran-

oside was obtained and used in the next step without

further puriﬁcation. A MeOH solution of this product

was treated with dimethylmaleic anhydride (281 mg,

2.21 mmol) and stirred for 20 min. Et₃N (471 lL,

3.34 mmol) was added, and the reaction mixture was

again treated with dimethylmaleic anhydride (281 mg,

2.21 mmol). The reaction mixture was warmed to

60 ꢁC with stirring for 5.15 h, then dried well in vacuo.

The residue from the last step was treated with pyridine

(9 mL), Ac₂O (4.3 mL) and stirred at room temperature.

After 22 h water was added, and the reaction mixture

was stirred for 10 min and extracted with Et₂O. The

organic layer was washed with satd aq NaHCO₃, dried

(Na₂SO₄), and evaporated. The residue was recrystal-

lized (EtOAc, (iPr)₂O) to give pure 13a (1.04 g, 66%)

1

3.1.2.1. Disaccharide 10b. Spectral data were identi-

cal to those described in Ref. 6.

27

3.1.2.2. Disaccharide 10c. ½aꢁ_D+26.1 (c 1.02,

CHCl₃); R_f0.02 ((iPr)₂O); ¹H NMR (300 MHz): d

8.15–7.90, 7.55–7.35 (m, 10H, ArH), 5.91 (dd, 1H, J_3,4

8.5, J_3,210.6 Hz, H-3), 5.24 (d, 1H, J_1,28.4 Hz, H-1),

5.14–5.09 (m, 1H, H-4⁰), 5.08 (dd, 1H, J_{2 ;1}7:9,

0

J_{2 ;3}10:2 Hz, H-2⁰), 4.79 (dd, 1H, J_{3 ;4}3:5 Hz, H-3⁰),

4.77 (dd, 1H, J_6a,51.5, J_6a,6b12.1 Hz, H-6a), 4.56 (d,

1H, H-1⁰), 4.42 (dd, 1H, J_6b,54.8 Hz, H-6b), 4.17 (dd,

1H, H-2), 4.08 (dd, 1H, J_4,510.0 Hz, H-4), 4.02–3.93

0

1

0

(m, 1H, H-5), 3.51 (dd, 1H, J_{6 a;5}7:8, J_{6 a;6 b}10:5 Hz,

as a solid: mp 196.3–196.8 ꢁC; H NMR (200 MHz): d

H-6⁰a), 3.44 (s, 3H, OCH₃), 3.40 (d, 1H, J_{6 a;5}10:5 Hz,

H-6⁰a), 3.38–3.33 (m, 1H, H-5⁰), 2.00, 1.98, 1.93, 1.91

(4s, 12H, COCH₃· 4), 1.88 (br s, 6H, CCH₃· 2); ¹³C

6.39 (dd, 1H, J_3,49.1, J_3,211.5 Hz, H-3), 5.01 (dd with

appearance of t, 1H, J_4,59.5 Hz, H-4), 4.73 (d, 1H,

J_1,23.6 Hz, H-1), 4.43–4.30 (m, 1H, H-6a), 4.33 (dd,

1H, H-2), 4.17–4.03 (m, 2H, H-5, H-6b), 3.33 (s, 3H,

OCH₃), 2.10, 2.02, 1.96, 1.90 (4s, 15H, COCH₃· 3,

CCH₃· 2); ¹³C NMR (50 MHz): d 170.98–169.16

(CO), 137.10 (C · 2), 98.19 (C-1), 69.84, 67.24, 67.18

(C-3, C-4, C-5), 61.81 (C-6), 55.22 (OCH₃), 53.30 (C-

2), 20.49 (COCH₃· 3), 8.60 (CCH₃· 2). HRCIMS:

calcd for C₁₉H₂₅NO₁₀[M+NH₄]⁺, m/z 445.1817; found,

m/z 445.1833.

0

NMR (75 MHz):

d 169.97–164.91 (CO), 133.28,

129.55–128.38 (C-Ar, C · 2), 100.65 (C-1⁰), 99.00 (C-

1), 77.10 (C-4), 72.58 (C-5), 71.47 (C-3), 70.82 (C-3⁰),

70.37 (C-5⁰), 69.09 (C-2⁰), 66.18 (C-4⁰), 62.64 (C-6),

59.90 (C-6⁰), 56.86 (OCH₃), 54.54 (C-2), 20.50–20.39

(COCH₃· 4), 8.62 (CCH₃).

3.2. General procedure for glycosylation and acetylation

reactions

A mixture of triacetate 13a (462 mg, 1.08 mmol), an-

hyd MeOH (10.5 mL), and NaOMe (0.169 M, 650 lL)

was stirred at room temperature. After 1 h, the solution

was neutralized with Amberlite IR-120 (H⁺) resin, ﬁl-

tered, and evaporated. The residue was chromato-

graphed (9:1 EtOAc–MeOH) to yield 13b (299 mg,

92%) as a foamy solid. To a stirred solution of triol

13b (131 mg, 0.44 mmol) in anhyd pyridine (3.2 mL) at

ꢀ40 ꢁC was added dropwise freshly distilled benzoyl

chloride (157 lL, 1.35 mmol). After 2 h at ꢀ20 ꢁC the

reaction mixture was allowed to warm to room temper-

ature. After 3 h, water was added, and the mixture was

stirred for 10 min and then extracted with EtOAc. The

organic layer was washed with 1 N HCl, satd aq NaH-

CO₃and brine, dried (Na₂SO₄), and evaporated. The

residue was chromatographed to give 11a (131 mg,

A suspension of acceptor 11a, 11b, 11c, 12a, 12b, or 12c

(0.1 mmol), donor 9a^8,9or 2b¹⁰(0.11 mmol), activated

˚

4 A molecular sieves (106 mg) in anhyd CH₂Cl₂

(4.9 mL) and CH₃CN (133 lL) was stirred at room tem-

perature. After 40 min, the mixture was cooled to

ꢀ25 ꢁC, TMSOTf (0.21 mmol) was slowly added, and

stirring was continued for 30 min. The mixture was then

neutralized by addition of solid NaHCO₃(188 mg) and

ﬁltered through a silica gel pad with copious washings

with EtOAc. The ﬁltrate was dried (Na₂SO₄) and evap-

orated. The residue was chromatographed to give the

products, except where noted otherwise. The glycosyla-

tion of acceptors 11c and 12c was performed under the

same reaction conditions except that 0.037 mmol of

TMSOTf was used as a promoter. The acetylations were

carried out under standard conditions: pyridine,

DMAP, Ac₂O, room temperature, overnight. All disac-

charides were characterized as their corresponding ace-

32

74%) as a solid: mp 196.6–198.0 ꢁC; ½aꢁ_D+99.9 (c

1

1.02, MeOH); R_f0.09 (1:1 hexane–EtOAc); H NMR

(200 MHz): d 8.08 (d, 2H, J 7.1 Hz, ArH), 7.70–7.40

(m, 3H, ArH), 5.02 (dd, 1H, J_3,49.0, J_3,211.2 Hz, H-

3), 4.80 (d, 1H, J_1,23.4 Hz, H-1), 4.80 (dd, 1H, J_6a,5

4.5, J_6a,6b12.2 Hz, H-6a), 4.52 (dd, 1H, J_6b,52.1 Hz,

H-6b), 4.01–3.94 (m, 1H, H-5), 3.98 (dd, 1H, H-2),

3.50 (dd with appearance of t, 1H, J_4,59.4 Hz, H-4),

3.33 (s, 3H, OCH₃), 1.96 (s, 6H, CCH₃· 2); ¹³C NMR

(50 MHz): d 172.20, 167.06 (CO), 137.16 (C · 2),

133.17, 129.71–128.32 (C-Ar), 98.32 (C-1), 71.14 (C-4),

70.00 (C-5), 67.24 (C-3), 63.62 (C-6), 56.29 (C-2),

1

tates. In the H NMR data of the disaccharides and

their corresponding acetates listed below, the carbinolic

and the ‘new’ signals upon acylation are shown in italics.

3.2.1. Methyl 6-O-benzoyl-2-deoxy-2-dimethylmaleimido-

a-^D-glucopyranoside (11a). Starting with methyl 2-

deoxy-2-methoxycarbonylamido-a-^D-glucopyranoside¹⁸

and following the procedure described by Bauer and co-

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

2529

55.23 (OCH₃), 8.66 (CCH₃· 2). HRCIMS: calcd for

C₂₀H₂₃NO₈[M+H]⁺, m/z 406.1496; found, m/z

406.1503.

added. The organic layer was washed with water, dried

(Na₂SO₄), and evaporated. The residue was chromato-

graphed (CH₂Cl₂–MeOH) to give 11c (405 mg, 90%)

31

as a foamy solid: ½aꢁ_D+106.6 (c 1.02, CHCl₃); R_f0.22

3.2.2. Methyl 6-O-benzyl-2-deoxy-2-dimethylmaleimido-

a-^D-glucopyranoside (11b). To a stirred solution of 13b

(109 mg, 0.36 mmol) in anhyd DMF (1.8 mL) was

added benzaldehyde dimethyl acetal (112 lL,

0.20 mmol) and a catalytic amount of camphorsulfonic

acid. The mixture was stirred overnight at room temper-

ature, then neutralized with solid Na₂CO₃and diluted

with EtOAc. The organic layer was washed with brine,

dried (Na₂SO₄), and evaporated. The residue was chro-

matographed to yield the 4,6-O-benzylidene acetal

(7:3 hexane–EtOAc); ¹H NMR (300 MHz): d 7.75–

7.65, 7.45–7.30 (m, 5H, ArH), 4.96 (dd, 1H, J_3,49.4,

J_3,210.8 Hz, H-3), 4.72 (d, 1H, J_1,23.4 Hz, H-1), 3.97

(dd, 1H, H-2), 4.01–3.85 (m, 2H, H-6a, H-6b), 3.80–

3.69 (m, 1H, H-5), 3.56 (dd with appearance of t, 1H,

J_4,59.2 Hz, H-4), 3.26 (s, 3H, OCH₃), 1.94 (s, 6H,

CCH₃· 2), 1.06 (s, 9H, C(CH₃)₃); ¹³C NMR

(75 MHz): d 172.20 (CO), 137.05 (C · 2), 135.49,

132.99–132.96, 129.63, 127.60 (C-Ar), 98.12 (C-1),

72.85 (C-4), 71.06 (C-5), 67.48 (C-3), 64.34 (C-6),

56.35 (C-2), 54.96 (OCH₃), 26.66 (C (CH₃)₃), 19.09

(C(CH₃)₃), 8.61 (CCH₃· 2). HRFABMS: calcd for

C₂₉H₃₇NO₇Si [M+Na]⁺, m/z 562.2237; found, m/z

562.2244.

1

(84 mg, 59%), as a foamy solid. H NMR (200 MHz):

d 7.55–7.27 (m, 5H, ArH), 5.57 (s, 1H, CHPh), 5.25

(dd, 1H, J_3,49.4, J_3,210.8 Hz, H-3), 4.75 (d, 1H, J_1,2

3.6 Hz, H-1), 4.29 (dd, 1H, J_6a,54.3, J_6a,6b9.7 Hz, H-

6a), 4.10 (dd, 1H, H-2), 3.99–3.87 (m, 1H, H-5), 3.79

(dd, 1H, J_6b,51.9 Hz, H-6b), 3.54 (dd with appearance

of t, J_4,59.2 Hz, H-4), 3.33 (s, 3H, OCH₃), 1.96 (s,

3.2.4. Methyl 6-O-benzoyl-2-deoxy-2-dimethylmaleimido-

b-^D-glucopyranoside (12a). To a stirred solution of triol

14^16,20(490 mg, 1.63 mmol) in anhyd pyridine (6 mL) at

ꢀ40 ꢁC was added dropwise freshly distilled benzoyl

chloride (242 lL, 2.1 mmol). After 2 h at this tempera-

ture, the reaction mixture was allowed to warm to room

temperature. After 15 h, water was added, and the mix-

ture was stirred for 10 min and then extracted with

CH₂Cl₂. The organic layer was washed with 1 N HCl,

satd aq NaHCO₃and brine, dried (Na₂SO₄), and evap-

orated. The residue was chromatographed to give 12a

6H, CCH₃· 2); ¹³C NMR (50 MHz):

d 171.90

(CO · 2), 137.12 (C · 2), 129.13–126.27 (C-Ar), 101.87

(CHPh), 99.05 (C-1), 82.44 (C-4), 68.78 (C-6), 64.65

(C-3), 62.50 (C-5), 56.38 (C-2), 56.36 (OCH₃), 8.65

(CCH₃· 2).

To a solution of the 4,6-O-benzylidene acetal (142 mg,

0.37 mmol) and BH₃ÆN(CH₃)₃(52 mg, 0.74 mmol) in

CH₃CN (3.7 mL) in an ice-water bath was added drop-

wise BF₃ÆOEt₂(92 lL, 0.84 mmol). After 1 h at this tem-

perature, the solution was stirred at room temperature

for an additional 0.5 h (TLC). NaHCO₃(54 mg) was

then added, and the solution was evaporated to dryness.

The crude product in CH₂Cl₂was washed with brine,

dried (Na₂SO₄), and evaporated. The residue was chro-

matographed to yield 11b (103 mg, 72%), as a foamy

20

(280.9 mg, 55%): ½aꢁ_Dꢀ17.2 (c 1.02, MeOH); R_f0.12

(1:1 hexane–EtOAc); ¹H NMR (200 MHz): d 8.12–

8.02, 7.65–7.37 (m, 5H, ArH), 5.02 (d, 1H, J_1,28.4 Hz,

H-1), 4.84 (dd, 1H, J_6a,53.9, J_6a,6b12.2 Hz, H-6a),

4.53 (dd, 1H, J_6b,52.1 Hz, H-6b), 4.23 (dd, 1H, J_3,4

8.6, J_3,210.7 Hz, H-3), 3.89 (dd, 1H, H-2), 3.73–3.61

(m, 1H, H-5), 3.46 (dd with appearance of t, 1H, J_4,5

9.2 Hz, H-4), 3.44 (s, 3H, OCH₃), 1.95 (s, 6H,

CCH₃· 2); ¹³C NMR (50 MHz): d 171.94, 167.14

(CO), 137.17 (C · 2), 133.19, 129.72–128.28 (C-Ar),

99.22 (C-1), 73.86 (C-5), 71.48 (C-4), 71.40 (C-3),

63.65 (C-6), 56.59 (OCH₃), 55.89 (C-2), 8.60

(CCH₃· 2). HRFABMS: calcd for C₂₀H₂₃NO₈

[M+Na]⁺, m/z 428.1321; found, m/z 428.1322.

31

solid: ½aꢁ_D+136.1 (c 0.97, MeOH); R_f0.32 (1:1 hexane–

EtOAc); ¹H NMR (300 MHz): d 7.45–7.26 (m, 5H,

ArH), 4.94 (dd, 1H, J_3,49.0, J_3,211.1 Hz, H-3), 4.74

(d, 1H, J_1,23.3 Hz, H-1), 4.64 (d, 1H, J 12.3 Hz,

CH₂Ph), 4.59 (d, 1H, CH₂Ph), 3.99 (dd, 1H, H-2),

3.85–3.75 (m, 3H, H-5, H-6a, H-6b), 3.57 (dd with

appearance of t, J_4,59.3 Hz, H-4), 3.29 (s, 3H, OCH₃),

1.93 (s, 6H, CCH₃· 2); ¹³C NMR (50 MHz): d 172.39

(CO · 2), 137.26 (C · 2), 128.46–127.50 (C-Ar), 98.39

(C-1), 73.68 (CH₂Ph), 72.46 (C-4), 70.20 (C-5), 69.82

(C-6), 67.68 (C-3), 56.64 (C-2), 55.34 (OCH₃), 8.78

(CCH₃· 2). HRFABMS: calcd for C₂₀H₂₅NO₇

[M+Na]⁺, m/z 414.1529; found, m/z 414.1544.

3.2.5. Methyl 6-O-benzyl-2-deoxy-2-dimethylmaleimido-

b-^D-glucopyranoside (12b). To a stirred solution of

14^16,20(107 mg, 0.36 mmol) in anhyd DMF (1.8 mL)

were added benzaldehyde dimethyl acetal (109 lL,

0.19 mmol) and a catalytic amount of camphorsulfonic

acid, and the mixture was stirred overnight at room tem-

perature. The reaction mixture was neutralized with

solid Na₂CO₃and diluted with EtOAc. The organic layer

was washed with brine, dried (Na₂SO₄), and evaporated.

The residue was chromatographed to yield the 4,6-O-

benzylidene acetal (116.9 mg, 85%), as a foamy solid:

3.2.3. Methyl 6-O-tert-butyldiphenylsilyl-2-deoxy-2-dim-

ethylmaleimido-a-^D-glucopyranoside (11c). To a stirred

solution of triol 13b (250 mg, 0.81 mmol) in anhyd

DMF (2.6 mL) at room temperature were added imidaz-

ole (142 mg, 2.08 mmol) and tert-butylchlorodiphenylsi-

lane (294 lL, 1.21 mmol). After 2 h CH₂Cl₂(43 mL) was

2530

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

¹H NMR (200 MHz): d 7.52–7.32 (m, 5H, ArH), 5.55 (s,

1H, CHPh), 5.03 (d, 1H, J_1,28.4 Hz, H-1), 4.46 (dd, 1H,

J_3,48.8, J_3,210.5 Hz, H-3), 4.37 (dd, 1H, J_6a,54.3, J_6a,6b

10.9 Hz, H-6a), 3.98 (dd, 1H, H-2), 3.83 (dd with

appearance of t, 1H, J_4,59.9 Hz, H-4), 3.61–3.51 (m,

2H, H-5, H-6b), 3.44 (s, 3H, OCH₃), 1.96 (s, 6H,

CCH₃· 2); ¹³C NMR (50 MHz): d 171.61 (CO · 2),

137.02 (C · 2), 136.85, 128.96–126.07 (C-Ar), 101.51

(CHPh), 99.65 (C-1), 81.88 (C-4), 68.27 (C-3), 68.36

(C-6), 65.81 (C-5), 56.64 (OCH₃), 56.10 (C-2), 8.48

(CCH₃· 2).

(CH₃)₃),

19.07

(C(CH₃)₃),

8.68

(CCH₃· 2).

HRFABMS: calcd for C₂₉H₃₇NO₇Si [M+Na]⁺, m/z

562.2237; found, m/z 562.2239.

3.2.7. Methyl 2,3,5,6-tetra-O-benzoyl-b-^D-galactofuran-

osyl-(1!3)-4-O-acetyl-6-O-benzoyl-2-deoxy-2-dimethyl-

maleimido-a-^D-glucopyranoside (15b)

23

3.2.7.1. Disaccharide 15a. 68%; ½aꢁ_D+64.3 (c 0.91,

CHCl₃); R_f0.17 (7:3 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.15–7.75, 7.60–7.25 (m, 25H, ArH),

5.98–5.91 (m, 1H, H-5⁰), 5.60 (dd, 1H, J_{3 ;2}2:3,

0

J_{3 ;4}5:1 Hz, H-3⁰), 5.46 (br s, 1H, H-1⁰), 5.40 (dd, 1H,

0

To a solution of the 4,6-O-benzylidene acetal (420 mg,

1.08 mmol) and BH₃ÆN(CH₃)₃(154 mg, 2.2 mmol) in

CH₃CN (11 mL) in an ice-water bath was added drop-

wise BF₃ÆOEt₂(272 lL, 2.5 mmol). After 1 h at this tem-

perature, the solution was stirred at room temperature

for an additional 0.5 h (TLC). NaHCO₃(154 mg) was

then added, and the solution was evaporated to dryness.

The crude product in CH₂Cl₂was washed with brine,

dried (Na₂SO₄), and evaporated. The residue was chro-

matographed to yield 12b (308 mg, 73%), as a foamy

J_{2 ;1}1:4 Hz, H-2⁰), 5.10 (dd, 1H, J_3,48.6, J_3,211.2 Hz,

0

H-3), 4.87 (dd with appearance of t, 1H, J_{4 ;5}5:1 Hz,

H-4⁰), 4.77 (dd, 1H, J_{6 a;5}4:9, J_{6 a;6 b}11:8 Hz, H-6⁰a),

4.71 (d, 1H, J_1,23.3 Hz, H-1), 4.64–4.58 (m, 2H, H-6a,

H-6⁰b), 4.51 (dd, 1H, J_6b,55.7, J_6b,6a11.9 Hz, H-6b),

4.24 (dd, 1H, H-2), 4.21 (br s, 1H, OH), 4.04–3.95 (m,

1H, H-5), 3.66–3.56 (m, 1H, H-4), 3.32 (s, 3H, OCH₃),

1.85 (br s, 6H, CCH₃· 2); ¹³C NMR (75 MHz): d

166.24–164.72 (CO), 133.50–132.82 (C · 2, C-Ar),

129.60–128.24 (C-Ar), 107.48 (C-1⁰), 98.35 (C-1), 81.70

(C-2⁰), 81.19 (C-4⁰), 78.61 (C-3), 77.29 (C-3⁰), 70.45 (C-

4, C-5⁰), 69.73 (C-5), 63.70 (C-6), 63.62 (C-6⁰), 55.03

(OCH₃), 54.27 (C-2), 8.57 (CCH₃· 2).

0

28

solid: ½aꢁ_Dꢀ13.2 (c 1.03, MeOH); R_f0.08 (1:1 hexane–

1

EtOAc); H NMR (300 MHz): d 7.34 (br s, 5H, ArH),

4.98 (d, 1H, J_1,28.2 Hz, H-1), 4.65 (d, 1H, J 12.0 Hz,

CH₂Ph), 4.57 (d, 1H, CH₂Ph), 4.24–4.09 (m, 1H, H-3),

3.89 (dd, 1H, J_2,310.9 Hz, H-2), 3.82–3.77 (m, 2H, H-

6a, H-6b), 3.62–3.52 (m, 2H, H-4, H-5), 3.41 (s, 3H,

OCH₃), 3.00 (br s, 1H, OH), 2.32 (br s, 1H, OH), 1.96

(s, 6H, CCH₃· 2); ¹³C NMR (75 MHz): d 171.94

(CO · 2), 137.69 (C-Ar), 137.11 (C · 2), 128.29–127.60

(C-Ar), 99.09 (C-1), 74.10 (C-4^*), 73.51 (CH₂Ph), 73.17

(C-5^*), 71.65 (C-3), 70.00 (C-6), 56.41 (OCH₃), 55.87

(C-2), 8.55 (CCH₃· 2). HRFABMS: calcd for

C₂₀H₂₅NO₇[M+Na]⁺, m/z 414.1529; found, m/z

414.1532.

3.2.7.2. Acetate 15b. ½aꢁ²_D⁹+105.0 (c 1.03, CHCl₃); R_f

1

0.28 (7:3 hexane–EtOAc, two developments); H NMR

(300 MHz): d 5.24 (dd with appearance of t, 1H, J_4,5

9.7 Hz, H-4); HRMALDI-TOF MS: calcd for

C₅₆H₅₁NO₁₈[M+Na]⁺, m/z 1048.3004; found, m/z

1048.3005.

3.2.8. Methyl 2,3,5,6-tetra-O-benzoyl-b-^D-galactofuran-

osyl-(1!3)-4-O-acetyl-6-O-benzyl-2-deoxy-2-dimethyl-

maleimido-a-^D-glucopyranoside (15d) and methyl 2,3,5,6-

tetra-O-benzoyl-b-^D-galactofuranosyl-(1!4)-3-O-acetyl-

6-O-benzyl-2-deoxy-2-dimethylmaleimido-a-^D-glucopyran-

oside (16b)

3.2.6. Methyl 6-O-tert-butyldiphenylsilyl-2-deoxy-2-dim-

ethylmaleimido-b-^D-glucopyranoside (12c). To a stirred

solution of triol 14 (171 mg, 0.57 mmol) in anhyd DMF

(1.8 mL) at room temperature were added imidazole

(97 mg, 1.42 mmol) and tert-butylchlorodiphenylsilane

(201 lL, 0.83 mmol). After 2 h CH₂Cl₂(32 mL) was

added. The organic layer was washed with water, dried

(Na₂SO₄), and evaporated. The residue was chromato-

graphed (CH₂Cl₂–MeOH) to give 12c (224 mg, 73%)

24

3.2.8.1. Disaccharide 15c. 54%; ½aꢁ_D+70.6 (c 1.04,

CHCl₃); R_f0.18 (7:3 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.15–7.75, 7.60–7.20 (m, 25H, ArH),

6.00–5.90 (m, 1H, H-5⁰), 5.60 (dd, 1H, J_{3 ;2}2:1,

0

J_{3 ;4}5:6 Hz, H-3⁰), 5.45 (br s, 1H, H-1⁰), 5.37 (dd, 1H,

0

J_{2 ;1}1:2 Hz, H-2⁰), 5.06 (dd, 1H, J_3,48.5, J_3,211.1 Hz,

0

31

H-3), 4.85 (dd, 1H, J_{4 ;5}4:4 Hz, H-4⁰), 4.77 (dd, 1H,

0

as a foamy solid: ½aꢁ_Dꢀ23.6 (c 1.02, CHCl₃); R_f0.27

(1:1 hexane–EtOAc); ¹H NMR (300 MHz): d 7.80–

7.65, 7.55–7.45 (m, 10H, ArH), 4.96 (d, 1H, J_1,2

8.4 Hz, H-1), 4.18 (dd, 1H, J_3,48.5, J_3,210.4 Hz, H-3),

3.96 (d, 2H, J_6,54.7 Hz, H-6a, H-6b), 3.86 (dd, 1H, H-

2), 3.66–3.45 (m, 3H, H-4, H-5, OH), 3.58–3.50 (m,

1H, H-5), 3.39 (s, 3H, OCH₃), 1.97 (s, 6H, CCH₃· 2),

1.08 (s, 9H, C (CH₃)₃); ¹³C NMR (75 MHz): d 171.92

(CO), 137.17–132.53 (C · 2, C-Ar), 129.82–127.71 (C-

Ar), 98.97 (C-1), 74.22 (C-4^*), 74.09 (C-5^*), 71.78 (C-

3), 64.92 (C-6), 56.32 (OCH₃), 55.75 (C-2), 26.68 (C

J_{6 a;5}4:8, J_{6 a;6 b}11:9 Hz, H-6⁰a), 4.72 (d, 1H, J_1,2

0

3.5 Hz, H-1), 4.64 (dd, 1H, J_{6 b;5}6:4 Hz, H-6⁰b), 4.61

(s, 2H, CH₂Ph), 4.22 (dd, 1H, H-2), 4.04 (d, 1H, J_OH,4

1.5 Hz, OH), 3.88–3.79 (m, 1H, H-5), 3.76 (dd, 1H,

J_6a,52.2, J_6a,6b10.7 Hz, H-6a), 3.70 (dd, 1H, J_6b,5

5.0 Hz, H-6b), 3.61 (ddd, 1H, J_4,59.0 Hz, H-4), 3.31 (s,

3H, OCH₃), 1.86 (br s, 6H, CCH₃· 2); ¹³C NMR

0

(75 MHz):

d 165.73–164.63 (CO), 138.15 (C · 2),

133.42–132.93, 129.88–127.33 (C-Ar), 107.33 (C-1⁰),

98.35 (C-1), 81.60 (C-2⁰), 81.16 (C-4⁰), 78.69 (C-3),

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

2531

77.18 (C-3⁰), 73.31 (CH₂Ph), 70.81 (C-5), 70.32 (C-5⁰^*),

70.18 (C-4^*), 69.00 (C-6), 62.65 (C-6⁰), 54.96 (OCH₃),

54.31 (C-2), 8.50 (CCH₃· 2).

77.23 (C-3⁰), 72.31 (C-5), 70.42 (C-4, C-5⁰), 63.46 (C-

6), 62.63 (C-6⁰), 54.78 (OCH₃), 54.46 (C-2), 26.63

(C(CH₃)₃), 19.15 (C(CH₃)₃), 8.57 (CCH₃· 2).

27

30

3.2.8.2. Acetate 15d. ½aꢁ_D+73.5 (c 0.86, CHCl₃); R_f

3.2.9.2. Acetate 15f. ½aꢁ_D+70.5 (c 1.02, CHCl₃); R_f

0.21 ((iPr)₂O); ¹H NMR (300 MHz): d 5.13 (dd with

appearance of t, 1H, J_4,59.4 Hz, H-4); HRFABMS:

calcd for C₅₆H₅₃NO₁₇[M+Na]⁺, m/z 1034.3211; found,

m/z 1034.3218.

0.49 ((iPr)₂O, two developments); ¹H NMR (300 MHz):

d 5.02 (dd,1H, J_4,59.8 Hz, H-4); HRFABMS: calcd for

C₆₅H₆₅NO₁₇Si [M+Na]⁺, m/z 1182.3919; found, m/z

1182.3900.

27

28

3.2.8.3. Disaccharide 16a. 17%; ½aꢁ_D+57.9 (c 1.03,

3.2.9.3. Disaccharide 16c. 12%; ½aꢁ_D+46.8 (c 1.01,

CHCl₃); R_f0.14 (7:3 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.15–7.85, 7.65–7.10 (m, 25H, ArH),

CHCl₃); R_f0.47 (1:1 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.12–7.20 (m, 30H, ArH), 6.00–5.90 (m,

6.00–5.92 (m, 1H, H-5⁰), 5.67 (dd, 1H, J_{3 ;2}1:4,

1H, H-5⁰), 5.66 (d, 1H, J_{3 ;4}4:8 Hz, H-3⁰), 5.58 (s, 1H,

H-1⁰), 5.40 (s 1H, H-2⁰), 5.12 (dd with appearance of br

t, 1H, J_3,48.5 Hz, H-3), 4.93 (dd with appearance of t,

0

J_{3 ;4}5:6 Hz, H-3⁰), 5.45 (d, 1H, H-2⁰), 5.41 (s, 1H, H-

0

1⁰), 5.17–5.08 (m, 1H, H-3), 4.94 (dd, 1H, J_{4 ;5}3:8 Hz,

H-4⁰), 4.77–4.71 (m, 2H, H-6⁰a, H-6⁰b), 4.75 (d, 1H,

J_1,23.5 Hz, H-1), 4.58 (br s, 2H, CH₂Ph), 4.10 (dd,

1H, J_2,311.2 Hz, H-2), 3.98–3.91 (m, 2H, H-6a, H-6b),

3.88–3.74 (m, 2H, H-4, H-5), 3.34 (s, 3H, OCH₃), 1.98

(s, 6H, CCH₃· 2); ¹³C NMR (75 MHz): d 171.89,

166.04–165.41 (CO), 137.91 (C-Ar), 136.99 (C · 2),

133.44–132.90, 129.88–127.47 (C-Ar), 106.93 (C-1⁰),

98.55 (C-1), 82.27 (C-2⁰), 81.43 (C-4⁰), 79.23 (C-4),

77.20 (C-3⁰), 73.17 (CH₂Ph), 70.21 (C-5⁰), 69.78 (C-5),

68.16 (C-6), 65.93 (C-3), 63.19 (C-6⁰), 56.30 (C-2),

55.31 (OCH₃), 8.66 (CCH₃· 2).

0

1H, J_{4 ;5}4:7 Hz, H-4⁰), 4.70 (d, 1H, J_1,23.7 Hz, H-1),

4.80–4.65 (m, 2H, H-6⁰a, H-6⁰b), 4.15–4.00 (m, 2H, H-

2, H-6a), 3.97–3.78 (m, 3H, H-4, H-5, H-6b), 3.26 (s,

3H, OCH₃), 1.97 (s, 6H, CCH₃· 2), 0.99 (s, 9H, C

(CH₃)₃); ¹³C NMR (75 MHz): d 172.08–165.29 (CO),

137.12–133.00 (C · 2, C-Ar), 130.01–127.46 (C-Ar),

106.88 (C-1⁰), 98.38 (C-1), 82.37 (C-2⁰), 81.84 (C-4⁰),

78.90 (C-4), 77.22 (C-3⁰), 71.11 (C-5), 70.39 (C-5⁰),

66.07 (C-3), 63.37 (C-6⁰), 62.87 (C-6), 56.63 (C-2),

55.20 (OCH₃), 26.77 (C(CH₃)₃), 19.35 (C(CH₃)₃), 8.80

(CCH₃· 2).

0

21

29

3.2.8.4. Acetate 16b. ½aꢁ_D+55.8 (c 0.50, CHCl₃); R_f

3.2.9.4. Acetate 16d. ½aꢁ_D+47.9 (c 0.76, CHCl₃); R_f

0.33 ((iPr)₂O); ¹H NMR (300 MHz): d 6.41–6.33 (m, 1H,

H-3); HRFABMS: calcd for C₅₆H₅₃NO₁₇[M+Na]⁺,

m/z 1034.3211; found, m/z 1034.3188.

0.43 ((iPr)₂O, three developments); ¹H NMR

(300 MHz): d 6.37 (dd,1H, J_3,48.6, J_3,211.3 Hz, H-3);

HRFABMS: calcd for C₆₅H₆₅NO₁₇Si [M+Na]⁺, m/z

1182.3919; found, m/z 1182.3945.

3.2.9. Methyl 2,3,5,6-tetra-O-benzoyl-b-^D-galactofuran-

osyl-(1!3)-4-O-acetyl-6-O-tert-butyldiphenylsilyl-2-deoxy-

2-dimethylmaleimido-a-^D-glucopyranoside (15f) and methyl

2,3,5,6-tetra-O-benzoyl-b-^D-galactofuranosyl-(1!4)-3-O-

acetyl-6-O-tert-butyldiphenylsilyl-2-deoxy-2-dimethylmal-

eimido-a-^D-glucopyranoside (16d)

3.2.10. Methyl 2,3,5,6-tetra-O-benzoyl-b-^D-galactofur-

anosyl-(1!3)-4-O-acetyl-6-O-benzoyl-2-deoxy-2-dimethyl-

maleimido-b-^D-glucopyranoside (17b) and methyl 2,3,5,6-

tetra-O-benzoyl-b-^D-galactofuranosyl-(1!4)-3-O-acetyl-

6-O-benzoyl-2-deoxy-2-dimethylmaleimido-b-^D-glucopyran-

oside (18b)

25

3.2.9.1. Disaccharide 15e. 61%; ½aꢁ_D+62.9 (c 1.02,

25

CHCl₃); R_f0.56 (1:1 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.15–8.05, 8.00–7.65, 7.60–7.25 (m, 30H,

3.2.10.1. Disaccharide 17a. 37%; ½aꢁ_D+30.1 (c 0.99,

CHCl₃); R_f0.18 (7:3 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.10–7.90, 7.80–7.70, 7.60–7.20 (m, 25H,

ArH), 5.97–5.89 (m, 1H, H-5⁰), 5.59 (dd, 1H, J_{3 ;2}2:1,

0

J_{3 ;4}5:3 Hz, H-3⁰), 5.44 (br s, 1H, H-1⁰), 5.37 (dd, 1H,

ArH), 5.98–5.90 (m, 1H, H-5⁰), 5.64 (dd, 1H, J_{3 ;2}1:9,

0

J_{2 ;1}1:1 Hz, H-2⁰), 5.06 (dd, 1H, J_3,48.4, J_3,211.2 Hz,

J_{3 ;4}5:5 Hz, H-3⁰), 5.26 (dd, 1H, J_{2 ;1}1:0 Hz, H-2⁰),

0

H-3), 4.82 (dd, 1H, J_{4 ;5}4:5 Hz, H-4⁰), 4.73 (dd, 1H,

5.21 (s, 1H, H-1⁰), 4.93 (d, 1H, J_1,28.5 Hz, H-1), 4.86

(dd with appearance of t, 1H, J_{4 ;5}4:7 Hz, H-4⁰), 4.77

0

J_{6 a;5}4:6, J_{6 a,6 b}12.0 Hz, H-6⁰a), 4.72 (d, 1H, J_1,2

0

3.3 Hz, H-1), 4.64 (dd, 1H, J_{6 b;5}6:4 Hz, H-6⁰b), 4.20

(dd, 1H, H-2), 4.00 (d, 1H, J_6a,58.9 Hz, H-6a), 3.93

(d, 1H, J_OH,41.5 Hz, OH), 3.87–3.75 (m, 1H, H-5),

3.81 (d, 1H, H-6b), 3.49 (dd with appearance of t,

1H,H-4), 3.33 (s, 3H, OCH₃), 1.88 (br s, 6H,

(dd, 1H, J_{6 a;5}5:1, J_{6 a;6 b}11:9 Hz, H-6⁰a), 4.69–4.58

(m, 2H, H-6a, H-6⁰b), 4.50 (dd, 1H, J_6b,55.5, J_6b,6a

11.9 Hz, H-6b), 4.34 (dd, 1H, J_3,48.1, J_3,210.8 Hz, H-

3), 4.09 (dd, 1H, H-2), 3.94 (d, 1H, J_OH,41.7 Hz, OH),

3.77–3.69 (m, 1H, H-5), 3.64 (ddd with appearance of

dt, 1H, J_4,58.9 Hz, H-4), 3.42 (s, 3H, OCH₃), 1.90 (s,

6H, CCH₃· 2); ¹³C NMR (75 MHz): d 166.32–164.96

(CO), 137.21 (C · 2), 133.52–132.85, 129.88–128.35 (C-

Ar), 107.96 (C-1⁰), 99.19 (C-1), 82.21 (C-2⁰, C-3), 81.35

0

CCH₃· 2), 1.06 (s, 9H,

C

(CH₃)₃); ¹³C NMR

(75 MHz):

d

165.73–164.70 (CO), 135.54–132.91

(C · 2, C-Ar), 129.92–127.47 (C-Ar), 107.24 (C-1⁰),

98.14 (C-1), 81.68 (C-2⁰), 81.08 (C-4⁰), 78.71 (C-3),

2532

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

(C-4⁰), 76.73 (C-3⁰), 73.71 (C-5), 70.34 (C-5⁰), 70.26 (C-

4), 63.68 (C-6^*), 62.58 (C-6⁰^*), 56.50 (OCH₃), 54.44 (C-

2), 8.59 (CCH₃· 2).

5), 70.30 (C-5⁰), 69.58 (C-6), 62.88 (C-6⁰), 56.70

(OCH₃), 54.63 (C-2), 8.82 (CCH₃· 2).

3.2.11.2. Acetate 17d. ½aꢁ³_D²+33.2 (c 0.65, CHCl₃); R_f

0.55 ((iPr)₂O); ¹H NMR (300 MHz): d 5.08 (with appear-

ance of t, 1H, J_4,3ꢂ J_4,59.7 Hz, H-4); HRFABMS:

calcd for C₅₆H₅₃NO₁₇[M+Na]⁺, m/z 1034.3211; found,

m/z 1034.3218.

3.2.10.2. Acetate 17b. ½aꢁ²_D⁴+32.2 (c 1.03, CHCl₃); R_f

1

0.64 (7:3 hexane–EtOAc, two developments); H NMR

(300 MHz): d 5.22 (dd,1H, J_4,39.0, J_4,59.8 Hz, H-4);

HRMALDI-TOF MS: calcd for C₅₆H₅₁NO₁₈[M+Na]⁺,

m/z 1048.3004; found, m/z 1048.2958.

20

3.2.11.3. Disaccharide 18c. 53%; ½aꢁ_Dꢀ11.6 (c 1.00,

22

3.2.10.3. Disaccharide 18a. 38%; ½aꢁ_D+4.2 (c 1.01,

CHCl₃); R_f0.21 (7:3 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.10–7.70, 7.60–7.10 (m, 25H, ArH),

CHCl₃); R_f0.10 (7:3 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.10–7.90, 7.75–7.10 (m, 25H, ArH),

5.98–5.91 (m, 1H, H-5⁰), 5.64 (dd, 1H, J_{3 ;2}1:4,

0

5.98–5.90 (m, 1H, H-5⁰), 5.67 (dd, 1H, J_{3 ;2}1:6,

J_{3 ;4}5:3 Hz, H-3⁰), 5.42 (d, 1H, H-2⁰), 5.39 (s, 1H, H-

0

J_{3 ;4}5:4 Hz, H-3⁰), 5.47 (d, 1H, H-2⁰), 5.42 (s, 1H, H-

1⁰), 5.00 (d, 1H, J_1,28.5 Hz, H-1), 4.87 (dd, 1H,

0

1⁰), 5.06 (d, 1H, J_1,28.7 Hz, H-1), 4.85 (dd, 1H,

J_{4 ;5}3:8 Hz, H-4⁰), 4.75–4.68 (m, 2H, H-6⁰a, H-6⁰b),

4.59 (d, 1H, J 12.9 Hz, CH₂Ph), 4.55 (d, 1H, CH₂Ph),

4.33–4.22 (m, 1H, H-3), 3.96 (dd, 1H, J_2,310.9 Hz, H-

2), 3.90 (dd, 1H, J_6a,53.6, J_6a,6b11.0 Hz, H-6a), 3.83

(dd, 1H, J_6b,51.5 Hz, H-6b), 3.78 (dd, 1H, J_4,38.5, J_4,5

9.7 Hz, H-4), 3.70–3.62 (m, 1H, H-5), 3.54–3.50 (m,

1H, OH), 3.45 (s, 3H, OCH₃), 1.97 (s, 6H, CCH₃· 2);

¹³C NMR (75 MHz): d 171.78, 166.11–165.34 (CO),

137.98 (C · 2), 137.05–127.22 (C-Ar), 107.10 (C-1⁰),

99.08 (C-1), 82.06 (C-2⁰), 81.57 (C-4⁰), 79.66 (C-4),

77.18 (C-3⁰), 74.29 (C-5), 73.04 (CH₂Ph), 70.30 (C-3),

70.09 (C-5⁰), 68.13 (C-6), 63.11 (C-6⁰), 56.47 (C-2),

56.18 (OCH₃), 8.65 (CCH₃· 2).

0

J_{4 ;5}4:1 Hz, H-4⁰), 4.82–4.68 (m, 3H, H-6a, H-6⁰a, H-

0

6b), 4.64 (dd, 1H, J_{6 b;5}6:1, J_{6 b;6 a}12:0 Hz, H-6⁰b),

4.42–4.32 (m, 1H, H-3), 3.99 (dd, 1H, J_2,310.6 Hz, H-

2), 3.93–3.85 (m, 1H, H-5), 3.84–3.74 (m, 2H, H-4,

OH), 3.43 (s, 3H, OCH₃), 1.97 (s, 6H, CCH₃· 2); ¹³C

NMR (75 MHz): d 171.73, 165.95–165.31 (CO), 137.10

(C · 2), 133.46–132.74, 129.80–128.21 (C-Ar), 108.04

(C-1⁰), 99.18 (C-1), 82.46 (C-2⁰), 81.78 (C-4⁰), 81.29 (C-

4), 76.95 (C-3⁰), 72.37 (C-5), 70.22 (C-5⁰), 70.07 (C-3),

62.96 (C-6^*), 62.82 (C-6⁰^*), 56.55 (OCH₃), 55.88 (C-2),

8.65 (CCH₃· 2).

0

20

3.2.10.4. Acetate 18b. ½aꢁ_D+7.7 (c 0.97, CHCl₃); R_f

33

1

0.24 (7:3 hexane–EtOAc, two developments); H NMR

3.2.11.4. Acetate 18d. ½aꢁ_D+0.5 (c 0.73, CHCl₃); R_f

1

(300 MHz): d 5.70 (dd, 1H, J_3,48.5, J_3,210.6 Hz, H-3);

HRMALDI-TOF MS: calcd for C₅₆H₅₁NO₁₈

[M+Na]⁺, m/z 1048.3004; found, m/z 1048.2954.

0.42 (7:3 hexane–EtOAc, two developments); H NMR

(300 MHz): d 5.65 (dd, 1H, J_3,48.8, J_3,210.6 Hz, H-3);

HRFABMS: calcd for C₅₆H₅₃NO₁₇[M+Na]⁺, m/z

1034.3211; found, m/z 1034.3219.

3.2.11. Methyl 2,3,5,6-tetra-O-benzoyl-b-^D-galactofur-

anosyl-(1!3)-4-O-acetyl-6-O-benzyl-2-deoxy-2-dimethyl-

maleimido-b-^D-glucopyranoside (17d) and methyl 2,3,5,6-

tetra-O-benzoyl-b-^D-galactofuranosyl-(1!4)-3-O-acetyl-

6-O-benzyl-2-deoxy-2-dimethylmaleimido-b-^D-glucopyran-

oside (18d)

3.2.12. Methyl 2,3,5,6-tetra-O-benzoyl-b-^D-galactofuran-

osyl-(1!3)-4-O-acetyl-6-O-tert-butyldiphenylsilyl-2-de-

oxy-2-dimethylmaleimido-b-^D-glucopyranoside (17f) and

methyl

2,3,5,6-tetra-O-benzoyl-b-^D-galactofuranosyl-

(1!4)-3-O-acetyl-6-O-tert-butyldiphenylsilyl-2-deoxy-2-

22

3.2.11.1. Disaccharide 17c. 18%; ½aꢁ_D+28.1 (c 0.64,

dimethylmaleimido-b-^D-glucopyranoside (18f)

30

CHCl₃); R_f0.27 (7:3 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.10–7.70, 7.60–7.20 (m, 25H, ArH),

3.2.12.1. Disaccharide 17e. 27%; ½aꢁ_D+29.6 (c 1.01,

CHCl₃); R_f0.56 (1:1 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.15–7.90, 7.95–7.65, 7.60–7.20 (m, 30H,

ArH), 5.98–5.90 (m, 1H, H-5⁰), 5.63 (br d, 1H,

6.00–5.92 (m, 1H, H-5⁰), 5.63 (dd, 1H, J_{3 ;2}1:8,

0

J_{3 ;4}5:3 Hz, H-3⁰), 5.24 (m, 1H, H-2⁰), 5.20 (s, 1H, H-

0

1⁰), 4.90 (d, 1H, J_1,28.5 Hz, H-1), 4.84 (dd, 1H,

J_{3 ;4}5:6 Hz, H-3⁰), 5.26 (br s, 1H, H-2⁰), 5.20 (s, 1H,

H-1⁰), 4.91 (d, 1H, J_1,28.8 Hz, H-1), 4.83 (dd with

0

J_{4 ;5}4:1 Hz, H-4⁰), 4.76 (dd, 1H, J_{6 a;5}4:8,

0

J_{6 a;6 b}11:7 Hz, H-6⁰a), 4.64 (dd, 1H, J_{6 b;5}6:2 Hz, H-

6⁰b), 4.61 (s, 2H, CH₂Ph), 4.35–4.27 (m, 1H, H-3),

4.07 (dd, 1H, J_2,310.7 Hz, H-2), 3.85–3.77 (m, 2H, H-

6a, OH), 3.71–3.63 (m, 1H, H-6b), 3.61–3.56 (m, 2H,

H-4, H-5), 3.45 (s, 3H, OCH₃), 1.91 (br s, 6H,

CCH₃· 2); ¹³C NMR (75 MHz): d 166.02–165.12

(CO), 138.28 (C · 2), 133.69–126.50 (C-Ar), 107.96 (C-

1⁰), 99.27 (C-1), 82.41 (C-3^*), 82.33 (C-2⁰^*), 81.50 (C-

4⁰), 76.85 (C-3⁰), 75.18 (C-4), 73.56 (CH₂Ph), 70.75 (C-

appearance of t, 1H, J_{4 ;5}4:7 Hz, H-4⁰), 4.74 (dd, 1H,

0

J_{6 a;5}4:4, J_{6 a;6 b}12:0 Hz, H-6⁰a), 4.64 (dd, 1H,

0

J_{6 b;5}6:3 Hz, H-6⁰b), 4.32 (dd, 1H, J_3,47.0, J_3,2

10.3 Hz, H-3), 4.11–3.98 (m, 2H, H-2, H-6a), 3.84 (dd,

1H, J_6b,55.1, J_6b,6a11.0 Hz, H-6b), 3.69 (br s, 1H,

OH), 3.60–3.51 (m, 2H, H-4, H-5), 3.46 (s, 3H, OCH₃),

1.91 (br s, 6H, CCH₃· 2), 1.06 (s, 9H, C (CH₃)₃); ¹³C

NMR (75 MHz): d 165.81–164.95 (CO), 135.57–133.00

(C · 2, C-Ar), 129.90–127.52 (C-Ar), 107.75 (C-1⁰),

0

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

2533

99.00 (C-1), 82.34 (C-3), 82.19 (C-2⁰), 81.24 (C-4⁰), 77.10

(C-3⁰), 76.74 (C-4^*), 70.52 (C-5^*), 70.26 (C-5⁰), 63.59 (C-

6), 62.73 (C-6⁰), 56.32 (OCH₃), 54.62 (C-2), 26.62 (C

(CH₃)₃), 19.16 (C(CH₃)₃), 8.63 (CCH₃· 2).

J_{2 ;1}8:1, J_{2 ;3}10:4 Hz, H-2⁰), 5.07 (dd, 1H, J_3,48.4, J_3,2

11.1 Hz, H-3), 4.97 (dd, 1H, H-3⁰), 4.71–4.63 (m, 1H,

H-6a), 4.66 (d, 1H, J_1,23.6 Hz, H-1), 4.65 (d, 1H, H-

1⁰), 4.57 (dd, 1H, J_6b,55.1, J_6b,6a12.0 Hz, H-6b), 4.24–

4.10 (m, 4H, H-2, H-6⁰a, H-6⁰b, OH), 4.09–4.01 (m,

1H, H-5⁰), 4.01–3.93 (m, 1H, H-5), 3.66 (dd with appear-

ance of t, 1H, J_4,59.1 Hz, H-4), 3.31 (s, 3H, OCH₃), 2.14,

2.08, 1.94, 1.74 (4s, 12H, COCH₃· 4), 2.01, 1.96 (2br s,

6H, CCH₃· 2); ¹³C NMR (75 MHz): d 171.62–166.24

(CO), 132.87 (C-Ar, C · 2), 129.56–128.25 (C-Ar),

99.94 (C-1⁰), 98.25 (C-1), 78.74 (C-3), 71.16 (C-5⁰),

70.67 (C-3⁰), 69.56 (C-4, C-5), 68.65 (C-2⁰), 66.90 (C-

4⁰), 63.51 (C-6), 61.36 (C-6⁰), 55.11 (OCH₃), 54.34 (C-

2), 20.44–19.85 (COCH₃· 4), 8.79, 8.64 (CCH₃).

0

28

3.2.12.2. Acetate 17f. ½aꢁ_D+36.9 (c 1.05, CHCl₃); R_f

0.56 ((iPr)₂O, two developments); ¹H NMR (300 MHz):

d 5.08 (dd, 1H, J_4,39.0, J_4,59.8 Hz, H-4); HRFABMS:

calcd for C₆₅H₆₅NO₁₇Si [M+Na]⁺, m/z 1182.3919;

found, m/z 1182.3888.

32

3.2.12.3. Disaccharide 18e. 60%; ½aꢁ_Dꢀ4.1 (c 0.99,

CHCl₃); R_f0.47 (1:1 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.10–7.95, 7.85–7.70, 7.65–7.20 (m, 30H,

ArH), 6.00–5.93 (m, 1H, H-5⁰), 5.66 (dd, 1H, J_{3 ;2}1:0,

0

J_{3 ;4}5:4 Hz, H-3⁰), 5.62 (s, 1H, H-1⁰), 5.46 (d, 1H, H-

3.2.13.2. Acetate 19b. ½aꢁ²_D⁶+56.4 (c 0.97, CHCl₃); R_f

0

1

2⁰), 5.00 (d, 1H, J_1,28.5 Hz, H-1), 4.90 (dd, 1H,

0.17 (1:1 hexane–EtOAc); H NMR (300 MHz): d 5.11

J_{4 ;5}5:1 Hz, H-4⁰), 4.78 (dd, 1H, J_{6 a;5}4:2,

(dd with appearance of t, 1H, J_4,59.4 Hz, H-4);

HRFABMS: calcd for C₃₆H₄₃NO₁₈[M+Na]⁺, m/z

800.2378; found, m/z 800.2385.

0

J_{6 a;6 b}12:2 Hz, H-6⁰a), 4.71 (dd, 1H, J_{6 b;5}6:3 Hz,

H-6⁰b), 4.38–4.27 (m, 1H, H-3), 4.08 (dd, 1H, J_6a,52.9,

J_6a,6b11.7 Hz, H-6a), 4.03–3.90 (m, 3H, H-2, H-4, H-

6b), 3.58–3.50 (m, 1H, H-5), 3.46 (d, 1H, J_OH,34.7 Hz,

OH), 3.42 (s, 3H, OCH₃), 1.99 (s, 6H, CCH₃· 2), 0.99

(s, 9H, C (CH₃)₃); ¹³C NMR (75 MHz): d 171.85–

165.15 (CO), 137.08–132.96 (C · 2, C-Ar), 129.84–

127.34 (C-Ar), 107.01 (C-1⁰), 98.79 (C-1), 82.05 (C-2⁰),

81.89 (C-4⁰), 78.84 (C-4), 77.45 (C-3⁰), 75.04 (C-5),

70.29 (C-3), 70.20 (C-5⁰), 63.13 (C-6⁰), 62.44 (C-6),

56.46 (C-2), 56.11 (OCH₃), 26.58 (C(CH₃)₃), 19.16

(C(CH₃)₃), 8.70 (CCH₃· 2).

0

32

3.2.13.3. Disaccharide 20a. 30%; ½aꢁ_D+65.3 (c 0.86,

CHCl₃); R_f0.17 (1:1 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.10–8.00, 7.65–7.42 (m, 5H, ArH), 5.36

(br d, 1H, J_{4 ;3}3:0 Hz, H-4⁰), 5.25 (dd, 1H, J_{2 ;1}8:0,

0

J_{2 ;3}10:4 Hz, H-2⁰), 5.13 (ddd, 1H, J_3,OH1.6, J_3,48.2,

J_3,210.6 Hz, H-3), 4.96 (dd, 1H, H-3⁰), 4.69 (d, 1H,

J_1,23.6 Hz, H-1), 4.60 (d, 1H, H-1⁰), 4.56 (dd, 1H,

J_6a,51.8, J_6a,6b12.0 Hz, H-6a), 4.36 (dd, 1H, J_6b,5

4.9 Hz, H-6b), 4.17–4.00 (m, 5H, H-2, H-5, H-6⁰a, H-

6⁰b, OH), 3.99–3.92 (m, 1H, H-5⁰), 3.58 (dd, 1H,

J_4,3ꢂ J_4,59.8 Hz, H-4), 3.33 (s, 3H, OCH₃), 2.17, 2.08,

1.97, 1.96 (4s, 12H, COCH₃· 4), 1.95 (s, 6H,

CCH₃· 2); ¹³C NMR (75 MHz): d 171.68–166.10

(CO), 136.99 (C · 2, C-Ar), 133.22–128.47 (C-Ar),

101.69 (C-1⁰), 98.31 (C-1), 83.21 (C-4), 71.07 (C-5⁰),

70.83 (C-3⁰), 68.74 (C-2⁰), 67.47 (C-5), 66.64 (C-4⁰),

65.51 (C-3), 62.95 (C-6), 61.50 (C-6⁰), 55.31 (OCH₃),

55.22 (C-2), 20.50–20.23 (COCH₃· 4), 8.64 (CCH₃· 2).

0

30

3.2.12.4. Acetate 18f. ½aꢁ_Dꢀ8.5 (c 1.01, CHCl₃); R_f

0.34 ((iPr)₂O, two developments); ¹H NMR (300 MHz):

d 5.68 (dd, 1H, J_3,49.0, J_3,210.3 Hz, H-3); HRFABMS:

calcd for C₆₅H₆₅NO₁₇Si [M+Na]⁺, m/z 1182.3919;

found, m/z 1182.3934.

3.2.13. Methyl 2,3,4,6-tetra-O-acetyl-b-^D-galactopyran-

osyl-(1!3)-4-O-acetyl-6-O-benzoyl-2-deoxy-2-dimethyl-

maleimido-a-^D-glucopyranoside (19b) and methyl 2,3,4,6-

tetra-O-acetyl-b-^D-galactopyranosyl-(1!4)-3-O-acetyl-6-

O-benzoyl-2-deoxy-2-dimethylmaleimido-a-^D-glucopyran-

oside (20b). In spite of the fact that by column chroma-

tography of the crude reaction mixture disaccharides

19a and 20a could not be separated eﬃciently, using

3.2.13.4. Acetate 20b. ½aꢁ²_D⁸+78.1 (c 0.62, CHCl₃); R_f

1

0.10 (1:1 hexane–EtOAc); H NMR (300 MHz): d 6.27

(dd, 1H, J_3,49.0, J_3,211.4 Hz, H-3); HRFABMS: calcd

for C₃₆H₄₃NO₁₈[M+Na]⁺, m/z 800.2378; found, m/z

800.2393.

1

the data from the H NMR spectroscopy of the pure

fractions, a 2:1 ratio of regioisomeric disaccharides

was established for the mixture. On the other hand,

chromatography of the corresponding acetates allowed

the isolation of acetates 19b (48.1%) and 20b (20.8%)

that were fully characterized.

3.2.14. Methyl 2,3,4,6-tetra-O-acetyl-b-^D-galactopyran-

osyl-(1!3)-4-O-acetyl-6-O-benzyl-2-deoxy-2-dimethyl-

maleimido-a-^D-glucopyranoside (19d) and methyl 2,3,4,6-

tetra-O-acetyl-b-^D-galactopyranosyl-(1!4)-3-O-acetyl-6-

O-benzyl-2-deoxy-2-dimethylmaleimido-a-^D-glucopyran-

oside (20d). Since the mixture of disaccharides could

not be separated by column chromatography, the crude

reaction product was acetylated. On the basis of the

26

3.2.13.1. Disaccharide 19a. 61%; ½aꢁ_D+69.1 (c 1.05,

CHCl₃); R_f0.14 (1:1 hexane–EtOAc); ¹H NMR

(300 MHz): d 8.10–8.00, 7.65–7.42 (m, 5H, ArH), 5.35

1

analysis of the H NMR spectrum of the mixture, a

1:1 mixture of acetates was detected. Column chroma-

(dd, 1H, J_{4 ;5}0:9, J_{4 ;3}3:4 Hz, H-4⁰), 5.16 (dd, 1H,

0

2534

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

tography aﬀorded acetates 19d and 20d allowing their

full characterization.

reaction mixture aﬀorded a mixture of disaccharides

19e and 20e (50%), trisaccharide 21 (28%) and unreacted

acceptor 11c (9.6%). The inseparable mixture of disac-

charides was acetylated, and the acetates 19f and 20f

were isolated and fully characterized.

31

3.2.14.1. Acetate 19d. 27.3%; ½aꢁ_D+70.9 (c 1.01,

CHCl₃); R_f0.38 (3:7 hexane–EtOAc); ¹H NMR

(300 MHz): d 7.40–7.28 (m, 5H, ArH), 5.29 (dd, 1H,

29

J_{4 ;5}1:0, J_{4 ;3}3:4 Hz, H-4⁰), 5.15 (dd, 1H, J_3,48.8, J_3,2

10.9 Hz, H-3), 5.01 (dd, 1H, J_4,510.3 Hz, H-4), 4.94 (dd,

3.2.15.1. Acetate 19f. 49.8%; ½aꢁ_D+52.1 (c 1.04,

0

CHCl₃); R_f0.34 (1:1 hexane–EtOAc, two develop-

ments); ¹H NMR (300 MHz): d 7.75–7.60, 7.50–7.35

1H, J_{2 ;1}7:8, J_{2 ;3}10:4 Hz, H-2⁰), 4.85 (dd, 1H, H-3⁰),

4.63 (d, 1H, J_1,23.8 Hz, H-1), 4.56 (d, 1H, J 12.0 Hz,

CH₂Ph), 4.52 (d, 1H, CH₂Ph), 4.45 (d, 1H, H-1⁰), 4.24

(dd, 1H, H-2), 4.12–4.06 (m, 2H, H-6⁰a, H-6⁰b), 4.01–3.92

(m, 1H, H-5), 3.87–3.80 (m, 1H, H-5⁰), 3.57–3.52 (m, 2H,

H-6a, H-6b), 3.32 (s, 3H, OCH₃), 2.13, 2.06, 1.97, 1.93,

1.80 (5s, 15H, COCH₃· 5), 2.02, 1.98 (2br s, 6H,

CCH₃· 2); ¹³C NMR (75 MHz): d 170.15–168.61 (CO),

138.63–135.89 (C-Ar, C · 2), 128.17–127.49 (C-Ar),

99.32 (C-1⁰), 98.49 (C-1), 73.37 (CH₂Ph), 72.82 (C-3),

70.85 (C-3⁰), 70.32 (C-5⁰), 69.89 (C-4), 69.03 (C-2⁰), 68.76

(C-5, C-6), 66.77 (C-4⁰), 60.73 (C-6⁰), 55.19 (OCH₃), 55.00

(C-2), 20.71–20.21 (COCH₃· 5), 8.80, 8.67 (CCH₃);

HRFABMS: calcd for C₃₆H₄₅NO₁₇[M+Na]⁺, m/z

786.2585; found, m/z 786.2606.

0

(m, 10H, ArH), 5.29 (dd, 1H, J_{4 ;5}0:8, J_{4 ;3}3:2 Hz, H-

4⁰), 5.13 (dd, 1H, J_3,49.0, J_3,211.0 Hz, H-3), 4.93 (dd,

1H, J_{2 ;1}7:7, J_{2 ;3}10:6 Hz, H-2⁰), 4.89 (dd, 1H, J_4,5

10.0 Hz, H-4), 4.84 (dd, 1H, H-3⁰), 4.63 (d, 1H, J_1,2

3.8 Hz, H-1), 4.45 (d, 1H, H-1⁰), 4.21 (dd, 1H, H-2),

4.12–4.02 (m, 2H, H-6⁰a, H-6⁰b), 3.96–3.87 (m, 1H, H-

5), 3.87–3.79 (m, 1H, H-5⁰), 3.74 (dd, 1H, J_6a,56.2,

J_6a,6b11.1 Hz, H-6a), 3.66 (dd, 1H, J_6b,52.2 Hz, H-

6b), 3.33 (s, 3H, OCH₃), 2.11, 2.06, 1.92, 1.87, 1.79

(5s, 15H, COCH₃· 5), 2.02, 1.98 (2s, 6H, CCH₃· 2),

1.04 (s, 9H, C (CH₃)₃); ¹³C NMR (75 MHz): d 172.18–

168.67 (CO), 135.54–133.12 (C · 2, C-Ar), 129.54–

127.55 (C-Ar), 99.38 (C-1⁰), 98.33 (C-1), 73.09 (C-3),

70.91 (C-3⁰), 70.72 (C-5), 70.32 (C-5⁰), 69.73 (C-4),

69.08 (C-2⁰), 66.80 (C-4⁰), 63.19 (C-6), 60.79 (C-6⁰),

55.14 (C-2), 55.07 (OCH₃), 26.60 (C(CH₃)₃), 20.65–

20.26 (COCH₃), 19.04 (C(CH₃)₃), 8.86, 8.72 (CCH₃);

HRFABMS: calcd for C₄₅H₅₇NO₁₇Si [M+Na]⁺, m/z

934.3293; found, m/z 934.3274.

0

30

3.2.14.2. Acetate 20d. 28.9%; ½aꢁ_D+77.0 (c 1.02,

CHCl₃); R_f0.30 (3:7 hexane–EtOAc); ¹H NMR

(300 MHz): d 7.46–7.31 (m, 5H, ArH), 6.21 (dd, 1H,

0

J_3,48.5, J_3,211.4 Hz, H-3), 5.25 (dd, 1H, J_{4 ;5}0:9,

J_{4 ;3}3:5 Hz, H-4⁰), 4.98 (dd, 1H, J_{2 ;1}7.9, J_{2 ,3}

0

31

10.3 Hz, H-2⁰), 4.82 (d, 1H, J 12.0 Hz, CH₂Ph), 4.76

(dd, 1H, H-3⁰), 4.70 (d, 1H, J_1,23.8 Hz, H-1), 4.46 (d,

1H, CH₂Ph), 4.39 (d, 1H, H-1⁰), 4.34 (dd, 1H, H-2),

3.2.15.2. Acetate 20f. 30.5%; ½aꢁ_D+69.3 (c 1.01,

CHCl₃); R_f0.25 (1:1 hexane–EtOAc); ¹H NMR

(300 MHz): d 7.82–7.68, 7.50–7.35 (m, 10H, ArH),

6.25 (dd, 1H, J_3,49.5, J_3,211.4 Hz, H-3), 5.29 (dd, 1H,

4.05 (d, 2H, J_{6 ;5}6:8 Hz, H-6⁰a, H-6⁰b), 3.98–3.78 (m,

3H, H-4, H-5, H-6a), 3.67 (dd, 1H, J_6b,51.2, J_6b,6a

10.6 Hz, H-6b), 3.59 (ddd with appearance of dt, 1H,

H-5⁰), 3.30 (s, 3H, OCH₃), 2.12, 2.07, 1.954, 1.95, 1.91

(5s, 15H, COCH₃· 5), 1.94 (s, 6H, CCH₃· 2); ¹³C

NMR (75 MHz): d 170.20–168.38 (CO), 137.37, 137.02

(C-Ar, C · 2), 128.57–128.09 (C-Ar), 99.82 (C-1⁰),

98.58 (C-1), 75.57 (C-4), 73.59 (CH₂Ph), 70.96 (C-3⁰),

70.34 (C-5⁰), 69.70 (C-5), 69.12 (C-2⁰), 67.12 (C-3, C-

6), 66.77 (C-4⁰), 60.87 (C-6⁰), 55.20 (OCH₃), 53.39 (C-

2), 20.84–20.38 (COCH₃· 5), 8.67 (CCH₃· 2);

HRFABMS: calcd for C₃₆H₄₅NO₁₇[M+Na]⁺, m/z

786.2585; found, m/z 786.2613.

0

J_{4 ;5}0:9, J_{4 ;3}3:1 Hz, H-4⁰), 5.07 (dd, 1H, J_{2 ;1}8.0,

0

J_{2 ;3}10:2 Hz, H-2⁰), 4.87 (dd, 1H, H-3⁰), 4.81 (d, 1H,

H-1⁰), 4.71 (d, 1H, J_1,23.7 Hz, H-1), 4.34 (dd, 1H, H-

2), 4.16–4.05 (m, 3H, H-4, H-6⁰a, H-6⁰b), 3.98 (dd,

1H, J_6a,52.3, J_6a,6b11.8 Hz, H-6a), 3.90 (dd, 1H, J_6b,5

1.1 Hz, H-6b), 3.80–3.67 (m, 2H, H-5⁰, H-5), 3.24 (s,

3H, OCH₃), 2.14, 2.06, 1.98, 1.96, 1.82 (5s, 15H,

COCH₃· 5), 1.96 (s, 6H, CCH₃· 2), 1.11 (s, 9H, C

(CH₃)₃); ¹³C NMR (75 MHz): d 170.23–168.50 (CO),

137.08–135.31 (C · 2, C-Ar), 133.37–127.56 (C-Ar),

99.85 (C-1⁰), 98.46 (C-1), 75.32 (C-4), 71.14 (C-3⁰),

70.62 (C-5^*), 70.54 (C-5⁰^*), 69.32 (C-2⁰), 67.24 (C-3),

66.90 (C-4⁰), 61.15 (C-6^*), 61.04 (C-6⁰^*), 54.98 (OCH₃),

53.64 (C-2), 26.76 (C (CH₃)₃), 20.95–20.42 (COCH₃),

19.35 (C(CH₃)₃), 8.76 (CCH₃· 2); HRFABMS: calcd

for C₄₅H₅₇NO₁₇Si [M+Na]⁺, m/z 934.3293; found, m/z

934.3310.

0

3.2.15. Methyl 2,3,4,6-tetra-O-acetyl-b-^D-galactopy-

ranosyl-(1!3)-4-O-acetyl-6-O-tert-butyldiphenylsilyl-2-

deoxy-2-dimethylmaleimido-a-^D-glucopyranoside (19f),

methyl

2,3,4,6-tetra-O-acetyl-b-^D-galactopyranosyl-

(1!4)-3-O-acetyl-6-O-tert-butyldiphenylsilyl-2-deoxy-2-di-

methylmaleimido-a-^D-glucopyranoside (20f) and methyl

2,3,4,6-tetra-O-acetyl-b-^D-galactopyranosyl-(1!3)-[2,3,4,6-

tetra-O-acetyl-b-^D-galactopyranosyl-(1!4)]-6-O-tert-butyl-

diphenylsilyl-2-deoxy-2-dimethylmaleimido-a-^D-glucopy-

ranoside (21). Column chromatography of the crude

28

3.2.15.3. Trisaccharide 21. 28%; ½aꢁ_D+39.3 (c 1.04,

CHCl₃); R_f0.19 (1:1 hexane–EtOAc); ¹H NMR

(300 MHz): d 7.80–7.70, 7.50–7.25 (m, 10H, ArH),

5.34 (d, 1H, J_{3 ;4}3:1 Hz, H-4⁰⁰), 5.30 (d, 1H,

00 00

J_{3 ;4}3:2 Hz, H-4⁰), 5.16 (dd, 1H, J_3,29.3, J_3,410.6 Hz,

0

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

2535

28

H-3), 5.09 (dd, 1H, J_{2 ;1}8:1, J_{2 ;3}10:5 Hz, H-2⁰⁰), 5.00

3.2.16.2. Disaccharide 23a. 68.3%; ½aꢁ_D+10.6 (c

00 00

1

(dd, 1H, J_{2 ;1}7:9, J_{2 ;3}10:5 Hz, H-2⁰), 4.92 (dd, 1H, H-

3⁰), 4.86 (dd, 1H, H-3⁰⁰), 4.85 (d, 1H, H-1⁰⁰), 4.58 (d, 1H,

J_1,23.8 Hz, H-1), 4.51 (d, 1H, H-1⁰), 4.31 (dd, 1H,

1.02, CHCl₃); R_f0.22 (1:1 hexane–EtOAc); H NMR

0

(300 MHz): d 8.09–8.02, 7.66–7.45 (m, 5H, ArH), 5.35

(br d, 1H, J_{4 ;3}2:9 Hz, H-4⁰), 5.25 (dd, 1H, J_{2 ;1}8:1,

0

J_{6 a;5}1:9, J_{6 a;6 b}11:0 Hz, H-6⁰a), 4.35–4.25 (m, 1H, H-

6⁰⁰a), 4.24–4.09 (m, 3H, H-2, H-6⁰b, H-6⁰⁰b), 3.98 (dd

with appearance of t, 1H, J_4,59.5 Hz, H-4), 4.03–3.77

(m, 4H, H-5⁰, H-5⁰⁰, H-6a, H-6b), 3.72–3.64 (m, 1H,

H-5), 3.21 (s, 3H, OCH₃), 2.14, 2.05, 2.04, 1.99, 1.92,

1.88, 1.85 (7s, 24H, COCH₃· 8), 1.97 (s, 6H,

CCH₃· 2), 1.10 (s, 9H, C(CH₃)₃); ¹³C NMR

J_{2 ;3}10:4 Hz, H-2⁰), 5.07 (d, 1H, J_1,28.5 Hz, H-1),

4.94 (dd, 1H, H-3⁰), 4.60 (dd, 1H, J_6a,51.8, J_6a,6b

11.7 Hz, H-6a), 4.58 (d, 1H, H-1⁰), 4.37–4.24 (m, 2H,

H-3, OH), 4.32 (dd, 1H, J_6b,54.9 Hz, H-6b), 4.14–4.06

(m, 2H, H-6⁰a, H-6⁰b), 4.05–3.90 (m, 1H, H-5⁰), 3.95

(dd, 1H, J_2,310.9 Hz, H-2), 3.87–3.79 (m, 1H, H-5),

3.65 (dd, 1H, J_4,38.4, J_4,59.5 Hz, H-4), 3.44 (s, 3H,

OCH₃), 2.14, 2.08, 1.98, 1.956 (4s, 12H, COCH₃· 4)

1.96 (s, 6H, CCH₃· 2); ¹³C NMR (75 MHz): d

171.62–166.03 (CO), 137.08 (C · 2, C-Ar), 133.20–

128.41 (C-Ar), 101.86 (C-1⁰), 99.11 (C-1), 83.32 (C-4),

71.80 (C-5), 71.16 (C-5⁰), 70.70 (C-3⁰), 69.85 (C-3),

68.50 (C-2⁰), 66.58 (C-4⁰), 62.92 (C-6), 61.49 (C-6⁰),

56.61 (OCH₃), 55.33 (C-2), 20.45–20.11 (COCH₃· 4),

8.59 (CCH₃· 2).

0

(75 MHz):

d

170.39–168.80 (CO), 135.92–132.77

(C · 2, C-Ar), 129.91–127.62 (C-Ar), 99.32 (C-1⁰⁰),

98.75 (C-1⁰), 98.62 (C-1), 74.52 (C-4), 71.94 (C-3),

0

00

0

*

71.19 (C-3 ^*), 71.12 (C-3 ), 70.65 (C-5), 70.46 (C-5 ,

C-5⁰⁰), 69.13 (C-2⁰, C-2⁰⁰), 67.41 (C-4⁰, C-4⁰⁰), 61.79 (C-

0

00

*

6 ^*, C-6 ), 61.37 (C-6^*), 55.80 (C-2), 55.11 (OCH₃),

26.87 (C (CH₃)₃), 20.62–20.53 (COCH₃· 8), 19.40

(C(CH₃)₃), 8.88 (CCH₃· 2); HRFABMS: calcd for

C₅₇H₇₃NO₂₅Si [M+Na]⁺, m/z 1222.4138; found, m/z

1222.4108.

29

3.2.16.3. Acetate 23b. ½aꢁ_D+5.4 (c 1.04, CHCl₃); R_f

1

0.43 (3:7 hexane–EtOAc); H NMR (300 MHz): d 5.60

3.2.16. Methyl 2,3,4,6-tetra-O-acetyl-b-^D-galactopyran-

osyl-(1!3)-4-O-acetyl-6-O-benzoyl-2-deoxy-2-dimethyl-

maleimido-b-^D-glucopyranoside (22b) and methyl 2,3,4,6-

tetra-O-acetyl-b-^D-galactopyranosyl-(1!4)-3-O-acetyl-

6-O-benzoyl-2-deoxy-2-dimethylmaleimido-b-^D-glucopy-

(dd, 1H, J_3,48.5, J_3,210.6 Hz, H-3); HRFABMS: calcd

for C₃₆H₄₃NO₁₈[M+Na]⁺, m/z 800.2378; found, m/z

800.2353.

3.2.17. Methyl 2,3,4,6-tetra-O-acetyl-b-^D-galactopyran-

osyl-(1!4)-3-O-acetyl-6-O-benzyl-2-deoxy-2-dimethyl-

maleimido-b-^D-glucopyranoside (23d)

1

ranoside (23b). The analysis of the H NMR of the

crude reaction product allowed the identiﬁcation of

two disaccharides in a 13:1 ratio. The major one (23a)

was readily isolated and as usual characterized as its ace-

tate (23b). However, the minor disaccharide was better

puriﬁed as its acetate (22b) and fully characterized.

The ratio of acetates is coincident with the ratio

30

3.2.17.1. Disaccharide 23c. 88%; ½aꢁ_D+9.3 (c 1.02,

CHCl₃); R_f0.25 (1:1 hexane–EtOAc); ¹H NMR

(300 MHz): d 7.45–7.35 (m, 5H, ArH), 5.33 (dd, 1H,

J_{4 ;5}0:9, J_{4 ;3}3:5 Hz, H-4⁰), 5.17 (dd, 1H, J_{2 ;1}7:9,

0

J_{2 ;3}10:6 Hz, H-2⁰), 4.96 (d, 1H, J_1,28.5 Hz, H-1),

4.92 (dd, 1H, H-3⁰), 4.75 (d, 1H, J 12.0 Hz, CH₂Ph),

4.52 (d, 1H, CH₂Ph), 4.45 (d, 1H, H-1⁰), 4.24 (dd, 1H,

0

1

obtained by H NMR spectroscopy.

32

3.2.16.1. Acetate 22b. ½aꢁ_D+6.8 (c 0.38, CHCl₃); R_f

0

J_3,48.1, J_3,210.7 Hz, H-3), 4.10 (dd, 1H, J_{6 a;5}7:0,

0.37 (3:7 hexane–EtOAc); ¹H NMR (300 MHz): d 8.11–

J_{6 a;6 b}13:5 Hz, H-6⁰a), 4.08 (d, 1H, J_{6 b;5}6:2 Hz, H-

6⁰b), 3.92 (dd, 1H, H-2), 3.94–3.86 (m, 2H, H-5⁰, OH),

3.77–3.63 (m, 2H, H-6a, H6b), 3.68 (dd with appearance

of t, J_4,58.2 Hz, H-4), 3.61–3.54 (m, 1H, H-5), 3.44 (s,

3H, OCH₃), 2.13, 2.01, 2.00, 1.98 (4s, 12H, COCH₃· 4),

1.96 (s, 6H, CCH₃· 2); ¹³C NMR (75 MHz): d 171.76–

169.08 (CO), 138.06 (C-Ar), 137.15 (C · 2), 128.51–

127.82 (C-Ar), 101.38 (C-1⁰), 99.23 (C-1), 81.80 (C-4),

74.05 (C-5), 73.62 (CH₂Ph), 71.10 (C-5⁰), 70.72 (C-3⁰),

69.64 (C-3), 68.70 (C-2⁰), 67.84 (C-6), 66.83 (C-4⁰),

61.38 (C-6⁰), 56.62 (OCH₃), 55.63 (C-2), 20.64–20.37

(COCH₃· 4), 8.70 (CCH₃· 2).

0

8.04, 7.62–7.35 (m, 5H, ArH), 5.29 (br d, 1H,

J_{4 ;3}3:2 Hz, H-4⁰), 5.09 (dd with appearance of t, 1H,

0

J_4,3ꢂ J(_4,59.5 Hz, H-4), 4.95 (dd, 1H, J_{2 ;1}7:5,

J_{2 ;3}10:4 Hz, H-2⁰), 4.90–4.82 (m, 1H, H-3⁰), 4.85 (d,

1H, J_1,28.5 Hz, H-1), 4.65–4.51 (m, 2H, H-3, H-6a),

4.36 (dd, 1H, J_6b,55.3, J_6b,6a12.0 Hz, H-6b), 4.20 (d,

1H, H-1⁰), 4.15–4.07 (m, 2H, H-6⁰a, H-6⁰b), 4.06 (dd,

1H, J_2,310.5 Hz, H-2), 3.95–3.83 (m, 1H, H-5), 3.81–

3.73 (m, 1H, H-5⁰), 3.39 (s, 3H, OCH₃), 2.12, 2.06,

2.05, 1.95, 1.94 (5s, 15H, COCH₃· 5), 2.02 (s, 6H,

CCH₃· 2); ¹³C NMR (75 MHz): d 170.19–166.18

(CO), 137.50 (C · 2), 133.03–128.31 (C-Ar), 100.23 (C-

1⁰), 98.89 (C-1), 74.95 (C-3), 71.80 (C-5), 70.75 (C-3⁰),

70.43 (C-5⁰), 69.64 (C-4), 68.97 (C-2⁰), 66.63 (C-4⁰),

63.01 (C-6), 60.58 (C-6⁰), 56.52 (OCH₃), 55.20 (C-2),

0

30

3.2.17.2. Acetate 23d. ½aꢁ_D+4.8 (c1.05, CHCl₃); R_f

1

0.19 (1:1 hexane–EtOAc, two developments); H NMR

20.70–20.41

(COCH₃· 5),

8.86

(CCH₃· 2);

(300 MHz): d 5.50 (dd, 1H, J_3,49.1, J_3,210.6 Hz, H-3);

HRFABMS: calcd for C₃₆H₄₅NO₁₇[M+H]⁺, m/z

764.2766; found, m/z 764.2752.

HRFABMS: calcd for C₃₆H₄₃NO₁₈[M+Na]⁺, m/z

800.2378; found, m/z 800.2393.

2536

M. L. Bohn et al. / Carbohydrate Research 342 (2007) 2522–2536

´

5. (a) Figueroa-Perez, S.; Verez-Bencomo, V. Tetrahedron

3.2.18. Methyl 2,3,4,6-tetra-O-acetyl-b-D-galactopyran-

osyl-(1!4)-3-O-acetyl-6-O-tert-butyldiphenylsilyl-2-deoxy-

2-dimethylmaleimido-b-^D-glucopyranoside (23f)

Lett. 1998, 39, 9143–9146; (b) Cao, S.; Gan, Z.; Roy, R.

Carbohydr. Res. 1999, 318, 75–81; (c) Gan, Z.; Cao, S.;

Wu, Q.; Roy, R. J. Carbohydr. Chem. 1999, 18, 755–773;

32

3.2.18.1. Disaccharide 23e. 88.3%; ½aꢁ_D+8.9 (c 1.04,

(d) Zhang, Y.-M.; Esnault, J.; Mallet, J.-M.; Sinay, P. J.

¨

CHCl₃); R_f0.38 (1:1 hexane–EtOAc); ¹H NMR

(300 MHz): d 7.80–7.70, 7.43–7.35 (m, 10H, ArH),

Carbohydr. Chem. 1999, 18, 419–427; (e) Xia, J.; Srikrish-

nan, T.; Alderfer, J. L.; Jain, R. K.; Piskorz, C. F.; Matta,

K. L. Carbohydr. Res. 2000, 329, 561–577; (f) Ercegovic,

T.; Meijer, A.; Magnusson, G.; Ellervik, U. Org. Lett.

2001, 3, 913–915; (g) Gu, G.; Du, Y.; Pan, J. Carbohydr.

Res. 2002, 337, 1313–1317; (h) Xia, J.; Alderfer, J. L.;

Srikrishnan, T.; Chandrasekaran, E. V.; Matta, K. L.

Biorg. Med. Chem. 2002, 10, 3673–3684; (i) Xia, J.;

Alderfer, J. L.; Locke, R. D.; Piskorz, C. F.; Matta, K. L.

J. Org. Chem. 2003, 68, 2752–2759; (j) Yang, F.; Hua, Y.;

Du, Y. Carbohydr. Res. 2003, 338, 1313–1318; (k) Xue, J.;

Khaja, D.; Locke, R. D.; Matta, K. L. Synlett 2004, 861–

865; (l) Tanaka, H.; Matoba, N.; Tsukamoto, H.; Takim-

oto, H.; Yamada, H.; Takahashi, T. Synlett 2005, 824–

828; (m) Gourmala, C.; Zhu, Z.; Luo, Y.; Bo, T. F.;

Ghalem, S.; Hu, Y.; Zhang, Y. Tetrahedron: Asymmetry

2005, 16, 3024–3029; (n) Mukherjee, D.; Sarkar, S. K.;

Chattopadhyay, P.; Chowdhury, U. S. J. Carbohydr.

Chem. 2005, 24, 251–259; (o) Sundgren, A.; Lahmann, M.;

Oscarson, S. J. Carbohydr. Chem. 2005, 24, 379–391; (p)

Mukhopadhyay, B.; Maurer, S. V.; Rudolph, N.; van

Well, R. M.; Russell, D. A.; Field, R. A. J. Org. Chem.

2005, 70, 9059–9062.

5.35 (dd, 1H, J_{5 ;4}1:0, J_{3 ;4}3:4 Hz, H-4⁰), 5.20 (dd,

0

1H, J_{2 ;1}8:0, J_{2 ;3}10:2 Hz, H-2⁰), 4.964 (dd, 1H, H-

3⁰), 4.962 (d, 1H, J_1,28.6 Hz, H-1), 4.70 (d, 1H, H-1⁰),

4.30 (dd, 1H, J_3,28.4, J_3,410.9 Hz, H-3), 4.15–4.08 (m,

2H, H-6⁰a, H-6⁰b), 4.00–3.78 (m, 4H, H-4, H-5⁰, H-6a,

H-6b), 3.92 (dd, 1H, H-2), 3.72 (br s, 1H, OH), 3.54–

3.46 (m, 1H, H-5), 3.42 (s, 3H, OCH₃), 2.13, 2.03,

1.98, 1.96, 1.69 (5s, 18H, COCH₃· 4, CCH₃· 2), 1.09

(s, 9H, C (CH₃)₃); ¹³C NMR (75 MHz): d 171.78–

169.04 (CO), 137.17–132.62 (C · 2, C-Ar), 129.88–

127.66 (C-Ar), 101.20 (C-1⁰), 98.88 (C-1), 80.93 (C-4),

74.56 (C-5), 71.24 (C-5⁰), 70.84 (C-3⁰), 69.42 (C-3),

68.79 (C-2⁰), 66.78 (C-4⁰), 61.78 (C-6), 61.22 (C-6⁰),

56.20 (OCH₃), 55.94 (C-2), 26.84 (C (CH₃)₃), 20.53–

20.25 (COCH₃· 4), 19.33 (C(CH₃)₃), 8.72 (CCH₃· 2).

0

27

3.2.18.2. Acetate 23f. ½aꢁ_D+3.6 (c 1.04, CHCl₃); R_f

1

0.40 (1:1 hexane–EtOAc, two developments); H NMR

6. Bohn, M. L.; Colombo, M. I.; Stortz, C. A.; Ru´veda, E. A.

Carbohydr. Res. 2006, 341, 1096–1104, and references

cited therein.

7. Kong, F. Curr. Org. Chem. 2003, 7, 841–865.

8. Gallo-Rodriguez, C.; Gandolﬁ, L.; Lederkremer, R. M.

Org. Lett. 1999, 1, 245–247.

(300 MHz): d 5.55 (dd, 1H, J_3,29.1, J_3,410.7 Hz, H-3);

HRFABMS: calcd for C₄₅H₅₇NO₁₇Si [M+Na]⁺, m/z

934.3293; found, m/z 934.3320.

9. Wang, H.; Ning, J. J. Org. Chem. 2003, 68, 2521–2524.

10. Schmidt, R. R.; Stumpp, M. Justus Liebigs Ann. Chem.

1983, 1249–1256.

Acknowledgments

´

We thank Dr. Manuel Gonzalez-Sierra for spectral

11. Lu, J.; Fraser-Reid, B. Org. Lett. 2004, 6, 3051–3054.

´

12. Uriel, C.; Agocs, A.; Gomez, A. M.; Lopez, C. J.; Fraser-

determinations. Financial support from UNR, UBA,

and CONICET and a fellowship (M.L.B.) are also

acknowledged. M.I.C., C.A.S., and E.A.R. are Research

Members of the National Research Council of Argen-

tina (CONICET).

Reid, B. Org. Lett. 2005, 7, 4899–4902.

13. Lederkremer, R. M.; Colli, W. Glycobiology 1995, 5, 547–

552.

14. Houseknecht, J. B.; Lowary, T. L. Curr. Opin. Chem. Biol.

2001, 5, 677–682.

15. Gallo-Rodriguez, C.; Gil-Libarona, M. A.; Mendoza, V.

M.; Lederkremer, R. M. Tetrahedron 2002, 58, 9373–9380.

16. Aly, M. R. E.; Casto Palomino, J. C.; Ibahim, E.-S. I.;

El-Ashay, E.-S. H.; Schmidt, R. R. Eur. J. Org. Chem.

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Biochemistry 1994, 50, 21–123.

18. Ikeda, D.; Tsuchiya, T.; Ohgi, T.; Umezawa, S. Bull.

Chem. Soc. Jpn. 1971, 44, 2529–2537.

Supplementary data

Supplementary data associated with this article can be

found, in the online version, at doi:10.1016/j.carres.

2007.08.006.

19. Bauer, T.; Tarasiuk, J.; Paniiczek, K. Tetrahedron: Asym-

metry 2002, 13, 77–82.

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Article Doi

Differential O-3/O-4 regioselectivity in the glycosylation of α and β anomers of 6-O-substituted N-dimethylmaleoyl-protected d-glucosamine acceptors

DOI: 10.1016/j.carres.2007.08.006

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