Synthesis of monodeoxy and mono-O-methyl congeners of methyl β-d-mannopyranosyl-(1→2)-β-d-mannopyranoside for epitope mapping of anti-Candida albicans antibodies

Carbohydrate Research 344 (2009) 1397–1411

Contents lists available at ScienceDirect

Carbohydrate Research

journal homepage: w ww.elsevier.com/locate/carres

Synthesis of monodeoxy and mono-O-methyl congeners of methyl

b-^D-mannopyranosyl-(1?2)-b-D-mannopyranoside for epitope mapping

of anti-Candida albicans antibodies

*

Corwin M. Nycholat, David R. Bundle

Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, The University of Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, AB, Canada T6G 2G2

a r t i c l e i n f o

a b s t r a c t

Article history:

A panel of six complementary monodeoxy and mono-O-methyl congeners of methyl b-D-mannopyrano-

syl-(1?2)-b-D-mannopyranoside (1) were synthesized by stereoselective glycosylation of monodeoxy

Received 23 July 2009

Accepted 23 July 2009

Available online 25 July 2009

and mono-O-methyl monosaccharide acceptors with a 2-O-acetyl-glucosyl trichloroacetimidate donor,

followed by a two-step oxidation–reduction sequence at C-2⁰. The b-manno conﬁgurations of the ﬁnal

deprotected congeners 2–7 were conﬁrmed by measurement of ¹J_C1,H1heteronuclear and ³J_{1 ,2}homonu-

clear coupling constants. These disaccharide derivatives will be used to map the protective epitope rec-

ognized by a protective anti-Candida albicans monoclonal antibody C3.1 (IgG3) and to determine its key

polar contacts with the binding site.

0

Dedicated to Professor Dr. Hans Kamerling

on the occasion of his 65th birthday

Keywords:

Ó 2009 Published by Elsevier Ltd.

Methyl b-

D-mannopyranosyl-(1?2)-b-D-

mannopyranoside

Monodeoxy and mono-O-methyl congeners

Mapping of anti-Candida albicans antibodies

Functional group modiﬁcation

1. Introduction

Two monoclonal antibodies, an IgM (B6.1) and an IgG (C3.1),

raised against the PMC in mice, were found to protect against sub-

Candida albicans, the causative agent of candidiasis, is a com-

mensal fungus that commonly inhabits the gastrointestinal tract,

oropharyngeal cavity and vulvovaginal tract of healthy humans.^1,2

However, risk of serious infection and occurrence of disease caused

by this opportunistic pathogenic is increased in immunocompro-

mised patients and individuals undergoing long-term antibiotic

treatment or major invasive surgery. Therapeutics to combat infec-

tion have been limited to triazole derivatives and amphotericin B.³

However, the toxicity, emergence of resistance and costs of these

antifungal agents are potential problems and highlight the need

for alternative treatment strategies. The development of a vaccine

against Candida is attracting attention and appears to be a potential

sequent infection.^8–10Interestingly, though the b-(1?2)-linked

mannan polymers vary in length from 1 to 7 residues, inhibition

assays revealed that both mAbs were speciﬁc for a di- or trisaccha-

ride. Furthermore, a novel pattern of antibody inhibition was ob-

served using synthetic di- to hexasaccharides of (1?2)-b-D-

mannopyranans, where maximum activity was reached with di-

and trisaccharides and diminished signiﬁcantly for larger struc-

tures.¹¹This is in marked contrast to the paradigm elaborated by

Kabat, wherein larger dextran homo-oligomers up to a hexa- or

heptasaccharide exhibit increasing inhibitory activity with poly-

clonal antibodies.¹²Beyond the unique size dependence of the

two C. albicans monoclonal antibodies described by Cutler and

the conformational analysis of the homo-oligosaccharides,⁹no

additional structural data are available for either the antibody or

the antigenic determinant. Knowledge of the recognition elements

of the protective epitope could provide important insights into the

minimum-sized hapten that might be employed in a synthetic con-

jugate vaccine.

A strategy of chemical mapping, devised by Lemieux, is used to

deﬁne the key polar contacts required for binding of the sugar to

the antibody.^13,14The relative activity of complementary monode-

oxy and mono-O-methyl analogues in combination with conforma-

tional analysis helps to provide a three-dimensional model of the

topography of the oligosaccharide epitope. To investigate in further

solution.^4,5Whereas the

a-mannan component of the Candida cell

wall phosphomannan complex does not afford protective antibod-

ies, the relatively short b-(1?2) mannan oligosaccharides that are

attached to the a-mannan side chains are immunogenic and capa-

ble of raising protective antibodies. Consequently antigens com-

posed of this epitope have become an attractive component of a

conjugate vaccine.^6,7

DOI of original article: 10.1016/j.carres.2008.12.011

* Corresponding author. Tel.: +1 780 492 8808; fax: +1 780 492 7705.

E-mail address: dave.bundle@ualberta.ca (D.R. Bundle).

0008-6215/$ - see front matter Ó 2009 Published by Elsevier Ltd.

doi:10.1016/j.carres.2009.07.008

1398

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

Oxidation of 12 by Me₂SO/Ac₂O¹⁷was followed by reduction

1

, R = R²= R³= OH

1

2

with L-Selectride^Òin THF at ꢀ78 °C to give 13. Lichtenthaler

et al.¹⁸investigated the reduction of 2-keto groups with various

hydride reagents and found L-Selectride^Òto reduce the carbonyl

of several substrates with high manno-selectivity. Conversely,

NaBH₄was found to be selective with only fully benzylated sub-

strates and gave poor manno-selectivity versus gluco-selectivity

(7:1) with benzylidene-containing substrates.¹⁵In our case oxida-

tion then reduction of the benzylidene substrate 12 with L-Select-

ride^Ògave the desired 3-deoxy mannose acceptor 13 in 83% yield

(exclusively manno); the observed ³J_1,21.3 Hz for the product when

compared to that of compound 12 indicated b-manno stereochem-

istry. A small amount of side product (usually 5–10%) was obtained

and identiﬁed as methyl 4,6-O-benzylidene-3-deoxy-2-O-meth-

HO

OH

O

1

, R = H, R²= R³= OH

3, R¹= OCH₃, R²= R³= OH

4, R²= H, R¹= R³= OH

O

HO

R³

5, R²= OCH₃, R¹= R³= OH

R²

O

3

, R = H, R¹= R²= OH

6

7

R¹

OMe

3

, R = OCH₃, R¹= R²= OH

Figure 1. Native disaccharide 1 and the corresponding target deoxy and O-methyl

congeners 2–7.

detail the size and topology of the mAb IgG3 (C3.1) antibody bind-

ing site, a panel of six monodeoxy and mono-O-methyl congeners

2–7 of the disaccharide methyl b-D-mannopyranosyl-(1?2)-b-D-

mannopyranoside (1) have been synthesized. For each congener a

single hydroxyl group on the reducing-end residue of the parent

disaccharide 1 has been modiﬁed by either deoxygenation or

methylation (Fig. 1).

ylthiomethyl-b-D-glucopyranoside. It has previously been noted,

that the methylthiomethyl ether substituted by-product is formed

under Me₂SO/Ac₂O oxidation conditions.¹⁷

The 3-O-methyl mannose acceptor 15 was prepared by direct

methylation of methyl 4,6-O-benzylidene-b-D-glucopyranoside

(8) using stannylidene chemistry (Scheme 1). Reaction with dibu-

tyltin oxide in toluene at reﬂux, followed by treatment with

methyl iodide in DMF, gave 14 in 71% yield. The gluco-intermediate

14 was then reacted following the standard oxidation–reduction

sequence to afford the 3-O-methyl mannose acceptor 15 in 80%

2. Results and discussion

2.1. Synthesis of 3-deoxy and 3-O-methyl disaccharides 2 and 3

3

As illustrated in Scheme 1, the 3-deoxy and 3-O-methyl

acceptors 13 and 15 were readily available from methyl 4,6-O-ben-

yield. The measured J_1,2coupling constant (1.0 Hz) indicated

inversion to the b-manno-conﬁguration.

zylidene-b-D

-glucopyranoside (8).¹⁵Initial reaction of 8 under

Glycosylation of the prepared 3-deoxy and 3-O-methyl acceptors

phase-transfer conditions¹⁶with p-methoxybenzyl chloride gave a

mixture of 2-O- and 3-O-monobenzylated regioisomers. Although,

the desired 2-O-p-methoxybenzyl intermediate 9 was obtained in

lower yield (30% yield), reaction scale-up provided sufﬁcient quan-

tities to proceed. Temporary protection of the 2-hydroxyl as the

p-methoxybenzyl ether allowed for straightforward manipulation

of the 3-hydroxyl group. The regiochemistry of 9 was conﬁrmed

by subsequent reaction with thiocarbonyl diimidazole in toluene

at 80 °C to give 10 in 64% yield in which the chemical shift of H-3

moved downﬁeld from d 3.82 to 6.11 ppm. The Barton–McCombie

substrate 10 was then treated with tributyltin hydride in the pres-

ence of AIBN to afford the 3-deoxy intermediate 11 in 78% yield.

Removal of the p-methoxybenzyl ether with DDQ in wet CH₂Cl₂

gave 12 in 86% yield and exposed the 2-hydroxyl group, which

was then inverted from the gluco to the manno conﬁguration via a

standard two-step oxidation–reduction sequence.

13 and 15, with 2-O-acetyl-3,4,6-tri-O-benzyl-b-D-glucopyranosyl

trichloroacetimidate¹⁹donor 16 gave intermediate disaccharides

17 (59% yield) and 20 (97% yield), respectively (Scheme 2). The syn-

thesis of 17 was not optimized. Transesteriﬁcation followed by the

standard two-step oxidation–reduction sequence converted disac-

charides 17 and 20 to intermediates 19 and 22. For all oxidation–

reduction sequences performed at C-2⁰described in this paper, the

inversion of stereochemistry was monitored by comparison of the

3

0

J_{1 ,2}coupling constants preceding and following the two-step

sequence. Typically, ³J_1,2coupling for b-gluco structures is between

8 and 10 Hz and for b-manno <1 Hz. For compounds 18 and 21, the

3

0

J_{1 ,2}coupling constants measured 8.0 Hz, while the J_{1 ,2}proton

coupling constants measured 0.8 Hz for both 19 and 22, indicating

inversion from b-gluco to b-manno stereochemistry. Global deben-

zylation by hydrogenolysis afforded the desired 3-deoxy 2 and

3-O-methyl 3 target analogues in 75% and 74% yields, respectively.

Ph

O

Ph

O

a

d

O

OMe

OPMB

OMe

HO

R

OH

8

12

9

, R = OH

b

e

10, R = C(S)Im

11, R = H

f

c

Ph

O

OH

O

MeO

OH

14

13

f

OH

O

Ph

O

OMe

MeO

15

Scheme 1. Reagents and conditions: (a) PMBCl, CH₂Cl₂, n-Bu₄NHSO₄, 5% aq NaOH, 30%; (b) 1,1⁰-thiocarbonyldiimidazole, toluene, 64%; (c) n-Bu₃SnH, AIBN, toluene, 78%; (d)

DDQ, CH₂Cl₂, H₂O, 86%; (e) n-Bu₂SnO, toluene, then MeI, DMF, 71%; (f) Me₂SO, Ac₂O, then L-Selectride, THF, ꢀ78 °C, 83% over two steps.

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

1399

BnO

17

, R = OAc

O

R

BnO

c

O

BnO

18, R = OH (gluco)

19, R = OH (manno)

a

b

e

d

2

3

Ph

O

BnO

O

OMe

O

R

BnO

OAc

BnO

16

20, R = OAc

, R= OC(NH)CCl₃

O

R

BnO

c

O

BnO

Ph

21, R = OH (gluco)

d

22

, R = OH (manno)

O

OMe

MeO

Scheme 2. Reagents and conditions: (a) 13, TMSOTf, CH₂Cl₂, 0 °C, 59%; (b) 15, TMSOTf, CH₂Cl₂, 0 °C, 97%; (c) NaOCH₃, CH₃OH, quant. (for 18), 88% (for 21); (d) Me₂SO, Ac₂O,

then L-Selectride, THF, ꢀ78 °C, 65% (for 19 over two steps), 72% (for 22 over two steps); (e) H₂, Pd/C, CH₃OH, CH₂Cl₂, 75% (for 2), 74% (for 3).

The b-manno conﬁgurations of the ﬁnal deprotected analogues

(83% yield) and 34 (97% yield), respectively (Scheme 4). The disac-

charides were then treated with NaOCH₃–CH₃OH, followed by the

standard oxidation–reduction sequence to provide intermediates

33 and 36. Subsequent hydrogenolysis then afforded the 4-deoxy

4 (52% yield) and 4-O-methyl 5 (88% yield) disaccharide analogues,

1

described in this paper were conﬁrmed by J_C1,H1heteronuclear²⁰

3

1

0

and J_{1 ,2}homonuclear coupling constants. In all cases, the J_C1,H1

3

0

values were between 160 and 164 Hz and the J_{1 ,2}values were

<1 Hz.

respectively. The ¹J_C1,H1and ³J_{1 ,2}coupling constants conﬁrmed the

b-manno conﬁgurations of both 4 and 5.

0

2.2. Synthesis of 4-deoxy and 4-O-methyl disaccharides 4 and 5

The fully protected intermediate 24 obtained from benzoylation

2.3. Synthesis of 6-deoxy and 6-O-methyl disaccharides 6 and 7

of methyl 3-O-benzyl-4,6-O-benzylidene-b-D-mannopyranoside

(23)¹⁵provided a convenient strategy for accessing and modifying

the C-4 hydroxyl group, while allowing temporary protection of

the C-2 hydroxyl (Scheme 3). Regioselective reductive opening of

the benzylidene acetal with sodium cyanoborohydride and HCl in

ether²¹gave 25 in 81% yield and allowed for straightforward mod-

iﬁcation at C-4. The regioselectivity was conﬁrmed by subsequent

reaction of the hydroxyl with thiocarbonyl diimidazole in toluene

at reﬂux to give 26 (60% yield) in which the chemical shift of H-4

moved downﬁeld from d 4.04 to 6.24. Treatment of the Barton–

McCombie substrate with tributyltin hydride in the presence of

AIBN gave the 4-deoxy substrate 27. The temporary benzoyl group

was removed by transesteriﬁcation using sodium methoxide in

methanol to give the 4-deoxy acceptor 28.

Reductive benzylidene acetal opening of methyl 3-O-benzyl-

4,6-O-benzylidene-b-D

-glucopyranoside (37)¹⁵under anhydrous

conditions with BH₃ꢁTHF and dibutylboron triﬂate²²gave diol 38

in 83% yield (Scheme 5). Controlled reaction of the C-6 primary hy-

droxyl with methanesulfonyl chloride in pyridine gave intermedi-

ate 39 (66% yield). The downﬁeld shift of the C-6 proton

resonances (from d 3.89 and 3.75 to d 4.47 and 4.37) conﬁrmed

the regioselectivity of both the benzylidene acetal opening and

selective sulfonylation. The 6-deoxy intermediate 40 was obtained

in 80% yield by reductive displacement of the sulfonate using

NaBH₄. The standard two-step oxidation–reduction sequence was

then used to invert the gluco-conﬁguration to yield the desired 6-

3

deoxy mannose acceptor 41 (88% yield). The change in the J_1,2

Methylation of intermediate 25 using methyl iodide and so-

dium hydride, followed by quenching with acetic acid, gave inter-

mediate 29 (Scheme 3). Transesteriﬁcation of the benzoyl group

afforded the desired 4-O-methyl acceptor 30 in 95% yield.

coupling constant (from 7.6 to 1.1 Hz) indicated inversion to the

b-manno conﬁguration.

Reductive benzylidene acetal opening of methyl 2-O-benzoyl-

3-O-benzyl-4,6-O-benzylidene-b-D

-glucopyranoside (42)²³under

Glycosylation of 28 and 30 with benzylated trichloroacetimi-

anhydrous conditions with BH₃ꢁTHF and dibutylboron triﬂate²²

gave 43 in 80% yield (Scheme 6). Methylation of the free C-6

date¹⁹donor 16 under TMSOTf activation gave disaccharides 31

OR

O

BnO

OBz

Ph

a

O

b

O

R

OMe

BnO

23

BnO

e

, R = OH

25

29

, R = OMe

, R = OH

c

24, R = OBz

26, R = C(S)Im

27, R = H

d

f

BnO

MeO

BnO

OH

O

OH

O

OMe

28

30

Scheme 3. Reagents and conditions: (a) BzCl, pyridine, quant.; (b) NaCNBH₃, HCl, Et₂O, 81%; (c) 1,1⁰-thiocarbonyldiimidazole, toluene, 60%; (d) n-Bu₃SnH, AIBN, toluene, 68%;

(e) MeI, NaH, DMF, 0 °C then AcOH, 97%; (f) NaOCH₃, CH₃OH, 89% (for 28), 95% (for 30).

1400

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

BnO

O

R

BnO

31

, R = OAc

32, R = OH (gluco)

33

O

BnO

c

a

b

BnO

e

d

, R = OH (manno)

4

5

O

BnO

OMe

O

R

BnO

OAc

O

34, R = OAc

16

, R= OC(NH)CCl₃

O

BnO

c

R

35, R = OH (gluco)

BnO

MeO

d

36

, R = OH (manno)

O

OMe

BnO

Scheme 4. Reagents and conditions: (a) 28, TMSOTf, CH₂Cl₂, 0 °C, 83%; (b) 30, TMSOTf, CH₂Cl₂, 0 °C, 97%; (c) NaOCH₃, CH₃OH, 78% (for 32), 97% (for 35); (d) Me₂SO, Ac₂O, then

L-Selectride, THF, ꢀ78 °C, 65% (for 33 over two steps), 61% (for 36 over two steps); (e) H₂, Pd/C, CH₃OH, CH₂Cl₂, 52% (for 4), 88% (for 5).

Ph

HO

BnO

MsO

BnO

O

a

b

O

OMe

BnO

OMe

BnO

OH

37

38

39

41

OH

O

d

c

O

BnO

OMe

OH

40

Scheme 5. Reagents and conditions: (a) BH₃ꢁTHF, n-Bu₂BOTf, CH₂Cl₂, 0 °C, 83%; (b) MsCl, pyridine, 0 °C, 66%; (c) NaBH₄, DMF, 80 °C, 80%; (d) Me₂SO, Ac₂O, then L-Selectride,

THF, ꢀ78 °C, 88%.

hydroxyl group afforded 44, which was subsequently reacted un-

der Zemplén conditions to provide intermediate 45 (86% yield

two steps). Again, the standard two-step oxidation–reduction se-

quence was used to give the desired 6-O-methyl mannose acceptor

(C-3, C-4 and C-6) of methyl b-D-mannopyranosyl-(1?2)-b-D-man-

nopyranoside (1) have been synthesized. All deoxygenations and

O-methylations were performed at the monosaccharide level pro-

ducing six modiﬁed acceptors. The synthesis of the challenging

3

46 (85% yield). The change in the J_1,2coupling constant (from 7.6

(1?2)-b-D-manno linkage was approached by initial highly b-ster-

to 1.0 Hz) indicated inversion to the b-manno conﬁguration.

Reaction of the 6-deoxy 41 and 6-O-methyl 46 acceptors with

benzylated trichloroacetimidate¹⁹donor 16 under TMSOTf activa-

tion gave disaccharides 47 (96% yield) and 50 (68% yield), respec-

tively (Scheme 7). The disaccharides were then treated with

NaOCH₃–CH₃OH followed by the oxidation–reduction sequence

to provide intermediates 49 and 52. Subsequent hydrogenolysis

of 49 and 52 gave the desired 6-deoxy 6 (86% yield) and 6-O-

eoselective glucosylation employing a common trichloroacetimi-

date donor capable of neighbouring group participation, followed

by a two-step oxidation–reduction sequence at C-2⁰. The b-manno

conﬁgurations of the ﬁnal deprotected analogues were conﬁrmed

1

3

0

by measurement of J_C1,H1heteronuclear and J_{1 ,2}homonuclear

coupling constants. These ﬁnal structures will serve as valuable

tools to probe the key polar contacts involved in the binding of

the protective anti-C. albicans mAb C3.1 (IgG3).^8–11

methyl 7 (69% yield) disaccharide analogues, respectively. The

1

J_C1,H1and ³J_{1 ,2}coupling constants conﬁrmed the b-manno conﬁg-

0

3. Experimental

uration for both 6 and 7.

3.1. General methods

2.4. Conclusion

All chemical reagents were of analytical grade and used as ob-

tained from commercial sources unless otherwise indicated. Sol-

vents used in water-sensitive reactions were puriﬁed by

In conclusion, a panel of six complementary deoxy and O-

methyl analogues (2–7) modiﬁed on the reducing-end residue

MeO

HO

Ph

O

a

c

b

d

O

BnO

O

BnO

OMe

BnO

OMe

BnO

OBz

44

46

42

43

45

MeO

BnO

MeO

BnO

OH

O

BnO

OMe

BnO

OH

Scheme 6. Reagents and conditions: (a) BH₃ꢁTHF, n-Bu₂BOTf, CH₂Cl₂, 0 °C, 80%; (b) MeI, NaH, DMF, 0 °C, then AcOH, 96%; (c) NaOCH₃, CH₃OH, 90%; (d) Me₂SO, Ac₂O, then

L-Selectride, THF, ꢀ78 °C, 85%.

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

1401

BnO

O

R

BnO

47

, R = OAc

48, R = OH (gluco)

49

O

BnO

c

a

b

e

d

, R = OH (manno)

6

7

O

BnO

OMe

O

R

BnO

OAc

O

R

16, R= OC(NH)CCl₃

O

BnO

50, R = OAc

c

51, R = OH (gluco)

MeO

BnO

d

52

, R = OH (manno)

O

OMe

BnO

Scheme 7. Reagents and conditions: (a) 41, TMSOTf, CH₂Cl₂, 0 °C, 96%; (b) 46, TMSOTf, CH₂Cl₂, 0 °C, 68%; (c) NaOCH₃, CH₃OH, quant. (for 48), 96% (for 51); (d) Me₂SO, Ac₂O,

then L-Selectride, THF, ꢀ78 °C, 82% (for 49 over two steps), 78% (for 52 over two steps); (e) H₂, Pd/C, CH₃OH, CH₂Cl₂, 86% (for 6), 69% (for 7).

successive passage through columns of alumina and copper under

nitrogen, except for DMSO, which was distilled under vacuum and

collected over 4 Å molecular sieves. Unless otherwise noted, reac-

tions were carried out at room temperature, and water-sensitive

reactions were performed under an atmosphere of argon. Molecu-

lar sieves were ﬂame dried and then allowed to cool to room tem-

perature under argon before use. Reactions were monitored by

analytical thin-layer chromatography (TLC) performed on Silica

Gel 60-F₂₅₄(E. Merck). Plates were visualized under UV light,

and/or by treatment with 5% sulfuric acid in ethanol followed by

heating. Organic solvents were removed under vacuum at <40 °C.

Medium-pressure chromatography was conducted using silica gel

(230–400 mesh, Silicycle, Montreal) at ﬂow rates between 5 and

3.3. Methyl b-

mannopyranoside (3)

D-mannopyranosyl-(1?2)-3-O-methyl-b-D-

Compound 22 (50.7 mg, 0.070 mmol) was dissolved in 1:1

CH₂Cl₂–methanol (10 mL) and stirred with 10% Pd/C (50 mg) under

a H₂atmosphere then processed as described for 2. Filtration, then

lyophilization, gave 3 (19.1 mg, 74%) as a clear glass: R_f0.23

(6.0:3.5:0.5, CH₂Cl₂–MeOH–H₂O); [

a

]

D

ꢀ86 (c 0.37, H₂O); ¹H

NMR (500 MHz, D₂O) d 4.83 (s, 1H, H-1⁰), 4.60 (s, 1H, H-1), 4.52

(d, 1H, J_2,33.1 Hz, H-2), 4.09 (d, 1H, J_{2 ,3}1.8 Hz, H-2⁰), 3.93 (dd,

0

1H, J_5,62.0, J_gem12.3 Hz, H-6a), 3.93 (dd, 1H, J_{5 ,6}1.8, J_gem

12.2 Hz, H-6a⁰), 3.77 (dd, 1H, J_{5 ,6}5.8, J_gem12.2 Hz, H-6b⁰), 3.74

(dd, 1H, J_5,66.5, J_gem12.3 Hz, H-6b), 3.64 (dd, 1H, J_3,4ꢂ J_4,59.9 Hz,

H-4), 3.58–3.64 (m, 2H, H-3⁰, H-4⁰), 3.54 (s, 3H, CH₃O), 3.49 (s,

3H, CH₃O), 3.41 (ddd, 1H, J_4,59.2, J_5,62.2, 6.5 Hz, H-5), 3.38 (dd,

0

10 mL min^ꢀ1

. Following deprotection, ﬁnal compounds were

passed through an Alltech Carbograph ﬁlter and then lyophilized.

¹H NMR spectra were recorded at 500 or 600 MHz, and chemical

shifts, reported in d (ppm), were referenced to internal residual

protonated solvent signals or to external acetone (0.1% ext. acetone

@ d 2.225 ppm) in the case of D₂O. ¹³C NMR spectra were recorded

at 125 MHz, and chemical shifts are referenced to internal CDCl₃(d

77.23) or external acetone (d 31.07).

0

1H, J_2,33.1, J_3,49.8 Hz, H-3), 3.34 (ddd, 1H, J_{4 ,5}9.5, J_{5 ,6}2.2,

5.8 Hz, H-5⁰); ¹³C NMR (125 MHz, D₂O) d 102.6 (C-1, J_C1,H1

1

158.5 Hz, b), 101.4 (C-1⁰, J_{C1 ,H1}164.1 Hz, b), 82.2 (C-3), 77.3,

77.0 (C-5, C-5⁰), 73.9, 73.6 (C-2, C-4⁰), 71.3 (C-2⁰), 67.5, 66.7 (C-4,

C-3⁰), 62.0, 61.9 (C-6, C-6⁰), 58.0 (CH₃O–C1), 57.2 (CH₃O–C3); HRE-

SIMS: Calcd for C₁₄H₂₆O₁₁Na 393.1367. Found 393.1366.

0

3.4. Methyl b-

hexopyranoside (4)

D-mannopyranosyl-(1?2)-4-deoxy-b-D-lyxo-

3.2. Methyl b-

hexopyranoside (2)

D-mannopyranosyl (1?2) 3-deoxy-b-D-arabino-

Compound 33 (49.1 mg, 0.062 mmol) was dissolved in 1:1

CH₂Cl₂–methanol (10 mL) and stirred with 10% Pd/C (50 mg) under

a H₂atmosphere, then processed as described for 2. Filtration, then

lyophilization, gave 4 (11.0 mg, 52%) as a clear glass: R_f0.27

Compound 19 (49.0 mg, 0.070 mmol) was dissolved in 1:1

CH₂Cl₂–MeOH (10 mL) and stirred with 10% Pd/C (50 mg) under

a H₂atmosphere. The catalyst was separated by ﬁltration through

a Whatman membrane (0.45 lm, PVDF), and the ﬁltrate was con-

(6:3.5:0.5, CH₂Cl₂–CH₃OH–H₂O); [

a

]

ꢀ60 (c 0.58, H₂O); ¹H NMR

D

centrated under reduced pressure. The residue was redissolved in

H₂O, passed through an Alltech Carbograph ﬁlter and then lyophi-

lized to yield 2 (17.8 mg, 75%) as a clear glass: R_f0.25 (6:3.5:0.5,

(500 MHz, D₂O) d 4.83 (s, 1H, H-1⁰), 4.51 (s, 1H, H-1), 4.12–4.13

(m, 2H, H-2⁰, H-2), 3.92 (dd, 1H, J_{5 ,6}2.3, J_gem12.3 Hz, H-6a⁰),

3.88 (ddd, 1H, J_2,33.0, J_3,4eq5.0, J_3,4ax12.1 Hz, H-3) 3.63–3.73 (m,

0

CH₂Cl₂–CH₃OH–H₂O); [

a

]

ꢀ33 (c 0.27, H₂O); ¹H NMR (500 MHz,

D

5H, H-3⁰, H-6b⁰, H-5, H-6a, H-6b) 3.55 (dd, 1H, J_{3 ,4}ꢂ J_{4 ,5}9.8, H-

0

D₂O) d 4.78 (d, 1H, J_{1 ,2}0.8 Hz, H-1⁰), 4.63 (d, 1H, J_1,21.2 Hz, H-1),

0

4⁰), 3.54 (s, 3H, CH₃O), 3.36 (ddd, 1H, J_{5 ,6b}6.8 Hz, H-5⁰), 1.71

(ddd, 1H, J_gem12.6, J_4,50.8 Hz, H-4eq), 1.55 (ddd, 1H, J_4ax,5

0

4.14 (m, 1H, H-2), 4.05 (dd, 1H, J_{1 ,2}0.8, J_{2 ,3}3.3 Hz, H-2⁰), 3.92

0

(dd, 1H, J_{5 ,6}2.3, J_gem12.3 Hz, H-6a⁰), 3.91 (dd, 1H, J_5,62.7, J_gem

12.2 Hz, H-6a), 3.83 (ddd, 1H, J_3,44.7, 11.0, J_4,59.6 Hz, H-4), 3.73

0

12.2 Hz, H-4ax); ¹³C NMR (125 MHz, D₂O) d 102.7 (C-1, J_C1,H1

1

159.4 Hz, b), 101.3 (C-1⁰, J_{C1 ,H1}162.4 Hz, b), 77.4 (C-2), 77.2 (C-

5⁰), 74.0, 73.7 (C-3⁰, C-5), 71.3 (C-2⁰), 68.3 (C-3), 67.7 (C-4⁰), 64.6

(C-6), 62.0 (C-6⁰), 57.8 (CH₃O), 30.7 (C-4); HRESIMS: Calcd for

C₁₃H₂₄O₁₀Na 363.1262. Found 363.1261.

0

(dd, 1H, J_{5 ,6}6.5, J_gem12.3 Hz, H-6b⁰), 3.72 (dd, 1H, J_5,66.8, J_gem

0

12.2 Hz, H-6b), 3.63 (dd, 1H, J_{2 ,3}3.3, J_{3 ,4}9.6 Hz, H-3⁰), 3.56 (dd,

0

1H, J_{3 ,4}ꢂ J_{4 ,5}9.6 Hz, H-4⁰), 3.53 (s, 3H, CH₃O), 3.50 (ddd, 1H, J_4,5

0

9.3, J_5,62.7, 6.8 Hz, H-5), 3.35 (ddd, 1H, J_{4 ,5}9.6, J_{5 ,6}2.3, 6.5 Hz,

H-5⁰), 2.41 (ddd, 1H, J_2,3ꢂ J_3,44.3, J_gem13.6 Hz, H-3eq), 1.72 (ddd,

1H, J_2,32.9, J_gem13.6, J_3,411.1 Hz, H-3ax); ¹³C NMR (125 MHz,

3.5. Methyl b-D-mannopyranosyl-(1?2)-4-O-methyl-b-D-

1

0

D₂O)

d

102.9 (C-1, J_C1,H1160.3 Hz, b), 101.8 (C-1⁰, J_{C1 ,H1}

mannopyranoside (5)

160.6 Hz, b), 80.9 (C-5), 77.1 (C-5⁰), 75.7 (C-2), 73.7 (C-3⁰), 71.3

(C-2⁰), 67.7 (C-4⁰), 63.1 (C-4), 62.2, 62.0 (C-6⁰, C-6), 57.6 (CH₃O),

36.9 (C-3); HRESIMS: Calcd for C₁₃H₂₄O₁₀Na 363.1262. Found

363.1264.

Compound 36 (51.8 mg, 0.063 mmol) was dissolved in 1:1

CH₂Cl₂–MeOH (10 mL) and stirred with 10% Pd/C (50 mg) under

a H₂atmosphere, then processed as described for 2. Filtration, then

1402

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

lyophilization, gave 5 (20.4 mg, 88%) as a clear glass: R_f0.48

on silica gel (4:1 hexanes–EtOAc) gave both the 2-O-(4-methoxy-

benzyl) derivative 9 (1.28 g, 30%) and the 3-O-(4-methoxybenzyl)

derivative (1.93 g, 45%) as white solids; 9: R_f0.48 (1:1 hexanes–

(6:3.5:0.5, CH₂Cl₂–MeOH–H₂O); [

a

]

ꢀ56 (c 0.50, H₂O); ¹H NMR

D

(500 MHz, D₂O) d 4.82 (s, 1H, H-1⁰), 4.61 (s, 1H, H-1), 4.23 (d, 1H,

J_2,33.2 Hz, H-2), 4.12 (d, 1H, J_{2 ,3}3.3 Hz, H-2⁰), 3.91–3.93 (m, 2H,

EtOAc); [a]

ꢀ18 (c 0.73, CHCl₃); ¹H NMR (600 MHz, CDCl₃) d

0

D

H-6a⁰, H-6a), 3.71–3.77 (m, 3H, H-6b⁰, H-3, H-6b), 3.63 (ddd, 1H,

7.48–7.50 (m, 2H, ArH), 7.30–7.38 (m, 5H, ArH), 6.89–6.91 (m,

2H, ArH), 5.53 (s, 1H, PhCHO₂), 4.86 (d, 1H, J_gem11.1 Hz, PhCH₂O),

4.66 (d, 1H, PhCH₂O), 4.43 (d, 1H, J_1,27.7 Hz, H-1), 4.35 (dd, 1H, J_5,6

4.9, J_gem10.4 Hz, H-6a), 3.82 (dd, 1H, J_2,3ꢂ J_3,49.1 Hz, H-3), 3.81 (s,

3H, CH₃O), 3.78 (dd, 1H, J_5,6ꢂ J_gem10.3 Hz, H-6b), 3.60 (s, 3H,

CH₃O), 3.53 (dd, 1H, J_3,4ꢂ J_4,59.3 Hz, H-4), 3.42 (ddd, 1H, J_4,59.7,

J_5,65.1, 9.7 Hz, H-5), 3.32 (dd, 1H, J_1,27.8, J_2,38.9 Hz, H-2); ¹³C

NMR (125 MHz, CDCl₃) d 159.4 (Ar), 137.0 (Ar), 130.3 (Ar), 129.8

(Ar), 129.2 (Ar), 128.3 (Ar), 126.3 (Ar), 114.0 (Ar), 105.0 (C-1),

101.8 (PhCHO₂), 81.4 (C-2), 80.5 (C-4), 74.3 (PhCH₂O), 73.1 (C-3),

68.7 (C-6), 66.1 (C-5), 57.4 (CH₃O), 55.3 (CH₃O); HRESIMS: Calcd

for C₂₂H₂₆O₇Na 425.1571. Found 425.1570.

J_{2 , 3}0.9, J_{3 ,4}9.7 Hz, H-3⁰), 3.56 (dd, 1H, J_{3 ,4}ꢂ J_{4 ,5}9.7 Hz, H-4⁰),

0

3.53 (s, 6H, CH₃OC-1, CH₃OC-4), 3.34–3.39 (m, 3H, H-5⁰, H-4, H-

5); ¹³C NMR (125 MHz, D₂O) d 102.2 (C-1, J_C1,H1159.7 Hz, b),

1

101.3 (C-1⁰, J_{C1 ,H1}162.7 Hz, b), 78.7 (C-2), 78.0 (C-4), 77.2 (C-5⁰),

76.3 (C-5), 73.7 (C-3⁰), 73.0 (C-3), 71.2 (C-2⁰), 67.7 (C-4⁰), 62.0,

61.5 (C-6⁰, C-6), 61.1 (CH₃OC-4), 58.0 (CH₃OC-1); HRESIMS: Calcd

for C₁₄H₂₆O₁₁Na 393.1367. Found 393.1366.

0

3.6. Methyl b-D-mannopyranosyl-(1?2)-6-deoxy-b-D-mannopy-

ranoside (6)

Compound 49 (55.0 mg, 0.070 mmol) was dissolved in 1:1

CH₂Cl₂–MeOH (10 mL) then stirred with 10% Pd/C (50 mg) under

a H₂atmosphere, then processed as described for 2. Filtration, then

lyophilization, gave 6 (20.4 mg, 86%) as a clear glass: R_f0.49

3.9. Methyl 4,6-O-benzylidene-2-O-(4-methoxybenzyl)-3-O-

thiocarbonylimidazole-b-D-glucopyranoside (10)

(6:3.5:0.5, CH₂Cl₂–MeOH–H₂O); [

a

]

ꢀ45 (c 1.1, H₂O); ¹H NMR

The 2-O-(4-methoxybenzyl) derivative 9 (1.20 g, 2.98 mmol)

was dissolved in dry toluene (20 mL). 1,1⁰-Thiocarbonyldiimidaz-

ole (1.06 g, 5.96 mmol) was added, and the reaction mixture was

stirred at reﬂux under argon overnight. The reaction mixture was

cooled, then concentrated under reduced pressure. The black oily

residue was subjected to chromatography on silica gel (7:3 hex-

anes–EtOAc) to give the Barton–McCombie substrate 10 (978 mg,

D

(600 MHz, D₂O) d 4.82 (s, 1H, H-1⁰), 4.61 (s, 1H, H-1), 4.24 (d, 1H,

J_2,33.3 Hz, H-2), 4.10 (d, 1H, J_{2 ,3}3.3 Hz, H-2⁰), 3.92 (dd, 1H, J_{5 ,6}

0

2.3, J_gem12.3 Hz, H-6a⁰), 3.73 (dd, 1H, J_{5 ,6}6.8, J_gem12.3 Hz, H-

0

6b⁰), 3.63 (dd, 1H, J_{2 ,3}3.3, J_{3 ,4}9.3 Hz, H-3⁰), 3.58 (dd, 1H, J_2,33.3,

0

J_3,49.3 Hz, H-3) 3.55 (dd, 1H, J_{3 ,4}ꢂ J_{4 ,5}9.7 Hz, H-4⁰), 3.51 (s, 3H,

0

CH₃O), 3.34–3.42 (m, 3H, H-5⁰, H-4, H-5), 1.32 (d, 3H, J_5,65.6 Hz,

CH₃); ¹³C NMR (125 MHz, D₂O) d 102.1 (C-1, J_C1,H1152.3 Hz, b),

64%) as a white solid: R_f0.24 (1:1 hexanes–EtOAc); [a] +10 (c

1

D

1

101.3 (C-1⁰, J_{C1 ,H1}162.7 Hz, b), 78.6 (C-2), 77.2 (C-5⁰), 73.7, 73.4,

73.2, 72.9 (C-3⁰, C-3, C-4, C-5), 71.2 (C-2⁰), 67.7 (C-4⁰), 62.0 (C-6⁰),

57.9 (CH₃O), 17.5 (C-6); HRESIMS: Calcd for C₁₃H₂₄O₁₀Na

363.1262. Found 363.1261.

0.84, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 8.10 (br s, 1H, imidazole),

7.44 (br s, 1H, imidazole), 7.36–7.38 (m, 2H, ArH), 7.31–7.32 (m,

3H, ArH), 7.08–7.10 (m, 2H, ArH), 6.99 (br s, 1H, imidazole),

6.66–6.67 (m, 2H, ArH), 6.11 (dd, 1H, J_2,3ꢂ J_3,49.3 Hz, H-3), 5.46

(s, 1H, PhCHO₂), 4.74 (d, 1H, J_gem11.8 Hz, PhCH₂O), 4.59 (d, 1H,

J_1,27.5 Hz, H-1), 4.54 (d, 1H, J_gem11.8 Hz, PhCH₂O), 4.41 (dd, 1H,

J_5,65.0, J_gem10.5 Hz, H-6a), 3.80 (dd, 1H, J_5,6ꢂ J_gem10.3 Hz, H-

6b), 3.76 (dd, 1H, J_3,4ꢂ J_4,59.5 Hz, H-4), 3.74 (s, 3H, CH₃O), 3.64

(s, 3H, CH₃O), 3.56–3.61 (m, 2H, H-2, H-5); ¹³C NMR (125 MHz,

CDCl₃) d 183.7 (C@S), 159.5 (Ar), 136.7 (Ar), 136.5 (Ar), 130.5

(Ar), 130.0 (Ar), 129.2 (Ar), 129.1 (Ar), 128.2 (Ar), 126.1 (Ar),

118.2 (Ar), 113.6 (Ar), 105.3 (C-1), 101.4 (PhCHO₂), 81.0 (C-3),

78.7 (C-4), 78.0 (C-2/C-5), 73.6 (PhCH₂O), 68.7 (C-6), 65.7 (C-2/C-

5), 57.7 (CH₃O), 55.1 (CH₃O); HRESIMS: Calcd for C₂₆H₂₈N₂O₇SNa

535.1509. Found 535.1511. Anal. Calcd for C₂₆H₂₈N₂O₇S: C, 60.92;

H, 5.51; N, 5.47; S, 6.26. Found: C, 61.03; H, 5.58; N, 5.46; S, 5.96.

0

3.7. Methyl b-D-mannopyranosyl-(1?2)-6-O-methyl-b-D-manno-

pyranoside (7)

Compound 52 (50.0 mg, 0.061 mmol) was dissolved in 1:1

CH₂Cl₂–MeOH (10 mL) and stirred with 10% Pd/C (50 mg) under a

H₂atmosphere, then processed as described for 2. Filtration, then

lyophilization, gave 7 (15.6 mg, 69%) as a clear glass: R_f0.33

(6:3.5:0.5, CH₂Cl₂–CH₃OH–H₂O); [

a

]

ꢀ73 (c 0.25, H₂O); ¹H NMR

D

(500 MHz, D₂O) d 4.82 (d, 1H, J_{1 ,2}0.8 Hz, H-1⁰), 4.63 (s, 1H, H-1),

0

4.25 (d, 1H, J_2,32.9 Hz, H-2), 4.11 (dd, 1H, J_{1 ,2}0.7, J_{2 ,3}3.3 Hz, H-

2⁰), 3.92 (dd, 1H, J_{5 ,6}2.3, J_gem12.3 Hz, H-6a⁰), 3.80 (dd, 1H, J_5,62.1,

0

J_gem11.2 Hz, H-6a), 3.73 (dd, 1H, J_{5 ,6}6.7, J_gem12.3 Hz, H-6b⁰), 3.67

(dd, 1H, J_5,66.3, J_gem11.3 Hz, H-6b), 3.62–3.64 (m, 2H, H-3⁰, H-3),

0

3.10. Methyl 4,6-O-benzylidene-3-deoxy-2-O-(4-methoxybenzyl)-

0

3.59 (dd, 1H, J_3,4ꢂ J_4,59.3 Hz, H-4), 3.56 (dd, 1H, J_{3 ,4}ꢂ J_{4 ,5}9.7 Hz,

b-D-ribo-hexopyranoside (11)

H-4⁰), 3.53 (s, 3H, CH₃O–C1), 3.49 (ddd, 1H, J_4,59.2, J_5,62.2, 6.3 Hz,

0

H-5), 3.42 (s, 3H, CH₃O–C6), 3.36 (ddd, 1H, J_{4 ,5}9.7, J_{5 ,6}2.2, 6.6 Hz,

To a solution of compound 10 (880 mg, 1.72 mmol) in dry toluene

H-5⁰); ¹³C NMR (125 MHz, D₂O) d 102.3 (C-1, J_C1,H1160.1 Hz, b),

(20 mL) were added tributyltin hydride (1.50 mL, 5.16 mmol) and

AIBN (71 mg, 0.43 mmol). The reaction mixture was stirred at reﬂux

under argon for 16 h, cooled then concentrated under reduced pres-

sure. The residue was redissolved in a small volume of CH₂Cl₂and

passed through a plug of silica gel containing 10% (w/w) KF. The

ﬁltrate was concentrated, and the residue was subjected to chroma-

tography on silica gel (4:1 hexane–EtOAc) to give the deoxygenated

product 11 (515 mg, 78%) as a white solid: R_f0.55 (1:1 hexanes–

1

101.3 (C-1⁰, J_C1,H1162.4 Hz, b), 78.5 (C-2), 77.2 (C-5⁰), 75.8 (C-5),

73.6, 73.1 (C-3⁰, C-3), 72.1 (C-6), 71.2 (C-2⁰), 68.1 (C-4), 67.7 (C-4⁰),

62.0 (C-6⁰), 59.4 (CH₃OC-6), 58.1 (CH₃OC-1); HRESIMS: Calcd for

C₁₄H₂₆O₁₁Na 393.1367. Found 393.1365.

3.8. Methyl 4,6-O-benzylidene-2-O-(4-methoxybenzyl)-b-D-glu-

copyranoside (9)

EtOAc); [

a]

D

ꢀ40 (c 0.76, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d

Methyl 4,6-O-benzylidene-b-

D

-glucopyranoside (8)¹⁵(3.0 g,

7.47–7.48 (m, 2H, ArH), 7.34–7.47 (m, 3H, ArH), 7.26–7.29 (m, 2H,

ArH), 6.87–6.89 (m, 2H, ArH), 5.49 (s, 1H, PhCHO₂), 4.72 (d, 1H, J_gem

11.5 Hz, PhCH₂O), 4.59 (d, 1H, J_gem11.5 Hz, PhCH₂O), 4.39 (d, 1H, J_1,2

7.5 Hz, H-1), 4.32 (dd, 1H, J_5,65.0, J_gem10.6 Hz, H-6a), 3.81 (s, 3H,

CH₃O), 3.74 (dd, 1H, J_5,6ꢂ J_gem10.3 Hz, H-6b), 3.59 (s, 3H, CH₃O),

3.51 (ddd, 1H, J_3eq,44.4, J_3ax,411.9, J_4,59.1 Hz, H-4), 3.37–3.43 (m,

2H, H-2, H-5), 2.39 (ddd, 1H, J_2,3ꢂ J_3,44.7, J_gem12.1 Hz, H-3eq),

1.74 (ddd, 1H, J_2,3ꢂ J_3,4ꢂ J_gem11.8 Hz, H-3ax); ¹³C NMR (125 MHz,

10.63 mmol), tetrabutylammonium hydrogensulfate (902 mg,

2.66 mmol) and 4-methoxybenzyl chloride (1.8 mL, 13.28 mmol)

were dissolved in CH₂Cl₂(80 mL). Aq NaOH (20 mL of a 5% solu-

tion) was added, and the mixture was stirred under reﬂux over-

night. The reaction mixture was cooled, and the organic layer

was separated, washed with water, dried (Na₂SO₄) and then con-

centrated under reduced pressure. Puriﬁcation by chromatography

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

1403

CDCl₃) d 159.3 (Ar), 137.3 (Ar), 130.4 (Ar), 129.4 (Ar), 129.1 (Ar),

128.3 (Ar), 126.1 (Ar), 113.8 (Ar), 106.4 (C-1), 101.6 (PhCHO₂), 76.1

(C-4), 75.1 (C-2), 72.3 (PhCH₂O), 70.0 (C-5), 69.2 (C-6), 57.2

(CH₃O), 55.3 (CH₃O), 34.7 (C-3); HRESIMS: Calcd for C₂₂H₂₆O₆Na

409.1622. Found 409.1618. Anal. Calcd for C₂₂H₂₆O₆: C, 68.38; H,

6.78. Found: C, 68.22; H, 6.77.

overnight in toluene (40 mL) with azeotropic removal of water

using a Dean–Stark trap. The reaction mixture was cooled to room

temperature, then concentrated under reduced pressure. The solid

residue was redissolved in DMF (15 mL), methyl iodide (3.3 mL,

53.4 mmol) was added, and the reaction mixture was stirred at

40 °C. After 15 h, the reaction mixture was cooled, then concen-

trated under reduced pressure. Puriﬁcation by chromatography

over silica gel (1:1 toluene–EtOAc) gave 14 (1.11 g, 71%) as a white

3.11. Methyl 4,6-O-benzylidene-3-deoxy-b-D-ribo-hexopyrano-

side (12)

solid: R_f0.22 (1:1 hexanes–EtOAc); [

a]

_Dꢀ50 (c 1.0, CHCl₃); ¹H NMR

(500 MHz, CDCl₃) d 7.48–7.50 (m, 2H, ArH), 7.34–7.40 (m, 3H, ArH),

5.56 (s, 1H, PhCHO₂), 4.36 (dd, 1H, J_5,65.0, J_gem10.4 Hz, H-6eq),

4.35 (d, 1H, J_1,27.5 Hz, H-1), 3.80 (dd, 1H, J_5,6ꢂ J_gem10.3 Hz, H-

6ax), 3.68 (s, 3H, CH₃O), 3.63 (dd, 1H, J_3,4ꢂ J_4,59.2 Hz, H-4), 3.59

(s, 3H, CH₃O), 3.42–3.49 (m, 3H, H-2, H-3, H-5), 2.53 (d, 1H, J_2,OH

1.9 Hz, OH); ¹³C NMR (125 MHz, CDCl₃) d 137.2 (Ar), 129.0 (Ar),

128.3 (Ar), 126.0 (Ar), 104.2 (C-1), 101.3 (PhCHO₂), 82.2 (C-3),

81.6 (C-4), 74.1 (C-2), 68.7 (C-6), 66.4 (C-5), 60.9 (CH₃O), 57.4

(CH₃O); HRESIMS: Calcd for C₁₅H₂₀O₆Na 319.1152. Found

319.1152. Anal. Calcd for C₁₅H₂₀O₆: C, 60.80; H, 6.80. Found: C,

60.92; H, 6.75.

To a solution of 11 (499 mg, 1.29 mmol) in CH₂Cl₂(22 mL) and

H₂O (3 mL) at 0 °C (ice-water bath) was added 2,3-dichloro-5,6-

dicyano-1,4-benzoquinone (879 mg, 3.87 mmol). The reaction

was allowed to slowly warm to room temperature, and after 5 h

it was diluted with CH₂Cl₂. The organic phase was washed with

10% aq NaHCO₃, distilled H₂O and brine, then dried (Na₂SO₄). Con-

centration under reduced pressure, followed by puriﬁcation by col-

umn chromatography over silica gel (3:2 hexanes–EtOAc) gave 12

(294 mg, 86%) as a white solid: R_f0.27 (1:1 hexanes–EtOAc); [a]

D

ꢀ52 (c 0.47, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 7.48–7.50 (m,

2H, ArH), 7.34–7.40 (m, 3H, ArH), 5.54 (s, 1H, PhCHO₂), 4.34 (dd,

1H, J_5,64.9, J_gem10.5 Hz, H-6a), 4.26 (d, 1H, J_1,27.5 Hz, H-1), 3.78

(dd, 1H, J_5,6ꢂ J_gem10.4 Hz, H-6b), 3.57–3.63 (m, 2H, H-2, H-4),

3.58 (s, 3H, CH₃O), 3.46 (ddd, 1H, J_4,59.1, J_5,64.9, 10.1 Hz, H-5),

2.47 (ddd, 1H, J_2,3ꢂ J_3,44.7, J_gem11.9 Hz, H-3eq), 2.32 (br s, 1H,

OH), 1.76 (ddd, 1H, J_2,3ꢂ J_gemꢂ J_3,411.7 Hz, H-3ax); ¹³C NMR

(125 MHz, CDCl₃) d 137.3 (Ar), 129.1 (Ar), 128.3 (Ar), 126.2 (Ar),

106.4 (C-1), 101.8 (PhCHO₂), 76.2 (C-4), 70.6 (C-5), 69.2, 69.1 (C-

2, C-6), 57.3 (CH₃O), 35.0 (C-3); HRESIMS: Calcd for C₁₄H₁₈O₅Na

289.1047. Found 289.1046. Anal. Calcd for C₁₄H₁₈O₅: C, 63.15; H,

6.81. Found: C, 63.11; H, 6.80.

3.14. Methyl 4,6-O-benzylidene-3-O-methyl-b-D-mannopyrano-

side (15)

Compound 14 (446 mg, 1.51 mmol) was dissolved in a mixture

of Me₂SO (6 mL) and Ac₂O (3 mL). After stirring overnight, the mix-

ture was concentrated under reduced pressure. The remaining so-

lid was redissolved in 1:1 CH₂Cl₂–MeOH (10 mL) and cooled to 0 °C

(ice-water bath). NaBH₄(286 mg, 7.53 mmol) was added, and the

reaction mixture was stirred until starting material was consumed

according to TLC. The reaction mixture was diluted with CH₂Cl₂,

then washed successively with 2% aq citric acid, and brine, dried

(Na₂SO₄), then concentrated under reduced pressure. Chromatog-

raphy over silica gel (7:3 hexanes–EtOAc) gave 15 (356 mg, 80%)

3.12. Methyl 4,6-O-benzylidene-3-deoxy-b-D-arabino-hexopyrano-

side (13)

as a white solid: R_f0.07 (1:1 hexanes–EtOAc); [

a

]

ꢀ74 (c 1.0,

D

Compound 12 (294 mg, 1.10 mmol) was dissolved in a mixture

of freshly distilled Me₂SO (6 mL) and Ac₂O (3 mL). After stirring for

8 h at room temperature, the reaction mixture was concentrated

under reduced pressure. The residue was redissolved in dry THF

(10 mL) and cooled to ꢀ78 °C. A 1.0 M solution of L-Selectride^Ò

in THF (4.4 mL, 4.41 mmol) was added dropwise and stirring was

continued for 2 h at ꢀ78 °C. The reaction was quenched with

MeOH then diluted with CH₂Cl₂. The mixture was washed with

10% aq H₂O₂, 1 M aq NaOH, distilled H₂O, then brine. The organic

phase was dried (Na₂SO₄), then concentrated under reduced pres-

sure. Puriﬁcation by chromatography over silica gel (3:2 hexanes–

EtOAc) gave 13 (243 mg, 83%) as a white solid: R_f0.28 (1:1 hex-

CHCl₃); ¹H NMR (600 MHz, CDCl₃) d 7.48–7.50 (m, 2H, ArH),

7.33–7.38 (m, 3H, ArH), 5.59 (s, 1H, PhCHO₂), 4.48 (d, 1H, J_1,2

1.0 Hz, H-1), 4.35 (dd, 1H, J_5,65.0, J_gem10.3 Hz, H-6eq), 4.21 (d,

1H, J_2,33.2 Hz, H-2), 4.06 (dd, 1H, J_3,4ꢂ J_4,59.5 Hz, H-4), 3.89 (dd,

1H, J_5,6ꢂ J_gem10.3 Hz, H-6ax), 3.59 (s, 3H, CH₃O), 3.58 (s, 3H,

CH₃O), 3.47 (dd, 1H, J_2,33.2, J_3,49.6 Hz, H-3), 3.39 (ddd, 1H, J_4,5

9.8, J_5,64.9, 9.8 Hz, H-5), 2.49 (br s, 1H, OH); ¹³C NMR (125 MHz,

CDCl₃) d 137.4 (Ar), 129.0 (Ar), 128.2 (Ar), 126.1 (Ar), 101.7,

101.4 (C-1, PhCHO₂), 79.3 (C-3), 78.4 (C-4), 69.0 (C-2), 68.6 (C-6),

66.8 (C-5), 58.6 (CH₃O), 57.3 (CH₃O); HRESIMS: Calcd for

C₁₅H₂₀O₆Na 319.1152. Found 319.1154. Anal. Calcd for C₁₅H₂₀O₆:

C, 60.80; H, 6.80. Found: C, 61.20; H, 6.73.

anes–EtOAc); [

a

]

D

ꢀ64 (c 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃)

d 7.47–7.50 (m, 2H, ArH), 7.32–7.39 (m, 3H, ArH), 5.57 (s, 1H,

PhCHO₂), 4.50 (d, 1H, J_1,21.3 Hz, H-1), 4.31 (dd, 1H, J_5,65.0, J_gem

10.4 Hz, H-6eq), 3.98–4.03 (m, 2H, H-2, H-4), 3.84 (dd, 1H,

J_5,6ꢂ J_gem10.3, H-6ax), 3.58 (s, 3H, CH₃O), 3.45 (dd, 1H, J_4,59.3,

J_5,65.0, 10.1 Hz, H-5), 2.44 (dd, 1H, J_2,OHꢂ J_3ax,OH1.7 Hz, C2–OH),

2.39 (ddd, 1H, J 3.2, 4.5, J_gem13.4 Hz, H-3eq), 1.79 (dddd, 1H, J_2,3

3.0, J_3,411.8, J_gem13.5, J_3,OH1.9 Hz, H-3ax); ¹³C NMR (125 MHz,

CDCl₃) d 137.5 (Ar), 129.0 (Ar), 128.3 (Ar), 126.1 (Ar), 102.0,

101.8 (C-1, PhCHO₂), 73.5 (C-4), 70.6 (C-5), 69.0 (C-6), 67.9 (C-2),

56.8 (CH₃O), 33.9 (C-3); HRESIMS: Calcd for C₁₄H₁₈O₅Na

289.1046. Found 289.1043. Anal. Calcd for C₁₄H₁₈O₅: C, 63.15; H,

6.81. Found: C, 63.05; H, 6.88.

3.15. Methyl 2-O-acetyl-3,4,6-tri-O-benzyl-b-

D

-glucopyranosyl-

(1?2)-4,6-O-benzylidene-3-deoxy-b-

D-arabino-hexopyranoside

(17)

Monosaccharide acceptor 13 (120 mg, 0.45 mmol) was reacted

with 2-O-acetyl-3,4,6-tri-O-benzyl-b- -glucopyranosyl trichloro-

acetimidate (16) (344 mg, 0.54 mmol) in CH₂Cl₂(5 mL) using

TMSOTf (5 L, 0.03 mmol) under argon at 0 °C. The reaction mix-

D

l

ture was neutralized with Et₃N, ﬁltered through Celite then con-

centrated under reduced pressure. The product was puriﬁed by

chromatography over silica gel (7:3 hexanes–EtOAc) to give 17

(196 mg, 59%) as a white solid: R_f0.52 (1:1 hexanes–EtOAc); [a]

D

ꢀ24 (c 0.24, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 7.46–7.48 (m,

3.13. Methyl 4,6-O-benzylidene-3-O-methyl-b-D-glucopyranoside

2H, ArH), 7.25–7.38 (m, 16H, ArH), 7.18–7.20 (m, 2H, ArH), 5.57

(s, 1H, PhCHO₂), 5.00 (dd, 1H, J_{1 ,2}8.0, J_{2 ,3}9.3 Hz, H-2⁰), 4.81 (d,

1H, J_gem10.8 Hz, PhCH₂O), 4.78 (d, 1H, J_gem11.5 Hz, PhCH₂O),

0

(14)

-glucopyranoside (8)¹⁵(1.5 g,

4.73 (d, 1H, J_gem11.2 Hz, PhCH₂O), 4.73 (d, 1H, J_{1 ,2}8.0 Hz, H-1⁰),

4.62 (d, 1H, J_gem12.4 Hz, PhCH₂O), 4.57 (d, 1H, J_gem10.9 Hz,

0

Methyl 4,6-O-benzylidene-b-

5.31 mmol) and dibutyltin oxide (1.46 g, 5.88 mmol) were reﬂuxed

D

1404

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

PhCH₂O), 4.55 (d, 1H, J_gem12.3 Hz, PhCH₂O), 4.39 (d, 1H, J_1,20.8 Hz,

H-1), 4.26 (dd, 1H, J_5,64.9, J_gem10.3 Hz, H-6eq), 4.03 (ddd, 1H, J_1,2

0.9, J_2,33.1 Hz, H-2), 3.93 (ddd, 1H, J_3,44.6, 12.6 Hz, J_4,59.5 Hz, H-

4), 3.80 (dd, 1H, J_5,6ꢂ J_gem10.2 Hz, H-6ax), 3.63–3.74 (m, 4H,

12.3 Hz, PhCH₂O), 4.46 (d, 1H, J_1,21.1 Hz, H-1), 4.31 (dd, 1H, J_5,6

4.9, J_gem10.4 Hz, H-6eq), 4.29 (dd, 1H, J_{1 ,2}0.9, J_{2 ,3}3.0 Hz, H-2⁰),

4.14 (ddd, 1H, H-2), 4.01 (ddd, 1H, J_3,43.3, 12.0, J_4,59.2 Hz, H-4),

0

3.87 (dd, 1H, J_5,6ꢂ J_gem10.3 Hz, H-6ax), 3.85 (dd, 1H, J_{3 ,4}ꢂ J_{4 ,5}

H-3⁰, H-4⁰, H-6a⁰, H-6b⁰), 3.48 (ddd, 1H, J_{4 ,5}9.6, J_{5 ,6}2.6, 4.7 Hz,

H-5⁰), 3.47 (s, 3H, CH₃O), 3.40 (ddd, 1H, J_4,59.4, J_5,64.9, 10.1 Hz,

H-5), 2.39 (ddd, 1H, J_2,34.0, J_gem12.7, J_3,44.0 Hz, H-3eq), 2.00 (s,

3H, CH₃C(O)O), 1.76 (ddd, 1H, J_2,32.7, J_gem12,4, J_3,412.4 Hz, H-

3ax); ¹³C NMR (125 MHz, CDCl₃) d 169.9 (C@O), 138.4 (Ar), 138.2

(Ar), 138.0 (Ar), 137.7 (Ar), 128.9 (Ar), 128.3(8) (Ar), 128.3(6)

(Ar), 128.3 (Ar), 128.0 (Ar), 127.8 (Ar), 127.7(4) (Ar), 127.6(7)

(Ar), 127.6(2) (Ar), 127.5(7) (Ar), 126.1 (Ar), 103.2 (C-1), 101.8

(PhCHO₂), 101.5 (C-1⁰), 82.8 (C-3⁰), 77.9 (C-4⁰), 75.0(4), 75.0(0),

74.8 (C-5⁰, PhCH₂O ꢃ 2), 73.7, 73.6 (C-2⁰, C-2, C-4), 73.4 (PhCH₂O),

71.1 (C-5), 69.0, 68.9 (C-6⁰, C-6), 56.8 (CH₃O), 34.7 (C-3), 21.1

(CH₃C(O)O); HRESIMS: Calcd for C₄₃H₄₈O₁₁Na 763.3089. Found

763.3084. Anal. Calcd for C₄₃H₄₈O₁₁: C, 69.71; H, 6.53. Found: C,

69.68; H, 6.64.

9.3 Hz, H-4⁰), 3.76 (dd, 1H, J_{5 ,6}2.0, J_gem10.8 Hz, H-6a⁰), 3.68 (dd,

0

1H, J_{5 ,6}5.7, J_gem10.8 Hz, H-6b⁰), 3.57 (dd, 1H, J_{2 ,3}3.0, J_{3 ,4}

0

9.1 Hz, H-3⁰), 3.52 (s, 3H, CH₃O), 3.42–3.48 (m, 2H, H-5⁰, H-5),

2.51 (ddd, 1H, J_2,3ꢂ J_3,44.0, J_gem13.1 Hz, H-3eq), 1.83 (ddd, 1H,

J_2,32.9, J_gem13.0, J_3,412.0 Hz, H-3ax); ¹³C NMR (125 MHz, CDCl₃)

d

138.2(8), 138.2(6), 137.9, 137.5, 129.0, 128.4, 128.3(4),

128.2(8), 128.1, 127.9, 127.8, 127.7(1), 127.6(9), 127.5, 126.1,

103.2, 101.8, 100.9, 81.4, 75.4, 75.1, 74.3, 74.1, 73.8, 73.5, 71.1(3),

71.0(9), 69.5, 68.9, 67.8, 57.3, 34.7; HRESIMS: Calcd for

C₄₁H₄₆O₁₀Na 721.2983. Found 721.2985.

3.18. Methyl 2-O-acetyl-3,4,6-tri-O-benzyl-b-

D

-glucopyranosyl-

(1?2)-4,6-O-benzylidene-3-O-methyl-b-

D-mannopyranoside

(20)

3.16. Methyl 3,4,6-tri-O-benzyl-b-

D

-glucopyranosyl-(1?2)-4,6-

Monosaccharide acceptor 15 (205 mg, 0.69 mmol) was reacted

with 2-O-acetyl-3,4,6-tri-O-benzyl-b- -glucopyranosyl trichloro-

acetimidate (16) (484 mg, 0.76 mmol) in CH₂Cl₂(5 mL) using

TMSOTf (6 L, 0.03 mmol) under argon at 0 °C, then processed as

described for 17. The product was puriﬁed by chromatography

over silica gel (7:3 hexanes–EtOAc) to give 20 (513 mg, 97%) as a

O-benzylidene-3-deoxy-b- -arabino-hexopyranoside (18)

D

Disaccharide 17 (176 mg, 0.24 mmol) was dissolved in 1:1

CH₂Cl₂–MeOH (2 mL) and treated with 0.5 M NaOCH₃–CH₃OH

(2 mL). After 2 h, the reaction mixture was neutralized with

Amberlite IR-120 (H⁺) resin and ﬁltered. Puriﬁcation of the product

by chromatography over silica gel (7:3 hexanes–EtOAc) gave 18

(166 mg, quant.) as a white solid: R_f0.33 (1:1 hexanes–EtOAc);

l

white solid: R_f0.49 (1:1 hexanes–EtOAc); [

a

]

_Dꢀ40 (c 0.67, CHCl₃);

¹H NMR (600 MHz, CDCl₃) d 7.46–8.48 (m, 2H, ArH), 7.27–7.36 (m,

16H, ArH), 7.21–7.22 (m, 2H, ArH), 5.57 (s, 1H, PhCHO₂), 5.10 (dd,

ꢀ5 (c 0.82, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 7.47–7.50

1H, J_{1 ,2}8.0, J_{2 ,3}9.6 Hz, H-2⁰), 4.82 (d, 1H, J_gem11.0 Hz, PhCH₂O),

0

[

a

]

D

4.79 (d, 1H, J_gem11.5 Hz, PhCH₂O), 4.77 (d, 1H, J_{1 ,2}8.0 Hz, H-1⁰),

4.75 (d, 1H, J_gem11.5 Hz, PhCH₂O), 4.58 (d, 1H, J_gem12.1 Hz,

PhCH₂O), 4.57 (d, 1H, J_gem11.0 Hz, PhCH₂O), 4.54 (d, 1H, J_gem

12.0 Hz, PhCH₂O), 4.35 (s, 1H, H-1), 4.28 (dd, 1H, J_5,64.7, J_gem

10.1 Hz, H-6eq), 4.26 (d, 1H, J_2,33.0 Hz, H-2), 3.99 (dd, 1H,

J_3,4ꢂ J_4,59.6 Hz, H-4), 3.82 (dd, 1H, J_5,6ꢂ J_gem10.2 Hz, H-6b), 3.75

0

(m, 2H, ArH), 7.23–7.42 (m, 16H, ArH), 7.18–7.20 (m, 2H, Ar),

5.59 (s, 1H, PhCHO₂), 5.05 (d, 1H, J_gem11.2 Hz, PhCH₂O), 4.87 (d,

1H, J_gem10.9 Hz, PhCH₂O), 4.80 (d, 1H, J_gem11.2 Hz, PhCH₂O),

4.60 (d, 1H, J_gem12.2 Hz, PhCH₂O), 4.55 (d, 1H, J_gem12.4 Hz,

PhCH₂O), 4.54 (d, 1H, J_gem10.8 Hz, PhCH₂O), 4.50 (s, 1H, H-1),

4.41 (d, 1H, J_{1 ,2}7.3 Hz, H-1⁰), 4.32 (dd, 1H, J_5,64.9, J_gem10.4 Hz,

H-6eq), 4.01–4.06 (m, 2H, H-2, H-4), 3.87 (dd, 1H, J_5,6ꢂ J_gem

10.4 Hz, H-6ax), 3.63–3.74 (m, 4H, H-2⁰, H-3⁰, H-6a⁰, H-6b⁰), 3.56–

3.60 (m, 4H, H-4⁰, CH₃O), 3.44–3.52 (m, 2H, H-5⁰, H-5), 2.55 (ddd,

1H, J_2,3ꢂ J_3,43.8, J_gem13.1 Hz, H-3eq), 1.84 (ddd, 1H, J_2,31.8,

J_3,4ꢂ J_gem12.9 Hz, H-3ax); ¹³C NMR (125 MHz, CDCl₃) d 138.9

(Ar), 138.2 (Ar), 138.1 (Ar), 137.5 (Ar), 129.0 (Ar), 128.3(8) (Ar),

128.3(5) (Ar), 128.3(2) (Ar), 128.3(1) (Ar), 128.0(0) (Ar), 127.9(8)

(Ar), 127.7 (Ar), 127.6 (Ar), 127.5 (Ar), 126.1 (Ar), 106.0 (C-1⁰),

102.5 (C-1), 101.9 (PhCHO₂), 84.8 (C-2⁰), 77.6 (C-2), 77 (C-4⁰),

75.6, 75.3 (C-5⁰, C-3), 75.1 (PhCH₂O), 74.9 (PhCH₂O), 73.7, 73.5

(C-4, PhCH₂O), 70.9 (C-5), 69.0(2), 68.9(7) (C-6⁰, C-6), 57.2

(CH₃O), 35.0 (C-3); HRESIMS: Calcd for C₄₁H₄₆O₁₀Na 721.2983.

Found 721.2986. Anal. Calcd for C₄₁H₄₆O₁₀: C, 70.47; H, 6.63.

Found: C, 70.47; H, 6.68.

0

(dd, 1H, J_{2 ,3}9.5, J_{3 ,4}8.5 Hz, H-3⁰), 3.74 (dd, 1H, J_{5 ,6}1.8, J_gem

0

10.9 Hz, H-6a⁰), 3.63 (dd, 1H, J_{5 ,6}6.2, J_gem10.9 Hz, H-6b⁰), 3.57

0

(dd, 1H, J_{3 ,4}8.6, J_{4 ,5}9.8 Hz, H-4⁰), 3.53 (ddd, 1H, J_{4 ,5}9.8, J_{5 ,6}

0

1.7, 6.0 Hz, H-5⁰), 3.49 (s, 3H, CH₃O), 3.46 (s, 3H, CH₃O), 3.37 (dd,

1H, J_2,33.0, J_3,410.0 Hz H-3), 3.33 (ddd, 1H, J_4,59.9, J_5,65.0,

9.9 Hz, H-5), 1.99 (s, 3H, CH₃C(O)O); ¹³C NMR (125 MHz, CDCl₃) d

169.7 (C@O), 138.5 (Ar), 138.2 (Ar), 138.0 (Ar), 137.5 (Ar), 128.9

(Ar), 128.4 (Ar), 128.3(4) (Ar), 128.3(3) (Ar), 128.2 (Ar), 128.1

(Ar), 127.8 (Ar), 127.7(2) (Ar), 127.6(9) (Ar), 127.5(9) (Ar),

127.5(7) (Ar), 126.2 (Ar), 102.7 (C-1), 101.9 (PhCHO₂), 101.1 (C-

1⁰), 83.0 (C-3⁰), 78.6 (C-3), 78.1 (C-4⁰), 77.7 (C-4), 75.1, 75.0, 74.8

(C-5⁰, PhCH₂O ꢃ 2), 73.6(1), 73.5(8), 73.2 (C-2⁰, C-2, PhCH₂O), 69.7

(C-6⁰), 68.6 (C-6), 67.7 (C-5), 57.0 (CH₃O), 56.8 (CH₃O), 21.1

(CH₃C(O)O); HRESIMS: Calcd for C₄₄H₅₀O₁₂Na 793.3195. Found

793.3195.

3.17. Methyl 3,4,6-tri-O-benzyl-b-D-mannopyranosyl-(1?2)-

4,6-O-benzylidene-3-deoxy-b- -arabino-hexopyranoside (19)

D

3.19. Methyl 3,4,6-tri-O-benzyl-b-D-glucopyranosyl-(1?2)-4,6-

O-benzylidene-3-O-methyl-b- -mannopyranoside (21)

D

Disaccharide 18 (140 mg, 0.200 mmol) was dissolved in freshly

distilled Me₂SO (5 mL) and Ac₂O (5 mL). The mixture was concen-

trated under reduced pressure, then the residue was redissolved in

dry THF and cooled to ꢀ78 °C under argon. The reaction mixture

was then treated with 1.0 M L-Selectride^Òin THF (1 mL, 1 mmol)

in dry THF (10 mL). Puriﬁcation by column chromatography over

silica gel (7:3 hexanes–EtOAc) gave 19 (90.8 mg, 65%) as a white

Disaccharide 20 (513 mg, 0.67 mmol) was dissolved in 1:1

CH₂Cl₂–MeOH (4 mL) and treated with 0.5 M CH₃ONa–CH₃OH

(1 mL) then processed as described for 18. Puriﬁcation of the prod-

uct by chromatography over silica gel (7:3 hexanes–EtOAc) gave

21 (428 mg, 88%) as a white solid: R_f0.27 (1:1 hexanes–EtOAc);

[a]

ꢀ38 (c 0.37, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 7.47–7.49

D

solid: R_f0.26 (1:1 hexanes–EtOAc); [

a]

D

ꢀ15 (c 0.60, CHCl₃); ¹H

(m, 2H, ArH), 7.42–7.46 (m, 16H, ArH), 7.19–7.21 (m, 2H, ArH),

5.55 (s, 1H, PhCHO₂), 5.06 (d, 1H, J_gem11.2 Hz, PhCH₂O), 4.87 (d,

1H, J_gem11.0 Hz, PhCH₂O), 4.81 (d, 1H, J_gem11.2 Hz, PhCH₂O),

4.54 (s, 2H, PhCH₂O), 4.54 (d, 1H, J_gem10.9 Hz, PhCH₂O), 4.50 (d,

NMR (500 MHz, CDCl₃) d 7.47–7.49 (m, 2H, ArH), 7.21–7.39 (m,

18H, ArH), 5.56 (s, 1H, PhCHO₂), 4.91 (d, 1H, J_gem10.9 Hz, PhCH₂O),

4.80 (d, 1H, J_gem11.9 Hz, PhCH₂O), 4.71 (d, 1H, J_{1 ,2}0.8 Hz, H-1⁰),

4.65 (d, 1H, J_gem12.0 Hz, PhCH₂O), 4.60 (d, 1H, J_gem12.2 Hz,

PhCH₂O), 4.56 (d, 1H, J_gem10.9 Hz, PhCH₂O), 4.55 (d, 1H, J_gem

0

1H, J_{1 ,2}7.7 Hz, H-1⁰), 4.46 (d, 1H, J_1,20.6 Hz, H-1), 4.34 (dd, 1H,

J_5,64.9, J_gem10.4 Hz, H-6eq), 4.26 (d, 1H, J_2,33.2, H-2), 4.02 (dd,

0

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

1405

1H, J_3,4ꢂ J_4,59.7 Hz, H-4), 3.87 (dd, 1H, J_5,6ꢂ J_gem10.3 Hz, H-6ax),

PhCH₂O), 4.69 (d, 1H, PhCH₂O), 4.60 (d, 1H, J_1,21.2 Hz, H-1), 4.41

(dd, 1H, J_5,6eq4.9, J_gem10.5 Hz, H-6eq), 4.14 (dd, 1H, J_3,4ꢂ J_4,5

9.6 Hz, H-4), 3.98 (dd, 1H, J_5,6ax9.7, J_gem10.4 Hz, H-6ax) 3.84 (dd,

1H, J_2,33.4, J_3,49.8 Hz, H-3), 3.53 (s, 3H, CH₃O), 3.47 (ddd, 1H, J_4,5

9.7, J_5,64.8, 9.7 Hz, H-5); ¹³C NMR (125 MHz, CDCl₃) d 166.1

(C°O), 137.7 (Ar), 137.4 (Ar), 133.1 (Ar), 130.1 (Ar), 129.9 (Ar),

129.0 (Ar), 128.3(3) (Ar), 128.3(0) (Ar), 128.2 (Ar), 127.7 (Ar),

126.1 (Ar), 101.6 (PhCHO₂), 101.1 (C-1), 78.4 (C-4), 75.6 (C-3),

71.6 (PhCH₂O), 69.3 (C-2), 68.7 (C-6), 67.4 (C-5), 57.5 (CH₃O); HRE-

SIMS: Calcd for C₂₈H₂₈O₇Na 499.1727. Found 499.1729. Anal. Calcd

for C₂₈H₂₈O₇: C, 70.57; H, 5.92. Found: C, 70.81; H, 5.73.

3.76 (dd, 1H, J_{5 ,6}1.7, J_gem10.5 Hz, H-6a⁰), 3.74 (dd, 1H, J_{1 ,2}8.0,

0

J_{2 ,3}8.9 Hz, H-2⁰), 3.67 (dd, 1H, J_{2 ,3}ꢂ J_{3 ,4}8.8 Hz, H-3⁰), 3.63 (dd,

0

1H, J_{5 ,6}6.4, J_gem10.5 Hz, H-6b⁰), 3.58 (s, 3H, CH₃O), 3.56 (ddd,

0

1H, J_{4 ,5}10.0, J_{5 ,6}1.7, 6.5 Hz, H-5⁰), 3.47 (dd, 1H, J_{3 ,4}8.5, J_{4 ,5}

0

9.7 Hz, H-4⁰), 3.48 (s, 3H, CH₃O), 3.42 (dd, 1H, J_2,33.2, J_3,410.0 Hz,

H-3), 3.38 (ddd, 1H, J_4,59.9, J_5,64.9, 9.9 Hz, H-5); ¹³C NMR

(125 MHz, CDCl₃) d 139.0 (Ar), 138.3 (Ar), 138.2 (Ar), 137.4 (Ar),

128.9 (Ar), 128.4 (Ar), 128.3(1) (Ar), 128.2(9) (Ar), 128.2 (Ar),

128.1 (Ar), 128.0 (Ar), 127.8 (Ar), 127.7 (Ar), 127.5(4) (Ar),

127.4(8) (Ar), 126.2 (Ar), 105.1 (C-1⁰), 102.1 (C-1), 101.8 (PhCHO₂),

85.2 (C-3⁰), 78.8 (C-3), 77.8 (C-4), 77.3 (C-4⁰), 76.4 (C-2), 75.4(9),

75.4(6) (C-2⁰, C-5⁰), 75.0 (PhCH₂O), 74.8 (PhCH₂O), 73.5 (PhCH₂O),

69.8 (C-6⁰), 68.6 (C-6), 67.5 (C-5), 57.5 (CH₃O), 57.4 (CH₃O); HRE-

SIMS: Calcd for C₄₂H₄₈O₁₁Na 751.3089. Found 751.3089. Anal.

Calcd for C₄₂H₄₈O₁₁: C, 69.21; H, 6.64. Found: C, 68.95; H, 6.82.

3.22. Methyl 2-O-benzoyl-3,6-di-O-benzyl-b-D-mannopyranoside

(25)

Compound 24 (3.43 g, 6.77 mmol) was dissolved in dry THF,

and the solution was cooled to 0 °C (ice-water bath) under argon.

Activated 4 Å molecular sieves and NaCNBH₃(2.13 g, 33.86 mmol)

were added. A satd solution of HCl in Et₂O was added dropwise un-

til the solution was acidic (pH paper, gas evolution). After 3 h, the

reaction mixture was diluted with EtOAc and ﬁltered through Cel-

ite. The organic phase was washed with satd aq NaHCO₃, dried

(Na₂SO₄) and concentrated under reduced pressure. The crude

product was puriﬁed by column chromatography (4:1 hexanes–

EtOAc) to give 25 (2.80 g, 81%) as a white solid: R_f0.40 (1:1 hex-

3.20. Methyl 3,4,6-tri-O-benzyl-b-

4,6-O-benzylidene-3-O-methyl-b-

D

-mannopyranosyl-(1?2)-

D

-mannopyranoside (22)

Disaccharide 21 (428 mg, 0.59 mmol) was dissolved in freshly

distilled Me₂SO (10 mL) and Ac₂O (5 mL) then processed as de-

scribed for compound 19. The concentrated reaction mixture was

then treated with 1.0 M L-Selectride^Òin THF (2.4 mL, 2.35 mmol)

in dry THF (10 mL) at ꢀ78 °C under argon. Puriﬁcation by column

chromatography over silica gel (7:3 hexanes–EtOAc) gave 22

anes–EtOAc); [

a

]

_Dꢀ113 (c 0.22, CHCl₃); ¹H NMR (500 MHz, CDCl₃)

(308 mg, 72%) as a white solid: R_f0.19 (1:1 hexanes–EtOAc); [

a

]

d 8.07–8.09 (m, 2H, ArH), 7.54 (m, 1H, ArH), 7.26–7.41 (m, 12H,

ArH), 5.84 (dd, 1H, J_1,20.9, J_2,33.1 Hz, H-2) 4.85 (d, 1H, J_gem

11.4 Hz, PhCH₂O) 4.72 (d, 1H, J_gem12.1 Hz, PhCH₂O) 4.64 (d, 1H,

J_gem12.1 Hz, PhCH₂O) 4.55 (d, 1H, J_1,20.9 Hz, H-1) 4.50 (d, 1H, J_gem

11.4 Hz, PhCH₂O), 4.04 (ddd, 1H, J_4,OH2.0, J_3,4ꢂ J_4,59.4 Hz, H-4),

3.92 (ABX, 1H, J_5,63.2, J_gem10.7 Hz, H-6a), 3.88 (ABX, 1H, J_5,65.3,

J_gem10.7 Hz, H-6b), 3.54–3.58 (m, 2H, H-3, H-5), 3.53 (s, 3H,

CH₃O), 2.57 (d, 1H, J_4,OH2.1 Hz, OH); ¹³C NMR (125 MHz, CDCl₃) d

166.1 (C@O), 138.2 (Ar), 137.3 (Ar), 133.0 (Ar), 130.1 (Ar), 129.9

(Ar), 128.5 (Ar), 128.4 (Ar), 128.3 (Ar), 128.2 (Ar), 128.0 (Ar),

127.6 (Ar), 100.3 (C-1), 79.6 (C-3), 75.3 (C-5), 73.7 (PhCH₂O), 71.2

(PhCH₂O), 70.2 (C-6), 67.8(4), 67.8(0) (C-2, C-4), 57.2 (CH₃O); HRE-

SIMS: Calcd for C₂₈H₃₀O₇Na 501.1884. Found 501.1884.

D

ꢀ60 (c 0.47, CHCl₃); ¹H NMR (600 MHz, CDCl₃) d 7.49–7.50 (m,

2H, ArH), 7.24–7.40 (m, 18H, ArH), 5.58 (s, 1H, PhCHO₂), 4.94 (d,

1H, J_gem11.0 Hz, PhCH₂O), 4.85 (d, 1H, J_{1 ,2}0.8 Hz, H-1⁰), 4.82 (d,

1H, J_gem12.1 Hz, PhCH₂O), 4.65 (d, 1H, J_gem12.0 Hz, PhCH₂O),

4.58 (d, 1H, J_gem12.0 Hz, PhCH₂O), 4.57 (d, 1H, J_gem11.0 Hz,

PhCH₂O), 4.52 (m, 1H, H-2), 4.51 (d, 1H, J_gem12.0 Hz, PhCH₂O),

4.42 (d, 1H, J_1,20.9 Hz, H-1), 4.33 (dd, 1H, J_5,65.0, J_gem10.4 Hz, H-

0

6eq), 4.28 (dd, 1H, J_{1 ,2}0.7, J_{2 ,3}3.0 Hz, H-2⁰), 4.01 (dd, 1H,

0

J_3,4ꢂ J_4,59.6 Hz, H-4), 3.89 (dd, 1H, J_{3 ,4}ꢂ J_{4 ,5}9.4 Hz, H-4⁰), 3.88

0

(dd, 1H, J_5,610.3 Hz, H-6ax), 3.77 (dd, 1H, J_{5 ,6}2.0, J_gem10.8 Hz,

H-6a⁰), 3.71 (dd, 1H, J_{5 ,6}5.8 J_gem10.8 Hz, H-6b⁰), 3.55 (dd, 1H,

0

J_{2 ,3}3.0, J_{3 ,4}9.1 Hz, H-3⁰), 3.52 (s, 3H, CH₃O), 3.47 (ddd, 1H, J_{4 ,5}

0

9.7, J_{5 ,6}1.9, 5.7 Hz, H-5⁰), 3.45 (s, 3H, CH₃O), 3.43 (dd, 1H, J_2,3

3.3, J_3,49.9 Hz, H-3), 3.38 (ddd, 1H, J_4,59.9, J_5,64.9, 9.9 Hz, H-5);

¹³C NMR (125 MHz, CDCl₃) d 138.4 (Ar), 138.3 (Ar), 138.1 (Ar),

137.3 (Ar), 129.0 (Ar), 128.4 (Ar), 128.3 (Ar), 128.2 (Ar), 128.0

(Ar), 127.9 (Ar), 127.7 (Ar), 127.6(4) (Ar), 127.5(7) (Ar), 126.2

(Ar), 102.9 (C-1), 101.8 (PhCHO₂), 98.1 (C-1⁰), 81.4 (C-3⁰), 78.8 (C-

3), 77.7 (C-4), 75.3, 75.1, 74.3 (C-4⁰, C-5⁰, PhCH₂O), 73.4 (PhCH₂O),

70.8, 70.7 (C-2, PhCH₂O), 69.8 (C-6⁰), 68.6 (C-6), 67.8, 67.5 (C-2⁰,

C-5), 57.5 (CH₃O), 57.1 (CH₃O); HRESIMS: Calcd for C₄₂H₄₈O₁₁Na

751.3089. Found 751.3087. Anal. Calcd for C₄₂H₄₈O₁₁: C, 69.21;

H, 6.64. Found: C, 68.85; H, 6.70.

0

3.23. Methyl 2-O-benzoyl-3,6-di-O-benzyl-4-O-thiocarbonyl

imidazole-b-D-mannopyranoside (26)

To a solution of 25 (1.43 g, 2.98 mmol) in dry toluene (20 mL)

under argon was added 1,1⁰-thiocarbonyldiimidazole (1.60 g,

8.95 mmol). The reaction mixture was stirred at 90 °C. After 20 h,

the reaction mixture was cooled to room temperature, then con-

centrated under reduced pressure to give a brown oily residue.

Puriﬁcation of the product by chromatography (1:1 hexanes–

EtOAc) yielded 26 (1.05 g, 60%) as a white solid: R_f0.28 (1:1 hex-

anes–EtOAc); [

a

]

_Dꢀ166 (c 0.29, CHCl₃); ¹H NMR (500 MHz, CDCl₃)

3.21. Methyl 2-O-benzoyl-3-O-benzyl-4,6-O-benzylidene-b-

D-

d 8.13–8.15 (m, 2H, ArH), 8.10 (m, 1H, ArH), 7.59 (m, 1H, ArH),

7.43–7.46 (m, 3H, ArH), 7.12–7.28 (m, 10H, ArH), 7.02 (m, 1H,

ArH), 6.24 (dd, 1H, J_3,4ꢂ J_4,59.3 Hz, H-4), 5.90 (dd, 1H, J_1,20.9, J_2,3

3.2 Hz, H-2), 4.69 (d, 1H, J_gem12.8 Hz, PhCH₂O), 4.61 (d, 1H, J_1,2

1.0 Hz, H-1), 4.54 (AB, 1H, J_gem11.7 Hz, PhCH₂O), 4.52 (AB, 1H, J_gem

11.7 Hz, PhCH₂O), 4.45 (d, 1H, J_gem12.8 Hz, PhCH₂O), 3.83 (dd, 1H,

J_2,33.2, J_3,49.4 Hz, H-3), 3.72–3.82 (m, 3H, H-5, H-6a, H-6b), 3.45 (s,

3H, CH₃O); ¹³C NMR (125 MHz, CDCl₃) d 183.4 (C@S), 166.0 (C@O),

137.6 (Ar), 136.8 (Ar), 136.6 (Ar), 133.2 (Ar), 130.8 (Ar), 130.2 (Ar),

129.7 (Ar), 128.5 (Ar), 128.4 (Ar), 128.3 (Ar), 128.2 (Ar), 127.9 (Ar),

127.7 (Ar), 127.6 (Ar), 118.2 (Ar), 100.2 (C-1), 77.2 (C-4), 75.8 (C-3),

73.9 (PhCH₂O), 73.6 (C-5), 70.6 (PhCH₂O), 69.7 (C-6), 67.8 (C-2),

57.4 (CH₃O); HRESIMS: Calcd for C₃₂H₃₂N₂O₇SNa 611.1822. Found

611.1820. Anal. Calcd for C₃₂H₃₂N₂O₇S: C, 65.29; H, 5.48; N, 4.76; S,

5.45. Found: C, 65.55; H, 5.53; N, 4.76; S, 5.27.

mannopyranoside (24)

Methyl 3-O-benzyl-4,6-O-benzylidene-b-D

-glucopyranoside (23)¹⁵

(1.54 g, 4.14 mmol) was dissolved in pyridine (40 mL). Benzoyl

chloride (1.5 mL, 12.41 mmol) was added, and the reaction mixture

was stirred at room temperature overnight, then concentrated un-

der reduced pressure. The residue was dissolved in EtOAc then

washed with 1 M aq HCl, satd aq NaHCO₃, distilled H₂O and brine.

The organic phase was dried (Na₂SO₄), then concentrated under re-

duced pressure. Column chromatography (4:1 hexanes–EtOAc) on

silica gel gave 24 (1.97 g, quant.) as a white solid: R_f0.51 (1:1 hex-

anes–EtOAc); [

a

]

_Dꢀ115 (c 0.26, CHCl₃); ¹H NMR (500 MHz, CDCl₃)

d 8.13–8.16 (m, 2H, ArH), 7.23–7.59 (m, 13H, ArH), 5.88 (dd, 1H, J_1,2

1.1, J_2,33.4 Hz, H-2), 5.68 (s, 1H, PhCHO₂), 4.79 (d, 1H, J_gem12.6 Hz,

1406

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

3.24. Methyl 2-O-benzoyl-3,6-di-O-benzyl-4-deoxy-b-

hexopyranoside (27)

D

-lyxo-

3.0, J_3,49.2 Hz, H-3), 3.55 (s, 3H, CH₃O), 3.52 (s, 3H, CH₃O), 3.46

(ddd, 1H, J_4,59.3, J_5,62.1, 4.3 Hz, H-5); ¹³C NMR (125 MHz, CDCl₃)

d 166.0 (C@O), 138.6 (Ar), 137.8 (Ar), 132.9 (Ar), 130.1 (Ar),

128.3(4) (Ar), 128.3(3) (Ar), 128.2(6) (Ar), 128.0 (Ar), 127.7 (Ar),

127.5(0) (Ar), 127.4(6) (Ar), 100.2 (C-1), 80.1 (C-3), 76.2 (C-4),

75.8 (C-5), 73.5 (PhCH₂O), 71.2 (PhCH₂O), 69.3 (C-6), 68.4 (C-2),

61.0 (CH₃O), 57.2 (CH₃O); HRESIMS: Calcd for C₂₉H₃₂O₇Na

515.2040. Found 515.2042. Anal. Calcd for C₂₉H₃₂O₇: C, 70.71; H,

6.55. Found: C, 70.58; H, 6.54.

To a solution of the Barton–McCombie substrate 26 (1.05 g,

1.78 mmol) in dry toluene (15 mL) were added tributyltin hydride

(1.43 mL, 5.33 mmol) and AIBN (73 mg, 0.25 mmol). The reaction

mixture was reﬂuxed under argon overnight, then cooled to room

temperature. The reaction mixture was ﬁltered through a plug of

silica gel containing 10% (w/w) KF. The ﬁltrate was concentrated,

then subjected to chromatography (4:1 hexanes–EtOAc) to give

27 (562.2 mg, 68%) as a white solid: R_f0.55 (1:1 hexanes–EtOAc);

3.27. Methyl 3,6-di-O-benzyl-4-O-methyl-b-D-mannopyranoside

(30)

[a

]

D

ꢀ101 (c 0.59, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 8.11–8.12

(m, 2H, ArH), 7.53–7.56 (m, 1H, ArH), 7.25–7.43 (m, 12H, ArH),

5.78 (dd, 1H, J_1,20.8, J_2,32.8 Hz, H-2), 4.74 (d, 1H, J_gem12.0 Hz,

PhCH₂O), 4.65 (s, 2H, PhCH₂O), 4.52 (d, 1H, J_gem12.0 Hz, PhCH₂O),

4.42 (d, 1H, J_1,21.1 Hz, H-1), 3.76 (dd, 1H, J_5,65.5, J_gem9.4 Hz, H-6a),

3.68–3.74 (m, 2H, H-3, H-5), 3.65 (dd, 1H, J_5,64.2, J_gem9.4 Hz, H-6b)

3.51 (s, 3H, CH₃O), 1.91–1.94 (m, 2H, H-4a, H-4b); ¹³C NMR

(125 MHz, CDCl₃) d 166.2 (C@O), 138.3 (Ar), 137.8 (Ar), 132.9

(Ar), 130.2 (Ar), 130.1 (Ar), 128.4 (Ar), 128.2 (Ar), 127.7(1) (Ar),

127.6(8) (Ar), 100.7 (C-1), 74.0 (C-3), 73.6 (PhCH₂O), 72.7 (C-6),

72.0 (C-5), 70.0 (PhCH₂O), 67.2 (C-2), 57.1 (CH₃O), 30.0 (C-4); HRE-

SIMS: Calcd for C₂₈H₃₀O₆Na 485.1935. Found 485.1936.

To a solution of mannopyranoside 29 (793.3 mg, 1.61 mmol) in

CH₂Cl₂(10 mL) and MeOH (10 mL) was added 0.5 M CH₃ONa–

CH₃OH (6 mL) and the reaction mixture was stirred overnight.

The reaction mixture was neutralized with Amberlite IR-120 (H⁺)

resin, the resin was ﬁltered, and the ﬁltrate was concentrated un-

der reduced pressure. Puriﬁcation of the product by chromatogra-

phy (1:1 hexanes–EtOAc) gave 30 (592.5 mg, 95%) as a white solid:

R_f0.28 (1:1 hexanes–EtOAc); [

a

]

D

ꢀ34 (c 0.44, CHCl₃); ¹H NMR

(500 MHz, CDCl₃) d 7.26–7.41 (m, 10H, ArH), 4.76 (d, 1H, J_gem

11.9 Hz, PhCH₂O), 4.69 (d, 1H, J_gem11.8 Hz, PhCH₂O), 4.67 (d, 1H,

J_gem12.0 Hz, PhCH₂O), 4.60 (d, 1H, J_gem12.1 Hz, PhCH₂O), 4.31 (d,

1H, H-1), 4.06 (m, 1H, H-2), 3.80 (dd, 1H, J_5,62.2, J_gem10.8 Hz, H-

6a), 3.75 (dd, 1H, J_5,65.3, J_gem10.9 Hz, H-6b), 3.57 (dd, 1H,

J_3,4ꢂ J_4,59.3 Hz, H-4), 3.55 (s, 3H, CH₃O), 3.53 (s, 3H, CH₃O), 3.46

(dd, 1H, J_2,33.1, J_3,49.0 Hz, H-3), 3.36 (ddd, 1H, J_4,59.6, J_5,62.1,

5.3 Hz, H-5), 2.39 (d, 1H, J_2,OH2.4 Hz, OH); ¹³C NMR (125 MHz,

CDCl₃) d 138.4 (Ar), 138.0 (Ar), 128.5 (Ar), 128.3 (Ar), 127.8(2)

(Ar), 127.8(0) (Ar), 127.7 (Ar), 127.5 (Ar), 100.7 (C-1), 81.3 (C-3),

76.2 (C-4), 75.4 (C-5), 73.6 (PhCH₂O), 71.5 (PhCH₂O), 69.4 (C-6),

68.3 (C-2), 60.8 (CH₃O), 56.9 (CH₃O); HRESIMS: Calcd for

C₂₂H₂₈O₆Na 411.1778. Found 411.1778.

3.25. Methyl 3,6-di-O-benzyl-4-deoxy-b-D-lyxo-hexopyranoside

(28)

Compound 27 (534.3 mg, 1.16 mmol) was dissolved in MeOH

(10 mL). A solution of 0.5 M CH₃ONa–CH₃OH (6 mL) was added,

then the reaction mixture was stirred at room temperature until

TLC (1:1 hexanes–EtOAc) indicated the consumption of starting

material. The reaction mixture was neutralized with Amberlite

IR-120 (H⁺) resin. The resin was ﬁltered and the ﬁltrate was con-

centrated under reduced pressure. Puriﬁcation by chromatogra-

phy (1:1 hexanes–EtOAc) gave 28 (369.5 mg, 89%) as a white

solid: R_f0.30 (1:1 hexanes–EtOAc); [

a

]

D

ꢀ45 (c 1.15, CHCl₃); ¹H

3.28. Methyl 2-O-acetyl-3,4,6-tri-O-benzyl-b-D-glucopyranosyl-

NMR (500 MHz, CDCl₃) d 7.28–7.36 (m, 10H, ArH), 4.56–4.66

(m, 4H, PhCH₂O ꢃ 4), 4.25 (d, 1H, J_1,21.0 Hz, H-1), 4.04 (br s,

1H, H-2), 3.67 (m, 1H, H-6a), 3.51–3.60 (m, 3H, H-3, H-5, H-6b),

3.56 (s, 3H, CH₃O), 2.28 (d, 1H, J_2,OH2.4 Hz, OH), 1.84 (m, 1H,

H-4a), 1.76 (m, 1H, H-4b); ¹³C NMR (125 MHz, CDCl₃) d 138.2

(Ar), 137.9 (Ar), 128.5 (Ar), 128.4 (Ar), 127.8 (Ar), 127.7(2) (Ar),

127.6(9) (Ar), 127.6(7) (Ar), 101.3 (C-1), 75.0 (C-3), 73.6

(PhCH₂O), 72.7 (C-6), 71.7 (C-5), 69.9 (PhCH₂O), 67.3 (C-2), 56.9

(CH₃O), 28.3 (C-4); HRESIMS: Calcd for C₂₁H₂₆O₅Na 381.1672.

Found 381.1671.

(1?2)-3,6-di-O-benzyl-4-deoxy-b- -lyxo-hexopyranoside (31)

D

Monosaccharide acceptor 28 (347 mg, 0.97 mmol) was reacted

with 2-O-acetyl-3,4,6-tri-O-benzyl-b- -glucopyranosyl trichloro-

acetimidate (16) (758 mg, 1.19 mmol) in CH₂Cl₂(5 mL) using

TMSOTf (5 L, 0.03 mmol) under argon at 0 °C (ice-water bath),

D

l

then processed as described for 17. The product was puriﬁed by

chromatography over silica gel (4:1 hexanes–EtOAc) to give 31

(669 mg, 83%) as a clear syrup: R_f0.59 (1:1 hexanes–EtOAc); [a]

D

ꢀ55 (c 0.43, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 7.18–7.34 (m,

25H, ArH), 5.09 (dd, 1H, J_{1 ,2}8.0, J_{2 ,3}9.5 Hz, H-2⁰), 4.84 (d, 1H,

0

3.26. Methyl 2-O-benzoyl-3,6-di-O-benzyl-4-O-methyl-b-D-

J_{1 ,2}8.0 Hz, H-1⁰) 4.81 (d, 1H, J_gem10.9 Hz, PhCH₂O), 4.80 (d, 1H,

J_gem12.2 Hz, PhCH₂O), 4.78 (d, 1H, J_gem11.5 Hz, PhCH₂O), 4.74 (d,

1H, J_gem11.4 Hz, PhCH₂O), 4.54–4.59 (m, 2H, PhCH₂O), 4.54 (d,

1H, J_gem11.0 Hz, PhCH₂O), 4.47 (d, 1H, J_gem12.2 Hz, PhCH₂O),

4.42–4.47 (m, 2H, PhCH₂O), 4.17 (d, 1H, J_2,32.5 Hz, H-2), 4.11 (s,

1H, H-1), 3.72–3.77 (m, 2H, H-3⁰, H-6a⁰), 3.54–3.63 (m, 5H, H-4⁰,

H-5⁰, H-6b⁰H-5, H-6a), 3.48 (dd, 1H, J_5,64.0, J_gem9.7 Hz, H-6b),

3.46 (s, 3H, CH₃O), 3.40 (ddd, 1H, J_2,32.7, J_3,4eq4.7, J_3,4ax11.7 Hz,

H-3), 1.96 (s, 3H, CH₃C(O)O), 1.75 (ddd, 1H, J_3,4ꢂ J_gemꢂ J_4,5

12.0 Hz, H-4ax), 1.65 (ddd, 1H, J_3,44.5, J_gem12.6, J_4,52.2 Hz, H-

4eq); ¹³C NMR (125 MHz, CDCl₃) d 169.7 (C@O), 138.5 (Ar), 138.4

(Ar), 138.3 (Ar), 138.2 (Ar), 138.0 (Ar), 128.4 (Ar), 128.3(2) (Ar),

128.2(9) (Ar), 128.2(6) (Ar), 128.1 (Ar), 127.9 (Ar), 127.8 (Ar),

127.7(2) (Ar), 127.6(7) (Ar), 127.6(1) (Ar), 127.5(8) (Ar), 127.5(5)

(Ar), 127.4(9) (Ar), 127.4 (Ar), 102.4 (C-1), 100.9 (C-1⁰), 83.1 (C-

3⁰), 78.2 (C-4⁰/C-5⁰/C-5), 75.0, 74.9, 74.7 (C-4⁰/C-5⁰/C-5,

PhCH₂O ꢃ 2), 73.9 (PhCH₂O), 73.7 (C-3), 73.5, 73.4, 73.2 (C-2⁰, C-

6, PhCH₂O), 72.0 (C-4⁰/C-5⁰/C-5), 71.4 (C-2), 69.9 (C-6⁰), 68.7

(PhCH₂O), 56.5 (CH₃O), 29.2 (C-4), 21.1 (CH₃C(O)O); HRESIMS:

0

mannopyranoside (29)

Compound 25 (643.3 mg, 1.34 mmol) was dissolved in dry DMF

(10 mL) under argon. Methyl iodide (167 L, 2.69 mmol) was

l

added, and the reaction mixture was cooled to 0 °C (ice-water

bath). NaH (107.5 mg, 2.69 mmol; 60% in oil) was added in one

portion, and the reaction mixture was stirred at 0 °C for 3 h. The

reaction was quenched with HOAc, then concentrated under re-

duced pressure. Puriﬁcation of the product by chromatography

(4:1 hexanes–EtOAc) yielded 29 (643.8 mg, 97%) as a white solid:

R_f0.54 (1:1 hexanes–EtOAc); [

a]

ꢀ96 (c 0.22, CHCl₃); ¹H NMR

D

(500 MHz, CDCl₃) d 8.09–8.11 (m, 2H, ArH), 7.53 (m, 1H, ArH),

7.42–7.44 (m, 2H, ArH), 7.26–7.38 (m, 10H, ArH), 5.81 (dd, 1H,

J_1,20.8, J_2,33.0 Hz, H-2), 4.83 (d, 1H, J_gem11.6 Hz, PhCH₂O), 4.81

(d, 1H, J_gem12.1 Hz, PhCH₂O), 4.65 (d, 1H, J_gem12.0 Hz, PhCH₂O),

4.58 (d, 1H, J_gem11.6 Hz, PhCH₂O), 4.49 (d, 1H, J_1,20.9 Hz, H-1),

3.90 (dd, 1H, J_5,64.3, J_gem11.0 Hz, H-6a), 3.87 (dd, 1H, J_5,62.1, J_gem

11.0 Hz, H-6b), 3.71 (dd, 1H, J_3,4ꢂ J_4,59.3 Hz, H-4), 3.66 (dd, 1H, J_2,3

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

1407

Calcd for C₅₀H₅₆O₁₁Na 855.3715. Found 855.3710. Anal. Calcd for

C₅₀H₅₆O₁₁: C, 72.10; H, 6.78. Found: C, 72.10; H, 6.79.

3.31. Methyl 2-O-acetyl-3,4,6-tri-O-benzyl-b-

D

-glucopyranosyl-

(1?2)-3,6-di-O-benzyl-4-O-methyl-b-

D-mannopyranoside (34)

3.29. Methyl 3,4,6-tri-O-benzyl-b-

D

-glucopyranosyl-(1?2)-3,6-

Monosaccharide acceptor 30 (238 mg, 0.44 mmol) was reacted

with 2-O-acetyl-3,4,6-tri-O-benzyl-b- -glucopyranosyl trichloro-

acetimidate (16) (469 mg, 0.74 mmol) in CH₂Cl₂(5 mL) using

TMSOTf (7 L, 0.04 mmol) under argon at 0 °C, then processed as

described for 17. The product was puriﬁed by chromatography

over silica gel (4:1 hexanes–EtOAc) to give 34 (511 mg, 97%) as a

di-O-benzyl-4-deoxy-b- -lyxo-hexopyranoside (32)

D

Disaccharide 31 (448 mg, 0.54 mmol) was dissolved in 1:1

CH₂Cl₂–MeOH (10 mL) and treated with 0.5 M CH₃ONa–CH₃OH

(2 mL), then processed as described for 18. Puriﬁcation of the prod-

uct by chromatography over silica gel (7:3 hexanes–EtOAc) gave

32 (334 mg, 78%) as a colourless syrup: R_f0.42 (1:1 hexanes–

l

colourless syrup: R_f0.54 (1:1 hexanes–EtOAc); [

a

]

D

ꢀ53 (c 0.65,

CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 7.17–7.39 (m, 25H, ArH),

ꢀ60 (c 0.88, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d

5.09 (dd, 1H, J_{1 ,2}8.1, J_{2 ,3}9.6 Hz, H-2⁰), 4.86 (d, 1H, J_gem12.1 Hz,

PhCH₂O), 4.80 (d, 1H, J_gem11.9 Hz, PhCH₂O), 4.79 (d, 1H, H-1⁰),

4.78 (d, 1H, J_gem11.5 Hz, PhCH₂O), 4.74 (d, 1H, J_gem11.5 Hz,

PhCH₂O), 4.61 (d, 1H, J_gem12.3 Hz, PhCH₂O), 4.57 (d, 1H, J_gem

12.2 Hz, PhCH₂O), 4.54 (d, 1H, J_gem11.0 Hz, PhCH₂O), 4.52 (d, 1H,

J_gem12.1 Hz, PhCH₂O), 4.43–4.48 (m, 2H, PhCH₂O), 4.18–4.19 (m,

2H, H-1, H-2), 3.71–3.79 (m, 3H, H-3⁰, H-6a⁰, H-6a), 3.56–3.66 (m,

4H, H-4⁰, H-5⁰, H-6b⁰, H-6b), 3.51 (s, 3H, CH₃O), 3.47 (s, 3H,

CH₃O), 3.36 (dd, 1H, J_2,32.9, J_3,48.9 Hz, H-3), 3.34 (ddd, 1H, J_4,5

9.5 Hz, J_5,61.6, 6.8 Hz, H-5), 3.28 (dd, 1H, J_3,4ꢂ J_4,59.2 Hz, H-4),

1.95 (s, 3H, CH₃C(O)O)); ¹³C NMR (125 MHz, CDCl₃) d 169.8

(C@O), 138.6 (Ar), 138.5 (Ar), 138.3 (Ar), 138.1 (Ar), 138.0 (Ar),

128.4 (Ar), 128.3(2) (Ar), 128.3(0) (Ar), 128.2 (Ar), 128.1 (Ar),

127.9 (Ar), 127.8 (Ar), 127.7 (Ar), 127.5(7) (Ar), 127.5(6) (Ar),

127.4(5) (Ar), 127.4 (Ar), 101.6, 101.1 (C-1, C-1⁰), 83.1 (C-3⁰), 79.9

(C-3), 78.0, 76.4, 75.7, 74.9, 74.8, 74.7, 73.5(4), 73.4(8), 73.3, 72.4,

70.7, 69.9, 69.7 (C-2⁰, C-4⁰, C-5⁰, C-6⁰, C-2, C-4, C-5, C-6,

PhCH₂O ꢃ 5), 61.0 (CH₃O), 56.6 (CH₃O), 21.0 (CH₃C(O)O); HRESIMS:

Calcd for C₅₁H₅₈O₁₂Na 885.3821. Found 885.3828.

0

EtOAc); [a]

D

7.40–7.42 (m, 2H, ArH), 7.22–7.37 (m, 21H, ArH), 7.17–7.18 (m,

2H, ArH), 5.06 (d, 1H, J_gem11.3 Hz, PhCH₂O), 4.86 (d, 1H, J_gem

10.9 Hz, PhCH₂O), 4.79 (d, 1H, J_gem11.3 Hz, PhCH₂O), 4.78 (d, 1H,

J_gem12.5 Hz, PhCH₂O), 4.61 (d, 1H, J_gem12.0 Hz, PhCH₂O) 4.59 (d,

1H, J_{1 ,2}8.8 Hz, H-1⁰), 4.56 (d, 1H, J_gem12.0 Hz, PhCH₂O), 4.52 (d,

1H, J_gem11.0 Hz, PhCH₂O), 4.51 (d, 1H, J_gem12.5 Hz, PhCH₂O),

4.46 (d, 1H, J_gem12.0 Hz, PhCH₂O), 4.42 (d, 1H, J_gem12.0 Hz,

PhCH₂O), 4.22 (s, 1H, H-1), 4.15 (d, 1H, J_2,32.5 Hz, H-2) 3.44–3.74

(m, 11H, H-2⁰, H-3⁰, H-4⁰, H-5⁰, H-6a⁰, H-6b⁰, OH, H-3, H-5, H-6a,

H-6b), 3.54 (s, 3H, CH₃O), 1.85 (ddd, 1H, J_3,4ꢂ J_gemꢂ J_4,512.5 Hz,

H-4ax), 1.78 (ddd, 1H, J 2.0, 4.6, J_gem12.4 Hz, H-4eq); ¹³C NMR

(125 MHz, CDCl₃) d 139.1 (Ar), 138.3 (Ar), 138.2(3) (Ar), 138.1(8)

(Ar), 128.4 (Ar), 128.3(1) (Ar), 128.2(5) (Ar), 128.0 (Ar), 127.9

(Ar), 127.7(3) (Ar), 127.6(9) (Ar), 127.6(8) (Ar), 127.6(5) (Ar),

127.5 (Ar), 127.4(4) (Ar), 127.3(9) (Ar), 104.5 (C-1⁰), 101.9 (C-1),

85.2, 77.4, 75.5, 75.4, 75.0, 74.7, 74.3, 74.1, 73.6, 73.4, 72.7, 72.1,

69.7, 69.3 (C-2⁰, C-3⁰, C-4⁰, C-5⁰, C-6⁰, C-2, C-3, C-5, C-6,

PhCH₂O ꢃ 5), 56.9 (CH₃O), 29.4 (C-4); HRESIMS: Calcd for

C₄₈H₅₄O₁₀Na 813.3609. Found 813.3608.

0

3.32. Methyl 3,4,6-tri-O-benzyl-b-D-glucopyranosyl-(1?2)-3,6-

3.30. Methyl 3,4,6-tri-O-benzyl-b-

D-mannopyranosyl-(1?2)-

di-O-benzyl-4-O-methyl-b- -mannopyranoside (35)

D

3,6-di-O-benzyl-4-deoxy-b- -lyxo-hexopyranoside (33)

D

Disaccharide 34 (511 mg, 0.59 mmol) was dissolved in 1:1

CH₂Cl₂–MeOH (10 mL) and treated with 0.5 M CH₃ONa–CH₃OH

(5 mL) then processed as described for 18. Puriﬁcation of the product

by chromatography over silica gel (7:3 hexanes–EtOAc) gave 35

Disaccharide 32 (312 mg, 0.39 mmol) was dissolved in Me₂SO

(5 mL), Ac₂O (2.5 mL) was added, and the reaction mixture was

stirred overnight, then concentrated under reduced pressure. The

residue was redissolved in dry THF (5 mL), and the solution was

cooled to ꢀ78 °C. L-Selectride^Ò(1.7 mL, 1.0 M in THF) was added

dropwise, and the reaction mixture was allowed to slowly warm

to room temperature. The reaction was quenched with MeOH

and concentrated under reduced pressure. Puriﬁcation by column

chromatography over silica gel (7:3 hexanes–EtOAc) gave 33

(470 mg, 97%) as a clear syrup: R_f0.38 (1:1 hexanes–EtOAc); [a]

D

ꢀ52 (c 0.20, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 7.24–7.41 (m,

23H, ArH), 7.16–7.18 (m, 2H, ArH), 5.06 (d, 1H, J_gem11.3 Hz,

PhCH₂O), 4.84–4.87 (m, 2H, PhCH₂O), 4.78 (d, 1H, J_gem11.2 Hz,

0

PhCH₂O), 4.67 (d, 1H, J_gem12.1 Hz, PhCH₂O), 4.61 (d, 1H, J_{1 ,2}

7.6 Hz, H-1⁰), 4.59 (d, 1H, J_gem11.1 Hz, PhCH₂O), 4.56 (d, 1H, J_gem

11.9 Hz, PhCH₂O), 4.52 (d, 1H, J_gem11.0 Hz, PhCH₂O), 4.47 (d, 1H, J_gem

12.1 Hz, PhCH₂O), 4.44 (d, 1H, J_gem12.0 Hz, PhCH₂O), 4.27 (s, 1H, H-

1), 4.19 (d, 1H, J_2,33.1 Hz, H-2), 3.78 (dd, 1H, J_5,62.1, J_gem10.9 Hz, H-

6a), 3.73 (dd, 1H, J_5,65.1, J_gem11.0 Hz, H-6b), 3.49–3.72 (m, 7H, H-2⁰,

H-3⁰, H-4⁰, H-5⁰, H-6a⁰, H-6b⁰, H-4), 3.52 (s, 6H, CH₃O ꢃ 2), 3.41 (dd,

1H, J_2,33.2, J_3,49.3 Hz, H-3), 3.32 (ddd, 1H, J_4,59.5, J_5,62.0,4.9 Hz, H-

5), 3.31 (br s, 1H, OH); ¹³C NMR (125 MHz, CDCl₃) d 139.1 (Ar),

138.4 (Ar), 138.2(5) (Ar), 138.1(8) (Ar), 138.1(7) (Ar), 128.3(1) (Ar),

128.2(8) (Ar), 128.2 (Ar), 128.0 (Ar), 127.9(4) (Ar), 127.9(0) (Ar),

127.7 (Ar), 127.6(4) (Ar), 127.6(3) (Ar), 127.5 (Ar), 127.4 (Ar),

104.2 (C-1⁰), 101.5 (C-1), 85.2 (C-3⁰), 80.1 (C-3), 77.1 (C-5⁰), 76.0,

75.8 (C-4, C-5), 75.4, 75.3, 75.0, 74.8, 74.7 (C-2, C-2⁰, C-4⁰,

PhCH₂O ꢃ 2), 73.5 (PhCH₂O), 73.4 (PhCH₂O), 70.4 (PhCH₂O), 69.7

(C-6⁰), 69.4 (C-6), 61.0 (CH₃O), 57.1 (CH₃O); HRESIMS: Calcd for

C₄₉H₅₆O₁₁Na 843.3715. Found 843.3719. Anal. Calcd for

C₄₉H₅₆O₁₁: C, 71.69; H, 6.88. Found: C, 71.48; H, 7.09.

(200 mg, 65%) as a white solid: R_f0.28 (1:1 hexanes–EtOAc); [a]

D

ꢀ66 (c 0.73, CHCl₃) ¹H NMR (500 MHz, CDCl₃) d 7.21–7.41 (m,

0

25H, ArH), 4.95 (d, 1H, J_gem11.1 Hz, PhCH₂O), 4.93 (d, 1H, J_{1 ,2}

0.7 Hz, H-1⁰), 4.87 (d, 1H, J_gem11.4 Hz, PhCH₂O), 4.83 (d, 1H, J_gem

12.2 Hz, PhCH₂O), 4.64 (d, 1H, J_gem12.1 Hz, PhCH₂O), 4.60 (d, 1H,

J_gem11.9 Hz, PhCH₂O), 4.55 (d, 1H, J_gem12.0 Hz, PhCH₂O), 4.54 (d,

1H, J_gem11.0 Hz, PhCH₂O), 4.45 (d, 1H, J_2,32.7 Hz, H-2), 4.41 (d,

1H, J_gem11.5 Hz, PhCH₂O), 4.38–4.43 (m, 2H, PhCH₂O), 4.33 (d,

1H, J_{2 ,3}2.8 Hz, H-2⁰), 4.21 (d, 1H, J_1,20.7 Hz, H-1), 3.88 (dd, 1H,

0

J_{3 ,4}ꢂ J_{4 ,5}9.3 Hz, H-4⁰), 3.75 (dd, 1H, J_{5 ,6}1.8, J_gem10.5 Hz, H-

6a⁰), 3.66 (dd, 1H, J_5,65.9, J_gem9.6 Hz, H-6a), 3.47–3.62 (m, 6H, H-

3⁰, H-5⁰, H-6b⁰, H-3, H-5, H-6b), 3.50 (s, 3H, CH₃O), 2.74 (br s, 1H,

OH), 1.74–1.85 (m, 2H, H-4ax, H-4eq); ¹³C NMR (125 MHz, CDCl₃)

d 138.5 (Ar), 138.2(2) (Ar), 138.2(1) (Ar), 138.1(7) (Ar), 138.1(5)

(Ar), 128.3(9) (Ar), 128.3(6) (Ar), 128.3(5) (Ar), 128.3(0) (Ar),

128.2(7) (Ar), 128.1 (Ar), 128.0 (Ar), 127.9 (Ar), 127.7(0) (Ar),

127.6(8) (Ar), 127.6(4) (Ar), 127.5(9) (Ar), 127.5(8) (Ar), 127.5(3)

(Ar), 127.4(7) (Ar), 102.7 (C-1), 98.8 (C-1⁰), 81.4 (C-3⁰), 75.0(9),

75.0(5), 74.5, 74.0, 73.6, 73.3, 72.8 (C-3, C-6, C-4⁰, C-5⁰, PhCH₂O ꢃ

3), 72.0 (C-5), 70.7 (PhCH₂O), 70.0 (C-6⁰), 69.2 (PhCH₂O), 68.7 (C-

2), 67.7 (C-2⁰), 57.1 (CH₃O), 29.7 (C-4); HRESIMS: Calcd for

C₄₈H₅₄O₁₀Na 813.3609. Found 813.3609.

0

3.33. Methyl 3,4,6-tri-O-benzyl-b-D-mannopyranosyl-(1?2)-

3,6-di-O-benzyl-4-O-methyl-b- -mannopyranoside (36)

D

As described for compound 19, disaccharide 35 (446 mg,

0.54 mmol) was dissolved in freshly distilled Me₂SO (10 mL) and

1408

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

Ac₂O (5 mL). The concentrated reaction mixture was then treated

with 1.0 M L-Selectride^Òin THF (2.2 mL, 2.17 mmol) in dry THF

(10 mL) at ꢀ78 °C under argon. Puriﬁcation by column chromatog-

raphy over silica gel (7:3 hexanes–EtOAc) gave 36 (273 mg, 61%) as

yielded 39 (389 mg, 66%) as a white solid: R_f0.23 (1:1 hexanes–

EtOAc); [

a]

ꢀ17 (c 0.34 CHCl₃); ¹H NMR (500 MHz, CDCl₃) d

D

7.29–7.40 (m, 10H, ArH), 4.96 (d, 1H, J_gem11.3 Hz, PhCH₂O), 4.92

(d, 1H, J_gem10.8 Hz, PhCH₂O), 4.87 (d, 1H, J_gem11.3 Hz, PhCH₂O),

4.65 (d, 1H, J_gem10.8 Hz, PhCH₂O), 4.47 (dd, 1H, J_5,61.7, J_gem

11.1 Hz, H-6a), 4.37 (dd, 1H, J_5,64.2, J_gem11.2 Hz, H-6b), 4.21 (d,

1H, J_1,27.7 Hz, H-1), 3.63 (dd, 1H, J_2,3ꢂ J_3,48.8 Hz, H-3), 3.49–

3.58 (m, 3H, H-2, H-4, H-5), 3.55 (s, 3H, CH₃O), 3.03 (s, 3H,

CH₃S(O)₂O), 2.37 (d, 1H, J_1,22.2 Hz, OH); ¹³C NMR (125 MHz, CDCl₃)

d 138.3 (Ar), 137.5 (Ar), 128.5(8) (Ar), 128.5(4) (Ar), 128.2 (Ar),

128.1 (Ar), 127.9(4) (Ar), 127.8(9) (Ar), 103.7 (C-1), 84.1 (C-3),

76.7 (C-4), 75.2(2) (PhCH₂O), 75.1(7) (PhCH₂O), 74.6 (C-2), 73.1

(C-5), 68.3 (C-6), 57.3 (CH₃O), 37.7 (CH₃S(O)₂O); HRESIMS: Calcd

for C₂₂H₂₈O₈SNa 475.1397. Found 475.1395.

a white solid: R_f0.29 (1:1 hexanes–EtOAc); [

a

]

ꢀ60 (c 0.47,

D

CHCl₃); ¹H NMR (600 MHz, CDCl₃) d 7.21–740 (m, 25H, ArH),

4.94 (d, 1H, J_gem10.9 Hz, PhCH₂O), 4.89–4.90 (m, 2H, H-1⁰,

PhCH₂O), 4.82 (d, 1H, J_gem12.1 Hz, PhCH₂O), 4.66 (d, 1H, J_gem

12.1 Hz, PhCH₂O), 4.63 (d, 1H, J_gem12.0 Hz, PhCH₂O), 4.57 (d, 1H,

J_gem12.0 Hz, PhCH₂O), 4.54 (d, 1H, J_gem11.0 Hz, PhCH₂O), 4.41–

0

4.48 (m, 4H, H-2, 3(PhCH₂O)), 4.31 (dd, 1H, J_{1 ,2}0.7, J_{2 ,3}3.0 Hz,

H-2⁰), 4.26 (d, 1H, J_1,20.6 Hz, H-1), 3.88 (dd, 1H, J_{3 ,4}ꢂ J_{4 ,5}

0

9.5 Hz, H-4⁰), 3.78 (dd, 1H, J_5,62.1, J_gem10.9 Hz, H-6a), 3.75 (dd,

1H, J_{5 ,6}2.0, J_gem10.4 Hz, H-6a⁰), 3.73 (dd, 1H, J_5,65.4, J_gem

0

10.8 Hz, H-6b), 3.62 (dd, 1H, J_{5 ,6}6.2, J_gem10.6 Hz, H-6b⁰), 3.56

0

(dd, 1H, J_{2 ,3}3.0, J_{3 ,4}9.1 Hz, H-3⁰), 3.47–3.52 (m, 2H, H-5⁰, H-4),

3.49 (s, 3H, CH₃O), 3.48 (s, 3H, CH₃O), 3.43 (dd, 1H, J_2,33.3, J_3,4

9.2 Hz, H-3), 3.33 (ddd, 1H, J_4,59.6, J_5,61.9, 5.4 Hz, H-5); ¹³C NMR

(125 MHz, CDCl₃) d 138.4(4) (Ar), 138.3(6) (Ar), 138.3 (Ar), 138.2

(Ar), 138.1 (Ar), 128.4 (Ar), 128.3(1) (Ar), 128.2(6) (Ar), 128.1

(Ar), 128.0 (Ar), 127.9 (Ar), 127.8 (Ar), 127.7 (Ar), 127.6 (Ar),

127.5(4) (Ar), 127.5(3) (Ar), 127.4 (Ar), 102.1 (C-1), 99.1 (C-1⁰),

81.5 (C-3⁰), 80.1 (C-3), 75.9, 75.7, 75.1, 75.0, 74.4 (C-4, C-5, C-4⁰,

C-5⁰, PhCH₂O), 73.5 (PhCH₂O), 73.4 (PhCH₂O), 70.7 (PhCH₂O), 70.3

(C-2), 69.9(7), 69.9(6), 69.6 (C-6, C-6⁰, PhCH₂O), 67.7 (C-2⁰), 60.9

(CH₃O), 57.2 (CH₃O); HRESIMS: Calcd for C₄₉H₅₆O₁₁Na 843.3715.

Found 843.3716.

3.36. Methyl 3,4-di-O-benzyl-6-deoxy-b-D-glucopyranoside (40)

0

To a solution of 39 (370 mg, 0.82 mmol) in DMF (8 mL) was

added NaBH₄(309 mg, 8.2 mmol). The mixture was heated at

80 °C for 3 h. The reaction mixture was diluted with CH₂Cl₂and

washed with 2% aq citric acid, distilled water, and then brine,

dried (Na₂SO₄) and concentrated under reduced pressure. Puriﬁca-

tion by chromatography over silica gel (1:1 hexanes–EtOAc) gave

40 (235 mg, 80%) as a white solid: R_f0.48 (1:1 hexanes–EtOAc);

[a]

ꢀ16 (c 1.0, CHCl₃); ¹H NMR (600 MHz, CDCl₃) d 7.28–7.40

D

(m, 10H, ArH), 4.93 (d, 1H, J_gem11.3 Hz, PhCH₂O), 4.90 (d, 1H, J_gem

10.9 Hz, PhCH₂O), 4.87 (d, 1H, J_gem11.3 Hz, PhCH₂O), 4.66 (d, 1H,

J_gem10.9 Hz, PhCH₂O), 4.17 (d, 1H, J_1,27.6 Hz, H-1), 3.56 (dd, 1H,

J_2,3ꢂ J_3,49.2 Hz, H-3), 3.55 (s, 3H, CH₃O), 3.52 (ddd, 1H, J_1,27.6,

J_2,39.6, J_2,OH2.0 Hz, H-2), 3.44 (dq, 1H, J_4,59.5, J_5,66.3 Hz, H-5),

3.22 (dd, 1H, J_3,4ꢂ J_4,58.8 Hz, H-4), 2.35 (d, 1H, J_2,OH2.1 Hz, OH),

1.34 (d, 3H, J_5,66.2 Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃) d 138.6

(Ar), 138.1 (Ar), 128.5 (Ar), 128.4 (Ar), 128.0 (Ar), 127.9 (Ar),

127.8 (Ar), 127.7 (Ar), 103.5 (C-1), 84.3 (C-3), 82.3 (C-4), 75.3,

75.1, 74.9 (C-2, PhCH₂O ꢃ 2), 71.5 (C-5), 57.1 (CH₃O), 17.9 (C-6);

HRESIMS: Calcd for C₂₁H₂₆O₅Na 381.1672. Found 381.1670.

Anal. Calcd for C₂₁H₂₆O₅: C, 70.37; H, 7.31. Found: C, 70.68; H,

7.19.

3.34. Methyl 3,4-di-O-benzyl-b-D-glucopyranoside (38)

Methyl

3-O-benzyl-4,6-O-benzylidene-b-D-glucopyranoside

(37)¹⁵(1.56 g, 4.19 mmol) in a ﬂame-dried ﬂask was dissolved in

dry CH₂Cl₂(20 mL) and cooled to 0 °C (ice-water bath) under ar-

gon.

A

1.0 M solution of BH₃ꢁTHF complex in THF (21 mL,

20.95 mmol) was added, followed by the dropwise addition of a

1.0 M solution of dibutylboron triﬂate (2.1 mL, 2.10 mmol). After

3 h, the reaction was quenched with MeOH, neutralized with

Et₃N, then concentrated under reduced pressure. Chromatography

over silica gel (1:1 hexanes–EtOAc) yielded 38 (1.30 g, 83%) as a

white solid: R_f0.12 (1:1 hexanes–EtOAc); [

a

]

_Dꢀ10 (c 0.25, CHCl₃);

3.37. Methyl 3,4-di-O-benzyl-6-deoxy-b-D-mannopyranoside

(41)

¹H NMR (500 MHz, CDCl₃) d 7.28–7.40 (m, 10H, ArH), 4.93 (d, 1H,

J_gem11.3 Hz, PhCH₂O), 4.89 (d, 1H, J_gem11.0 Hz, PhCH₂O), 4.88 (d,

1H, J_gem11.3 Hz, PhCH₂O), 4.67 (d, 1H, J_gem10.9 Hz, PhCH₂O),

4.24 (d, 1H, J_1,27.8 Hz, H-1), 3.89 (ddd, 1H, J_5,62.7, J_gem12.0, J_6,OH

5.5 Hz, H-6a), 3.75 (ddd, 1H, J_5,64.4, J_gem12.0, J_6,OH8.0 Hz, H-6b),

3.60–3.62 (m, 2H, H-3, H-4), 3.56 (s, 3H, CH₃O), 3.50 (m, 1H, H-

2), 3.40 (ddd, 1H, J_4,59.2, J_5,62.8, 4.4 Hz, H-5), 2.45 (d, 1H, J_2,OH

2.3 Hz, C2–OH), 1.97 (dd, 1H, J_6,OH5.7, 8.0 Hz, C6–OH); ¹³C NMR

(125 MHz, CDCl₃) d 138.5 (Ar), 137.9 (Ar), 128.5 (Ar), 128.1 (Ar),

127.9(4) (Ar), 127.9(3) (Ar), 127.8(Ar), 103.8 (C-1), 84.3, 77.3 (C-

3, C-4), 75.4, 75.2, 75.1 (C-5, PhCH₂O ꢃ 2), 74.6 (C-2), 61.9 (C-6),

57.3 (CH₃O); HRESIMS: Calcd for C₂₁H₂₆O₆Na 397.1622. Found

397.1619. Anal. Calcd for C₂₁H₂₆O₆: C, 67.36; H, 7.00. Found: C,

67.10; H, 7.02.

Compound 40 (362 mg, 1.01 mmol) was dissolved in a mixture

of Me₂SO (6 mL) and Ac₂O (3 mL). After stirring overnight at room

temperature, the reaction mixture was concentrated under re-

duced pressure. The remaining residue was dissolved in a mixture

of 1:1 CH₂Cl₂–MeOH (10 mL) and cooled to 0 °C (ice-water bath).

NaBH₄(192 mg, 5.05 mmol) was added and the reaction mixture

was allowed to slowly warm to room temperature. After 3 h, the

reaction mixture was diluted with CH₂Cl₂and washed with 2%

aq citric acid, distilled water and brine. The organic phase was

dried (Na₂SO₄) then concentrated under reduced pressure. Chro-

matography over silica gel (7:3 hexanes–EtOAc) yielded 41

(320 mg, 88%) as a white solid: R_f0.27 (1:1 hexanes–EtOAc); [a]

D

ꢀ36 (c 1.0, CHCl₃); ¹H NMR (600 MHz, CDCl₃) d 7.29–7.39 (m,

10H, ArH), 4.95 (d, 1H, J_gem10.9 Hz, PhCH₂O), 4.77 (d, 1H, J_gem

11.9 Hz, PhCH₂O), 4.69 (d, 1H, J_gem11.9 Hz, PhCH₂O), 4.66 (d, 1H,

J_gem10.9 Hz, PhCH₂O), 4.30 (d, 1H, J_1,21.1 Hz, H-1), 4.10 (m, 1H,

H-2), 3.51–3.55 (m, 5H, H-3, H-4, CH₃O), 3.33 (dq, 1H, J_4,59.8, J_5,6

6.0 Hz, H-5), 2.37 (br s, 1H, OH), 1.36 (d, 3H, J_5,66.2 Hz, CH₃); ¹³C

NMR (125 MHz, CDCl₃) d 138.4 (Ar), 137.9 (Ar), 128.5 (Ar), 128.4

(Ar), 128.1 (Ar), 127.9(1) (Ar), 127.8(8) (Ar), 127.7 (Ar), 100.6 (C-

1), 81.4, 79.7 (C-3, C-4), 75.5 (PhCH₂O), 71.4(7), 71.4(6) (C-5,

PhCH₂O), 68.4 (C-2), 56.9 (CH₃O), 17.9 (C-6); HRESIMS: Calcd for

C₂₁H₂₆O₅Na 381.1672. Found 381.1672. Anal. Calcd for C₂₁H₂₆O₅:

C, 70.37; H, 7.31. Found: C, 70.59; H, 7.38.

3.35. Methyl 3,4-di-O-benzyl-6-O-methanesulfonyl-b-D-

glucopyranoside (39)

Compound 38 (489 mg, 1.31 mmol) was dissolved in dry CH₂Cl₂

(5 mL) and dry pyridine (5 mL), and the mixture was cooled to 0 °C

(ice-water bath) under argon. Methanesulfonyl chloride (152 lL,

1.96 mmol) was added dropwise, and the reaction mixture was

stirred overnight. The reaction mixture was diluted with CH₂Cl₂

and washed with 1 M aq HCl, satd aq NaHCO₃, distilled water,

and brine, then dried (Na₂SO₄) and concentrated under reduced

pressure. Chromatography over silica gel (1:1, toluene–EtOAc)

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

1409

3.38. Methyl 2-O-benzoyl-3,4-di-O-benzyl-b-

D

-glucopyranoside

centrated under reduced pressure. Chromatography over silica gel

(43)

(1:1 hexanes–EtOAc) gave 45 (663 mg, 90%) as a white powdery

solid: R_f0.31 (1:1 hexanes–EtOAc); [

a]

D

ꢀ15 (c 0.59, CHCl₃); ¹H

Methyl 2-O-benzoyl-3-O-benzyl-4,6-O-benzylidene-b-

D

-gluco-

NMR (500 MHz, CDCl₃) d 7.26–7.39 (m, 10H, ArH), 4.92 (d, 1H, J_gem

11.4 Hz, PhCH₂O), 4.88 (d, 1H, J_gem11.0 Hz, PhCH₂O), 4.87 (d, 1H,

J_gem11.4 Hz, PhCH₂O), 4.63 (d, 1H, J_gem11.0 Hz, PhCH₂O), 4.18 (d,

1H, J_1,27.6 Hz, H-1), 3.66 (dd, 1H, J_5,62.2, J_gem10.8, H-6a), 3.57–

3.63 (m, 3H, H-3, H-4, H-6b), 3.56 (s, 3H, CH₃O), 3.53 (ddd, 1H,

J_2,OH2.0, J_1,2ꢂ J_2,37.9 Hz, H-2), 3.45 (ddd, 1H, J_4,59.3, J_5,62.1,

4.1 Hz, H-5), 3.39 (s, 3H, CH₃O), 2.35 (d, 1H, J_2,OH2.1 Hz, OH); ¹³C

NMR (125 MHz, CDCl₃) d 138.6 (Ar), 138.2 (Ar), 128.5 (Ar), 128.0

(Ar), 127.9 (Ar), 127.8 (Ar), 127.7 (Ar), 103.7 (C-1), 84.4 (C-3),

77.5 (C-4), 75.1, 75.0(2), 75.0(0) (C-5, PhCH₂O ꢃ 2), 74.6 (C-2),

71.2 (C-6), 59.4 (CH₃O), 57.2 (CH₃O); HRESIMS: Calcd for

C₂₂H₂₈O₆Na 411.1778. Found 411.1775. Anal. Calcd for C₂₂H₂₈O₆:

C, 68.02; H, 7.27. Found: C, 68.11; H, 7.39.

pyranoside (42)²³(1.28 g, 2.68 mmol) in a ﬂame-dried ﬂask was

dissolved in dry CH₂Cl₂(20 mL) and cooled to 0 °C (ice-water bath)

under argon. A 1.0 M solution of BH₃ꢁTHF complex in THF (13.4 mL,

13.43 mmol) was added, followed by the dropwise addition of a

1.0 M solution of dibutylboron triﬂate (1.3 mL, 1.34 mmol). After

2 h, the reaction was quenched with MeOH, neutralized with

Et₃N and then concentrated under reduced pressure. Chromatogra-

phy over silica gel (7:3 hexanes–EtOAc) yielded 43 (1.03 g, 80%) as

a white solid: R_f0.29 (1:1 hexanes–EtOAc); [

a]

+39 (c 0.65.

D

CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 8.02–8.04 (m, 2H, ArH), 7.57

(m, 1H, ArH) 7.43–7.46 (m, 2H, ArH), 7.29–7.37 (m, 5H, ArH),

7.14 (br s, 5H, ArH), 5.25 (dd, 1H, J_1,28.0, J_2,39.3 Hz, H-2), 4.88

(d, 1H, J_gem11.0 Hz, PhCH₂O), 4.76 (d, 1H, J_gem11.1 Hz, PhCH₂O),

4.69 (m, 2H, PhCH₂O), 4.50 (d, 1H, J_1,28.0 Hz, H-1), 3.93 (ddd, 1H,

J_6,OH5.6, J_5,62.8, J_gem12.0 Hz, H-6a), 3.86 (dd, 1H, J_2,3ꢂ J_3,4

9.1 Hz, H-3), 3.78 (ddd, 1H, J_6,OH8.0, J_5,64.5, J_gem12.3 Hz, H-6b),

3.73 (dd, 1H, J_3,49.0, J_4,59.5 Hz, H-4), 3.48 (ddd, 1H, J_4,59.4, J_5,6

2.7, 4.4 Hz, H-5), 3.48 (s, 3H, CH₃O), 1.93 (dd, 1H, OH); ¹³C NMR

(125 MHz, CDCl₃) d 165.2 (C@O), 137.8 (Ar), 137.7 (Ar), 133.1

(Ar), 129.9 (Ar), 129.8 (Ar), 128.5 (Ar), 128.4 (Ar), 128.3 (Ar),

128.1 (Ar), 128.0(0) (Ar), 127.9(7) (Ar), 127.7 (Ar), 102.1 (C-1),

82.6 (C-3), 77.7 (C-4), 75.4, 75.1(2), 75.0(8) (C-5, PhCH₂O ꢃ 2),

73.7 (C-2), 61.9 (C-6), 57.0 (CH₃O); HRESIMS: Calcd for C₂₈H₃₀O₇Na

501.1884. Found 501.1886. Anal. Calcd for C₂₈H₃₀O₇: C, 70.28; H,

6.32. Found: C, 70.30; H, 6.45.

3.41. Methyl 3,4-di-O-benzyl-6-O-methyl-b-D-mannopyranoside

(46)

Compound 45 (600 mg, 1.54 mmol) was dissolved in a mixture

of Me₂SO (5 mL) and Ac₂O (5 mL). After stirring overnight at room

temperature, the reaction mixture was concentrated under re-

duced pressure. The remaining residue was dissolved in a mixture

of 1:1 CH₂Cl₂–MeOH (10 mL) and cooled to 0 °C (ice-water bath).

NaBH₄(294 mg, 7.72 mmol) was added, and the reaction mixture

was allowed to slowly warm to room temperature. After 3 h, the

reaction mixture was diluted with CH₂Cl₂and washed with 2%

aq citric acid, distilled water and brine. The organic phase was

dried (Na₂SO₄), and then concentrated under reduced pressure.

Chromatography over silica gel (7:3 hexanes–EtOAc) yielded 46

3.39. Methyl 2-O-benzoyl-3,4-di-O-benzyl-6-O-methyl-b-D-

glucopyranoside (44)

(508 mg, 85%) as a white solid: R_f0.14 (1:1 hexanes–EtOAc); [a]

D

ꢀ27 (c 0.6, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 7.27–7.39 (m,

10H, ArH), 4.93 (d, 1H, J_gem10.9 Hz, PhCH₂O), 4.78 (d, 1H, J_gem

11.9 Hz, PhCH₂O), 4.69 (d, 1H, J_gem11.9 Hz, PhCH₂O), 4.62 (d, 1H,

J_gem11.0 Hz, PhCH₂O), 4.32 (d, 1H, J_1,21.0 Hz, H-1), 4.09 (m, 1H,

J_1,20.9, J_2,33.0 Hz, H-2), 3.88 (dd, 1H, J_3,4ꢂ J_4,59.4 Hz, H-4), 3.68

(dd, 1H, J_5,62.2, J_gem10.7 Hz, H-6a), 3.63 (dd, 1H, J_5,65.0, J_gem

10.6 Hz, H-6b), 3.57 (dd, 1H, J_2,33.1, J_3,49.1 Hz, H-3), 3.54 (s, 3H,

CH₃O), 3.39 (s, 3H, CH₃O), 3.38 (ddd, 1H, J_4,59.6, J_5,62.1, 4.9 Hz,

H-5), 2.38 (d, 1H, J_2,OH2.3 Hz, OH); ¹³C NMR (125 MHz, CDCl₃) d

138.4 (Ar), 137.9 (Ar), 128.5 (Ar), 128.4 (Ar), 128.1 (Ar), 127.8(8)

(Ar), 127.8(4) (Ar), 127.7(6) (Ar), 100.8 (C-1), 81.4 (C-3), 75.2(1)

(PhCH₂O), 75.1(5) (C-5), 74.2 (C-4), 71.5(4), 71.4(7) (C-6, PhCH₂O),

68.3 (C-2), 59.4 (CH₃O), 56.9 (CH₃O); HRESIMS: Calcd for

C₂₂H₂₈O₆Na 411.1778. Found 411.1782.

To a solution of compound 43 (953 mg, 1.99 mmol) in dry DMF

(20 mL) was added methyl iodide (248 L, 3.98 mmol). The reac-

l

tion mixture was cooled to 0 °C (ice-water bath) under argon be-

fore the addition of NaH (159 mg, 3.98 mmol). After 3 h of

stirring at 0 °C, the reaction was quenched with HOAc, then con-

centrated under reduced pressure. Puriﬁcation by chromatography

over silica gel (4:1 hexanes–EtOAc) gave 44 (937 mg, 96%) as a

white solid: R_f0.51 (1:1 hexanes–EtOAc); [a]_D+34 (c 0.27, CHCl₃);

¹H NMR (500 MHz, CDCl₃) d 8.02–8.04 (m, 2H, ArH), 7.57 (m, 1H,

ArH), 7.42–7.45 (m, 2H, ArH), 7.29–7.37 (m, 5H, ArH), 7.13 (br s,

5H, ArH), 5.27 (dd, 1H, J_1,28.0, J_2,39.2 Hz, H-2), 4.86 (d, 1H, J_gem

11.0 Hz, PhCH₂O), 4.75 (d, 1H, J_gem11.1 Hz, PhCH₂O), 4.64–4.69

(m, 2H, PhCH₂O), 4.45 (d, 1H, J_1,27.9 Hz, H-1), 3.84 (dd, 1H,

J_2,3ꢂ J_3,49.1 Hz, H-3), 3.76 (dd, 1H, J_3,4ꢂ J_4,59.4 Hz, H-4), 3.70

(ABX, 1H, J_5,64.6, J_gem10.8 Hz, H-6a), 3.66 (ABX, 1H, J_5,61.9, J_gem

10.8 Hz, H-6b), 3.53 (ABX, 1H, J_4,59.7, J_5,61.9, 4.6 Hz, H-5), 3.47

(s, 3H, CH₃O), 3.42 (s, 3H, CH₃O);¹³C NMR (125 MHz, CDCl₃) d

165.2 (C@O), 138.1 (Ar), 137.8 (Ar), 133.0 (Ar), 130.0 (Ar), 129.8

(Ar), 128.5 (Ar), 128.3 (Ar), 128.2 (Ar), 128.0 (Ar), 127.9(9) (Ar),

127.9(5) (Ar), 127.6 (Ar), 102.0 (C-1), 82.8 (C-3), 77.9 (C-4), 75.1,

75.0(4), 74.9(8) (C-5, PhCH₂O ꢃ 2), 73.7 (C-2), 71.2 (C-6), 59.5

(CH₃O), 56.7 (CH₃O); HRESIMS: Calcd for C₂₉H₃₂O₇Na 515.2040.

Found 515.2042. Anal. Calcd for C₂₉H₃₂O₇: C, 70.71; H, 6.55. Found:

C, 70.82; H, 6.64.

3.42. Methyl 2-O-acetyl-3,4,6-tri-O-benzyl-b-D-glucopyranosyl-

(1?2)-3,4-di-O-benzyl-6-deoxy-b- -mannopyranoside (47)

D

Monosaccharide acceptor 41 (250 mg, 0.70 mmol) was reacted

with 2-O-acetyl-3,4,6-tri-O-benzyl-b- -glucopyranosyl trichloro-

acetimidate (16) (533 mg, 0.84 mmol) in CH₂Cl₂(5 mL) using

TMSOTf (8 L, 0.04 mmol) under argon at 0 °C, then processed as

D

l

described for 17. The product was puriﬁed by chromatography

over silica gel (4:1 hexanes–EtOAc) to give 47 (560 mg, 96%) as a

colourless syrup: R_f0.65 (1:1 hexanes–EtOAc); [

a

]

ꢀ43 (c 0.8,

D

CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 7.19–7.39, (m, 25H, ArH),

5.13 (dd, 1H, J 8.1, 9.5 Hz, H-2⁰), 4.99 (d, 1H, J_gem10.8 Hz, PhCH₂O),

4.88 (d, 1H, J_gem12.1 Hz, PhCH₂O), 4.82–4.84 (m, 2H, H-1⁰,

PhCH₂O), 4.80 (d, 1H, J_gem11.5 Hz, PhCH₂O), 4.76 (d, 1H, J_gem

11.4 Hz, PhCH₂O), 4.59 (d, 1H, J_gem10.8 Hz, PhCH₂O), 4.52–4.57

(m, 2H, PhCH₂O), 4.51 (d, 1H, J_gem12.2 Hz, PhCH₂O), 4.48 (d, 1H,

J_gem12.1 Hz, PhCH₂O), 4.23 (d, 1H, J_2,32.8 Hz, H-2), 4.15 (s, 1H,

H-1), 3.74–3.79 (m, 2H, H-3⁰, H-6a⁰), 3.55–3.67 (m, 3H, H-4⁰, H-5⁰,

H-6b⁰), 3.48 (dd, 1H, J_3,4ꢂ J_4,59.1 Hz, H-4), 3.43 (s, 3H, CH₃O),

3.40. Methyl 3,4-di-O-benzyl-6-O-methyl-b-D-glucopyranoside

(45)

Compound 44 (937 mg, 1.90 mmol) was dissolved in a mixture

of 1:1 CH₂Cl₂–MeOH (20 mL). A 0.5 M solution of NaOMe in MeOH

(5 mL) was added, and the reaction mixture was stirred at room

temperature overnight. The reaction mixture was neutralized with

Amberlite IR-120 (H⁺) resin, and ﬁltered, and the ﬁltrate was con-

1410

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

3.41 (dd, 1H, J_3,49.3 Hz, H-3), 3.24 (dq, 1H, J_4,59.1, J_5,66.0 Hz, H-5),

2.03 (s, 3H, CH₃C(O)O), 1.32 (d, 3H, J_5,66.0 Hz, CH₃); ¹³C NMR

(125 MHz, CDCl₃) d 169.8 (C@O), 138.8 (Ar), 138.6 (Ar), 138.3

(Ar), 138.1 (Ar), 128.4 (Ar), 128.3(4) (Ar), 128.3(0) (Ar), 128.2

(Ar), 128.1(2) (Ar), 128.1(0) (Ar), 127.8 (Ar), 127.7 (Ar), 127.6

(Ar), 127.5 (Ar), 127.4 (Ar), 101.7 (C-1), 101.1 (C-1⁰), 83.1 (C-3⁰),

79.9, 79.8 (C-3, C-4), 78.1 (C-4⁰), 75.5 (PhCH₂O), 75.0, 74.8, 74.7

(C-5⁰, PhCH₂O ꢃ 2), 73.6, 73.5 (C-2⁰, PhCH₂O), 72.5 (C-2), 71.7 (C-

5), 69.9, 69.8 (C-6, PhCH₂O), 56.5 (CH₃O), 21.1 (CH₃C(O)O), 18.0

(C-6); HRESIMS: Calcd for C₅₀H₅₆O₁₁Na 855.3715. Found 855.3715.

127.6(4) (Ar), 127.6(3) (Ar), 127.5(5) (Ar), 127.5(0) (Ar), 102.0 (C-

1), 99.1 (C-1⁰), 81.4 (C-3⁰), 80.1 (C-3/C-5⁰), 79.4 (C-4), 75.4

(PhCH₂O), 75.1 (PhCH₂O), 75.0 (C-3/C-5⁰), 74.4 (C-4⁰), 73.4

(PhCH₂O), 71.8 (C-5), 70.7 (PhCH₂O), 70.4, 70.1, 70.0 (C-2, C-6⁰,

PhCH₂O), 67.7 (C-2⁰), 57.1 (CH₃O), 18.0 (C-6); HRESIMS: Calcd for

C₄₈H₅₄O₁₀Na 813.3609. Found 813.3614. Anal. Calcd for

C₄₈H₅₄O₁₀: C, 71.90; H, 6.21. Found: C, 71.95; H, 6.22.

3.45. Methyl b-D-mannopyranosyl-(1?2)-6-deoxy-b-D-

mannopyranoside (6)

3.43. Methyl 3,4,6-tri-O-benzyl-b-

D

-glucopyranosyl-(1?2)-3,4-

Compound 49 (55.0 mg, 0.070 mmol) was dissolved in 1:1

CH₂Cl₂–MeOH (10 mL), then stirred with 10% Pd/C (50 mg) under

a H₂atmosphere. The reduction mixture was then processed as de-

scribed for 2. Filtration then lyophilization gave 6 (20.4 mg, 86%) as

di-O-benzyl-6-deoxy-b- -mannopyranoside (48)

D

Disaccharide 47 (529 mg, 0.63 mmol) was dissolved in 1:1

CH₂Cl₂–MeOH (20 mL) and treated with 0.5 M CH₃ONa–CH₃OH

(5 mL), then processed as described for 18. Puriﬁcation of the prod-

uct by chromatography over silica gel (7:3 hexanes–EtOAc) gave

48 (502 mg, quant.) as a colourless syrup: R_f0.49 (1:1 hexanes–

a clear glass: R_f0.49 (6:3.5:0.5, CH₂Cl₂–MeOH–H₂O); [

a

]

ꢀ45 (c

D

1

1.1, H₂O); H NMR (600 MHz, D₂O) d 4.82 (s, 1H, H-1⁰), 4.61 (s,

0

1H, H-1), 4.24 (d, 1H, J_2,33.3 Hz, H-2), 4.10 (d, 1H, J_{2 ,3}3.3 Hz, H-

2⁰), 3.92 (dd, 1H, J_{5 ,6}2.3, J_gem12.3 Hz, H-6a⁰), 3.73 (dd, 1H, J_{5 ,6}

0

ꢀ45 (c 0.57, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d

6.8, J_gem12.3 Hz, H-6b⁰), 3.63 (dd, 1H, J_{2 ,3}3.3, J_{3 ,4}9.3 Hz, H-3⁰),

0

EtOAc); [

a

]

D

0

7.24–7.44 (m, 23H, ArH), 7.17–7.19 (m, 2H, ArH), 5.09 (d, 1H, J_gem

11.3 Hz, PhCH₂O), 5.00 (d, 1H, J_gem10.8 Hz, PhCH₂O), 4.90 (d, 1H,

J_gem12.1 Hz, PhCH₂O), 4.87 (d, 1H, J_gem10.9 Hz, PhCH₂O), 4.82 (d,

1H, J_gem11.3 Hz, PhCH₂O), 4.61 (d, 1H, J_gem10.8 Hz, PhCH₂O),

3.58 (dd, 1H, J_2,33.3, J_3,49.3 Hz, H-3) 3.55 (dd, 1H, J_{3 ,4}ꢂ J_{4 ,5}

9.7 Hz, H-4⁰), 3.51 (s, 3H, CH₃O), 3.34–3.42 (m, 3H, H-5⁰, H-4, H-

5), 1.32 (d, 3H, J_5,65.6 Hz, CH₃); ¹³C NMR (125 MHz, D₂O) d 102.1

1

(C-1, J_C1,H1152.3 Hz, b), 101.3 (C-1⁰, J_{C1 ,H1}162.7 Hz, b), 78.6 (C-

2), 77.2 (C-5⁰), 73.7, 73.4, 73.2, 72.9 (C-3⁰, C-3, C-4, C-5), 71.2 (C-

2⁰), 67.7 (C-4⁰), 62.0 (C-6⁰), 57.9 (CH₃O), 17.5 (C-6); HRESIMS: Calcd

for C₁₃H₂₄O₁₀Na 363.1262. Found 363.1261.

0

4.59 (d, 1H, J_{1 ,2}7.9 Hz, H-1⁰), 4.56 (d, 1H, J_gem12.4 Hz, PhCH₂O),

4.54 (d, 1H, J_gem11.1 Hz, PhCH₂O), 4.49 (d, 1H, J_gem12.1 Hz,

PhCH₂O), 4.45 (d, 1H, J_gem12.0 Hz, PhCH₂O), 4.27 (s, 1H, H-1),

0

4.22 (d, 1H, J_2,33.0 Hz, H-2), 3.75 (dd, 1H, J_{2 ,3}9.0 Hz, H-2⁰), 3.64–

3.72 (m, 3H, H-3⁰, H-6a⁰, H-6b⁰), 3.52–3.59 (m, 3H, H-4⁰, H-5⁰, H-

4), 3.52 (s, 3H, CH₃O), 3.49 (dd, 1H, J_2,33.1, J_3,49.3 Hz, H-3), 3.31

(dq, 1H, J_4,59.0, J_5,66.1 Hz, H-5), 1.37 (d, 3H, J_5,66.1 Hz, CH₃); ¹³C

NMR (125 MHz, CDCl₃) d 139.1 (Ar), 138.6 (Ar), 138.3 (Ar), 138.2

(Ar), 138.1 (Ar), 128.3(4) (Ar), 128.3(0) (Ar), 128.2(8) (Ar),

128.0(7) (Ar), 128.0(6) (Ar), 127.9(6) (Ar), 127.8 (Ar), 127.6(8)

(Ar), 127.6(5) (Ar), 127.5(4) (Ar), 127.5(3) (Ar), 127.4 (Ar), 104.7

(C-1⁰), 101.3 (C-1), 85.3 (C-3⁰), 80.1, 79.9 (C-3, C-4), 77.3 (C-4⁰, C-

5⁰), 75.5(3), 75.5(2), 75.5(0) (C-2, C-2⁰, PhCH₂O), 75.3 (PhCH₂O),

75.0 (PhCH₂O), 74.8 (C-4⁰, C-5⁰), 73.4 (PhCH₂O), 71.8 (C-5), 70.4

(PhCH₂O), 69.7 (C-6⁰), 57.0 (CH₃O), 18.0 (C-6); HRESIMS: Calcd

for C₄₈H₅₄O₁₀Na 813.3609. Found 813.3609.

0

3.46. Methyl 2-O-acetyl-3,4,6-tri-O-benzyl-b-

D

-glucopyranosyl-

(1?2)-3,4-di-O-benzyl-6-O–O-methyl-b-

D-mannopyranoside

(50)

Monosaccharide acceptor 46 (198 mg, 0.51 mmol) was reacted

with 2-O-acetyl-3,4,6-tri-O-benzyl-b- -glucopyranosyl trichloro-

acetimidate (16) (390 mg, 0.61 mmol) in CH₂Cl₂(5 mL) using

TMSOTf(6 L, 0.03 mmol) under argon at 0 °C. The mixture was then

D

l

processed as described for 17. The product was puriﬁed by chroma-

tography over silica gel (4:1 hexanes–EtOAc) to give 50 (298 mg,

68%) as a colourless syrup: R_f0.43 (1:1 hexanes–EtOAc); [

a]

ꢀ43

D

(c 0.47, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 7.18–7.37 (m, 25H,

ArH), 5.12 (dd, 1H, J_{1 ,2}8.1, J_{2 ,3}9.5 Hz, H-2⁰), 4.96 (d, 1H,

J_gem11.1 Hz, PhCH₂O), 4.89 (d, 1H, J_gem11.9 Hz, PhCH₂O), 4.82 (d,

0

3.44. Methyl 3,4,6-tri-O-benzyl-b-D-mannopyranosyl-(1?2)-

1H, J_gem11.5 Hz, PhCH₂O), 4.82 (d, 1H, J_{1 ,2}7.9 Hz, H-1⁰), 4.79 (d,

1H, J_gem11.6 Hz, PhCH₂O), 4.75 (d, 1H, J_gem11.5 Hz, PhCH₂O), 4.55

(d, 1H, J_gem10.9 Hz, PhCH₂O), 4.53 (d, 1H, J_gem10.9 Hz, PhCH₂O),

4.52 (d, 1H, J_gem11.9 Hz, PhCH₂O), 4.48 (d, 1H, J_gem12.1 Hz, PhCH₂O),

0

3,4-di-O-benzyl-6-deoxy-b- -mannopyranoside (49)

D

As described for compound 19, disaccharide 48 (475 mg,

0.60 mmol) was dissolved in freshly distilled Me₂SO (10 mL) and

Ac₂O (5 mL). The concentrated reaction mixture was then treated

with 1.0 M L-Selectride^Òin THF (2.4 mL, 2.40 mmol) in dry THF

(10 mL) at ꢀ78 °C under argon. Puriﬁcation by column chromatog-

raphy over silica gel (1:1 hexanes–EtOAc) gave 49 (390 mg, 82%) as

4.46 (d, 1H, J_gem11.9 Hz, PhCH₂O), 4.23 (d, 1H, J_2,32.9 Hz, H-2), 4.19

0

(s, 1H, H-1), 3.76 (dd, 1H, J_{2 ,3}8.2, J_{3 ,4}9.4 Hz, H-3 ), 3.74 (dd, 1H, J_{5 ,6}

1.4, J_gem8.9 Hz, H-6a⁰), 3.53–3.66 (m, 6H, H-4⁰, H-5⁰, H-6b⁰, H-4, H-6a,

H-6b), 3.46–3.48 (m, 4H, H-3, CH₃O), 3.36–3.39 (m, 4H, H-5, CH₃O),

2.03 (s, 3H, CH₃C(O)O); ¹³C NMR (125 MHz, CDCl₃) d 169.8 (C@O),

138.7 (Ar), 138.5 (Ar), 138.2 (Ar), 138.1 (Ar), 138.0 (Ar), 128.4 (Ar),

128.3(3) (Ar), 128.3(0) (Ar), 128.2(5) (Ar), 128.1(3) (Ar), 128.0(9)

(Ar), 128.0 (Ar), 127.8 (Ar), 127.7(2) (Ar), 127.7(1) (Ar), 127.6 (Ar),

127.5(5) (Ar), 127.4(8) (Ar), 101.7 (C-1), 101.1 (C-1⁰), 83.2 (C-3⁰),

80.0 (C-3), 78.1 (C-4⁰/C-5⁰/C-4), 75.5, 75.2, 74.9, 74.8(2), 74.7(5) (C-

4⁰/C-5⁰/C-4, C-5, PhCH₂O ꢃ 3), 73.6, 73.5, 72.8, 72.2 (C-2, C-6, C-2⁰,

PhCH₂O), 69.8(4), 69.8(0) (C-6⁰, PhCH₂O), 59.3 (CH₃O), 56.7 (CH₃O),

21.1 (CH₃C(O)O); HRESIMS: Calcd for C₅₁H₅₈O₁₂Na 885.3821. Found

885.3811.

a white solid: R_f0.41 (1:1 hexanes–EtOAc); [

a

]

ꢀ52 (c 0.71,

D

CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 7.22–7.24 (m, 25H, ArH),

4.96 (d, 1H, J_gem11.3 Hz, PhCH₂O), 4.94 (d, 1H, J_gem12.2 Hz,

0

PhCH₂O), 4.93 (d, 1H, J_gem10.9 Hz, PhCH₂O), 4.90 (d, 1H, J_{1 ,2}

0.7 Hz, H-1⁰), 4.85 (d, 1H, J_gem12.0 Hz, PhCH₂O), 4.65 (d, 1H, J_gem

12.1 Hz, PhCH₂O), 4.60 (d, 1H, J_gem10.8 Hz, PhCH₂O), 4.56 (d, 1H,

J_gem11.0 Hz, PhCH₂O), 4.50 (d, 1H, J_2,32.8 Hz, H-2), 4.46 (d, 1H, J_gem

11.4 Hz, PhCH₂O), 4.45 (d, 1H, J_gem12.0 Hz, PhCH₂O), 4.42 (d, 1H,

J_gem12.0 Hz, PhCH₂O), 4.34 (d, 1H, J_{2 ,3}2.8 Hz, H-2⁰), 4.26 (s, 1H,

0

H-1), 3.91 (dd, 1H, J_{3 ,4}ꢂ J_{4 ,5}9.3 Hz, H-4⁰), 3.76 (dd, 1H, J_{5 ,6}2.0,

0

J_gem10.6 Hz, H-6a⁰), 3.63 (dd, 1H, J_{5 ,6}6.1, J_gem10.5 Hz, H-6b⁰),

3.58 (dd, 1H, H-3⁰), 3.44–3.52 (m, 3H, H-5⁰, H-3, H-4), 3.48 (s, 3H,

CH₃O), 3.31 (dq, 1H, J_4,58.7, J_5,66.0 Hz, H-5), 1.37 (d, 3H, J_5,6

6.1 Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃) d 138.4(9) (Ar), 138.4(5)

(Ar), 138.2 (Ar), 138.1 (Ar), 128.4 (Ar), 128.3(1) (Ar), 128.2(8)

(Ar), 128.2(1) (Ar), 128.2(0) (Ar), 128.1 (Ar), 127.9(Ar), 127.7 (Ar),

0

3.47. Methyl 3,4,6-tri-O-benzyl-b-D-glucopyranosyl-(1?2)-3,4-

di-O-benzyl-6-O-methyl-b- -mannopyranoside (51)

D

Disaccharide 50 (281 mg, 0.33 mmol) was dissolved in 1:1

CH₂Cl₂–MeOH (10 mL) and treated with 0.5 M CH₃ONa–CH₃OH

C. M. Nycholat, D. R. Bundle / Carbohydrate Research 344 (2009) 1397–1411

1411

0

(3 mL), then processed as described for 18. Puriﬁcation of the prod-

uct by chromatography over silica gel (7:3 hexanes–EtOAc) gave

10.6 Hz, H-6a), 3.62 (dd, 1H, J_{5 ,6}6.0, J_gem10.7 Hz, H-6b⁰), 3.61

(dd, 1H, J_5,65.2, J_gem10.7 Hz, H-6b), 3.56 (dd, 1H, J_2,33.0, J_3,4

0

51 (257 mg, 96%): R_f0.31 (1:1 hexanes–EtOAc); [

a

]

ꢀ42 (c 0.80,

9.1 Hz, H-3), 3.54 (dd, 1H, J_{2 ,3}3.4, J_{3 ,4}9.3 Hz, H-3⁰), 3.49 (ddd,

D

CHCl₃); ¹H NMR (500 MHz, CDCl₃) d 7.23–7.43 (m, 23H, ArH),

7.16–7.18 (m, 2H, ArH), 5.08 (d, 1H, J_gem11.2 Hz, PhCH₂O), 4.97

(d, 1H, J_gem10.9 Hz, PhCH₂O), 4.90 (d, 1H, J_gem12.0 Hz, PhCH₂O),

4.86 (d, 1H, J_gem10.9 Hz, PhCH₂O), 4.80 (d, 1H, J_gem11.4 Hz,

1H, J_{4 ,5}9.7, J_{5 ,6}1.9, 6.1 Hz, H-5⁰), 3.48 (s, 3H, CH₃O), 3.38 (s, 3H,

CH₃O), 3.36 (ddd, 1H, J_4,59.8, J_5,62.0, 5.2 Hz, H-5), 2.78 (br s, 1H,

OH); ¹³C NMR (125 MHz, CDCl₃) d 138.4(8) (Ar), 138.4(6) (Ar),

138.2 (Ar), 138.1(4) (Ar), 138.1(1) (Ar), 128.4 (Ar), 128.3(2) (Ar),

128.3(0) (Ar), 128.2(9) (Ar), 128.2(7) (Ar), 128.2 (Ar), 128.1 (Ar),

128.0 (Ar), 127.9 (Ar), 127.7 (Ar), 127.6(4) (Ar), 127.6(1) (Ar),

127.5(2) (Ar), 127.4(9) (Ar), 102.2 (C-1), 99.0 (C-1⁰), 81.4 (C-3),

80.2 (C-3⁰), 75.3, 75.2, 75.1, 75.0 (C-5, C-5⁰, PhCH₂O ꢃ 2), 74.4 (C-

4⁰), 73.9 (C-4), 73.4 (PhCH₂O), 71.6 (C-6), 70.6 (PhCH₂O), 70.1,

70.0 (C-6⁰, PhCH₂O), 67.7 (C-2⁰), 59.2 (CH₃O), 57.2 (CH₃O); HRE-

SIMS: Calcd for C₄₉H₅₆O₁₁Na 843.3715. Found 843.3705.

0

PhCH₂O), 4.61 (d, 1H, J_{1 ,2}7.8 Hz, H-1⁰), 4.57 (d, 1H, J_gem10.9 Hz,

PhCH₂O), 4.55 (d, 1H, J_gem12.2 Hz, PhCH₂O), 4.53 (d, 1H, J_gem

11.0 Hz, PhCH₂O), 4.48 (d, 1H, J_gem12.1 Hz, PhCH₂O), 4.44 (d, 1H,

J_gem12.0 Hz, PhCH₂O), 4.28 (s, 1H, H-1), 4.23 (d, 1H, J_2,33.2 Hz,

0

H-2), 3.84 (dd, 1H, J_3,4ꢂ J_4,59.5 Hz, H-4), 3.73 (dd, 1H, J_{1 ,2}8.0,

J_{2 ,3}8.9 Hz, H-2⁰), 3.61–3.71 (m, 5H, H-3⁰, H-6a⁰, H-6b⁰, H-6a, H-

6b), 3.51–3.55 (m, 3H, H-4⁰, H-3, H-4), 3.53 (s, 3H, CH₃O), 3.39 (s,

3H, CH₃O), 3.37 (ddd, 1H, J_4,59.7, J_5,62.0, 5.2 Hz, H-5); ¹³C NMR

(125 MHz, CDCl₃) d 139.1 (Ar), 138.5 (Ar), 138.2 (Ar), 138.1(3)

(Ar), 138.1(1) (Ar), 128.3(5) (Ar), 128.3(2) (Ar), 128.3(0) (Ar),

128.2(5) (Ar), 128.1 (Ar), 128.0(4) (Ar), 128.0(3) (Ar), 127.9 (Ar),

127.8 (Ar), 127.7 (Ar), 127.6 (Ar), 127.5 (Ar), 127.4 (Ar), 104.4 (C-

1⁰), 101.6 (C-1), 85.2 (C-3⁰), 80.2 (C-3), 77.3 (C-4⁰/C-5⁰) 75.6, 75.5,

75.3, 75.0, 74.9, 74.8 (C-2⁰, C-4⁰/C-5⁰, C-2, C-5, PhCH₂O ꢃ 3), 74.4

(C-4), 73.4 (PhCH₂O), 71.7 (C-6), 70.4 (PhCH₂O), 69.7 (C-6⁰), 59.4

(CH₃O), 57.2 (CH₃O); HRESIMS: Calcd for C₄₉H₅₆O₁₁Na 843.3715.

Found 843.3718.

0

Supplementary data

Supplementary data associated with this article can be found, in

the online version, at doi:10.1016/j.carres.2009.07.008.

References

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3.48. Methyl 3,4,6-tri-O-benzyl-b-

D-mannopyranosyl-(1?2)-

3,4-di-O-benzyl-6-O-methyl-b- -mannopyranoside (52)

D

As described for compound 19, disaccharide 51 (257 mg,

0.31 mmol) was dissolved in freshly distilled Me₂SO (8 mL) and

Ac₂O (4 mL). The concentrated reaction mixture was then treated

with 1.0 M L-Selectride^Òin THF (1.3 mL, 1.25 mmol) in dry THF

(10 mL) at ꢀ78 °C under argon. Puriﬁcation by column chromatog-

raphy over silica gel (7:3 hexanes–EtOAc) gave 52 (200 mg, 78%) as

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Chem., Int. Ed. 2005, 44, 1665–1668.

a white solid: R_f0.25 (1:1 hexanes–EtOAc); [

a

]

ꢀ49 (c 0.62,

D

CHCl₃); ¹H NMR (600 MHz, CDCl₃) d 7.37–7.41 (m, 4H, ArH),

7.21–7.34 (m, 21H, ArH), 4.96 (d, 1H, J_gem11.0 Hz, PhCH₂O), 4.93

(d, 1H, J_gem10.7 Hz, PhCH₂O), 4.91 (d, 1H, J_{1 ,2}0.8 Hz, H-1⁰), 4.91

(d, 1H, J_gem10.0 Hz, PhCH₂O), 4.84 (d, 1H, J_gem12.1 Hz, PhCH₂O),

4.64 (d, 1H, J_gem12.1 Hz, PhCH₂O), 4.56 (d, 1H, J_gem10.9 Hz,

PhCH₂O), 4.55 (d, 1H, J_gem11.0 Hz, PhCH₂O), 4.50 (d, 1H, J_2,3

3.1 Hz, H-2), 4.46 (d, 1H, J_gem11.5 Hz, PhCH₂O), 4.45 (d, 1H, J_gem

12.1 Hz, PhCH₂O), 4.42 (d, 1H, J_gem11.9 Hz, PhCH₂O), 4.34 (d, 1H,

0

J_{2 ,3}2.9 Hz, H-2⁰), 4.27 (d, 1H, J_1,20.7 Hz, H-1), 3.90 (dd, 1H,

0

J_{3 ,4}ꢂ J_{4 ,5}9.3 Hz, H-4⁰), 3.80 (dd, 1H, J_3,4ꢂ J_4,59.6 Hz, H-4), 3.76

0

(dd, 1H, J_{5 ,6}2.0, J_gem10.6 Hz, H-6a⁰), 3.67 (dd, 1H, J_5,62.0, J_gem

0

Article Doi

Synthesis of monodeoxy and mono-O-methyl congeners of methyl β-d-mannopyranosyl-(1→2)-β-d-mannopyranoside for epitope mapping of anti-Candida albicans antibodies

DOI: 10.1016/j.carres.2009.07.008

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Article abstract of DOI:10.1016/j.carres.2009.07.008

Full text of DOI:10.1016/j.carres.2009.07.008

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