Glycosylation with 2-Acetamido-2-deoxyglycosyl Donors at a Low Temperature: Scope of the Non-Oxazoline Method

Article

pubs.acs.org/joc

Glycosylation with 2‑Acetamido-2-deoxyglycosyl Donors at a Low

Temperature: Scope of the Non-Oxazoline Method

Ryoichi Arihara, Kosuke Kakita, Noritoshi Suzuki, Seiichi Nakamura,*^,†and Shunichi Hashimoto*

Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

S

* Supporting Information

ABSTRACT: A direct construction of 1,2-trans-β-linked 2-acetamido-2-

deoxyglycosides was investigated. The 3,4,6-tri-O-benzyl- and 3,4,6-tri-O-

acetyl-protected glycosyl diethyl phosphites and 4,6-O-benzylidene-protected

galactosyl diethyl phosphite each reacted with a variety of acceptor alcohols in

the presence of a stoichiometric amount of Tf₂NH in CH₂Cl₂at −78 °C to aﬀord the corresponding β-glycosides in good to high

yields with complete stereoselectivity. Some experiments provided strong evidence that the corresponding oxazolinium ions are

not responsible for the reaction. We demonstrated that glycosylations with the corresponding glycosyl imidate and thioglycoside

also proceeded at a low temperature, indicating the possibility of these donors being attractive alternatives to the phosphite. A

plausible reaction mechanism, which features glycosyl triﬂimide and contact ion pair as reactive intermediates, is proposed on the

basis of the results obtained with 2-acetamido-2-deoxymannosyl donors.

Scheme 1. Glycosylation with 2-Acetamido-2-deoxyglycosyl

Donor 1

INTRODUCTION

■

2-Acetamido-2-deoxy-D-glycosides are ubiquitous building

blocks of glycolipids, glycoproteins, proteoglycans, and

peptidoglycans and are associated with a wide range of

biological processes.¹For example, serine/threonine hydroxy

groups in nuclear and cytoplasmic proteins are glycosylated

with 2-acetamido-2-deoxy-^D-glucoses as a posttranslational

modiﬁcation of proteins that are thought to modulate the

functions of proteins in cells. The majority of 2-acetamido-2-

deoxysugars are found as β-linked glycosides, whereas 2-

acetamido-2-deoxy-^D-galactose residues are α-linked to serine/

threonine hydroxy groups.^2,3

For the synthesis of 1,2-trans-β-glycosides of 2-acetamido-2-

deoxysugars,⁴the most general and extensively developed

strategy utilizes donors containing a participating group as the

amino-protecting functionality that are replaced by an acetyl

group after the glycosylation event. A variety of 2-amino

protecting groups such as N-phthaloyl,⁵N-2,2,2-trichloroethox-

ycarbonyl (Troc),^6,7N-allyloxycarbonyl (Alloc),⁷N-benzylox-

ycarbonyl (Cbz),⁷N-trichloroacetyl (TCA),⁸N-tetrachloroph-

thaloyl (TCP),⁹N-dithiasuccinoyl (Dts),¹⁰N,N-diacetyl,¹¹N-

4,5-dichlorophthaloyl (DCPhth),¹²N-acetyl-N-2,2,2-trichloroe-

thoxycarbonyl,¹³N-p-nitrobenzyloxycarbonyl,¹⁴N-dimethylma-

leoyl (DMM),¹⁵N,N-dibenzyl,¹⁶N-thiodiglycoloyl (TDG),¹⁷

and N-dimethylphosphoryl (DMP)¹⁸have been employed for

this purpose. Despite their electronically nonparticipating

nature, the synthetic utility of 2,5-dimethyl-1-pyrrolyl¹⁹and

azido groups^20,21as amino group equivalents has also been

demonstrated.^22,23

however, the reaction of donor 1 generally leads to the

preferential formation of oxazoline derivative 3 via neighboring

group participation and subsequent abstraction of a proton

from the formed oxazolinium ion intermediate 2.²⁴Oxazoline 3

can be activated with Brønsted or Lewis acids to regenerate

oxazolinium ion 2 or 4, which upon treatment with an acceptor

alcohol provides 2-acetamido-2-deoxy-β-glycoside 5,²⁵but the

harsh reaction conditions required for this conversion have

precluded its wide application in the synthesis of complex

oligosaccharides.

Over the past 25 years, we have developed novel

glycosylation reactions capitalizing on phosphorus-containing

leaving groups.²⁶Using donors with these leaving groups,

various types of glycosidic linkages could be constructed in a

stereoselective manner by appropriate choice of reaction

conditions.²⁷⁻²⁹We anticipated that, with the proper selection

of reaction conditions, high-yielding access to 1,2-trans-β-

glycosides might be realized by glycosylation with a 2-

Although these indirect methods provide reliable access to

1,2-trans-β-glycosides of 2-acetamido-2-deoxysugars, additional

synthetic steps are required for the substrate preparation.

Therefore, it is clear that the use of donor 1 with natural N-

acetyl functionality would constitute an ideal procedure in

terms of eﬃciency and practicality (Scheme 1). In practice,

Received: January 20, 2015

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acetamido-2-deoxyglycosyl donor carrying a phosphorus-

containing leaving group. In this article, we document the

scope and mechanism of Tf₂NH-promoted glycosylation with

2-acetamido-2-deoxyglycosyl diethyl phosphite.³⁰An extension

of this study using a variety of 2-acetamido-2-deoxyglycosyl

donors revealed that 2-acetamido-2-deoxyglycosides could be

obtained by glycosylations at a low temperature irrespective of

the leaving group employed, although the reaction did not

proceed through the intermediacy of the corresponding

oxazolinium ions. The details of this investigation are also

reported herein.

phosphorochloridate in THF/HMPA (eq 1).²⁸On the other

hand, 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-^D-glucosyl di-

phenyl phosphate could not be obtained since it decomposed

upon puriﬁcation by silica gel column chromatography,

although the reaction of 8a with diphenyl chlorophosphate

and DMAP proceeded in CH₂Cl₂at 0 °C.

RESULTS AND DISCUSSION

■

2-Acetamido-2-deoxy-D-glycosyl donors were prepared accord-

ing to standard procedures. While α-linked glycosyl diethyl

phosphites 9a, 9c, 11a, and 11c were stereoselectively obtained

in excellent yields (87−90%) by phosphitylation of the

corresponding hemiacetals with diethyl chlorophosphite,^29a,31

the reaction of 4,6-O-benzylidene-protected hemiacetals 8b and

10b under identical conditions gave anomeric mixtures, which

were recrystallized from n-hexane/acetone (4:1) to provide

pure α-phosphites 9b and 11b (Table 1). Tetramethylphos-

phorodiamidate 12 was prepared by condensing a lithium

alkoxide derived from 8a with bis(dimethylamino)-

Having prepared 2-acetamido-2-deoxyglycosyl donors with a

phosphorus-containing leaving group, we initially explored

TMSOTf-promoted glycosylations of 1.1 equiv of 6-O-

unprotected glucoside 13 with 3,4,6-tri-O-benzyl-protected

glucosyl donors 9a and 12 (Table 2). The reaction involved

the addition of a 1.0 M solution of TMSOTf (1.1 equiv) in

CH₂Cl₂to a cooled mixture of a donor and 1.1 equiv of

acceptor 13.³²To date, glycosylations with 2-acetamido-2-

deoxyglycosyl donors have been performed at temperatures

above 0 °C. The reaction of phosphite 9a with alcohol 13 at 0

°C aﬀorded a mixture of β-linked disaccharide 14 and oxazoline

1

Table 1. Preparation of 2-Acetamido-2-deoxy-α-glycosyl

15 in a ratio of 0.3:1 as determined by 500 MHz H NMR

Diethyl Phosphites

spectroscopic analysis of the crude mixture (entry 1). An

examination of the temperature proﬁle of the reaction

demonstrated that a decrease in the reaction temperature is

accompanied by a signiﬁcant increase in the yield of

disaccharide 14 (entries 1−3). The temperature limit for

smooth reaction was −60 °C, at which β-linked disaccharide 14

was obtained in 36% yield (entry 3). Glycosylation with

phosphorodiamidate 12 proceeded at −45 °C to give almost

the same result (40% yield), but a protracted reaction time

(120 min) was required (entry 4). Given the diversity of

promoters available, the phosphite method was chosen for

further optimization. Due to its highly crystalline nature, diethyl

phosphite 9a is insoluble in solvents other than CH₂Cl₂and

THF at −60 °C: exclusive formation of oxazoline 15 was

observed by the use of THF as a solvent (entry 5), and the

addition of either toluene or EtCN as a cosolvent aﬀorded no

discernible beneﬁt (entries 6 and 7 vs 3).

In an eﬀort to improve the chemical yield of disaccharide 14,

several promoters were screened in the reaction of diethyl

phosphite 9a with alcohol 13, and the results are compiled in

Table 3. Although the product ratio (14:15) was improved to

2:1, the use of BF₃·OEt₂, an eﬀective promoter in the

glycosylation with per-O-benzylated glycosyl diethyl phosphi-

tes,^29adid not increase the yield of 14 due to the formation of a

number of byproducts. Of various metal triﬂates examined,³³

Sn(OTf)₂and Hf(OTf)₄³⁴were found to promote the reaction

at −60 °C, aﬀording disaccharide 14 in 46% and 66% yields,

respectively. Since some Brønsted acids have been shown to

activate glycosyl phosphites,^29b,35our interest was then directed

to the use of promoters with Brønsted acidity. As expected

from the precedent,^29c,ddiethyl phosphite 9a could be activated

at lower temperature (−78 °C) with a variety of Brønsted acids

than with TMSOTf (entries 5−9). A signiﬁcantly longer

reaction time (12 h) was required to reach completion when

HClO₄, prepared from t-BuBr and AgClO₄in toluene,³⁶was

employed as a promoter (entry 5). The reaction rate was

enhanced by the use of sulfonic acids in place of HClO₄

a

Pure α-phosphites 9b and 11b were obtained upon puriﬁcation by

recrystallization from n-hexane/acetone (4:1).

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a

Table 2. TMSOTf-Promoted Glycosylation of Alcohol 13 with 2-Acetamido-3,4,6-tri-O-benzyl-2-deoxyglucosyl Donors

donor

b

entry

L

solvent

temp (°C)

time (min)

ratio 14:15

yield of 14 (%)

1

2

3

4

5

6

7

9a

12

9a

OP(OEt)₂

CH₂Cl₂

0

10

0.3:1

0.4:1

0.7:1

0.8:1

<0.1:1

0.7:1

18

24

−23

−60

−45

−60

OP(OEt)₂

CH₂Cl₂

30

36

OP(O)(NMe₂)₂

OP(OEt)₂

CH₂Cl₂

120

10

40

THF

trace

35

OP(OEt)₂

PhMe/CH₂Cl₂(1:1)

30

OP(OEt)₂

EtCN/CH₂Cl₂(1:1)

−60

1

30

37

a

b

The reaction was carried out on a 0.1 mmol scale. Determined by 500 MHz H NMR.

a

Table 3. Eﬀects of Promoters in the Glycosylation of Alcohol 13 with Diethyl Phosphite 9a

promoter

b

entry

equiv

temp (°C)

time (h)

ratio 14:15

yield of 14 (%)

c

1

TMSOTf

BF₃·OEt₂

Sn(OTf)₂

Hf(OTf)₄

1.1

1.5

1.1

−60

−78

0.5

4

0.7:1

2.0:1

1.6:1

2.9:1

2.2:1

0.8:1

1.8:1

4.2:1

4.1:1

36

39

46

66

59

38

51

75

73

2

3

4

5

6

7

8

9

1

d

HClO₄

12

1

MsOH

TsOH

TfOH

Tf₂NH

1

5

1

a

b

c

d

1

The reaction was carried out on a 0.1 mmol scale. Determined by 500 MHz H NMR. In the absence of 4 Å MS. Prepared from t-BuBr and

AgClO₄.

a

Table 4. Eﬀects of Donor/acceptor/Tf₂NH Molar Ratio

b

c

entry

Tf₂NH (equiv)

molar ratio 9a:13

time (h)

ratio 14:15

yield of 14 (%)

d

1

0.2

0.5

1.1

1.5

1.1

1.0:1.1

1.0:1.5

1.0:2.0

2.0:1.0

24

2

0.9:1

2.3:1

4.1:1

5.2:1

7.8:1

−

22

57

73

77

84

93

2

3

4

5

6

7

1

a

b

c

d

The reaction was carried out on a 0.1 mmol scale. Based on the donor used. Determined by 500 MHz ¹H NMR. Donor 9a was recovered in ca.

50% yield.

(entries 6−8). We noticed that sulfonic acids with greater

Brønsted acidity³⁷resulted in higher yield of 14: good chemical

yield (75%) was achieved by the TfOH-promoted reaction,

albeit with somewhat long reaction time (5 h). Switching the

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a b

,

Table 5. Tf₂NH-Promoted Glycosylation of Alcohol 13 with 2-Acetamido-2-deoxyglycosyl Diethyl Phosphites

a

b

The reaction was carried out on a 0.1 mmol scale. Donor/Tf₂NH molar ratio =1.0/1.1.

counterion in super Brønsted acids from triﬂate to

triﬂimide^38,39signiﬁcantly shortened the reaction time (5 →

1 h), providing disaccharide 14 in comparable yield (entry

9).^40,41

Having optimized the reaction conditions, the scope of the

Tf₂NH-promoted glycosylation was explored. Results of

experiments for probing the scope of the donor component

with 6-O-unprotected glucoside 13 are summarized in Table

5.⁴⁴As with donor 9a, glycosylation with 3,4,6-tri-O-benzyl-

protected galactosyl diethyl phosphite 11a proceeded to

completion within 1 h to furnish disaccharide 16 in good

yields irrespective of the molar ratio (11a:13) used (entries 1

and 2). Consistent with a general trend of 4,6-O-benzylidene-

protected glycosyl donors exhibiting reduced reactivities,⁴⁵

protracted reaction times were required for the complete

consumption of donors 9b and 11b (entries 3−6). The use of

glucosyl donor 9b was disappointing because the yields were

modest (up to 49%, entries 3 and 4). In stark contrast,

glycosylation with galactosyl donor 11b gave disaccharides 18

in good yields (entries 5 and 6). The diﬀerence in reactivity

between these donors may be explained by considering that

glucosyl donor 9b is a trans-fused bicyclic compound, whereas

galactosyl donor 11b has a relatively ﬂexible, cis-decaline-like

architecture. We speculate that the greater conformational

rigidity of 9b relative to 11b facilitates oxazoline formation.⁴⁶

While switching the protecting groups from benzyl to acetyl

groups further lowers the reactivity of donors, 3,4,6-tri-O-

acetyl-protected glucosyl donor 9c could be activated by

Some Brønsted acids have been employed as catalysts to

activate glycosyl phosphites.^35a,42Therefore, we next inves-

tigated the glycosylation under catalytic conditions (Table 4).

In the presence of 0.2 equiv of Tf₂NH, the glycosylation of

alcohol 13 with diethyl phosphite 9a did not proceed beyond a

50% conversion, providing disaccharide 14 in 22% yield (entry

1). We surmised that the result is attributed to the presence of

HP(O)(OEt)₂and oxazoline 15, which were formed as the

reaction progressed and would buﬀer the acidity of the

promoter. While the use of 0.5 equiv of Tf₂NH was found to

be suﬃcient for the reaction to reach completion, product

selectivity (14:15) eroded signiﬁcantly (entry 2). Since an

excess amount of Tf₂NH has essentially no eﬀect on the

reaction (entry 4), 1.1 equiv of Tf₂NH was typically employed

for the glycosylation. The eﬀect of molar ratio of donor 9a and

acceptor 13 was also examined. When the amount of alcohol 13

used was increased from 1.1 to 2.0 equiv, higher yields were

obtained (entries 3 vs 5 and 6). The use of donor 9a in 2-fold

excess aﬀorded the best yield (93% yield, entry 7).⁴³These

results revealed the possibility that an excess of either reaction

component can be used depending on their availability.

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Tf₂NH at −78 °C, aﬀording disaccharide 19 in acceptable

yields (entries 7 and 8).⁴⁷

In an eﬀort to deﬁne the scope of the glycosylation method,

we next examined the reaction employing a range of alcohols

with diﬀerent reactivities as acceptors (Table 6, Figure 1).⁴⁴As

corresponding β-glycosides in good to excellent yields (entries

1, 2, and 10). It is noteworthy that even some of the secondary

alcohols were successfully utilized in this reaction, leaving the

acid-sensitive epoxy or acetal groups unaﬀected (entries 3−5, 9,

and 11). On the other hand, less reactive secondary alcohols 25

and 26 could not be glycosylated under these conditions,

indicating the possibility of regioselective glycosylation with

2,3,4-tri-O-unprotected glucoside (entries 4 vs 6 and 7).

Isomerization of (Z)-trisubstituted oleﬁn was not observed

during the reaction between diethyl phosphite 11a and nerol

(27, entry 8). We conﬁrmed that similar results could be

obtained irrespective of the reaction component employed in

excess.

Table 6. Tf₂NH-Promoted Glycosylation of Various

Acceptor Alcohols with 2-Acetamido-2-deoxyglycosyl

a

Donors

As mentioned above, glycosylations with 2-acetamido-2-

deoxyglycosyl donors have been performed at temperatures

higher than 0 °C due to the low reactivity of oxazolinium ion

intermediates. The feasibility that oxazolinium ions are not

reactive intermediates in Tf₂NH-promoted reactions with 2-

acetamido-2-deoxyglycosyl diethyl phosphites is suggested by

the following: (1) the reaction occurred at −78 °C and (2)

prolonged reaction times had no eﬀect on the yield of

disaccharides (eq 2). To validate this speculation, we ﬁrst

yield, %

b

c

entry donor acceptor time (h) product condition A condition B

d

e

1

2

9a

20

21

22

23

24

25

26

27

28

21

22

1

29

30

31

32

33

34

35

36

37

38

39

80

83

89

79

65

57

0

92

78

64

44

−

3

9a

1

4

9a

1

5

9a

1

6

9a

1

7

9a

1

0

−

f

g

8

11a

11c

1

81

79

d

e

9

1

74

67

59

71

10

11

24

70

59

a

b

The reaction was carried out on a 0.1 mmol scale. Condition A:

donor/acceptor/Tf₂NH molar ratio = 1.0/2.0/1.1 unless otherwise

c

noted. Condition B: donor/acceptor/Tf₂NH molar ratio = 2.0/1.0/

d

2.2 unless otherwise noted. Donor/acceptor/Tf₂NH molar ratio =

e

1.0/1.5/1.1. Donor/acceptor/Tf₂NH molar ratio = 1.5/1.0/1.7.

f

g

Donor/acceptor/Tf₂NH molar ratio = 1.0/1.1/1.1. Donor/accept-

or/Tf₂NH molar ratio = 1.1/1.0/1.2.

attempted glycosylation of alcohol 13 with oxazoline 15 in the

presence of Tf₂NH in CH₂Cl₂, but desired disaccharide 14 was

not formed even at −10 °C (eq 3).⁴⁸To monitor the formation

of the oxazolinium ion species, ¹H NMR spectra were recorded

expected, glycosylations of reactive primary alcohols such as

linker 20 and 6-O-unprotected galactoside 21 gave the

Figure 1. Acceptor alcohols and products in Table 6.

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Figure 2. Protonation of oxazoline 15 monitored by ¹H NMR in CD₂Cl₂: (a) oxazoline 15 at 23 °C; (b) 23 °C, after addition of Tf₂NH (1.5 equiv);

(c) oxazoline 15 at −60 °C; (d) −60 °C, after addition of Tf₂NH (1.5 equiv).

Table 7. Eﬀects of Leaving Group and Anomeric Conﬁguration

donor

X

promoter

a

entry

Y

equiv

time (h)

ratio 14:15

yield of 14 (%)

1

2

3

4

5

6

9a

40

41

42

OP(OEt)₂

OC(NH)CCl₃

SPh

H

Tf₂NH

1.1

0.5

0.2

1.1

1

4.1:1

1.5:1

2.6:1

2.0:1

0.6:1

0.2:1

73

50

56

45

37

16

H

0.5

40

18

6

H

NIS/Tf₂NH

H

SPh

a

1

Determined by 500 MHz H NMR.

in CD₂Cl₂before and after the addition of a 50% excess of

Tf₂NH (Figure 2). Inspection of the spectra unambiguously

revealed a downﬁeld shift of the resonances of H-1, H-2, and

CH₃, which are positioned close to the nitrogen atom.⁴⁹This

result clearly indicated that, irrespective of the reaction

temperature, oxazoline 15 was protonated to generate the

corresponding oxazolinium ion, decreasing the electron density

of the oxazoline ring.

The fact that the reaction did not proceed through the

common oxazolinium ion intermediate revealed that the

glycoside/oxazoline ratio could be inﬂuenced by the leaving

group and the anomeric conﬁguration of the donor. To provide

evidence, we selected the two representative and most

successful leaving groups in oligosaccharide synthesis, the

trichloroacetimidate⁵⁰and phenylthio groups,⁵¹and prepared

2-acetamido-2-deoxyglucosyl donors 40−42⁵²for the reaction

with alcohol 13 at −78 °C (Table 7). Whereas all attempts to

obtain 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-^D-glucosyl di-

ethyl phosphite met with failure in accord with precedents in

which a β-oriented anomeric leaving group of a 2-acetamido-2-

deoxyglucosyl donor was readily eliminated to form the

corresponding oxazoline derivative,⁵⁴β-thioglycoside 42 could

be safely obtained. The reaction of 2-acetamido-2-deoxy-α-^D-

glucosyl trichloroacetimidate 40 under optimized conditions for

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phosphite 9a was completed within 30 min to give a 1.5:1

mixture of disaccharide 14 and oxazoline 15, from which

disaccharide 14 was obtained in 50% yield after chromato-

graphic separation (entry 2). Interestingly, in contrast to the

phosphite method, the chemical yield of disaccharide 14 was

somewhat improved (50% → 56%) by a decrease in the

amount of Tf₂NH (1.1 → 0.5 equiv), although the reason is not

clear at present (entries 2 vs 3). It is also noteworthy that

disaccharide 14 was obtained in 45% yield even with the aid of

0.2 equiv of Tf₂NH (entry 4). For the glycosylation with

thioglycosides, the eﬀectiveness of the combinational use of

NIS and an acid was documented by van Boom and co-

workers.⁵⁵In order to preclude the counterion eﬀect, the NIS/

Tf₂NH system was chosen for activation of thioglycosides 41

and 42 (entries 5 and 6). Glycosylation with α-thioglycoside 41

in CH₂Cl₂at −78 °C required 18 h to reach completion,

whereas the reaction time was decreased to 6 h under identical

conditions when using β-thioglycoside 42. The diﬀerence in

reaction rate is a consequence of both the intramolecular

assistance of the neighboring acetamido group for elimination

of the β-oriented leaving group and the stability of the donor

stemming from the anomeric eﬀect. The intramolecular

assistance also facilitated formation of the oxazolinium ion,

thus leading to preferential production of oxazoline 15 from β-

thioglycoside 42. On the basis of these results, we concluded

that the oxazolinium ion formed from these donors is not

responsible for the glycosylation at a low temperature. These

experiments also indicate that the donors 40 and 41 have the

potential to be attractive alternatives to the phosphite 9a,

although the reaction conditions need to be optimized.

proposal seems to be supported by the predominant formation

of α-mannoside 52 from thioglycoside 49 (eq 6).⁶⁰On the

basis of these reports, we propose plausible reaction pathways

for the Tf₂NH-promoted glycosylation with 2-acetamido-2-

deoxyglycosyl diethyl phosphites (Scheme 2).

Upon activation by protonation of the phosphorus atom,⁶¹

diethyl phosphite is eliminated to generate an equilibrium

mixture of CIPs 6α and 6β, solvent-separated ion pair (SSIP)

55, and glycosyl triﬂimides 7α and 7β, whose equilibrium

would heavily lie to α-glycosyl triﬂimide 7α on kinetic and

thermodynamic grounds.⁶²The β-glycosyl triﬂimide 7β

smoothly undergoes an intramolecular nucleophilic substitution

by the adjacent acetamido group, resulting in the exclusive

formation of oxazoline 3 through oxazolinium ion 2. In

contrast, α-CIP 6α and/or α-glycosyl triﬂimide 7α would

undergo nucleophilic attack by acceptor alcohols at the

anomeric carbon from the β-face to provide β-glycosides 5

(path a). However, once the counterion is separated from 6α

and 7α, the acetamido oxygen atom can access the electrophilic

anomeric carbon along the stereoelectronically favored axial

direction to generate short-lived intermediate 57 as mentioned

by the Yamago group. Although the intramolecular reaction

that gives oxazoline 3 via oxazolinium ion 2 is energetically

favored compared to the intermolecular process, the possibility

of nucleophilic attack of acceptor alcohols from the less

hindered β-face of 57 leading to the formation of β-glycosides 5

cannot be excluded (path b). The fact that α-glycosides have

not been obtained reveals that the α-face of SSIP is completely

shielded by the acetamido group. S_N2-like displacement of

protonated phosphite 54 with acceptor alcohols is also a

conceivable pathway for the formation of β-glycosides 5 (path

c).

In 1997, Crich and Sun revealed on the basis of NMR

experiments that glycosyl triﬂates are cleanly generated from

the corresponding glycosyl sulfoxides even with participating

protecting groups at O-2 when treated with Tf₂O in the

presence of 2,6-di-tert-butyl-4-methylpyridine (DTBMP, eq

4).⁵⁶Stimulated by the pioneering work of Crich, considerable

While glycosyl triﬂates and triﬂimides with participating

protecting groups at O-2 were cleanly generated as shown in

eqs 4−6, predominant formation of 1,2-trans-glycosides was

observed in all cases. Therefore, it is not clear from these

precedents whether the glycosyl triﬂates/triﬂimides are actual

reactive species in glycosylation reactions, because nucleophilic

substitution of α-CIP, α-glycosyl triﬂate/triﬂimide, or short-

lived ionic intermediate resulting from neighboring group

participation provides β-glycosides in the gluco/galacto series.

Since intermediates are prone to oxazoline formation and are

labile and NMR experiments were therefore precluded in our

case,⁶³we decided to investigate the reactions with 2-

acetamido-2-deoxy-1-thiomannosides 58 and 59 in order to

gain an insight into the reaction pathways for glycosylation with

2-acetamido-2-deoxyglycosyl donors.⁶⁴

The preparation of thioglycosides 58 and 59 began with

phosphorylation of 2-azido-2-deoxymannose 60 (Scheme 3).⁶⁵

Reaction of diphenyl phosphate 61 with thiophenol in the

presence of BF₃·OEt₂followed by chromatographic separation

gave thioglycosides 62 and 63 in 25% and 67% yields,

respectively. A two-step sequence involving reduction of the

azido group with Ph₃P in aq THF and acetylation furnished

thioglycosides 58 and 59 in 75% and 80% yields, respectively.

Consistent with the general trend,^45dmannosyl donors 58

and 59 are less reactive than are glucosyl donors 41 and 42;

donors 58 and 59 are unreactive toward NIS/Tf₂NH at −78 °C

and were activated upon raising the temperature to −60 °C.

While oxazoline 66 was obtained as a major product

irrespective of the anomeric conﬁguration of the donor, a

mixture of disaccharides 64 and 65 was obtained in ca. 20%

yield by the reaction with 6-O-unprotected glycoside alcohol

eﬀorts have been devoted to clarify the mechanism of chemical

glycosylation reactions.⁵⁷Very recently, Crich, Pratt, and co-

workers suggested on the basis of computed and experimentally

determined primary ¹³C kinetic isotope eﬀect values that β-

glucoside formation occurs by an associative mechanism in

which the incoming alcohols displace the leaving group from α-

glucosyl triﬂates and/or α-contact ion pair (α-CIP).⁵⁸With

regard to the glycosylation with a participating group at O-2,

Yamago and co-workers proposed that glycosyl triﬂates exist in

equilibrium through neighboring group participation with

short-lived ionic intermediates, which react with alcohols

from the less hindered side to give 1,2-trans-glycosides, since

they monitored the formation of 2-deoxy-2-phthalimido-β-

glucosyl triﬂimide 46 from thioglycoside 45 (eq 5).⁵⁹This

G

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The Journal of Organic Chemistry

Article

Scheme 2. Plausible Mechanism of Tf₂NH-Promoted Glycosylation with 2-Acetamido-2-deoxyglycosyl Diethyl Phosphites at a

Low Temperature

Scheme 3. Preparation and Glycosidation of 2-Acetamido-2-deoxy-1-thiomannosides 58 and 59

13. On the basis of the literature precedents,^51a2-acetamido-2-

deoxymannosyl triﬂimide 70α would be formed through α-CIP

68α and/or SSIP 69 upon exposure of donors 58 and 59 to the

promoter (Scheme 4). Since both the anomeric eﬀect and the

steric repulsion between the acetamido group disposed axially

at C-2 and an incoming alcohol uniformly favor the formation

of α-mannosidic linkages, the formation of thermodynamically

less stable β-glycoside 65 unambiguously indicates an

associative S_N2-like mechanism, wherein α-CIP 68α and/or

α-glycosyl triﬂimide 70α undergo nucleophilic attack of

acceptor alcohols. To the best of our knowledge, this result is

the ﬁrst example that provides experimental evidence for the

S_N2-like displacement of glycosyl triﬂates/triﬂimides in a

system capable of neighboring group participation. However,

participation of the adjacent acetamido group in species 68α

and 70α that leads to the formation of oxazoline 66 competes

with the intermolecular process, resulting in low conversion to

β-linked disaccharide 65. Due to the steric reason, it is unlikely

H

DOI: 10.1021/acs.joc.5b00138

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The Journal of Organic Chemistry

Article

Scheme 4. Plausible Mechanism of the Reaction with 2-Acetamido-2-deoxymannosyl Donors 58 and 59

that β-CIP 68β and β-triﬂimide 70β exist in the reaction

mixture. Therefore, the formation of α-glycoside 64 would be

attributed to nucleophilic attack from the less hindered face of

SSIP 69 (path a) as reported by the Crich group for α-

mannoside formation.^58,66While participation of the acetamido

group in SSIP 69 leads to the formation of oxazoline 66 via 72,

access of the oxygen atom from the stereoelectronically

unstabilized equatorial orientation permits the formation of

α-glycoside 64 from SSIP 69, albeit in low yield. This result is

in stark contrast to the GlcNAc/GalNAc series, in which α-

glycosides have never been obtained from SSIP 55.

Nucleophilic attack of acceptor alcohol 13 on transient species

72 to give α-glycoside 64 would be disfavored for steric and

electronic reasons (path b).

Because of the alignment of the acetamido group anti to the

leaving group, α-thioglycoside 58 underwent cyclization (67α

→ 66) more easily to give oxazoline 66 than was the case for β-

isomer 59. The slightly higher α-selectivity observed with β-

thioglycoside 59 would be a result of the backside attack of

alcohol 13 on 67β (path c). From these results, we conclude

that the success of glycosylations at a low temperature is due to

the rate retardation of oxazolinium ion formation from α-

glycosyl triﬂimides and α-CIPs, thereby enabling these

intermediates to react with acceptor alcohols.

glycosides. A wide range of glycosyl acceptors, including allyl

alcohols and some secondary alcohols as well as glycoside

alcohols bearing acid-sensitive acetal or epoxy groups, can be

employed in this coupling. While a limitation was encountered

with less reactive acceptor alcohols, such as 4- or 2-O-

unprotected glucosides, these results indicate the feasibility of

regioselective glycosylation of polyols. The glycosyl donor is

not conﬁned to highly reactive per-O-benzyl-protected 2-

acetamido-2-deoxyglucosyl and galactosyl diethyl phosphites,

and the scope of this reaction is extended to include less

reactive per-O-acetyl-protected 2-acetamido-2-deoxyglycosyl

diethyl phosphites and 4,6-O-benzylidene-protected galactosyl

diethyl phosphite as donors. The use of 2-acetamido-2-

deoxyglucosyl trichloroacetimidate or the corresponding

thioglycoside clearly revealed that the same coupling could be

realized with these donors, though glycosylations with 2-

acetamido-2-deoxyglycosyl donors have never been performed

at temperatures below 0 °C.

Although the lability of intermediates precludes their direct

detection by NMR, some experiments provide strong evidence

that the corresponding oxazolinium ions are not responsible for

the reaction. On the basis of the literature reports by the groups

of Crich and Yamago, we propose a plausible reaction

mechanism in which β-glycosides are formed by S_N2-like

displacement of α-glycosyl triﬂimides and/or nucleophilic

attack from the less hindered face of α-CIP. The fact that the

acetamido group capable of anchimeric assistance behaves as a

nonparticipating group in the present glycosylation was

supported by the formation of a mixture of α- and β-

mannosides from 2-acetamido-2-deoxythiomannosides. The

reaction at a low temperature led to the rate retardation of

oxazolinium ion formation from α-glycosyl triﬂimides and α-

CIPs through their β-counterparts or SSIPs, thereby enabling

these intermediates to react with acceptor alcohols.

CONCLUSION

■

A direct construction of 1,2-trans-β-linked 2-acetamido-2-

deoxyglycosides using 2-acetamido-2-deoxyglycosyl donors

has been documented. Tf₂NH was found to be the promoter

of choice for activation of diethyl phosphite donors, aﬀording

the corresponding β-glycosides in good to high yields with

complete stereoselectivity, albeit by the use of either a donor or

acceptor in 2-fold excess in most cases. It is noteworthy that

lowering the reaction temperature increased the yields of

I

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The Journal of Organic Chemistry

Article

Calcd for C₂₆H₃₄NO₈P: C, 60.11; H, 6.60; N, 2.70. Found: C, 60.00;

H, 6.57; N, 2.65.

To the best of our knowledge, this protocol represents the

ﬁrst example of glycosylation with 2-acetamido-2-deoxyglycosyl

donors that does not proceed through the corresponding

oxazolinium ion intermediate. In the following article, we

describe the stereoselective synthesis of the tetrasaccharide

repeating unit of the polymeric O antigen isolated from

Acinetobacter baumannii serogroup O18 to demonstrate the

synthetic utility of the present method.

2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-^D-glucopyranosyl

Diethyl Phosphite (9c). The reaction was performed according to

the typical procedure with hemiacetal 8c (508 mg, 1.46 mmol), Et₃N

(0.61 mL, 4.38 mmol), diethyl chlorophosphite (0.26 mL, 1.83 mmol),

and CH₂Cl₂(10 mL). The crude product (743 mg, slightly yellow

amorphous) was puriﬁed by column chromatography (Wako gel 14 g,

2:1 AcOEt/n-hexane with 3% Et₃N) to give diethyl phosphite 9c (610

mg, 89%) as a colorless amorphous. R_f0.39 (1:2 n-hexane/AcOEt,

19

with Et₃N-doped silica gel plate); [α]_D+86.3 (c 1.05, CHCl₃); IR

EXPERIMENTAL SECTION

■

(Nujol) 3474, 3240, 1744, 1640, 1559, 1292, 1223, 1126, 1031, 922,

1

831 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 1.29 (t, J = 7.0 Hz, 3H),

Typical Procedure for Preparation of 2-Acetamido-2-

deoxyglycopyranosyl Diethyl Phosphite: 2-Acetamido-3,4,6-

tri-O-benzyl-2-deoxy-α-^D-glucopyranosyl Diethyl Phosphite

(9a). Diethyl chlorophosphite (0.26 mL, 1.78 mmol) was added to a

stirred suspension of hemiacetal 8a (700 mg, 1.42 mmol) and Et₃N

(0.60 mL, 4.26 mmol) in CH₂Cl₂(14 mL) at 0 °C. After 30 min of

stirring, the reaction was quenched with crushed ice, followed by

stirring at room temperature for 10 min. The mixture was poured into

a two-layer mixture of AcOEt (15 mL) and saturated aqueous

NaHCO₃(10 mL), and the resulting mixture was extracted with

AcOEt (25 mL). The organic extract was washed with brine (10 mL)

and dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (945 mg, white solid), which was puriﬁed

by column chromatography (Wako gel 20 g, 2:1:1 CH₂Cl₂/AcOEt/n-

hexane with 3% Et₃N) to give diethyl phosphite 9a (778 mg, 90%) as a

white solid. The donors were recrystallized from 4:1 n-hexane/acetone

when possible for the following glycosylation reaction. R_f0.50 (2:1:1

CH₂Cl₂/AcOEt/n-hexane, with Et₃N-doped silica gel plate); mp

108.0−109.0 °C (colorless needles from 4:1 n-hexane/acetone);

1.30 (t, J = 7.0 Hz, 3H), 1.95 (s, 3H), 2.03 (s, 3H), 2.04 (s, 3H), 2.09

(s, 3H), 3.88−3.99 (m, 4H), 4.08 (dd, J = 2.2, 12.3 Hz, 1H), 4.16

(ddd, J = 2.2, 4.4, 9.8 Hz, 1H), 4.24 (dd, J = 4.4, 12.3 Hz, 1H), 4.37

(ddd, J = 3.3, 9.5, 10.4 Hz, 1H), 5.17 (dd, J = 9.8, 10.2 Hz, 1H), 5.24

(dd, J = 10.2, 10.4 Hz, 1H), 5.54 (dd, J = 3.3, 8.1 Hz, 1H), 5.73 (d, J =

9.5 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 16.8 (d, J_C−P= 5.0 Hz),

16.9 (d, J_C−P= 5.2 Hz), 20.5, 20.59, 20.63, 23.0, 52.2 (d, J_C−P= 3.4

Hz), 58.7 (d, J_C−P= 11.1 Hz), 58.8 (d, J_C−P= 11.1 Hz), 61.8, 67.8,

68.1, 68.8, 70.9, 91.8 (d, J_C−P= 13.1 Hz), 169.2, 169.8, 170.6, 171.3;

³¹P NMR (109 MHz, CDCl₃) δ 141.1; HRMS (FAB) m/z [M + H]⁺

calcd for C₁₈H₃₁NO₁₁P 468.1635; found 468.1623. Anal. Calcd for

C₁₈H₃₀NO₁₁P: C, 46.25; H, 6.47; N, 3.00. Found: C, 46.11; H, 6.47;

N, 2.99.

2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-^D-galactopyrano-

syl Diethyl Phosphite (11a). The reaction was performed according

to the typical procedure with hemiacetal 10a (770 mg, 1.57 mmol),

Et₃N (0.66 mL, 4.71 mmol), diethyl chlorophosphite (0.30 mL, 2.04

mmol), and CH₂Cl₂(14 mL). Puriﬁcation by column chromatography

(Wako gel 20 g, 2:1:1 CH₂Cl₂/AcOEt/n-hexane with 3% Et₃N)

aﬀorded diethyl phosphite 11a (778 mg, 90%) as a white solid. R_f0.47

(2:1:1 CH₂Cl₂/AcOEt/n-hexane, with Et₃N-doped silica gel plate);

mp 134.0−135.0 °C (colorless needles from 4:1 n-hexane/acetone);

20

[α]_D+101.1 (c 1.00, CHCl₃); IR (Nujol) 3314, 1642, 1547, 1121,

1065, 1031, 947, 903, 858 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.22

(t, J = 7.1 Hz, 6H), 1.80 (s, 3H), 3.65 (dd, J = 1.7, 10.9 Hz, 1H), 3.70

(dd, J = 9.3, 10.2 Hz, 1H), 3.76−3.89 (m, 6H), 3.97 (m, 1H), 4.25

(ddd, J = 3.3, 9.1, 10.5 Hz, 1H), 4.52 (d, J = 12.1 Hz, 1H), 4.55 (d, J =

10.7 Hz, 1H), 4.63 (d, J = 12.1 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H),

4.83 (d, J = 10.7 Hz, 1H), 4.87 (d, J = 11.7 Hz, 1H), 5.18 (d, J = 9.1

Hz, 1H), 5.48 (dd, J = 3.3, 8.2 Hz, 1H), 7.21 (m, 2H), 7.21−7.34 (m,

13H); ¹³C NMR (126 MHz, CDCl₃) δ 16.7 (d, J_C−P= 5.3 Hz), 16.8

(d, J_C−P= 5.2 Hz), 23.2, 52.7, 58.38 (d, J_C−P= 11.1 Hz), 58.42 (d, J_C−P

= 11.3 Hz), 68.3, 72.0, 73.3, 74.6, 75.0, 78.1, 79.3, 92.7 (d, J = 15.3

Hz), 127.5, 127.6, 127.67, 127.73, 127.8, 127.9, 128.2, 128.27, 128.33,

128.4, 137.9, 138.3, 169.6; ³¹P NMR (109 MHz, CDCl₃) δ 141.5;

HRMS (FAB) m/z [M + H]⁺calcd for C₃₃H₄₃NO₈P 612.2726; found

612.2749. Anal. Calcd for C₃₃H₄₂NO₈P: C, 64.80; H, 6.92; N, 2.29.

Found: C, 64.81; H, 6.96; N, 2.19.

23

[α]_D+102.8 (c 1.00, CHCl₃); IR (Nujol) 3314, 1641, 1539, 1305,

1167, 1124, 1103, 1028, 936, 893 cm⁻¹; ¹H NMR (500 MHz, CDCl₃;

spectrum contains a mixture of rotamers, only the major rotamer

signals are reported) δ 1.17 (t, J = 7.2 Hz, 6H), 1.87 (s, 3H), 3.51 (dd,

J = 5.5, 9.2 Hz, 1H), 3.60 (dd, J = 2.5, 11.0 Hz, 1H), 3.62 (dd, J = 7.5,

9.2 Hz, 1H), 3.70−3.85 (m, 4H), 4.04 (br s, 1H), 4.07 (m, 1H), 4.41

(d, J = 11.6 Hz, 1H), 4.42 (d, J = 12.3 Hz, 1H), 4.45 (d, J = 11.6 Hz,

1H), 4.58 (d, J = 11.6 Hz, 1H), 4.68 (ddd, J = 3.5, 8.7, 11.0 Hz, 1H),

4.72 (d, J = 12.3 Hz, 1H), 4.94 (d, J = 11.6 Hz, 1H), 5.17 (d, J = 8.7

Hz, 1H), 5.54 (dd, J = 3.5, 8.0 Hz, 1H), 7.23−7.34 (m, 15H); ¹³C

NMR (126 MHz, CDCl₃; spectrum contains a mixture of rotamers,

only the major rotamer signals are reported) δ 16.7 (d, J_C−P= 4.9 Hz),

2-Acetamido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α-^D-

glucopyranosyl Diethyl Phosphite (9b). The reaction was

performed according to the typical procedure with hemiacetal 8b

(388 mg, 0.97 mmol), Et₃N (0.41 mL, 2.91 mmol), diethyl

chlorophosphite (0.17 mL, 1.17 mmol), and CH₂Cl₂(15 mL). The

crude product was puriﬁed by column chromatography (Wako gel 12

g, 5:2:2 CH₂Cl₂/AcOEt/n-hexane with 3% Et₃N) to give the

corresponding diethyl phosphite (426 mg) as a white solid, which

was recrystallized from 4:1 n-hexane/acetone (10 mL) to give α-linked

diethyl phosphite 9b (335 mg, 66%) as colorless needles. R_f0.35 (10:1

16.9 (d, J_C−P= 4.9 Hz), 23.3, 49.1 (d, J_C−P= 3.7 Hz), 58.3 (d, J_C−P

=

11.7 Hz), 58.4 (d, J_C−P= 11.7 Hz), 68.6, 70.6, 71.1, 72.3, 73.4, 74.5,

76.3, 93.0 (d, J_C−P= 15.5 Hz), 127.5, 127.7, 127.81, 127.84, 127.9,

128.0, 128.2, 128.3, 128.4, 137.8, 138.0, 138.4, 169.7; ³¹P NMR (109

MHz, CDCl₃) δ 142.1; HRMS (ESI) m/z [M + Na]⁺calcd for

C₃₃H₄₂NO₈PNa 634.2546; found 634.2547. Anal. Calcd for

C₃₃H₄₂NO₈P: C, 64.80; H, 6.92; N, 2.29. Found: C, 64.60; H, 6.72;

N, 2.35.

2-Acetamido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α-^D-

galactopyranosyl Diethyl Phosphite (11b). The reaction was

performed according to the typical procedure with hemiacetal 10b

(218.5 mg, 0.547 mmol), Et₃N (0.23 mL, 1.64 mmol), diethyl

chlorophosphite (95 μL, 0.656 mmol), and CH₂Cl₂(5 mL).

Puriﬁcation by column chromatography (Wako gel 9 g, 4:1:1

CH₂Cl₂/AcOEt/n-hexane with 2% Et₃N) aﬀorded the corresponding

diethyl phosphite (243.8 mg) as a white solid, which was recrystallized

from 4:1 n-hexane/acetone (5 mL) to give α-linked diethyl phosphite

11b (216 mg, 76%) as colorless needles. R_f0.31 (10:1 CH₂Cl₂/

23

CH₂Cl₂/acetone); mp 179.0−179.5 °C; [α]_D+112.2 (c 1.00,

CHCl₃); IR (KBr) 3314, 1648, 1551, 1371, 1128, 1089, 1029 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 1.24 (t, J = 7.4 Hz, 3H), 1.26 (t, J =

7.4 Hz, 3H), 1.89 (s, 3H), 3.72 (t, J = 9.7 Hz, 1H), 3.75−3.91 (m,

6H), 4.02 (m, 1H), 4.26 (dd, J = 4.6, 10.3 Hz, 1H), 4.29 (m, 1H), 4.65

(d, J = 12.6 Hz, 1H), 4.93 (d, J = 12.6 Hz, 1H), 5.27 (d, J = 8.6 Hz,

1H), 5.49 (dd, J = 3.4, 8.0 Hz, 1H), 5.61 (s, 1H), 7.27−7.42 (m, 8H),

7.52 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 16.8 (d, J_C−P= 4.8 Hz),

23

16.9 (d, J_C−P= 4.8 Hz), 23.2, 52.7 (d, J_C−P= 3.6 Hz), 58.5 (d, J_C−P

=

acetone); mp 147.5−148.0 °C; [α]_D+157.0 (c 1.00, CHCl₃); IR

12.0 Hz), 58.6 (d, J_C−P= 12.0 Hz), 63.7, 68.8, 73.9, 75.2, 82.4, 92.9 (d,

J_C−P= 15.6 Hz), 101.2, 125.9, 127.7, 128.1, 128.2, 128.3, 128.9, 137.2,

138.4, 169.7; ³¹P NMR (202 MHz, CDCl₃) δ 142.1; HRMS (ESI) m/z

[M + H]⁺calcd for C₂₆H₃₅NO₈P 520.2100; found 520.2104. Anal.

(KBr) 3318, 1653, 1546, 1368, 1100, 1029 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃; spectrum contains a 10:1 mixture of rotamers, * denotes

minor rotamer signals) δ 1.24 (t, J = 7.5 Hz, 3H), 1.25 (t, J = 7.0 Hz,

3H), *1.26 (t, J = 7.0 Hz, 3H), *1.28 (t, J = 7.0 Hz, 3H), 1.91 (s, 3H),

J

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The Journal of Organic Chemistry

Article

*2.09 (s, 3H), *3.70 (dd, J = 3.4, 10.9 Hz, 1H), 3.76 (dd, J = 3.4, 10.9

Hz, 1H), 3.78−3.94 (m, 5H), 4.05 (dd, J = 2.0, 12.5 Hz, 1H), *4.10

(m, 1H), 4.23 (dd, J = 1.5, 12.5 Hz, 1H), *4.27 (br d, J = 3.4 Hz, 1H),

4.32 (br d, J = 3.4 Hz, 1H), 4.57 (d, J = 12.5 Hz, 1H), *4.62 (d, J =

12.5 Hz, 1H), 4.70 (ddd, J = 3.4, 8.6, 10.9 Hz, 1H), *4.72 (d, J = 12.5

Hz, 1H), 4.75 (d, J = 12.5 Hz, 1H), 5.27 (d, J = 8.6 Hz, 1H), *5.45 (d,

J = 8.6 Hz, 1H), 5.52 (s, 1H), *5.54 (s, 1H), *5.63 (dd, J = 3.4, 8.0 Hz,

1H), 5.75 (dd, J = 3.4, 8.0 Hz, 1H), 7.28−7.39 (m, 8H), 7.53 (m, 2H);

¹³C NMR (126 MHz, CDCl₃; spectrum contains a mixture of

rotamers, * denotes minor rotamer signals) δ 16.7 (d, J_C−P= 6.0 Hz),

16.8 (d, J_C−P= 6.0 Hz), *20.9, 23.2, 48.4 (d, J_C−P= 3.6 Hz), *52.5 (d,

J_C−P= 4.8 Hz), 58.3 (d, J_C−P= 3.6 Hz), 58.4 (d, J_C−P= 2.4 Hz), *58.6

(d, J_C−P= 12.0 Hz), *58.9 (d, J_C−P= 12.0 Hz), 63.7, *63.8, 69.2, 70.4,

*71.1, *71.4, *72.2, 72.7, 73.3, *75.0, 93.2 (d, J_C−P= 14.4 Hz), *93.4

(d, J_C−P= 13.2 Hz), *100.5, 100.8, *125.9, 126.2, *127.5, *127.7,

127.76, 127.78, 127.98, *128.01, 128.3, 128.8, 137.5, *137.6, 138.1,

169.7, *173.4; ³¹P NMR (202.5 MHz, CDCl₃; spectrum contains a

mixture of rotamers, * denotes minor rotamer signals) δ *142.3, 142.8;

HRMS (FAB) m/z [M + H]⁺calcd for C₂₆H₃₅NO₈P 520.2100; found

520.2094. Anal. Calcd for C₂₆H₃₄NO₈P: C, 60.11; H, 6.60; N, 2.70.

Found: C, 60.16; H, 6.62; N, 2.69.

C₆D₆) δ 23.3, 36.48, 36.51, 53.6 (d, J_C−P= 4.8 Hz), 69.4, 73.4, 73.9,

74.8, 75.2, 78.5, 80.2, 95.8 (d, J_C−P= 3.8 Hz), 127.76, 127.83, 128.1,

128.2, 128.4, 128.51, 128.55, 138.8, 139.0, 139.2, 170.0; ³¹P NMR

(109 MHz, CDCl₃) δ 18.5; HRMS (FAB) m/z [M + H]⁺calcd for

C₃₃H₄₅N₃O₇P 626.2995; found 626.2989.

Typical Procedure for Glycosylation with 2-Acetamido-2-

deoxyglycopyranosyl Diethyl Phosphite: Methyl 6-O-(2-Acet-

amido-3,4,6-tri-O-benzyl-2-deoxy-β-^D-glucopyranosyl)-2,3,4-

tri-O-benzyl-α-^D-glucopyranoside (14).^22cA 1.0 M solution of

Tf₂NH in EtCN (0.11 mL, 0.11 mmol) was added to a cooled (−78

°C) mixture of diethyl phosphite 9a (61.2 mg, 0.10 mmol), 6-O-

unprotected glucoside 13 (51.2 mg, 0.11 mmol) and pulverized 4 Å

molecular sieves (61.2 mg) in CH₂Cl₂(1.0 mL). After 1 h of stirring at

this temperature, the reaction was quenched with Et₃N (0.15 mL).

The mixture was diluted with AcOEt (5 mL) and passed through a

Celite pad. The ﬁltrate was partitioned between AcOEt (15 mL) and

saturated aqueous NaHCO₃(6 mL). The organic layer was washed

with brine (6 mL), and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the crude products (138.5 mg), whose

ratio was determined to be 4.1:1 by 500 MHz ¹H NMR spectroscopic

analysis. For easy puriﬁcation, a solution of the crude mixture in

AcOEt (10 mL) and CH₂Cl₂(2 mL) was vigorously stirred with 10%

aqueous HCl (2 mL) for 10 min, during which time the oxazoline 15

was completely hydrolyzed to form the corresponding hemiacetal 8a.

The resulting mixture was extracted with AcOEt (6 mL), and the

organic extract was successively washed with saturated aqueous

NaHCO₃(6 mL) and brine (6 mL), and dried over anhydrous

Na₂SO₄. Filtration and evaporation in vacuo followed by ﬂash column

chromatography (silica gel 20 g, 7:1 toluene/acetone) aﬀorded β-

linked disaccharide 14 (68.0 mg, 73%) as a white solid. R_f0.28 (5:1

2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-^D-galactopyrano-

syl Diethyl Phosphite (11c). The reaction was performed according

to the typical procedure with hemiacetal 10c (500 mg, 1.44 mmol),

Et₃N (0.60 mL, 4.32 mmol), diethyl chlorophosphite (0.27 mL, 1.87

mmol), and CH₂Cl₂(10 mL). The crude product (725 mg, slightly

yellow amorphous) was puriﬁed by column chromatography (Wako

gel 12 g, 2:1 AcOEt/n-hexane with 3% Et₃N) to give diethyl phosphite

11c (588 mg, 87%) as a colorless amorphous. R_f0.34 (2:1 AcOEt/n-

19

hexane, with Et₃N-doped silica gel plate); [α]_D+99.5 (c 1.00,

toluene/acetone); mp 190.0−190.5 °C (lit.^22c209−211 °C); [α]_D

24

CHCl₃); IR (Nujol) 3348, 1746, 1723, 1671, 1539, 1277, 1244, 1167,

1125, 1024, 912, 842 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.29 (t, J =

7.0 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H), 1.96 (s, 3H), 2.01 (s, 3H), 2.04

(s, 3H), 2.17 (s, 3H), 3.90−3.99 (m, 4H), 4.06 (dd, J = 6.8, 11.3 Hz,

1H), 4.13 (dd, J = 6.2, 11.3 Hz, 1H), 4.35 (dd, J = 6.2, 6.8 Hz, 1H),

4.62 (ddd, J = 3.5, 9.6, 11.3 Hz, 1H), 5.20 (dd, J = 3.2, 11.3 Hz, 1H),

5.41 (br d, J = 3.2 Hz, 1H), 5.58 (dd, J = 3.5, 8.0 Hz, 1H), 5.61 (d, J =

9.6 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 16.7 (d, J_C−P= 5.3 Hz),

16.8 (d, J_C−P= 5.4 Hz), 20.5, 20.57, 20.62, 23.1, 48.0 (d, J_C−P= 3.9

Hz), 58.6 (d, J_C−P= 11.2 Hz), 58.7 (d, J_C−P= 12.4 Hz), 61.7, 67.1,

67.6, 68.0, 92.4 (d, J_C−P= 13.2 Hz), 170.0, 170.16, 170.22, 170.8; ³¹P

NMR (109 MHz, CDCl₃) δ 141.2: HRMS (FAB) m/z [M + H]⁺calcd

for C₁₈H₃₁NO₁₁P 468.1635; found 468.1649. Anal. Calcd for

C₁₈H₃₀NO₁₁P: C, 46.25; H, 6.47; N, 3.00. Found: C, 46.09; H,

6.39; N, 3.01.

+22.4 (c 1.00, CHCl₃) [lit.^22c+23.6 (c 1.56, CHCl₃)]; IR (Nujol)

1

3279, 3029, 1655, 1564, 1155, 1092, 1067, 949, 912 cm⁻¹; H NMR

(500 MHz, CDCl₃) δ 1.70 (s, 3H), 3.34 (s, 3H), 3.44 (m, 1H), 3.50

(dd, J = 3.7, 9.3 Hz, 1H), 3.52 (t, J = 9.3 Hz, 1H), 3.59−3.61 (m, 2H),

3.66−3.77 (m, 4H), 3.97 (t, J = 9.3 Hz, 1H), 4.06−4.12 (m, 2H), 4.50

(d, J = 12.1 Hz, 1H), 4.55 (d, J = 11.6 Hz, 1H), 4.56 (d, J = 10.8 Hz,

1H), 4.57 (d, J = 10.8 Hz, 1H), 4.59 (d, J = 3.7 Hz, 1H), 4.62 (d, J =

11.6 Hz, 1H), 4.64 (d, J = 12.1 Hz, 1H), 4.76 (d, J = 11.6 Hz, 2H),

4.80 (d, J = 11.6 Hz, 1H), 4.81 (d, J = 11.0 Hz, 1H), 4.80−4.84 (m,

2H), 4.97 (d, J = 11.0 Hz, 1H), 5.44 (d, J = 7.7 Hz, 1H), 7.20 (m, 2H),

7.25−7.35 (m, 28H); ¹³C NMR (100 MHz, CDCl₃) δ 23.5, 55.0, 56.7,

67.3, 69.0, 69.5, 73.2, 74.4, 74.5, 74.6, 74.8, 75.6, 77.5, 78.6, 79.6, 80.1,

81.9, 97.9, 99.7, 127.35, 127.40, 127.5, 127.58, 127.61, 127.64, 127.67,

127.72, 127.8, 128.0, 128.05, 128.14, 128.2, 128.25, 128.27, 128.30,

137.8, 137.95, 138.03, 138.1, 138.2, 138.6, 169.9.

2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-^D-glucopyrano-

syl N,N,N′,N′-Tetramethylphosphorodiamidate (12). n-BuLi in

n-hexane (1.56 M, 0.82 mL, 1.28 mmol) was added to a cooled (−78

°C) suspension of hemiacetal 8a (600 mg, 1.22 mmol) in 12:1 THF/

HMPA (19.5 mL). After 15 min of stirring, bis(dimethylamino)-

phosphoryl chloride (0.18 mL, 1.16 mmol) was added, and the

reaction mixture was allowed to warm to −23 °C over 30 min. After

1.5 h of stirring at this temperature, the reaction was quenched with

crushed ice, followed by stirring at 0 °C for 15 min. The mixture was

partitioned between AcOEt (50 mL) and saturated aqueous NaHCO₃

(15 mL), and the organic layer was washed with brine (2 × 15 mL)

and dried over anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (950 mg), which was puriﬁed by ﬂash

column chromatography (silica gel 30 g, 3:2 → 1:3 CH₂Cl₂/acetone)

to give phosphorodiamidate 12 (633 mg, 83%) as a colorless

Methyl 6-O-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-^D-

galactopyranosyl)-2,3,4-tri-O-benzyl-α-^D-glucopyranoside

(16). The glycosylation was performed according to the typical

procedure employing diethyl phosphite 11a (61.2 mg, 0.10 mmol), 6-

O-unprotected glucoside 13 (92.9 mg, 0.20 mmol), pulverized 4 Å

molecular sieves (61.2 mg), and Tf₂NH (1.0 M in EtCN, 0.11 mL,

0.11 mmol). β-Linked disaccharide 16 (78.2 mg, 83%) was obtained as

a white solid from the crude product (186.0 mg) after column

chromatography (silica gel 18 g, 5:1 toluene/acetone). When the

glycosylation was performed employing diethyl phosphite 11a (122.3

mg, 0.20 mmol), 6-O-unprotected glucoside 13 (46.5 mg, 0.10 mmol),

pulverized 4 Å molecular sieves (61.2 mg), and Tf₂NH (1.0 M in

EtCN, 0.22 mL, 0.22 mmol), disaccharide 16 (81.4 mg, 87%) was

obtained as a white solid from the crude product (234.0 mg) after

column chromatography (silica gel 18 g, 5:1 toluene/acetone). R_f0.50

(3:1 toluene/acetone); mp 198.5−199.5 °C (colorless needles from

22

amorphous. R_f0.37 (2:3 CH₂Cl₂/acetone); [α]_D+54.0 (c 1.00,

1

CHCl₃); IR (Nujol) 3304, 1678, 1547, 1226 cm⁻¹; H NMR (400

24

CH₂Cl₂/n-hexane); [α]_D+19.1 (c 1.00, CHCl₃); IR (Nujol) 3295,

MHz, CDCl₃) δ 1.91 (s, 3H), 2.59 (s, 3H), 2.62 (s, 3H), 2.64 (s, 3H),

2.67 (s, 3H), 3.67 (dd, J = 1.8, 10.9 Hz, 1H), 3.72 (dd, J = 9.5, 10.6

Hz, 1H), 3.77 (dd, J = 3.6, 10.9 Hz, 1H), 3.83 (t, J = 9.5 Hz, 1H), 3.97

(ddd, J = 1.8, 3.6, 9.5 Hz, 1H), 4.35 (ddd, J = 2.9, 9.1, 10.6 Hz, 1H),

4.49 (d, J = 11.8 Hz, 1H), 4.53 (d, J = 10.9 Hz, 1H), 4.62 (d, J = 11.8

Hz, 1H), 4.69 (d, J = 11.3 Hz, 1H), 4.836 (d, J = 11.3 Hz, 1H), 4.842

(d, J = 10.9 Hz, 1H), 5.43 (dd, J = 2.9, 7.5 Hz, 1H), 6.32 (d, J = 9.1

Hz, 1H), 7.19 (m, 2H), 7.26−7.33 (m, 13H); ¹³C NMR (100 MHz,

1

3063, 3028, 1651, 1556, 1496, 1310, 1209, 1063, 910 cm⁻¹; H NMR

(500 MHz, CDCl₃) δ 1.78 (s, 3H), 3.33 (s, 3H), 3.49−3.67 (m, 6H),

3.70−3.73 (m, 2H), 3.95−3.98 (m, 2H), 4.04 (m, 1H), 4.33 (dd, J =

2.4, 10.9 Hz, 1H), 4.41 (d, J = 11.8 Hz, 1H), 4.45 (d, J = 11.8 Hz, 1H),

4.46 (d, J = 11.4 Hz, 1H), 4.54 (d, J = 11.2 Hz, 1H), 4.56 (d, J = 10.9

Hz, 1H), 4.59 (d, J = 3.3 Hz, 1H), 4.64 (d, J = 12.2 Hz, 1H), 4.65 (d, J

= 11.2 Hz, 1H), 4.76 (d, J = 12.2 Hz, 1H), 4.81 (d, J = 10.9 Hz, 2H),

K

DOI: 10.1021/acs.joc.5b00138

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

4.86 (d, J = 11.4 Hz, 1H), 4.96 (d, J = 10.9 Hz, 1H), 4.99 (d, J = 8.4

Hz, 1H), 5.52 (d, J = 7.2 Hz, 1H), 7.24−7.34 (m, 30H); ¹³C NMR

(126 MHz, CDCl₃) δ 23.8, 54.9, 55.1, 67.1, 68.5, 69.6, 72.3, 72.7,

73.27, 73.34, 73.4, 74.6, 74.8, 75.8, 77.6, 79.6, 82.0, 97.9, 99.8, 127.4,

127.5, 127.6, 127.7, 127.8, 127.90, 127.94, 128.0, 128.1, 128.29,

128.33, 128.4, 137.8, 137.9, 138.0, 138.1, 138.5, 138.7, 170.5; HRMS

(FAB) m/z [M + H]⁺calcd for C₅₇H₆₄NO₁₁938.4479; found

938.4485. Anal. Calcd for C₅₇H₆₃NO₁₁: C, 72.98; H, 6.77; N, 1.49.

Found: C, 73.03; H, 6.88; N, 1.77.

1H), 4.83 (d, J = 10.9 Hz, 1H), 4.84 (d, J = 10.3 Hz, 1H), 4.98 (d, J =

10.9 Hz, 1H), 5.15 (d, J = 8.6 Hz, 1H), 5.46 (s, 1H), 5.64 (br d, J = 6.9

Hz, 1H), 7.26−7.36 (m, 23H), 7.50 (m, 2H); ¹³C NMR (126 MHz,

CDCl₃) δ 23.2, 54.1, 55.0, 66.4, 67.5, 69.2, 69.7, 71.4, 73.0, 73.1, 74.65,

74.68, 75.6, 77.8, 79.8, 81.8, 97.9, 99.6, 100.8, 126.2, 127.4, 127.6,

127.7, 127.75, 127.79, 127.9, 128.0, 128.22, 128.24, 128.3, 128.7,

137.8, 138.0, 138.12, 138.15, 138.6, 171.4; HRMS (FAB) m/z [M +

H]⁺calcd for C₅₀H₅₆NO₁₁846.3854; found 846.3856. Anal. Calcd for

C₅₀H₅₅NO₁₁: C, 70.99; H, 6.55; N, 1.66. Found: C, 70.87; H, 6.57; N,

1.69.

Methyl 6-O-(2-Acetamido-3-O-benzyl-4,6-O-benzylidene-2-

deoxy-β-^D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyra-

noside (17). The glycosylation was performed according to the

typical procedure employing diethyl phosphite 9b (52.0 mg, 0.10

mmol), 6-O-unprotected glucoside 13 (92.9 mg, 0.20 mmol),

pulverized 4 Å molecular sieves (100 mg), and Tf₂NH (1.0 M in

EtCN, 0.11 mL, 0.11 mmol). β-Linked disaccharide 17 (41.2 mg,

49%) was obtained as a white solid from the crude product (170.8 mg)

after column chromatography (silica gel 12 g, 12:1 → 8:1 CH₂Cl₂/

AcOEt). When the glycosylation was performed employing diethyl

phosphite 9b (103.9 mg, 0.20 mmol), 6-O-unprotected glucoside 13

(46.5 mg, 0.10 mmol), pulverized 4 Å molecular sieves (100 mg), and

Tf₂NH (1.0 M in EtCN, 0.22 mL, 0.22 mmol), disaccharide 17 (30.2

mg, 36%) was obtained as a white solid from the crude product (175.2

mg) after column chromatography (silica gel 12 g, 12:1 → 8:1

CH₂Cl₂/AcOEt). R_f0.23 (8:1 CH₂Cl₂/AcOEt); mp 248−254 °C

(decomp) (colorless needles from CH₂Cl₂/n-hexane); [α]_D²⁰+13.8 (c

1.00, CHCl₃); IR (KBr) 3299, 1656, 1559, 1370, 1114, 1062, 737

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.68 (s, 3H), 3.27 (ddd, J = 7.4,

8.6, 9.2 Hz, 1H), 3.35 (s, 3H), 3.51 (dd, J = 2.9, 9.7 Hz, 1H), 3.52 (m,

1H), 3.55 (t, J = 9.7 Hz, 1H), 3.67 (t, J = 9.2 Hz, 1H), 3.71−3.76 (m,

2H), 3.77 (t, J = 9.7 Hz, 1H), 3.98 (t, J = 9.7 Hz, 1H), 4.06 (br d, J =

8.6 Hz, 1H), 4.30 (t, J = 9.2 Hz, 1H), 4.31 (dd, J = 4.6, 10.3 Hz, 1H),

4.52 (d, J = 10.3 Hz, 1H), 4.60 (d, J = 2.9 Hz, 1H), 4.61 (d, J = 12.0

Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.81 (d,

J = 10.9 Hz, 1H), 4.83 (d, J = 10.3 Hz, 1H), 4.87 (d, J = 12.0 Hz, 1H),

4.98 (d, J = 10.9 Hz, 1H), 5.05 (d, J = 8.6 Hz, 1H), 5.45 (br d, J = 7.4

Hz, 1H), 5.55 (s, 1H), 7.26−7.40 (m, 23H), 7.49 (m, 2H); ¹³C NMR

(126 MHz, 5:1 CDCl₃/CD₃OD) δ 22.5, 54.7, 56.3, 65.7, 67.5, 68.4,

69.3, 73.0, 73.9, 74.5, 75.4, 79.5, 81.6, 81.9, 97.7, 100.5, 101.0, 125.7,

127.3, 127.4, 127.5, 127.6, 127.7, 127.8, 127.89, 127.93, 128.0, 128.1,

128.7, 137.0, 137.7, 137.8, 138.0, 138.3, 171.1; HRMS (FAB) m/z [M

+ H]⁺calcd for C₅₀H₅₆NO₁₁846.3854; found 846.3851. Anal. Calcd

for: C₅₀H₅₅NO₁₁: C, 70.99; H, 6.55; N, 1.66. Found: C, 70.63; H, 6.55;

N, 1.68.

Methyl 6-O-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-^D-

glucopyranosyl)-2,3,4-tri-O-benzyl-α-^D-glucopyranoside

(19).⁶⁷The glycosylation was performed according to the typical

procedure employing diethyl phosphite 9c (46.7 mg, 0.10 mmol), 6-

O-unprotected glucoside 13 (92.9 mg, 0.20 mmol), pulverized 4 Å

molecular sieves (61.2 mg), and Tf₂NH (1.0 M in EtCN, 0.11 mL,

0.11 mmol). β-Linked disaccharide 19 (54.6 mg, 70%) was obtained as

a white solid from the crude product (187.5 mg) after column

chromatography (silica gel 12 g, 1:2 → 1:3 n-hexane/AcOEt). When

the glycosylation was performed employing diethyl phosphite 9c (93.5

mg, 0.20 mmol), 6-O-unprotected glucoside 13 (46.5 mg, 0.10 mmol),

pulverized 4 Å molecular sieves (61.2 mg), and Tf₂NH (1.0 M in

EtCN, 0.22 mL, 0.22 mmol), disaccharide 19 (57.2 mg, 72%) was

obtained as a white solid from the crude product (198.5 mg) after

column chromatography (silica gel 12 g, 1:2 → 1:3 n-hexane/AcOEt).

R_f0.36 (1:3 n-hexane/AcOEt); mp 186.5−187.5 °C (lit.⁶⁷187−188

21

°C); [α]_D+10.0 (c 1.00, CHCl₃); IR (Nujol) 3277, 1746, 1655,

1557, 1232, 1161, 1136, 1044, 910 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 1.82 (s, 3H), 2.02 (s, 3H), 2.03 (s, 6H), 3.37 (s, 3H), 3.44

(t, J = 9.4 Hz, 1H), 3.50 (dd, J = 3.4, 9.4 Hz, 1H), 3.63 (ddd, J = 2.4,

4.7, 9.8 Hz, 1H), 3.70 (dd, J = 3.8, 10.6 Hz, 1H), 3.75 (m, 1H), 3.82

(dt, J = 10.2, 8.6 Hz, 1H), 3.98 (t, J = 9.4 Hz, 1H), 4.04 (dd, J = 1.8,

10.6 Hz, 1H), 4.09 (dd, J = 2.4, 12.3 Hz, 1H), 4.22 (dd, J = 4.7, 12.3

Hz, 1H), 4.51 (br d, J = 8.6 Hz, 1H), 4.58 (d, J = 11.1 Hz, 1H), 4.63

(d, J = 3.4 Hz, 1H), 4.66 (d, J = 12.1 Hz, 1H), 4.77 (d, J = 12.1 Hz,

1H), 4.79 (d, J = 10.9 Hz, 1H), 4.84 (d, J = 11.1 Hz, 1H), 4.99 (d, J =

10.9 Hz, 1H), 5.04 (t, J = 9.8 Hz, 1H), 5.21 (dd, J = 9.8, 10.2 Hz, 1H),

5.36 (d, J = 8.6 Hz, 1H), 7.27−7.37 (m, 15H).

Methyl 9-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-^D-

glucopyranosyl)oxynonanoate (29). The glycosylation was

performed according to the typical procedure employing diethyl

phosphite 9a (61.2 mg, 0.10 mmol), hydroxy ester 20 (28.2 mg, 0.15

mmol), pulverized 4 Å molecular sieves (61.2 mg), and Tf₂NH (1.0 M

in EtCN, 0.11 mL, 0.11 mmol). β-Glucoside 29 (52.7 mg, 80%) was

obtained as a white solid from the crude product (95.0 mg) after

column chromatography (silica gel 9 g, 7:1 toluene/acetone). When

the glycosylation was performed employing diethyl phosphite 9a (91.8

mg, 0.15 mmol), hydroxy ester 20 (18.8 mg, 0.10 mmol), pulverized 4

Å molecular sieves (61.2 mg), and Tf₂NH (1.0 M in EtCN, 0.17 mL,

0.17 mmol), β-glucoside 29 (54.8 mg, 83%) was obtained as a white

solid from the crude product (160.2 mg) after column chromatog-

raphy (silica gel 12 g, 7:1 toluene/acetone). R_f0.28 (5:1 toluene/

acetone); mp 119.0−120.0 °C (colorless needles from CH₂Cl₂/n-

hexane); [α]_D²³+11.8 (c 1.00, CHCl₃); IR (Nujol) 3263, 3107, 3032,

1739, 1653, 1570, 1194, 1116, 1060 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 1.23−1.35 (m, 8H), 1.50−1.63 (m, 4H), 1.85 (s, 3H), 2.29

(t, J = 7.5 Hz, 2H), 3.38 (dt, J = 9.4, 7.9 Hz, 1H), 3.44 (dt, J = 9.5, 6.9

Hz, 1H), 3.58 (ddd, J = 2.0, 4.3, 9.2 Hz, 1H), 3.61 (dd, J = 8.2, 9.2 Hz,

1H), 3.65 (s, 3H), 3.70 (dd, J = 4.3, 10.8 Hz, 1H), 3.76 (dd, J = 2.0,

10.8 Hz, 1H), 3.84 (dt, J = 9.5, 6.4 Hz, 1H), 4.12 (dd, J = 8.2, 9.4 Hz,

1H), 4.54 (d, J = 12.2 Hz, 1H), 4.58 (d, J = 11.0 Hz, 1H), 4.61 (d, J =

12.2 Hz, 1H), 4.66 (d, J = 11.6 Hz, 1H), 4.78 (d, J = 11.0 Hz, 1H),

4.806 (d, J = 7.9 Hz, 1H), 4.811 (d, J = 11.6 Hz, 1H), 5.67 (d, J = 7.9

Hz, 1H), 7.19 (m, 2H), 7.20−7.32 (m, 13H); ¹³C NMR (126 MHz,

CDCl₃) δ 23.4, 24.7, 25.7, 28.9, 28.98, 29.04, 29.4, 34.0, 51.4, 56.9,

68.9, 69.4, 73.3, 74.47, 74.49, 74.7, 78.6, 80.4, 99.8, 127.5, 127.6, 127.7,

127.8, 127.9, 128.2, 128.30, 128.33, 138.0, 138.1, 138.4, 170.2, 174.3;

HRMS (FAB) m/z [M + H]⁺calcd for C₃₉H₅₂NO₈662.3693; found

662.3705. Anal. Calcd for C₃₉H₅₁NO₈: C, 70.78; H, 7.77; N, 2.12.

Found: C, 70.72; H, 7.93; N, 2.12.

Methyl 6-O-(2-Acetamido-3-O-benzyl-4,6-O-benzylidene-2-

deoxy-β-^D-galactopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyra-

noside (18). The glycosylation was performed according to the

typical procedure employing diethyl phosphite 11b (52.0 mg, 0.10

mmol), 6-O-unprotected glucoside 13 (92.9 mg, 0.20 mmol), 4 Å

molecular sieves (100 mg), and Tf₂NH (1.0 M in EtCN, 0.11 mL, 0.11

mmol). β-Linked disaccharide 18 (62.3 mg, 74%) was obtained as a

white solid from the crude product (178 mg) after column

chromatography (silica gel 12 g, 20:1 → 15:1 CH₂Cl₂/acetone).

When the glycosylation was performed employing diethyl phosphite

11b (103.9 mg, 0.20 mmol), 6-O-unprotected glucoside 13 (46.5 mg,

0.10 mmol), pulverized 4 Å molecular sieves (100 mg), and Tf₂NH

(1.0 M in EtCN, 0.22 mL, 0.22 mmol), disaccharide 18 (66.2 mg,

78%) was obtained as a white solid from the crude product (187 mg)

after column chromatography (silica gel 12 g, 20:1 → 15:1 CH₂Cl₂/

acetone). R_f0.26 (15:1 CH₂Cl₂/acetone); mp 279−280 °C (decomp)

20

(colorless needles from CH₂Cl₂/n-hexane); [α]_D+43.3 (c 0.20,

CHCl₃); IR (KBr) 3299, 1656, 1559, 1370, 1112, 1063, 737 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ 1.84 (s, 3H), 3.36 (s, 3H), 3.41 (br s,

1H), 3.52 (dd, J = 3.4, 9.5 Hz, 1H), 3.53 (t, J = 9.5 Hz, 1H), 3.55 (ddd,

J = 6.9, 8.6, 10.9 Hz, 1H), 3.74 (dd, J = 4.3, 10.6 Hz, 1H), 3.77 (ddd, J

= 2.0, 4.3, 9.5 Hz, 1H), 3.98 (t, J = 9.5 Hz, 1H), 3.99 (dd, J = 2.0, 12.3

Hz, 1H), 4.11 (d, J = 3.4 Hz, 1H), 4.12 (dd, J = 2.0, 10.6 Hz, 1H), 4.27

(dd, J = 1.4, 12.3 Hz, 1H), 4.52 (dd, J = 3.4, 10.9 Hz, 1H), 4.57 (d, J =

10.3 Hz, 1H), 4.60 (d, J = 12.6 Hz, 1H), 4.62 (d, J = 3.4 Hz, 1H), 4.64

(d, J = 12.6 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.77 (d, J = 12.0 Hz,

L

DOI: 10.1021/acs.joc.5b00138

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

6-O-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-D-glucopyr-

anosyl)-1,2:3,4-di-O-isopropylidene-α-^D-galactopyranose

(30).^25f,68The glycosylation was performed according to the typical

procedure employing diethyl phosphite 9a (61.2 mg, 0.10 mmol),

alcohol 21 (52.0 mg, 0.20 mmol), pulverized 4 Å molecular sieves

(61.2 mg), and Tf₂NH (1.0 M in EtCN, 0.11 mL, 0.11 mmol). β-

Linked disaccharide 30 (65.6 mg, 89%) was obtained as a white

amorphous solid from the crude product (145.3 mg) after column

chromatography (silica gel 12 g, 7:1 → 5:1 toluene/acetone). When

the glycosylation was performed employing diethyl phosphite 9a

(122.3 mg, 0.20 mmol), alcohol 21 (26.0 mg, 0.10 mmol), pulverized

4 Å molecular sieves (61.2 mg), and Tf₂NH (1.0 M in EtCN, 0.22 mL,

0.22 mmol), disaccharide 30 (67.5 mg, 92%) was obtained as a white

solid from the crude product (172.3 mg) after column chromatog-

raphy (silica gel 17 g, 7:1 → 6:1 toluene/acetone). R_f0.36 (3:1

mg, 0.20 mmol), 3-O-unprotected galactoside 23 (46.5 mg, 0.10

mmol), pulverized 4 Å molecular sieves (61.2 mg), and Tf₂NH (1.0 M

in EtCN, 0.22 mL, 0.22 mmol), disaccharide 32 (59.6 mg, 64%) was

obtained as a white solid from the crude product (220.0 mg) after

column chromatography (silica gel 18 g, 7:1 toluene/acetone). R_f0.28

(5:1 toluene/acetone); mp 127.0−127.5 °C (colorless needles from

24

CH₂Cl₂/n-hexane); [α]_D+9.0 (c 1.00, CHCl₃); IR (Nujol) 3306,

3088, 3063, 3030, 1952, 1875, 1811, 1657, 1556, 1496, 1205, 1111

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.63 (s, 3H), 3.33 (s, 3H), 3.42

(dd, J = 6.0, 9.7 Hz, 1H), 3.50 (dd, J = 6.3, 9.7 Hz, 1H), 3.52 (m, 1H),

3.65 (t, J = 9.2 Hz, 1H), 3.71−3.75 (m, 3H), 3.89 (dd, J = 6.0, 6.3 Hz,

1H), 3.92 (m, 1H), 3.94 (dd, J = 3.6, 10.1 Hz, 1H), 4.02 (d, J = 2.8 Hz,

1H), 4.08 (dd, J = 2.8, 10.1 Hz, 1H), 4.35 (d, J = 11.9 Hz, 1H), 4.44

(d, J = 11.9 Hz, 1H), 4.48 (d, J = 12.2 Hz, 1H), 4.55 (d, J = 11.6 Hz,

1H), 4.56 (d, J = 11.8 Hz, 1H), 4.601 (d, J = 12.2 Hz, 1H), 4.603 (d, J

= 10.2 Hz, 1H), 4.61 (d, J = 3.6 Hz, 1H), 4.64 (d, J = 12.2 Hz, 2H),

4.77 (d, J = 8.0 Hz, 1H), 4.785 (d, J = 10.2 Hz, 1H), 4.788 (d, J = 11.8

Hz, 1H), 4.96 (d, J = 11.6 Hz, 1H), 5.01 (d, J = 8.9 Hz, 1H), 7.20−

7.33 (m, 30H); ¹³C NMR (126 MHz, CDCl₃) δ 23.4, 55.2, 55.8, 60.3,

68.4, 68.9, 69.31, 69.34, 72.9, 73.3, 74.4, 74.5, 74.8, 76.4, 78.1, 78.2,

78.3, 82.1, 98.2, 102.3, 127.3, 127.4, 127.45, 127.54, 127.6, 127.7,

127.8, 127.9, 128.0, 128.2, 128.30, 128.32, 128.5, 137.8, 137.9, 138.0,

138.2, 138.3, 138.7, 169.7; HRMS (FAB) m/z [M + H]⁺calcd for

C₅₇H₆₄NO₁₁938.4479; found 938.4474. Anal. Calcd for C₅₇H₆₃NO₁₁:

C, 72.98; H, 6.77; N, 1.49. Found: C, 73.07; H, 6.77; N, 1.57.

Benzyl 4-O-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-^D-

glucopyranosyl)-2,3-O-cyclohexylidene-α-^L-rhamnopyrano-

side (33).^22cThe glycosylation was performed according to the

typical procedure employing diethyl phosphite 9a (61.2 mg, 0.10

mmol), 4-O-unprotected rhamnoside 24 (66.9 mg, 0.20 mmol),

pulverized 4 Å molecular sieves (61.2 mg), and Tf₂NH (1.0 M in

EtCN, 0.11 mL, 0.11 mmol). β-Linked disaccharide 33 (45.8 mg,

57%) was obtained as a white solid from the crude product (168.9 mg)

after column chromatography (silica gel 18 g, 12:1 → 10:1 toluene/

acetone). When the glycosylation was performed employing diethyl

phosphite 9a (122.3 mg, 0.20 mmol), 4-O-unprotected rhamnoside 24

(33.4 mg, 0.10 mmol), pulverized 4 Å molecular sieves (61.2 mg), and

Tf₂NH (1.0 M in EtCN, 0.22 mL, 0.22 mmol), disaccharide 33 (35.6

mg, 44%) was obtained as a white solid from the crude product (213.3

mg) after column chromatography (silica gel 18 g, 12:1 → 10:1

toluene/acetone). R_f0.45 (5:1 toluene/acetone); mp 155.0−155.5 °C

25

toluene/acetone); [α]_D−32.2 (c 1.42, CHCl₃) [lit. [α]_D−29 (c

0.5, CHCl₃),^25f[α]_D−35 (c 1.00, CHCl₃)⁶⁸]; IR (Nujol) 3297, 1728,

1

1657, 1552, 1496, 1310, 1226, 1211, 920, 899 cm⁻¹; H NMR (500

MHz, CDCl₃) δ 1.30 (s, 3H), 1.31 (s, 3H), 1.42 (s, 3H), 1.51 (s, 3H),

1.88 (s, 3H), 3.54 (ddd, J = 2.9, 3.5, 9.3 Hz, 1H), 3.62−3.77 (m, 5H),

3.92−3.96 (m, 2H), 4.00 (dd, J = 3.8, 9.3 Hz, 1H), 4.16 (dd, J = 1.6,

8.0 Hz, 1H), 4.28 (dd, J = 2.4, 5.0 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H),

4.56 (dd, J = 2.4, 8.0 Hz, 1H), 4.57 (d, J = 11.1 Hz, 1H), 4.62 (d, J =

12.1 Hz, 1H), 4.68 (d, J = 11.1 Hz, 1H), 4.70 (d, J = 7.7 Hz, 1H), 4.78

(d, J = 10.7 Hz, 1H), 4.80 (d, J = 10.7 Hz, 1H), 5.50 (d, J = 5.0 Hz,

1H), 5.55 (d, J = 8.2 Hz, 1H), 7.18−7.20 (m, 2H), 7.25−7.34 (m,

13H).

Benzyl 4-O-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-^D-

glucopyranosyl)-2,3-anhydro-β-^D-ribopyranoside (31). The gly-

cosylation was performed according to the typical procedure

employing diethyl phosphite 9a (61.2 mg, 0.10 mmol), epoxy alcohol

22 (44.4 mg, 0.20 mmol), pulverized 4 Å molecular sieves (61.2 mg),

and Tf₂NH (1.0 M in EtCN, 0.11 mL, 0.11 mmol). β-Glucoside 31

(54.8 mg, 79%) was obtained as a white solid from the crude product

(137.3 mg) after column chromatography (silica gel 18 g, 5:1 → 4:1

toluene/acetone). When the glycosylation was performed employing

diethyl phosphite 9a (122.3 mg, 0.20 mmol), epoxy alcohol 22 (22.2

mg, 0.10 mmol), pulverized 4 Å molecular sieves (61.2 mg), and

Tf₂NH (1.0 M in EtCN, 0.22 mL, 0.22 mmol), β-glucoside 31 (54.3

mg, 78%) was obtained as a white solid from the crude product (198.2

mg) after column chromatography (silica gel 18 g, 5:1 → 4:1 toluene/

acetone). R_f0.29 (5:1 toluene/acetone); mp 218.5−219.5 °C

(lit.^22c153−154 °C) (colorless needles from AcOEt/n-hexane); [α]_D

24

−20.5 (c 1.00, CHCl₃) [lit.^22c[α]_D−13.8 (c 0.55, CHCl₃)]; IR

25

(colorless needles from CH₂Cl₂/n-hexane); [α]_D+18.5 (c 1.00,

(Nujol) 3341, 3266, 3067, 3032, 1651, 1551, 1456, 1130, 1098, 1067,

CHCl₃); IR (Nujol) 3269, 3090, 3063, 3030, 1651, 1564, 1497, 1316,

1116, 1069, 1022, 984, 872 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.86

(s, 3H), 3.18 (d, J = 3.8 Hz, 1H), 3.31 (ddd, J = 7.4, 8.2, 9.6 Hz, 1H),

3.47 (dd, J = 3.2, 12.6 Hz, 1H), 3.52 (dd, J = 3.8, 4.1 Hz, 1H), 3.56−

3.62 (m, 2H), 3.69 (dd, J = 3.5, 10.8 Hz, 1H), 3.72 (br d, J = 10.8 Hz,

1H), 3.81 (dd, J = 4.6, 12.6 Hz, 1H), 4.07 (ddd, J = 3.2, 4.1, 4.6 Hz,

1H), 4.27 (dd, J = 8.2, 9.6 Hz, 1H), 4.53 (d, J = 11.9 Hz, 2H), 4.58 (d,

J = 10.9 Hz, 1H), 4.59 (d, J = 11.9 Hz, 1H), 4.67 (d, J = 11.5 Hz, 1H),

4.77 (d, J = 11.5 Hz, 1H), 4.80 (d, J = 10.9 Hz, 1H), 4.83 (d, J = 11.9

Hz, 1H), 4.98 (s, 1H), 5.17 (d, J = 8.2 Hz, 1H), 5.93 (d, J = 7.4 Hz,

1H), 7.20 (m, 2H), 7.25−7.36 (m, 18H); ¹³C NMR (126 MHz,

CDCl₃) δ 23.5, 51.5, 52.1, 57.7, 59.6, 69.0, 69.3, 70.3, 73.3, 74.7, 74.9,

78.8, 80.4, 94.9, 98.9, 127.6, 127.65, 127.69, 127.74, 127.8, 128.05,

128.12, 128.3, 128.39, 128.43, 128.5, 137.0, 138.1, 138.2, 138.5, 170.9;

HRMS (FAB) m/z [M + H]⁺calcd for C₄₁H₄₆NO₉696.3173; found

696.3168. Anal. Calcd for C₄₁H₄₅NO₉: C, 70.77; H, 6.52; N, 2.01.

Found: C, 70.82; H, 6.53; N, 2.17.

Methyl 3-O-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-^D-

glucopyranosyl)-2,4,6-tri-O-benzyl-α-^D-galactopyranoside

(32). The glycosylation was performed according to the typical

procedure employing diethyl phosphite 9a (61.2 mg, 0.10 mmol), 3-

O-unprotected galactoside 23 (92.9 mg, 0.20 mmol), pulverized 4 Å

molecular sieves (61.2 mg), and Tf₂NH (1.0 M in EtCN, 0.11 mL,

0.11 mmol). β-Linked disaccharide 32 (60.9 mg, 65%) was obtained as

a white solid from the crude product (190.2 mg) after column

chromatography (silica gel 18 g, 7:1 toluene/acetone). When the

glycosylation was performed employing diethyl phosphite 9a (122.3

1

1019, 936 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 1.32 (d, J = 6.2 Hz,

3H), 1.35−1.42 (m, 2H), 1.43−1.74 (m, 8H), 1.88 (s, 3H), 3.44 (ddd,

J = 2.2, 4.0, 9.5 Hz, 1H), 3.46 (dd, J = 7.4, 9.9 Hz, 1H), 3.64 (dd, J =

9.0, 9.7 Hz, 1H), 3.68−3.74 (m, 3H), 3.74 (dd, J = 4.3, 11.2 Hz, 1H),

3.86 (ddd, J = 8.1, 8.8, 9.0 Hz, 1H), 4.08 (dd, J = 5.5, 7.4 Hz, 1H), 4.11

(d, J = 5.5 Hz, 1H), 4.48 (d, J = 11.5 Hz, 1H), 4.57 (d, J = 12.2 Hz,

1H), 4.62 (d, J = 10.8 Hz, 1H), 4.63 (d, J = 12.2 Hz, 1H), 4.69 (d, J =

11.5 Hz, 2H), 4.71 (d, J = 8.1 Hz, 1H), 4.82 (d, J = 10.8 Hz, 1H), 4.84

(d, J = 11.5 Hz, 1H), 5.06 (s, 1H), 5.52 (d, J = 8.8 Hz, 1H), 7.24−7.35

(m, 20H).

1-Neryl 2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-^D-galac-

topyranoside (36). The glycosylation was performed according to

the typical procedure employing diethyl phosphite 11a (61.2 mg, 0.10

mmol), nerol (27, 17.0 mg, 0.11 mmol), pulverized 4 Å molecular

sieves (61.2 mg), and Tf₂NH (1.0 M in EtCN, 0.11 mL, 0.11 mmol).

β-Glycoside 36 (51.0 mg, 81%) was obtained as a white solid from the

crude product (104.7 mg) after column chromatography (silica gel 12

g, 10:1 toluene/acetone). When the glycosylation was performed

employing diethyl phosphite 11a (67.3 mg, 0.11 mmol), nerol (15.4

mg, 0.10 mmol), pulverized 4 Å molecular sieves (61.2 mg), and

Tf₂NH (1.0 M in EtCN, 0.12 mL, 0.12 mmol), β-glycoside 36 (49.6

mg, 79%) was obtained as a white solid from the crude product (124.7

mg) after column chromatography (silica gel 12 g, 10:1 toluene/

acetone). R_f0.33 (5:1 toluene/acetone); mp 148.0−148.5 °C

25

(colorless needles from CH₂Cl₂/n-hexane); [α]_D+9.6 (c 1.00,

CHCl₃); IR (Nujol) 3301, 1653, 1552, 1496, 1167, 1111, 1067, 905

M

DOI: 10.1021/acs.joc.5b00138

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.57 (s, 3H), 1.65 (s, 3H), 1.72

(s, 3H), 1.90 (s, 3H), 1.99−2.06 (m, 4H), 3.44 (ddd, J = 7.0, 8.3, 10.7

Hz, 1H), 3.59 (dd, J = 5.6, 8.8 Hz, 1H), 3.63 (dd, J = 7.1, 8.8 Hz, 1H),

3.67 (dd, J = 5.6, 7.1 Hz, 1H), 3.96 (d, J = 2.4 Hz, 1H), 4.09 (dd, J =

7.6, 11.7 Hz, 1H), 4.27 (dd, J = 6.5, 11.7 Hz, 1H), 4.42 (dd, J = 2.4,

10.7 Hz, 1H), 4.43 (d, J = 12.2 Hz, 1H), 4.478 (d, J = 12.2 Hz, 1H),

4.482 (d, J = 11.4 Hz, 1H), 4.59 (d, J = 11.6 Hz, 1H), 4.64 (d, J = 11.4

Hz, 1H), 4.87 (d, J = 11.6 Hz, 1H), 5.04 (d, J = 8.3 Hz, 1H), 5.05 (m,

1H), 5.30 (dd, J = 6.5, 7.6 Hz, 1H), 5.64 (d, J = 7.0 Hz, 1H), 7.24−

7.36 (m, 15H); ¹³C NMR (126 MHz, CDCl₃) δ 17.6, 23.5, 23.7, 25.7,

26.7, 32.1, 55.6, 65.2, 68.6, 72.3, 72.7, 73.2, 73.4, 74.5, 77.5, 98.3,

120.9, 123.8, 127.5, 127.7, 127.80, 127.84, 128.0, 128.12, 128.13,

128.38, 128.44, 131.9, 137.9, 138.1, 138.6, 141.2, 170.7; HRMS (FAB)

m/z [M + H]⁺calcd for C₃₉H₅₀NO₆628.3638; found 628.3649. Anal.

Calcd for C₃₉H₄₉NO₆: C, 74.61; H, 7.87; N, 2.23. Found: C, 74.43; H,

7.72; N, 2.23.

3.3 Hz, 1H), 5.48 (d, J = 8.7 Hz, 1H), 5.53 (d, J = 5.1 Hz, 1H); ¹³C

NMR (126 MHz, CDCl₃) δ 20.58, 20.63, 23.3, 24.2, 24.9, 25.9, 26.0,

50.9, 61.3, 66.7, 68.2, 68.9, 70.2, 70.56, 70.59, 71.1, 96.2, 102.0, 108.6,

109.3, 170.25, 170.34, 170.5; HRMS (FAB) m/z [M + H]⁺calcd for

C₂₆H₄₀NO₁₄590.2449; found 590.2454.

Benzyl 4-O-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-^D-gal-

actopyranosyl)-2,3-anhydro-β-^D-ribopyranoside (39). The gly-

cosylation was performed according to the typical procedure

employing diethyl phosphite 11c (46.7 mg, 0.10 mmol), epoxy

alcohol 22 (44.4 mg, 0.20 mmol), pulverized 4 Å molecular sieves

(61.2 mg), and Tf₂NH (1.0 M in EtCN, 0.11 mL, 0.11 mmol). β-

Galactoside 39 (32.5 mg, 59%) was obtained as a white solid from the

crude product (114.3 mg) after column chromatography (silica gel 12

g, 3:1 CH₂Cl₂/acetone). When the glycosylation was performed

employing diethyl phosphite 11c (93.5 mg, 0.20 mmol), epoxy alcohol

22 (22.2 mg, 0.10 mmol), pulverized 4 Å molecular sieves (61.2 mg),

and Tf₂NH (1.0 M in EtCN, 0.22 mL, 0.22 mmol), β-galactoside 39

(32.6 mg, 59%) was obtained as a white solid from the crude product

(134.2 mg) after column chromatography (silica gel 12 g, 3:1 CH₂Cl₂/

acetone). R_f0.24 (4:1 CH₂Cl₂/acetone); mp 155.5−156.5 °C

l-Menthyl 2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-^D-gal-

actopyranoside (37). The glycosylation was performed according

to the typical procedure employing diethyl phosphite 11a (61.2 mg,

0.10 mmol), l-menthol (28, 23.4 mg, 0.15 mmol), pulverized 4 Å

molecular sieves (61.2 mg), and Tf₂NH (1.0 M in EtCN, 0.11 mL,

0.11 mmol). β-Galactoside 37 (46.5 mg, 74%) was obtained as a white

solid from the crude product (108.1 mg) after column chromatog-

raphy (silica gel 12 g, 12:1 toluene/acetone). When the glycosylation

was performed employing diethyl phosphite 11a (91.8 mg, 0.15

mmol), l-menthol (15.6 mg, 0.10 mmol), pulverized 4 Å molecular

sieves (61.2 mg), and Tf₂NH (1.0 M in EtCN, 0.17 mL, 0.17 mmol),

β-galactoside 37 (44.9 mg, 71%) was obtained as a white solid from

the crude product (148.1 mg) after column chromatography (silica gel

14 g, 12:1 toluene/acetone). R_f0.50 (5:1 toluene/acetone); mp

22

(colorless needles from AcOEt/n-hexane); [α]_D−21.3 (c 1.00,

CHCl₃); IR (Nujol) 3343, 1740, 1667, 1539, 1312, 1258, 1225, 1142,

1084, 1022, 972, 912, 812 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.96

(s, 3H), 2.00 (s, 3H), 2.05 (s, 3H), 2.15 (s, 3H), 3.22 (d, J = 4.0 Hz,

1H), 3.52 (t, J = 4.0 Hz, 1H), 3.58 (dd, J = 2.8, 12.8 Hz, 1H), 3.85 (dt,

J = 11.2, 8.5 Hz, 1H), 3.87 (dd, J = 4.6, 12.8 Hz, 1H), 3.97 (t, J = 6.7

Hz, 1H), 4.13 (dd, J = 6.7, 11.2 Hz, 1H), 4.14 (m, 1H), 4.15 (dd, J =

6.7, 11.2 Hz, 1H), 4.57 (d, J = 11.6 Hz, 1H), 4.79 (d, J = 11.6 Hz, 1H),

5.03 (s, 1H), 5.25 (d, J = 8.5 Hz, 1H), 5.38 (d, J = 3.4 Hz, 1H), 5.45

(dd, J = 3.4, 11.2 Hz, 1H), 5.76 (d, J = 8.5 Hz, 1H), 7.32−7.40 (m,

5H); ¹³C NMR (126 MHz, CDCl₃) δ 20.61, 20.64, 20.7, 23.3, 51.3,

51.7, 51.9, 59.7, 61.6, 66.9, 69.0, 69.5, 70.4, 70.9, 93.9, 99.4, 128.09,

128.10, 128.6, 136.8, 170.17, 170.22, 170.4, 170.8; HRMS (FAB) m/z

[M + H]⁺calcd for C₂₆H₃₄NO₁₂552.2081; found 552.2094. Anal.

Calcd for C₂₆H₃₃NO₁₂: C, 56.62; H, 6.03; N, 2.54. Found: C, 56.29;

H, 5.88; N, 2.51.

24

160.0−161.0 °C (colorless needles from AcOEt/n-hexane); [α]_D

−32.8 (c 1.00, CHCl₃); IR (Nujol) 3304, 1653, 1550, 1308, 1167,

1105, 1071 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.72 (d, J = 6.8 Hz,

3H), 0.77−0.82 (m, 2H), 0.85 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz,

3H), 0.95 (m, 1H), 1.16 (m, 1H), 1.30 (m, 1H), 1.58−1.64 (m, 2H),

1.88 (s, 3H), 1.93 (m, 1H), 2.30 (dquin, J = 2.2, 6.8 Hz, 1H), 3.31−

3.39 (m, 2H), 3.54 (dd, J = 5.5, 8.9 Hz, 1H), 3.59 (dd, J = 7.0, 8.9 Hz,

1H), 3.63 (dd, J = 5.5, 7.0 Hz, 1H), 3.92 (d, J = 3.0 Hz, 1H), 4.41 (d, J

= 11.8 Hz, 1H), 4.46 (d, J = 11.8 Hz, 1H), 4.48 (dd, J = 3.0, 10.7 Hz,

1H), 4.50 (d, J = 11.6 Hz, 1H), 4.59 (d, J = 11.6 Hz, 1H), 4.62 (d, J =

11.6 Hz, 1H), 4.87 (d, J = 11.6 Hz, 1H), 5.03 (d, J = 8.3 Hz, 1H), 5.66

(d, J = 6.9 Hz, 1H), 7.24−7.35 (m, 15H); ¹³C NMR (126 MHz,

CDCl₃) δ 15.5, 21.2, 22.3, 22.9, 23.7, 24.8, 31.4, 34.4, 41.0, 47.7, 55.9,

69.1, 72.3, 73.1, 73.4, 74.4, 77.4, 78.7, 97.6, 127.4, 127.6, 127.70,

127.73, 128.0, 128.07, 128.09, 128.3, 128.4, 128.5, 137.9, 138.0, 138.6,

170.6; HRMS (FAB) m/z [M + H]⁺calcd for C₃₉H₅₂NO₆630.3795;

found 630.3797. Anal. Calcd for C₃₉H₅₁NO₆: C, 74.21; H, 8.14; N,

2.29. Found: C, 74.37; H, 8.16; N, 2.22.

2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-^D-glucopyrano-

syl Trichloroacetimidate (40). DBU (37 μL, 0.25 mmol) was added

to an ice-cooled (0 °C) solution of hemiacetal 8a (600 mg, 1.22

mmol) and trichloroacetonitrile (0.20 mL, 1.95 mmol) in CH₂Cl₂(30

mL). After 1.5 h of stirring at room temperature, the volatile elements

were removed in vacuo, and the residue (1.07 g) was puriﬁed by

column chromatography (Wako gel 22 g, 2:1:1 n-hexane/AcOEt/

CH₂Cl₂with 3% Et₃N) to give trichloroacetimidate 40 (692 mg, 89%)

as a colorless crystalline solid. R_f0.44 (2:1:1 n-hexane/AcOEt/CH₂Cl₂,

with Et₃N-doped silica gel plate); mp 144.5−145.0 °C (colorless

20

needles from acetone/n-hexane); [α]_D+105.2 (c 1.02, CHCl₃); IR

(Nujol) 3310, 1672, 1649, 1543, 1285, 1148, 1127, 1105, 1074, 1022,

966, 945, 909, 842, 801 cm⁻¹; ¹H NMR (500 MHz, CDCl₃; spectrum

contains a mixture of rotamers, only the major rotamer signals are

reported) δ 1.68 (s, 3H), 3.69 (d, J = 11.2 Hz, 1H), 3.75−3.84 (m,

2H), 3.87−3.95 (m, 2H), 4.30 (ddd, J = 3.5, 8.5, 10.6 Hz, 1H), 4.51

(d, J = 12.0 Hz, 1H), 4.62 (d, J = 10.5 Hz, 1H), 4.65 (d, J = 12.0 Hz,

1H), 4.66 (d, J = 11.9 Hz, 1H), 4.73 (d, J = 8.5 Hz, 1H), 4.86 (d, J =

10.5 Hz, 1H), 4.91 (d, J = 11.9 Hz, 1H), 6.30 (d, J = 3.5 Hz, 1H),

7.22−7.38 (m, 15H), 8.60 (s, 1H); ¹³C NMR (126 MHz, CDCl₃;

spectrum contains a mixture of rotamers, only the major rotamer

signals are reported) δ 23.0, 52.1, 67.9, 73.4, 73.8, 74.5, 75.3, 77.7,

77.8, 91.1, 95.9, 127.6, 127.75, 127.80, 127.84, 127.9, 128.0, 128.1,

128.2, 128.3, 128.36, 128.42, 128.6, 128.9, 137.7, 137.8, 137.9, 160.2,

169.9; HRMS (ESI) m/z [M + Na]⁺calcd for C₃₁H₃₃Cl₃N₂O₆Na

657.1302; found 657.1292. Anal. Calcd for C₃₁H₃₃Cl₃N₂O₆: C, 58.55;

H, 5.23; N, 4.40; Cl, 16.72. Found: C, 58.55; H, 5.22; N, 4.38; Cl,

16.58.

6-O-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-^D-galacto-

pyranosyl)-1,2:3,4-di-O-isopropylidene-α-^D-galactopyranose

(38). The glycosylation was performed according to the typical

procedure employing diethyl phosphite 11c (46.7 mg, 0.10 mmol),

alcohol 21 (52.0 mg, 0.20 mmol), pulverized 4 Å molecular sieves

(61.2 mg), and Tf₂NH (1.0 M in EtCN, 0.11 mL, 0.11 mmol). β-

Linked disaccharide 38 (39.5 mg, 67%) was obtained as a white solid

from the crude product (121.1 mg) after column chromatography

(silica gel 12 g, 4:1 → 3:1 CH₂Cl₂/acetone). When the glycosylation

was performed employing diethyl phosphite 11c (93.5 mg, 0.20

mmol), alcohol 21 (26.0 mg, 0.10 mmol), pulverized 4 Å molecular

sieves (61.2 mg), and Tf₂NH (1.0 M in EtCN, 0.22 mL, 0.22 mmol),

disaccharide 38 (41.2 mg, 70%) was obtained as a white solid from the

crude product (134.2 mg) after column chromatography (silica gel 12

g, 4:1 → 3:1 CH₂Cl₂/acetone). R_f0.26 (4:1 CH₂Cl₂/acetone); mp

22

151.5−152.5 °C; [α]_D−60.8 (c 1.00, CHCl₃); IR (Nujol) 3293,

1

1744, 1665, 1561, 1308, 1258, 1176, 1071, 1015, 966, 895 cm⁻¹; H

Phenyl 2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-1-thio-α-^D-

glucopyranoside (41) and Phenyl 2-Acetamido-3,4,6-tri-O-

benzyl-2-deoxy-1-thio-β-^D-glucopyranoside (42).⁶⁹SnCl₄(0.15

mL, 1.22 mmol) was added to an ice-cooled (0 °C) mixture of 2-azido-

3,4,6-tri-O-benzyl-2-deoxy-^D-glucosyl acetate⁵³(573 mg, 1.11 mmol),

PhSH (0.18 mL, 1.66 mmol), and pulverized 5 Å molecular sieves

NMR (500 MHz, CDCl₃) δ 1.33 (s, 6H), 1.46 (s, 3H), 1.52 (s, 3H),

1.97 (s, 3H), 2.00 (s, 3H), 2.05 (s, 3H), 2.15 (s, 3H), 3.76 (dt, J = 3.7,

9.4 Hz, 1H), 3.91 (t, J = 6.8 Hz, 1H), 3.95−4.00 (m, 2H), 4.11−4.20

(m, 4H), 4.32 (dd, J = 2.4, 5.1 Hz, 1H), 4.59 (dd, J = 2.4, 8.0 Hz, 1H),

4.72 (d, J = 8.6 Hz, 1H), 5.14 (dd, J = 3.3, 11.2 Hz, 1H), 5.34 (d, J =

N

DOI: 10.1021/acs.joc.5b00138

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(500 mg) in 1:1 CH₂Cl₂/Et₂O (10 mL). After 5 h of stirring at this

temperature, the reaction was quenched with Et₃N (0.4 mL), and the

mixture was poured into a two-layer mixture of Et₂O (20 mL) and

10% aqueous NaOH (10 mL) and extracted with AcOEt (20 mL).

The organic extract was successively washed with brine (5 mL),

saturated aqueous NH₄Cl (10 mL), and brine (10 mL) and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo furnished the

yellow oil (780 mg), which was puriﬁed by column chromatography

(silica gel 20 g, 7:1 n-hexane/AcOEt) to give an anomeric mixture of

the corresponding thioglycoside (534 mg, 85%, α:β = 60:40) as a

colorless oil.

successively washed with saturated aqueous NaHCO₃(60 mL) and

brine (60 mL) and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the crude product (737 mg, pale yellow

oil), which was puriﬁed by column chromatography (silica gel 30 g, 4:1

n-hexane/AcOEt with 1% Et₃N) to give α-linked diphenyl phosphate

61 (613 mg, 84%) as a colorless syrup. R_f0.61 (2:1 n-hexane/AcOEt,

23

with Et₃N-doped silica gel plate); [α]_D+32.8 (c 1.06, CHCl₃); IR

(neat) 3064, 3030, 2913, 2868, 2112, 1590, 1489, 1297, 1188, 957, 734

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 3.44 (dd, J = 2.0, 11.1 Hz, 1H),

3.67 (dd, J = 3.6, 11.1 Hz, 1H), 3.83 (ddd, J = 2.0, 3.6, 10.1 Hz, 1H),

3.88 (dd, J = 1.8, 2.5 Hz, 1H), 3.99 (dd, J = 2.5, 9.3 Hz, 1H), 4.01 (dd,

J = 9.3, 10.1 Hz, 1H), 4.45 (d, J = 12.2 Hz, 1H), 4.50 (d, J = 10.4 Hz,

1H), 4.62 (d, J = 12.2 Hz, 1H), 4.64 (s, 2H), 4.82 (d, J = 10.4 Hz, 1H),

5.87 (dd, J = 1.8, 6.3 Hz, 1H), 7.13−7.22 (m, 8H), 7.27−7.35 (m,

17H); ¹³C NMR (100 MHz, CDCl₃) δ 61.0 (d, J_C−P= 9.6 Hz), 67.7,

72.8, 73.4, 73.5, 73.9, 75.4, 77.2, 78.7, 97.5 (d, J_C−P= 5.7 Hz), 120.0

(d, J_C−P= 5.7 Hz), 120.1 (d, J_C−P= 5.7 Hz), 127.6, 127.8, 127.86,

127.88, 128.0, 128.1, 128.3, 128.4, 128.6, 129.8, 129.9, 137.4, 137.85,

137.89, 150.1 (d, J_C−P= 4.8 Hz), 150.2 (d, J_C−P= 3.8 Hz); ³¹P NMR

(160 MHz, CDCl₃) δ −13.7; HRMS (ESI) m/z [M + Na]⁺calcd for

C₃₉H₃₈N₃O₈PNa 730.2294; found 730.2289.

Phenyl 2-Azido-3,4,6-tri-O-benzyl-2-deoxy-1-thio-α-^D-man-

nopyranoside (62) and Phenyl 2-Azido-3,4,6-tri-O-benzyl-2-

deoxy-1-thio-β-^D-mannopyranoside (63). BF₃·OEt₂(0.23 mL,

1.88 mmol) was added to an ice-cooled (0 °C) solution of diphenyl

phosphate 61 (557 mg, 0.79 mmol) and PhSH (0.18 mL, 1.88 mmol)

in CH₂Cl₂(13 mL). After 5 min of stirring, the reaction was quenched

with Et₃N (0.5 mL), and the mixture was poured into a two-layer

mixture of AcOEt (50 mL) and saturated aqueous NaHCO₃(50 mL).

The resulting mixture was extracted with AcOEt (150 mL), and the

organic extract was successively washed with saturated aqueous

NaHCO₃(50 mL) and brine (50 mL) and dried over anhydrous

Na₂SO₄. Filtration and evaporation in vacuo furnished the crude

product (900 mg, pale yellow oil), which was puriﬁed by column

chromatography (silica gel 27 g, 8:1 n-hexane/AcOEt) to give 2-azido-

2-deoxy-α-thioglycoside 62 (111 mg, 25%, colorless oil) and its β-

isomer 63 (300 mg, 67%, white solid).

Triphenylphosphine (269 mg, 1.45 mmol) was added to a stirred

solution of the 2-azido-2-deoxythioglycoside (530 mg, 0.93 mmol) in

THF (6 mL). After 30 min of stirring, H₂O (1 mL) was added and the

mixture was heated at 80 °C for 10 h. The resulting mixture was

partitioned between AcOEt (30 mL) and brine (10 mL), and the

organic layer was dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the 2-amino-2-deoxythioglycoside as a

colorless oil, which was dissolved in pyridine (5 mL). Ac₂O (0.26 mL,

2.80 mmol) was added, and the solution was stirred for 3 h. The

reaction mixture was partitioned between AcOEt (30 mL) and 10%

aqueous HCl (15 mL). The organic layer was successively washed with

H₂O (5 mL), saturated aqueous NaHCO₃(10 mL), and brine (10

mL), and dried over anhydrous Na₂SO₄. Filtration and evaporation in

vacuo furnished the crude product (801 mg, slightly yellow solid),

which was puriﬁed by ﬂash column chromatography (silica gel 50 g,

5:1 toluene/acetone) to give 2-acetamido-2-deoxy-α-thioglycoside 41

(288 mg, 53%) and its β-isomer 42 (193 mg, 35%) as white solids.

Data for α-isomer 41. R_f0.33 (5:1 toluene/acetone); mp 168.5−

21

170.0 °C (colorless needles from AcOEt/n-hexane); [α]_D+198.6 (c

1.00, CHCl₃); IR (KBr) 3314, 1651, 1541, 1127, 1105, 1071 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ 1.79 (s, 3H), 3.63 (dd, J = 8.6, 10.9 Hz,

1H), 3.68 (dd, J = 1.7, 10.9 Hz, 1H), 3.80 (dd, J = 8.6, 9.7 Hz, 1H),

3.84 (dd, J = 4.6, 10.9 Hz, 1H), 4.32 (ddd, J = 1.7, 4.6, 9.7 Hz, 1H),

4.42 (ddd, J = 4.6, 8.6, 10.9 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.58

(d, J = 10.9 Hz, 1H), 4.63 (d, J = 12.0 Hz, 1H), 4.65 (d, J = 11.5 Hz,

1H), 4.81 (d, J = 10.9 Hz, 1H), 4.87 (d, J = 11.5 Hz, 1H), 5.18 (d, J =

8.6 Hz, 1H), 5.65 (d, J = 4.6 Hz, 1H), 7.21−7.44 (m, 20H); ¹³C NMR

(126 MHz, CDCl₃) δ 23.3, 52.7, 68.3, 72.5, 73.3, 74.5, 74.9, 78.3, 79.4,

88.2, 127.3, 127.56, 127.63, 127.7, 127.8, 127.9, 128.1, 128.27, 128.32,

128.4, 128.6, 129.0, 131.4, 131.8, 137.8, 137.9, 138.0, 169.7; HRMS

(FAB) m/z [M + H]⁺calcd for C₃₅H₃₈NO₅S 584.2471; found

584.2469. Anal. Calcd for C₃₅H₃₇NO₅S: C, 72.01; H, 6.39; N, 2.40; S,

5.49. Found: C, 71.81; H, 6.41; N, 2.40; S, 5.57.

Data for α-isomer 62. R_f0.56 (4:1 n-hexane/AcOEt); [α]_D²⁶+93.9

(c 1.08, CHCl₃); IR (neat) 3062, 3029, 2867, 2105, 1584, 1496, 1454,

1267, 1099, 741, 697 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 3.68 (dd, J

= 1.7, 10.9 Hz, 1H), 3.79 (dd, J = 4.6, 10.9 Hz, 1H), 3.94 (t, J = 9.6

Hz, 1H), 4.02 (dd, J = 3.4, 9.6 Hz, 1H), 4.10 (dd, J = 1.7, 3.4 Hz, 1H),

4.28 (ddd, J = 1.7, 4.6, 9.6 Hz, 1H), 4.46 (d, J = 12.6 Hz, 1H), 4.52 (d,

J = 10.9 Hz, 1H), 4.64 (d, J = 12.6 Hz, 1H), 4.75 (s, 2H), 4.85 (d, J =

10.9 Hz, 1H), 5.48 (d, J = 1.7 Hz, 1H), 7.18 (dd, J = 1.7, 7.4 Hz, 2H),

7.24−7.46 (m, 18H); ¹³C NMR (126 MHz, CDCl₃) δ 62.6, 68.5, 72.5,

73.2, 74.5, 75.2, 79.8, 86.1, 127.4, 127.6, 127.65, 127.69, 127.85,

127.94, 128.16, 128.24, 128.5, 129.0, 131.7, 137.3, 137.9, 138.0;

HRMS (ESI) m/z [M + Na]⁺calcd for C₃₃H₃₃N₃O₄SNa 590.2089;

found 590.2084.

Data for β-isomer 42. R_f0.30 (5:1 toluene/acetone); mp 209.5−

21

210.5 °C (colorless needles from AcOEt/n-hexane); [α]_D+16.0 (c

1.03, CHCl₃) [lit.⁶⁹[α]_D+14.5 (c 1.0, CHCl₃)]; IR (KBr) 3286,

23

1650, 1547, 1129, 1073 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.87 (s,

3H), 3.59 (ddd, J = 1.8, 4.6, 9.0 Hz, 1H), 3.62 (dd, J = 8.5, 9.0 Hz,

1H), 3.63 (ddd, J = 8.0, 8.5, 10.3 Hz, 1H), 3.73 (dd, J = 4.6, 10.9 Hz,

1H), 3.78 (dd, J = 1.8, 10.9 Hz, 1H), 3.97 (br t, J = 9.0 Hz, 1H), 4.53

(d, J = 12.1 Hz, 1H), 4.59 (d, J = 12.1 Hz, 1H), 4.60 (d, J = 11.5 Hz,

1H), 4.64 (d, J = 11.5 Hz, 1H), 4.79 (d, J = 11.5 Hz, 1H), 4.82 (d, J =

11.5 Hz, 1H), 5.03 (d, J = 10.3 Hz, 1H), 5.43 (d, J = 8.0 Hz, 1H),

7.20−7.23 (m, 5H), 7.26−7.36 (m, 13H), 7.49−7.52 (m, 2H); ¹³C

NMR (126 MHz, CDCl₃) δ 23.5, 55.3, 69.1, 73.4, 74.7, 74.8, 78.5,

79.2, 82.2, 85.6, 127.4, 127.5, 127.6, 127.75, 127.79, 127.82, 128.1,

128.3, 128.4, 128.5, 128.8, 131.9, 133.3, 138.0, 138.2, 138.3, 170.2;

HRMS (FAB) m/z [M + H]⁺calcd for C₃₅H₃₈NO₅S 584.2471; found

584.2485. Anal. Calcd for C₃₅H₃₇NO₅S: C, 72.01; H, 6.39; N, 2.40; S,

5.49. Found: C, 71.90; H; 6.36; N, 2.38; S, 5.53.

Data for β-isomer 63. R_f0.50 (4:1 n-hexane/AcOEt); mp 99.0−

25

99.5 °C (colorless needles from n-hexane/AcOEt); [α]_D−18.0 (c

1.04, CHCl₃); IR (KBr) 3030, 2862, 2099, 1583, 1481, 1455, 1362,

1278, 1128, 1070, 741, 689 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 3.46

(ddd, J = 1.8, 6.1, 9.3 Hz, 1H), 3.68 (dd, J = 6.1, 11.1 Hz, 1H), 3.77

(dd, J = 3.6, 9.3 Hz, 1H), 3.78 (dd, J = 1.8, 11.1 Hz, 1H), 3.84 (t, J =

9.3 Hz, 1H), 4.16 (dd, J = 1.4, 3.6 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H),

4.58 (d, J = 10.9 Hz, 1H), 4.60 (d, J = 12.2 Hz, 1H), 4.71 (d, J = 11.8

Hz, 1H), 4.73 (d, J = 1.4 Hz, 1H), 4.77 (d, J = 11.8 Hz, 1H), 4.87 (d, J

= 10.9 Hz, 1H), 7.19−7.39 (m, 18H), 7.49−7.52 (m, 2H); ¹³C NMR

(100 MHz, CDCl₃) δ 63.4, 69.2, 72.6, 73.4, 74.3, 75.3, 79.8, 83.1, 85.5,

127.45, 127.47, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.4, 128.6,

129.0, 130.1, 134.4, 137.2, 137.8, 138.2; HRMS (ESI) m/z [M + Na]⁺

calcd for C₃₃H₃₃N₃O₄SNa 590.2089; found 590.2079. Anal. Calcd for

C₃₃H₃₃N₃O₄S: C, 69.82; H, 5.86; N, 7.40; S, 5.65. Found: C, 69.94; H,

5.84; N, 7.37; S, 5.65.

2-Azido-3,4,6-tri-O-benzyl-2-deoxy-α-^D-mannopyranosyl Di-

phenyl Phosphate (61). Diphenylphosphoryl chloride (0.23 mL,

1.13 mmol) was added to an ice-cooled (0 °C) solution of hemiacetal

60⁶⁵(490 mg, 1.03 mmol) and DMAP (304 mg, 2.49 mmol) in

CH₂Cl₂(10 mL). After 30 min of stirring, the reaction was quenched

with crushed ice, followed by stirring at room temperature for 15 min.

The mixture was poured into a two-layer mixture of AcOEt (30 mL)

and saturated aqueous NaHCO₃(30 mL), and the resulting mixture

was extracted with AcOEt (150 mL). The organic extract was

Phenyl 2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-1-thio-α-^D-

mannopyranoside (58). Triphenylphosphine (55.4 mg, 0.21

mmol) was added to a stirred solution of 2-azido-1-thio-α-mannoside

62 (100 mg, 0.18 mmol) in THF (4 mL). After 30 min of stirring,

O

DOI: 10.1021/acs.joc.5b00138

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

H₂O (0.5 mL) was added, and the reaction mixture was heated at 80

°C for 1 h. The reaction mixture was partitioned between AcOEt (50

mL) and brine (10 mL), and the aqueous layer was extracted with

AcOEt (40 mL). The combined organic extracts were dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo furnished the

colorless oil, which was dissolved with pyridine (2 mL). Ac₂O (0.02

mL, 0.22 mmol) was added, and the solution was stirred for 1 h. The

reaction was quenched with crushed ice, followed by stirring for 15

min. The mixture was partitioned between AcOEt (100 mL) and 10%

aqueous HCl (15 mL), and the organic layer was successively washed

with 10% aqueous HCl (30 mL), H₂O (30 mL), saturated aqueous

NaHCO₃(30 mL), and brine (30 mL) and dried over anhydrous

Na₂SO₄. Filtration and evaporation in vacuo furnished the crude

product (190 mg, slightly yellow oil), which was puriﬁed by column

chromatography (silica gel 6 g, 4:1 n-hexane/AcOEt) to give 2-

acetamido-2-deoxy-α-thioglycoside 58 (77.1 mg, 75%) as a colorless

mmol), and pulverized 4 Å molecular sieves (82 mg) in CH₂Cl₂(0.08

mL). After 14 h of stirring, the reaction was quenched with Et₃N (0.1

mL), and the mixture was ﬁltrated through a Celite pad. The ﬁltrate

was partitioned between AcOEt (35 mL) and 20% aqueous Na₂S₂O₃

(6 mL), and the organic layer was successively washed with 20%

aqueous Na₂S₂O₃(10 mL), saturated aqueous NaHCO₃(10 mL), and

brine (10 mL) and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo followed by gel permeation chromatography

(Bio-Beads S-X, toluene) aﬀorded a mixture of disaccharides 64 and

65 (12.1 mg, 16%, 64:65 = 62:38) as a colorless oil, along with

oxazoline 66 (31.3 mg, 81%) as a colorless oil. The ratio of

disaccharides 64 and 65 was determined by 500 MHz ¹H NMR

spectroscopic analysis. The α- and β-glycosides were separated by

column chromatography (silica gel 1 g, 3:1 n-hexane/AcOEt). When

the glycosylation was performed employing thioglycoside 59 (60.8 mg,

0.10 mmol), 6-O-unprotected glucoside 13 (53.2 mg, 0.12 mmol),

NIS (25.9 mg, 0.12 mmol), pulverized 4 Å molecular sieves (100 mg),

and Tf₂NH (1.0 M in EtCN, 0.12 mL, 0.12 mmol), a mixture of

disaccharides 64 and 65 (22.6 mg, 23%, 64:65 = 74:26) and oxazoline

66 (36.9 mg, 75%) were obtained as colorless oils from the crude

product (190 mg) after gel permeation chromatography (Bio-Beads S-

X, toluene).

22

oil. R_f0.51 (1:2 n-hexane/AcOEt); [α]_D+65.4 (c 1.04, CHCl₃); IR

(neat) 3430, 3283, 3061, 3031, 2868, 1655, 1543, 1454, 1370, 1097,

740, 698 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.98 (s, 3H), 3.64 (dd,

J = 1.7, 10.9 Hz, 1H), 3.78 (t, J = 9.5 Hz, 1H), 3.84 (dd, J = 3.4, 10.9

Hz, 1H), 4.01 (dd, J = 4.3, 9.5 Hz, 1H), 4.33 (ddd, J = 1.7, 3.4, 9.5 Hz,

1H), 4.41 (d, J = 11.5 Hz, 1H), 4.47 (d, J = 10.3 Hz, 1H), 4.50 (d, J =

10.9 Hz, 1H), 4.59 (d, J = 11.5 Hz, 1H), 4.76 (d, J = 10.9 Hz, 1H),

4.89 (d, J = 10.3 Hz, 1H), 4.93 (ddd, J = 1.1, 4.3, 9.2 Hz, 1H), 5.53 (d,

J = 1.1 Hz, 1H), 6.25 (d, J = 9.2 Hz 1H), 7.19−7.45 (m, 20H); ¹³C

NMR (126 MHz, CDCl₃) δ 23.3, 50.5, 68.5, 71.2, 71.6, 73.4, 74.0,

75.1, 77.9, 87.3, 127.4, 127.7, 127.8, 127.9, 128.27, 128.32, 128.4,

128.9, 131.5, 133.8, 137.4, 137.6, 138.1, 170.0; HRMS (ESI) m/z [M +

Na]⁺calcd for C₃₅H₃₇NO₅SNa 606.2290; found 606.2290.

23

Data for α-anomer 64. R_f0.43 (1:2 n-hexane/AcOEt); [α]_D

+39.5 (c 0.73, CHCl₃); IR (neat) 3306, 3030, 2923, 1662, 1496, 1454,

1

1362, 1091, 737, 698 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 1.95 (s,

3H), 3.27 (s, 3H), 3.39 (t, J = 9.5 Hz, 1H), 3.44 (dd, J = 1.4, 10.6 Hz,

1H), 3.50 (dd, J = 3.7, 9.5 Hz, 1H), 3.54 (dd, J = 1.1, 10.9 Hz, 1H),

3.57 (dd, J = 2.9, 10.6 Hz, 1H), 3.61 (m, 1H), 3.64 (t, J = 9.5 Hz, 1H),

3.68 (m, 1H), 3.72 (dd, J = 4.6, 10.9 Hz, 1H), 3.93 (t, J = 9.5 Hz, 1H),

3.95 (dd, J = 4.6, 9.5 Hz, 1H), 4.32 (d, J = 12.0 Hz, 1H), 4.36 (d, J =

11.5 Hz, 1H), 4.43 (d, J = 11.5 Hz, 1H), 4.44 (d, J = 10.9 Hz, 1H),

4.51 (d, J = 12.0 Hz, 1H), 4.54 (d, J = 3.7 Hz, 1H), 4.64 (d, J = 12.6

Hz, 1H), 4.691 (d, J = 11.5 Hz, 1H), 4.694 (ddd, J = 1.7, 4.6, 9.7 Hz,

1H), 4.740 (d, J = 10.3 Hz, 1H), 4.742 (d, J = 12.6 Hz, 1H), 4.82 (d, J

= 1.7 Hz, 1H), 4.83 (d, J = 11.5 Hz, 1H), 4.84 (d, J = 10.9 Hz, 1H),

4.94 (d, J = 10.3 Hz, 1H), 5.84 (d, J = 9.7 Hz, 1H), 7.08−7.34 (m,

30H); ¹³C NMR (126 MHz, CDCl₃) δ 23.5, 49.0, 55.1, 66.2, 68.4,

69.5, 70.5, 71.0, 73.3, 73.5, 73.8, 74.8, 75.0, 75.7, 77.2, 77.6, 80.0, 82.1,

97.8, 99.5, 127.4, 127.50, 127.53, 127.6, 127.7, 127.77, 127.84, 127.9,

128.0, 128.1, 128.2, 128.3, 128.36, 128.39, 128.5, 137.7, 138.1, 138.2,

138.5, 138.6, 170.2; HRMS (ESI) m/z [M + Na]⁺calcd for

C₅₇H₆₃NO₁₁Na 960.4299; found 960.4298.

Phenyl 2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-1-thio-β-^D-

mannopyranoside (59). Triphenylphosphine (138 mg, 0.53

mmol) was added to a stirred solution of 2-azido-1-thio-β-mannoside

63 (250 mg, 0.44 mmol) in THF (9 mL). After 30 min of stirring,

H₂O (1 mL) was added, and the reaction mixture was heated at 80 °C

for 1 h. The reaction mixture was partitioned between AcOEt (120

mL) and brine (20 mL), and the aqueous layer was extracted with

AcOEt (100 mL). The combined organic extracts were dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo furnished the

colorless oil, which was dissolved in pyridine (5 mL). Ac₂O (0.05 mL,

0.53 mmol) was added, and the solution was stirred for 1 h. The

reaction was quenched with crushed ice, followed by stirring for 15

min. The mixture was partitioned between AcOEt (170 mL) and 10%

aqueous HCl (20 mL), and the organic layer was successively washed

with 10% aqueous HCl (50 mL), H₂O (50 mL), saturated aqueous

NaHCO₃(50 mL), and brine (50 mL) and dried over anhydrous

Na₂SO₄. Filtration and evaporation in vacuo furnished the crude

product (465 mg, slightly yellow oil), which was puriﬁed by column

chromatography (silica gel 15 g, 6:1 n-hexane/AcOEt) to give 2-

acetamido-2-deoxy-β-thioglycoside 59 (206 mg, 80%) as a colorless

Data for β-anomer 65. R_f0.70 (1:2 n-hexane/AcOEt); [α]_D²³+2.5

(c 1.09, CHCl₃); IR (neat) 3309, 3031, 2927, 2871, 1656, 1520, 1454,

1367, 1270, 1070, 738, 698 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.99

(s, 3H), 3.34 (s, 3H), 3.37 (m, 1H), 3.40 (t, J = 9.5 Hz, 1H), 3.48 (dd,

J = 3.4, 9.7 Hz, 1H), 3.52 (dd, J = 5.7, 10.9 Hz, 1H), 3.59 (m, 2H),

3.70 (m, 2H), 3.76 (ddd, J = 1.3, 5.6, 10.2 Hz, 1H), 3.98 (dd, J = 9.2,

9.7 Hz, 1H), 4.03 (dd, J = 1.4, 10.6 Hz, 1H), 4.29 (br s, 1H), 4.45 (d, J

= 10.9 Hz, 1H), 4.478 (d, J = 12.0 Hz, 1H), 4.482 (d, J = 10.9 Hz,

1H), 4.53 (d, J = 3.4 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.57 (d, J =

11.5 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.72 (br d, J = 9.7 Hz, 1H),

4.79 (d, J = 12.0 Hz, 1H), 4.81 (d, J = 10.9 Hz, 1H), 4.85 (d, J = 10.9

Hz, 1H), 4.87 (d, J = 10.3 Hz, 1H), 4.88 (d, J = 11.5 Hz, 1H), 4.98 (d,

J = 10.9 Hz, 1H), 5.80 (d, J = 9.7 Hz, 1H), 7.08−7.34 (m, 30H); ¹³C

NMR (126 MHz, CDCl₃) δ 23.3, 49.2, 54.9, 68.1, 68.6, 69.6, 71.0,

73.3, 73.4, 73.9, 74.7, 74.9, 75.6, 77.6, 79.6, 80.2, 82.0, 97.7, 99.6,

127.51, 127.53, 127.6, 127.66, 127.70, 127.73, 127.76, 127.80, 127.82,

127.9, 128.1, 128.25, 128.27, 128.30, 128.34, 137.6, 137.7, 137.9,

138.0, 138.3, 138.5, 170.7; HRMS (ESI) m/z [M + Na]⁺calcd for

C₅₇H₆₃NO₁₁Na 960.4299; found 960.4297.

26

amorphous. R_f0.64 (1:1 n-hexane/AcOEt); [α]_D−69.5 (c 1.04,

CHCl₃); IR (KBr) 3261, 3060, 2866, 1652, 1547, 1454, 1369, 1299,

1

1075, 735, 696 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 2.10 (s, 3H),

3.50 (ddd, J = 2.1, 4.0, 9.5 Hz, 1H), 3.65 (t, J = 9.5 Hz, 1H), 3.72 (dd,

J = 4.6, 9.5 Hz, 1H), 3.74 (dd, J = 4.0, 10.9 Hz, 1H), 3.78 (dd, J = 2.1,

10.9 Hz, 1H), 4.49 (d, J = 10.9 Hz, 1H), 4.50 (d, J = 10.9 Hz, 1H),

4.51 (d, J = 12.0 Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.84 (d, J = 1.1

Hz, 1H), 4.89 (d, J = 10.9 Hz, 1H), 4.91 (d, J = 10.9 Hz, 1H), 5.06

(ddd, J = 1.1, 4.6, 10.3 Hz, 1H), 6.03 (d, J = 10.3 Hz, 1H), 7.19−7.50

(m, 20H); ¹³C NMR (126 MHz, CDCl₃) δ 23.4, 50.5, 69.0, 71.3, 73.4,

73.9, 75.1, 79.3, 81.4, 86.5, 127.3, 127.69, 127.73, 127.75, 127.77,

128.3, 128.35, 128.37, 128.44, 128.9, 130.9, 134.2, 137.5, 137.9, 138.1,

170.5; HRMS (ESI) m/z [M + Na]⁺calcd for C₃₅H₃₇NO₅SNa

606.2290; found 606.2290.

Methyl 6-O-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-^D-

mannopyranosyl)-2,3,4-tri-O-benzyl-α-^D-glucopyranoside (64)

and Methyl 6-O-(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-^D-

mannopyranosyl)-2,3,4-tri-O-benzyl-α-^D-glucopyranoside (65).

Tf₂NH (1.0 M in EtCN, 0.09 mL, 0.09 mmol) was added to a cooled

(−60 °C) mixture of thioglycoside 58 (47.6 mg, 0.08 mmol), 6-O-

unprotected glucoside 13 (41.7 mg, 0.09 mmol), NIS (20.2 mg, 0.09

Data for oxazoline 66. R_f0.56 (1:2 n-hexane/AcOEt); [α]_D²³+7.8

(c 1.06, CHCl₃); IR (neat) 3062, 3029, 2866, 1674, 1454, 1108, 1027,

1

739, 698 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 1.98 (d, J = 1.4 Hz,

3H), 3.531 (d, J = 4.0 Hz, 1H), 3.532 (d, J = 5.0 Hz, 1H), 3.63 (dd, J =

7.4, 8.8 Hz, 1H), 3.71 (ddd, J = 4.0, 5.0, 7.4 Hz, 1H), 3.88 (dd, J = 5.2,

8.8 Hz, 1H), 4.23 (ddq, J = 5.2, 5.9, 1.4 Hz, 1H), 4.51 (d, J = 10.9 Hz,

1H), 4.52 (s, 2H), 4.76 (d, J = 11.8 Hz, 1H), 4.84 (d, J = 10.9 Hz, 1H),

4.87 (d, J = 11.8 Hz, 1H), 5.71 (d, J = 5.9 Hz, 1H), 7.21 (m, 2H),

7.25−7.34 (m, 11H), 7.40 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ

P

DOI: 10.1021/acs.joc.5b00138

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

14.3, 66.7, 70.1, 72.2, 73.4, 74.4, 74.9, 76.1, 76.3, 100.4, 127.6, 127.7,

127.8, 127.96, 128.00, 128.32, 128.34, 137.9, 138.06, 138.12, 165.6;

HRMS (ESI) m/z [M + H]⁺calcd for C₂₉H₃₁NO₅Na 496.2100; found

496.2107.

Eur. J. Org. Chem. 2003, 1009−1021. (d) Imamura, A.; Ando, H.;

Korogi, S.; Tanabe, G.; Muraoka, O.; Ishida, H.; Kiso, M. Tetrahedron

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M.; Schmidt, R. R. J. Org. Chem. 2007, 72, 4367−4377. (h) Wei, G.;

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ASSOCIATED CONTENT

■

S

* Supporting Information

Additional text with general information and ¹H and ¹³C NMR

spectra for all new compounds. This material is available free of

charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: nakamura@phar.nagoya-cu.ac.jp.

*E-mail: hsmt@pharm.hokudai.ac.jp.

■

Present Address

^†(S.N.) Graduate School of Pharmaceutical Sciences, Nagoya

City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-

8603, Japan.

(6) (a) Imoto, M.; Yoshimura, H.; Shimamoto, T.; Sakaguchi, N.;

Kusumoto, S.; Shiba, T. Bull. Chem. Soc. Jpn. 1987, 60, 2205−2214.

(b) Ellervik, U.; Magnusson, G. Carbohydr. Res. 1996, 280, 251−260.

(7) Boullanger, P.; Jouineau, M.; Bouammali, B.; Lafont, D.;

Descotes, G. Carbohydr. Res. 1990, 202, 151−164.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

(8) Blatter, G.; Beau, J.; Jacquinet, J. Carbohydr. Res. 1994, 260, 189−

202.

■

This research was supported in part by a Grant-in-Aid for

Scientiﬁc Research from the Ministry of Education, Culture,

Sports, Science and Technology, Japan. We also acknowledge

the Japan Society for the Promotion of Science for graduate

fellowships to R.A., K.K., and N.S. We thank S. Oka and M.

Kiuchi of the Center for Instrumental Analysis, Hokkaido

University, for mass measurements and elemental analysis.

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1

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J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Glycosylation with 2-Acetamido-2-deoxyglycosyl Donors at a Low Temperature: Scope of the Non-Oxazoline Method

DOI: 10.1021/acs.joc.5b00138

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